CA2474277C - 2,4-pyrimidinediamine compounds and their uses - Google Patents

2,4-pyrimidinediamine compounds and their uses Download PDF

Info

Publication number
CA2474277C
CA2474277C CA 2474277 CA2474277A CA2474277C CA 2474277 C CA2474277 C CA 2474277C CA 2474277 CA2474277 CA 2474277 CA 2474277 A CA2474277 A CA 2474277A CA 2474277 C CA2474277 C CA 2474277C
Authority
CA
Canada
Prior art keywords
compound
fluoro
group
chloro
pyrimidineamine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CA 2474277
Other languages
French (fr)
Other versions
CA2474277A1 (en
Inventor
Rajinder Singh
Ankush Argade
Donald G. Payan
Susan Molineaux
Sacha J. Holland
Jeffrey Clough
Holger Keim
Somasekhar Bhamidipati
Catherine Sylvain
Hui Li
Alexander B. Rossi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rigel Pharmaceuticals Inc
Original Assignee
Rigel Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=32996332&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA2474277(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Rigel Pharmaceuticals Inc filed Critical Rigel Pharmaceuticals Inc
Publication of CA2474277A1 publication Critical patent/CA2474277A1/en
Application granted granted Critical
Publication of CA2474277C publication Critical patent/CA2474277C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more nitrogen atoms in the same ring, e.g. oxadiazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/027—Organoboranes and organoborohydrides

Abstract

The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compunds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.

Description

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PL US D'UN TOME.

NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.
JUMBO APPLICATIONS / PATENTS
THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

NOTE: For additional volumes please contact the Canadian Patent Office.

=
2,4¨PYRIMIDINEDIAMINE COMPOUNDS AND THEIR USES
1. FIELD OF THE INVENTION
The present invention relates generally to 2,4-pyrimidinediamine compounds, pharmaceutical compositions comprising the compounds, intermediates and synthetic methods of making the compounds and methods of using the compounds and compositions in a variety of contexts.
2. BACKGROUND OF THE INVENTION
Crosslinking of Fc receptors, such as the high affinity receptor for IgE
(FcERI) and/or the high affinity receptor for IgG (FcyRI) activates a signaling cascade in mast, basophil and other immune cells that results in the release of chemical mediators responsible for numerous adverse events. For example, such crosslinking leads to the release of preformed mediators of Type I (immediate) anaphylactic hypersensitivity reactions, such as histamine, from storage sites in granules via degranulation. It also leads to the synthesis and release of other mediators, including leukotrienes, prostaglandins and platelet-activating factors (PAFs), that play important roles in inflammatory reactions.
Additional mediators that are synthesized and released upon crosslinking Fe receptors include cytokines and nitric oxide.
The signaling cascade(s) activated by crosslinking Fe receptors such as FcERI
and/or FcyRI comprises an array of cellular proteins. Among the most important intracellular signal propagators are the tyrosine kinases. And, an important tyrosine kinase involved in the signal transduction pathways associated with crosslinking the FcERI
and/or FcyRI receptors, as well as other signal transduction cascades, is Syk kinase (see Valent et al., 2002, Intl. J Hematol. 75(4):257-362 for review).

As the mediators released as a result of FcERI and FcitRI receptor cross-linking are responsible for, or play important roles in, the manifestation of numerous adverse events, the availability of compounds capable of inhibiting the signaling cascade(s) responsible for their release would be highly desireable. Moreover, owing to the critical role that Syk kinase plays these and other receptor signaling cascade(s), the availability of compounds capable of inhibiting Syk kinase would also be highly desirable.
4. SUMMARY OF THE INVENTION
In one aspect, the present invention provides novel 2,4-pyrimidinediamine compounds that, as will be discussed in more detail below, have myriad biological activities. The compounds generally comprise a 2,4-pyrimidinediamine "core"
having the following structure and numbering convention:
The compounds of the invention are substituted at the C2 nitrogen (N2) to form a secondary amine and are optionally further substituted at one or more of the following positions: the C4 nitrogen (N4), the C5 position and/or the C6 position. When substituted at N4, the substituent forms a secondary amine. The substituent at N2, as well as the optional substituents at the other positions, may range broadly in character and physico-chemical properties. For example, the substituent(s) may be a branched, straight-chained or cyclic alkyl, a branched, straight-chained or cyclic heteroalkyl, a mono- or polycyclic aryl a mono- or polycyclic heteroaryl or combinations of these groups. These substituent groups may be further substituted, as will be described in more detail below.
The N2 and/or N4 substituents may be attached directly to their respective nitrogen atoms, or they may be spaced away from their respective nitrogen atoms via linkers, which may be the same or different. The nature of the linkers can vary widely, and can include virtually any combination of atoms or groups useful for spacing one molecular moiety from another. For example, the linker may be an acyclic hydrocarbon bridge (e.g, a saturated or unsaturated alkyleno such as methano, ethano, etheno, propano, prop[l]eno, butano, but[l]eno, but[2]eno, buta[1,3]dieno, and the like), a monocyclic or polycyclic hydrocarbon bridge (e.g., [1,2Thenzeno, [2,3]naphthaleno, and the like), a simple acyclic heteroatomic or heteroalkyldiyl bridge (e.g., -0-, -S-, -S-0-, -NH-, -PH-, -C(0)-, -C(0)NH-, -S(0)-, -S(0)2-, -S(0)NH-, -S(0)2NH-, -0-CH2-, -CH2-0-CH2-, -0-CH=CH-CH2-, and the like), a monocyclic or polycyclic heteroaryl bridge (e.g., [3,4]furano, pyridino, thiopheno, piperidino, piperazino, pyrazidino, pyrrolidino, and the like) or combinations of such bridges.
The substituents at the N2, N4, C5 and/or C6 positions, as well as the optional linkers, may be further substituted with one or more of the same or different substituent groups. The nature of these substituent groups may vary broadly. Non-limiting examples of suitable substituent groups include branched, straight¨chain or cyclic alkyls, mono- or polycyclic aryls, branched, straight¨chain or cyclic heteroalkyls, mono- or polycyclic heteroaryls, halos, branched, straight¨chain or cyclic haloalkyls, hydroxyls, oxos, thioxos, branched, straight-chain or cyclic alkoxys, branched, straight-chain or cyclic haloalkoxys, trifluoromethoxys, mono- or polycyclic aryloxys, mono- or polycyclic heteroaryloxys, ethers, alcohols, sulfides, thioethers, sulfanyls (thiols), imines, azos, azides, amines (primary, secondary and tertiary), nitiles (any isomer), cyanates (any isomer), thiocyanates (any isomer), nitrosos, nitros, diazos, sulfoxides, sulfonyls, sulfonic acids, sulfamides, sulfonamides, sulfamic esters, aldehydes, ketones, carboxylic acids, esters, amides, amidines, formadines, amino acids, acetylenes, carbamates, lactones, lactams, glucosides, gluconurides, sulfones, ketals, acetals, thioketals, oximes, oxamic acids, oxamic esters, etc., and combinations of these groups. Substituent groups bearing reactive functionalities may be protected or unprotected, as is well-known in the art.
In one illustrative embodiment, the 2,4-primidinediamine compounds of the invention are compounds according to structural formula (I):

N

"N N =-=R2 H
including salts, hydrates, solvates and N-oxides thereof, wherein:
LI. and L2 are each, independently of one another, selected from the group consisting of a direct bond and a linker;
R2 is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R8 groups, cyclohexyl optionally substituted with one or more of the same or different R8 groups, 3-8 membered cycloheteroalkyl optionally substituted with one or more of the same or different R8 groups, (C5-C15) aryl optionally substituted with one or more of the same or different R8 groups, phenyl optionally substituted with one or more of the same or different R8 groups and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R4 is selected from the group consisting of hydrogen, (C1-C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R8 groups, cyclohexyl optionally substituted with one or more of the same or different R8 groups, 3-8 membered cycloheteroalkyl optionally substituted with one or more of the same or different R8 groups, (C5-C15) aryl optionally substituted with one or more of the same or different R8 groups, phenyl optionally substituted with one or more of the same or different R8 groups and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R5 is selected from the group consisting of R6, (C1-C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C1-C4) alkanyl optionally substituted with one or more of the same or different R8 groups, (C2-C4) alkenyl optionally substituted with one or more of the same or different R8 groups and (C2-C4) alkynyl optionally substituted with one or more of the same or different R8 groups;
each R6 is independently selected from the group consisting of hydrogen, an electronegative group, -ORd, -SRd, (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, -NRcRe, halogen, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, -CF3, -CH2CF3, -CF2CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, -N3, -S(0)Rd, -S(0)2R', -S(0)20Rd, -S(0)NRcRc;
-S(0)2NReRc, -0S(0)Rd, -0S(0)2Rd, -0S(0)20Rd, -0S(0)NReRc, -0S(0)2NReRe, -C(0)Rd, -C(0)0Rd, -C(0)NRcRe, -C(NH)NRcW, -0C(0)Rd, -SC(0)Rd, -0C(0)0R', -SC(0)0Rd, -0C(0)NRcRc, -SC(0)NReRc, -0C(NH)NReRe, -SC(NH)NRcRe, -[NHC(0)]õRd, -[NHC(0)}nORd, -INHC(0)1NReRc and -[NHC(NB)]nNRcRc, (C5-C10) aryl optionally substituted with one or more of the same or different R8 groups, phenyl optionally substituted with one or more of the same or different R8 groups, (C6-C16) arylalkyl optionally substituted with one or more of the same or different R8 groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R8 groups and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R8 groups;

R8 is selected from the group consisting of le, Rb, Ra substituted with one or more of the same or different Ra or le, -0Ra substituted with one or more of the same or different Ra or Rb, -B(01e)2, -13(1 TReRc)2, -(CH2)mRb, -(CHRa),õ-Rb, -0-(CH2)m-Rb, -S-(CH2)m-Rb, \--0-CHRaRb, -0-CRa(Rb)2, -0-(CHRa)1-Rb, -0- (CH2)111-CH[(CH2)1Rb]Rb, -S-(CHRa)m-Rb, -C(0)NH-(CH2)m-R", -C(0)NH-(CHRa)m-Rb, -0-(CH2)m-C(0)NH-(CH2)m-Rb, -S-(CH2)m-C(0)NH-(CH2)m-R', -0-(CHRa)õ,-C(0)NH-(CHRa)õ,-Rb, -S-(CHRa)m-C(0)NH-(CHRa)m-Rb, -NH-(CH2)m-R1', -NH-(CHRa)m-Rb, -NH[(CH2),Rb], -NRCH2)mR112, -NH-C(0)-NH-(CH2)m-R", -NH-C(0)-(CH2)m-CHRbRb and -NH-(CH2).-C(0)-NH-(CH2),,-Rb;
each Ra is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each le is a suitable group independently selected from the group consisting of =0, -OW', (C1-C3) haloalkyloxy, -0CF3, =S, -SW', =NRd, =NORd, -NReRe, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(0)Rd, -S(0)2Rd, -S(0)20Rd, -S(0)NRele, -S(0)2NReRe, -0S(0)Rd, -0S(0)2R', -OS(0)20W', -0S(0)2NReRe, -C(0)Rd, -C(0)OR, -C(0)NReRe, -C(NH)NReRe, -C(NRa)NleRe, -C(NOH)Ra, -C(NOH)NRele, -0C(0)Rd, -0C(0)0R", -0C(0)NRcRe, -0C(NH)NRcRe, -0C(NRa)NRcRe, -[NHC(0)],1Rd, -[NRaC(0)],Rd, -[NHC(0)]ORd, -[NRaC(0)bORd, -{NHC(0)]õNRele, -[NRaC(0)]õNReRe, -[NHC(NH)]nNleRe and -[NRaC(NRa)JõNReRe;
each Re is independently a protecting group or Ra, or, alternatively, each Re is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different Ra or suitable Rb groups;
each Rd is independently a protecting group or Ra;
each in is independently an integer from 1 to 3; and each n is independently an integer from 0 to 3.
In another aspect, the present invention provides prodrugs of the 2,4-pyrimidinediamine compounds. Such prodrugs may be active in their prodrug form, or may be inactive until converted under physiological or other conditions of use to an active drug form. In the prodrugs of the invention, one or more functional groups of the 2,4-pyrimidinediamine compounds are included in promoieties that cleave from the molecule under the conditions of use, typically by way of hydrolysis, enzymatic cleavage or some other cleavage mechanism, to yield the functional groups. For example, primary or secondary amino groups may be included in an amide promoiety that cleaves under conditions of use to generate the primary or secondary amino group. Thus, the prodrugs of the invention include special types of protecting groups, termed "progroups,"
masking one or more functional groups of the 2,4-pyrimidinediamine compounds that cleave under the conditions of use to yield an active 2,4-pyrimidinediamine drug compound.
Functional groups within the 2,4-pyrimidinediamine compounds that may be masked with progroups for inclusion in a promoiety include, but are not limited to, amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, carbonyls, phenols, catechols, diols, alkynes, phosphates, etc. Myriad progroups suitable for masking such functional groups to yield promoieties that are cleavable under the desired conditions of use are known in the art. All of these progroups, alone or in combinations, may be included in the prodrugs of the invention. Specific examples of promoieties that yield primary or secondary amine groups that can be included in the prodrugs of the invention include, but are not limited to amides, carbamates, imines, ureas, phosphenyls, phosphoryls and sulfenyls. Specific examples of promoieties that yield sulfanyl groups that can be included in the prodrugs of the invention include, but are not limited to, thioethers, for example S-methyl derivatives (monothio, dithio, oxythio, aminothio acetals), silyl thioethers, thioesters, thiocarbonates, thiocarbamates, asymmetrical disulfides, etc. Specific examples of promoieties that cleave to yield hydroxyl groups that can be included in the prodrugs of the invention include, but are not limited to, sulfonates, esters and carbonates. Specific examples of promoieties that yield carboxyl groups that can be included in the prodrugs of the invention included, but are not limited to, esters (including silyl esters, oxamic acid esters and thioesters), amides and hydrazides.
In one illustrative embodiment, the prodrugs of the invention are compounds according to structural formula (I) in which the protecting group of Re and Rd is a progroup.
Replacing the hydrogens attached to N2 and N4 in the 2,4-pyrimidinediamines of structural formula (I) with substituents adversely affects the activity of the compounds.
However, as will be appreciated by skilled artisans, these nitrogens may be included in promoieties that, under conditions of use, cleave to yield 2,4-pyrimidinediamines according to structural formula (I). Thus, in another illustrative embodiment, the prodrugs of the invention are compounds according to structural formula (1):

L2, *N,LI,R2 R4' N N
RI 4b RI 2b including salts, hydrates, solvates and N-oxides thereof, wherein:
R2, R4, R5, R6, L1 an L2 are as previously defined for structural formula (I); and R2b and .t.c. ¨44) are each, independently of one another, a pro group.
In another aspect, the present invention provides compositions comprising one or more compounds and/or prodrugs of the invention and an appropriate carrier, excipient or diluent. The exact nature of the carrier, excipient or diluent will depend upon the desired use for the composition, and may range from being suitable or acceptable for veterinary uses to being suitable or acceptable for human use.
In still another aspect, the present invention provides intermediates useful for synthesizing the 2,4-pyrimidinediamine compounds and prodrugs of the invention. In one embodiment, the intermediates are 4-pyrimidineamines according to structural formula (III):

N
R4L2,NN jLG
R4c including salts, hydrates, solvates and N-oxides thereof, wherein R4, R5, R6 and L2 are as previously defined for structural formula (I); LG is a leaving group such as, for example, ¨S(0)2Me, -SMe or halo (e.g., F, Cl, Br, I); and R4e is hydrogen or a progroup.
In another embodiment, the intermediates are 2-pyrimidineamines according to structural formula (IV):

R5jN
,I, LG L

I 2c including salts, hydrates, solvates and N-oxides thereof, wherein R2, R5, R6 and L1 are as previously defined for structural formula (I); LG is a leaving group, such as, for example, ¨S(0)2Me, -SMe or halo (e.g., F, Cl, Br, I) and R2C is hydrogen or a progroup.
In yet another embodiment, the intermediates are 4-amino- or 4-hydroxy-2-pyrimidineamines according to structural formula (V):

N
R7 N*N LI. R2 I
Rµc including salts, hydrates, solvates and N-oxides thereof, wherein R2, R5, R6 and L1 are as previously defined for structural formula (I), R7 is an amino or hydroxyl group and R2c is hydrogen or a progroup.
In another embodiment, the intermediates are N4-substituted cytosines according to structural formula (VI):

NH
L2, I 4c including salts, hydrates, solvates and N-oxides thereof, wherein R4, R5, R6 and L2 are as previously defm.ed for structural formula (I) and R4e is hydrogen or a progroup.
In yet another aspect, the present invention provides methods of synthesizing the 2,4-pyrimidinediamine compounds and prodrugs of the invention. In one embodiment, the method involves reacting a 4-pyrimidineamine according to structural formula (III) with an amine of the formula HR
2eN-L1-R2, where LI., R2 and R2c are as previously defined for structural formula (IV) to yield a 2,4-pyrimidinediamine according to structural formula (I) or a prodrug according to structural formula (II).
In another embodiment, the method involves reacting a 2-pyrimidineamine according to structural formula (IV) with an amine of the formula R4L 2_ -NHR4' where L4, R4 and R4c are as previously defined for structural formula (HI) to yield a 2,4-pyrimidinediamine according to structural formula (I) or a prodrug according to structural formula (II).
In yet another embodiment, the method involves reacting a 4-amino-2-pyrimidineamine according to structural formula (V) (in which R7 is an amino group) with an amine of the formula R 2_ NHR4c, where L2, R4 and R4c are as defined for structural formula (III), to yield a 2,4-pyrimidinediamine according to structural formula (I) or a prodrug according to structural formula (II). Alternatively, the 4-amino-2-pyrimidineamine may be reacted with a compound of the formula R4-L2-LG, where R4 and L2 are as previously defined for structural formula (I) and LG is a leaving group.
In still another embodiment, the method involves halogenating a 4-hydroxy-2-pyrimidineamine according to structural formula (V) (R7 is a hydroxyl group) to yield a 2-pyrimidineamine according to structural formula (IV) and reacting this pyrimidineamine with an appropriate amine, as described above.
In yet another embodiment, the method involves halogenating an N4-substituted cytosine according to structural formula (VI) to yield a 4-pyrimidineamine according to structural formula (III) and reacting this pyrimidineamine with an appropriate amine, as described above.
The 2,4-pyrimidinediamine compounds of the invention are potent inhibitors of degranulation of immune cells, such as mast, basophil, neutrophil and/or eosinophil cells.
Thus, in still another aspect, the present invention provides methods of regulating, and in particular inhibiting, degranulation of such cells. The method generally involves contacting a cell that degranulates with an amount of a 2,4-pyrimidinediamine compound or prodrug of the invention, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to regulate or inhibit degranulation of the cell. The method may be practiced in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by or associated with cellular degranulation.
While not intending to be bound by any theory of operation, biochemical data confirm that the 2,4-pyrimidinediamine compounds exert their degranulation inhibitory effect, at least in part, by blocking or inhibiting the signal transduction cascade(s) initiated by crosslinking of the high affinity Fc receptors for IgE ("FceRI") and/or IgG
("Fc7121").
Indeed, the 2,4-pyrimidinediamine compounds are potent inhibitors of both FceRI-mediated and FcTRI-mediated degranulation. As a consequence, the 2,4-pyrimidine compounds may be used to inhibit these Fc receptor signalling cascades in any cell type expressing such FccRI and/or FcTRI receptors including but not limited to macrophages, mast, basophil, neutrophil and/or eosinophil cells.
The methods also permit the regulation of, and in particular the inhibition of, downstream processes that result as a consequence of activating such Fc receptor signaling cascade(s). Such downstream processes include, but are not limited to, FccRI-mediated and/or Fc-yRI-mediated degranulation, cytokine production and/or the production and/or release of lipid mediators such as leukotrienes and prostaglandins. The method generally involves contacting a cell expressing an Fc receptor, such as one of the cell types discussed above, with an amount of a 2,4-pyrimidinediamine compound or prodrug of the invention, or an acceptable salt, hydrate, solvent, N-oxide and/or composition thereof, effective to regulate or inhibit the Fc receptor signaling cascade and/or a downstream process effected by the activation of this signaling cascade. The method may be practiced in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by or associated with the Fc receptor signaling cascade, such as diseases effected by the release of granule specific chemical mediators upon degranulation, the release and/or synthesis of cytokines and/or the release and/or synthesis of lipid mediators such as leukotrienes and prostaglandins.
In yet another aspect, the present invention provides methods of treating and/or preventing diseases characterized by, caused by or associated with the release of chemical mediators as a consequence of activating Fc receptor signaling cascades, such as FceRI
and/or Fc-yRI- signaling cascades. The methods may be practiced in animals in veterinary contexts or in humans. The methods generally involve administering to an animal subject or human an amount of a 2,4-pyrimidinediamine compound or prodrug of the invention, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to treat or prevent the disease. As discussed previously, activation of the FcERI or Fc-yRI receptor signaling cascade in certain immune cells leads to the release and/or synthesis of a variety of chemical substances that are pharmacological mediators of a wide variety of diseases.
Any of these diseases may be treated or prevented according to the methods of the invention.
For example, in mast cells and basophil cells, activation of the FceRI or Fc-yRI
signaling cascade leads to the immediate (i.e., within 1-3 min. of receptor activation) release of preformed mediators of atopic and/or Type I hypersensitivity reactions (e.g., histamine, proteases such as tryptase, etc.) via the degranulation process. Such atopic or Type I
hypersensitivity reactions include, but are not limited to, anaphylactic reactions to environmental and other allergens (e.g., pollens, insect and/or animal venoms, foods, drugs, contrast dyes, etc.), anaphylactoid reactions, hay fever, allergic conjunctivitis, allergic rhinitis, allergic asthma, atopic dermatitis, eczema, urticaria, mucosal disorders, tissue disorders and certain gastrointestinal disorders.
The immediate release of the preformed mediators via degranulation is followed by the release and/or synthesis of a variety of other chemical mediators, including, among other things, platelet activating factor (PAF), prostaglandins and leukotrienes (e.g., LTC4) and the de novo synthesis and release of cytokines such as TNFa, IL-4, IL-5, IL-6, IL-13, etc. The first of these two processes occurs approximately 3-30 mm. following receptor activation;
the latter approximately 30 min. ¨7 hrs. following receptor activation. These "late stage"
mediators are thought to be in part responsible for the chronic symptoms of the above-listed atopic and Type I hypersensitivity reactions, and in addition are chemical mediators of inflammation and inflammatory diseases (e.g., osteoarthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, idiopathic inflammatory bowel disease, irritable bowel syndrome, spastic colon, etc.), low grade scarring (e.g., scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury and post myocardial infarction), and sicca complex or syndrome. All of these diseases may be treated or prevented according to the methods of the invention.
Additional diseases which can be treated or prevented according to the methods of the invention include diseases associated with basophil cell and/or mast cell pathology.
Examples of such diseases include, but are not limited to, diseases of the skin such as scleroderma, cardiac diseases such as post myocardial infarction, pulmonary diseases such as pulmonary muscle changes or remodeling and chronic obstructive pulmonary disease (COPD) and diseases of the gut such as inflammatory bowel syndrome (spastic colon).
The 2,4-pyrimidinediamine compounds of the invention are also potent inhibitors of the tyrosine kinase Syk kinase. Thus, in still another aspect, the present invention provides methods of regulating, and in particular inhibiting, Syk kinase activity. The method generally involves contacting a Syk kinase or a cell comprising a Syk kinase with an amount of a 2,4-pyrimidinediamine compound or prodrug of the invention, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to regulate or inhibit Syk kinase activity. In one embodiment, the Syk kinase is an isolated or recombinant Syk kinase. In another embodiment, the Syk kinase is an endogenous or recombinant Syk kinase expressed by a cell, for example a mast cell or a basophil cell. The method may be practiced in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by or associated with Syk kinase activity.
While not intending to be bound by any particular theory of operation, it is believed that the 2,4-pyrimdinediamine compounds of the invention inhibit cellular degranulation and/or the release of other chemical mediators primarily by inhibiting Syk kinase that gets activated through the gamma chain homodimer of FceRI (see, e.g., FIG. 2). This gamma chain homodimer is shared by other Fc receptors, including Fel/RI, FcyRIII and FcaRI. For all of these receptors, intracellular signal transduction is mediated by the common gamma chain homodimer. Binding and aggregation of those receptors results in the recruitment and activation of tyrosine kinases such as Syk kinase. As a consequence of these common signaling activities, the 2,4-pylimidinediamine compounds described herein may be used to regulate, and in particular inhibit, the signaling cascades of Fc receptors having this gamma chain homodimer, such as FccRI, FcryRI, Fc-yRIII and FcaRI, as well as the cellular responses elicited through these receptors.
Syk kinase is known to play a critical role in other signaling cascades. For example, Syk kinase is an effector of B-cell receptor (BCR) signaling (Turner et al., 2000, Immunology Today 21:148-154) and is an essential component of integrin beta(1), beta(2) and beta(3) signaling in neutrophils (Mocsai et al., 2002, Immunity 16:547-558). As the 2,4-pyrimidinediamine compounds described herein are potent inhibitors of Syk kinase, they can be used to regulate, and in particular inhibit, any signaling cascade where Syk plays a role, such as, fore example, the Fc receptor, BCR and integrin signaling cascades, as well as the cellular responses elicited through these signaling cascades. The particular cellular response regulated or inhibited will depend, in part, on the specific cell type and receptor signaling cascade, as is well known in the art. Non-limiting examples of cellular responses that may be regulated or inhibited with the 2,4-pyrimidinediamine compounds include a respiratory burst, cellular adhesion, cellular degranulation, cell spreading, cell migration, phagocytosis (e.g., in macrophages), calcium ion flux (e.g., in mast, basophil, neutrophil, eosinophil and B-cells), platelet aggregation, and cell maturation (e.g., in B-cells).
Thus, in another aspect, the present invention provides methods of regulating, and in particular inhibiting, signal transduction cascades in which Syk plays a role.
The method generally involves contacting a Syk-dependent receptor or a cell expressing a Syk-dependent receptor with an amount of a 2,4-pyrimidinediamine compound or prodrug of the invention, or an acceptable salt, hydrate, solvate, N-oxide and/or composition thereof, effective to regulate or inhibit the signal transduction cascade. The methods may also be used to regulate, and in particular inhibit, downstream processes or cellular responses elicited by activation of the particular Syk-dependent signal transduction cascade. The methods may be practiced to regulate any signal transduction cascade where Syk is not known or later discovered to play a role. The methods may be practiced in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by or associated with activation of the Syk-dependent signal transduction cascade. Non-limited examples of such diseases include those previously discussed.
In another aspect, the present invention provides a 2,4-pyrimidinediamine compound according to structural formula (I):

Rt.
N N N
and salts, hydrates, solvates, and N-oxides thereof, wherein:
R2 is selected from the group consisting of phenyl mono substituted at the 3 -or 5-position with an R8 group, phenyl di- or tri-substituted with one or more of the same or different R8 groups and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R4 is selected from the group consisting of phenyl substituted with one or more of the same or different R8 groups and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R5 is selected from the group consisting of -CN, -NC, fluoro, (C1 -C3) haloalkyl, (C I -C3) perhaloalkyl, (C1-C3) fluoroalkyl, (C1-C3) perfluoroalkyl, -CF3, (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, (C I -C3) fluoroalkoxy, (C1-C3) perfluoroalkoxy, -0CF3, -C(0)R', -C(0)01e, -C(0)CF3 and -C(0)0CF3;
R8 is selected from the group consisting all!, Rb, Re substituted with one or more of the same or different Ra or Rb, -0Ra substituted with one or more of the same or different Ra or Rb, -B(Op)2, -B(NReRc)2, -(CF12)m-Rh, -(CHRa)m-Rh, -0-(CH2)m-Rh, -S-(CH2)m-Rh, -0-CHRaRh, -0-CRa(Rh)2, -0-(CHRa),õ-Rb, -0- (CH2)õ,-CH[(CH2).Rb]Rb, -S-(CHRa)m-Rb, -C(0)NH-(CH2)m-Rb, -C(0)NH-(CHRa)õ,-Rb, -0-(CH2)m-C(0)NH-(CH2)m-Rb, -S-(CH2)õ,-C(0)NH-(CH2)õ,-Rb, -0-(CHRa)m-C(0)NH-(CHRa)m-Rb, -S-(CHRa)m-C(0)NH-(CHRa)m-Rh, -NH-(CH2)m-Rh, -NH-(CHRa)m-Rb, -NFI[(CH2)mRh], -NRCH2),nle12, -NH-C(0)-NH-(CH2)m-Rh, -NH-C(0)-(CH2)m-CHRhRh and -NH-(CH2)m-C(0)-NH-(CH2)m-Rb;

each le is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each le is a suitable group independently selected from the group consisting of =0, -ORd, (C1-C3) haloalkyloxy, =S, -SRd, =NRd, =NORd, -Nlele, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(0)Rd, -S(0)2R", -S(0)20R", -S(0)NRcle, -S(0)2Nlele, -0S(0)Rd, -0S(0)2Rd, -0S(0)20Rd, -0S(0)2Nlele, -C(0)Rd, -C(0)0Rd, -C(0)Nlele, -C(NH)Nlele, -C(Nle)Nlele, -C(NOH)Ra, -C(NOH)Nlele, -0C(0)Rd, -0C(0)0Rd, -0C(0)Nlele, -0C(NH)Nlele, -0C(NRa)Nlele, -[NHC(0)]Rd, -[NleC(0)]õRd, -[NHC(0)]ORd, -[NleC(0)]ORd, -[NHC(0)]õNlele, -[NleC(0)]õNlele, -[NHC(NH)]õNI:ele and -[NleC(Nle)],,Nlele;
each le is independently a protecting group or le, or, alternatively, two le are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different Ra groups;
each Rd is independently a protecting group or le;
each le is independently selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each m is independently an integer from 1 to 3; and each n is independently an integer from 0 to 3;
wherein a protecting group may be an amino protecting group which is formyl, acetyl, trifluoroacetyl, benzyl, benzylcarbonyl, tert-butoxycarbonyl, trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl, substituted trityl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl or nitro-veratryloxycarbonyl;
or a hydroxyl protecting group in which the hydroxyl group is acylated or alkylated to form a benzyl ether, trityl ether, alkyl ether, tetrahydro pyranylether, trialkylsilyl ether or allyl ether;
with the provisos that:
13a (1) when R2 is a substituted phenyl, then R5 is other than cyano;
(2) when R2 and R4 are each independently a substituted or unsubstituted pyrrole or indole, then the R2 and R4 are attached to the remainder of the molecule via a ring carbon atom;
= and (3) the compound is not N2,N4-bis(3-methylpheny1)-5-fluoro-2,4-pyrimidinediamine (R092788);
N2,N4-bis(3-chloropheny1)-5-fluoro-2,4-pyrimidinediamine (R067962);
N2,N4-bis(2,5-dimethylpheny1)-5-fluoro-2,4-pyrimidinediamine (R067963);
N2,N4-bis(3,4-dimethylpheny1)-5-fluoro-2,4-pyrimidinediamine (R067964);
N2,N4-bis(2,4-dimethylpheny1)-5-fluoro-2,4-pyrimidinediamine (R070791);
N2,N4-bis(3-bromopheny1)-5-fluoro-2,4-pyrimidinediamine (R008958); or N2,N4-bis[(3-chloro-4-methoxypheny1)]-5-fluoro-2,4-pyrimidinediamine.
In another aspect, the present invention provides N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine and salts, hydrates, solvates, and/or N-oxides thereof.
In another aspect, the present invention provides N4-(1,4-Benzoxazin-6-y1)-5-fluoro-N243-(N-methylamino)carbonylmethyleneoxypheny1]-2,4-pyrimidinediamine and salts, hydrates, solvates, and/or N-oxides thereof.
In another aspect, the present invention provides N4-[(2,2-difluoro-4H-benzo[1,41oxazin-3-one)-6-y11-5-fluoro-N243-(methylaminocarbonylmethy1eneoxy)pheny1]-2,4-pyrimidinediamine and salts, hydrates, solvates, and/or N-oxides thereof.
In another aspect, the present invention provides N4-[(2,2-dimethy1-4H-benzo[1,4]oxazin-3-one)-6-y1]-5-fluoro-N243-(methylaminocarbonylmethyleneoxy)pheny11-2,4-pyrimidinediamine and salts, hydrates, solvates, and/or N-oxides thereof.
3b In another aspect, the present invention provides N4-[(2,2-difluoro-4H-benzo[ I ,4]oxazin-3-one)-6-y1]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine and salts, hydrates, solvates, and/or N-oxides thereof.
In another aspect, the present invention provides N4t2H-pyrido[3,2-13]-1,4-oxazin-3(4H)-one-6-y1]-5-fluoro-N2-(3-methylaminocarbonylmethyleneoxypheny1)-2,4-pyrimidinediamine and salts, hydrates, solvates, and/or N-oxides thereof.
5. BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 provides a cartoon illustrating allergen-induced production of IgE and consequent release of preformed and other chemical mediators from mast cells;
FIG. 2 provides a cartoon illustrating the FcgR1 signal transduction cascade leading to degranulation of mast and/or basophil cells;
FIG. 3 provides a cartoon illustrating the putative points of action of compounds that selectively inhibit upstream FceRI-mediated degranulation and compounds that inhibit both FcERI-mediated and ionomycin- induced degranulation;
FIG. 4 provides graphs illustrating the effects of certain 2,4-pyrimidinediamine compounds, DMSO (control) and ionomycin on Ca2+ flux in CFIMC cells;
FIG. 5 provides graphs illustrating the immediacy of the inhibitory activity of compounds R921218 and R926495;
FIG. 6 provides a graph illustrating the effect of washout on the inhibitory activity of compounds R921218 and R921302;
FIG. 7 provides data showing that varying concentratiohs of compounds R921218 (A) and R921219 (B) inhibit phosporylation of various proteins downstream of Syk kinase in the IgE
receptor signal transduction cascade in activated BMMC cells;
FIG. 8 provides data showing dose responsive inhibition of Syk kinase phosphorylation of an endogenous substrate (LAT) and a peptide substrate in the presence of increasing concentrations of compounds R921218 (X), R921219 (Y) and R921304 (Z);
FIG. 9 provides data showing that the inhibition of Syk kinase by compound R921219 is ATP competitive;
13c FIG. 10 provides data showing that varying concentrations of compounds R921219 (A) and R218218 (B) inhibit phosphorylation of proteins downstream of Syk kinase, but not LYN kinase, in the FccRI signal transduction cascade in activated CHMC cells;
also shown is inhibition of phosphorylation of proteins downstream of LYN kinase but not Syk kinase, in the presence of a known LYN kinase inhibitor (PP2); and FIGS. 11A-D provide data showing inhibition of phosphorylation of proteins downstream of Syk kinase in the FcÃR1 signal transduction cascade in BMMC
cells.
6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
6.1 Definitions As used herein, the following terms are intended to have the following meanings:
"Alkyl" by itself or as part of another substituent refers to a saturated or unsaturated branched, straight-chain or cyclic monovalent hydrocarbon radical having the stated number of carbon atoms (i.e., C1-C6 means one to six carbon atoms) that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or allgne.
Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-l-yl, propan-2-yl, cyclopropan-l-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, cycloprop-1-en-1-y1; cycloprop-2-en-1-yl, prop-1-yn-l-y1 , prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan- 1 -yl, but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-1-en-l-yl, but-2-en-1-y1 , but-2-en-2-yl, buta-1,3-dien-l-yl, buta-1,3-dien-2-yl, cyclobut-l-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-1,3-dien-l-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-l-yl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature "alkanyl," "alkenyl" and/or "alkynyl" is used, as defined below. In preferred embodiments, the alkyl groups are (C1-C6) alkyl.
"Alkanyl" by itself or as part of another substituent refers to a saturated branched, straight-chain or cyclic alkyl derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-l-yl, propan-2-y1 (isopropyl), cyclopropan-l-yl, etc.; butanyls such as butan-l-yl, butan-2-y1 (sec-butyl), 2-methyl-propan-1 -yl (isobutyl), 2-methyl-propan-2-y1 (t-butyl), cyclobutan-l-yl, etc.; and the like. In preferred embodiments, the alkanyl groups are (C1-C6) alkanyl.

"Alkenyl" by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-y1, prop-1-en-2-yl, prop-2-en-l-yl, prop-2-en-2-yl, cycloprop-1-en-1-y1; cycloprop-2-en-l-y1 ;
butenyls such as but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-1-en-l-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-l-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-1,3-dien-l-yl, etc.; and the like. In preferred embodiments, the alkenyl group is (C2-C6) alkenyl.
"Alkynyl" by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-y1 , prop-2-yn-l-yl, etc.; butynyls such as but-l-yn-l-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. In preferred embodiments, the alkynyl group is (C2-C6) alkynyl.
"Alkyldiyl" by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon group having the stated number of carbon atoms (i.e., Cl-C6 means from one to six carbon atoms) derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne. The two monovalent radical centers or each valency of the divalent radical center can form bonds with the same or different atoms.
Typical alkyldiyl groups include, but are not limited to, methandiyl; ethyldiyls such as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diy1; propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as, butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl, cyclobutan-1,1-diy1; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl, but-l-en-1,1-diyl, but-l-en-1,2-diyl, but-l-en-1,3-diyl, but-l-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl, 2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl, buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl, cyclobut-1-en-1,2-diyl, cyclobut-l-en-1,3-diyl, cyclobut-2-en-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl, but-l-yn-1,3-diyl, but-l-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Where it is specifically intended that the two valencies are on the same carbon atom, the nomenclature "alkylidene" is used. In preferred embodiments, the alkyldiyl group is (C1-C6) alkyldiyl. Also preferred are saturated acyclic alkanyldiyl groups in which the radical centers are at the terminal carbons, e.g., methandiyl (methano); ethan-1,2-diy1 (ethano); propan-1,3-diy1 (propano); butan-1,4-diy1 (butano); and the like (also referred to as alkylenos, defined infra).
"Alkyleno" by itself or as part of another substituent refers to a straight-chain saturated or unsaturated alkyldiyl group having two terminal monovalent radical centers derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of straight-chain parent alkane, alkene or alkyne. The locant of a double bond or triple bond, if present, in a particular alkyleno is indicated in square brackets.
Typical alkyleno groups include, but are not limited to, methano; ethylenos such as ethano, etheno, ethynD;
propylenos such as propano, prop[l]eno, propa[1,2]dieno, prop[l]yno, etc.;
butylenos such as butano, but[l]eno, but[2]eno, buta[1,3]dieno, but[l]yno, but[2]yno, buta[1,3]diyno, etc.;
and the like. Where specific levels of saturation are intended, the nomenclature alkali , alkeno and/or alk3mo is used. In preferred embodiments, the alkyleno group is (C1-C6) or (C1-C3) alkyleno. Also preferred are straight-chain saturated alkano groups, e.g., methano, ethano, propano, butano, and the like.
"Heteroalkyl," Heteroalkanyl," Heteroalkenyl," Heteroalkynyl,"
Heteroalkyldiyl"
and "Heteroalkyleno" by themselves or as part of another substituent refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyl and alkyleno groups, respectively, in which one or more of the carbon atoms are each independently replaced with the same or different heteratoms or heteroatornic groups. Typical hetero atoms and/or heteroatomic groups which can replace the carbon atoms include, but are not limited to, -0-, -S-, -S-0-, -NR'-, -PH-, -S(0)-, -S(0)2-, -S(0) NR'-, -S(0)2NR'-, and the like, including combinations thereof, where each R' is independently hydrogen or (C1-C6) alkyl.
"Cycloalkyl" and "Heterocycloalkyl" by themselves or as part of another substituent refer to cyclic versions of "alkyl" and "heteroalkyl" groups, respectively.
For heteroalkyl groups, a heteroatom can occupy the position that is attached to the remainder of the molecule. Typical cycloalkyl groups include, but are not limited to, cyclopropyl;
cyclobutyls such as cyclobutanyl and cyclobutenyl; cyclopentyls such as cyclopentanyl and cyclopentenyl; cyclohexyls such as cyclohexanyl and cyclohexenyl; and the like. Typical heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, etc.), piperidinyl (e.g., piperidin-l-yl, piperidin-2-yl, etc.), morpholinyl (e.g., morpholin-3-yl, morpholin-4-yl, etc.), piperazinyl (e.g., piperazin-l-yl, piperazin-2-yl, etc.), and the like.
"Acyclic Hetero atomic Bridge" refers to a divalent bridge in which the backbone atoms are exclusively heteroatoms and/or heteroatomic groups. Typical acyclic heteroatomic bridges include, but are not limited to, -0-, -S-, -S-0-, -NR'-, -PH-, -S(0)-, -S(0)2-, -S(0) NR'-, -S(0)2NR'-, and the like, including combinations thereof, where each R' is independently hydrogen or (C1-C6) alkyl.
"Parent Aromatic Ring System" refers to an unsaturated cyclic or polycyclic ring system having a conjugated it electron system. Specifically included within the definition of "parent aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, tetrahydronaphthalene, etc. Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and the like, as well as the various hydro isomers thereof.
"Aryl" by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon group having the stated number of carbon atoms (i.e., C5-C15 means from 5 to 15 carbon atoms) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like, as well as the various hydro isomers thereof. In preferred embodiments, the aryl group is (C5-C15) aryl, with (C5-C10) being even more preferred.
Particularly preferred aryls are cyclopentadienyl, phenyl and naphthyl.
"Arylaryl" by itself or as part of another sub stituent refers to a monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a ring system in which two or more identical or non-identical parent aromatic ring systems are joined directly together by a single bond, where the number of such direct ring junctions is one less than the number of parent aromatic ring systems involved. Typical arylaryl groups include, but are not limited to, biphenyl, triphenyl, phenyl-naphthyl, "Biaryl" by itself or as part of another substituent refers to an arylaryl group having two identical parent aromatic systems joined directly together by a single bond. Typical "Arylalkyl" by itself or as part of another sub stituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 "Parent Heteroaromatic Ring System" refers to a parent aromatic ring system in which one or more carbon atoms are each independently replaced with the same or different heteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomic groups to replace the carbon atoms include, but are not limited to, N, NH, P, 0, S, S(0), S(0)2, Si, etc.
Specifically included within the definition of "parent heteroaromatic ring systems" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Also included in the definition of "parent heteroaromatic ring system" are those recognized rings that include common substituents, such as, for example, benzopyrone and 1-methyl-1,2,3,4-tetrazole. Specifically excluded from the definition of "parent heteroaromatic ring system" are benzene rings fused to cyclic polyalkylene glycols such as cyclic polyethylene glycols. Typical parent heteroaromatic ring systems include, but are not limited to, acridine, benzimidazole, benzisoxazole, benzodioxan, benzodioxole, benzofuran, benzopyrone, benzothiadiazole, benzothiazole, benzotnazole, benzoxaxine, benzoxazole, benzoxazoline, carbazole, P-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.
"Heteroaryl" by itself or as part of another substituent refers to a monovalent heteroaromatic group having the stated number of ring atoms (e.g., "5-14 membered" means from 5 to 14 ring atoms) derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, benzimidazole, benzisoxazole, benzodioxan, benzodiaxole, benzofuran, benzopyrone, benzothiadiazole, benzothiazole, benzotriazole, benzoxazine, benzoxazole, benzoxazoline, carbazole,13-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like, as well as the various hydro isomers thereof. In preferred embodiments, the heteroaryl group is a 5-14 membered heteroaryl, with 5-10 membered heteroaryl being particularly preferred.
"Heteroaryl-Heteroaryl" by itself or as part of another substituent refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a ring system in which two or more identical or non-identical parent heteroaromatic ring systems are joined directly together by a single bond, where the number of such direct ring junctions is one less than the number of parent heteroaromatic ring systems involved. Typical heteroaryl-heteroaryl groups include, but are not limited to, bipyridyl, tripyridyl, pyridylpurinyl, bipurinyl, etc. Where the number of atoms are specified, the numbers refer to the number of atoms comprising each parent heteroaromatic ring systems. For example, 5-15 membered heteroaryl-heteroaryl is a heteroaryl-heteroaryl group in which each parent heteroaromatic ring system comprises from 5 to 15 atoms, e.g., tripuridyl, etc. Preferably, each parent heteroaromatic ring system is independently a 5-15 membered heteroaromatic, more preferably a 5-10 membered heteroaromatic. Also preferred are heteroaryl-heteroaryl groups in which all of the parent heteroaromatic ring systems are identical.
"Biheteroaryl" by itself or as part of another substituent refers to a heteroaryl-heteroaryl group having two identical parent heteroaromatic ring systems joined directly together by a single bond. Typical biheteroaryl groups include, but are not limited to, bipyridyl, bipurinyl, biquinolinyl, and the like. Preferably, the heteroaromatic ring systems are 5-15 membered heteroaromatic rings, more preferably 5-10 membered heteroaromatic rings.
"Heteroarvlalkyl" by. itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylakenyl and/or heteroarylalkynyl is used. In preferred embodiments, the heteroarylalkyl group is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is (C1-C6) alkyl and the heteroaryl moiety is a 5-15-membered heteroaryl. In particularly preferred embodiments, the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety is (C1-C3) alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

"Halogen" or "Halo" by themselves or as part of another substituent, unless otherwise stated, refer to fluoro, chloro, bromo and iodo.
"Haloalkyl" by itself or as part of another substituent refers to an alkyl group in which one or more of the hydrogen atoms is replaced with a halogen. Thus, the term "haloalkyl" is meant to include monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls. For example, the expression "(C1-C2) haloalkyl" includes fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.
The above-defined groups may include prefixes and/or suffixes that are commonly used in the art to create additional well-recognized substituent groups. As examples, "alkyloxy" or "alkoxy" refers to a group of the formula -OR", "alkylamine"
refers to a group of the formula ¨NHR" and "dialkylamine" refers to a group of the formula ¨NR"R", where each R" is independently an alkyl. As another example, "haloalkoxy" or "haloalkyloxy" refers to a group of the formula ¨OR'", where R" is a haloalkyl.
"Protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity, of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY
and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifiuoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC") and the like. Representative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or MPS groups) and allyl ethers.
"Prodrug" refers to a derivative of an active 2,4-pyrimidinediamine compound (drug) that requires a transformation under the conditions of use, such as within the body, to release the active 2,4-pyrimidinediamine drug. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug. Prodrugs are typically obtained by masking a functional group in the 2,4-pyrimidinediarnine drug believed to be in part required for activity with a progroup (defined below) to form a promoiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active 2,4-pyrimidinediamine drug.
The cleavage of the promoiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid or base, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature. The agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously.
A wide variety of progroups, as well as the resultant promoieties, suitable for masking functional groups in the active 2,4-pyrimidinediamines compounds to yield prodrugs are well-known in the art. For example, a hydroxyl functional group may be masked as a sulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivo to provide the hydroxyl group. An amino functional group may be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety, which may be hydrolyzed in vivo to provide the amino group. A carboxyl group may be masked as an ester (including silyl esters and thioesters), amide or hydrazide promoiety, which may be hydrolyzed in vivo to provide the carboxyl group. Other specific examples of suitable progroups and their respective promoieties will be apparent to those of skill in the art.
"Progroup" refers to a type of protecting group that, when used to mask a functional group within an active 2,4-pyrimidinediamine drug to form a promoiety, converts the drug into a prodrug. Progroups are typically attached to the functional group of the drug via bonds that are cleavable under specified conditions of use. Thus, a progroup is that portion of a promoiety that cleaves to release the functional group under the specified conditions of use. As a specific example, an amide promoiety of the formula ¨NH-C(0)CH3 comprises the progroup ¨C(0)CH3.
"Fc Receptor" refers to a member of the family of cell surface molecules that binds the Fc portion (containing the specific constant region) of an immtmoglobulin.
Each Fc receptor binds immunoglobulins of a specific type. For example the Fca receptor ("Fcalt.") binds IgA, the FcER binds IgE and the FciR binds IgG.
The FcaR family includes the polymeric Ig receptor involved in epithelial transport of IgA/IgM, the myeloid specific receptor RcaRI (also called CD89), the Fca/AR
and at least two alternative IgA receptors (for a recent review see Monteiro & van de Winkel, 2003, Annu. Rev. Immunol, advanced e-publication. The FcaRI is expressed on neutrophils, eosinophils, moncytes/macrophages, dendritic cells and kupfer cells. The FcaRI inclues one alpha chain and the FcR gamma homodimer that bears an activation motif (ITAM) in the cytoplasmic domain and phosphorylates Syk kinase.
The FcER family includes two types, designated FcERI and FceRII (also known as CD23). FccRI is a high affinity receptor (binds IgE with an affinity of about 1010M-1) found on mast, basophil and eosinophil cells that anchors monomeric IgE to the cell surface. The FeERI possesses one alpha chain, one beta chain and the gamma chain homodimer discussed above. The FeeRII is a low affinity receptor expressed on mononuclear phagocytes, B lymphocytes, eosinophils and platelets. The FcERII comprises a single polypeptide chain and does not include the gamma chain homodimer.
The Fc7R family includes three types, designated FcryRI (also known as CD64), FcryRII (also known as CD32) and Fc'yRIII (also known as CD16). FcyRI is a high affinity receptor (binds IgG1 with an affinity of 108M-1) found on mast, basophil, mononuclear, neutrophil, eosinophil, deudritic and phagocyte cells that anchors nomomeric IgG to the cell surface. The FcryRI includes one alpha chain and the gamma chain dimer shared by FcaRI
and FceRI.
The Fc-yRII is a low affinity receptor expressed on neutrophils, monocytes, eosinophils, platelets and B lymphocytes. The FcryRII includes one alpha chain, and does not include the gamma chain homodimer discussed above.
The Fc'yRIII is a low affinity (bindes IgG1 with an affinity of 5x105M-1) expressed on NK, eosinophil, macrophage, neutrophil and mast cells. It comprises one alpha chain and the gamma homodimer shared by FcaRI, FcERI and FcryRI.
Skilled artisans will recognize that the subunit structure and binding properties of these various Fc receptors, cell types expressing them, are not completely characterized.
The above discussion merely reflects the current state-of-the-art regarding these receptors (see, e.g., Immunobiology: The Immune System in Health & Disease, 5th Edition, Janeway et al., Eds, 2001, ISBN 0-8153-3642-x, Figure 9.30 at pp. 371), and is not intended to be limiting with respect to the myriad receptor signaling cascades that can be regulated with the compounds described herein.
"Fc Receptor-Mediated Degranulation" or "Fe Receptor-Induced Degranulation"
refers to degranulation that proceeds via an Fc receptor signal transduction cascade initiated by crosslinking of an Fc receptor.
"IgE-Induced Degranulation" or "FcERI-Mediated Degranulation" refers to degranulation that proceeds via the IgE receptor signal transduction cascade initiated by crosslinking of FcsR1-bound IgE. The crosslinking may be induced by an IgE-specific allergen or other multivalent binding agent, such as an anti-IgE antibody.
Referring to FIG. 2, in mast and/or basophil cells, the FcERI signaling cascade leading to degranulation may be broken into two stages: upstream and downstream. The upstream stage includes all of the processes that occur prior to calcium ion mobilization (illustrated as "Ca2+" in FIG. 2;
see also FIG. 3). The downstream stage includes calcium ion mobilization and all processes downstream thereof. Compounds that inhibit FcERI-mediated degranulation may act at any point along the FcERI-mediated signal transduction cascade. Compounds that selectively inhibit upstream FcERI-mediated degranulation act to inhibit that portion of the FcERI
signaling cascade upstream of the point at which calcium ion mobilization is induced. In cell-based assays, compounds that selectively inhibit upstream FcERI-mediated degranulation inhibit degranulation of cells such as mast or basophil cells that are activated or stimulated with an IgE-specific allergen or binding agent (such as an anti-IgE antibody) but do not appreciably inhibit degranulation of cells that are activated or stimulated with degranulating agents that bypass the FcERI signaling pathway, such as, for example the calcium ionophores ionomycin and A23187.
"IgG-Induced Degranulation" or "Fc-yRI-Mediated Degranulation" refers to degranulation that proceeds via the FcyRI signal transduction cascade initiated by crosslinking of Fc-yRI-bound IgG. The crosslinking may be induced by an IgG-specific allergen or another multivalent binding agent, such as an anti-IgG or fragment antibody.
Like the FcERI signaling cascade, in mast and basophil cells the FcyRI
signaling cascade also leads to degranulation which may be broken into the same two stages:
upstream and downstream. Similar to FcERI-mediated degranulation, compounds that selectively inhibit upstream FcyRI-mediated degranulation act upstream of the point at which calcium ion mobilization is induced. In cell-based assays, compounds that selectively inhibit upstream Fc7RI-mediated degranulation inhibit degranulation of cells such as mast or basophil cells that are activated or stimulated with an IgG-specific allergen or binding agent (such as an anti-IgG antibody or fragment) but do not appreciably inhibit degranulation of cells that are activated or stimulated with degranulating agents that bypass the Fc'yRI
signaling pathway, such as, for example the calcium ionophores ionomycin and A23187.
"Ionophore-Induced Degranulation" or "Ionophore-Mediated Degranulation" refers to degranulation of a cell, such as a mast or basophil cell, that occurs upon exposure to a calcium ionophore such as, for example, ionomycin or A23187.

"Syk Kinsase" refers to the well-known 72kDa non-receptor (cytoplasmic) spleen protein tyrosine kinase expressed in B-cells and other hematopoetic cells. Syk kinase includes two consensus Src-homology 2 (SH2) domains in tandem that bind to phosphorylated immunoreceptor tyrosine-based activation motifs (TTAMs"), a "linker"
domain and a catalytic domain (for a review of the structure and function of Syk kinase see Sada et al., 2001, J. Biochem. (Tokyo) 130:177-186); see also Turner etal., 2000, Immunology Today 21:148-154). Syk kinase has been extensively studied as an effector of B-cell receptor (BCR) signaling (Turner et al., 2000, supra). Syk kinage is also critical for tyrosine phosphorylation of multiple proteins which regulate important pathways leading from immunoreceptors, such as Ca' mobilization and mitogen-activated protein kinase (MAPK) cascades (see, e.g., FIG. 2) and degranulation. Syk kinase also plays a critical role in integrin signaling in neutrophils (see, e.g., Mocsai et al. 2002, Immunity 16:547-558).
As used herein, Syk kinase includes kinases from any species of animal, including but not limited to, homosapiens, simian, bovine, porcine, rodent, etc., recognized as belonging to the Syk family. Specifically included are isoforms, splice variants, allelic variants, mutants, both naturally occuring and man-made. The amino acid sequences of =
such Syk kinases are well known and available from GENBANK. Specific examples of mRNAs encoding different isoforrns of human Syk kinase can be found at GENBANK

accession no. giI213615521refINM__003177.21, gi1496899lemblZ29630.1IHSSYKYTK[496899] and gi1150302581gbIBC011399.11BC011399[15030258].
Skilled artisans will appreciate that tyrosine kinases belonging to other families may have active sites or binding pockets that are similar in three-dimensional structure to that of Syk. As a consequence of this structural similarity, such kinases, referred to herein as "Svk mimics," are expected to catalyze phosphorylation of substrates phosphorylated by Syk.
Thus, it will be appreciated that such Syk mimics, signal transduction cascades in which such Syk mimics play a role and biological responses effected by such Syk mimics and Syk mimic-dependent signaling cascades may be regulated, and in particular inhibited, with the 2,4-pyrimidinediamine compounds described herein.
"Syk-Dependent Signaling Cascade" refers to. a signal transduction cascade in which Syk kinase plays a role. Non-limiting examples of such Syk-dependent signaling cascades include the FcoRI, FccRI, FcyRITE, BCR and integrin signaling cascades.

6.2 The 2,4-Pyrimidinediamine Compounds =
The compounds of the invention are generally 2,4-pyrimidinediamine compounds according to structural formula (I):

including salts, hydrates, solvates and N-oxides thereof, wherein:
L1 and L2 are each, independently of one another, selected from the group consisting of a direct bond and a linker;
R2 is selected from the group consisting of (C1-C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R8 groups, cyclohexyl optionally substituted with one or more of the same or different R8 groups, 3-8 membered cycloheteroalkyl optionally substituted with one or more of the same or different R8 groups, (C5-C15) aryl optionally substituted with one or more of the same or different R8 groups, phenyl optionally substituted with one or more of the same or different R8 groups and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R4 is selected from the group consisting of hydrogen, (C1-C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C3-C8) cycloalkyl optionally substituted with one or more of the same or different R8 groups, cyclohexyl optionally substituted with one or more of the same or different R8 groups, 3-8 membered cycloheteroalkyl optionally substituted with one or more of the same or different R8 groups, (C5-C15) aryl optionally substituted with one or more of the same or different R8 groups, phenyl optionally substituted with one or more of the same or different R8 groups and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
R5 is selected from the group consisting of R6, (C1-C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C1-C4) alkanyl optionally substituted with one or more of the same or different R8 groups, (C2-C4) alkenyl optionally substituted with one or more of the same or different R8 groups and (C2-C4) alkynyl optionally.
substituted with one or more of the same or different R8 groups;

each R6 is independently selected from the group consisting of hydrogen, an electronegative group, -ORd, -SR", (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, -NReRc, halogen, (C1-C3) haloalkyl,(C1-C3) perhaloalkyl, -CF3, -CH2CF3, -CF2CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, -N3, -S(0)Rd, -S(0)2Rd, -S(0)20Rd, -S(0)NRcRc, -S(0)2NRcRc, -0S(0)Rd, -0S(0)2Rd, -0S(0)20R', -0S(0)NRcRe, -0S(0)2NRcRe, -C(0)Rd, -C(0)0Rd, -C(0)NRcRe, -C(NH)NReRc, -0C(0)Rd, -SC(0)Rd, -0C(0)0R', -SC(0)OR', -0C(0)NRcRe, -SC(0)NRcRe, -0C(NH)NRcRe, -SC(NH)NReRc, -{NHC(0)ble, -[NHC(0)]õORd, -[NHC(0)]õNRcRe and -[NHC(NH)]õNRcRc, (C5-C10) aryl optionally substituted with one or more of the same or different R8 groups, phenyl optionally substituted with one or more of the same or different R8 groups, (C6-C16) arylalkyl optionally substituted with one or more of the same or different R8 groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R8 groups and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R8 groups;
R8 is selected from the group consisting of Ra, Rb, Ra substituted with one or more of the same or different Ra or Rb, -0Ra substituted with one or more of the same or different Ra or Rb, -B(ORa)2, -B(NRcRc)2, -(CHOniab, -(CHRa)m-Rb, -0-(CH2)2-Rb, -S-(CH2)m-R1' , -0-CHRaRb, -0-CRa(Rb)2, -0-(CHRa),-Rb, -0- (CH2),-CH[(CH2),Rb]Rb, -S-(CHRa)m-Rb, -C(0)NH-(CH2),-Rb, -C(0)NH-(CBRa)m-Rb, -0-(CH2)1-C(0)NH-(CH2),-Rb, -S-(CH2)m-C(0)NH-(CH2)m-Rb, -0-(CHRa)m-C(0)NH-(CHRa)m-R1' , -S-(CliRa)m-C(0)NH-(CHRa)m-Rb, -NH-(CH2),-Rb, -NH-(CHRa)m-Rb, -NH[(C112)nabi, -NRCH2)mR112, -NH-C(0)-NH-(CH2)m-Rb, -NH-C(0)-(CH2),-CHRbRb and each Ra is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each Rb is a suitable group independently selected from the group consisting of =0, -OR', (C1-C3) haloalkyloxy, -0CF3, =S, -SRd, =-NRd, =NORd, -WIZ% halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(0)Rd, -S(0)2Rd, -S(0)20R', -S(0)NRcitc, -S(0)2NRcRc, -0S(0)Rd, -0S(0)2Rd, -0S(0)20R', -0S(0)2NRcRe, -C(0)Rd, -C(0)0Rd, -C(0)NReRc, -C(NH)NRcitc, -C(NRa)NRele, -C(NOH)Ra, -C(NOH)NRcRc, -0C(0)Rd, -0C(0)0Rd, -0C(0)NRele, -0C(NH)NRcie, -OC(NRa)NRcRe, -[NHC(0)]õRd, -[NRaC(0)]ad, -{I\THC (0)], ORd, - [1\TRaC (0)], ORd, 41\111C(0)1,NReRc, -[NRaC (0)I ,NReRc, _ F\THQNHA ,N-RcRe and _NRac(NRa)JnNReRc;
each Re is independently Ra, or, alternatively, each Re is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which is optionally substituted with one or more of the same or different Ra or suitable Rb groups;
each Rd is independently Ra;
each in is independently an integer from 1 to 3; and each n is independently an integer from 0 to 3.
In the compounds of structural formula (I), L1 and L2 represent, independently of one another, a direct bond or a linker. Thus, as will be appreciated by skilled artisans, the sub stituents R2 and/or R4 may be bonded either directly to their respective nitrogen atoms or, alternatively, spaced away from their respective nitrogen atoms by way of a linker. The identity of the linker is not critical and typical suitable linkers include, but are not limited to, (C1-C6) alkyldiyls, (C1-C6) alkanos and (C1-C6) heteroalkyldiyls, each of which may be optionally substituted with one or more of the same or different R8 groups, where R8 is as previously defined for structural formula (I). In a specific embodiment, L1 and L2 are each, independently of one another, selected from the group consisting of a direct bond, (C1-C3) alkyldiyl optionally substituted with one or more of the same or different Ra, suitable le or R9 groups and 1-3 membered heteroalkyldiyl optionally substituted with one or more of the same or different Ra, suitable le or R9 groups, wherein R9 is selected from the group consisting of (C1-C3) alkyl, -0Ra, -C(0)OR', (C5-C10) aryl optionally substituted with one or more of the same or different halogens, phenyl optionally substituted with one or more of the same or different halogens, 5-10 membered heteroaryl optionally substituted with one or more of the same or different halogens and 6 membered heteroaryl optionally substituted with one or more of the same or different halogens; and Ra and Rb are as previously defmed for structural formula (I). Specific R9 groups that may be used to substitute L1 and L2 include -0Ra, -C(0)0Ra, phenyl, halophenyl and 4-halophenyl, wherein Ra is as previously defined for structural formula (I).
In another specific embodiment, LI and L2 are each, independently of one another, selected from the group consisting of methano, ethano and propano, each of which may be optionally monosubstituted with an R9 group, where R9 is as previously defined above.

In all of the above embodiments, specific Ra groups that may be included in R9 .
groups are selected from the group consisting of hydrogen, (C1-C6) alkyl, phenyl and benzyl.
In still another specific embodiment, L1 and L2 are each a direct bond such that the 2,4-pyrimidinediamine compounds of the invention are compounds according to structural formula (La):

R61) N

including salts, hydrates, solvates and N-oxides thereof, wherein R2, R4, R5 and R6 are as previously defined for structural formula (I). Additional specific embodiments of the 2,4-pyrimidinediamine compounds of the invention are described below.
In a first embodiment of the compounds of structural formulae (I) and (la), R2, R4, R5, R6, 12 and L2 are as previously defined for their respective structures (I) and (1a), with the proviso that R2 is not 3,4,5-trimethoxyphenyl, 3,4,5-tri (C1-C6) alkoxyphenyl or ¨/ OR22 where R21, R22 and R23 are as defined for R1, R2 and R3, respectively of U.S.
Patent No.
6,235,746. In a specific embodiment of this first embodiment, R21 is hydrogen, halo, straight-chain or branched (C1-C6) alkyl optionally substituted with one or more of the same or different R25 groups, hydroxyl, (C1-C6) alkoxy optionally substituted with one or more of the same or different phenyl or R25 groups, thiol (-SH), (C1-C6) alkylthio optionally substituted with one or more of the same or different phenyl or R25 groups, amino (-NH2), -NR26 R26; R22 and +-. x23 are each, independently of one another, a (C1-C6) straight-chain or branched alkyl optionally substituted with one or more of the same or different R25 groups;
R25 is selected from the group consisting of halo, hydroxyl, (C1-C6) alkoxy, thiol, (C1-C6) alkylthio, (C1-C6) alkylamino and (C1-C6) dialkylamino; and each R26 is independently a (C1-C6) alkyl optionally substituted with one or more of the same or different phenyl or R25 groups or a -C(0)R27, where R27 is a (C1-C6) alkyl optionally substituted with one or more of the same or different phenyl or R25 groups.
In another specific embodiment of this first embodiment, R21 is methoxy optionally substituted with one or more of the same or different halo groups and/or R22 and R23 are each, independently of one another, a methyl or ethyl optionally substituted with one or more of the same or different halo groups.
In a second embodiment of the compounds of structural formulae (I) and (Ia), R2, R4, R5 and L2 are as previously described for their respective structures (I) and (Ia), L1 is a direct bond and R6 is hydrogen, with the proviso that R2 is not 3,4,5-trimethoxyphenyl, 3,4,5-tri (C1-C6) alkoxyphenyl or where R21, R22 and R23 are as defined above, in connection with the first embodiment.
In a third embodiment, the 2,4-pyrimidinediamine compounds of structural formulae (I) and (Ia) exclude one or more of the following compounds:
N2,N4-bis(4-ethoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R070790);
N2,N4-bis(2-methoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R081166);
N2,N4-bis(4-methoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R088814);
N2,N4-bis(2-chloropheny1)-5-fluoro-2,4-pyrimidinediamine (R088815);
N2,N4-bispheny1-5-fluoro-2,4-pyrimidinediamine (R091880);
N2,N4-bis(3-methylpheny1)-5-fluoro-2,4-pyrimidinediamine (R092788);
N2,N4-bis(3-chloropheny1)-5-fluoro-2,4-pyrimidinediamine (R067962);
N2,N4-bis(2,5-dimethylpheny1)-5-fluoro-2,4-pyrimidinediamine (R067963);
N2,N4-bis(3,4-dimethylpheny1)-5-fluoro-2,4-pyrimidinediamine (R067964);
N2,N4-bis(4-chloropheny1)-5-fluoro-2,4-pyrimidinediamine (R0707153);
N2,N4-bis(2,4-dimethylpheny1)-5-fluoro-2,4-pyrimidinediamine (R070791);
N2,N4-bis(3-bromopheny1)-5-fluoro-2,4-pyrimidinediamine (R008958);
N2,N4-bis(pheny1)-5-fluoro-2,4-pyrimidinediamine;
N2,N4-bis(morpholino)-5-fluoro-2,4-pyrimidinediamine; and N2,N4-bis[(3-chloro-4-methoxypheny1)]-5-fluoro-2,4-pyrimidinediamine.

-=
In a fourth embodiment, the compounds of structural formulae (I) and (la) exclude = compounds according to the following structural formula (Tb):

=
=
wherein R24 is (C1-C6) alkyl; and R21, le and ¨23 are as previously defin.ed in connection with the first embodiment.
In a fifth embodiment, the compounds of structural formulae (I) and (Ia) exclude the compounds described in Examples 1-141 of U.S. Patent No. 6,235,746.
In a sixth embodiment, the compounds of structural formulae (I) and (la) exclude compounds defined by formula (1) or formula 1(a) of this U.S. Patent No.
6,235,746 (see, e.g., the disclosure at Col. 1, line 48 through Col. 7, line 49 and Col. 8, lines 9-36) .
In a seventh embodiment, the compounds of structural formulae (I) and (la) exclude compounds in which R5 is cyano or ¨C(0)NHR, where R is hydrogen or (C1-C6) alkyl, when R2 is a substituted phenyl; R4 is a substituted or unsubstituted (C1-C6) alkyl, (C3-C9) cycloalkyl, 3-8 membered cycloheteralkyl or 5-15. membered heteroaryl; and R6 is hydrogen.
In an eighth embodiment, the compounds of structural formulae (I) and (Ta) exclude the compounds defined by formulae (I) and (X) of WO 02/04429 or any compound disclosed in WO 02/04429.
In a ninth embodiment of the compounds of structural formulae (I) and (Ta), when R5 is cyano or ¨C(0)NHR, where R is hydrogen or (C1-C6) alkyl; and R6 is hydrogen, then R2 is other than a substituted phenyl group.
In a tenth embodiment, the compounds of structural formulae (I) and (Ta) exclude 25. compounds in which R2 and R4 are each independently a substituted or unsubstituted pyrrole or indole ring which is attached to the remainder of the molecule via its ring nitrogen atom.
In an eleventh embodiment, the compounds of structural formulae (I) and (Ta) exclude compounds defined by formulae (I) and (IV) of U.S. Patent No.
4,983,608 or any.

compound disclosed in U.S. Patent No. 4,983,608, Those of skill in the art will appreciate that in the compounds of formulae (1) and (Ia), R2 and R4 may be the same or different, and may vary broadly. When R2 and/or R4 are optionally substituted rings, such as optiOnally substituted cycloalkyls, cycloheteroalkyls, aryls and heteroaryls, the ring may be attached to the remainder of the molecule through any available carbon or heteroatom. The optional substituents may be attached to any available carbon atoms and/or heteroatoms.
In a twelfth embodiment of the compounds of structural formulae (I) and (Ia.), and/or R4 is an optionally substituted phenyl or an optionally substituted (C5-C15) aryl, subject to the provisos that (1) when R6 is hydrogen, then R2 is not 3,4,5-trimethoxyphenyl or 3,4,5-tri (C1-C6) allcoxyphenyl; (2) when R2 is a 3,4;5-trisubstituted phenyl, then the substituents at the 3- and 4-positions are not simultaneously methoxy or (C1-C6) alkoxy; or (3) when R6 is hydrogen and R4 is (C1-C6) alkyl, (C3-C8) cycloalkyl, 3-8 membered 15. cycloheteroalkyl or 5-15 membered heteroaryl, then R5 is other than cyano. Alternatively, R2 is subject to the provisos described in connection with the first or second embodiments.
The optionally substituted aryl or phenyl group may be attached to the remainder of the molecule through any available carbon atom. Specific examples of optionally substituted phenyls include phenyls that are optionally mono-, di- or tri-substituted with the same or different R8 groups, where R8 is as previously defined for structural formula (I) and subject to the above provisos. When the phenyl is mono-substituted, the R8 substituent may be positioned at either the ortho, meta or para position. When positioned at the ortho, meta or para position, R8 is preferably selected from the group consisting of (CI-CIO) alkyl, (C1-C10) branched alkyl, ¨0Ie optionally substituted with one or more of the same or different le groups, -0-C(0)0Ra, -0-(CH2),,,-C(0)01V, -C(0)01e, -04CH2).4RW, -0-C(0)NRele, -0-(CH2),õ-C(0)NRcle, -0-C(NH)Nler, -0-(CH2)m-C(NH)Ner. and 4411-(CH2).-Nler, where m, le and R.' are as previously defined for structural formula (1).
In one embodiment of these compounds, -NRele is a 5-6 membered heteroaryl which optionally includes one or more of the same or different additional heteroatoms. Specific examples of such 5-6 membered heteroaryls include, but are not limited to, oxadiazolyl, triazolyl, thiazolyl, oxazolyl, tetrazolyl and isoxazolyl.
In another embodiment of these compounds, -Nine is a 5-6 membered saturated cycloheteroalkyl ring which optionally includes one or more of the same or different hetero atoms. Specific examples of such cycloheteroalkyls include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, pip eridinyl, pip erazinyl and morpholinyl.
In still another embodiment of these compounds, each Ra is independently a (C1-C6) alkyl and/or each ¨NRcRc is ¨NHRa, where Ra is a (C1-C6) alkyl. In one specific positioned at any combination of positions. For example, the R8 substituents may be positioned at the 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6-, 2,5,6- or 3,4,5-positions. In one embodiment of compounds including a disubstituted phenyl, the Specific examples of R8 substituents in such di- and trisubstituted phenyls include In another specific embodiment, R8 substituents useful for substitituting such di-and trisubstituted phenyls include (C1-C6) alkyl, (C1-C6) alkoxy, methoxy, halo, chloro, (C1-C6) perhaloalkyl, -CF3, (C1-C6) perhaloalkoxy and -0CF3. In a preferred embodiment, previously described for structural formula (I); and/or (5) R2 and/or R4 is not 3,4,5-tri(C1-C6)alkoxyphenyl or 3,4,5-trimethoxyphenyl, especially when R5 and R6 are each hydrogen..
In another embodiment of compounds including a trisubstituted phenyl, the trisubstituted phenyl has the formula:

wherein: R31 is methyl or (C1-C6) alkyl; R32 is hydrogen, methyl or (C1-C6) alkyl;
and R33 is a halo group.
In a thirteenth embodiment of the compounds of structural formulae (I) and (Ia), R2 and/or R4 is an optionally substituted heteroaryl. Typical heteroaryl groups according to this thirteenth embodiment comprise from 5 to 15, and more typically from 5 to 11 ring atoms, and include one, two, three or four of the same or different heteratoms or heteroatomic groups selected from the group consisting of N, NET, 0, S, S(0) and S(0)2.
The optionally substituted heteroaryl may be attached to its respective C2 or C4 nitrogen atom or linker L1 or L2 through any available carbon atom or hetero atom, but is typically attached via a carbon atom. The optional substituents may be the same or different, and may be attached to any available carbon atom or heteroatom. In one embodiment of these compounds, R5 is other than bromo, nitro, trifluoromethyl, cyano or ¨C(0)NHR, where R is hydrogen or (C1-C6) alkyl. In another embodiment of these compounds, when R2 and R4 are each a substituted or unsubstituted pynole or indole, then the ring is attached to the remainder of the molecule via a ring carbon atom. In still another embodiment of compounds including an optionally substituted heteroaryl group, the heteroaryl is tmsubstituted or substituted with from one to four of the same or different R8 groups, where R8 is as previously defined for structural formula (I). Specific examples of such optionally substituted heteroaryls include, but are not limited to, the following heteroaryl groups:

/
r..-7--,--N , rj\_.--0 1 \

I __ R35 1 ----1 N -i ),_.,.) R35 , H H
-i-Lil-r-DY, ______ R35 --jj _______ R35 . 1 -R35 . ., S
y 1 R35 H
R35 , f,._--N

P
1 = .1 . . . .,.,,, , , , , .. ,õ . . . R3 5 t . . , , 0 y2 35 R
-:- I -I-, ....õ1õ,, ==,._ ,...l,...______, , Y' --,R35 N
H
, r:%'''--/, ---./ , .-1-';''''--',o'=
-I- I

-, r%-' '-=
N 0' -I- I ,y2-R35 -:- I -i ) yl ___________________________________ R35 , . . ...r .xi...,,;,,...,... ..õ,0 . ,..r.;,,..,..,.,yi ,.....0 : - I -:-I
y2 --..S.-- ' 2<F
Y F N---N
0, _:
, r.-''''---',o'== _,_al , ,,.0, .,N.

oNo I N"ki , vl 2&<
' ''''''. .A.ZZ,. ' ='' l''' X'1\1 0 N Y 0 N Y 0 yo vi w Rio , /=\LRio -:- - I -:- - I R11 'XYiA
A II N y.----12 \--=-_-/ Z
z R9 vi R9 _______________________________________________________ R10 1 ==/¨R1 D.11 , ,1 r= \---1' W2 ' %1R11 R I

wi R9R1 v2 Q
, - o -:-- I
Ril .
-:- - I , -----------1..."-\--z: ' '=
' ===:-. --Ri._ Q XY2 , -----=-7-R35 1 1 =*,-----.) Y....) -- - ,(R35) , ,......., ), 4 -'1µ1R3 N ' i : ro -:, (:, ¨.1 , 1----1>----------.

XN0 -!¨

' )(-N.0 IR- R I

y2 0, /F
-I
-I-1- F 01( X ..õ2..õ, N" --*0 ' ,\

y2 R
+it X
o wherein:
p is an integer from one to three;
each - - - independently represents a single bond or a double bond;
5 R35 is hydrogen or R8, where R8 is as previously defined for structural formula (I);
X is selected from the group consisting of CH, N and N-0;
each Y is independently selected from the group consisting of 0, S and NH;
each Y1 is independently selected from the group consisting of 0, 5, SO, 10 SO2, SONR36, NH and NR37;
each Y2 is independently selected from the group consisting of CH, CH2, 0, S, N, NH and NR37;

R36 is hydrogen or alkyl;
R37 is selected from the group consisting of hydrogen and a progroup, preferably hydrogen or a progroup selected from the group consisting of aryl, arylalkyl, heteroaryl, Ra, Rb¨CRaRb-O-C(0)R8, -CleRb-O-PO(OR8)2, -CH2-0-P0(0R8)2, -CH2-P0(0R8)2, -C(0)-CRaRb-N(CH3)2, -CRaRb-O-C(0)-CRaRb-N(CH3)2, -C(0)R8, -C(0)CF3 and -C(0)-NR8-C(0)R8;
A is selected from the group consisting of 0, NH and NR38;
R38 is selected from the group consisting of alkyl and aryl;
R9, R10, R11 and R12 12 a are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R9and R1 (van nr K-11 and R12 are taken together form a ketal;
each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester, carbamate and sulfonyl;
Q is selected from the group consisting of -OH, OR8, -NHR39-c(o)R8, -N11R39-c(o)0R8,-NR39_cHR4o_ , ¨b _ K NR39-(CH2).-Rb and -NR39-C(0)-CHR4 -NReRe;
R39 and R4 are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryLarylalkyl and NHR8; and Ra, Rb and Re are as previously defined for structural formula (I). Preferred R1' substitutents for Q are selected from -C(0)0R8, -0-C(0)R8, -0-P(0)(0R8)2 and -P(0)(0R8)2.
In one embodiment of the above-depicted heteroaryls, as well as other 5-15 membered heteroaryls according to this embodiment of the invention, each R8 is independently selected from the group consisting of Rd, -NReRe, -(CH2),,-NRelte, -C(0)NReRe, -(CH2)õ,-C(0)NReRe, -C(0)0Rd, -(CH2).-C(0)0Rd and -(CH2).-ORd, where m, Re and Rd are as previously defined for structural formula (I).
In a specific embodiment, Rd and/or Re is selected from the group consisting of le and (C3-C8) cycloalkyl optionally substituted with one or more of the same or different hydroxyl, amino or carboxyl groups.
In another embodiment of the above-depicted heteroaryls, each R35 is hydrogen or (C1-C6) ethyl or methyl.
In still another embodiment of the above-depicted heteroaryls, the aromatic ring connectivity is either at the 5 or 6 position. It should be understood that either R2 or R4 can utilize the heteroaryl groups discussed throughout this specification.

In a fourteenth embodiment of the compounds of structural formulae (I) and (Ia), R2 and R4 are each, independently of one another, an optionally substituted phenyl, aryl or heteroaryl, with the provisos that: (1) when L1 is a direct bond and R6 and optionally R5 is hydrogen, then R2 is other than 3,4,5-trimethoxyphenyl or 3,4,5-tri(C1-C6) alkoxyphenyl;
(2) when L1 and L2 are each a direct bond, R6 is hydrogen and R5 is halo, then R2 and R4 are not each simultaneously 3,4,5-trimethoxyphenyl or 3,4,5-tri(C1-C6) alkoxyphenyl; (3) when R4 is 3-methoxyphenyl or 3-(C1-C6) alkoxyphenyl and R2 is a 3,4,5-trisubstituted phenyl, the sub stituents positioned at the 3 and 4 positions are not both simultaneously methoxy or (C1-C6) alkoxy; (4) when R2 is a substituted phenyl and R6 is hydrogen, then R5 is other than cyano or ¨C(0)NHR, where R is hydrogen or (C1-C6) alkyl;
and/or (5) when R2 and R4 are each independently a substituted or unsubstituted pyrrole or indole, then the pyrrole or indole is attached to the remainder of the molecule via a ring carbon atom.
Alternatively, R2 is subject to the provisos described in connection with the first or second embodiment.
In this fourteenth embodiment of the invention, the R2 and R4 substituents may be the same or different. Specific optionally substituted phenyl, aryl and/or heteroaryls include those illustrated above in connection with the twelfth and thirteenth embodiments.
In a fifteenth embodiment of the compounds of structural formulae (I) and (Ia), including the above-described first through fourteenth embodiments thereof, R6 is hydrogen and R5 is an electronegative group. As will be recognized by skilled artisans, electronegative groups are atoms or groups of atoms that have a relatively great tendency to attract electrons to themselves. Specific examples of electronegative groups according to this fourteenth embodiment include, but are not limited to, -CN, -NC, -NO2, halo, bromo, chloro, fluoro, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, (C1-C3) fluoroalkyl, (C1-C3) perfluoroalkyl, -CF3, (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, (C1-C3) fluoroalkoxy, (C1-C3) perfluoroalkoxy, -0CF3, -C(0)Ra, -C(0)011a, -C(0)CF3 and -C(0)0CF3. In a specific embodiment, the electronegative group is a halogen-containing electronegative group, such as ¨0CF3, ¨CF3, bromo, chloro or fluoro. In another specific embodiment, R5 is fluoro, subject to the proviso that the the compound is not any compound according to the third embodiment.
In a sixteenth embodiment, the compounds of structural formulae (1) and (Ia) are compounds according to structural formula (Ib):

N

and salts, hydrates, solvates and N-oxides thereof, wherein R11, R12, R13 and R14 are each, independently of one another, selected from the group consisting of hydrogen, hydroxy, (C1-C6) alkoxy and ¨NR'Re; and R5, R6 and Rc are as previously defined for structural formula (I), with the proviso that when R13, R5 and R6 are each hydrogen, then R11 and R12 are not simultaneously methoxy, (C1-C6) alkoxy or (C1-C6) haloalkoxy In a seventeenth embodiment, the compounds of structural formulae (I) and (Ia) are compounds according to structural formula (Ic):

and salts, hydrates, solvates and N-oxides thereof, wherein:
R4 is selected from the group consisting of 5-10 membered heteroaryl and 3-hydroxyphenyl;
5 =
R F or -CF3; and R8 is ¨0(CH2).-R", where m and Rb are as previously defined for structural formula (I). In a specific embodiment, R8 is -0-CH2-C(0)NH-CH3 and/or R4 is a heteroaryl according to the thirteenth embodiment.
In an eighteenth embodiment, the compounds of structural formulae (I) and (Ia) include any compound selected from TABLE 1 that inhibits an Fc receptor signal transduction cascade, a Syk kinase activity, a Syk-ldnase dependent receptor signal transduction cascade orcell degranulation as measured in an in vitro assay, optionally subject to the proviso that the compound is not a compound excluded by the above-described third embodiment and/or other embodiments. In a specific embodiment, such compounds have an IC50 of about 20 M or less as measured in an in vitro degranulation assay, such as one of the degranulation assays described in the Examples section.
In a nineteenth embodiment, the compounds of structural formulae (I) and (Ia) include any compound selected from TABLE 1 that inhibits the Fc7R1 or FcÃR1 receptor cascade with an IC50 of about 20 i..LM or less as measured in an in vitro assay, such as one of the in vitro assays provided in the Examples section, optionally subject to the proviso that the compound is not a compound excluded by the above-described third embodiment and/or other embodiments.
Also specifically described are combinations of the above first through nineteenth specific embodiments.
Those of skill in the art will appreciate that the 2,4-pyrimidinediamine compounds described herein may include functional groups that can be masked with progroups to create prodrugs. Such prodrugs are usually, but need not be, pharmacologically inactive until converted into their active drug form. Indeed, many of the active 2,4-pyrimidinediamine compounds described in TABLE 1, infra, include promoieties that are hydrolyzable or otherwise cleavable under conditions of use. For example, ester groups commonly undergo acid-catalyzed hydrolysis to yield the parent carboxylic acid when exposed to the acidic conditions of the stomach, or base-catalyzed hydrolysis when exposed to the basic conditions of the intestine or blood. Thus, when administered to a subject orally, 2,4-pyrimidinediamines that include ester moieties may be considered prodrugs of their corresponding carboxylic acid, regardless of whether the ester form is pharmacologically active. Referring to TABLE 1, numerous ester-containing 2,4-pyrimidinediamines of the invention are active in their ester, "prodrug" form.
In the prodrugs of the invention, any available functional moiety may be masked with a progroup to yield a prodrug. Functional groups within the 2,4-pyrimidinediamine compounds that may be masked with progroups for inclusion in a promoiety include, but are not limited to, amines (primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc. Myriad progroups suitable for masking such functional groups to yield promoieties that are cleavable under the desired conditions of use are known in the art. All of these progroups, alone or in combinations, may be included in the prodrugs of the invention.
In one illustrative embodiment, the prodrugs of the invention are compounds according to structural formula (I) in which Re and Rd may be, in addition to their previously-defined alternatives, a progroup.
Replacing the hydrogens attached to N2 and N4 in the 2,4-pyrimidinediamines of structural formula (I) with substituents adversely effects the activity of the compounds.
However, as will be appreciated by skilled artisans, these nitrogens may be included in promoieties that, under conditions of use, cleave to yield 2,4-pyrirnidinediamines according to structural formula (I). Thus, in another embodiment, the prodrugs of the invention are compounds according to structural formula (II):

RI 4b RI 2b including salts, hydrates, solvates and N-oxides thereof, wherein:
R2, R4, R5, R6, L1 and L2 are as previously defined for structural formula (I); and R21' and R4b are each, independently of one another, a progroup. Specific examples of progroups according to this embodiment of the invention include, but are not limited to, (C1-C6) alkyl, -C(0)CH3, -C(0)NHR36 and ¨S(0)2R36, where R36 is (C1-C6) alkyl, (C5-C15) aryl and (C3-C8) cycloalkyl.
In the prodrugs of structural formula (II), the various sub stituents may be as described for the various first through twentieth embodiments previously described for the compounds of structural formulae (I) and (Ia), or combinations of such embodiments.
Those of skill in the art will appreciate that many of the compounds and prodrugs of the invention, as well as the various compound species specifically described and/or illustrated herein, may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism. For example, the compounds and prodrugs of the invention may include one or more chiral centers and/or double bonds and as a consequence may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers and diasteromers and mixtures thereof, such as racemic mixtures. As another example, the compounds and prodrugs of the invention may exist in several tautomeric forms, including the enol form, the keto form and mixtures thereof.
As the various compound names, formulae and compound drawings within the specification and claims can represent only. one of the possible tautomeric, conformational isomeric, optical isomeric or geometric isomeric forms, it should be understood that the invention encompasses any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of the compounds or prodrugs having one or more of the utilities described herein, as well as mixtures of these various different isomeric forms. In cases of limited rotation around the 2,4-pryimidinediamine core structure, atrop isomers are also possible and are also specifically included in the compounds of the invention.

Moreover, skilled artisans will appreciate that when lists of alternative substituents include members which, owing to valency requirements or other reasons, cannot be used to substitute a particular group, the list is intended to be read in context to include those members of the list that are suitable for substituting the particular group.
For example, skilled artisans will appreciate that while all of the listed alternatives for Rb can be used to substitute an alkyl group, certain of the alternatives, such as =0, cannot be used to substitute a phenyl group. It is to be understood that only possible combinations of substituent-group pairs are intended.
The compounds and/or prodrugs of the invention may be identified by either their chemical structure or their chemical name. When the chemical structure and the chemical name conflict, the chemical structure is determinative of the identity of the specific compound.
Depending upon the nature of the various substituents, the 2,4-pyrimidinediamine compounds and prodrugs of the invention may be in the form of salts. Such salts include salts suitable for pharmaceutical uses ("pharmaceutically-acceptable salts"), salts suitable for veterinary uses, etc. Such salts may be derived from acids or bases, as is well-known in the art.
In one embodiment, the salt is a pharmaceutically acceptable salt. Generally, pharmaceutically acceptable salts are those salts that retain substantially.
one or more of the desired pharmacological activities of the parent compound and which are suitable for administration to humans. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids. Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g., hydrochloric acid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, furnaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, etc.), 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, - -glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.
Pharmaceutically acceptable salts also. include salts formed when an acidic proton present in the parent compound is either replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion or an aluminum ion) or coordinates with an organic base (e.g., ethanolamine, diethanolamine, hiethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, etc.).
The 2,4-pyrimidinediamine compounds and of the invention, as well as the salts thereof, may also be in the form of hydrates, solvates and N-oxides, as are well-known in the art.
6.3 Methods of Synthesis The compounds and prodrugs of the invention may be synthesized via a variety of different synthetic routes using commercially available starting materials and/or starting materials prepared by conventional synthetic methods. Suitable exemplary methods that may be routinely adapted to synthesize the 2,4-pyrimidinediamine compounds and prodrugs of the invention are found in U.S. Patent No. 5,958,935. Specific examples describing the synthesis of numerous compounds and prodrugs of the invention, as well as intermediates therefor, are provided in the Examples section. All of the compounds of structural formulae (I), (Ia) and (1) may be prepared by routine adaptation of these methods.
A variety of exemplary synthetic routes that can be used to synthesize the 2,4-pyrimidinediamine compounds of the invention are described in Schemes (1)-(XI), below.
In Schemes (1)-(X), like-numbered compounds have similar structures. These methods may be routinely adapted to synthesize the prodrugs according to structural formula (II).
In one exemplary embodiment, the compounds can be synthesized from substituted or =substituted uracils or thiouracils as illustrated in Scheme (I), below:

Scheme (I) R5 R5j N 4N2x 1 equiv N 4 (I) R4- L2, NH2 1 equiv R5 Rsj 3 (other halogenating agents) X N - X
excess R.
õ LI, Ll 4 ' N 4 N

2 C4 halide is more ) 4 12 reactive towards nucleophiles excess A A
N , 4 5 In Scheme (I), R2, R4, R5, R6, Li and 2 t, are as previously defined for structural formula (I), X is a halogen (e.g., F, Cl, Br or I) and Y and Y' are each, independently of one another, selected from the group consisting of 0 and S. Referring to Scheme (I), uracil or thiouracil 2 is dihalogenated at the 2- and 4-positions using standard halogenating agent PDX3 (or other standard halogenating agent) under standard conditions to yield 2,4-bishalo 10 pyrimidine 4. Depending upon the R5 substituent, in pyrimidine 4, the halide at the C4 position is more reactive towards nucleophiles than the halide at the C2 position. This differential reactivity can be exploited to synthesize 2,4-pyrimidinediamines according structural formula (I) by first reacting 2,4-bishalopyrimidine 4 with one equivalent of amine 10, yielding 4N-substituted-2-halo-4-pyrimidineamine 8, followed by amine 6 to yield a 2,4-pyrimidinediamine according structural formula (I). 2N,4N-bis(substituted)-2,4-pyrimidinediamines 12 and 14 can be obtained by reacting 2,4-bishalopyrimidine 4 with excess 6 or 10, respectively.

In most situations, the C4 halide is more reactive towards nucleophiles, as illustrated in the Scheme. However, as will be recognized by skilled artisans, the identity of the R5 substituent may alter this reactivity. For example, when R5 is trifluoromethyl, a 50:50 mixture of 4N-substituted-4-pyrimidineamine 8 and the corresponding 2N-substituted-2-pyrimidineamine is obtained. Regardless of the identity of the R5 substituent, the regioselectivity of the reaction can be controlled by adjusting the solvent and other synthetic conditions (such as temperature), as is well-known in the art.
The reactions depicted in Scheme (I) may proceed more quickly when the reaction mixtures are heated via microwave. When heating in this fashion, the following conditions may be used: heat to 175 C in ethanol for 5-20 min. in a Smith Reactor (Personal Chemistry) in a sealed tube (at 20 bar pressure).
The uracil or thiouracil 2 starting materials may be purchased from commercial sources or prepared using standard techniques of organic chemistry.
Commercially available uracils and thiouracils that can be used as starting materials in Scheme (I) include, by way of example and not limitation, m-acil (Aldrich #13,078-8; CAS Registry 66-22-8); 2-thio-uracil (Aldrich #11,558-4; CAS Registry 141-90-2); 2,4-dithiouracil (Aldrich #15,846-1; CAS Registry 2001-93-6); 5-acetouracil (Chem. Sources Inel 2000; CAS
Registry 6214-65-9); 5-azidouracil; 5-aminouracil (Aldrich #85,528-6; CAS Registry 932-52-5);
5-bromouracil (Aldrich #85,247-3; CAS Registry 51-20-7); 5-(trans-2-bromoviny1)-uracil (Aldrich #45,744-2; CAS Registry 69304-49-0); 5-(trans-2-chloroviny1)-uracil (CAS
Registry 81751-48-2); 5-(trans-2-carboxyvinyl)-uracil; uracil-5-carboxylic acid (2,4-dihydroxypyrimidine-5-carboxylic acid hydrate; Aldrich #27,770-3; CAS
Registry 23945-44-0); 5-chlorouracil (Aldrich #22,458-8; CAS Registry 1820-81-1); 5-cyanouracil (Chem. Sources Intl 2000; CAS Registry 4425-56-3); 5-ethyluracil (Aldrich #23,044-8;
CAS Registry 4212-49-1); 5-ethenyluracil (CAS Registry 37107-81-6); 5-fluorouracil (Aldrich #85,847-1; CAS Registry 51-21-8); 5-iodouracil (Aldrich #85,785-8;
CAS
Registry 696-07-1); 5-methyluracil (thymine; Aldrich #13,199-7; CAS Registry 65-71-4);
5-nitrouracil (Aldrich #85,276-7; CAS Registry 611-08-5); uracil-5-sulfamic acid (Chem.
Sources Intl 2000; CAS Registry 5435-16-5); 5-(trifluoromethyl)-uracil (Aldrich #22,327-1; CAS Registry 54-20-6); 5-(2,2,2-trifluoroethyl)-uracil (CAS Registry 155143-31-6);
5-(pentafluoroethyl)-uracil (CAS Registry 60007-38-3); 6-aminouracil (Aldrich #A5060-6;
CAS Registry 873-83-6) uracil-6-carboxylic acid (orotic acid; Aldrich #0-840-2; CAS
Registry 50887-69-9); 6-methyluracil (Aldrich #D11,520-7; CAS Registry 626-48-2);
uracil-5-amino-6-carboxylic acid (5-aminoorotic acid; Aldrich #19,121-3; CAS
Registry #7164-43-4); 6-amino-5-nitrosouracil (6-amino-2,4-dihydroxy-5-nitrosopyrimidine; Aldrich #27,689-8; CAS Registry 5442-24-0); uracil-5-fluoro-6-carboxylic acid (5-fluoroorotic acid; Aldrich #42,513-3; CAS Registry 00000-00-0); and uracil-5-nitro-6-carboxylic acid (5-nitroorotic acid; Aldrich #18,528-0; CAS Registry 600779-49-9). Additional 5-, 6- and 5,6-substituted uracils and/or thiouracils are available from General Intermediates of Canada, Inc., Edmonton, CA and/or Interchim, Cedex, France, or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
Amines 6 and 10 may be purchased from commercial sources or, alternatively, may be synthesized utilizing standard techniques. For example, suitable amines may be synthesized from nitro precursors using standard chemistry. Specific exemplary reactions are provided in the Examples section. See also Vogel, 1989, Practical Organic Chemistry, Addison Wesley Longman, Ltd. and John Wiley. & Sons, Inc.
Skilled artisans will recognize that in some instances, amines 6 and 10 and/or substituents R5 and/or R6 on uracil or thiouracil 2 may include functional groups that require =
protection during synthesis. The exact identity of any protecting group(s) used will depend =
upon the identity of the functional group being protected, and will be apparent to these of skill in the art. Guidance for selecting appropriate protecting groups, as well as synthetic strategies for their attachment and removal, may be found, for example, in Greene & Wuts, Protective Groups in Organic Synthesis, 3d Edition, John Wiley & Sons, Inc., New York (1999) and the references cited therein (hereinafter "Greene & Wuts").
A specific embodiment of Scheme (I) utilizing 5-fluorouracil (Aldrich #32,937-1) as a starting material is illustrated in Scheme (Ia), below:

Scheme (Ia) FN
5 õ

equiv Fr- N 4 =

1 equiv I
NH
5 POCI3 õ 6 N
excess excess Ni 5 õ
L2, N 4 ' =

In Scheme (Ia), R2, R4, L1 and L2 are as previously defined for Scheme (I).
5 According to Scheme (Ia), 5-fluorouracil 3 is halogenated with POC13 to yield 2,4-dichloro-5-fluoropyrimidine 5, which is then reacted with excess amine 6 or 10 to yield N2,N4-bis substituted 5-fluoro-2,4-pyrimidinediamine 11 or 13, respectively.
Alternatively, asymmetric 2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine 9 may be obtained by reacting 2,4-dichloro-5-fluoropyrimidine 5 with one equivalent of amine 10 (to yield 2-10 chloro-N4-substituted-5-fluoro-4-pyrimidineamine 7) followed by one or more equivalents of amine 6.
In another exemplary embodiment, the 2,4-pyrimidinediamine compounds of the invention may be synthesized from substituted or unsubstituted cytosines as illustrated in Schemes (IIa) and (M), below:

Scheme (11a) R.5,,) 1 R5.........".16, acylation, R6j, iN
7 NH silylation, etc. 3 NH pox3 5 1 * \

1 ______________________________ )1, /=,, (other halogenating agents) PGHN 4 N* 2 X
/ \ 3 ; 4 2 4 NV0 PGHNN0 R6 R6j 1 R61),6,R5N1 s ,.,. , 1:1 deprotect t -4 7 N' 5 1 A ____________________________________ PGHN ), 4 N 2 N' NR2 ,2, )., ,, 3 H
R4 N 4N 2 N R2 H N.4 N)2 N'LlsR2 (0 Scheme (11b) R5....,..õ16, i 5V NH 10 5 7 N1-1 PO; V N

1 _______ IP-acid- or baseL2 ,,,.. ,..,,,N (other halogenating agents) H2N 4 N 2 0 catalyzed R4 N 4 N 20 , L2 PR'S 'NH2 V
V

R6jFej 1 R5 , 7 NH PDX3 V N 1) 6 ''''..--7 -.....5 N' - I I

, /\ , Li, L.2 7' A., PGR4 N 4 N 2 0 (other halogenating agents) pG_A. R4 N 4N 2N

H 3 I=C' N 4 N 2 X 2) deprotect 27 29 (I) , A
In Schemes (Ha) and (lb), R2, R4, Rs, R6, 1, L L2 and X are as previously defined for Scheme (I) and PG represents a protecting group. Referring to Scheme (Ha), the exocyclic amine of cytosine 20 is first protected with a suitable protecting group PG to yield N4-protected cytosine 22. For specific guidance regarding protecting groups useful in this context, see Vorbruggen and Ruh-Pohlenz, 2001, Handbook of Nucleoside Synthesis, John Wiley & Sons, NY, pp. 1-631 ("Vorbniggen"). Protected cytosine 22 is halogenated at the C2 position using a standard halogenation reagent under standard conditions to yield 2-chloro-4N-protected-4-pyrimidineamine 24. Reaction with amine 6 followed by deprotection of the C4 exocyclic amine and reaction with amine 10 yields a 2,4-pyrimidinediamine according to structural formula (I).
Alternatively, referring to Scheme (J1b), cytosine 20 may be reacted with amine 10 or protected amine 21 to yield N4-substituted cytosine 23 or 27, respectively.. These substituted cytosines may then be halogenated as previously described, deprotected (in the case of N4-substituted cytosine 27) and reacted with amine 6 to yield a 2,4-pyrirnidinediamine according to structural formula (I).
Commercially-available cytosines that may be used as starting materials in Schemes (Ha) and (Mb) include, but are not limited to, cytosine (Aldrich #14,201-8;
CAS Registry 71-30-7); N4-acetylcytosine (Aldrich #37,791-0; CAS Registry 14631-20-0);
5-fluorocytosine (Aldrich #27,159-4; CAS Registry 2022-85-7); and 5-(trifluoromethyl)-cytosine. Other suitable cytosines useful as starting materials in Schemes (a) are available from General Intermediates of Canada, Inc., Edmonton, CA
and/or Interchim, Cedex, France, or may be prepared using standard techniques.
Myraid textbook references teaching suitable synthetic methods are provided infra.
In still another exemplary embodiment, the. 2,4-pyrimidinediamine compounds of the invention may. be synthesized from substituted or unsubstituted 2-amino-4-pyrimidinols as illustrated in Scheme (III), below:

=
Scheme (Ell) Ft5) N Fts 6 or N

õ

= R6fN- 10 N Fee 1 R4 N 4N`N R4 X 4 N 2 N
õ

=

In Scheme (ll), R2, R4, R5, R6, LI, L2 and X are as previously defined for Scheme 5 (I) and Z is a leaving group as discussed in more detail in connection with Scheme W, infra.
Referring to Scheme (ITI), 2-amino-4-pyrimidinol 30 is reacted with amine 6 (or optionally protected amine 21) to. yield N2-substituted-4-pyrimidinol 32, which is then halogenated as previously described to yield N2-substituted-4-halo-2-pyrimidineamine 34.
Optional deprotection (for example if protected amine 21 was used in the first step) followed by.
reaction with amine 10 affords a 2,4-pyrimidinediamine according to.
structural formula (1).
Alternatively, pyrimidinol 30 can be reacted with acylating agent 31.
Suitable commercially-available 2-amino-4-pyrimidinols 30 that can be used as starting materials in Scheme (III) include, but are not limited to, 2-amino-6-chloro-4-pyrimidinol hydrate (Aldrich #A4702-8; CAS Registry 00000-00-0) and 2-amino-6-hydroxy-4-pyrimidino1 (Aldrich #A5040-1; CAS Registry 56-09-7).
Other 2-amino-4-pyrimidinols 30 useful as starting materials in Scheme (DI) are available from General Intermediates of Canada, Inc., Edmonton, CA and/or Interchim, Cedex, France, or may be prepared using standard techniques. Myraid textbook references teaching suitable synthetic methods are provided infra.

Alternatively, the 2,4-pyrimidinediamine compounds of the invention may be prepared from substituted or tmsubstituted 4-amino-2-pyrimidinols as illustrated in Scheme (IV), below:
Scheme (IV) R R

L2, Ll H2N 4 N 2 OH H2N 4 N 2 N R2 or 10 40 42 (I) In Scheme (IV), R2, R4, R5, R6, Ll and L2 are as previously defined for Scheme (I) and Z represents a leaving group. Referring to Scheme (IV), the C2-hydroxyl of 4-amino-2-pyrimidinol 40 is more reactive towards nucleophiles than the C4-amino such that reaction with amine 6 yields N2-substituted-2,4-pyrimidinediamine 42.
Subsequent reaction with compound 44, which includes a good leaving group Z, or amine 10 yields a 2,4-pyrimidinediamine according to structural formula (I). Compound 44 may include virtually any leaving group that can be displaced by the C4-amino of N2-substituted-2,4-pyrimidinediamine 42. Suitable leaving groups Z include, but are not limited to, halogens, methanesulfonyloxy (mesyloxy; "OMs"), trifluoromethanesulfonyloxy ("OW") and p-toluenesulfonyloxy (tosyloxy; "OTs"), benzene sulfonyloxy ("besylate") and metanitro benzene sulfonyloxy ("nosylate"). Other suitable leaving groups will be apparent to those of skill in the art.
Substituted 4-amino-2-pyrimidinol starting materials may be obtained commercially or synthesized using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
In still another exemplary embodiment, the 2,4-pyrimidinediamine compounds of the invention can be prepared from 2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines as illustrated in Scheme (V), below:
=

Scheme (V) R5 N., to CI 4 N 2 NH2 R4 "N 4 N 2 NH2 R5f..) .1 ) R4 4 ti 2 ri (0 44 R58 8 ts11 H2N 4 N 2 CI R4 N = N 2 CI

In Scheme (V), R2, R4, R5, R6, LI, L2 and X are as defined for Scheme (I) and Z is as 5 defined for Scheme (IV). Referring to Scheme (V), 2-amino-4-chloropyrimicline 50 is reacted with amino 10 to yield 4N-substituted-2-pyrimidineamine 52 which, following reaction with compound 31 Or amine 6, yields a 2,4-pyrimidinediamine according to structural formula (1). Alternatively, 2-chloro-4-amino-pyrimidine 54 may be reacted with compound 44 followed by amine 6 to yield a compound according to structural formula (I).
10 A variety of pyriznidines 50 and 54 suitable for use as starting materials in Scheme (V) are commercially. available, including by way of example and not limitation, 2-amino-4,6-dichloropyrimidine (Aldrich #A4860-1; CAS Registry 56-05-3);
2-amino-4-chloro-6-methoxy-pyrimidine (Aldrich #51,864-6; CAS Registry 5734-64-5);
2-amino-4-chloro-6-methylpyrimidine (Aldrich #12,288-2; CAS Registry 5600-21-5); and 15. 2-amino-4-chloro-6-methyltlziopyrimicline (Aldrich #A4600-5; CAS
Registry 1005-38-5).
Additional pyrimidine starting materials are available from General Intermediates of Canada, Inc., Edmonton, CA and/or Interchim, Cedex, France, or may be prepared using standard techniques. Myriad textbook references teaching suitable synthetic methods are provided infra.
20 Alternatively, 4-chloro-2-pyrimidineamines 50 may be prepared as illustrated in Scheme (Va):

Scheme (Va) R5 +
4 *

1 ArCO3H

R6 1 POCI3 1=26 No In Scheme (Va), R5 and R6 are as previously defined for structural formula (I). In Scheme (Va), dicarbonyl 53 is reacted with guanidine to yield 2-pyrimidineamine 51.
5 Reaction with peracids like m-chloroperbenzoic acid, trifluoroperacetic acid or urea hydrogen peroxide complex yields N-oxide 55, which is then halogenated to give 4-chloro-2-pyrimidineamine 50. The corresponding 4-halo-2-pyrimidineamines may be obtained by using suitable halogenation reagents.
In yet another exemplary embodiment, the 2,4-pyrimidinediamine compounds of the 10 invention can be prepared from substituted or unsubstituted uridines as illustrated in Scheme (VI), below:

Scheme (VI) HO, R5 1166 N::(1-==CH2OH

, HO, PH

:=: 10 H 3 R5, 6 õ

HO, PH

HC
/". N 0 H2OH
C4 reactive 60 center , N 4 N -"3"7-`0 acid-catalyzed deprotection Ft5 R5)1 N 1) PDX3 NH

%1\
N 4 N 2 HN R2 2) 6 N 4 (I) 28 In Scheme (VI), R2, R4, R5, R6, Ll, 2 and X are as previously defined for Scheme 5 (I) and the superscript PG represents a protecting group, as discussed in connection with Scheme (lb). According to Scheme (VI), uridine 60 has a C4 reactive center such that reaction with amine 10 or protected amine 21 yields N4-substituted cytidine 62 or 64, respectively. Acid-catalyzed deprotection of N4-substituted 62 or 64 (when "PG"
represents an acid-labile protecting group) yields N4-substituted cytosine 28, which may be subsequently halogenated at the C2-position and reacted with amine 6 to yield a 2,4-pyrimidinediamine according to structural formula (I).
Cytidines may. also be used as starting materials in an analogous manner, as illustrated in Scheme (VII), below:

Scheme (VII) HO, HO, pHL2, 3 =
C4 reactive j N CH2OH

center 5 õ

acid-catalyzed deprotection N 1) PDX3 NH
Ii II

, R4- N 4 N 2 N R2 2) 6 R4- N 4 NO

(I) 28 In Scheme (VII), R2, R4, R5, R6, Ll, L2 and X are as previously defined in Scheme (I) and the superscript PG represents a protecting group as discussed above.
Referring to 5 Scheme (VII), like uridine 60, cytidine 70 has a C4 reactive center such that reaction with amine 10 or protected amine 21 yields N4-substituted cytidine 62 or 64, respectively. These cytidines 62 and 64 are then treated as previously described for Scheme (VI) to yield a 2,4-pyrimidinediamine according to structural formula (I).
Although Schemes (VI) and (VII) are exemplified with ribosylnucleosides, skilled 10 artisans will appreciate that the corresponding 2'-deoxyribo and 2',3'-dideoxyribo nucleosides, as well as nucleosides including sugars or sugar analogs other than ribose, would also work.
Numerous uridines and cytidines useful as starting materials in Schemes (VI) and (VII) are known in the art, and include, by way of example and not limitation, 5-trifluoromethy1-2'-deoxycytidine (Chem. Sources #ABCR F07669; CAS Registry 66,384-66-5); 5-bromouridine (Chem. Sources Intl 2000; CAS Registry 957-75-5);
5-iodo-2'-deoxyuridine (Aldrich #1-775-6; CAS Registry 54-42-2); 5-fluorouridine (Aldrich #32,937-1; CAS Registry 316-46-1); 5-iodouridine (Aldrich #85,259-7;
CAS

Registry 1024-99-3); 5-(trifluoromethypuridine (Chem. Sources Int'l 2000; CAS
Registry 70-00-8); 5-trifluoromethy1-2'-deoxyuridine (Chem. Sources Intl 2000; CAS
Registry 70-00-8). Additional uridines and cytidines that can be used as starting materials in Schemes (VI) and (VII) are available from General Intermediates of Canada, Inc., Edmonton, CA
and/or Interchim, Cedex, France, or may be prepared using standard techniques.
Myraid textbook references teaching suitable synthetic methods are provided infra.
The 2,4-pyrimidinediamine compounds of the invention can also be synthesized from substituted pyrimidines, such as chloro-substituted pyrimidines, as illustrated in Schemes (VIII) and (DC), below:
Scheme (VIII) HN,L2,R4 a s =-='=
;CLitsl L1õ
Ll , 10 '1st 4 N i - N equiv I"- R2Ll- -N 4 ti 2 N R2 CI CIõ
HN
= 8 6 :CLN: 10 6 /4 CI N4'CI,L1, a 4 ti ti R2 igi 4 1;1 N

HN"-CLR2 I.
R2' 4 tj Scheme (IX) r N
õ
Ll, Ll LI, H 3 Suzuki CI CI SRa RaSNa N 6 Ni 5 , CI 4 N 2 CI R2LNNNLR2Li.
J.

HN,L1,R2 I Bn3SnH

, R<LI
- N N-2--ci C1-&`

,LI, In Schemes (VIII) and (IX), R2, R4, L1, L2 and Ra are as previously defined for structural formula (I) and "Ar" represents an aryl group. Referring to Scheme (VIII), 5 reaction of 2,4,6-trichloropyrimidine 80 (Aldrich #T5,620-0; CAS#3764-01-0) with amine 6 yields a mixture of three compounds: substituted pyrimidine mono-, di- and triamines 81, 82 and 83, which can be separated and isolated using HPLC or other conventional techniques. Mono- and diamines 81 and 82 may be further reacted with amines 6 and/or 10 to yield N2,N4,N6-trisubstituted-2,4,6-pyrimidinetriamines 84 and 85, respectively.
N2,N4-bis-substituted-2,4-primidinediamines can be prepared in a manner analogous to Scheme (VIII) by employing 2,4-dichloro-5-methylpyrimidine or 2,4-dichloro-pyrimidine as starting materials. In this instance, the mono-substituted pyrimidineamine corresponding to compound 81 is not obtained. Instead, the reaction proceeds to yield the N2,N4-bis-substituted-2,4-pylimidinediamine directly.
Referring to Scheme (IX), 2,4,5,6-tetrachloropyrimidine 90 (Aldrich #24,671-9;
CAS#1780-40-1) is reacted with excess amine 6 to yield a mixture of three compounds: 91, 92, and 93, which can be separated and isolated using HPLC or other conventional techniques. As illustrated, N2,N4-bis-substituted-5,6,-dichloro-2,4-pyrimidinediamine 92 may be further reacted at the C6 halide with, for example a nucleophilic agent 94 to yield compound 95. Alternatively, compound 92 can be converted into N2,N4-bis-subsituted-5-chloro-6-aryl-2,4-pyrimidinediamine 97 via a Suzuki reaction. 2,4-Pyrimidinediamine 95 may be converted to 2,4-pyrimidinediamine 99 by reaction with Bn3SnH.
As will be recognized by skilled artisans, 2,4-pyrimidinediamines according to the invention, synthesized via the exemplary methods described above or by other well-known means, may also be utilized as starting materials and/or intermediates to synthesize additional 2,4-primidinediamine compounds of the invention. A specific example is illustrated in Scheme (X), below:
Scheme (X) R61,11 y 0 FI2NRa R5AN1 y 2, OR' L N N 4 2 N
Fr,'" N 4 N 2 N

1:26 N
N OR' 102 In Scheme (X), R4, R5, R6, L2 and Ra are as previously defined for structural formula (1). Each Ra' is independently an Ra, and may. be the same or different from the illustrated Ra. Referring to Scheme (X), carboxylic acid or ester 100 may be converted to amide 104 by reaction with amine 102. In amine 102, Ra' may be the same or different than Ra of acid or ester 100. Similarly, carbonate ester 106 may be converted to carbamate 108.

A second specific example is illustrated in Scheme (XI), below:
Scheme (XI) o (cH3)2s.BH3 Y

Y
R4LA/ NRcRe NRciRc N 4 N-- 2-N

, NR-õR- N /

N / 112 ¨0 NRCRC

¨0 A

5 In Scheme (XI), R4, R5, R6, 2 I., and Re are as previously defined for structural formula (I). Referring to Scheme (XI), amide 110 or 116 may be converted to amine 114 or 118, respectively, by borane reduction with borane methylsulfide complex 112.
Other suitable reactions for synthesizing 2,4-pyrimidinediamine compounds from 2,4-pyrimidinediamine starting materials will be apparent to those of skill in the art.
Although many of the synthetic schemes discussed above do not illustrate the use of protecting groups, skilled artisans will recognize that in some instances substituents R2, R4, R5, R6, Ll and/or L2 may include functional groups requiring protection. The exact identity.
of the protecting group used will depend upon, among other things, the identity of the functional group being protected and the reaction conditions used in the particular synthetic scheme, and will be apparent to those of skill in the art. Guidance for selecting protecting groups and chemistries for their attachment and removal suitable for a particular application can be found, for example, in Greene & Wuts, supra.
Prodrugs according to structural formula (II) may be prepared by routine modification of the above-described methods. Alternatively, such prodrugs may be prepared by reacting a suitably protected 2,4-pyrimidinediamine of structural formula (I) with a suitable progroup. Conditions for carrying out such reactions and for deprotecting the product to yield a prodmg of formula (II) are well-known.
Myriad references teaching methods useful for synthesizing pyrimidines generally, as well as starting materials described in Schemes (I)-(IX), are known in the art. For specific guidance, the reader is referred to Brown, D. J., "The Pyrimidines", in The Chemistry of Heterocyclic Compounds, Volume 16 (Weissberger, A., Ed.), 1962, Interscience Publishers, (A Division of John Wiley & Sons), New York ("Brown I");
Brown, D. J., "The Pyrimidines", in The Chemistry of Heterocyclic Compounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C., Ed.), 1970, Wiley-Interscience, (A
Division of John Wiley & Sons), New York (Brown II"); Brown, D. J., "The Pyrimidines", in The Chemistry of Heterocyclic Compounds, Volume 16, Supplement II
(Weissberger, A.
and Taylor, E. C., Ed.), 1985, An Interscience Publication (John Wiley &
Sons), New York ("Brown III"); Brown, D. J., "The Pyrimidines" in The Chemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. and Taylor, E. C., Ed.), 1994, John Wiley &
Sons, Inc., New York, pp. 1-1509 (Brown IV"); Kermer, G. W. and Todd, A., in Heterocyclic Compounds, Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter 7 (pyrimidines); Paquette, L. A., Principles of Modern Heterocyclic Chemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1 ¨401 (uracil synthesis pp. 313, 315;
pyrimidine synthesis pp. 313-316; amino pyrimidine synthesis pp. 315); Joule, J. A., Mills, K. and Smith, G. F., Heterocyclic Chemistry, 3rd Edition, 1995, Chapman and Hall, London, UK, pp. 1 ¨ 516; Vorbrfiggen, H. and Ruh-Pohlenz, C., Handbook of Nucleoside Synthesis, John Wiley & Sons, New York, 2001, pp. 1-631 (protection of pyrimidines by acylation pp.
90-91; silylation of pyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G. F., Heterocyclic Chemistry, 4th Edition, 2000, Blackwell Science, Ltd, Oxford, UK, pp. 1 ¨
589; and Comprehensive Organic Synthesis, Volumes 1-9 (Trost, B. M. and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.
6.4 Inhibition of Fe Receptor Signal Cascades Active 2,4-pyrimidinediamine compounds of the invention inhibit Fc receptor signalling cascades that lead to, among other things, degranulation of cells.
As a specific example, the compounds inhibit the FccRI and/or FcTRI signal cascades that lead to degranulation of immune cells such as neutrophil, eosinophil, mast and/or basophil cells.
Both mast and basophil cells play a central role in allergen-induced disorders, including, for example, allergic rhinitis and asthma. Referring to FIG. 1, upon exposure allergens, which may be, among other things, pollen or parasites, allergen-specific IgE
antibodies are synthesized by B-cells activated by IL-4 (or IL-13) and other messengers to switch to IgE
class specific antibody synthesis. These allergen-specific IgEs bind to the high affinity FcERI. Upon binding of antigen, the FcsRl -bound IgEs are cross-linked and the IgE

receptor signal transduction pathway is activated, which leads to degranulation of the cells and consequent release and/or synthesis of a host of chemical mediators, including histamine, proteases (e.g., tryptase and chymase), lipid mediators such as leukotrienes (e.g., LTC4), platelet-activating factor (PAF) and prostaglandins (e.g., PGD2) and a series of cytokines, including TNF-a, IL-4, IL-13, IL-5, IL-6, IL-8, GMCSF, VEGF and TGF-(3.
The release and/or synthesis of these mediators from mast and/or basophil cells accounts for the early and late stage responses induced by allergens, and is directly linked to downstream events that lead to a sustained inflammatory state.
The molecular events in the FccRI signal transduction pathway that lead to release of preformed mediators via degranulation and release and/or synthesis of other chemical mediators are well-known and are illustrated in FIG. 2. Referring to FIG. 2, the FccRI is a heterotetrameric receptor composed of an IgE-binding alpha-subunit, a beta subunit, and two gamma subunits (gamma homodimer). Cross-linking of FcERI-bound IgE by multivalent binding agents (including, for example IgE-specific allergens or anti-IgE
antibodies or fragments) induces the rapid association and activation of the Src-related kinase Lyn. Lyn phosphorylates immunoreceptor tyrosine-based activation motifs (ITAMS) on the intracellular beta and gamma subunits, which leads to the recruitment of additional Lyn to the beta subunit and Syk kinase to the gamma homodimer.
These receptor-associated kinases, which are activated by intra- and intermolecular phosphorylation, phosphorylate other components of the pathway, such as the Btk kinase, LAT, and phospholipase C-gamma PLC-gamma). Activated PLC-gamma initiates pathways that lead to protein kinase C activation and Ca2+ mobilization, both of which are required for degranulation. FcgR1 cross-linking also activates the three major classes of mitogen activated protein (MAP) kinases, i.e. ERK1/2, JNK1/2, and p38.
Activation of these pathways is important in the transcriptional regulation of proinflammatory mediators, such as TNF-a and IL-6, as well as the lipid mediator leukotriene CA (LTC4).
Although not illustrated, the FcTRI signaling cascade is believed to share some common elements with the FceRI signaling cascade. Importantly, like FeERL the FcTRI
includes a gamma homodimer that is phosphorylated and recruits Syk, and like FccRI, activation of the FcyRI signaling cascade leads to, among other things, degranulation.
Other Fc receptors that share the gamma homodimer, and which can be regulated by the active 2,4-pyrimidinediamine compounds include, but are not limited to, FcaRI
and Fc-yRIII.

- --=
The ability of the 2,4-pyrimidinediamine compounds of the invention to inhibit Fc receptor signaling cascades may be simply determined or confirmed in in vitro assays.
Suitable assays for confirming inhition of FcERI-mediated degranulation are provided in the Examples section. In one typical assay, cells capable of undergoing FcERI-mediated degranulation, such as mast or basophil cells, are first grown in the presence of IL-4, Stem Cell Factor (SCF), IL-6 and IgE to increase expression of the FcERI, exposed to a 2,4-pyrimidinediamine test compound of the invention and stimulated with anti-IgE
antibodies (or, alternatively, an IgE-specific allergen). Following incubation, the amount of a chemical mediator or other chemical agent released and/or synthesized as a consequence of activating the FcERI signaling cascade may be quantified using standard techniques and compared to the amount of the mediator or agent released from control cells (i.e., cells that are stimulated but that are not exposed to test compound). The concentration of test compound that yields a 50% reduction in the quantity of the mediator or agent measured as compared to control cells is the IC50 of the test compound. The origin of the mast or basophil cells used in the assay will depend, in part, on the desired use for the compounds and will be apparent to those of skill in the art. For example, if the compounds will be used to treat or prevent a particular disease in humans, a convenient source of mast or basophil cells is a human or other animal which constitutes an accepted or known clinical model for the particular disease. Thus, depending upon the particular application, the mast or basophil cells may be derived from a wide variety of animal sources, ranging from, for example, lower mammals such as mice and rats, to dogs, sheep and other mammals commonly employed in clinical testing, to higher mammals such as monkeys, chimpanzees and apes, to humans.
Specific examples of cells suitable for carrying out the in vitra assays include, but are not limited to, rodent or human basophil cells, rat basophil leukemia cell lines, primary mouse mast cells (such as bone marrow-derived mouse mast cells "BMMC') and primary human mast cells isolated from cord blood ('CHIVIC) or other tissues such as lung. Methods for isolating and culturing these cell types are well-known or are provided in the Examples section (see, e.g., Demo et al., 1999, Cytometry 36(4):340-348 and copending application Serial No.
10/053,355, filed November 8, 2001, issued as U.S. Patent No. 7,070,996). Of course, other types of immune cells that degranulate upon activation of the FceRI signaling cascade may also be used, including, for example, eosinophils.
As will be recognized by skilled artisans, the mediator or agent quantified is not critical. The only requirement is that it be a mediator or agent released and/or synthesized as a consequence of initiating or activating the Fc receptor signalling cascade.
For example, referring to FIG. 1, activation of the FccRI signaling cascade in mast and/or basophil cells leads to numerous downstream events. For example, activation of the FceRI
signal cascade leads to the immediate release (i.e., within 1-3 min. following receptor activation) of a variety of preformed chemical mediators and agents via degranulation. Thus, in one embodiment, the mediator or agent quantified may be specific to granules (i.e., present in granules but not in the cell cytoplasm generally). Examples of granule-specific mediators or agents that can be quantified to determine and/or confirm the activity of a 2,4-ppimidinediamine compound of the invention include, but are not limited to, granule-specific enzymes such as hexosaminidase and tryptase and granule-specific components such as histamine and serotonin. Assays for quantifying such factors are well-known, and in many instances are commercially available. For example, tryptase and/or hexosaminidase release may be quantified by incubating the cells with cleavable substrates that fluoresce upon cleavage and quantifying the amount of fluorescence produced using, conventional techniques. Such cleavable fluorogenic substrates are commercially available.
For example, the fluorogenic substrates Z-Gly-Pro-Arg-AMC
(Z=benzyloxycarbonyl;
AMC=7-amino-4-methylcoumarin; BIOMOL Research Laboratories, Inc., Plymouth Meeting, PA 19462, Catalog No. P-142) and Z-Ala-Lys-Arg-AMC (Enzyme Systems Products, a division of ICN Biomedicals, Inc., Livermore, CA 94550, Catalog No. AMC-246) can be used to quantify the amount of tryptase released. The fluorogenic substrate 4-methylumbelliferyl-N-acetyl-P-D-glucosaminide (Sigma, St. Louis, MO, Catalog #69585) can be used to quantify the amount of hexosaminidase released. Histamine release may be quantified using a commercially available enzyme-linked immunosorbent assay (ELISA) such as Immunotech histamine ELISA assay #IM2015 (Beckman-Coulter, Inc.).
Specific methods of quantifying the release of tryptase, hexosaminidase and histamine are provided in the Examples section. Any of these assays may be used to determine or confirm the activity of the 2,4-pyrimidinediamine compounds of the invention.
Referring again to FIG. 1, degranulation is only one of several responses initiated by the FcERI signaling cascade. In addition, activation of this signaling pathway leads to the de novo synthesis and release of cytokines and chemokines such as IL-4, IL-5, IL-6, TNF-a, IL-13 and MIP1-a), and release of lipid mediators such as leukotrienes (e.g., LTC4), platelet activating factor (PAF) and prostaglandins. Accordingly, the 2,4-pyrimidinediamine compounds of the invention may also be assessed for activity by quantifying the amount of one or more of these mediators released and/or synthesized by activated cells.
Unlike the granule-specific components discussed above, these "late stage"
mediators are not released immediately following activation of the FcERI
signaling cascade.
Accordingly, when quantifying these late stage mediators, care should be taken to insure that the activated cell culture is incubated for a time sufficient to result in the synthesis (if necessary) and release of the mediator being quantified. Generally, PAF and lipid mediators such as leukotriene C4 are released 3-30 min. following FcERI
activation. The cytokines and other late stage mediators are released approx. 4-8 hrs.
following FcERI
activation. Incubation times suitable for a specific mediator will be apparent to those of skill in the art. Specific guidance and assays are provided in the Examples section.
The amount of a particular late stage mediator released may be quantified using any standard technique. In one embodiment, the amount(s) may be quantified using ELISA
assays. ELISA assay kits suitable for quantifying the amount of TNFcc, IL-4, IL-5, IL-6 and/or IL-13 released are available from, for example, Biosource International, Inc., Camarillo, CA 93012 (see, e.g., Catalog Nos. KHC3011, KHC0042, KHC0052, and KHC0132). ELISA assay kits suitable for quantifying the amount of leukotriene C4 (LTC4) released from cells are available from Cayman Chemical Co., Ann Arbor, MI
48108 (see, e.g., Catalog No. 520211).
Typically, active 2,4-pyrimidinediamine compounds of the invention will exhibit IC5os with respect to FccRI-mediated degranulation and/or mediator release or synthesis of about 20iuM or lower, as measured in an in vitro assay, such as one of the in vitro assays described above or in the Examples section. Of course, skilled artisans will appreciate that compounds which exhibit lower IC50s, for example on the order of 10 p,M, 1 M, 100 nM, 10 nM, 1 nM, or even lower, are particularly useful.
Skilled artisans will also appreciate that the various mediators discussed above may induce different adverse effects or exhibit different potencies with respect to the same adverse effect. For example, the lipid mediator LTC4 is a potent vasoconstrictor ¨ it is approximately 1000-fold more potent at inducing vasoconstriction than histamine. As another example, in addition to mediating atopic or Type I hypersensitivity reactions, cytokines can also cause tissue remodeling and cell proliferation. Thus, although compounds that inhibit release and/or synthesis of any one of the previously discussed chemical mediators are useful, skilled artisans will appreciate that compounds which inhibit the release and/or synthesis of a plurality, or even all, of the previously described mediators find particular use, as such compounds are useful for ameliorating or avoiding altogether a plurality, or even all, of the adverse effects induced by the particular mediators. For example, compounds which inhibit the release of all three types of mediators¨granule-specific, lipid and cytokine¨are useful for treating or preventing immediate Type I
hypersensitivity reactions as well as the chronic symptoms associated therewith.
Compounds of the invention capable of inhibiting the release of more than one type of mediator (e.g., granule-specific or late stage) may be identified by determining the IC50 with respect to a mediator representative of each class using the various in vitro assays described above (or other equivalent in vitro assays). Compounds of the invention which are capable of inhibiting the release of more than one mediator type will typically exhibit an IC50 for each mediator type tested of less than about 20 [tM. For example, a compound which exhibits an IC50 of 1 i_tM with respect to histamine release (IC50histamine) and an IC50 of 1 nM with respect to leukotriene LTC4 synthesis and/or release (IC50LTC4) inhibits both immediate (granule-specific) and late stage mediator release. As another specific example, a compound that exhibits an IC50frYPtase of 10 M, an IC50urc4 of 1 [tM and an IC501-4 of 1 j.M inhibits immediate (granule-specific), lipid and cytokine mediator release. Although the above specific examples utilize the IC5os of one representative mediator of each class, skilled artisans will appreciate that the IC5os of a plurality, or even all, mediators comprising one or more of the classes may be obtained. The quantity(ies) and identity(ies) of mediators for which IC50 data should be ascertained for a particular compound and application will be apparent to those of skill in the art.
Similar assays may be utilized to confirm inhibition of signal transduction cascades initiated by other Fc receptors, such as FcaRI, Fel/RI and/or Fc-yRIII
signaling, with routine modification. For example, the ability of the compounds to inhibit Fc7RI
signal transduction may be confirmed in assays similar to those described above, with the exception that the Fc7RI signaling cascade is activated, for example by incubating the cells with IgG and an IgG-specific allergen or antibody, instead of IgE and an IgE-specific allergen or antibody. Suitable cell types, activating agents and agents to quantify to confirm inhibition of other Fc receptors, such as Fc receptors that comprise a gamma homodimer, will be apparent to those of skill in the art.
One particularly useful class of compounds includes those 2,4-pyrimidinediamMe compounds that inhibit the release of immediate granule-specific mediators and late stage mediators with approximately equivalent IC50s. By approximately equivalent is meant that the IC50s for each mediator type are within about a 10-fold range of one another. Another particularly useful class of compounds includes those 2,4-pyrimidinediamine compounds that inhibit the release of immediate granule-specific mediators, lipid mediators and cytokine mediators with approximately equivalent ICsos. In a specific embodiment, such compounds inhibit the release of the following mediators with approximately equivalent IC50s: histamine, tryptase, hexosaminidase, IL-4, IL-5, IL-6, IL-13, TNFa and LTC4. Such compounds are particularly useful for, among other things, ameliorating or avoiding altogether both the early and late stage responses associated with atopic or immediate Type I hypersensitivity reactions.
Ideally, the ability to inhibit the release of all desired types of mediators will reside in a single compound. However, mixtures of compounds can also be identified that achieve the same result. For example, a first compound which inhibits the release of granule specific mediators may be used in combination with a second compound which inhibits the release and/or synthesis of cytokine mediators.
In addition to the FcERI or FcyRI degranulation pathways discussed above, degranulation of mast and/or basophil cells can be induced by other agents.
For example, ionomycin, a calcium ionophore that bypasses the early FcERI or Fc-yRI signal transduction machinery of the cell, directly induces a calcium flux that triggers degranulation. Referring again to FIG. 2, activated PLCy initiates pathways that lead to, among other things, calcium ion mobilization and subsequent degranulation. As illustrated, this Ca2+
mobilization is triggered late in the FcERI signal transduction pathway. As mentioned above, and as illustrated in FIG. 3, ionomycin directly induces Ca2+ mobilization and a Ca2+
flux that leads to degranulation. Other ionophores that induce degranulation in this manner include A23187. The ability of granulation-inducing ionophores such as ionomycin to bypass the early stages of the Fait' and/or FcyRI signaling cascades may be used as a counter screen to identify active compounds of the invention that specifically exert their degranulation-inhibitory activity by blocking or inhibiting the early FcERI or FcyRI
signaling cascades, as discussed above. Compounds which specifically inhibit such early FcERI or FcyRI-mediated degranulation inhibit not only degranulation and subsequent rapid release of histamine, tryptase and other granule contents, but also inhibit the pro-inflammatory activation pathways causing the release of TNFa, IL-4, IL-13 and the lipid mediators such as LTC4. Thus, compounds which specifically. inhibit such early FcERI and/or FcyRI-mediated degranulation block or inhibit not only acute atopic or Type I
hypersensitivity reactions, but also late responses involving multiple inflammatory mediators.
Compounds of the invention that specifically inhibit early FeeRI and/or Fcl/RI-mediated degranulation are those compounds that inhibit FceRI and/or Fel/RI-mediated degranulation (for example, have an IC50 of less than about 20 pAl with respect to the release of a granule-specific mediator or component as measured in an in vitro assay with cells stimulated with an IgE or IgG binding agent) but that do not appreciably inhibit ionophore-induced degranulation. In one embodiment, compounds are considered to not appreciably inhibit ionophore-induced degranulation if they exhibit an IC50 of ionophore-induced degranulation of greater than about 20 M, as measured in an in vitro assay. Of course, active compounds that exhibit even higher IC5os of ionophore-induced degranulation, or that do not inhibit ionophore-induced degranulation at all, are particularly useful. In another embodiment, compounds are considered to not appreciably inhibit ionophore-induced degranulation if they exhibit a greater than 10-fold difference in their IC5os of FccRI and/or Fel/RI-mediated degranulation and ionophore-induced degranulation, as measured in an in vitro assay. Assays suitable for determining the IC50 of ionophore-induced degranulation include any of the previously-described degranulation assays, with the modification that the cells are stimulated or activated with a degranulation-inducing calcium ionophore such as ionomycin or A23187 (A.G. Scientific, San Diego, CA) instead of anti-IgE antibodies or an IgE-specific allergen. Specific assays for assessing the ability of a particular 2,4-pyrimidinediamine compound of the invention to inhibit ionophore-induced degranulation are provided in the Examples section.
As will be recognized by skilled artisans, compounds which exhibit a high degree of selectivity of FceRI-mediated degranulation find particular use, as such compounds selectively target the FceRI cascade and do not interfere with other degranulation mechanisms. Similarly, compounds which exhibit a high degree of selectivity of Fci/RI-mediated degranulation find particular use, as such compounds selectively target the Fcl/RI
cascade and do not interfere with other degranulation mechanisms. Compounds which exhibit a high degree of selectivity are generally 10-fold or more selective for FceRI- or Fc-yRI -mediated degranulation over ionophore-induced degranulation, such as ionomycin-induced degranulation.
Biochemical and other data confirm that the 2,4-pyrimidinediamine compounds described herein are potent inhibitors of Syk kinase activity. For example, in experiments with an isolated Syk kinase, of twenty four 2,4-pyrimidinediamine compounds tested, all but two inhibited the Syk kinase catalyzed phosphorylation of a peptide substrate with IC5Os in the submicromolar range. The remaining compounds inhibited phosphorylation in the micromolar range. In addition, of sixteen compounds tested in an in vitro assay with mast cells, all inhibited phosphorylation of Syk kinase substrates (e.g., PLC-gammal, LAT) and proteins downstream of Syk kinase (e.g., JNK, p38, Erk1/2 and PKB, when tested), but not proteins upstream of Syk kinase in the cascade (e.g., Lyn).
Phosphorylation of Lyn substrates was not inhibited by the 2,4-pyrimidinediamine compounds tested.
Moreover, for the following compounds, a high correlation was observed between their inhibition of Syk kinase activity in biochemical assays (IC5os in the range of 3 to 1850 nM) and their inhibition of FaR1-mediated degranulation in mast cells (IC5os in the range of 30 to 1650 nM): R950373, R950368, R921302, R945371, R945370, R945369, R945365, R921304, R945144, R945140, R945071, R940358, R940353, R940352, R940351, R940350, R940347, R921303, R940338, R940323, R940290, R940277, R940276, R940275, R940269, R940255, R935393, R935372, R935366, R935310, R935309, R935307, R935304, R935302, R935293, R935237, R935198, R935196, R935194, R935193, R935191, R935190, R935138, R927050, R926968, R926956, R926931, R926891, R926839, R926834, R926816, R926813, R926791, R926782, R926780, R926757, R926753, R926745, R926715, R926508, R926505, R926502, R926501, R926500, R921218, R921147, R920410, R909268, R921219, R908712, R908702.
Accordingly, the activity of the 2,4-pyrimidinediamine compounds of the invention may also be confirmed in biochemical or cellular assays of Syk kinase activity. Referring again to FIG. 2, in the FccRI signaling cascade in mast and/or basophil cells, Syk kinase phosphorylates LAT and PLC-gammal, which leads to, among other things, degranulation.
Any of these activities may be used to confirm the activity of the 2,4-pyrimidinediamine compounds of the invention. In one embodiment, the activity is confirmed by contacting an isolated Syk kinase, or an active fragment thereof with a 2,4-pyrimidinediamine compound in the presence of a Syk kinase substrate (e.g., a synthetic peptide or a protein that is known to be phophorylated by Syk in a signaling cascade) and assessing whether the Syk kinase phosphorylated the substrate. Alternatively, the assay may be carried out with cells that express a Syk kinase. The cells may express the Syk kinase endogenously or they may be engineered to express a recombinant Syk kinase. The cells may optionally also express the Syk kinase substrate. Cells suitable for performing such confirmation assays, as well as methods of engineering suitable cells will be apparent to those of skill in the art. Specific examples of biochemical and cellular assays suitable for confirming the activity of the 2,4-pyrimidinediarnine compounds are provided in the Examples section.
Generally, compounds that are Syk kinase inhibitors will exhibit an IC50 with respect to a Syk kinase activity, such as the ability of Syk kinase to phosphorylate a synthetic or endogenous substrate, in an in vitro or cellular assay in the range of about 20 pM or less.
Skilled artisans will appreciate that compounds that exhibit lower IC50s, such as in the range of 10 M, 1 M, 100 nM, 10 nM, 1 nM, or even lower, are particularly useful.
63 Uses and Compositions As previously discussed, the active compounds of the invention inhibit Fc receptor signaling cascades, especially those Fc receptors including a gamma homodimer, such as the FcÃR1 and/or al/RI signaling cascades, that lead to, among other things, the release and/or synthesis of chemical mediators from cells, either via degranulation or other processes. As also discussed, the active compounds are also potent inhibitors of Syk kinase.
As a consequence of these activities, the active compounds of the invention may be used in a variety of in vitro, in vivo and ex vivo contexts to regulate or inhibit Syk kinase, signaling cascades in which Syk kinase plays a role, Fc receptor signaling cascades, and the biological responses effected by such signaling cascades. For example, in one embodiment, the compounds may be used to inhibit Syk kinase, either in vitro or in vivo, in virtually any.
cell type expressing Syk kinase. They may also be used to regulate signal transduction cascades in which Syk kinase plays a role. Such Syk-dependent signal transduction cascades include, but are not limited to, the FcÃR1, FcTRI, BCR and integiin signal transduction cascades. The compounds may also be used in vitro or in vivo to regulate, and in particular inhibit, cellular or biological responses effected by such Syk-dependent signal transduction cascades. Such cellular or biological responses include, but are not limited to, respiratory burst, cellular adhesion, cellular degranulation, cell spreading, cell migration, cell aggregation, phagcytosis, cytokine synthesis and release, cell maturation and Ca2+ flux.
Importantly, the compounds may be used to inhibit Syk kinase in vivo as a therapeutic approach towards the treatment or prevention of diseases mediated, either wholly or in part, by a Syk kinase activity. Non-limiting examples of Syk kinase mediated diseases that may be treated or prevented with the compounds are those discussed in more detail, below.
In another embodiment, the active compounds may be used to regulate or inhibit the Fc receptor signaling cascades and/or FcERI- and/or Fc7R1-mediated degranulation as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by and/or associated with the release or synthesis of chemical mediators of such Fc receptor signaling cascades or degranulation. Such treatments may be administered to animals in veterinary contexts or to humans. Diseases that are characterized by, caused by or associated with such mediator release, synthesis or degranulation, and that can therefore be treated or prevented with the active compounds include, by way of example and not limitation, atopy or anaphylactic hypersensitivity or allergic reactions, allergies (e.g., allergic conjunctivitis, allergic rhinitis, atopic asthma, atopic dermatitis and food allergies), low grade scarring (e.g., of scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury and post myocardial infarction), diseases associated with tissue destruction (e.g., of COPD, cardiobronchitis and post myocardial infarction), diseases associated with tissue inflammation (e.g., irritable bowel syndrome, spastic colon and inflammatory bowel disease), inflammation and scarring.
When used to treat or prevent such diseases, the active compounds may be administered singly, as mixtures of one or more active compounds or in mixture or combination with other agents useful for treating such diseases and/or the symptoms associated with such diseases. The active compounds may also be administered in mixture or in combination with agents useful to treat other disorders or maladies, such as steroids, membrane stablizers, 5L0 inhibitors, leukotriene synthesis and receptor inhibitors, inhibitors of IgE isotype switching or IgE synthesis, IgG isotype switching or IgG synthesis, P-agonists, tryptase inhibitors, aspirin, COX inhibitors, methotrexate, anti-TNF drugs, retuxin, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors, and antihistamines, to name a few.
The active compounds may be administeredper se in the form of prodrugs or as pharmaceutical compositions, comprising an active compound or prodrug.
Pharmaceutical compositions comprising the active compounds of the invention (or prodrugs thereof) may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making levigating, emulsifying, encapsulating, entrapping or lyophilization processes. The compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
The active compound or prodrug may be formulated in the pharmaceutical compositions per se, or in the form of a hydrate, solvate, N-oxide or pharmaceutically acceptable salt, as previously described. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases may also be formed.
Pharmaceutical compositions of the invention may take a form suitable for virtually any mode of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation.
For topical administration, the active compound(s) or prodrug(s) may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.
Useful injectable preparations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles. The compositions may also contain formulating agents, such as suspending, stabilizing and/or dispersing agent.
The formulations for injection may be presented in unit dosage form, e.g., in ampules or in multidose containers, and may contain added preservatives.
Alternatively, the injectable formulation may be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc., before use. To this end, the active compound(s) may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.
For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.
For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art with, for example, sugars, films or enteric coatings.
Compounds which are particularly suitable for oral administration include Compounds R940350, R935372, R935193, R927050 and R935391.

Liquid preparations for oral administration may take the form of; for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats);
emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophorem or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring, coloring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound or prodrug, as is well known.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
For rectal and vaginal routes of administration, the active compound(s) may be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.
For nasal administration or administration by inhalation or insufflation, the active compound(s) or prodrug(s) can be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount Capsules and cartridges for use in an inhaler or insufflator (for example capsules and cartridges comprised of gelatin) may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
A specific example of an aqueous suspension formulation suitable for nasal administration using commercially-available nasal spray devices includes the following ingredients: active compound or prodrug (0.5-20 mg/ml); benzalkonium chloride (0.1-0.2 mg/mL); polysorbate 80(TWEENS 80; 0.5-5 mg/m1); carboxymethylcellulose sodium or microcrystalline cellulose (1-15 mg/ml); phenylethanol (14 mg/nil); and dextrose (20-50 mg/nil). The pH of the final suspension can be adjusted to range from about pH5 to pH7, with a pH of about pH 5.5 being typical.
Another specific example of an aqueous suspension suitable for administration of the compounds via inhalation, and in particular for such administration of Compound *Trade-mark 72 R921218, contains 1-20 mg/mL Compound or prodrug, 0.1-1% (v/v) Polysorbate 80 (TWEEN680), 50 mM citrate and/or 0.9% sodium chloride.
For ocular administration, the active compound(s) or prodrug(s) may be formulated as a solution, emulsion, suspension, etc. suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art.
Specific non-limiting examples are described in U.S. Patent No. 6,261,547; U.S. Patent No.
6,197,934; U.S. Patent No. 6,056,950; U.S. Patent No. 5,800,807; U.S. Patent No.
5,776,445; U.S. Patent No. 5,698,219; U.S. Patent No. 5,521,222; U.S. Patent No.
5,403,841; U.S. Patent No. 5,077,033; U.S. Patent No. 4,882,150; and U.S.
Patent No.
4,738,851.
For prolonged delivery, the active compound(s) or prodrug(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt. Alternatively, transdermal delivery systems manufactured as an adhesive disc or patch which slowly releases the active compound(s) for percutaneous absorption may be used. To this end, permeation enhancers may be used to facilitate transdermal penetration of the active compound(s). Suitable transdermal patches are described in for example, U.S. Patent No. 5,407,713.; U.S. Patent No.
5,352,456; U.S.
Patent No. 5,332,213; U.S. Patent No. 5,336,168; U.S. Patent No. 5,290,561;
U.S. Patent No. 5,254,346; U.S. Patent No. 5,164,189; U.S. Patent No. 5,163,899; U.S.
Patent No.
5,088,977; U.S. Patent No. 5,087,240; U.S. Patent No. 5,008,110; and U.S.
Patent No.
4,921,475.
Alternatively, other pharmaceutical delivery systems may be employed.
Liposomes and emulsions are well-known examples of delivery vehicles that may be used to deliver active compound(s) or prodrug(s). Certain organic solvents such as dimethylsulfoxide (DMSO) may also be employed, although usually at the cost of greater toxicity.
The pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound(s). The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

6.6 Effective Dosages The active compound(s) or prodrug(s) of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular disease being treated. The compound(s) may be administered therapeutically to achieve therapeutic benefit or prophylactically to achieve prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, notwithstanding that the patient may still be afflicted with the underlying disorder. For example, administration of a compound to a patient suffering from an allergy provides therapeutic benefit not only when the underlying allergic response is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of the symptoms associated with the allergy following exposure to the allergen. As another example, therapeutic benefit in the context of asthma includes an improvement in respiration following the onset of an asthmatic attack, or a reduction in the frequency or severity of asthmatic episodes. Therapeutic benefit also includes halting or " slowing the progression of the disease, regardless of whether improvement is realized.
For prophylactic administration, the compound may be administered to a patient at risk of developing one of the previously described diseases. For example, if it is unknown whether a patient is allergic to a particular drug, the compound may be administered prior to administration of the drug to avoid or ameliorate an allergic response to the drug.
Alternatively, prophylactic administration may be applied to avoid the onset of symptoms in a patient diagnosed with the underlying disorder. For example, a compound may be administered to an allergy sufferer prior to expected exposure to the allergen. Compounds may also be administered prophylactically to healthy individuals who are repeatedly exposed to agents known to one of the above-described maladies to prevent the onset of the disorder. For example, a compound may be administered to a healthy individual who is repeatedly exposed to an allergen known to induce allergies, such as latex, in an effort to prevent the individual from developing an allergy. Alternatively, a compound may be administered to a patient suffering from asthma prior to partaking in activities which trigger asthma attacks to lessen the severity of, or avoid altogether, an asthmatic episode.
The amount of compound administered will depend upon a variety of factors, including, for example, the particular indication being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the indication being treated and the age and weight of the patient, the bioavailability of the particular active compound, etc. Determination of an effective dosage is well within the capabilities of those skilled in the art.
Effective dosages may be estimated initially from in vitro assays. For example, an initial dosage for use in animals may be formulated to achieve a circulating blood or serum concentration of active compound that is at or above an IC50 of the particular compound as measured in as in vitro assay, such as the in vitro CHMC or BMMC and other in vitro assays described in the Examples section. Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound is well within the capabilities of skilled artisans. For guidance, the reader is referred to Fingl & Woodbury, "General Principles," In: Goodman and Gilman 's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest edition, Pagamonon Press, and the references cited therein.
Initial dosages can also be estimated from in vivo data, such as animal models.
Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described above are well-known in the art. Suitable animal models of hypersensitivity or allergic reactions are described in Foster, 1995, Allergy 50(21Suppl):6-9, discussion 34-38 and Tumas etal., 2001, J. Allergy Clin. Immunol.
107(6):1025-1033.
Suitable animal models of allergic rhinitis are described in Szelenyi et al., 2000, Arzneimittelforschung 50(11):1037-42; Kawaguchi et al., 1994, Clin. Exp.
Allergy 24(3):238-244 and Sugimoto et al., 2000, Immunopharmacology 48(1):1-7.
Suitable animal models of allergic conjunctivitis are described in Carreras et al., 1993, Br.
J. Ophthalmol.
77(8):509-514; Saiga et al., 1992, Ophthalmic Res. 24(1):45-50; and Kunert et al., 2001, Invest. Ophthalmol. Vis. Sci. 42(11):2483-2489. Suitable animal models of systemic mastocytosis are described in O'Keefe etal., 1987, J. Vet. Intern. Med.
1(2):75-80 and Bean-Knudsen et al., 1989, Vet. Pathol. 26(1):90-92. Suitable animal models of hyper IgE
syndrome are described in Claman etal., 1990, Clin. Immunol. Immunopathol.
56(1):46-53.
Suitable animal models of B-cell lymphoma are described in Hough et al., 1998, Proc. Natl.
Acad. Sci. USA 95:13853-13858 and Hakim etal., 1996, J. Immunol. 157(12):5503-5511.
Suitable animal models of atopic disorders such as atopic dermatitis, atopic eczema and atopic asthma are described in Chan etal., 2001, J. Invest. Dermatol.
117(4):977-983 and Suto et al., 1999, Int. Arch. Allergy Immunol. 120(Suppl 1):70-75. Ordinarily skilled artisans can routinely adapt such information to determine dosages suitable for human administration. Additional suitable animal models are described in the Examples section.
Dosage amounts will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower, depending upon, among other factors, the activity of the compound, its bioavailability, the mode of administration and various factors discussed above. Dosage amount and interval may be adjusted individually to provide plasma levels of the compound(s) which are sufficient to maintain therapeutic or prophylactic effect. For example, the compounds may be administered once per week, several times per week (e.g., every other day), once per day or multiple times per Preferably, the compound(s) will provide therapeutic or prophylactic benefit without causing substantial toxicity. Toxicity of the compound(s) may be determined using standard pharmaceutical procedures. The dose ratio between toxic and therapeutic (or prophylactic) effect is the therapeutic index. Compounds(s) that exhibit high therapeutic indices are preferred.
The invention having been described, the following examples are offered by way of illustration and not limitation.
7. EXAMPLES
7.1 Synthesis of Starting Materials and Intermediates Useful for Synthesizing The 2,4-Pyrimidinediamine Compounds According to Schemes (I)¨(V) A variety of starting materials and N4-monosubstituted-2-prirnidineamines and N2-monosubstituted-4-pyrimidinediamines [mono Substitution Nucleophilic Aromatic Reaction (SNAR) products] useful for synthesizing the 2,4-pyrimidinediamine compounds of the invention according to Schemes (I)-(V) were prepared as described below.
Conditions suitable for synthesizing the mono SNAR products are exemplified with 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine (R926087).

7.1.1 2,4-Dichloro-5-fluoropyrimidine To a dry reaction flask equipped with a stir bar and a reflux condenser was placed 5-fluorouracil (0.65g, 5mmol) followed by phosphorus oxychloride (POC13) (1.53g, lOmmol). The resultant mixture was heated at 110 C for 8 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, phosphorus pentachloride (PC15) (3.12g, 15mmol) was added and heated to 110 C for a period of 12 hours. After cooling to room temperature, the mixture was poured into ice-water, saturated with sodium chloride and left for 1 hour at 0 C to complete the decomposition of POC13 and PC15.
The solid of 2,4-dichloro-5-fluoropyrimidine was collected by rapid filtration, dried using blotting paper and stored at low temperature. 1H NMR (CDC13): 8 8.47 (s, 111); 13C NMR
(CDC13): 8 155.42, 151.87, 147.43 and 147.13; 19F NMR (CDC13): ¨ 38149.
7.1.2 2,4-Dichloro-5-nitropyrimidine (Aldrich D6, 930-0) A suspension of 5-nitrouracil (10g, 63 mmol) in POC13 (100 mL) was refluxed for 5h in the presence of N,N-dimethylaniline (10 mL), cooled to room temperature and poured on to crushed ice with vigorous stirring. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent was evaporated under reduce pressure. The residue was purified by chromatography on silica gel (hexane/ethyl acetate; 1/1; v/v) to give the desired 2,4-dichloro-5-nitropyrimidine. LCMS:
ret. time: 23.26 min.; purity: 95%; 1H NMR (CDC13): 8 9.16 (1H, s).
7.1.3 2,4-Dichloro-5-cyanopyrimidine In like manner to the preparation of 2,4-dichloro-5-nitropyrimidine, the reaction of 5-cyanouracil with POC13 and N,N-dimethyla.niline gave 2,4-dichloro-5-cyanopyrimidine.
LCMS: ret. time: 13.75 min.; purity: 95%.
7.1.4 2,4-Dichloro-5-trifluoromethylpyrimidine In like manner to the preparation of 2,4-dichloro-5-nitropyrimidine, the reaction of 5-cyanouracil with POC13 and N,N-dimethylaniline gave 2,4-dichloro-5-cyanopyrimidine.
1H NMR (CD30D): 8 9.07; LCMS: ret. time: 16.98 min. (fast method); purity:
70%.

7.1.5 2-Chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine (R926087) The reaction flask equipped with a magnetic stirring bar and a rubber septum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N2 inlet was charged with 3,4-ethylenedioxyaniline (34 g, 225 mmol), Me0H (100 mL), H20 (300 mL) and 2,4-dichloro-5-fluoropyrimidine (25 g, 150 mmol). The reaction mixture was stirred at room temperature for lh, diluted with 1120 (1.5 liter), acidified with 2N HC1 (200 mL) and sonicated. The solid obtained was filtered, washed with 1120 and dried to obtain 33 g (78%) of the desired product, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine (R926087).
1H NMR (CDC13): 8 8.02 (111, d, J= 3Hz), 7.25 (d, 1H, J= 1.2 Hz), 6.98 (dd, 1H, J= 2.4 and 8.1 Hz), 6.85 (d, 111, J= 5.7 Hz), 4.27 (m, 4H); 19F NMR (CDC13): - 44570;
LCMS: ret.
time: 26.70 min.; purity 100%; MS (m/e): 283 (M114).
7.1.6 2-Chloro-N4-(3,4-ethylenedioxypheny1)-5-nitro-4-pyrimidineamine (R940094) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-nitropyrimidine and 3,4-ethylenedioxyaniline were reacted to prepare 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-nitro-4-pyrimidineamine.
LCMS: ret. time: 28.79 min.; purity: 90%; MS (m/e): 308 (M+);11INMR (CDC13): 8 10.07 (1H, s), 9.15 (1H, s), 7.02-6.88 (311, m), 4.29 (4H, s).
7.1.7 2-Chloro-N4-(3-hydroxypheny1)-5-nitro-4-pyrimidineamine (R940097) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-nitropyrirnidine and 3-hydroxyaniline were reacted to prepare 2-chloro-N4-(3-hydroxypheny1)-5-nitro-4-pyrimidineamine.
LCMS: ret.
time: 24.21 min.; purity: 93%; MS (m/e): 267 (M11+); 111NMR (CDC13): 8 10.20 (111, s), 9.19(111, s), 7.32 (1H, t, J= 2.2 Hz), 7.28 (1H, d, J= 7.8 Hz), 7.11 (1H, dd, J= 7.8 and 1.8 Hz), 7.76 (1H, dd, J= 8.4 and 2.4 Hz), 5.20 (111, s).
7.1.8 2-Chloro-N4-(3-hydroxypheny1)-5-fluoro-4-pyrimidineamine (R926111) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-hydroxyaniline were reacted to prepare product 2-chloro-N4-(3-hydroxypheny1)-5-fluoro-4-pyrimidineamine. 111 NMR (CD30D): 5 8.06 (bd, 1H), 7.26 (bd, 1H), 7.20-7.00 (m, 2H), 6,57 (d, 111, J= 7.2 Hz);
19F NMR (CD30D): - 44374; LCMS: ret. time: 22.02; purity: 100%, MS (m/e): 240 (M+).
7.1.9 2-Chloro-N4-(3,4-dimethoxypheny1)-5-fluoro-4-pyrimidineamine (R926073) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3,4-dimethoxyaniline were reacted to prepare 2-chloro-N4-(3,4-dimethoxypheny1)-5-fluoro-4-pyrimidineamine.1H
NMR (CDC13): 8 8.02 (d, 1H, J= 2.7 Hz), 7.38 (d, 1H, J= 2.4 Hz), 7.05 (dd, 1H, J= 2.4 and 9.0 Hz), 6.89 (bs, 1H), 6.88 (d, 1H, J= 9 Hz), 3.91 (s, 3H), 3.89 (s, 3H); 19F
NMR (CDC13):
- 44593; LCMS: ret. time: 24.95 min.; purity: 98%; MS (m/e): 285 (MH+).
7.1.10 2-Chloro-N4-(4-ethoxypheny1)-5-fluoro-4-pyrimidineamine (R926066) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-ethoxyaniline were reacted to prepare 2-chloro-N4-(4-ethoxypheny1)-5-fluoro-4-pyrimidineamine.1H
NMR
(CDC13): 8 8.01 (d, 1H, J= 3Hz), 7.49 (bdd, 2H, J= 8.7 Hz), 6.92 (bdd, 211, J=
9.6 Hz), 4.03 (q, 2H, J= 7.2 Hz), 1.42 (t, 311, J= 7.2 Hz); 19F NMR (CDC13): - 44627; LCMS:
ret. time:
29.50 min.; purity: 99%, MS (m/e): 268 (MH+).
7.1.11 2-Chloro-N4-(4-chloropheny1)-5-fluoro-4-pyrimidineamine (R926207) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-chloroaniline were reacted to prepare 2-chloro-N4-(4-chloropheny1)-5-fluoro-4-primidineamine.111 NMR
(CDC13): 8 8.1 (bs, 1H), 8.60 (bdd, 211), 8.36 (bdd, 2H), 6.90 (bs, 111); 19F
NMR (CDC13): -44407; LCMS: ret. time: 31.63 min.; purity: 85%; MS (m/e): 258 (MTV).
7.1.12 2-Chloro-5-fluoro-N4-(3-hydroxy-4-methoxycarbonylmethyleneoxypheny1)-4-pyrimidineamine (R926393) In like marmer to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidinearnine, 2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methoxycarbonylmethylenoxyaniline were reacted to prepare 2-chloro-5-fluoro-N4-(3-hydroxy-4-methoxycarbonylmethyleneoxypheny1)-4-pyrimidineamine. 111 NMR
(CD30D):

8 8.03 (d, 111, J= 3.6 Hz), 7.35 (dd, 1H, J= 2.4 Hz), 7.12 (dd, 1H, J= 2.4 and 8.7 Hz), 6.82 (d, 1H, J= 8.1 Hz), 4.86 (s, 211), 3.81 (s, 3H).
7.1.13 N4-(4-tert-Butoxycarbonylmethyleneoxypheny1)-2-chloro-5-fluoro-4-pyrimidineamine (R926573) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and tert-butyl 4-aminophenoxyacetate were reacted to prepare product N4-(4-tert-butoxycarbonylmethyleneoxypheny1)-2-chloro-5-fluoro-4-pyrimidineamine. 111 NMR

(CDC13): 8 8.02 (d, 1H, J= 2.7 Hz), 7.51 (d, 111, J= 8.7 Hz), 6.93 (d, 111, J=
8.7 Hz), 4.52 (s, 211)), 1.49 (s, 911); LCMS: ret. time: 29.50 min.; purity: 97%; MS (m/e): 354 (MO.
7.1.14 2-Chloro-5-fluoro-N4-(indo1-5-y1)-4-pyrimidineamine (R926581) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 5-aminoindole were reacted to prepare 2-chloro-5-fluoro-N4-(indo1-5-y1)-4-pyrimidineamine. 1H NMR (CDC13 +
CD30D): 8 9.45 (bs, 111), 8.00 (bs, 1H),7.82 (bd, 111), 7.75 (s, 111), 7.38-7.10 (m, 311), 6.40 (bs, 111); LCMS: ret. time: 23.85 min.; purity: 100%; MS (m/e): 263 (MH+).
7.1.15 2-Chloro-5-fluoro-N4-(4-methoxymethyl-coumarin-7-y1)-4-pyrimidineamine (R926618) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-methoxymethy1-aminocoumarin were reacted to prepare 2-chloro-5-fluoro-N4-(4-methoxymethyl-coumarin-7-y1)-4-pyrimidineamine. 1H NMR (CD30D): 8 8.05 (d, 111), 7.90 (s, 1H), 7.70 (dd, 1H, J=
2.4 and 8.7 Hz), 7.53 (d, 111, J= 8.7 Hz), 6.42 (s, 1H), 4.61 (s, 211), 3.49 (s, 311); LCMS: ret.
time: 26.38 min.; purity: 87%; MS (m/e): 336 (MH+).
7.1.16 2-Chloro-N4-(2,5-dimethy1-4-hydroxypheny1)-5-fluoro-4-pyrimidineamine (R926619) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 2,5-dimethy1-4-hydroxyaniline were reacted to prepare 2-chloro-N4-(2,5-dimethy1-4-hydroxypheny1)-5-fluoro-4-pyrimidineamine. LCMS: ret. time: 23.31 min.; purity: 96%; MS (m/e):

(MM.
7.1.17 2-Chloro-N4-(5-chloropyrid-2-y1)-5-fluoro-4-pyrimidineamine (R926061) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 5-chloro-2-aminopyridine were reacted to prepare 2-chloro-N4-(5-chloropyrid-2-y1)-5-fluoro-4-pyrimidineamine. 1H
NMR (CDC13): 8 8.40 (d, 111, J= 8.7 Hz), 8.28 (d, 111, J= 1.8 Hz), 8.17 (d, 1H, J= 2.1 and 9 Hz); LCMS: ret. time: 28.58 min.; purity: 100%; MS (m/e): 259 (M11+).
7.1.18 2-Chloro-5-fluoro-N4-(5-methylpyrid-2-y1))-4-pyrimidineamine (R926062) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 5-methyl-2-aminopyridine were reacted to prepare 2-chloro-5-fluoro-N4-(5-methylpyrid-2-y1)-5-4-pyrimidineamine.
1H NMR (CDC13): 8 9.20 (s, 1H), 8.51 (s, 111), 7.63 (d, 111, J= 5.7 Hz), 7.45 (dd, 1H, J= 1.8 and 9.3 Hz), 2.43 (s, 3H); LCMS: ret. time: 21.29 min.; purity: 97%; MS (m/e):
239 (MH+).
7.1.19 N446-(1,4-Benzoxaziny1)]-N2-chloro-5-fluoro-4-pyrimidineamine In like manner to 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-1,4-benzoxazine were reacted (in methanol or methanol:water) to yield N446-(1,4-benzoxazinyl)]-N2-chloro-5-fluoro-4-pyrimidineamine. 111NMR (DMSO-d6): 8 8.2 (d, 1H), 6.8 (m,111), 6.75 (m, 1E1), 6.60 (m,1H), 4.05 (m, 211), 3.2 (m, 2H); LCMS: ret. time: 20.8 min.; purity:
95 %; MS
(m/e): 295 (MM.
7.1.20 N2-Chloro-N4-(2,3-dihydrobenzofuran-5-y1)-5-fluoro-4-pyrimidinediamine In like manner to 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoroppirnidine and 5-amino-2,3-dihydrobenzofuran were reacted to yield N2-chloro-N4-(2,3-dihydrobenzofuran-5-y1)-5-fluoro-4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 8.09 (d, 1H), 8.00 (m, 1H), 7.42 (m, 211), 7.05 (m, 1H), 4.53 (m, 2H), 4.25 (s, 2H), 3.15 (m, 2H); LCMS: ret. time: 20.35 min.; purity: 90 %; MS (m/e): 266 (MO.
7.1.21 2-Chloro-N4-(2-carboxy-4-chloropheny1)-5-fluoro-4-pyrimidineamine (R940050) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrirnidineamine, 2,4-dichloro-5-fluoropyrimidine and 2-carboxy-4-chloroaniline were reacted to prepare 2-chloro-N4-(2-carboxy-4-chloropheny1)-5-fluoro-4-pyrimidineamine. LCMS: ret. time: 20.83 min.; purity: 98%; 1H NMR (CDC13): 8 8.64 (1H, d, J= 4.8 Hz), 8.24 (1H, d, J= 2.7 Hz), 7.76 (1H, dd, J= 8.7 and 2.7 Hz), 7.70 (1H, dd, J= 8.7 and J= 0.9 Hz).
7.1.22 N-(2-Chloro-5-fluoro-4-pyrimidiny1)-L-tyrosine Methyl Ester (R940108) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and L-tyro sine methyl ester were reacted to prepare N-(2-chloro-5-fluoro-4-pyrimidiny1)-L-tyrosine Methyl Ester.
LCMS: ret. time: 23.32 min.; purity: 83%; MS (mle): 325 (M+); 1H NMR (CDC13):
8 7.90 (1H, d, J= 2.7 Hz), 6.95 (2H, d, J= 8.1 Hz), 6.75 (2H, d, J= 8.7 Hz), 5.95 (1H, s), 5.72 (111, d, J= 7.5 Hz), 5.05 (1H, dt, J= 7.5 and 5.3 Hz), 3.77 (3H, s), 3.16 (2H, m).
7.1.23 2-Chloro-N443-(5-cyano-2-methy1-4-thiomethy1-6-pyrimidinyl)pheny1]-5-fluoro-4-pyrimidineamine (R940141) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-(5-cyano-2-methy1-4-thiomethy1-6-pyrimidinypaniline were reacted to prepare 2-chloro-N443-(5-cyano-methy1-4-thiomethy1-6-pyrimidinyl)pheny1]-5-fluoro-4-pyrimidineamine. LCMS:
ret. time:
18.23 min.; purity: 84%; MS (m/e): 386 (AO; 1H NMR (CDC13): 8 8.19 (1H, t, J=
1.9 Hz), 8.11 (1H, d, J= 3.1 Hz), 7.98 (111, dd, J= 8.1 and J= 2.4 Hz), 7.82 (1H, dd, J=7.8 and 1.8 Hz), 7.57 (1H, t, J= 7.8 Hz), 7.11 (1H, s), 2.79 (3H, s), 2.69 (3H, s).
7.1.24 N444-(N-Benzylpiperazino)pheny11-2-chloro-5-fluoro-4-pyrimidineamine (R945154) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 4-(N-benzylpiperazino)aniline and 2,4-dichloro-5-fluoropyrimidine gave N444-(N-benzylpiperazino)pheny1]-2-chloro-5-fluoro-4-pyrimidineamine. 1H NMR (CDC13): 8 2.81 (m, 4 H), 3.37 (m, 6 H), 6.85 (br, 1 H), 6.93 (d, J= 9.0 Hz, 2 H), 7.40 (m, 5 H), 7.50 (d, J= 9.3 Hz, 2 H), 8.02 (d, J= 2.7 Hz, 1 H); LCMS:
ret. time: 20.56 min, purity: 97.75%; MS (mile): 398.00 (MW).
7.1.25 2-Chloro-N4-(4-cyanomethyleneoxypheny1)-5-fluoro-4-pyrimidineamine (R945069) In a manner analogous to the preparation of N2,N4-bis(4-cyanomethyleneoxypheny1)-5-fluoro-2,4-pyrimidinediamine, N4-(4-aminocarbonyhnethyleneoxypheny1)-2-chloro-5-fluoro-4-pyrimidineamine (178 mg, 0.6 mmol), trifluoroacetic anhydride (0.17 mL, 1.2 mmol) and pyridine (0.15 mL, 1.84 mmol) gave 2-chloro-N4-(4-cyanomethyleneoxypheny1)-5-fluoro-4-pyrimidineamine (110 mg, 66%). 1H NMR (acetone-d6): 8 5.22 (s, 2 H), 7.24 (d, J= 9.3 Hz, 2 H), 7.62 (d, J= 9.0 Hz, 2 H), 8.94 (d, J= 1.8 Hz, 1 H); 19F NMR (acetone-d6): -137.60; LCMS: ret. time:
26.19 min.;
purity: 89.93%; MS (m/e): 279.06 (MH+).
7.1.26 N4-(4-Acetoxypheny1)-2-chloro-5-fluoro-4-pyrimidineamine (R940210) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-acetoxyaniline were reacted to prepare N4-(4-acetoxypheny1)-2-chloro-5-fluoro-4-pyrimidineamine.
LCMS: ret.
time: 25.97 min.; purity: 98%; MS (m/e): 281 (M+); 1H NMR (CDC13): 8 8.07 (1H, d, J= 2.7 Hz), 7.64 (2H, d, J= 9 Hz), 7.12 (211, d, J= 9 Hz), 7.00 (1H, s), 2.31 (3H, s).
7.1.27 2-Chloro-5-fluoro-N4-(4-hydroxypheny1)-4-pyrimidineamine (R940211) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-hydroxyaniline were reacted to prepare 2-chloro-5-fluoro-N4-(4-hydroxypheny1)-4-pyrimidineamine.
LCMS:
ret. time: 20.10 min.; purity: 98%; MS (m/e): 240 (MH); 111 NMR (CDC13): 8 8.02 (111, d, J= 2.7 Hz), 7.46 (211, d, J= 8.7 Hz), 6.86 (2H, d, J= 9 Hz), 6.85 (111, s), 4.94 (111, s).

7.1.28 2-Chloro-N4-(2,3-dimethy1-4-hydroxypheny1)-5-fluoro-4-pyrimidineamine (R940213) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-primidineamine, 2,4-dichloro-5-fluoropyrimidine and 2,3-dimethy1-4-hydroxyaniline were reacted to prepare 2-chloro-N4-(2,3-dimethy1-4-hydroxypheny1)-5-fluoro-4-pyrimidineamine. LCMS: ret. time: 23.29 min.; purity: 93%; MS (m/e):

(M114); 1H NMR (CDC13): ö 8.00 (1H, d, J= 2.7 Hz), 7.16 (1H, d, J= 8.7 Hz), 6.68 (1H, d, J= 8.7 Hz), 6.61 (1H, s), 4.87 (1H, s), 2.21 (3H, s), 2.16 (3H, s).
7.1.29 2-Chloro-N4-(3-ehloro-4-hydroxy-5-methylpheny1)-5-fluoro-4-pyrimidineamine (R940230) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-hydroxy-5-methylaniline were reacted to prepare 2-chloro-N4-(3-chloro-4-hydroxy-5-methylpheny1)-5-fluoro-4-pyrimidineamine. LCMS: ret. time: 26.26 min.; purity: 90%; 111NMR
(DMS0-d6): 8 9.94 (111, s), 9.21 (1H, s), 8.37 (1H, d, 3.6 Hz), 7.68 (1H, s), 7.41 (1H, s), 2.30 (3H, s).
7.1.30 2-Chloro-5-fluoro-N44443-(N-morpholino)propylloxypheny1]-4-pyrimidineamine (R940247) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 413-(N-morpholino)propyl]oxyaniline were reacted to prepare 2-chloro-5-fluoro-N44443-(N-morpholino)propylioxypheny1]-4-pyrimidineamine. LCMS: ret. time: 17.15 min.;
purity:
99%; MS (m/e): 367 (MH+); 1H NMR (CDC13): 8 8.02 (1H, d, J= 2.7 Hz), 7.49 (2H, d, J=
8.7 Hz), 6.92 (2H, d, J= 9 Hz), 6.85 (1H, s), 4.03 (2H, t, J= 6.3 Hz), 3.73 (4H, t, J= 4.6 Hz), 2.53 (2H, t, J= 6.7 Hz), 2.47 (4H, m), 1.98 (2H, m).
7.1.31 N44244-(N-Senzylpiperazino)ethy111-2-chloro-5-fluoro-pyrimidineamine (R940259) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine 2,4-dichloro-5-fluoropyrimidine and 244-(N-benzylpiperazino)ethylamine were reacted to prepare N44244-(N-benzylpiperazino)ethyl]]-2-chloro-5-fluoro-4-pyrimidineamine. LCMS: ret. time: 21.11 min.; purity: 96%;
MS (m/e):
349 (M+); 1H NMR (CDC13): 8 7.88 (1H, d, J= 2.6 Hz), 7.31-7.17 (4H, m), 7.14 (1H, d, J=

1.7 Hz), 7.10 (111, s), 3.76 (2H, m), 3.24 (2H, m), 2.90 (211, m), 2.59 (21I, m), 2.34 (211, m), 1.76 (411, m).
7.1.32 N4-(3-tert-Butylpheny1)-2-chloro-5-fluoro-4-pyrimidineamine (R940268) In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-tert-butylaniline were reacted to prepare N4-(3-tert-butylpheny1)-2-chloro-5-fluoro-4-pyrimidineamine. LCMS:
ret. time: 33.96 mm.; purity: 98 %; MS (m/e): 279 (M+); 111NMR (CDC13): 8 8.05 (111, d, J= 3 Hz), 7.62 (1H, t, J= 1.3 Hz), 7.50 (111, m), 7.34 (111, t, J= 7.8 Hz), 7.22 (1H, m), 6.96 (1H, sl), 1.34 (91I, s).
7.1.33 2-Chloro-5-fluoro-N443-(hydroxymethyl)pheny11-4-pyrimidineamine (R925756) In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-aminobenzylalcohol were reacted to yield 2-chloro-5-fluoro-N443-(hydroxyrnethyl)phenyl]-4-pyrimidineamine. 1H
NMR (CDC13): 8 8.45 (bs, 1H), 7.96 (d, 1H, 31= 2.9 Hz), 7.65 (d, 111, J= 8.2 Hz), 7.34 (s, 111), 7.31 (t,1H, J= 8.2 Hz), 7.07 (d, 111, J= 8.2), 4.52 (s, 2H) ); 19F NMR
(CDC13): -44394 (s, 1F); LCMS: ret. time: 20.29 min.; purity: 100 %; MS (mile): 254 (We).
7.1.34 2-Chloro-5-fluoro-N444-(hydroxymethyl)pheny1]-4-pyrimidineamine (R925759) In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-aminobenzylalcohol were reacted to yield 2-chloro-5-fluoro-N444-(hydroxymethyl)pheny1]-4-pyrimidineamine. 1H
NMR (CDC13): 8 8.08 (d, 1H, J= 2.7 Hz), 7.62 (d, 2H, J= 9.0 Hz), 7.40 (d, 2H, J= 8.1 Hz), 6.99 (bs, 111), 4.70 (s, 211); 19F NMR (CDC13): -44570 (s, 1F); LCMS: ret.
time: 19.57 min.;
purity: 99%; MS (m/e): 254 (ME).
7.1.35 2-Chloro-N4-(3,3-dihydroisobenzofuranyn1-1-one-6-y1)-5-fluoro-4-pyrimidineamine R940279 In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-3,3-dihydroisobenzofuran-l-one were reacted to give 2-chloro-N4-(3,3-dihydroisobenzofaranyn1-1-one-6-y1)-5-fluoro-4-pyrimidineamine. LCMS: ret.
time: 21.15 min.; purity: 94.7 %; MS (m/e): 280 (MH4).
7.1.36 2-Chloro-5-fluoro-N4-02R)-hydroxy-(1S)-methy1-2-phenylethyl)-4-pyrimidineamine (R925762) In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and (1R,2S)-(-)-norephedrine were reacted to yield 2-chloro-5-fluoro-N4-(2R-hydroxy-1S-methy1-2-phenylethyl)-4-pyrimidineamine. 1H NMR (CDC13): 8 7.85 (d, 1H, J= 3.0 Hz), 7.38 (m, 5H), 5.56 (d, 111, J= 7.5 Hz), 5.00 (d, 1H, J= 3.0 Hz), 4.54 (m, 1H), 2.87 (bs, 1H), 1.10 (d, 1H, J= 6.9 Hz); 19F
NMR (CDC13): - 44408.
7.1.37 N-(2-Chloro-6-ethoxyearbony1-5-nitro-4-pyrimidinyl)glycine Ethyl Ester (1R925850) In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-6-ethoxycarbony1-5-nitropyrimidine and glycine ethyl ester hydrochloride salt were reacted to yield N-(2-chloro-6-ethoxycarbony1-5-nitro-4-pyrimidinyl)glycine Ethyl Ester. 1H NMR (CDC13): 8 8.87 (bs, 1H), 4.48 (q, 2H, J= 7.2 Hz), 4.39 (d, 2H, J= 5.1 Hz), 1.40 (t, 3H, J= 6.9 Hz), 1.33 (t, 3H, J= 7.2 Hz); LCMS: ret.
time: 28.27 min.; purity: 97%; MS (m/e): 332 (M+).
7.1.38 2-Chloro-5-fluoro-N4-(2-hydroxy-2-phenylethyl)-4-pyrimidineamine (R925763) In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 2-amino-l-phenylethanol were reacted to yield 2-chloro-5-fluoro-N4-(2-hydroxy-2-phenylethyl)-4-pyrimidineamine.
1H NMR (CDC13): 6 7.88 (d, 1H, J= 3.0 Hz), 7.41-7.32 (m, 5H), 5.71 (bs, 1H), 4.97 (d, 1H, J= 8.1 Hz), 3.98 (m, 1H), 3.56 (m, 1H), 2.57 (s, 1H); 19F NMR (CDC13): -45149; LCMS:
ret. time: 22.27 min.; purity: 98%; MS (m/e): 263 (M4).
7.1.39 2-Chloro-5-fluoro-N4-(furfury1)-4-pyrimidineamine (R925764) In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and furfurylamine were reacted to yield 2-chloro-5-fluoro-N4-(furfury1)-4-pyrimidineamine.
1H NMR (CDC13): ö 7.91 (d, 1H, J= 1.8 Hz), 7.39 (d, 1H, J= 1.2 Hz), 6.35 (m, 213), 5.50 (bs, 1H), 4.69 (d, 2H, J= 5.1 Hz); 19F NMR (CDC13): - 45163; LCMS: ret. time:
24.52 min.;
purity: 97%; MS (nlie): 228 (M+).
7.1.40 R935010: ( )-2-Chloro-5-fluoro-N4-[1-(4-hydroxyphenyl)ethy11-4-pyrimidineamine In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-primidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 1-(4-hydroxyphenyl)ethylamine to provide ( )-2-chloro-5-fluoro-N441-(4-hydroxyphenypethy1]-4-pyrimidineamine. 111 NMR (CDC13): 8 7.88 (d,111, J= 2.3 Hz), 7.50-7.47 (dd, 2H, J= 1.7 and 8.7 Hz), 7.26-7.23 (dd, J= 8.7 and 1.7 Hz), 5.35-5.28 (m, 2H), 1.59 (d, 311, J= 7.0 Hz).
7.1.41 R935011: ( )-N441-(4-Bromophenyl)ethyl]-2-chloro-5-fluoro-4-pyrimidineamine In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 1-(4-bromophenyl)ethylamine to provide ( )-N441-(4-bromophenypethy1]-2-chloro-5-fluoro- 4-pyrimidineamine:1H NMR (CDC13): 8 7.88 (d, 1H, J= 2.3 Hz), 7.49 (d, 2H, J= 8.7 Hz), 7.25 (d, 2H, J= 8.7 Hz), 4.45-5.26 (m, 2H), 1.59 (d, 3H, J=7.0 Hz).
7.1.42 R935007: 2-chloro-5-fluoro-N441-[(15)-phenyllethy1]-4-pyrimidineamine In like manner to the preparation of of 2-chloro-N4-(3,4-ethylenedioxypheny1)-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 1-(1S)-phenyl ethylamine were reacted to produce 2-chloro-5-fluoro-N441-[(1S)-phenyl]ethy11-4-pyrimidineamine.
111NMR (CDC13): 8 7.86 (d, 1H, J = 2.9 Hz), 7.37 (d, 411, J = 4.7 Hz), 7.34-7.30 (m, 1H), 5.40-5.32 (m, 211), 1.62 (d, 311, J = 6.4 Hz); LCMS: ret. time: 29.5 mm.;
purity: 98%; MS
(m/ e): 252 (MM.
7.1.43 11935008: 2-Chloro-5-fluoro-N4-[1-[(1R)-pheny]lethyll-4-pyrimidineamine In like manner to the preparation of of 2-chloro-N4-(3,4-ethylenedioxypheny1)-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 1-(/R)-phenyl ethylamine were reacted to produce 2-chloro-5-fluoro-N441-MR)-phenyllethyl]-4-pyrimidineamine.
1H NMR (CDC13): 8 7.87 (d, 111, J = 2.9 Hz), 7.37 (d, 4H, J = 4.1 Hz), 7.34-7.30 (m, 111), 5.38-5.31 (m, 2H), 1.62 (d, 3H, J = 6.4 Hz).
7.1.44 R935012: 2-Chloro-N4-[[di(3,5-di(trifluoromethyl)phenyl)]methyl]-5-fluoro-4-pyrimidineamine In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with di[3,5-di(trifluoromethyl)phenyl]methylamine to provide 2-chloro-N4-[[di(3,5-di(trifluoromethyl)phenyl)]methyl]-5-fluoro-4-pyrimidineamine. 1H NMR (CDC13):
8 8.06 (d, 111, J= 2.3 Hz), 7.92 (s, 2H), 7.74 (s, 4H), 6.75 (d, 1H, J= 7.6 Hz), 5.80 (d, 111, J= 7.0 Hz).
7.1.45 R935014: 2-Chloro-5-fluoro-N441-[(1R)-4-methoxyphenyl]ethyll-4-pyrimidineamine In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-primidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with (R)-(+)-1-(4-methoxyphenyl)ethylamine to provide 2-chloro-5-fluoro-N4-[1-[(1R)-4-methoxyphenyl]ethy1]-4-pyrimidineamine. 1H NMR (CDC13): 67.84 (d, 111, J= 2.3 Hz), 7.30 (d, 2H, J= 8.8 Hz), 6.89 (d, 211, J= 8.8 Hz), 5.39-5.26 (m, 2H), 3.80 (s, 311), 1.59 (d, 3H, J= 6.4 Hz).
7.1.46 R935015: 2-Chloro-5-fluoro-N4-[1-[(15)-4-methoxyphenyflethy1]-4-pyrimidineamine In like manner to the preparation of 2-chloro-5-fluoro-N4-(3,4-ethylenedioxypheny1)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with (S)-(-)-1-(4-methoxyphenyl)ethylamMe to provide 2-chloro-5-fluoro-N441-[(1S)-4-methoxyphenyl]ethyl]-4-pyrimidineamine. 1H NMR (CDC13): 8 7.85 (d, 111, J= 2.3 Hz), 7.31 (d, 2H, J= 8.8 Hz), 6.89 (d, 211, J= 8.8 Hz), 5.38-5.29 (m, 2H), 3.80 (s, 3H), 1.59 (d, 311, J= 7.7 Hz).
7.1.47 R935013: 2-Chloro-N-(fluoren-9-y1)-5-fluoro-4-pyrimidineamine In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro 4-pyrimidineamine, 9-aminofluorene hydrochloride and 2,4-dichloro-5-fluoropyrimidine with added diisopropylethylamine were reacted to produce 2-chloro-N-(fluoren-9-y1)-5-fluoro-4-pyrimidineamine. 1H NMR (CDC13): 8 7.97 (d, 111, J= 2.3 Hz), 7.73 (d, 2H, J= 7.6 Hz), 7.59(d, 2H, J= 7.6 Hz), 7.44 (t, 2H, J= 7.6 Hz), 7.32 ( app t, 2H, J= 7.6 Hz), 6.50 (d, 1H, J= 8.8 Hz), 5.45 (d, 1H, J= 8.4 Hz).
7.1.48 R935210: 2-Chloro-5-fluoro-N41-(methoxycarbonyl)methyl-indazoline-6-y11-4-pyrimidineamine In like manner to the prepartation of 2-chloro-N-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, experiment, 2,4-dichloro-5-fluoropyrimidine was reacted with 4-(methoxycarbonylmethyleneoxy)aniline to produce 2-chloro-5-fluoro-N44-(methoxycarbonylmethyleneoxy)pheny1]-4-pyrimidineamine. 1H NMR (DMSO-d6):
8 10.17 (s, 1H), 8.33 (d, 111, J= 3.5 Hz), 8.05 (s, 1H), 7.91 (s, 1H), 7.74 (d, 1H, J= 8.2 Hz), 7.40 (d, 1H, J= 7.6 Hz), 5.31 (s, 2H), 3.66 (s, 3H).
7.1.49 R935200: 2-Chloro-5-fluoro-N-(1-methyl-indazoline-5-y1)-4-pyrimidineamine:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 5-amino-l-methyl-indazoline were reacted to provide 2-chloro-5-fluoro-N-(1-methyl-indazoline-5-y1)-4-pyrimidineamine. 11-1NMR (DMSO-d6): 8 10.01 (s, 1H), 8.27 (d, 1H, J= 3.5 Hz), 8.04 (d, 1H, J= 1.7 Hz), 7.98 (d, 1H, J= 1.7 Hz), 7.64 (d, 1H, J= 8.8 Hz), 7.56 (dd, 1H, J= 1.7 and 8.8 Hz), 4.02 (s, 3H). LCMS: ret. time: 21.72 min.; purity: 99%; MS (m/e): 278 (MH+).
7.1.50 11935017: N-(5-Bromo-2-chloropyrimidiny1)-4-fluorophenylethylamine In like manner to the preparation of 2-chloro-N4-(3,4-ethy1enedioxypheny1)-5-fluoro 4-pyrimidineamine, 4-fluoro-a-methylbenzylamine and 5-bromo-2,4-dichloropyrimidine were reacted to produce N-(5-bromo-2-chloropyrimidiny1)-4-fluorophenylethylamine. 1H
NMR (CDC13): 8 8.12 (s, 111), 7.35-7.25 (dd, 211, J= 3.5 and 8.7 Hz), 7.05 (t, 111, J= 8.7 Hz), 5.63 (d, 111, J= 6.4 Hz), 5.36 (dq, 111, 111, J= 6.4 and 7.0 Hz), 1.60 (d, 3H, J= 7.0 Hz);
LCMS: ret. time: 30.73 min.; purity: 94%; MS (m/e): 331 (MO.

7.1.51 R935009: ( )-N-(2-Chloro-5-fluoropyrimidiny1)-1-(4-fluorophenyl)ethylamine In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro 4-pyrimidineamine, 4-fluoro-a-methylbenzylamine and 2,4-dichloro-5-fluoropyrimidine were reacted to produce (+)-N-(2-chloro-5-fluoropyrimidiny1)-1-(4-fluorophenypethylamine. 1H NMR (CDC13): 8 7.87 (d, 1H, J= 2.3 Hz), 7.37-7.33 (dd, 211, J= 5.4 and 8.4 Hz), 7.04 (t, 2H, J= 8.4 Hz), 5.35-5.31 (m, 211), 1.60 (d, 311, J= 6.4 Hz);
LCMS: ret. time: 32.90 min.; purity: 98%; MS (m/e): 270 (M11 ).
7.1.52 R935022: 5-Bromo-2-chloro-N4-[4-(N-methy1-2-methoxycarbonyl)ypyrroly1)-4-pyrimidineamine In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro 4-pyrimidineamine, 5-bromo-2,4-dichloropyrimidine and N-methy1-2-carbomethoxy-4-aminopyrrole hydrochloride with added diisopropylethylamine were reacted to produce the desired product 5-bromo-2-chloro-N-(N-methy1-2-carbomethoxypyrrol-4-y1)-4-pyrimidineamine. 1H NMR (CDC13): 8 8.21 (s, 1H), 7.43 (d, 111, J= 1.8 Hz), 7.13 (br s, 1}1), 6.84 (d,111, J= 1.8 Hz), 3.95 (s, 311), 3.82 (s, 311); LCMS:
ret. time: 26.96 min.; purity: 91%; MS (m/e): 346 (MH+).
7.1.53 R935234: 2-Chloro-5-fluoro-N444-(3-pheny1-1,2,4-oxadiazol-5-yl)methyleneoxypheny11-4-pyrimidineamine In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 544-aminophenoxymethyl)-3-pheny1-1,2-4-oxadiazole were reacted to produce 2-chloro-fluoro-N444-(3-pheny1-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine. 1H
NMR (DMSO-d6): 8 9.92 (s, 111), 8.26 (d, 111, J= 3.5 Hz), 8.02-7.99 (m, 211), 7.60-7.56 (m, 5H), 7.11 (d, 211, J= 8.8 Hz), 5.58 (s, 211); LCMS: ret. time: 32.09 min.;
purity: 96%; MS
(m/e): 398 (MH4).
7.1.54 R935235: 2-Chloro-5-fluoro-N444-(3-methy1-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 544-aminophenoxymethyl)-3-methy1-1,2-4-oxadiazole were reacted to produce 2-chloro-fluoro-N444-(3-methy1-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-4-pyrimidineamine. 1H

NMR (DMSO-d6): 8 9.91 (s, 1H), 8.26 (d, 111, J= 3.5 Hz), 7.56 (d, 2H, J.= 8.8 Hz), 7.05 (d, 2H, J= 8.8 Hz), 5.46 (s, 2H), 2.34 (s, 3H); LCMS: ret. time: 25.05 min.;
purity: 98%; MS
(m/e): 336 (iI\41H1).
7.1.55 R935236: 2-Chloro-5-fluoro-N444-[(1-ethoxycarbony1-1-methyl)ethyl]pheny11-4-pyrimidineamine In like manner to the preparation of 2-chloro-N4-(3,4-ethyleneioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 441-ethoxycarbony1-1-methypethyl]aniline were reacted to produce 2-chloro-5-fluoro-N444-[(1-ethoxycarbony1-1-methybethyl]phenyl]-4-pyrimidineamine. 1H NMR (DMSO-d6): 8 9.99 (s, 111), 8.30 (d, 1H, j= 3.5 Hz), 7.60 (d, 211, J= 8.8 Hz), 7.30 (d, 211, J= 8.8 Hz), 4.04 (qt, 211, J= 7.0 Hz), 1.47 (s, 6H), 1.10 (t, 3H, J= 7.0 Hz); LCMS: ret. time: 31.07 min.; purity:
97%; MS (m/e):
338 (.MIH).
7.1.56 2,4-Dichloro-5-ethoxycarbonylpyrimidine A dry reaction flask equipped with a stirring bar and a reflux condenser was charged with 5-ethoxycarbonyluracil (1.84g, 10 mmol), POC13 (10 mL) and N,N-dimethylaniline (1 mL) and heated at 90 C for 2h. The excess POC13 was removed under a reduced pressure and quenched with ice-water (100 g). The aqueous solution was extracted with ethyl ether (3 x 100 mL), washed with saturated aqueous NaHCO3 solution and water (100 mL, each).
After drying over sodium sulfate, the ethyl ether was removed and the residue was dried under a high vacuum to afford 2,4-dichloro-5-ethoxycarbonylpyrimidine.1H NMR
(CDC13):
8 9.00 (s, 111), 4.45 (q, 211, J= 6.9 Hz), 1.42 (t, 311, J= 6.9 Hz).
7.1.57 N-(2-Chloro-5-ethoxycarbony1-4-pyrimidiny1)-L-phenylalanine Ethyl Ester (R926518) and N-(4-Chloro-5-ethoxycarbony1-2-pyrimidiny1)-L-phenylalanine Ethyl Ester (R926519) A mixture of L-phenylalanine Ethyl Ester Hydrochloride (0.137g, 0.6 mmol) 2,4-dichloro5-ethoxycarbonylpyrimidine (0.112g, 0.5 mmol), triethylamine (0.7 mL, 0.6 mmol) in THF (4 mL) in a sealed tube was heated at 100 C for 3h. The reaction was diluted with H20 (20 ML), extracted with CH2C12 (3 x 50 mL), washed with 2N HC1 (10 mL), water (10 mL) and solvent was evaporated. The residue obtained was purified by preparative TLC
using 15% EtOAc in hexanes to obtain two products mainly, N-(2-chloro-5-ethoxycarbony1-4-pyrimidiny1)-L-phenylalanine Ethyl Ester (R926518). 1H NMR (CDC13): 8 8.72 (d, 111, J= 6.92 Hz), 8.66 (s, 111), 7.32-7.17 (m, 5H), 5.05 (dq, 1H, J= 1.2 and 5.7 Hz), 4.34 (q, 2H, J= 6.9 Hz), 4.20 (q, 2H, J= 5.1 Hz), 3.24 (dd, 1H, J= 5.4 Hz), 3.16 (dd, 1H, J= 7.5 Hz), 1.35 (t, 3H, J= 7.2 Hz), 1.24 (t, 3H, J= 7.2 Hz); LCMS: ret. time: 37.15 min.;
purity: 99%; MS
(m/e): 378 (MH+) and N-(4-chloro-5-ethoxycarbony1-2-pyrimidiny1)-L-phenylalanine Ethyl Ester (R926519). 11-1NMR (CDC13): 5 8.83 (s, 111), 7.28 (m, 3H), 7.18 (m, 211), 6.00 (bt, 1H), 4.99 (bdq, 111), 4.36 (q, 2H, J= 7.8 Hz), 4.19 (q, 2H, J= 6.9 Hz), 3.20 (t, 2H, J= 6.9 Hz). 1.38 (t, 3H, J= 4.5 Hz), 1.24 (t, 3H, J= 6 Hz); LCMS: ret. time: 34.80 min.; purity:
88%; MS (mile): 378 (M+).
7.1.58 N-(2-Chloro-5-ethoxycarbony1-4-pyrimidiny1)-L-valine Ethyl Ester (R926520) and N-(4-Chloro-5-ethoxycarbony1-2-pyrimidiny1)-L-valine Ethyl Ester (R926521) In like manner to the preparation of N-(2-chloro-5-ethoxycarbony1-4-pyrimidiny1)-L-phenylalanine Ethyl Ester, 2,4-dichloro-5-ethoxycarbonylprimidine and L-valine Ethyl Ester were reacted to prepare N-(2-chloro-5-ethoxycarbony1-4-pyrimidiny1)-L-valine Ethyl Ester (R926520). 1H NMR (CDC13): 8 8.80 (d, 111, J= 8.1 Hz), 8.68 (s, 1H), 4.77 (dd, 111, J= 4.8 Hz), 4.36 (q, 2H, J= 7.2 Hz), 4.24 (q, 211, J= 6.6 Hz), 2.38 (m, 111), 1.39 (t, 3H, J=
6.9 Hz), ,1.29 (t, 311, J= 7.2 Hz), 1.03 (d, 311, J= 3 Hz), 1.00 (d, 311, J=
2.7 Hz); LCMS: ret.
time: 36.54 min.; purity: 89%; MS (m/e): 330 (Mill) and N-(4-chloro-5-ethoxycarbony1-2-pyrimidiny1)-L-valine Ethyl Ester (R926521). 1H NMR (CDC13): 8 8.82 (s, 111), 6.02 (m, 111), 4.69 (dd, 111, J= 4.8 and 4.5 Hz), 4.33 (q, 2H, J= 7.5 Hz), 4.23 (q, 211, J= 7.5 Hz), 2.28 (sept, 111). 1.34 (t, 311, J= 6.9 Hz), 1.28 (t, 311, J= 7 Hz), 1.00 (d, 6H, J=
7.2 Hz); LCMS:
ret. time: 33.53 min.; purity: 91%; MS (m/e): 330 (M).
7.1.59 N-(2-Chloro-5-ethoxyearbony1-4-pyrimidiny1)-L-leucine Ethyl Ester (R926522) In like manner to the preparation of N-(2-chloro-5-ethoxycarbony1-4-ppimidiny1)-L-phenylalanine Ethyl Ester, 2,4-dichloro-5-ethoxycarbonylpyrimidine and L-leucine Ethyl Ester were reacted to prepare N-(2-chloro-5-ethoxycarbony1-4-pyrimidiny1)-L-leucine Ethyl Ester. 1H NMR (CDC13): 5 8.69 (s, 111), 8.64 (d, 111, 7.8 Hz), 4.84 (s, 111), 4.38 (q, 211, J=
7.2 Hz), 3.75 (s, 311), 1.73 (m, 211), 1.39 (t, 311, J= 6.9 Hz), 0.97 (d, 3H, J= 4.2 Hz), 0.95 (d, 3H, J= 4.8 Hz) ; LCMS: ret. time: 36.09 min.; purity: 92%; MS (m/e): 330 (MH+).

7.1.60 N-(2-Chloro-5-ethoxyearbony1-4-pyrimidiny1)-L-alanine Ethyl Ester (R926523) and N-(4-Chloro-5-ethoxycarbony1-2-pyrimidiny1)-L-alanine Ethyl Ester (R926524) In like manner to the preparation of N-(2-chloro-ethoxycarbony1-4-pyrimidiny1)-L-phenylalanine Ethyl Ester, 2,4-dichloro-5-ethoxycarbonylpyrimidine and L-valine Ethyl Ester were reacted to prepare N-(2-chloro-5-ethoxycarbony1-4-pyrimidiny1)-L-alanine Ethyl Ester (R926523). 111 NMR (CDC13): 8 8.80 (bd, 111), 8.68 (s, 1H), 4.79 (q, 1H, J= 7.2 Hz), 4.35 (q, 211, J= 7.2 Hz), 4.24 (m, 2H), 1.53 (d, 3H, J= 7.2 Hz), 1.38 (t, 3H, J= 7.2 Hz), 1.29 (t, 311, J= 7.2 Hz); LCMS: ret. time: 31.89 min.; purity: 94%; MS (m/e): 303 (M11+) and N-(4-chloro-5-ethoxycarbony1-2-pyrimidiny1)-L-alanine Ethyl Ester (1R926524).

(CDC13): 6 8.80 (s, 1H), 6.01 (bs, 111), 4.65 (bq, 1H), 4.35 (q, 2H), 4.20 (q, 2H), 1.55, t, 311), 1.40 (t, 3H), 1.25 (t, 3H); LCMS: ret. time: 28.78 min.; purity: 84%; MS
(m/e): 302 (M).
7.1.61 2-Chloro-N4-(4-n-butyloxypheny1)-5-fluoro-4-pyrimidineamine To a solution of 2,4-dichloro-5-fluoropyrimidine (0.5 g, 3.0 mmol) and 4-n-butoxyaniline (0.49 g, 3 mmol) in acetone/H20 (1:9 mL) at room temperature was added concentrated HC1 (0.1 mL). The mixture was heated at rally( for 1 h, cooled to room temperature, and made basic with 2 N NaOH (2 mL). The aqueous layer was extracted with Et0Ac (2 x 50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude black solid was purified by chromatography (4:1 hexanes/Et0Ac) to afford 2-chloro-N4-(4-n-butyloxypheny1)-5-fluoro-4-pyrimidineamine (0.71 g, 80%) as a brown oil: 111 NMR (300 MHz, CDC13) 8 8.01 (d, J= 2.7 Hz, 1H), 7.51-7.46 (m, 211), 6.95-6.89 (m, 2H), 6.83 (bs, 111), 3.99-3.95 (t, J= 6.5 Hz, 211), 1.82-1.57 (m, 211), 1.53-1.43 (m, 211), 0.98 (t, J= 7.2 Hz, 311).
7.1.62 2-Chloro-N4-(4-n-hexyloxypheny1)-5-fluoro-4-pyridineamine In like manner to the preparartion of 2-chloro-N4-(4-n-butyloxypheny1)-5-fluoro-4-pyrimidineamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-n-hexyloxyaniline gave 2-chloro-N4-(4-n-hexyloxypheny1)-5-fluoro-4-pyridineamine. The crude product was purified by chromatography (4:1 CHC13/Et0Ac) to afford (14) (0.74 g, 76%) as a red-brown oil that solidified upon standing: 1H NMR (300 MHz, CDC13) 8 8.01 (d, J= 2.7 Hz, 111), 7.50 (d, J= 9.0 Hz, 2H), 6.92 (d, J= 9.0 Hz, 2H), 6.84 (bs, 1H), 3.96 (t, J=
6.5 Hz, 2H), 1.83-1.74 (m, 2H), 1.48-1.41 (m, 2H), 1.36-1.34 (m, 4H), 0.93-0.89 (m, 3H).
7.1.63 N4-(3-Benzyloxypheny1)-2-chloro-4-pyrimidineamine A mixture of 2,6-dichloropyrirnidine (2.00 g, 13.4 mmol), 3-benzyloxoaniline (2.07 g, 13.4 mmol) and triethylamine (2.72 g, 26.8 mmol) in 1-butanol (20 mL) was stirred at 50 C for 17 h. The reaction mixture was concentrated to remove most of the 1-butanol, the crude product was preadsorbed onto silica gel using chloroform and purified by flash chromatography (95:5 chloroform/ methanol) to afford N4-(3-benzyloxypheny1)-2-chloro-4-pyrimidineamine (1.70 g, 40%) as colorless oil: 1H NMR (300 MHz, DMSO-d6) 10.2 (s, 1H), 8.16 (d, J= 6.0 Hz, 111), 7.48-7.24 (m, 7H), 7.12 (d, J= 9.0 Hz, 111), 6.78 (m, 2H), 5.11 (s, 2H); ESI MS m/z 312 [C171-114C1N30 + Hr.
7.1.64 N4-[4-(tert-Butoxycarbonylmethyleneoxy)pheny11-3-chloro-5-ethoxycarbony1-4-pyrimidineamine (R926578) In like manner to the preparation of N-(2-chloro-5-ethoxycarbony1-4-pyrimidiny1)-L-phenylalanine Ethyl Ester, 5-carboxyethoxy-2,4-dichloropyrimidine and tert-butyl 4-aminophenoxyacetatewere reacted to prepare N444-(tert-butoxycarbonylmethyleneoxy)pheny1]-2-chloro-5-ethoxycarbony1-2-chloro-4-pyrimidineamine. LCMS: MS (m/e): 407 (MH+).
7.1.65 N4-(4-Ethoxypheny1)-5-ethoxycarbony1-2-trifluoromethyl-4-pyrimidineamine (R926059) In like manner to the preparation of N-(2-chloro-5-ethoxycarbony1-4-pyrimidiny1)-L-phenylalanine Ethyl Ester, 4-chloro-5-ethoxycarbony1-2-trifluoromethylpyrimidine and 4-ethoxyaniline were reacted to prepare N4-(4-ethoxypheny1)-5-ethoxycarbony1-2-trifluoromethy1-4-pyrimidineamine. 111 NMR (CDC13): 8 10.39 (s, 1H), 9.02 (s, 111), 7.59 (dd, 2H, J= 2.1 and 7.2 Hz), 6.91 (dd, 2H, J= 1.8 and 6.6 Hz), 4.44 (q, 2H, J=
7.5 Hz), 4.06 (q, 2H, J= 7.2 Hz), 1.44 (in, 6H); LCMS: ret. time: 38.49 mm.; purity: 100%;
MS (m/e):
356 (MH+).
7.1.66 N2-(4-Ethoxypheny1)-5-methoxycarbony1-4-trifluoromethyl-2-pyrimidineamine (R926060) In like manner to the preparation of N-(2-chloro-5-ethoxycarbony1-4-pyrimidiny1)-L-phenylalanine Ethyl Ester, 2-chloro-5-methoxycarbony1-4-trifluoromethylpyrimidine and 4-ethoxyaniline were reacted to prepare N2-(2-ethoxypheny1)-5-methoxycarbony1-trifluoromethy1-2-pyrimidineamine. 1H NMR (CDC13): 8 8.98 (s, 1H), 7.47 (m, 3H), 6.91 (dd, 2H, J= 2.1 and 6.9 Hz), 4.05 (q, 2H, 6.9 Hz), 1.42 (t, 3H, J= 6.8 Hz);

(CDC13): -19105; LCMS: ret. time: 33.87 min; purity: 100%; MS (m/e): 342 (MH).
7.1.67 2-Chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)pheny11-4-pyrimidineamine (R926853) A reaction mixture containing 2,4-dichloro-5-fluoro-pyrimindine (1.2 equivalents) and 3-(tetrazol-5-ypaniline (1 equivalents) in methanol:water (1:1; v/v) was heated at 60 C
for 24 h. Upon dilution with water and acidification, the solid formed was fitered, washed with water, dried and analyzed to give 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine (R926853). Alternatively this reaction can be achieved by treating 2,4-dichloro-5-fluoropyrimidine (1 equivalent) with 3-(tetrazol-5-ypaniline (3 equivalents) in methanol:water (1:1; v/v) at 60 oC for 2-3 hours or at room temperature for 24 h to give 2-chloro-5-fluoro-N413-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine. 1H NMR (DMS0-d6): 8 10.25 (s, 111), 8.43 (s, 1H), 8.37 (d, 1H, J= 3.6 Hz), 7.90 (dd, 1H, J=
0.9 and 9 Hz), 7.75 (d, 1H, J= 7.5 Hz), 7.61 (t, 1H, J= 7.8 Hz); LCMS: purity: 90%; MS (m/e):
292 (MH4).
7.1.68 2-Chloro-N4-(2,5-dimethoxy-4-chloropheny1)-5-fluoro-4-pyrimidineamine (R926858) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 2,5-dimethoxy-4-chloroaniline gave 2-chloro-N4-(2,5-dimethoxy-4-chloropheny1)-5-fluoro-4-pyrimidineamine. LCMS: purity: 97%; MS (rn/e): 316 (M-2H) and 320 (M+2H).
7.1.69 2-Chloro-5-fluoro-N4-(3-methoxycarbony1-5-trifluoromethylpheny1)-4-pyrimidineamine (14926861) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-methoxycarbony1-5-frifluoromethylaniline gave 2-chloro-5-fluoro-N4-(3-methoxycarbony1-5-trifluoromethylpheny1)-4-pyrimidineamine. 1H NMR (CD30D): 6 8.60 (s, 111), 8.43 (s, 1H), 8.20 (d, 111, J= 3 Hz), 7.99 (s, 1H), 3.96 (s, 3H); 19F NMR (CD30D): -18332, - 18374;
and - 44259; LCMS: purity: 91%; MS (rn/e): 350 (MO.

7.1.70 2-Chloro-5-fluoro-N443-(2-pheny1-1,3,4-oxadiazol-5-yl)pheny1)-4-pyrimidineamine (R926869) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-(2-phenyl-1,3,4-oxadiazol-5-ypaniline gave 2-chloro-5-fluoro-N443-(2-pheny1-1,3,4-oxadiazol-5-yl)pheny1)-4-pyrimidineamine. 1H NMR (DMSO-d6): 8 10.28 (s, 111), 8.62 (s, 111), 8.39 (d, 1H, J= 3.3 Hz), 8.11 (m, 2H), 7.98 (bd, 111, J= 6.9 Hz), 7.88 (bd, 1H, J= 8.4 Hz), 7.65 (m, 4H); LCMS: purity: 76%; MS (m/e): 76%.
7.1.71 2-Chloro-N4-[3-(2-ethoxyearbonylmethylene-1,3,4-oxadiazol-5-yl)pheny1)-5-fluoro-4-pyrimidineamine (R926873) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)aniline gave 2-chloro-N443-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)phenyll-5-fluoro-4-pyrimidineamine. 1H
NMR (CD30D): 8 8.42 (t, 111, J= 1.8 Hz), 8.19 (d, 111, J= 3.3 Hz), 7.99 (dt, 111, J= 1.2 and 8.1 Hz), 7.82 (dt, 1H, J= 1.2 and 8.1 Hz), 7.58 (t, 1H, J= 9 Hz), 4.24 (q, 2H, J= 3.9 Hz), 4.17 (s, 2H), 1.28 (t, 3H, J= 7.2 Hz); LCMS: purity: 85%; MS (m/e): 379 (MH+).
7.1.72 2-Chloro-5-fluoro-N4-(4-trifluoromethoxypheny1)-4-pyrimidineamine (R926875) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-frifluoromethoxyaniline gave 2-chloro-5-fluoro-N4-(4-trifluoromethoxypheny1)-4-pyrimidineamine. 1H NMR (CDC13): 8 8.11 (d, 111, J=2.1 Hz), 7.68 (dd, 2H, J=2.4 and 7.6 Hz), 7.26 (dd, 211, J= 3 and 8.7 Hz), 7.0 (bs, 1H); 19F NMR (CD30D): 8 ¨16517 and ¨
44523; LCMS: purity: 94%; MS (m/e): 308 (MH+).
7.1.73 2-Chloro-5-fluoro-N4-(4-trifluoromethylpheny1)-4-pyrimidineamine (R926876) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-trifluoromethylaniline gave 2-chloro-5-fluoro-N4-(4-trifluoromethylpheny1)-4-pyrimidineamine. 1H NMR (CDC13): 8 8.15 (d, 2.1 Hz), 7.80 (d, 2H, J= 7.1 Hz), 7.66 (d, 2H, J= 9 Hz), 7.10 (bs, 1H); 19F NMR (CDC13): -17682 and - 44362; LCMS:
purity: 91%
and MS (rn/z): 292 (MI1+).
7.1.74 2-Chloro-N4-(4-chloro-3-trifluoromethylpheny1)-5-fluoro-4-pyrimidineamine (R926877) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-primidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-chloro-3-trifluoromethylaniline gave 2-chloro-N4-(4-chloro-3-trifluoromethylpheny1)-5-fluoro-4-pyrimidineamine. 111 NMR (CDC13): 8 8.15 (d, 1H, J= 2.1 Hz), 7.96 (d, 111, J= 3 Hz), 7.91 (dd, 111, J= 2.7 Hz and 8.7 Hz), 7.53 (d, 111, J= 8.1 Hz), 7.06 (bs, 111); 19F NMR
(CDC13): - 17892 and - 44402; LCMS: purity: 93%; MS (m/e): 326 (M+).
7.1.75 2-Chloro-5-fluoro-N4-(6-methoxypyridin-3-y1)-4-pyrimidineamine (R926878) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-amino-6-methoxypyridine gave 2-chloro-5-fluoro-N4-(6-methoxypyridin-3-y1)-4-pyrimidineamine. 1H NMR (CD30D): 8 8.39 (d, 111, J= 3.0 Hz), 8.10 (d, 111, J=
3.6 Hz), 7.95 (dd, 111, J= 2.4 and 9 Hz), 8.30 (d, 111, J= 9 Hz), 3.91 (s, 311); 19F
NMR (CD30D): -44737; LCMS: purity: 97%; MS (m/e): 255 (M+).
7.1.76 2-Chloro-N4-(3,4-difluoropheny1)-5-fluoro-4-pyrimidineamine (R926882) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-difluoroaniline gave 2-chloro-N4-(3,4-difluoropheny1)-5-fluoro-4-pyrimidineamine. 1H
NMR (CDC13): 8 8.10 (d, 111, J= 2.1 Hz), 7.72 (m, 111), 7.22 (m, 211), 6.95 (bs, 111);
LCMS: purity: 93%; MS (m/e): 260 (Mt).
7.1.77 2-Ch1oro-N4-(3,4-Dich1oropheny1)-5-fluoro-4-pyrimidineamine (R926884) In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-y1)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-dichloroaniline gave 2-chloro-N4-(3,4-dichloropheny1)-5-fluoro-4-pyrimidineamine.
LCMS: purity: 95%; MS (m/e): 294 (M+ 211).

7.1.78 2-Chloro-5-fluoro-N4-(6-methylpyridin-2-y1)-4-pyrimidineamine (R926888) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 2-amino-6-methylpyridine gave 2-chloro-5-fluoro-N4-(6-methylpyridin-2-y1)-4-pyrimidineamine. 1H NMR (CDC13): 8 8.23 (s, 1H), 8.19 (s, 1H), 8.12 (d, 111, J= 3 Hz), 7.55 (bs, 1H), 7.69 (t, 111, J= 7.4 Hz), 9.35 (d, 1H, J= 7.5 Hz); 19F NMR
(CDC13): - 44073;
LCMS: purity: 96%; MS (m/e): 239 (MI).
7.1.79 2-Chloro-N4-(2,6-Dimethoxypyridin-3-y1)-5-fluoro-4-pyrimidineamine (R926889) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-amino-2.6-dimethoxypyridine gave 2-chloro-N4-(2,6-dimethoxypyridin-3-y1)-5-fluoro-4-pyrimidineamine. 1H NMR (CDC13): 8 8.57 (d, 111, J= 8.7 Hz), 8.02 (d, 111, J=
2.7 Hz), 6.
40 (d, 1H, J= 8.1 Hz), 4.03 (s, 3H), 3.98 (s, 311); 19F NMR (CDC13): - 44640;
LCMS: purity:
90%; MS (m/e): 285 (M+).
7.1.80 2-Chloro-N4-(6-chloropyridin-3-y1)-5-fluoro-4-pyrimidineamine (R920400) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-amino-6-chloropyridine gave 2-chloro-N4-(6-chloropyridin-3-y1)-5-fluoro-4-ppimidineamine. 1H NMR (CDC13): 8 8.53 (d, 111, J= 3 Hz), 8.25 (dd, 111, J= 3 and 9 Hz), 8.15 (d, 1H, J= 2.4 Hz), 7.39 (d, 111, J= 8.7 Hz), 7.00 (bs, 111); LCMS:
purity: 98%; MS
(in/e): 259 (MI).
7.1.81 2-Chloro-5-fluoro-N4-(4-methylpyridin-2-y1)-4-pyrimidineamine (R920401) In like mariner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrirnidine with 2-amino-4-methylpyridine gave 2-chloro-5-fluoro-N4-(4-methylpyridin-2-y1)-4-pyrimidineamine. 1H NMR (CDC13): 8 8.22 (s, 1H), 8.16 (d, 111, J= 8.4 Hz), 8.13 (d, 111, J=
2.4 Hz), 6.91 (d, 1H, J= 5.4 Hz), 2.42 (s, 3H); LCMS: purity: 87%; MS (m/e):
239 (MI-1).

7.1.82 2-Chloro-5-fluoro-N4-(3-trifluoromethoxypheny1)-4-pyrimidineamine (R920402) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)phenyl]-4-pyrirnidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-trifluoromethoxyaniline gave 2-chloro-5-fluoro-N4-(3-trifluoromethoxypheny1)-4-pyrimidineamine. 1H NMR (CDC13): 8 8.12 (d, 1H, J= 3 Hz), 7.68 (bs, 111), 7.53 (dd, 111, J= 1.2 and 8.4 Hz), 7.41 9t, 111, J= 8.1 Hz), 7.04 (bdt, 211); 19F NMR
(CDC13): -16430 and -44463; LCMS: purity: 89%; MS (m/e): 308 (MO.
7.1.83 2-Chloro-N4-(3,4-Difluoromethylenedioxypheny1)-5-fluoro-4-pyrimidineamine (R920403) In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-difluoromethylenedioxyaniline gave 2-chloro-N4-(3,4-difluoromethylenedioxypheny1)-5-fluoro-4-primidineamine. 111 NMR (CDC13): 8 8.09 (d,111, J= 3 Hz), 7.70 (d, 111, J= 2.4 Hz), 7.10 (dd, 1H, J= 2.4 and 8.7 Hz), 7.06 (t, 111, J= 8.1 Hz), 6.97 (bs, 111); 19F NMR
(CDC13): - 14175 and - 44562; LCMS: purity: 95%; MS (m/e): 304 (MH+).
7.1.84 2-Chloro-5-fluoro-N4-(quinolin-6-y1)-4-pyrimidineamine (R920409) In like manner to the preparation Of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 6-aminoquinoline gave 2-chloro-5-fluoro-N4-(quinolin-6-y1)-4-pyrimidineamine. 1H
NMR
(CDC13): 8 8.02 (dd, 111, J= 2.7 Hz), 8.00 (dd, 1H, J= 2.4 Hz), 7.73 (d, 1H, J= 9 Hz), 7.68 (dd, 111, J= 2.4 and 8.7 Hz), 7.28 (t, 111, J= 10.5 Hz), 6.42 (d, 111, J= 9.3 Hz); 19F NMR
(CDC13): - 44344; LCMS: purity: 91%; MS (m/e): 292 (M+).
7.1.85 2-Chloro-N4-(3-chloro-4-trifluoromethoxypheny1)-5-fluoro-4-pyrimidineamine In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-chloro-4-trifluoromethoxyaniline gave 2-chloro-N4-(3-chloro-4-trifluoromethoxypheny1)-5-fluoro-4-pyrimidineamine. 1H NMR (CDC13): 8 8.15 (d,111, J= 3.0 Hz), 7.86 (d, 1H, J= 2.1 Hz), 7.61 (dd, 1H, J= 2.1 and 8.7 Hz), 7.35 (dd, 1H, J= 1.2 and 8.7 Hz), 6.98 (bs, 111);
LCMS: purity: 97%; MS (m/e): 342 (M+2H).

7.1.86 2-Chloro-N4-(4-chloro-3-methoxypheny1)-5-fluoro-4-pyrimidineamine In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-chloro-3-methoxyaniline gave 2-chloro-N4-(4-chloro-3-methoxypheny1)-5-fluoro-4-aminopyrimidine. LCMS: purity: 88%; MS (m/e): 288 (MO.
7.1.87 2-Chloro-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-y1]-4-pyrimidinediamine In like manner to the preparation of 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 5-amino-2-(2-hydroxyethyloxy)pyridine gave 2-chloro-5-fluoro-N412-(2-hydroxyethyleneoxy)pyridin-5-y1]-4-pyrimidinediamine. 111 NMR (CDC13): 68.28 (d, 1H, J= 2.4 Hz), 8.08 (m, 1H), 7.99 (m, 111), 7.00 (bs, 1H), 6.87 (bd, 1H), 4.47 (m, 2H), 3.97 (m, 2H).
7.1.88 2-Chloro-N4-12-(2-chloro-5-fluoropyrimidin-4-y1)-1,2,3,4-tetrahydroisoquinolin-7-y11-5-fluoro-4-pyrimidineamine (R926910) In a like marmer to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-1,2,3,4-tetrahydroisoquinoline were reacted to provide 2-chloro-N442-(2-chloro-5-fluoropyrimidin-4-y1)-1,2,3,4-tetrahydroisoquinolin-7-y1]-5-fluoro-4-pyrimidineamine.1H NMR
(CDC13): 8 8.08 (d, 111, J= 3.0 Hz), 7.95 (d, 1H, J= 6.0 Hz), 7.50-7.42 (m, 2H), 7.21 (d, 1H, J= 8.4 Hz), 6.96-6.90 (m, 1H), 4.95 (s, 2H), 4.04 (t, 2H, J= 5.7 Hz), 2.99 (t, 2H, J= 5.7 Hz); 19F NMR
(282 MHz, CDC13): -42555, -44573; LCMS: purity: 98%; MS (m/e): 410(MH+).
7.1.89 2-Chloro-5-fluoro-N442-(t-butoxycarbony1)-1,2,3,4-tetrahydroisoquinolin-7-y11-4-pyrimidineamine (R926911) In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidinearnine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-2-(t-butoxycarbony1)-1,2,3,4-tetrahydroisoquinoline were reacted to provide 2-chloro-5-fluoro-N442-(t-butoxycarbony1)-1,2,3,4-tetrahydroisoquinolin-7-y1]-4-pyrimidineamine.

1H NMR (CDC13): 68.03 (s, 111), 7.50-7.26 (m, 211), 7.19-7.11 (m, 2H), 4.57 (s, 211), 3.64 (t, 2H, J= 5.7 Hz), 2.80 (t, 211, J= 5.7 Hz), 1.48 (s, 911); LCMS:
purity: 89%; MS
(m/e): 379(M4).
7.1.90 2-Chloro-5-fluoro-N4-(1,2,3,4-tetrahydroisoquinolin-7-y1)-4-pyrimidineamine (R926912) A solution of 2-chloro-5-fluoro-N442-(t-butoxycarbony1)-1,2,3,4-tetrahydroisoquinolin-7-y1]-4-pyrimidineamine in 40% trifiuoroacetic acid/dichloromethane was stirred at rt for 30 min. Removal of the solvent left an oily residue which was suspended in water, made basic with NaHCO3, and extracted with ethyl acetate.
Purification by column chromatography over silica gel provided 2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydroisoquinolin-7-y1)-4-pyrimidineamine. 1H NMR (CDC13): 8 8.04 (d, 1H, J= 3.0 Hz), 7.37 (dd, 1H, J= 2.4 and 8.4 Hz), 7.27 (d, 1H, J= 1.5 Hz), 7.11 (d, 111, J= 8.4 Hz), 6.92 (s, 1H), 4.04 (s, 2H), 3.15 (t, 211, J= 6.0 Hz), 2.79 (t, 2H, J= 6.0 Hz); 19F NMR
(282 MHz, CDC13): -44648; LCMS: purity: 97%; MS (m/e): 279(MH+).
7.1.91 2-Chloro-5-fluoro-N4-(4-methy1-3-trifluoromethylphenyl)-4-pyrimidineamine (R926920) In a like marmer to the preparation of 2-chloro-N4-(3,4-ethy1enedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-methy1-3-trifluoromethylaniline were reacted to provide 2-chloro-5-fluoro-N4-(4-methy1-trifluoromethylpheny1)-4-pyrimidineamine. 1H NMR (CDC13): 8 8.10 (d, 111, J=
3.0 Hz), 7.85-7.78 (m, 2H), 7.33 (d, 111, J= 9.3 Hz), 6.96 (bs, 1H), 2.48 (d, 311, J=
1.2 Hz); 19F NMR
(282 MHz, CDC13): -17641, -44541; LCMS: purity: 97%; MS (mile): 306(MH+).
7.1.92 2-Chloro-5-fluoro-N4-(4-fluoro-3-methylpheny1)-4-pyrimidineamine (R926921) In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-fluoro-3-methylaniline were reacted to provide 2-chloro-5-fluoro-N4-(4-fluoro-3-methylpheny1)-4-pyrimidineamine. 1H NMR (CDC13): 6.8.06.(d, 1H, J= 2.4 Hz), 7.48-7.43 (m, 113), 7.39 (dd, 1H, J= 2.7 and 6.3 Hz), 7.03 (t, 111, J= 9.0 Hz), 6.84 (bs, 111), 2.30 (d, 1H, J= 1.8 Hz); 19F
NMR (282 MHz, CDC13): -34285, -44676; LCMS: purity: 95%; MS (mile): 257(MH4).

7.1.93 N443-[(N-t-butoxycarbonyl)aminomethy1]-4-methylpheny11-2-chloro-5-fluoro-4-pyrimidineamine (R926924) In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-[(N-t-butoxycarbonyl)aminomethy1]-4-methylaniline were reacted to provide N443-[(N-t-butoxycarbonyl)aminomethyl]-4-methylpheny1]-2-chloro-5-fluoro-4-pyrimidineamine.
1H NMR (CDC13): 5 8.05 (d, 1H, J= 3.0 Hz), 7.52 (d, 1H, J= 9.3 Hz), 7.45 (s, 1H), 7.19 (d, 1H, J= 8.1 Hz), 6.96-6.89 (m, 1H), 4.80 (bs, 1H), 2.31 (s, 2H), 1.46 (s, 9H);
LCMS: purity:
97%; MS (m/e): 311 (M ¨ (t-butyl) +).
7.1.94 2-Chloro-N4[34[4-(ethoxycarbonyl)piperidino]
methyl]pheny11-5-fluoro-4-pyrimidineamine In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and ethyl 1-(3-aminobenzyl)piperidine-4-carboxylate were reacted to provide 2-chloro-N4434[4-(ethoxycarbonyl)piperidinoimethyl]phenyl]-5-fluoro-4-pyrimidineamine. LCMS:
purity:
97%; MS (m/e): 394(MH+).
7.1.95 2-Chloro-N4[344-(ethoxycarbonyl)piperidino carbonyllpheny11-5-fluoro-4-pyrimidineamine In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 34[4-(ethoxycarbonyl)piperidinoicarbonyl]aniline were reacted to provide 2-chloro-N4434[4-(ethoxycarbonyl)piperidino]carbonyliphenyl]-5-fluoro-4-pyrimidineamine. LCMS:
purity:
96%; MS (m/e): 407(M).
7.1.96 2-Chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-y1)-4-pyrimidineamine In a manner similar to the preparation of N4-(3,4-ethylenedioxy)-5-fluoro-N242-(hydroxymethyl)benzofuran-5-y1]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-y1)-4-pyrimidineamine was reduced with Dibal-H to yield 2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-y1)-4-pyrimidineamine.

1H NMR (CDC13): 6 8.05 (d, 1H, J= 3.0 Hz), 7.59 (d, 111, J= 2.4 Hz), 7.14 (d, 1H, J= 8.1 Hz), 6.93 (bs, 1H), 4.82-4.78 (m, 1H), 2.82-2.71 (m, 2H), 2.08-1.74 (m, 5H) ;

(282 MHz, CDC13): -44661; LCMS: purity: 94%; MS (m/e): 294(MH).
7.1.97 2-Chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-y0-4-pyrimidineamine.
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-l-tetralone were reacted to provide 2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-y1)-4-pyrimidineamine. 1H NMR (DMSO-d6): 610.08 (s, 1H), 8.31 (d, 1H, J= 3.3 Hz), 8.15 (d, 1H, J= 2.4 Hz), 7.82 (dd, 1H, J= 2.4 and 8.1 Hz), 7.36 (d, 1H, J= 8.1 Hz), 2.91 (t, 2H, J= 6.0 Hz), 2.59 (t, 2H, J= 6.0 Hz), 2.07-1.98 (m, 2H); LCMS: purity: 93%; MS (m/e):
294(MH+).
7.1.98 2-Chloro-5-fluoro-N443-(trifluoromethylthio)pheny1]-4-pyrimidineamine In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-(trifluoromethylthio)aniline were reacted to provide 2-chloro-5-fluoro-N443-(tifluoromethylthio)pheny1]-4-pyrimidineamine. 1H NMR (CDC13): 6 8.13 (bs, 1H), 7.92 (bs, 1H), 7.89-7.84 (m, 1H), 7.48-7.45 (m, 2H), 7.04 (bs, 1H); LCMS: purity:
97%; MS
(m/e): 325(MH ).
7.1.99 2-Chloro-5-fluoro-N4-[(3-dihydroxyboryl)pheny1)]-4-pyrimidineamine In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-aminobenzeneboronic acid were reacted to provide 2-chloro-5-fluoro-N4-[(3-dihydroxyboryl)pheny1)]-pyrimidineamine.
7.1.100 2-Chloro-5-fluoro-N4-[(1H)-indo1-6-y1]-4-pyrimidineamine In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-aminoindole were reacted to provide 2-chloro-5-fluoro-N4-[(1H)- indo1-6-y1]-4-ppimidineamine. LCMS:
purity:
92%; MS (m/e): 263(MH).

7.1.101 2-Chloro-5-fluoro-N4-(2-hydroxy-4-methylpheny1)-4-pyrimidineamine In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methylaniline were reacted to provide 2-chloro-5-fluoro-N4-(2-hydroxy-4-methylpheny1)-4-pyrimidineamine. LCMS: purity: 97%; MS (m/e): 255(MH+).
7.1.102 2-Chloro-5-fluoro-N442-(methoxycarbony1)-(1H)-indol-6-y11-4-pyrimidineamine In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-2-(methoxycarbony1)-(1H)-indole were reacted to provide 2-chloro-5-fluoro-N442-(methoxycarbony1)-(1H)-indo1-6-y1]-4-pyrimidineamine which was used without further purification. LCMS: purity: 65%; MS (m/e): 322(MH+).
7.1.103 N443-(4-(2-Chloro-5-fluoropyrimidine)-N-aminomethylene)-pheny11-2-ehloro-5-fluoro-4-pyrimidineamine (R940298) The reaction flask equipped with a magnetic stirring bar and a rubber septum (to prevent loss of 2,4-dichloro-5-fluoropyrimicline and N2 inlet was charged 3-aminobenzylamine (0.22 g, 1.79 mmol), Me0H (1 mL), H20 (3 mL) and 2,4-dichloro-fluoropyrimidine (0.3 g, 1.79 mmol). The reaction mixture was stirred at 80 C
for 30 min., cool to room temperature, diluted with H20 (30 mL). Upon saturation with sodium chloride it was extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate and the solvent was removed. The resulting residue was filtered through a pad of silica gel (200-400 mesh) using 1 to 3% Me0H in CH2C12 to obtain N443-(4-(2-chloro-5-fluoropyrimidine)-N-methylaminomethylene)-pheny1]-2-chloro-5-fluoro-4-pyrimidineamine R940298. 111 NMR. (DMSO-d6): 8 10.09 (1H, s), 8.88 (1H, t, J
5.85 Hz), 8.40 (1H, d, J= 3.6 Hz), 8.23 (1H, d, J= 3.3 Hz), 7.74 (1H, s), 7.70 (1H, d, J= 8.1 Hz), 7.44 (1H, t, J= 7.8 Hz), 7.19 (1H, d, J= 8.1 Hz), 4.69 (2H, d, J= 5.7 Hz ;
purity 92 %.
7.1.104 2-Chloro-5-fluoro-N4-(3-methyloxyearbony1-4-methoxypheny1)-4-pyrimidineamine (R940302) The reaction flask equipped with a magnetic stirring bar and a rubber septum (to prevent loss of 2,4-dichloro-5-fluoropyrirnidine and N2 inlet was charged with methyloxycarbony1-4-methoxyaniline (0.88 g, 4.86 mmol), Me0H (3 mL), 1120(7 mL) and 2,4-dichloro-5-fluoropyrimidine (0.81 g, 4.86 mmol). The reaction mixture was stirred at 60 C for 30 min., diluted with 1120 (50 mL), acidified with 2N HC1 (6 mL) and sonicated.
The solid obtained was filtered, washed with H20 and dried to produce 2-chloro-5-fluoro-N4-(3-methyloxycarbony1-4-methoxypheny1)-4-pyrimidineamine R940302. 1H NMR
(DMSO-d6): 8 10.10 (111, s), 8.39 (111, d, ..T=. 3.6 Hz), 8.04 (111, d, ./..=
2.7 Hz), 7.98-7.93 (111, m), 7.30 (1H, d, J= 9 Hz), 3.92 (3H, s), 3.89 (3H, m) ; purity 96% ; MS
(m/e): 312 (4}1 ).
7.1.105 2-Chloro-5-fluoro-N4-(4-phahthlimide)-4-pyrimidineamine (R940303) In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbony1-methoxypheny1)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-aminophthalimide were reacted to produce 2-chloro-5-fluoro-N4-(4-phahthlimide)-pyrimidineamine R940303. 11-1NMR (DMSO-d6): 8 11.38 (111, s), 10.60(111, s), 8.57 (1H, d, J= 3.3 Hz), 8.39 (111, d, J= 1.8 Hz), 8.18 (1H, dd, J= 8.4 Hz, J= 2.1 Hz), 7.93 (111, d, J=
8.1 Hz) ; purity 90% ; MS (mie): 293 (MI-1+).
7.1.106 2-Chloro-5-fluoro-N4-(3-methylaminocarbony1-4-methoxypheny1)-4-pyrimidineamine (R940305) In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbony1-methoxypheny1)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-methylaminocarbony1-4-methoxyaniline were reacted to produce 2-chloro-5-fluoro-N4-(3-methylaminocarbony1-4-methoxypheny1)-4-pyrimidineamine R940305. 111 NMR (DMSO-d6): 8 9.91 (111, s), 8.31 (1H, d, J= 3.6 Hz), 8.11 (1H, d, J= 2.7 Hz), 7.78 (111, dd, J=. 9 Hz, J= 2.7 Hz), 7.59 (111, m), 6.87 (111, d, J= 9 Hz), 3.90 (311, s), 2.96 (311, d, J= 4.5 Hz) ;
purity 93%.
7.1.107 N2-Chloro-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxypheny1]-4-pyrimidineamine (R940313) In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbony1-methoxypheny1)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-(N-morpholinomethylene)-4-methoxyaniline were reacted to produce 2-chloro-5-fluoro-N4-[3-(N-morpholinomethy1ene)-4-methoxypheny1]-4-pyrimidineamine R940313.1H NMR
(DMSO-d6): 8 10.00 (111, s), 8.35 (1H, d, J= 3.3 Hz), 7.72 (111, d, J= 3 Hz), 7.58 (111, d, J= 9.3 Hz), 7.12 (1H, d, J 8.4 Hz), 3.89 (3H, s), 3.8-3.5 (6H, m), 2.58 (4H, m) ; purity 96% ; MS (m/e): 352 (M).
7.1.108 N443-(N-tert-Butoxycarbonyl-N-methylaminomethylene)-pheny11-2-chloro-5-fluoro-4-pyrimidineamine (R940315) In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbony1-methoxypheny1)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrirnidine and 3-(N-tert-butoxycarbonyl-N-methylaminomethylene)-aniline were reacted to produce N443-(N-tert-butoxycarbonyl-N-methylaminomethylene)-pheny11-2-chloro-5-fluoro-4-pyrimidineamine R940315. 1H NMR (DMSO-d6): 6 10.13 (111, s), 8.42 (1H, d, J= 3.6 Hz), 7.69 (111, m), 7.64 (111, s), 7.45 (1H, t, 7.6 Hz), 7.09 (111, d, J= 7.8 Hz), 4.48 (211, s), 2.90 (311, s), 1.49 (911, m) ; purity 92% ; MS (m/e): 367 (MH+).
7.1.109 N4-(3-(N-tert-Butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxypheny1)- 2-chloro-5-fluoro-4-pyrimidineamine (R940320) In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbony1-methoxypheny1)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxy-aniline were reacted to produce N4-(3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxypheny1)-2-chloro-5-fluoro-4-pyrimidineamine R940320. 1H NMR (DMSO-d6): 6 10.01 (111, s), 8.34 (1H, d, J= 3.6 Hz), 7.52 (2H, m), 7.08 (111, d, J= 8.7 Hz), 4.33 (311, m), 3.90 (311, s), 1.50-1.30 (911, m), 1.18 (611, d, J= 6.9 Hz) ; purity 95%.
7.1.110 2-Chloro-N4-[(2,2-dimethy1-4H-benzo[1,4]oxazin-3-one)-6-y1]-5-fluoro-4-pyrimidineamine (R940322) In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbony1-methoxypheny1)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-2,2-dimethy1-4H-benzo[1,4]oxazin-3-one were reacted to produce 2-chloro-N4-[(2,2-dimethy1-4H-benzo[1,4]oxazin-3-one)-6-y1]-5-fluoro-4-pyrimidineamine R940322. 1H NMR
(DMSO-d6): 5 10.89 (111, s), 10.04 (1H, s), 8.38 (111, d, J= 3.6 Hz), 7.35 (211, m), 7.04 (111, d, J= 8.4 Hz), 1.50 (611, s) ; purity 91.4% ; MS (m/e): 322 (M).

7.1.111 2-Chloro-N443-dihydro-2,2-dimethy1-4-(2-(pyridy1-1-oxide)-benzo[1,41oxazin-6-y11-5-fluoro-4-pyrimidineamine (R940328) In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbony1-methoxypheny1)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 2-(6-amino-3-dihydro-2,2-dimethyl-benzo[1,4]oxazin-4-yl)pyridine 1-Oxide were reacted to produce 2-chloro-N443-dihydro-2,2-dimethy1-4-(2-(pyridy1-1-oxide)-benzo[1,4]oxazin-6-y1]-5-fluoro-4-pyrimidineamine R940328. 1H NMR (DMSO-d6): 5 9.82 (111, s), 8.39 (1H, dd, J=
6.3 Hz, µT=. 1.2 Hz), 8.30 (1H, d, J= 3.6 Hz), 7.63 (1H, dd, ./.= 8.4 Hz, J 2.4 Hz), 7.47 (1H, td, J= 7.5 Hz, J= 1.8 Hz), 7.34 (1H, m), 7.21 (1H, dd, J= 8.7 Hz, J= 2.4 Hz), 7.07 (1H, d, J= 2.7 Hz), 6.91 (1H, d, .T= 8.7 Hz), 3.64 (2H, s), 1.41 (6H, s) ; purity 95.8% ; MS
(m/e): 402 (MH+).
7.1.112 2-Chloro-N443-dihydro-2,2-dimethy1-4-(2-pyridy1)-benzo[1,41oxazin-6-y11-5-fluoro-4-pyrimidineamine (R940336) In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbony1-methoxypheny1)-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-dihydro-2,2-dimethy1-4-(2-pyridy1)-benzo[1,4]oxazine were reacted to produce 2-chloro-N443-dihydro-2,2-dimethy1-4-(2-pyridy1)-benzo[1,4]oxazin-6-y1]-5-fluoro-4-pyrimidineamine R940336. 1H NMR (DMSO-d6): 69.95 (111, s), 8.38 (1H, dd, ./.=
4.8 Hz, J-= 1.8 Hz), 8.33 (111, d, J= 3.6 Hz), 7.84 (1H, d, J= 2.1 Hz), 7.79 (1H, ddd, ../.= 15.6 Hz, J= 7.2 Hz, ./=. 2.1 Hz), 7.57 (111, d, J= 8.4 Hz), 7.19 (1H, dd, .1-= 8.4 Hz, J 2.4 Hz), 7.01-6.95 (21I, m), 3.96 (211, s), 1.32 (6H, s) ; purity 99.3% ; MS
(m/e): 386 (MI-1+).
7.1.113 2-Chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-y1]-5-fluoro-4-pyrimidineamine (R940342) In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbony1-methoxypheny1)-4-ppimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-2,2-difluoro-411-benzo[1,4]oxazin-3-one were reacted to produce 2-chloro-N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-y1]-5-fluoro-4-pyrimidineamine R940342. 1H NMR
(DMSO-d6): 8 12.24 (111, s), 10.23 (1H, s), 8.45 (111, dd, J= 3.3 Hz, J= 0.9 Hz), 7.66 (111, dd, ./.= 4.2 Hz, J= 2.4 Hz), 7.55 (114, dt, J= 9 Hz, J.= 2.5 Hz), 7.43 (111, d, J= 9 Hz+); 19F NMR (DMSO-d6): 5 -21582, -43415 ; purity 96.2%; MS (rn/e) : 331 (MH+).

7.1.114 2-Chloro-N4-[(2,2-dimethy1-4H-5-pyrido[1,41oxazin-3-one)-7-y11-5-fluoro-4-pyrimidineamine (R940344) In like manner to the preparation of 2-chloro-5-fluoro-N4-(3-methyloxycarbony1-methoxypheny1)-4-pyrimidineamine, 2,4-dichloro-5-fluoroprimidine and 7-amino-2,2-dimethy1-4H-5-pyrido[1,4]oxazin-3-one were reacted to produce 2-chloro-N4-[(2,2-dimethy1-4H-5-pyrido[1,4]oxazin-3-one)-7-y1]-5-fluoro-4-pyrimidineamine R940344. 1H
NMR (DMSO-d6): 8 11.32 (1H, s), 10.20 (111, s), 8.45 (1H, d, J= 3.6 Hz), 8.33 (111, d, J-2 .1 Hz), 7.84 (111, d, J= 2.1 Hz), 1.54 (6H, s) ; purity 90.8% ; MS (m/e):
324 (MH+).
7.1.115 N4-(4-Aminocarbonylmethyleneoxypheny1)-2-chloro-5-fluoro-4-pyrimidineamine (R945028) In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine (250 mg, 1.50 mmol) and 4-aminocarbonylmethyleneoxyaniline (540 mg, 3.25 mmol) were reacted to yield N4-(4-aminocarbonylmethyleneoxypheny1)-2-chloro-5-fluoro-4-pyrimidineamine. LCMS:
ret.
time: 18.34 mm.; purity: 100%; MS (m/e): 298.47 (M11+).
7.1.116 2-Chloro-5-fluoro-N442H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-y11-4-pyrimidineamine (R945298) In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-2H-pyrido[3,2-1A-1,4-oxazin-3(4H)-one were reacted to yield 2-chloro-5-fluoro-N442H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-y1]-4-pyrimidineamine. 111 NMR (DMSO-d6): 8 4.63 (s, 2H), 7.34 (d, J= 8.7 Hz, 1H), 7.44 (d, J= 8.4 Hz, 1H), 8.33 (d, J= 3.3 Hz, 1H), 10.14 (s, 1H, NH), 11.19 (s, 1H, NH); 19F NMR (282 MHz, DMSO-d6): 8 - 152.35; LCMS: ret. time: 26.74 mm.;
purity: 85.90%; MS (m/e): 296.13 (Mu).
7.1.117 N4-(1,4-Benzoxazin-6-y1)-N2-chloro-5-fluoropyrimidineamine In like manner to 2-Chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-1,4-benzoxazine were reacted to yield N4-(1,4-Benzoxazin-6-y1)-N2-chloro-5-fluoropyrimidineamine 1H
DMSO
8.2 (d, 1H),6.8 (m, 111), 6.75 (m, 1H), 6.60 (m,1H), 4.05 (m, 2H), 3.2 (m, 2H) purity 95 %
MS (m/e): 281(MH4).

7.1.118 N4-(1,4-13enzoxazin-7-371)1-N2-chloro-5-fluoropyrimidineamine In like manner to 2-Chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-1,4-benzoxazine were reacted to yield N4-(1,4-Benzoxazin-7-y1)J-N2-chloro-5-fluoropyrimidineamine 8.2 (d, 1H),6.8 (m, 111), 6.75 (m, 111), 6.60 (m,1H), 4.05 (m, 211), 3.2 (m, 2H) purity 94 %
MS (m/e):281 (MO.
7.1.119 N4-(1,4-Benzoxazin-3-on-6-y1)-N2-ehloro-5-fluoropyrimidineamine In like manner to 2-Chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-1,4-benzoxazine-3-one were reacted to yield N4-(1,4-Benzoxazin-3-on-6-y1)-N2-chloro-5-fluoropyrimidineamine 1H DMSO 8.2 (d, 1H), 6.8 (m, 111), 6.75 (m, 1H), 6.60 (m,1H), 4.73 (s, 211) purity 96 %
MS (m/e): 295 (MH+).
7.1.120 N4-(1,4-Benzoxazin-3-on-7-y1)-N2-ch1oro-5-fluoropyrimidineamine In like manner to 2-Chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-primidineamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-1,4-benzoxazine-3-one were reacted to yield N4-(1,4-Benzoxazin-3-on-7-y1)-N2-chloro-5-fluoropyrimidineamine 111 DMSO 8.2 (d, 1H),6.8 (m, 111), 6.79 (m, 111), 6.6 (m,1H), 4.68 (s, 211) purity. 93 % MS
(m/e): 295 (M114).
7.1.121 N2-Chloro-5-fluoro-N4-(N-methy1-1,4-benzoxazin-6-y1)-pyrimidineamine in like manner to 2-Chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-4-N-methy1-1,4-benzoxazine were reacted to yield N2-Chloro-5-fluoro-N4-(N-methy1-1,4-benzoxazin-6-y1)-pyrimidineamine 1H DMSO 8.2 (d, 1H),6.8 (m, 1H), 6.75 (m, 111), 6.60 (m,1H), 4.05 (m, 211), 3.2 (m, 2H) 2.8 (s, 311) purity 95 % MS (m/e): 295 (M1I+).
7.1.122 N2-Chloro-5-fluoro-N4-( N-methy1-1,4-b enzoxazin-7-y1)-pyrimidineamine In like manner to 2-Chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-4-N-methyl -1,4-benzoxazine were reacted to yield N2-Chloro-5-fluoro-N4-( N-methy1-1,4-benzoxazin-7-y1)-pyrimidineamine 111 DMSO 8.2 (d, 1H),6.8 (m, 1H), 6.75 (m, 111), 6.60 (m,1H), 4.05 (m, 2H), 3.2 (m, 2H) 2.8 (s, 3H) purity 94 % MS (m/e): 295 (MH+).
7.1.123 N2-Chloro-5-fluoro-N4-( N-methy1-1,4-benzoxazin-3-on-6-y1)-pyrimidineamine In like manner to 2-Chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-4-N-methyl -1,4-benzoxazine-3-one were reacted to yield N2-Chloro-5-fluoro-N4-( N-methy1-1,4-benzoxazin-3-on-6-y1)-pyrimidineamine 1H DMSO 8.2 (d, 1H),6.8 (m, 1H), 6.75 (m, 1H), 6.60 (m,1H), 4.73 (s, 211) 2.8 (s, 3H) purity 96 % MS (m/e): 309 (M114).
7.1.124 N2-Chloro-5-fluoro-N4-(N-methy1-1,4-benzoxazin-3-on-7-y1)-pyrimidineamine In like manner to 2-Chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-4-N-methy1-1,4-benzoxazine-3-one were reacted to N2-Chloro-5-fluoro-N4-(N-methy1-1,4-benzoxazin-3-on-7-y1)-pyrimidineamine 111 DMSO 8.2 (d, 1H),6.8 (m, 111), 6.75 (m, 111), 6.60 (m,1H), 4.68 (s, 2H) 2.8 (s, 311) purity 93 % MS (m/e): 309 (MH+).
7.1.125 N2-chloro-N4-(3-ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-y1)-5-fluoropyrimidinediamine (R909258) :
In like manner to 2-Chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and ethyl 6-amino-3-carboxy-imidazo[5,1-c]-1,4-benzoxazine were reacted to yield N2-chloro-N4-(3-ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-y1)-5-fluoropyrimidinediamine 111 (DMSO-d6) 8.42 (s, 111), 8.30 (m, 1H)õ 8.05 (m, 111), 7.43 (m, 111), 5.53 (s, 2H), 4.25 (q, 211 J=6.5 Hz), 1.28 (t, 211, J=6.5 Hz), purity 90 % MS (rn/e): 390 (MM.
7.1.126 N2-Chloro-N4-(3,3-dimethy1-1,4-benzoxazin-6-y1)-5-fluoro-pyrimidineamine In like marmer to 2-Chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-Amino-3,3-dimethy1-1,4-benzoxazine were reacted to yield N2-Chloro-N4-(3,3-dimethy1-1,4-benzoxazin-6-y1)-5-fluoro-pyrimidineamine 111 DMSO 8.18 (d, 111), 6.8 (d, 111), 6.67 (m, 211), 3.76 (s, 2I1), 1.05 (s, 611) purity 99 % MS (m/e): 309 (MO

7.1.127 2-Chloro-5-fluoro-N41-(methoxycarbonyl)methyl-indazoline-5-y11-4-pyrimidineamine (R935241) In like manner to the preparation of 2-chloro-N-(3, 4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrirnidine was reacted with 5-amino-1-(methoxycarbonyl)methyl-indazoline to produce 2-chloro-5-fluoro-N-[1-(methoxycarbonyl)methyl-indazoline-5-y1]-4-pyrimidineamine. 111 NMR (DMSO-d6):

8 10.04 (s, 1H), 8.28 (d, 111, J = 3.5 Hz), 8.12 (s, 1H), 8.00 (dd, 1H, J =
1.2 and 4.1 Hz), 7.64 (d, 1H, J = 8.8 Hz), 7.58-7.54 (m, 1H), 5.39 (s, 2H), 3.66 (s, 3H).
7.1.128 2-Chloro-5-fluoro-N44H-imidazo[2,1-c][1,4]-benzoxazin-8-y1]-4-pyrimidineamine (R935257) In like manner to the preparation of 2-chloro-N-(3, 4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 8-amino-4H-imidazo[2,1-c][1,4]-benzoxazine to produce 2-chloro-5-fluoro-N-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-y1]-4-pyrimidineamine. 1H NMR (DMSO-d6): 1H NMR (DMSO-d6): 8 10.08 (s, 1H), 8.31 (s, 1H), 7.91 (d, 1H, J = 2.3 Hz), 7.74 (d, 1H, J = 1.2 Hz), 7.37 (dd, 1H, J = 2.3 and 8.8 Hz), 7.16 (d, 1H, J = 8.8 Hz), 7.14 (d, 1H, J = 1.2 Hz), 5.29 (s, 2H).
LCMS: ret.
time: 18.74 mm.; purity: 99%; MS (m/e): 318 (MH+).
7.1.129 2-Chloro-5-fluoro-N-(indazoline-6-y1)-4-pyrhnidineamine (R935260) In like manner to the preparation of 2-chloro-N-(3, 4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 6-aminoindazole to produce 2-chloro-5-fluoro-N-(indazoline-6-y1)-4-pyrimidinearnine 111 NMR (CDC13): 8 13.03 (s, 111), 10.07 (s, 111), 8.32 (d, 1H, J = 3.5 Hz), 8.07 (s, 1H), 7.99 (s, 1H), 7.71 (d, 111, J = 8.8 Hz), 7.34 (dd, 1H, J = 1.7 and 8.8 Hz). LCMS: ret.
time: 18.52 min.; purity: 99%; MS (m/e): 263 (MH').
7.1.130 2-Chloro-5-fluoro-N-(indazoline-5-y1)-4-pyrimidineamine (R935265) In like manner to the preparation of 2-chloro-N-(3, 4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 5-aminoindazoline. 1H NMR (CDC13): 8 9.99 (s, 1H), 8.26 (d, 1H, J = 3.5 Hz), 8.07 (s, 1H), 7.99 (d, 1H, J = 1.1 Hz), 7.53 (dd, 2H, J = 1.7 and 8.8 Hz). LCMS: ret. time:
18.03 min.;
purity: 97%; MS (m/e): 264 (MO.

7.1.131 2-Chloro-5-fluoro-N-(1H-pyrrol-1-y1)-4-pyrimidineamine (R935275) In like manner to the preparation of 2-chloro-N-(3, 4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with 1-aminopyrrole to produce 2-chloro-5-fluoro-N-(1H-pyrrol-1-y1)-4-pyrimidineamine. 1H
NMR (CDC13): 8 11.39 (s, 1H), 8.35 (d, 111, J = 3.5 Hz), 6.83 (t, 2H, J = 2.3 Hz), 6.07 (t, 2H, J = 2.3 Hz). LCMS: ret. time: 18.95 min.; purity: 97%; MS (m/e): 213 (MH4).
7.1.132 2-Chloro-5-fluoro-N443-(1H-tetrazol-5-371)pheny11-4-pyrimidineamine (R926853) A reaction mixture containing 2,4-dichloro-5-fluoro-pyrimindine (1.2 equivalents) and 3-(tetrazol-5-ypaniline (1 equivalents) in methanol:water (1:1; v/v) was heated at 60 C
for 24 h. Upon dilution with water and acidification, the solid formed was fitered, washed with water, dried and analyzed to give 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)pheny1]-4-pyrimidineamine (R926853). Alternatively this reaction can be achieved by treating 2,4-dichloro-5-fluoropyrimidine (1 equivalent) with 3-(tetrazol-5-ypaniline (3 equivalents) in methanol:water (1:1; v/v) at 60 oC for 2-3 hours or at room temperature for 24 h to give 2-chloro-5-fluoro-N443-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine. 1H NMR (DMSO-d6): 8 10.25 (s, 111), 8.43 (s, 1H), 8.37 (d, 1H, J= 3.6 Hz), 7.90 (dd, 1H, J=
0.9 and 9 Hz), 7.75 (d, 1H, J= 7.5 Hz), 7.61 (t, 1H, J= 7.8 Hz); LCMS: purity: 90%; MS (m/e):
292 (MH+).
7.1.133 2-Chloro-N4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-y1)-5-fluoro-2,4-pyrimidineamine (R950297) A solution of 3,4-dihydro-4-hydroxy-6-amino-2H-1-benzopyran and 2,4-dichloro-5-fluoro-pyrimidine in Me0H was stirred for 2 hours at 70 C. The mixture was diluted with water and the resulting precipitate was filtered to give 2-chloro-N4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-y1)-5-fluoro-2,4-pyrimidineamine as a pale brown solid.
LCMS: purity:
99.3%; MS (m/e): 296.1 (MH+).
7.1.134 2-Chloro-N4-(4-methoxycarbonylethyleneoxypheny1)-5-fluoro-2,4-pyrimidineamine (R950375) A solution of 3-(p-aminopheny1)-propionic acid and 2,4-dichloro-5-fluoro-pyrimidine in Me0H was stirred for 2 hours at 70 C. The mixture was diluted with water and the resulting precipitate was filtered to give 2-chloro-N4-(4-methoxycarbonylethyleneoxypheny1)-5-fluoro-2,4-pyrimidineamine as a pale brown solid.
LCMS: purity: 93.3%; MS (m/e): 311.98 (M").
7.1.135 2-Chloro-N4-(3-carboxy-4-hydroxypheny1)-5-fluoro-2,4-pyrimidineamine (R950298) A solution of 3-carboxy-4-hydroxyaniline and 2,4-dichloro-5-fluoro-pyrimidine in Me0H was stirred for 2 hours at 70 C. The mixture was diluted with water and the resulting precipitate was filtered to give 2-chloro-N4-(3-carboxy-4-hydroxypheny1)-5-fluoro-2,4-pyrimidineamine as a pale brown solid. LCMS: purity: 87.4%; MS (m/e): 284.1 (MH+).
7.1.136 2-Chloro-N4-(4-trifluoromethy1-3-methoxycarb onylpheny1)-5-fluoro-2,4-pyrimidineamine (R950390) A solution of 4-trifluoromethy1-3-methoxycarbonylaniline and 2,4-dichloro-5-fluoro-pyrimidine in Me0H was stirred for 2 hours at 70 C. The mixture was diluted with water and the resulting precipitate was filtered to give 2-chloro-N4-(4-trifluoromethy1-3-methoxycarbonylpheny1)-5-fluoro-2,4-pyrimidineamine as a pale brown solid.
LCMS:
purity: 96.4%; MS (m/e): 366.34 (MH+).
7.1.137 2-Chloro-N4-(3-methylcarbonylpheny1)-5-fluoro-2,4-pyrimidineamine (R950369) A solution of 3-methylcarbonylaniline and 2,4-dichloro-5-fluoro-pyrimidine in Me0H was stirred for 2 hours at 70 C. The mixture was diluted with water and the resulting precipitate was filtered to give 2-chloro-N4-(3-methylcarbonylpheny1)-5-fluoro-2,4-pyrimidineamine as a pale brown solid. LCMS: purity: 99.1%; MS (mile): 266.12 (MH+).
7.1.138 2-Chloro-N4-(3-phenylcarbonylpheny1)-5-fluoro-2,4-pyrimidineamine (R950370) A solution of 3-phenylcarbonylaniline and 2,4-dichloro-5-fluoro-pyrimidine in Me0H was stirred for 2 hours at 70 C. The mixture was diluted with water and the resulting precipitate was filtered to give 2-chloro-N4-(3-phenylcarbonylpheny1)-5-fluoro-2,4-pyrirnidineamine as a pale brown solid. LCMS: purity: 78.5%; MS (m/e): 328.16 (MH+).
7.1.139 2-Chloro-N4-(3-nitropheny1)-5-fluoro-2,4-pyrimidineamine A solution of 3-nitroaniline and 2,4-dichloro-5-fluoro-pyrimidine in Me0H was stirred for 2 hours at 70 C. The mixture was diluted with water and the resulting precipitate was filtered to give 2-chloro-N4-(3-nitropheny1)-5-fluoro-2,4-pyrimidineamine as a pale brown solid. Ill NMR (DMS0): 5 10.34 (s, 1H), 8.73 (d, 1H, J = 2.4 Hz), 7.66-8.29 (in, 4H).
7.1.140 2-Chloro-N4-(3-hydroxymethylen-4-methoxypheny1)-5-fluoro-4-aminopyridine (R950384) A solution of 3-hydroxymethylen-4-methoxyaniline and 2,4-dichloro-5-fluoro-pyrimicline in Me0H was stirred for 2 hours at 70 C. The mixture was diluted with water and the resulting precipitate was filtered to give 2-chloro-N4-(3-hydroxymethylen-4-methoxypheuy1)-5-fluoro-4-aminopyridine as a pale brown solid. LCMS: purity:
91.8%;
MS (m/e): 266.03 (ME).
7.1.141 2-Chloro-N4-(3-amino-4-e,thoxypheny1)-5-fluoro-4-aminopyridine (R950387) A solution of 3-amino-4-ethoxyaniline and 2,4-dichloro-5-fluoro-pyrimidine in Me0H was stirred for 2 hours at 70 C. The mixture was diluted with water and the resulting precipitate was filtered to give 2-chloro-N4-(3-amino-4-ethoxypheny1)-5-fluoro-aminopyridin.e as a pale brown solid. LCMS: purity: 93.2%; MS (m/e): 252.06 (MID.
7.2 Synthesis of Amines and Amine Precursors 7.2.1 5-Amino-2-(2-hydroxyethyleneoxy)pyridine A methanolic solution (50 mL) of 2-(2-hydroxyethyleneoxy)-5-nitropyridine (0.5 g) was hydrogenated in the presence of Pd/C (10%; 0.05 g) using a balloon filled with hydrogen for 2h. After the filtration through a pad of celite and washing with methanol the solution was concentrated to give the 5-amino-2-(2-hydroxyethyloxy)pyridine.
111 NIVIR =
(CDC13): 8 7.5& (d, 1H, J= 3 Hz), 7.05 (dd, 1H, J= 2.7 and 8.1 Hz), 6.64 (d, 1H, J.= 8.7 Hz), 4.36 (m, 2H), 3.89. (m, 211).
7.2.2 4-Chloro-3-methoxyaniline In like manner to the preparation of 5-amino-2-(2-hydroxyethyleneoxy)pyridine, the hydrogenation of 4-chloro-3-methoxynitrobenzene gave 4-chloro-3-methoxyaniline.
LCMS: purity: 98%; MS: 199 (M+ acetonitrile).
*Trade-mark 7.2.3 2-[5-Amino-2-oxo-1,3-benzoxazol-3(2H)-yll acetamide In like manner to the preparation of 5-amino-2-(2-hydroxyethyleneoxy)pyridine, the hydrogenation of 241,3-benzoxazol-2-oxo-5-nitro-3(2H)-yl)acetamide gave 245-amino-2-oxo-1,3-benzoxazol-3(2H)-yliacetamide. LCMS: purity: 96%; MS: 208 (MO.
7.2.4 7-nitro-1,2,3,4-tetrahydroisoquinoline 7-nitro-1,2,3,4-tetrahydroisoquinoline was prepared by nitration of 1,2,3,4-tetrahydroisoquinoline according to the following reference: Gnmewald, Gary L.;
Dahanukar, Vilas H.; Caldwell, Timothy M.; Criscione, Kevin R.; Journal of Medicinal Chemistry (1997), 40(25), 3997-4005.
7.2.5 2-(t-Butoxycarbony1)-7-nitro-1,2,3,4-tetrahydroisoquinoline A mixture of 7-nitro-1,2,3,4-tetrahydroisoquinoline (0.55g, 3.1 mmole), di-t-butyldicarbonate (0.70g, 3.2 mmole), triethylamine (1.0 mL, 7.7 mmole) in dichloromethane (8 mL) was stirred at rt for 8h. The reaction mixture was diluted with water (50 mL) and stirred for lh. The organic phase was separated and washed with brine.
Concentration of the organic phase gave 2-(t-butoxycarbony1)-7-nitro-1,2,3,4-tetrahydroisoquinoline. 1H NMR (CDC13): 8 8.03-7.95 (m, 2H), 7.28 (d, 111, J=
8.4 Hz), 4.66 (s, 2H), 3.68 (t, 2H, J= 6.0 Hz), 2.92 (t, 211, J= 6.0 Hz),1.49 (s, 911).
7.2.6 2,3-Dihydro-6-nitro-4-benzypyranon 3-(p-Nitropheny1)-propionic acid is dissolved in concentrated sulfuric acid and treated with P205. The mixture is stirred for 1 hr at room temperature and poured onto ice.
Filtration gave 2,3-dihydro-6-nitro-4-benzypyranon as a white solid. 111 NMR
(DMS0): 8 8.47 (d, J = 3.0 Hz, 111), 8.35 (dd, J = 3.0, 9.0 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 4.70 (t, J =
7.2 Hz, 1H), 2.90 (t, J = 7.2 Hz, 111).
7.2.7 3,4-Dihydro-4-hydroxy-6-amino-2H-1-benzopyran A mixture 2,3-dihydro-6-nitro-4-benzypyranon and Pd/C (10%) in Me0H was hydrogenated at 22 C for 3 hours (40psi). The mixture was filtered and concentrated to dryness to give 3,4-dihydro-4-hydroxy-6-amino-2H-1-benzopyran as a brown oil.

(DMS0): 8 6.40-6.56 (m, 3H), 5.05 (bs, 1H), 4.45 (bs, 1H), 3.94-4.09 (m, 211), 1.76-1.98 (m, 2H).

7.2.8 N4-(3,4-Ethylenedioxypheny1)-5-ethoxycarbony1-2,4-pyrimidinediamine (R950287) A solution of 2-Chloro-5-ethoxycarbonyl-N4-(3,4-ethylenedioxypheny1)-2,4-pyrimidineamine in Et0H was treated with a 25% aqueous solution of NH3. The mixture was stirred for 30 min at 100 C and purified by flash chromatography on silica gel to give N4-(3,4-ethylenedioxypheny1)-5-ethoxycarbony1-2,4-pyrimidinediamine as a white solid.
LCMS: purity: 92.3%; MS (m/e): 317.28 (MH+, 100).
7.2.9 3-(1N-morpholinocarbonyl)aniline To a 0 C solution of 3-nitrobenzoylchloride (0.50g, 2.7 mmole) and pyridine (0.27 mL, 3.2 mmole) in anhydrous dichloromethane (15 mL) was added morpholine (0.28 mL, 3.2 mmole). The reaction mixture was allowed to warm to rt and was stirred for 20h. The solvents were removed under vacuum and the residue suspended in ethyl acetate and washed with 1N HC1. The organic layer was washed with a saturated solution of NaHCO3 and brine. Removal of the solvents under vacuum provided 1-(N-morpholinocarbony1)-3-nitrobenzene which was used without further purification.
A mixture of 1-(N-moTholinocarbony1)-3-nitrobenzene (0.64 g) and 10% Pd on activated carbon (60 mg) in degassed methanol (65 mL) was stirred under a balloon of H2 for 2h. The reaction mixture was filtered through Celite filter aid and then concentrated under reduced pressure to provide 3-(N-morpholinocarbonyl)aniline in quantitative yield.
1H NMR (CDC13): 8 7.19-7.14 (m, 111), 6.75-6.69 (m, 3H), 3.58-3.71 (m, 10H).
7.2.10 3-(N-propylcarbonyl)aniline In like manner to the preparation of 3-(N-morpholinocarbonyl)aniline, 3-nitrobenzoylchloride and n-propylamine were reacted to prepare 1-[(N-propylamino)carbony1]-3-nitrobenzene which underwent hydrogenation to provide 3-(N-propylcarbonyl)aniline. 1H NMR (CDC13): 8 7.18 (t, 1H, j= 7.5 Hz), 7.13 (t, 111, j= 1.8 Hz), 7.05-7.01 (m, 1H), 6.78 (ddd, 1H, J= 1.2, 2.4, and 7.5 Hz), 6.10 (bs, 1H), 3.58-3.53 (bs, 211), 3.43-3.34 (m, 2H), 1.68-1.57 (m, 2H), 0.97 (t, 3H, J= 7.2 Hz).
7.2.11 3[4-(Ethoxycarbonyl)piperidinocarbonylianiline In like manner to the preparation of 3-(N-morpholinocarbonyl)aniline, 3-nitrobenzoylchloride and ethyl isonipecotate were reacted to prepare 1-[4-(ethoxycarbonyl)piperidinocarbony1]-3-nitrobenzene which underwent hydrogenation to provide 3[4-(ethoxycarbonyl)piperidinocarbonyl]aniline.
7.2.12 3-(N-methylcarbonyl)aniline In like manner to the preparation of 3-(N-morpholinocarbonyl)aniline, 3-nitrobenzoylchloride and methylamine hydrochloride were reacted to prepare 1-RN-methylamino)carbony1]-3-nitrobenzene which underwent hydrogenation to provide 3-(N-methylcarbonyl)aniline. 1H NMR (CDC13): 67.18 (t, 1H, J= 7.5 Hz), 7.13 (t, 111, J= 1.8 Hz), 7.04-6.99 (m, 1H), 6.81-6.75 (m, 111), 6.05 (bs, 1H), 3.84 (bs, 2H), 2.99 (d, 311, J= 4.8 Hz).
7.2.13 7-Amino-1-tetralone In like manner to the preparation of ethyl 4-aminophenoxyacetate, hydrogenation of 7-nitro-1-tetralone was carried out to prepare 7-amino-1-tetralone. 111 NMR
(CDC13): 8 7.32 (d, 1H, J= 2.4 Hz), 7.05 (d, 1H, J= 8.1 Hz), 6.82 (dd, 111, J= 2.4 and 8.1 Hz), 2.85 (t, 2H, J= 6.6 Hz), 2.61 (t, 211, J= 6.6 Hz), 2.14-2.04 (m, 211).
7.2.14 7-Amino-2-(t-butoxycarbony1)-1,2,3,4-tetrahydroisoquinoline In like manner to the preparation of ethyl 4-aminophenoxyacetate, hydrogenation of 2-(t-butoxycarbony1)-7-nitro-1,2,3,4-tetrahydroisoquinoline was carried out to prepare 7-amino-2-(t-butoxycarbony1)-1,2,3,4-tetrahydroisoquinoline. 1H NMR (CDC13): 8 6.92 (d, 111, J= 8.4 Hz), 6.52 (dd, 1H, J= 2.4 and 8.4 Hz), 6.44 (bs, 1H), 4.47 (s, 211), 3.63-3.48 (m, 2H), 2.71 (t, 211, J= 5.1 Hz), 1.45 (s, 911).
7.2.15 7-Amino-1,2,3,4-tetrahydroisoquinoline In like marmer to the preparation of ethyl 4-aminophenoxyacetate, hydrogenation of 7-nitro-1,2,3,4-tetrahydroisoquinoline was carried out to prepare 7-amino-1,2,3,4-tetrahydroisoquinoline. 1H NMR (DMSO-d6): 69.35 (bs, 111), 6.82 (d, 1H, J= 8.1 Hz), 6.45 (dd, 111, J= 2.4 and 8.4 Hz), 6.30 (d, 1H, J= 2.4 Hz), 5.05 (s, 2H), 4.05 (s, 211), 3.24 (t, 211, J= 6.6 Hz), 2.78 (t, 2H, J= 6.6 Hz).
7.2.16 2-(3-aminophenoxy)-N,2-dimethylpropanamide In like manner to the preparation of ethyl 4-aminophenoxyacetate, hydrogenation of N,2-dimethy1-2-(3-nitrophenoxy)propanamide was carried out to prepare 2-(3-aminophenoxy)-N,2-dimethylpropanamide. 1H NMR (CDC13): 8 7.03 (t, 1H, J= 7.8 Hz), 6.71 (bs, 1H), 6.39 (dd, 1H, J= 1.2 and 6.9 Hz), 6.29 (dd, 1H, J= 2.4 and 9.6 Hz), 6.25-6.22 (m, 1H), 2.86 (d, 3H, J= 4.2 Hz), 2.86 (d, 3H, J= 4.2 Hz), 1.50 (s, 6H).
7.2.17 Ethyl 2-(3-aminophenoxy)-2-methylpropanate In like manner to the preparation of ethyl 4-aminophenoxyacetate, hydrogenation of ethyl 2-methyl-2-(3-nitrophenoxy)propanate was carried out to prepare ethyl aminophenoxy)-2-methylpropanate. 1H NMR (CDC13): 8 6.99 (t, 2H, J= 8.7 Hz), 6.32 (dt, 1H, J= 1.2 and 7.2 Hz), 6.24-6.18 (m, 2H), 4.23 (q, 2H, J= 7.2 Hz), 1.58 (s, 6H), 1.24 (t, 3H, J= 6.9 Hz).
7.2.18 N-methyl-2-(5-amino-2-methylphenoxy)acetamide In like manner to the preparation of ethyl 4-aminophenoxyacetate, hydrogenation of N-methyl-2-(2-methyl-5-nitrophenoxy)acetamide was carried out to prepare N-methy1-2-(5-amino-2-methylphenoxy)acetamide. 111 NMR (CD30D): 8 6.86 (d, 1H, J= 7.5 Hz), 6.32-6.25 (m, 2H), 4.43 (s, 2H), 2.82 (s, 3H), 2.14 (s, 3H).
7.2.19 6-Amino-2-(methoxycarbony1)-(1H)-indole 6-Amino-2-(methoxycarbony1)-(1H)-indole was prepared according to the following references:
1. Adams, Richard E.; Press, Jeffery B.; Deegan, Edward G.; Synthetic Communications (1991), 12 (5), 675-681.
2. Boger, Dale L.; Yun, Weiya; Han, Nianhe; Johnson, Douglas S.; Biiorganic &
Medicinal Chemistry (1995), 3(6), 611-621 7.2.20 Preparation of 3-hydroxy-5-(methoxycarbonylmethyleneoxy)aniline and 3,5-bis(methoxycarbonylmethyleneoxy)aniline HN-11--0"ph NH2 H2, Pd/C
H2 Ha 1Ø,ph 0 HO 111 benzyl chloroformate HN BNA
H. =H triethylamine K2CO3, acetone 0 HO = H NH, HN)L0 Ph io Benzyl N-(3,5-dihydroxyphenyl)carbamate To a mixture of 5-aminobenzene-1,3-diol (0.60 g, 3.7 mmole) and sodium hydrogencarbonate (1.4 g, 16 nunole) in THF/water (15 mL, 1:1 v/v) was added dropwise benzyl chloroformate 1.6 mL, 11 mmole). After 3h at rt, THF was removed under vacuum and the remaining aqueous layer was extracted with ethyl acetate. Purification by column chromatograpy over silica gel provided benzyl N-(3,5-dihydroxyphenyl)carbamate. 1H
NMR (CD30D): 8 7.42-7.25 (m, 5H), 6.46 (d, 2H, J= 2.4 Hz), 5.97-5.94 (m, 111), 5.14 (s, 2H).
Benzyl N[3-hydroxy-5-(methoxycarbonylmethyleneoxy) phenyl]carbamate and Benzyl N-[3,5-bis(methoxycarbonyl methyleneoxy)phenyl]carbamate In like manner to the preparation of ethyl 4-nitrophenoxyacetate, benzyl N-(3,5-dihydroxyphenyl)carbamate and methyl bromoacetate were reacted to give a mixture of benzyl N[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]carbamate 1H NMR
(DMSO-d6): 8 9.62 (s, 1H), 9.44 (s, 111), 7.42-7.31 (m, 511), 6.63 (s, 111), 6.50 (t, 1H, J= 2.4 Hz), 5.93 (t, 1H, J= 2.4 Hz), 5.10 (s, 2H), 4.63 (s, 211), 3.67 (s, 3H), and benzyl N-[3,5-bis(methoxycarbonylmethyleneoxy)phenyl]carbamate 1H NMR (CDC13): 8 7.38-7.32 (m, 5H), 6.86 (s, 111), 6.67 (d, 211, J= 1.8 Hz), 6.19 (t, 1H, J= 2.4 Hz), 5.16 (s, 2H), 4.57 (s, 4H), 3.78 (s, 611) which were separated by column chromatograpy over silica gel.

3-Hydroxy-5-(methoxycarbonylmethyleneoxy)aniline In like manner to the preparation of ethyl 4-aminophenoxyacetate, hydrogenation of benzyl N-[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]carbamate was carried out to prepare 3-hydroxy-5-(methoxycarbonylmethyleneoxy)aniline. 111 NMR (CD30D):

5.87-5.80 (m, 211), 5.78-5.72 (m, 1H), 4.56 (s, 2H), 3.76 (s, 3H).
3,5-Bis(methoxycarbonylmethyleneoxy)aniline In like manner to the preparation of ethyl 4-aminophenoxyacetate, hydrogenation of benzyl N-[3,5-bis(methoxycarbonylmethyleneoxy)phenyl]carbamate was carried out to prepare 3,5-bis(methoxycarbonyhnethyleneoxy)aniline. 1H NMR (CD30D): S 5.92 (d, 211, J= 2.4 Hz), 5.83 (t, 1H, J= 2.4 Hz), 4.58 (s, 411), 3.78 (s, 611).
7.2.21 N4-(3,4-Ethylenedioxypheny1)-5-ethoxycarbony1-2,4-pyrimidinediamine (R950287) A solution of 2-Chloro-5-ethoxycarbonyl-N4-(3,4-ethylenedioxypheny1)-2,4-pyrimidineamine in Et0H was treated with a 25% aqueous solution of NH3. The mixture was stirred for 30 min at 100 C and purified by flash chromatography on silica gel to give N4-(3,4-ethylenedioxypheny1)-5-ethoxycarbony1-2,4-pyrimidinediamine as a white solid.
LCMS: purity: 92.3%; MS (m/e): 317.28 (M11+, 100).
7.2.22 Ethyl 6-Nitro-3-carboxy-4H-imidazo15,1-d-1,4-benzoxazine Was prepared according to J. of Heterocyclic Chemistry, 26, 205, (1989) 7.2.23 Ethyl 6-Amino-3-carboxy-4H-imidazo[5,1-d-1,4-benzoxazine Ethyl 6-Nitro-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine was reduced shaken in Me0H under 40 p.s.i. 112 with 20 weight percent of 10% Pd/C (Degussa) for 1 h then filtered and the solvent evaporated. The compound was purified directly by column cliromatograph (Et0Ac/hexane) to yield Ethyl 6-Amino-3-carboxy-4H-imidazo[5,1-c]-1,4-benzoxazine 111 (DMSO-d6) 8.41 (s, 1H), 6.98 (m, 111), 6.82 (m, 111), 6.43 (m, 111), 5.28 ((s. 2H), 4.23 (q, 211, J=6.2 Hz), 1.27 (t, 211, J=6.2 Hz) purity 92 % MS
(m/e): 232 (mEr).
7.2.24 6-Amino-3,3-dimethy1-1,4-benzoxazine A mixture of 15 g 2-Amino-4-nitrophenol and 40 g Boc20 in 300 mL CHC13 was refluxed overnight filtered and the filtrate was evaporated to near dryness.
The residue was triturated with hexanes, collected by suction filtration, and dried to yield 2-N-Boc-amino-4-nitrophenol. The 2-N-Boc-amino-4-nitrophenol was refluxed in acetone with 15.6 mL of 1-Chloro-2-methylpropene and 25 g potassium carbonate overnight. The reaction mixture was poured into ice-slush, the solid was collected by suction filtration and washed with water. The solid was dissolved in Et0Ac and the organic was washed with 10%
NaOH
solution, water, then brine and dried over MgSO4. The organic was filtered to remove the drying agent and evaporated to yield 18 g 1-(2-N-Boc-amino-4-nitrophenoxy)-2-methy1-2-propene. 7.8 g of 1-(2-N-Boc-amino-4-nitrophenoxy)-2-methy1-2-propene was stirred overnight in methanolic HC1 in a round-bottom flask with a septum wired on, and then heated with a reflux condenser attached at 80 C for 10 minutes. The reaction was cooled and the methanol was removed by rotary-evaporation. The residue was dissolved in 30 mL
of 4N HC1, transferred to a new vessel to leave behind any undisolved solids and cooled to 0 C. 1.83 g of NaNO2 in 5 mL water was added drop wise and the solution was neutralized with solid sodium bicarbonate. A solution of 1.64 g NaN3 in 17 mL water was added slowly drop wise and the reaction was stirred 30 minutes. The precipitate was collected by suction filtration, washed well with water and dried on the funnel to yield 5.7 g 1-(2-Azido-4-nitrophenoxy)-2-methy1-2-propene. 7 g of 1-(2-Azido-4-nitrophenoxy)-2-methy1-propene was refluxed in 300 mL benzene overnight, cooled then evaporated. The crude product was recrystalized from Et0Ac/Hexanes to yield 3-Methy1-6-nitro-azirino[2,1-c]-1,4-benzoxazine in two crops with a combined mass of 5.1 1 g of 3-Methy1-6-nitro-azirino[2,1-c]-1,4-benzoxazine was dissolved in 500 mL of Me0H/5% THF, 200 mg of 10% Pd/C (Degussa) was added and the resulting mixture was shaken under 30 p.s.i. H2 atmosphere for 8 hours. The reaction mixture was filtered through a pad of celite and the solvent evaporated. The residue was dissolved in a minimum amount of DCM/THF/Me0H
and loaded onto a 5 cm by 20 cm 3% Me0H/DCM Si02 column and the compound was eluted isocratically with a small amount of positive pressure. The appropriate fractions were combined and evaporated to yield 590 mg of 6-Amino-3,3-dimethy1-1,4-benzoxazine.
1H (DMSO-d6) 6.30 (d, 1H), 5.75 (d, 1H), 5.65 (dd, 111), 3.58 (s, 2H), 1.08 (s, 6H) purity.
99 % MS (m/e): 179 (MH+).
=

7.2.25 Ethyl 4-Aminophenoxyacetate Ethyl 4-Nitrophenoxyacetate A dry reaction flask equipped with a reflux condenser, N2 inlet and a magnetic stirring bar was charged with 3-nitrophenol (76.45 g, 550 mmol), K2CO3 (76.45 g, 550 mmol) and dry acetone (500 mL) under N2 atmosphere. To this at room temperature was added ethyl bromoacetate (55.44 mL, 500 mmol) over a period of 15 min. The reaction mixture was refluxed for 16h, cooled and poured over ice-water (4 Kg). The resulting aqueous solution was extracted with CH2C12 (3 x 500 mL), dried over anhydrous Na2SO4 and solvent was removed to obtain 103g (92%) of the desired ethyl 4-nitrophenoxyacetate.
111 NMR (CDC13): 8 8.20 (d, 2H, J= 8.2 Hz), 6.95 (d, 2H, J= 8.1 Hz), 4.72 (s, 2H), 4.25 (q, 2H), 1.23 (t, 3H); LCMS: ret. time: 27.07 min.; purity: 100%; MS: 267 (M+
acetonitrile).
Ethyl 4-Aminophenoxyacetate A solution of ethyl 4-nitrophenoxyacetate (15 g) in Et0H (400 mL) was hydrogenated at 40 PSI for 40 minutes in the presence of 10% Pd/C (1.5 g, 10%
by weight).
After the filtration through a celite the solvent was removed under a reduced pressure to obtain ethyl 4-aminophenoxyacetate. 111 NMR (CDC13): 8 6.77 (d, 2H, 8.1 Hz), 6.60 (d, 2H, J= 8.0 Hz), 4.50 (s, 211), 4.24 (q, 2H), 1.24 (t, 3H); LCMS: ret. time:
12.00 min.; purity:
100%; MS (m/e): 196 (MH+).
7.2.26 tert-Butyl 4-Aminophenoxyacetate tert-Butyl 4-Nitrophenoxyacetate In like manner to the preparation of ethyl 4-nitrophenoxyacetate, 4-nitrophenol and tert-butyl bromoacetate were reacted to prepare tert-butyl 4-nitrophenoxyacetate. 111 NMR
(CDC13): 8 8.2 (d, 2H, J= 8.1 Hz), 6.95 (d, 2H, J= 8.2 Hz), 4.60 (s, 211), 1.42 (s, 9H).
tert-Butyl 4-Aminophenoxyacetate In like matmer to the preparation of ethyl 4-aminophenoxyacetate, hydrogenation of tert-butyl 4-nitrophenoxyacetate was carried out to prepare tert-butyl 4-aminophenoxyacetate. 111 NMR (CDC13): 8 6.74 (d, 2H, J= 9 Hz), 6.62 (d, 211, J= 9 Hz), 4.42 (s, 2H), 1.42 (s, 911); LCMS: ret. time: 16.35 min.; purity: 94%; MS
(m/e): 224 (MH+).

7.2.27 Ethyl 3-Aminophenoxyacetate Ethyl 3-Nitrophenoxyacetate In like manner to the preparation of ethyl 4-nitrophenoxyacetate, 3-nitrophenol and ethyl bromoacetate were reacted to prepare ethyl 3-nitrophenoxyacetate. 111 NMR (CDC13):
8 7.88 (dt, 1H, J= 1.2 and 8.7 Hz), 7.71 (t, 111, J= 2.4 Hz), 7.45 (t, 111, J=
8.4 Hz), 7.27 (dt, 1H, J= 2.4 and 8.4 Hz), 4.70 (s, 2H), 4.29 (q, 2H, J= 6.9 Hz), 1.30 (t, 3H, J=
6.9 Hz);
LCMS: ret. time: 27.28 min.; purity: 96%.
Ethyl 3-Aminophenoxyacetate In like manner to the preparation of ethyl 4-aminophenoxyacetate, hydrogenation of ethyl 3-nitrophenoxyacetate was carried out to prepare ethyl 3-aminophenoxyacetate. 111 NMR (CDC13): 8 7.05 (t, 1H, J= 7.2 Hz), 6.30 (m, 311), 4.56 (s, 2H), 4.25 (q, 2H, J= 7.2 Hz), 1.29 (t, 3H, J= 6.9 Hz); LCMS: ret. time: 10.69 min.; purity: 96%; MS
(m/e): 196 (MET).
7.2.28 ()-Ethyl 2-(4-Aminophenoxy)propionate In like manner to the preparation of ethyl 4-aminophenoxyacetate, hydrogenation of ethyl ( )-2-(4-nitrophenoxy)propionate was carried out to prepare ( ) ethyl 2-(4-aminophenoxy)propionate. 1H NMR (CDC13): 8 6.70 (d, 2H), 6.58 (d, 2H), 4.60 (m, 1H), 4.20 (q, 211), 3.2 (bs, 211), 1.45 (d, 3H), 1.22 (t, 3H).
7.2.29 N-Methyl 3-Aminophenoxyacetamide N-Methyl 3-Nitrophenoxyacetamide A mixture of ethyl 3-nitrophenoxyacetate (9.12g, 40 mmol), methylamine hydrochloride (26.8g, 400 mmol) and diisopropylethylamine (35.5 mL, 200 mL) in Me0H
(100 mL) was stirred in a pressure vial at 90 C for 6h. The reaction was cooled to room N-Methyl 3-Aminophenoxyacetamide In like manner to the preparation of ethyl 4-4minophenoxyacetate, the hydrogenation of N-methyl 3-nitrophenoxyacetamide (8 g, 39 mmol) was conducted to give the desired N-methyl 3-aminophenoxyacetamide (6g, 86%). 111 NMR (CD30D): 8 6.99 (t, 1H, J=
8.1 Hz), 6.37-6.25 (m, 311), 4.41 (s, 2H), 2.80 (s, 311); LCMS: ret. time: 19.80 min.; purity:
100%.
7.2.30 2-Methoxycarbony1-5-aminobenzofuran (R926610) 2-Methoxycarbony1-5-nitrobenzofuran (R926609) To a suspension of 5-nitro-2-benzofurancarboxylic acid (5 g, 24.15 mmol) in CH2C12 (250 mL) at 0 C was added DMF (0.100 mL) followed by (C0C1)2 (2M in CH2C12, 36.23 mL, 72.46 mL) over a period of 10 min. The reaction was stirred at 0 C
for lh and then at room temperature for 30 min. The reaction solvent was removed under a reduced pressure, dried under high vacuum and again suspended in CH2C12 (250 mL). The solution was cooled to 0 C, were added pyridine (4.8 mL, 48.03 mmol) followed by Me0H
(10 mL, excess) and stirred overnight. The extractive work-up with CH2C12 gave the expected 2-methoxycarbony1-5-nitrobenzofuran (R926609). 111 NMR (CDC13): 8 8.66 (d, 111, J= 2.4 Hz), 8.36 (dd, 111, J= 2.4 and 9.6 Hz), 7.71 (d, 111, J= 9.3 Hz), 7.65 (s, 111), 4.01 (s, 311);
LCMS: ret. time: 26.94 min.
2-Methoxycarbony1-5-aminobenzofuran (R926610) In like manner to the preparation of ethyl 4-aminophenoxyacetate, the hydrogenation of 2-methoxycarbony1-5-nitrobenzofuran (2 g) in Me0H gave 2-methoxycarbony1-5-aminobenzofuran. 111 NMR (CDC13): 67.38 (bt, 211), 6.90 (bd,111), 6.85 (bdd, 111), 3.98 (s, 311).
7.2.31 Methyl 2-(2-methyl-5-nitrophenoxy)acetate In like manner to the preparation of ethyl 4-nitrophenoxyacetate, 2-methy1-5-nitrophenol and methyl bromoacetate were reacted to prepare methyl 2-(2-methy1-nitrophenoxy)acetate. 111 NMR (CD30D): 67.80 (dd, 111, J= 2.4 and 8.1 Hz), 7.65 (d, 1H, J= 2.4 Hz), 7.38 (d, 1H, J= 8.1 Hz), 4.90 (s, 211), 3.80 (s, 3H), 2.36 (s, 3H).

7.2.32 Ethyl 2-methyl-2-(3-nitrophenoxy)propanate A mixture of 3-nitrophenol (0.50g, 3.6 mmole), ethyl bromodirnethylacetate (0.64g, 3.3 mmole), K2CO3 (1.3 g, 9.4 mmole), potassium iodide (catalytic) in absolute ethanol (8 mL) was heated at 70 C for 18h. The reaction mixture was cooled, poured into a saturated solution of NaHCO3, and extracted with dichloromethane. The product, ethyl 2-methy1-2-(3-nitrophenoxy)propanate, was obtained after purification by column chromatography over silica gel. 1H NMR (CDC13): 6 7.85 (dt, 1H, J= 1.2 and 8.1 Hz), 7.68 (t, 1H, J= 2.4 Hz), 7.40 (t, 1H, J= 8.4 Hz), 7.19-7.13 (m, 1H), 4.26 (q, 2H, J= 7.2 Hz), 1.64 (s, 6H), 1.26 (t, 3H, J= 7.21), 7.2.33 N-Methyl-2-(2-methyl-5-nitrophenoxy)acetamide In like manner to the preparation of N-methyl 3-nitrophenoxyacetamide, methyl methy1-5-nitrophenoxyacetate and methylamine hydrochloride were reacted to prepare N-methy1-2-(2-methy1-5-nitrophenoxy)acetamide. 1H NMR (CD30D): 67.82 (dd, 1H, J=
2.4 and 8.1 Hz), 7.69 (d, 1H, J= 2.4 Hz), 7.40 (d, 1H, J= 8.1 Hz), 4.66 (s, 2H), 2.83 (s, 3H), 2.40 (s, 3H).
7.2.34 N,2-Dimethy1-2-(3-nitrophenoxy)propanamide In like manner to the preparation of ethyl 2-methyl-2-(3-nitrophenoxy)propanate, 3-nitrophenol and N,2-dimethy1-2-bromopropanamide (prepared according to the following reference: Guziec, Frank S., Jr.; Torres, Felix F. Journal of Organic Chemistry (1993), 58(6), 1604-6) were reacted to prepare N,2-dimethy1-2-(3-nitrophenoxy)propanamide. 111 NMR (CDC13): 8 7.94 (dt, 1H, J= 1.2 and 8.1 Hz), 7.78 (t, 1H, J= 2.4 Hz), 7.45 (t, 1H, J=
8.4 Hz), 7.22 (ddd, 1H, J= 1.2,2.4, and 8.1 Hz), 6.61 (bs, 1H), 2.89 (d, 3H, J= 5.1 Hz), 1.55 (s, 6H).
7.2.35 4-Amino-[(1H,1,2,3,4-tetrazolyl)methyleneoxy]benzene 4-Nitro-[(1H,1,2,3,4-tetrazol-5-yOmethyleneoxy]benzene A mixture of 2-cyanomethoxy-4-nitrophenyl (5.8 g, 32.6 mmol), sodium azide (6.3 g, 98.0 mmol) and ammonium chloride (8.5 g, 163.3 mmol) was suspended in DMF
(100 mL) containing acetic acid (1 mL) and the mixture heated at 70 C. After 17 h, the reaction was cooled to room temperature and 2 N aqueous hydrochloric acid (100 mL) was added.

The solid which precipitated out of the reaction mixture was collected by filtration, washed with water (2 x 20 mL) then hexane (30 mL), affording compound 4-nitro-R1H,1,2,3,4-tetrazol-5-yl)methyleneoxyThenzene (6.7 g, 99%) as an orange solid: 111 NMR
(300 MHz, DMSO-d6) 8 8.25 (d, J= 9.2 Hz, 211), 7.29 (d, J= 9.1 Hz, 211), 5.68 (s, 211);
ESI MS m/z 220 [C81-171%03 - Hr.
4-Amino-[(1H,1,2,3,4-tetrazoly1)methyleneoxy]benzene A mixture of 4-nitro-[(1,2,3,4-tetrazol-5-yl)methyleneoxy]benzene (6.7 g, 30.4 mmol) and 5 wt % palladium on carbon (700 mg) suspended in ethanol/concentrated hydrochloric acid (14:1, 150 mL) was hydrogenated in a sealed vessel at 50 psi. The mixture was shaken until no further hydrogen uptake was observed, after which the reaction was filtered through diatomaccous earth with chloroform and the filtrate concentrated to afford crude product. Purification by flash chromatography (7:2.5:0.5 CHC13/CH3OH/NH4OH) afforded 4-amino-[(1H,1,2,3,4-tetrazolypmethyleneoxy)Menzene as a brown solid: 1H NMR (300 MHz, DMSO-d6) 6.76 (d, J= 8.7 Hz, 211), 6.52 (d, J=
8.7 Hz, 211), 5.07 (s, 2H); ESI MS m/z 190 [C8H9N50 - Hr.
7.2.36 4-Amino-[(1-methy1-1,2,3,4-tetrazol-5-yOmethyleneoxy]-benzene 4-Nitro-[(1-methy1-1,2,3,4-tetrazol-5-Amethyleneoxy]-benzene and 4-Nitro-[(2-methyl-1,2,3,4-tetrazol-5-Amethyleneoxy]benzene A mixture of 4-nitro-[(1H,1,2,3,4-tetrazolyl)methyleneoxy]benzene (10.00 g, 45.2 mmol), cesium carbonate (22.09 g, 67.8 mmol) and methyl iodide (7.70 g, 54.3 mmol) in DMF (200 mL) was stirred at room temperature for 24 h. The reaction mixture was concentrated to remove most of the DMF and the crude residue was partitioned between chloroform (100 mL) and water (50 mL). The organic phase was separated, washed with brine, dried (Na2SO4) and concentrated to afford crude product as a orange solid.
Purification by flash chromatography (chloroform) afforded 4-nitro-[(1-methy1-1,2,3,4-tetrazol-5-yl)methyleneoxyl-benzene: 1H NMR (300 MHz, DMSO-d6) ô 8.26 (d, J=
9.2 Hz, 2H), 7.31 (d, J= 9.2 Hz, 211), 5.72 (s, 211), 4.15 (s, 3H); and 4-nitro-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyThenzene: 1H NMR (300 MHz, DMSO-d6) & 8.24 (d, J=
9.3 Hz, 211), 7.29 (d, J= 9.3 Hz, 2H), 5.58 (s, 211), 4.41 (s, 311).

4-Amino-[(1-methy1-1,2,3,4-tetrazol-5-y1)methyleneoxy]-benzene A mixture of 4-nitro-[(1-methy1-1,2,3,4-tetrazol-5-yl)methyleneoxy]-benzene (3.60 g, 15.3 mmol) and 5% Pd/C (0.40 g) in 14:1 ethanol/concentrated hydrochloric acid (75 mL) was shaken at room temperature in a atmosphere of hydrogen at 50 psi.
After 4 h no further hydrogen uptake was observed. The reaction mixture was filtered through diatomaceous earth, the solids washed with a 6:3:1 chloroform/methanol/concentrated ammonium hydroxide solution and the filtrate concentrated to afford crude 4-amino-[(1-methy1-1,2,3,4-tetrazol-5-y1)methyleneoxy]-benzene, which was purified by flash chromatography (95:5 chloroform/ methanol): 1H NMR (300 MHz, DMSO-d6) 3 7.48 (br s, 2H), 6.79 (d, J= 6.9 Hz, 2H), 6.55 (d, J= 6.9 Hz, 2H), 5.36 (s, 2H), 4.10 (s, 3H).
7.2.37 4-Amino-[(2-methy1-1,2,3,4-tetrazol-5-Amethyleneoxy]benzene A mixture of 4-nitro-[(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyThenzene (3.60 g, 15.3 mmol) and 5% Pd/C (0.40 g) in 14:1 ethanol/concentrated hydrochloric acid (75 mL) was shaken at room temperature in a hydrogen atmosphere at 50 psi. After 3 h no further hydrogen uptake was observed. The reaction mixture was filtered through diatomaceous earth, the solids washed with a 6:3:1 chloroform/methanol/concentrated ammonium hydroxide solution and the filtrate concentrated to afford crude 4-amino-{(2-methy1-1,2,3,4-tetrazol-5-yl)methyleneoxy}benzene, which was purified by flash chromatography (95:5 chloroform/ methanol): 1H NMR (300 MHz, DMSO-d6) 6 6.80 (br s, 211), 6.75 (d, J= 9.0 Hz, 2H), 6.50 (d, J= 9.0 Hz, 2H), 5.17 (s, 211), 4.37 (s, 3H).
7.2.38 2-Ethoxycarbony1-5-aminoindole (R926611) In like manner to the preparation of ethyl 4-aminophenoxyacetate, the hydrogenation of 2-ethoxycarbony1-5-nitroindole gave the 2-ethoxycarbony1-5-aminoindol.
LCMS: ret.
time: 13.44 min.; purity: 93%; MS (m/e): 205 (MH+).

7.2.39 5-[(4-Aminophenoxy)methy11-3-phenyl-1,2,4-oaxadiazole OH
=

(101 ,[.....)L0,N acetone \
N--( reflux \
Na2S204 0, OOHn -2-m EDCI
i-Pr2NEt R = Me, Ph R =
Me, Ph H2N4N _________________________ HO' reflux NEt3HCI

Preparation of 5[4-(Nitrophenoxy)methy11-3-pheny1-1,2,4-oxadiazole 4-Nitrophenol (0.36 g, 2.56 mmole), 5-(chloromethyl)-3-pheny1-1,2,4-oxadiazole (0.5 g, 2.56 mmole) and anhydrous K2CO3 (0.39 g, 2.82 mmole) were dissolved in anhydrous acetone (20 mL) and heated to reflux for 12 h. Reaction mixture was cooled and the solvent removed under vacuum. The crude solid formed was collected by filtration, washed with water and dried under vacuum to provide 5-[(4-nitrophenoxy)methy1]-pheny1-1,2,4-oxadiazole (0.70 g, 92%). 1H NMR (CDC13): 8 8.25 (d, 2H, J= 8.8 Hz), 8.08 (dd, 2H, J= 8.2 Hz), 7.52-7.49 (m, 314), 7.13 (d, 2H, J= 8.8 Hz), 5.45 (s, 211).
Preparation of 5-[(4-Aminophenoxy)methy1]-3-phenyl-1,2,4-oxadiazole The 5-[(4-nitrophenoxy)methy1]-3-phenyl-1,2,4-oxadiazole (0.5 g, 1.68 mmole) was dissolved in methanol:methylenechloride (1:1) (120 mL). Aqueous solution of (15 mL) sodium hydrosulfite (0.88g, 5.05 mmole) and K2CO3 (0.70g, 5.06 mmole) was added dropwise under nitrogen for 10 min. The contents were allowed to stir at room temperature.
After consumption of starting material, reaction mixture was concentrated, diluted with water till the homogeneous layer formed. The aqueous layer was extracted with several times with ethylacetate and methylene chloride. The turbid organic layers were combined, dried with anhydrous Na2SO4 and concentrated. Purification of the solid concentrate by silica gel chromatography provided 5-[(4-aminophenoxy)methyl]-3-pheny1-1,2,4-oxadiazole (0.23g, 51%). 1H NMR (CDC13): 8 8.11 (m, 211), 7.52-7.46 (m, 3H), 6.87 (d, 2H, J= 8.8 Hz), 6.64 (d, 2H, J= 8.8 Hz), 5.26 (s, 211), 3.49 (br s, 2H).

Preparation of 5-[(4-Nitrophenoxy)methy1]-3-methyl-1,2,4-oxadiazole A mixture of 4-nitrophenoxy acetic acid (2.25 g, 11.4 mmole), acetamideoxime, triethylamine hydrochloride (3.85g, 27.62 mmole), EDCI.HC1 (4.37g, 22.79 mmole) and diisopropylethylamine (7.42g, 57.40 mmole) in anhydrous THF (250 ml) was refluxed for 18h. The unhomogenous brown colored reaction mixture was quenched with water and extracted with Et0Ac (3 x 300 mL). The combined organic layers washed successively with aqueous NaHCO3, brine and dried over anhydrous Na2SO4. Removal of solvent and purified by chromatographic purification provided 5-[(4-nitrophenoxy)methy1]-3-methyl-1,2,4-oxadiazole (1.62 g, 60 %). 1H NMR (CDC13): 5 8.24 (d, 211, J= 8.8 Hz), 7.08 (d, 2H, J= 8.8 Hz), 5.36 (s, 211), 2.44 (s, 311).
Preparation of 5-[(4-Aminophenoxy)methy1]-3-methyl-1,2,4-oxadiazole In like manner to the preparation of 5-[(4-aminophenoxy)methy1]-3-pheny1-1,2,4-oxadiazole, 5-(4-nitrophenoxymethyl)-3-methyl-1,2,4-oxadiazole was reacted with aqueous solution of sodium hydrosulfite and K2CO3 to prepare 5-[(4-aminophenox)ymethyl]-3-methyl-1,2,4-oxadiazole. 111 NMR (CDC13): 5 6.82 (d, 211, J= 8.8 Hz), 6.63 (d, 211, J= 8.8 Hz), 5.15 (s, 211), 3.38 (br s, 211), 2.41 (s, 311).
7.2.40 Ethyl 2-(4-aminopheny1)-2-methylpropionate 0 t-BuOK, Mel Pd IC/ H2 02N 110 18-Crown-6 = 30 psi = THF
MeON H 2N
io =

Ethyl 2-methyl-2-(4-nitrophenyl)propionate A dry reaction flask charged with ethyl 4-nifrophenylacetate (5.0 g, 23.89 mmole), iodomethane (8.48 g, 3.72 mL, 59.74 mmole), 18-crown-6 (1.57 g, 5.93 mmole) in dry THF
(200 mL) was cooled to -78 C under nitrogen atmosphere. While stirring the contents, t-BuOK (5.90 g, 52.57 mmole) was added portionwise. The resulting violet precipitate was stirred at -78 C for 2h and allowed the contents to warm to room temperature.
The reaction was stirred at room temperature for 6h. At this time, once again the contents were cooled to -78 C another portion of iodomethane, t-BuOK, and 18-crown-6 were added successively and stirred at the same temperature for 2h. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aq.
NH4C1 (75 mL), the resulting homogenous mixture extracted with ether (4 x 200 mL), dried over anhydrous Na2SO4, and concentrated. The concentrate was purified by silica gel column chromatography with 1%Et0Ac/hexanes to provide ethyl 2-methyl-2-(4-nitrophenyl)propionate as a pale yellow oil (2.38, 42%). 1H NMR (CDC13): 8 8.17 (d, 2H, J= 8.8 Hz), 7.49 (d, 2H, J= 8.8 Hz), 4.12 (qt, 2H, J= 7.0 Hz), 1.60 (s, 6H), 1.17 (t, 3H, J=
7.0 Hz).
Ethyl-2-(4-aminopheny1)-2-methylpropionate In like manner to the preparation of ethyl 4-aminophenoxyacetate, the hydrogenation of ethyl 2-methy1-2-(4-nitrophenyl)propionate provided ethy1-2-(4-aminopheny1)-methylpropionate. 111 NMR (CDC13): 8 7.16 (d, 2H, J= 8.8 Hz), 6.63 (d, 211, J=
8.8 Hz), 4.09 (qt, 2H, J= 7.0 Hz), 3.62 (br s, 2H), 1.52 (s, 6H), 1.17 (t, 311, J= 7.0 Hz).
7.2.41 Anilines substituted with 1,3,4-oxadiazole moieties Pyridine, CH2Cl2 101 + C =Pyr ___________________ 110 NH2 NO2 c NN 0 80 C
* 0 I.
[H2], Pd/C (10%) - NI-1µ1 NH2 *01 Me0H
O

N/-11 * 0 40 N'1-(3-Chlorobenzoy1)-3-nitrobenzene-1-carbohydrazide To a solution of 3-chlorobenzohydrazide (1 equivalent) and pyridine (2 equivalents) in CH2C12 at 0 C was added a CH2C12 solution of 3-nitrobenzoyl chloride (1 equivalents) and stirred at 0 C for 1 h and then at room temperature for overnight. The resulting solution was concentrated and diluted with water, basified with NalIC03, the solid was filtered, washed with water, dried and analyzed to obtain N'1-(3-chlorobenzoy1)-3-nitrobenzene-1-carbohydrazide. Ill NMR (DMSO-d6): 8 10.99 (s, 111), 10.79 (s, 111), 8.73 (bs, 111), 8.43 (bdd, 111, J= 1.2 and 8.1 Hz), 8.33 (bdd, 1J, J= 8.4 Hz), 7.95 (s, 111), 7.87 (m, 2H), 7.67 (bdd, 1H, J= 1.2 and 8.1 Hz), 7.57 (t, 1H, J= 7.8 Hz); LCMS: purity:
85%; MS
(m/e): 320 (M1I+).
[2-(3-Chloropheny1)-1,3,4-oxadiazol-5-y11-3-nitrobenzene A suspension of N'143-chlorobenzoy1)-3-nitrobenzene-1-carbohydrazide (0.321 g) in POC13 (3 mL) was stirred at 90 C for 24 h. The resulting clear solution was quenched with ice-water, solid obtained was filtered washed with water, dried and analyzed to give [2-(3-chloropheny1)-1,3,4-oxadiazol-5-y1]-3-nitrobenzene. 1H NMR (DMSO-d6): .5 8.86 (t, 1H, J= 1.8 Hz), 8.59 (dt, 1H, J= 1.8 and 8.4 Hz), 8.48 (m, 1H), 8.25 (t, 111, J= 1.8 Hz), 8.16 (dt, 1H, J= 1.2 and 7.5 Hz), 7.93 (t, 1H, J= 8.1 Hz), 7.75 (m, 1H), 7.66 (t, 1H, J= 7.5 Hz), LCMS: purity: 86%; MS (m/e): 302 (MH+).
Reduction of [2-(3-chloropheny1)-1,3,4-oxadiazol-5-y1]-3-nitrobenzene The hydrogenation of [2-(3-chloropheny1)-1,3,4-oxadiazol-5-y1]-3-nitrobenzene (0.2 g) using 10% Pd/C (0.04 g) in Me0H (200 mL) at 15 PSI for 1 h gave a mixture of two products viz. 3-amino-[2-(3-chloropheny1)-1,3,4-oxadiazol-5-yl]benzene and 3-amino-(2-phenyl-1,3,4-oxadiazol-5-yl)benzene which were separated by silica gel column chromatography using n-hexanes then n-hexanes: 5-10% Et0Ac as a solvent system. 3-Amino12-(3-chloropheny1)-1,3,4-oxadiazol-5-yl]benzene: 1H NMR (DMSO-d6): 8 8.08 (m, 2H), 7.64 (m, 4H), 7.42 (m, 1H), 7.10 (m, 1H); LCMS: purity: 82%; MS
(m/e): 272 (MH+). 3-Amino-(2-phenyl-1,3,4-oxadiazol-5-yl)benzene: 111 NMR (DMSO-d6): 5 8.13 (m, 111), 7.54 (m, 5H), 7.30 (m, 1H), 6.86 (dd, 1H, J= 1.5 and 8.1 Hz); LCMS:
purity: 93%;
MS (m/e): 238 (MH+).
N'1-(Ethoxycarbonylmethylenecabony1)-3-nitrobenzene-1-carbohydrazide In like manner to the preparation of N'143-chlorobenzoy1)-3-nitrobenzene-1-carbohydrazide, the reaction of 3-nitrobenzoyl chloride with ethoxycarbonylmethlenecarbohydrazide gave N'1-(ethoxycarbonylmethylenecabony1)-nitrobenzene-l-carbohydrazide. 1H NMR (CD30D): 5 8.74 (m, 1H), 8.44 (dd, 1H, 1.8 and 8.1 Hz), 8.25 (bd, 1H, J= 8.4 Hz), 7.76 (t, 1H, J= 8.4 Hz), 4.22 (q, 2H, J=
6.9 Hz), 3.44 (bs, 2H), 1.29 (t, 3H, J= 6.8 Hz); LCMS: purity: 93%; MS (m/e): 296 (MH+).

[2-(Ethoxycarbonylmethylene)-1,3,4-oxadiazol-5-y1]-3-nitrobenzene In like manner to the preparation of [2-(3-chloropheny1)-1,3,4-oxadiazol-5-y1]-nitrobenzene the reaction of POC13 with N'1-(ethoxycarbonylmethylenecabony1)-3-nitrobenzene-1-carbohydrazide gave [2-(ethoxycarbonylmethylene)-1,3,4-oxadiazol-5-y1]-3-nitrobenzene. 1H NMR (CDC13): 8 8.88 (t, 1H, J= 1.8 Hz), 8.42 (m, 211), 7.74 (t, 1H, J=
7.5 Hz), 4.27 (q, 2H, J= 7.2 Hz), 4.08 (s, 2H), 1.31 (t, 3H, J= 7.2 Hz); LCMS:
purity: 95%;
MS (m/e): 278 (MH4).
7.2.42 Synthesis of ( )-5-Amino-(2,3-dihydro-2-methoxycarbonyl)benzofuran Me0H, Conc.H2SO4 [H2], 55 PSI10% Pd/C
60 C, 2-3 h = Na2SO4, Me0H, 3 days 111101# COOH ___________________________ IN" COOMe ______________________ COOMe 2-Methoxyearbony1-5-nitrobenzofuran A mixture of 2-carboxy-5-nitrobenzofuran (2.0 g), Me0H (10 mL) and Concentrated H2SO4 (2.1 mL) was heated in a sealed tube at 60 C for 3 h. Upon cooling to the room temperature it was quenched with ice-water and carefully basified with addition of NaHCO3. The solid obtained was filtered, washed with water, dried and analyzed to give 2-methoxycarbony1-5-nitrobenzofuran. 111 NMR (CDC13): 8 8.66 (d, 111, f= 2.4 Hz), 8.36 (dd, 1H, J= 2.4 and 9.6 Hz), 7.71 (d, 1H, J= 9.3 Hz), 7.65 (s, 111), 4.01 (s, 311); LCMS:
purity: 97%; MS (m/e): 222 (MO.
( )-5-Amino-(2,3-dihydro-2-methoxycarbony1)benzofuran A suspension of 2-methoxycarbony1-5-nitrobenzofuran (2.0 g), 10% Pd/C (2.0 g), Na2SO4 (2.0 g) in Me0H (500 mL) was hydrogenated at 55 PSI for 3 days. The resulting solution was filtered through a pad of celite, concentrated and chromatographed using n-hexanes then 10%, 20% Et0Ac/n-hexanes to give ( )-5-amino-(2,3-dihydro-2-methoxycarbonyl)benzofuran. 1HNMR (CDC13): 8 6.69 (d, 1H, J= 8.1 Hz), 6.56 (d, 111, J=
1.2 Hz), 6.48 (dd, 111, J= 1.8 and 7.5 Hz), 5.14 (dd, 1H, J= 6.6 and 7.2 Hz), 3.79 (s, 3H), 3.47 (dd, 1H, J= 10.5 and 10.8 Hz), 3.26 (dd, 111, J= 7.2 and 6.6 Hz); LCMS:
purity: 100%;
MS (m/e): 194 (ME).

7.2.43 3-[l-Bis(eth oxycarb onyl)eth oxy] aniline Preparation of Diethyl 2-methyl-2-(3-nitrophenoxy)malonate Diethyl 2-bromo-2-methylmalonate (1.0 g, 3.95 mmole) was added to a stirred suspension of potassium fluoride (0.57 g, 9.8 mmole) in dry DMF (5 mL). After stirring for 20 min at room temperature, 3-nitrophenol (0.55 g, 3.95 mmole) was added. The resulting mixture was stirred at 60 C for 6 h, cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (3 X 200 mL). The organic layer was washed with aq.1N NaOH (2 X 75 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to provide diethyl 2-methyl-2-(3-nitrophenoxy)malonate (0.89 g, 80%). 1H NMR
(CDC13):
8 7.92 (dd, 111, J = 2.3 and 8.2 Hz), 7.82 (t, 1H, J = 2.3 Hz), 7.41 (t, 111, J = 8.2 Hz), 7.30 (dd, 1H, J = 2.3 and 8.2 Hz), 4.28 (qt, 4H, J = 7.0 Hz), 1.81 (s, 311), 1.26 (t, 6H, J = 7.0 Hz).
Preparation of 3[1-Bis(ethoxycarbonyl)ethoxy] aniline Diethyl 2-methyl-2-(3-nitrophenoxy)malonate (0.75 g, 2.40 mmole) was dissolved in toluene: ethanol (1:1, 100 mL), transferred to par shaker bottle containing Pd/C (0.15 g) and anhydrous Na2SO4 (5.0 g) in the presence of nitrogen atmosphere. The resulting mixture was treated with hydrogen (30 PSI) till the disappearance of diethyl 2-methy1-2-(3-nitrophenoxy)malonate (2 h). The mixture was filtered through celite covered with anhydrous Na2SO4 followed by washing the celite pad with Et0Ac. The filtrated was concentrated and dried under vacuo to furnish 3[1-bis(ethoxycarbonypethoxy]aniline in quantitative yield. 111 NMR (CDC13): 8 6.98 (t, 111, J = 8.2 Hz), 6.37-6.28 (m, 311), 4.26 (qt, 4H, J = 7.0 Hz), 3.65 (br s, 21I), 1.72 (s, 311), 1.24 (t, 6H, J = 7.0 Hz).
7.2.44 Preparation of 4-(4-aminophenoxymethyl)-2-methoxycarbonyl-furan crc) Pd / C

02N OH K2CO3 02N0 , tolue3neP:MSel Orl H2N * 0 ra, acetone 1XF =
reflux 1 Preparation of 4-(4-nitrophenoxymethyl)-2-methoxycarbonyl-furan 3-Nitrophenol (1.0 g, 7.19 mmole), methyl 5-(chloromethyl)-2-furoate (1.38 g, 7.90 mmole) and anhydrous K2CO3 (1.19 g, 8.60 mmole) in acetone (30 mL) were refluxed for 8 h. The reaction mixture was cooled and diluted with water. The resultant white solid was filtered, washed with water and air dried overnight to give 1.81 g (90%) of the desired product. 111 NMR (CDC13): 6 7.86 (dd, 1H, J = 2.3 and 8.2 Hz), 7.80 (t, 1H, J
= 2.3 Hz), 7.45 (t, 111, J = 8.2 Hz), 7.27 (dd, 111, J = 2.3 and 8.2 Hz), 7.17 (d, 1H, J
= 3.5 Hz), 6.58 (d, 111, J = 3.5 Hz), 5.13 (s, 211), 3.90 (s, 311).
Preparation of 4-(4-aminophenoxymethyl)-2-methoxycarbonyl-furan In like manner to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, 4-(4-nitrophenoxymethyl)-2-methoxycarbonyl-furan was reduced to provide 4-(4-aminophenoxymethyl)-2-methoxycarbonyl-furan. 111 NMR (CDC13): 6 7.15 (d, 1H, J
= 3.5 Hz), 7.05 (t, 1H, J = 8.2 Hz), 6.50 (d, 1H, J = 3.5 Hz), 6.37-6.27 (m, 311), 5.01 (s, 2H), 3.89 (s, 311).
7.2.45 Preparation of 6-amino-1-(methoxycarbonyl)methylindazoline P
02N-T ,N 30 SI toluene:Me0H
N
04)n RO( )11 I Br4OR IR/ 0 02N= NJ\1 _____________________ + 0 DMF
N ) n = 1 R = Me 0 n= 2 R=Et RO
Preparation of 1-(methoxycarbonyl)methy1-6-nitroindazoline To a solution of 6-nitroindazoline (2.0 g, 12.25 mmole) in dry DMF was added anhydrous K2CO3 (1.84 g, 13.31 mmole) and methyl 2-bromoacetate (2.04 g, 13.33 mmole).
The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water and the resulting solid was collected by filtration, washed with excessive water, and air dried. The yellow solid collected was purified by silica gel column chromatography using gradient solvent system to furnish two products. The desired product (1.12 g, 41%) with high Rf value on the TLC in 30% Et0Ac : hexanes was collected.
In like marmer to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, 1-(Methoxycarbonyl)methy1-6-nitro-indazoline was reduced to provide 6-amino-1-(methoxycarbonyl)methylindazoline. 1H NMR (CDC13): 8 7.73 (d, 1H, J = 1.1 Hz), 7.35 (d, 111, J = 8.2 Hz), 6.49 (dd, 111, J= 1.8 and 8.8 Hz), 6.39 (s, 111), 5.34 (br s, 211), 5.10 (s, 211), 3.64 (s, 3H).
Preparation of 1-(methoxyearbonyl)methy1-5-nitroindazoline In like manner to the preparation of 1-(methoxycarbonyl)methy1-6-nitroindazoline, 1-(methoxycarbonyl)methy1-5-nitroindazoline was prepared by alkylation of 5-nitroindazoline with methyl 2-bromoacetate in presence of K2CO3. The desired product (1.34 g, 46%) with high Rf value on the TLC in 30% Et0Ac : hexanes was collected by silica gel column chromatographic purification. 1H NMR (CDC13): 8 8.75 (d, 1H, J = 1.8 Hz), 8.30 (dd, 1H, J = 2.3 and 8.2 Hz), 8.26 (s, 1H), 7.40 (d, 1H, J = 8.2 Hz), 5.22 (s, 211), 3.78 (s, 311).
Preparation of 5-amino-1-(methoxycarbonyl)methylindazoline In like manner to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, 1-(Methoxycarbonyl)methy1-5-nitro-indazoline was reduced to provide 5-amino-1-(methoxycarbonyl)methylindazoline. Ill NMR (CDC13): 8 7.84 (d, 1H, J = 2.3 Hz), 7.15 (d, 111, J = 8.8 Hz), 6.95 (d, 1H, J= 2.3 Hz), 6.88 (dd, 1H, J = 2.3 and 8.8 Hz), 5.09 (s, 2H), 3.73 (s, 311).
Preparation of 1-(2-ethoxyearbonylethyl)-6-nitroindazoline In like manner to the preparation of 1-(methoxycarbonyl)methy1-6-nitroindazoline, 1-(ethoxycarbonypethy1-6-nitroindazoline was prepared by alkylation of 6-nitroindazoline with ethyl 3-bromopropionate in presence of K2CO3. The desired product (58%) with high Rf value on the TLC in 30% Et0Ac : Hexanes was collected by silica gel column chromatographic purification. 1H NMR (CDC13): 8 8.49 (s, 111), 8.12 (s, 1H), 8.01 (dd, 1H, J = 1.7 and 8.8 Hz), 7.82 (d, 1H, J = 8.8 Hz), 4.74 (t, 211, J = 6.4 Hz), 4.09 (qt, 211, J = 7.0 Hz), 3.03 (t, 211, J = 6.4 Hz), 1.18 (t, 3H, J = 7.0 Hz).
Preparation of 6-amino-1-(2-ethoxycarbonylethyl)indazoline In like manner to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, 1-(2-ethoxycarbonylethyl)-6-nitroindazoline was reduced to provide 6-amino-1-(2-ethoxycarbonylethyl)indazoline. 1H NMR (CDC13): 6.7.81.(s, 1H), 7.46 (d, 1H, J
= 8.8 Hz), 6.60 (app s, 1H), 6.55 (dd,111, J = 2.3 and 8.8 Hz), 4.51 (t, 2H, J = 7.0 Hz), 4.11 (qt, 2H, J =
7.0 Hz), 3.52 (br s, 2H), 2.91 (t, 2H, J = 7.0 Hz), 1.18 (t, 3H, J = 7.0 Hz).
Preparation of 1-(2-ethoxycarbonylethyl)-5-nitroindazoline In like manner to the preparation of 1-(methoxycarbonyl)methy1-5-nitroindazoline, 1-(ethoxycarbonyl)ethy1-5-nitroindazoline was prepared by alkylation of 5-nitroindazoline with ethyl 3-bromopropionate in presence of IC2CO3. The desired product (43%) with high Rf value on the TLC in 30% Et0Ac : Hexanes was collected by silica gel column chromatographic purification. 1H NMR (CDC13): 8 8.70 (d, 1H, J = 1.7 Hz), 8.27 (dd, 1H, J
= 2.3 and 8.8 Hz), 8.20 (d, 1H, J = 1.7 Hz), 7.59 (d, 1H, J = 8.8 Hz), 4.70 (t, 2H, J = 6.4 Hz), 4.07 (qt, 2H, J = 7.0 Hz), 3.01 (t, 2H, J = 6.4 Hz), 1.16 (t, 3H, J = 7.0 Hz).
Preparation of 5-amino-1-(2-ethoxycarbonylethypindazoline In like manner to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, 1-(2-ethoxycarbonylethyl)-5-nitroindazoline was reduced to provide 5-amino-1-(2-ethoxycarbonylethypindazoline. 1H NMR (CDC13): 8 7.78 (s, 111), 7.30 (d, 1H, J
= 8.8 Hz), 6.91 (d, 1H, J = 2.3 Hz), 6.87 (dd, 1H, J = 2.3 and 8.8 Hz), 4.59 (t, 2H, J =
6.4 Hz), 4.08 (qt, 2H, J = 7.0 Hz), 3.02 (br s, 2H), 2.92 (t, 2H, J = 7.0 Hz), 1.16 (t, 3H, J =
7.0 Hz).
Preparation of 5-amino-2-methylindazoline In like manner to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, conun.ercially available 2-methyl-5-nitroindazoline was reduced to provide 5-amino-2-methylindazoline. 111 NMR (CDC13): 8 7.61 (s, 1H), 7.53 (d, 1H, J = 8.8 Hz), 6.81 (dd, 1H, J = 2.3 and 8.8 Hz), 6.75 (d, 1H, J = 2.3 Hz), 4.13 (s, 3H), 3.85 (br s, 2H).
7.2.46 Preparation of methyl 3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate = Me B re&
W = Me H2 H21`14-rN = Me PSI
*
02N4 = me toluene:Me0H Ap. *Me IMF 02N \jµl = Me Pd / C
1-12Na\I = Me toluene:Me01-7 OMe OMe In like manner to the preparation of 1-(methoxycarbonyl)methy1-6-nitro-indazoline, methyl 3-methoxy-4-[(6-nitroindazol-1-y1)methylibenzoate was prepared by alkylation of 6-nitroindazoline with methyl (4-bromomethyl)-3-methoxybenzoate in presence of K2CO3.
The desired product (48%) with high Rf value on the TLC in 30% Et0Ac : hexanes was collected by silica gel column chromatographic purification. 1H NMR (CDC13): S
8.50 (d, 1H, J = 1.7 Hz), 8.14 (s, 1H), 8.00 (dd, 111, J = 1.8 and 8.8 Hz), 7.82 (d, 111, J = 8.8 Hz), 7.56 (s, 111), 7.54 (d, 1H, J = 1.8 Hz), 7.07 (d, 1H, J = 8.2 Hz), 5.70 (s, 211), 3.96 (s, 3H), 3.88 (s, 3H). Low Rf : Methyl 3-methoxy-4-[(6-nitroindazol-2-yl)methyl]benzoate: 1H
NMR (CDC13): 8 8.68 (br s, 111), 8.07 (s, 1H), 7.86 (dd, 111, J = 1.8 and 9.0 Hz), 7.72 (d, 1H, J = 9.0 Hz), 7.61 (d, 111, J = 7.7 Hz), 7.58 (s, 111), 7.19 (d, 1H, J =
7.7 Hz), 5.69 (s, 2H), 3.93 (s, 3H), 3.90 (s, 311).
Preparation of Methyl 4-[(6-aminoindazol-1-yl)methyl]benzoate In like manner to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, methyl 3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate was reduced to provide methyl 4-[(6-aminoindazol-1-yOmethylThenzoate. 111 NMR (CDC13): 8 7.88 (s, 111), 7.53 (d, 1H, J
= 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.50 (d, 111, J = 1.7 Hz), 6.67 (d, 111, J = 8.8 Hz), 6.56 (dd, 1H, J = 1.7 and 8.8 Hz), 6.45 (d, 111, J = 1.2 Hz), 5.50 (s, 211), 3.94 (s, 311), 3.87 (s, 3H), 3.79 (br s, 2H).
Preparation of Methyl 4[(6-aminoindazol-2-yl)methyllbenzoate In like manner to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, methyl 3-methoxy-4-[(6-nitroindazol-2-yl)methyl]benzoate was reduced to provide methyl 4-[(6-aminoindazol-2-yl)methylThenzoate. 1H NMR (CDC13): 8 7.78 (s, 111), 7.56-7.53 (m, 211), 7.43 (d, 1H, J = 8.8 Hz), 6.98 (d, 111, J = 8.2 Hz), 6.81 (app s, 111), 6.58 (dd, 111, J =
1.8 and 8.8 Hz), 5.53 (s, 211), 3.91 (s, 3H), 3.89 (s, 311).

7.2.47 Preparation of 6-amino-142-methoxy-4-(o-toluylsulfonamidocarboxy)benzyllindazoline .Me LION: H20 ,...02N-+N = Me 1. SOCl2, reflux 2N4a-' = Me H
'Me THF:H20.Me0H ,H 2. o-toluenissepnamide -g2 0 0 CH2Cl2 =
Pd / C
H2 H214-+ = Me toluene:Me0H * F4-82 Preparation of 6-nitro-1[2-methoxy-4-(o-toluylsuffonamidocarboxy) benzyllindazoline Ester hydrolysis of methyl 3-methoxy-4-[(6-nitroindazol-1-yl)methylibenzoate in presence of LiOH:H20 produced the corresponding acid. The acid (1.65 g, 5.04 mmole) thus formed was converted to the acid chloride by reacting with SOC12 (3.68 mL, 50.45 mmole) at reflux temperature for 5 h. The reaction mixture was cooled to room temperature and concentrated under vacuo. To acid chloride concentrate dissolved in dry CH202 (75 mL), o-toluylbenzenesulfonamide (0.95 g, 5.54 mmole) and 4-(dimethylamino)-pyridine (0.67 g, 5.54 mmole) were added successively at room temperature and stirred for 12 h.
The reaction mixture was concentrated, dissolved in Et0Ac (700 mL) and successively treated with 2 N HC1 (2 X 100 mL), water (150 mL) and brine (100 mL). Usual workup and purification by silica gel column chromatography provided the product (1.57 g, 64%). 111 NMR (DMSO-d6): 8 8.75 (s, 111), 8.31 (s, 1H), 8.00 (d, 1H, J = 8.8 Hz), 7.95-7.91 (m, 21I), 7.50 (d, 1H, J = 1.2 Hz), 7.46-7.27 (m, 41I), 6.92 (d, 1H, J = 7.6 Hz), 5.76 (s, 2H), 3.81 (s, 3H), 2.54 (s, 3H).
Preparation of 6-amino-142-methoxy-4-(o-toluylsulfonamidoearboxy)benzyllindazoline In like manner to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, 6-nitro-142-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline was reduced to provide 6-amino-142-methoxy-4-(o-toluylsulfonamidocarboxy)benzyllindazoline.

NMR (CDC13): 8 7.96 (dd,111, J = 1.2 and 8.2 Hz), 7.76 (s, 111), 7.51 (d, 1H, J = 1.2 Hz), 7.49-7.44 (m, 1H), 7.37 (d, 211, J = 8.8 Hz), 7.34-7.32 (m, 111), 7.30 (d, 111, J = 8.8 Hz), 6.51-6.47 (m, 211), 6.35 (s, 111), 5.35 (s, 2H), 3.89 (s, 311), 2.54 (s, 3H).

Preparation of methyl 3-methoxy-4-[(5-nitroindazol-1-yOmethyl]benzoate In like manner to the preparation of methyl 3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate, methyl 3-methoxy-4-[(5-nitroindazol-1-yl)methyl]benzoate was prepared by allcylation of 5-nitroindazoline with methyl (4-bromomethyl)-3-methoxybenzoate in presence of K2CO3. The desired product (47%) with high Rf value on the TLC in 30% Et0Ac : Hexanes as eluent was collected by silica gel column chromatographic purification. 1H NMR (CDC13): 8 8.73 (d, 1H, J = 1.8 Hz),8.26-8.22 (m, 2H), 7.56 (s, 1H), 7.54 (dd, 1H, J = 1.8 and 8.2 Hz), 7.49 (d, 111, J = 9.4 Hz), 6.98 (d, 1H, J
= 8.2 Hz), 5.66 (s, 2H), 3.91 (s, 311), 3.89 (s, 3H). Low Rf : Methyl 3-methoxy-4-[(5-nitroindazol-2-yl)methyl]benzoate.
Preparation of 5-nitro-142-methoxy-4-(o-toluylsulfonamidocarboxy)benzyllindazoline In like manner to the preparation of 6-nitro-142-methoxy-4-(o-toluylsulfonamidocarboxy)benzyllindazoline, 5-nitro-142-methoxy-4-(o-toluylsulfonamidocarboxy)benzyliindazoline was prepared from methyl 3-methoxy-4-[(5-nitroindazol-1-yl)methylThenzoate. 111 NMR (DMSO-d6): 8 8.81 (d, 111, J = 2.3 Hz), 8.39 (s, 111), 8.21 (dd, 111, J = 1.8 and 8.8 Hz), 7.87 (dd, 211, J = 3.6 and 8.8 Hz), 7.48 (d, 111, J =
1.2 Hz), 7.39 (dd, 111, J = 1.2 and 8.2 Hz), 7.33-7.15 (m, 3H), 6.85 (d, 1H, J
= 8.2 Hz), 5.65 (s, 211), 3.76 (s, 311), 2.49 (s, 3H).
Preparation of 5-amino-142-methoxy-4-(0-toluyl-sulfonamidocarboxy)benzyllindazoline . In like manner to the preparation of 6-amino-142-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline, 5-amino-142-methoxy-4-(o-toluylsulfonamidocarboxy)benzyllindazoline was prepared by reduction of 5-nitro-142-methoxy-4-(o-toluylsulfonarnidocarboxy)benzyl]indazoline . 111 NMR (DMSO-d6):
67.87 (dd, 111, J = 1.2 and 7.7 Hz), 7.73 (s, 1H), 7.50 (s, 111), 7.35-7.14 (m, 511), 6.78 (d, 111, J =
1.8 Hz), 6.75 (s, 111), 6.53 (d, 111, J = 8.2 Hz), 5.44 (s, 2H), 3.82 (s, 311), 2.50 (s, 311).

7.2.48 Preparation of 8-amino-4H-imidazo[2,1-c][1,4]-benzoxazine p4sio i& Mel ..4-0 H2isir=y0Me m NO
0 N 411)" NO2 =rice S".1 NO2 acetone MeS N = NO2 _______________________________________________ Et0 HMe OMe 2 reflux reflux .
Pd/C
twere NC X H2 so I NO2 WCy NH2 7.3 Synthesis of 2,4-Pyrimidinediamines A variety of 2,4-pyrimidinediamines of the invention were synthesized from the above starting materials and intermediates and other commercially available reagents.
Conditions suitable for synthesizing N2,N4-bis-substituted-2,4-pyrimidinediamine compounds ("general SNAr" reaction conditions; Substitution Nucleophilic Aromatic Reaction) are exemplified with N2,N4-bis(4-ethoxypheny1)-2,4-pyrimdinediamine (R926069) and N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R921218).
Conditions suitable for synthesizing asymmetric N2,N4-disubstituted-2,4-pyrimdinediarnines are exemplified by N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediame (R926210).
7.3.1 N2,N4-Bis(4-ethoxypheny1)-2,4-pyrimidinediamine (R926069) To a solution of 2,4-dichloropyrimidine (0.015g, 0.1 mmol) in Et0H (1 mL) was added 4-ethoxyaniline (0.034 g, 0.025 mmol) and heated in a sealed tube at 70-80 C for 24h. Upon cooling the reaction was diluted with 1120 (10 mL), acidified with 2N HC1, the solid obtained was filtered, washed with H20 and dried to give N2,N4-bis(4-ethoxypheny1)-2,4-pyrimidinediamine (R926069). 1H NMR (CD30D): 8 7.63 (d, 1H), 7.45 (d, 2H), J= 9 Hz), 7.32 (d, 211, J= 9.3 Hz), 6.95 (d, 2H, J= 6.9 Hz), 6.87 (d, 211, J= 8.7 Hz), 6.23 (d, 111, J= 7.2 Hz), 4.04 (m, 4H), 1.38 (m, 6H); LCMS: ret. time: 25.91 min.; purity:
99.5%; MS
(m/e): 351 (MT{).
7.3.2 N2,N4-Bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R921218) A mixture of 2,4-dichloro-5-fluoropyrimidine (0.0167 g, 0.1 mmol) and 3-aminophenol (0.033 g, 0.3 mmol) in MeOH: 1120 (1.8:0.2 mL; v/v) was shaken in a sealed tube at 100 C for 24h (or 80 oC for 3 days), cooled to room temperature, diluted with water (15 mL), acidified with 2N HC1 (pH >2). Upon saturation with sodium chloride it was extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate and solvent was removed. The resulting residue was filtered through a pad of silica gel (200-400 mesh) using CH2C12 - >1 >10% Me0H in CH2C12 to obtain the desired N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R921218). If the reaction scale is large enough, solid of the resulting product can be isolated by filtration. 111 NMR
(CDC13): 8 7.73 (d, 1H, J= 5.1 Hz), 7.12-6.90 (m, 6H), 6.64 (dd, 1H, J= 1.8 and 8.1 Hz), 6.53 (dd, 111, J= 1.2 and 5.7 Hz); LCMS: ret. time: 16.12 mm.; purity: 100%; MS (rn/e): 313 (MH+).
7.3.3 N2,N4-Bis(4-methoxypheny1)-5-fluoro-2,4-pyrimidinediamine (11926017) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-methoxyaniline were reacted to yield N2,N4-bis(4-methoxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR
(CD30D):
7.67 (d, 1H, J= 4.8 Hz), 7.43 (d, 2H, J= 9.3 Hz), 7.67 (d, 2H, J= 8.7 Hz), 6.87 (d, 2H, J= 9.6 Hz), 6.83 (d, 2H, J= 8.7 Hz), 3.83 (s, 3H), 3.81(s, 3H); LCMS: ret. time:
22.53 min.; purity:
100%; MS (m/e): 341 (MO.
7.3.4 N2,N4-Bis(3-fluoro-4-trifluoromethylpheny1)-5-fluoro-2,4-pyrimidinediamine (R926018) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-fluoro-4-trifluoromethylaniline were reacted to yield N2,N4-bis(3-fluoro-4-trifluoromethylpheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13): 8 8.01 (d, 1H, J= 3 Hz), 7.77 (m, 3H), 7.61 (dt, 1H, J= 4.2 and 3 Hz), 7.20 (t, 1H, 8.7 Hz), 7.12 (t, 111, J= 9.3 Hz), 6.95 (s, 1H), 6.82 (s, 1H); 19F
NMR (CDC13): 6-17505 (s, 3F), -17517 (s, 3F), -17525 (s, F), -17537 (s, F), -46835 (s,, 1F); LCMS: ret. time: 32.39 min.; purity: 95%, MS (m/e): 453 (MH ).
7.3.5 N2,N4-Bis(3,4-tetrafluoroethylendioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926037) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3,4-tetrafluoroethylenedioxyaniline were reacted to yield N2,N4-bis(3,4-tetrafluoroethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR
(CDC13): 8 8.01 (d, 1H, J= 3.0 Hz), 7.71 (d, 1H, J= 2.4 Hz), 7.70 (1H, d, J= 2.4 Hz), 7.18 (dd, 2H, J= 2.4 and 6 Hz), 7.07 (d, 2H, J= 1.8 Hz), 7.00 (1H, bs), 6.81 (d, 1H, J= 2.7 Hz); 19F
NMR (CDC13): -26029 (sept, 8F), -46791 (s, C5-F); LCMS: ret. time: 38.20 min.; purity: 85%;
MS (m/e):
541 (MH+).
7.3.6 N2,N4-Bis(3-trifluoromethoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926038) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-trifluoromethoxyaniline were reacted to yield N2,N4-bis(3-trifluoromethoxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H
NMR (CDC13): 8 8.03 (bd, 111), 7.62 (bs, 211), 7.48 (bd, 111), 7.39 (t, 1H, J=
8.1 Hz), 7.34 (m, 1H), 7.29 (t, 1H, J= 7.5 Hz), 7.01 (m, 211), 6.88 (m, 211); 19F NMR
(CDC13): -16447 (s, 3F), ¨16459 (s, 3F), -46738 (s, 1F); LCMS: ret. time: 33.77 min.; purity: 93%;
MS (m/e):
449 (M11+).
7.3.7 N2,N4-Bis(4-chloro-3-trifluoromethylpheny1)-5-fluoro-2,4-pyrimidinediamine (R926039) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-chloro-3-trifluoromethylaniline were reacted to yield N2,N4-bis(4-chloro-3-trifluoromethylpheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR (CDC13): 8 8.05 (bs, 111), 7.89 (bd, 111), 7.77 (dd, 111, J= 2.4 and 9 Hz), 7.65 (dd, 111, J= 2.4 and 8.7 Hz), 7.49 (d, J= 8.1 Hz), 7.40 (d, 111, J= 6.2 Hz), 7.03 (s, 111), 6.91 (s, 111); 19F NMR (CDC13): 8 ¨17864 (s, 3F), -17894 (s, 3F), -46550 (s, 1F); LCMS: ret. time: 38.81 min.; purity: 75%; MS (m/e): 485 (MH+).
7.3.8 N2,N4-Bis(3-ethoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926064) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-ethoxyaniline were reacted to yield N2,N4-bis(3-ethoxypheny1)-5-fluoro-2,4-pyiimidinediamine. 111 NMR
(CD30D): 8 7.96 (1H, d, J= 4.8 Hz), 7.22 (m, 611), 7.07 (t, 111, J= 1.8 Hz), 6.95 (dt, 111, J= 1.2 and 7.2 Hz), 6.77 (m, 211), 3.88 (q, 411, J= 6.3 Hz), 1.33 (two t, 611, J= 6.3 Hz);
19F NMR (CDC13): -46175; LCMS: ret. time: 26.86 min.; purity: 97%; MS (m/e): 369 (MH+).

7.3.9 N2,N4-Bis(3-hydroxy-4-methoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926339) In like manner to to N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methoxylaniline were reacted to yield N2,N4-bis(3-hydroxy-4-methoxypheny1)-5-fluoro--2,4-pyrimidinediamine. 111 NMR
(CD30D): 8 7.82 (d, 111 J= 4 Hz), 7.18 (m, 211), 6.95 (m, 2H), 6.83 (m, 2H) 3.93 (s, 6H);
LCMS: ret. time: 16.63 min.; purity: 97 %; MS (m/e): 373 (M11+).
7.3.10 N2,N4-Bis(4-ethoxycarbonylamino-3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926340) In like manner to to N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-primidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-ethoxycarbonylamino-3-hydroxyaniline were reacted to yield N2,N4-bis(4-ethoxycarbonylamino-3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD30D): 8 7.86 (d, 1H J= 4 Hz), 7.67 (m, 211), 7.20 (dd, 111, J= 8 Hz, J= 4.1 Hz), 7.13 (d, 1H), 6.90 (m, 211), 4.2(m, 4H), 1.32 (m, 611); LCMS: ret.
time: 20.92 mm.; purity: 98 %; MS (m/e): 487 (MI1+).
7.3.11 N2,N4-Bis(-3-hydroxy-4-methylpheny1)-5-fluoro-2,4-pyrimidinediaminediamine (R926341) In like manner to N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methylaniline were reacted to yield N2,N4-bis(-3-hydroxy-4-methylpheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR
(CD30D): 8 7.83 (d, 111 J= 4 Hz), 7.11 (m, 4H), 6.81 (m, 2H), 2.19 (m, 611);
LCMS: ret.
time: 20.69 min.; purity: 98 %; MS (m/e): 341 (MO.
7.3.12 N2,N4-Bis[4-(2-methoxyethyleneoxy)pheny11-5-fluoro--2,4-pyrimidinediamine (R926342) In like manner to N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-(2-methoxyethyloxy)aniline were reacted to yield N2,N4-bis[4-(2-methoxyethyleneoxy)pheny1]-5-fluoro-2,4-pyrimidinediamine. 111 NMR
(CD30D): 67.89 (d, 111 J= 4 Hz), 7.54 (dd, 2H, J= 6.8 and 2.7 Hz), 7.38 (dd, 2H, J= 6.8 and 2.7 Hz), 6.87 (dd, 2H, J= 6.8 and 2.7 Hz), 6.82 (dd, 211, J= 6.8 and 2.7 Hz) 4.6 (m, 411), 4.11 (m, 411), 3.35 (m, 611); LCMS: ret. time: 21.76 min.; purity: 97 %; MS
(m/e): 429 MO.

7.3.13 N2,N4-Bis(dihydrobenzofuran-5-y1)-5-fluoro-2,4-pyrimidinediaminediamine (R909237) In like manner to N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 5-amino-2,3-dihydrobenzofuran were reacted to yield N2,N4-bis(dihydrobenzofuran-5-y1)-5-fluoro-2,4-pyrimidinediaminediamine. 1H
NMR
(CD30D): 67.99 (d, 1H J= 4 Hz), 7.22 (m, 4H), 6.81 (m, 2H), 4.55 (m, 4H), 3.22 (m, 4H);
LCMS: ret. time: 23.80 min.; purity: 98 %; MS (m/e): 438 (MH+).
7.3.14 N2,N4-Bis(3-methoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926065) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrirnidine and 3-methoxyaniline were reacted to yield N2,N4-bis(3-methoxypheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR
(CD30D):
7.96 (d, 1H, J= 5.4 Hz), 7.24 (m, 6H), 7.06 (t, 1H, J= 2.4 Hz), 7.00 (dt, 111, J= 1.2 Hz), 6.79 (m, 1H), 3.72 (s, 3H), 3.70 (s, 3H); 19F NMR (CD30D): 8 - 46112; LCMS: ret.
time: 23.46 mm.; purity: 99%; MS (m/e): 341 (MH+).
7.3.15 N2,N4-Bis[4-(N,N-dimethylamino)pheny1]-5-fluoro-2,4-pyrimidinediamine (R926086) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-N,N-dimethylaniline were reacted to yield N2,N4-bis[4-(N,N-dimethylamino)pheny1]-5-fluoro-2,4-pyrimidinediamine.
1H NMR (CDC13): 8 7.84 (d, 1H, J= 3.6 Hz), 7.43 (d, 2H, J= 8.7 Hz), 7.34 (d, 2H, J= 8.7 Hz), 7.25 (s, 1H), 6.73 (m, 4H), 6.55 (s, 1H), 2.95 (s, 6H), 2.90 (s, 6H); 19F
NMR (CDC13): -47770; LCMS: ret. time: 12.48 min.; purity: 99%; MS (m/e): 367 (MH+).
7.3.16 N2,N4-Bis(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926109) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3,4-ethylenedioxyaniline were reacted to yield N2,N4-bis(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H
NMR (CDC13): 8 7.88 (d, 111, J= 3.6 Hz), 7.23 (d, 1H, J= 2.3 Hz), 7.15 (d, 1H, J= 2.4 Hz), 7.00 (dd, 1H, J= 3 and 8.1 Hz), 6.98 (dd, 1H, J= 3 and 8 Hz), 6.83 (d, 111, J=8.7 Hz), 6.81 (d, 1H, J= 8.7 Hz), 6.7(s, 1H), 6.58 (s, 1H), 4.23 (m, 4H), 4.24(m, 4H); 19F
NMR (CDC13):
6- 47445; LCMS: ret. time: 21.81 min.; purity: 96%; MS (m/e): 397 (MO.

7.3.17 N2,N4-Bis(3,4-dimethoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926110) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3,4-dimethoxyaniline were reacted to yield N2,N4-bis(3,4-dimethoxypheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR
(CDC13): 6 7.90 (d, 111, J= 1.8 Hz), 7.13 (d, 2H, J= 4.8 Hz), 7.08 (d, 111, J.= 8.7 Hz), 6.94 (d, 2H, J= 10.5 Hz), 6.81 (d, 1H, J= 8.7 Hz), 6.76 (d, 1H, J= 8.7 Hz), 6.70 (s, 111), 3.87 (s, 311), 3.84 (s, 3H), 3.74 (s, 3H), 3..71 (s, 3H); 19F NMR (CDC13): 8 - 47433; LCMS:
ret. time:
19.64 mm.; purity: 95%; MS (m/e): 401 (MO.
7.3.18 N2,N4-Bis[4-(N-morpholino)pheny1]-5-fluoro-2,4-pyrimidinediamine (R926114) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-N-morpholinylaniline were reacted to yield N2,N4-bis[4-N-morpholinyl)pheny1]-5-fluoro-2,4-pyrimidinediamine. 111 NMR (CD30D): 8 7.80 (s, 111), 7.78 (s, 1H, partially exchanged), 7.76 (bs, 111, partially exchanged), 7.53 (d, 2H, J= 8.1 Hz), 7.39 (d, 211, J= 9 Hz), 6.93 (d, 2H, J=
8.7 Hz), 6.86 (bd, 211), 3.84 (m, 8H), 3.11 (m, 811); 19F NMR (CD30D): 8 - 47697; LCMS: ret.
time:
18.15 min.; purity: 99.55%; MS (m/e): 451 (WO.
7.3.19 N2,N4-Bis(4-chloropheny1)-5-fluoro-2,4-pyrimidinediamine (R926206) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-chloroaniline were reacted to yield N2,N4-bis(4-chloropheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR (CDC13 +
CD30D): 67.80 (d, 1H, J= 4.2 Hz), 7.45 (d, 2H, J= 8.7 Hz), 7.33 (d, 2H, J= 9 Hz), 7.20 (d, 211, J= 8.7 Hz), 7.14 (d, 211, J= 9.6 Hz); LCMS: ret. time: 28.84 min.;
purity: 87%; MS
(m/e): 349 (MH+).
7.3.20 N2,N4-Bis(3-chloropheny1)-5-fluoro-2,4-pyrimidinediamine (R926209) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediarnine, 2,4-dichloro-5-fluoropyrimidine and 3-chloroaniline were reacted to yield N2,N4-bis(3-chloropheny1)-5-fluoro-2,4-pyrimidinediamine. 1E1 NMR
(CD30D): 8 8.08 (d, 1H, J= 5.4 Hz), 7.70 (t, 1H, J= 1.8 Hz), 7.57 (t, 1H, J= 1.2 Hz), 7.54 (m, 111), 7.35 (m, 4H), 7.28 (t, 1H, J= 1.8 Hz), 7.24 (m, 1H), 7.22 (t, 1H, J= 1.8 Hz); 19F
NMR (CD30D):
- 43631; LCMS: ret. time: 28.99 min.; purity: 99%; MS (m/e): 349 (M+).
7.3.21 N2,N4-Bis(4-tert-butylpheny1)-5-fluoro-2,4-pyrimidinediamine (R926222) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-tert-butylaniline were reacted to yield N2,N4-bis(4-tert-butylpheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR
(CDC13): 8 7.77 (d, 1H, J= 3.9 Hz), 7.47 (d, 211, J= 9Hz), 7.38 (m, 411), 7.30 (d, 211, J= 8.7 Hz), 1.34 (s, 9H), 1.32 (s, 9H); LCMS: ret. time: 34.09 mm.; purity: 93%; MS: 393 (M114).
7.3.22 N2,N4-Bis(3-ehloro-4-fluoropheny1)-5-fluoro-2,4-pyrimidinediamine (R926223) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline were reacted to yield N2,N4-bis(3-chloro-4-fluoropheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR (CDC13 + CD30D)): 67.81 (d, 111), 7.60 (m, 111), 7.58 (m, 111), 7.38 (m, 111), 7.19 (m, 111), 7.0 (m, 211); LCMS: ret. time: 28.98 mm.; purity: 97%; MS (rn/e):
385 (M4).
7.3.23 N2,N4-Bis(4-fluoropheny1)-5-fluoro-2,4-pyrimidinediamine (R926224) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-fluoroaniline were reacted to yield N2,N4-bis(4-fluoropheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR
(CDC13): 8 8.79 (d, 211, J= 5.4 Hz), 7.40 (m, 211), 7.30 (m, 211), 6.90 (m, 411); 19N4R
(CDC13): - 32425 (s, 1F), -32940 (s, 1F), -45525 (s, 1F); LCMS: ret. time: 23.53 min.; purity:
100%; MS
(m/e): 317 (MH4).
7.3.24 N2,N4-Bis(4-methylpheny1)-5-fluoro-2,4-pyrimidinediamine (R926225) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-methylaniline were reacted to yield N2,N4-bis(4-methylpheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR
(CDC13): 8 7.73 (d, 111, J= 4.2 Hz), 7.43 (d, 2H, J= 8.1 Hz), 7.36 (d, 211, J= 8.4 Hz), 7.14 (d, 211, J= 8.4 Hz), 7.10 (d, 211, J= 8.1 Hz), 2.39 (s, 3H), 2.35 (s, 3H); LCMS: ret. time:
25.81 min.; purity:
99.65%; MS (m/e): 309 (Mu').
7.3.25 N2,N4-Bis[(4-methoxycarbony1methy1eneoxy)pheny11-5-fluoro-2,4-pyrimidinediamine (R926240) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and ethyl 4-aminophenoxyacetate were reacted to yield N2,N4-bis[(4-methoxycarbonyhnethyleneoxy)pheny1]-5-fluoro-2,4-pyrimidinediamine. 111 NMR (CD30D): 8 7.8 (bs, 1H), 7.50 (d, 211, J= 9.3 Hz), 7.32 (d, 211, J= 8.41 Hz), 6.88 (m, 411), 4.72 (s, 2H), 4.70 (s, 211), 3.79 (s, 3H), 3.78 (s, 311); 19F
NMR (CDC13): -47570; LCMS: ret. time: 21.17 min.; purity: 95%; MS (m/e): 457 (MH+).
7.3.26 ( )-N2,N4-Bis[4-methoxycarbonyl(a-methyl)methyleneoxypheny1]-5-fluoro-2,4-pyrimidinediamine (R926254) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and ( )-ethyl 2-(4-aminophenoxy)propionate were reacted to yield ( )-N2,N4-bis[4-methoxycarbonyl(a-methyl)methyleneoxypheny1]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13):
67.89 (bs, 111), 7.48 (dd, 211, J= 2.4 and 6.9 Hz), 7.40 (dd, 2H, J= 1.8 and 6.9 Hz), 6.85 (m, 4H), 6.76 (s, 1H), 6.63 (s, 1H), 4.75 (hex, 211, J= 6.3 Hz), 3.77 (s, 311), 3.76 (s, 311), 1.62 (t, 6H, J= 7.5 Hz); LCMS: ret. time: 23.76 min.; purity: 97%; MS (mile): 485 (MH+).
7.3.27 N2,N4-Bis[(3-methoxycarbonylmethyleneoxy)pheny1]-5-fluoro-2,4-pyrimidinediamine (R926255) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and ethyl 3-aminophenoxyacetate were reacted to yield N2,N4-bis[(3-methoxycarbonylmethyleneoxy)pheny1]-5-fluoro-2,4-pyrimidinediamine. 111 NMR (CDC13): 67.96 (d, 1H, J= 2.4 Hz), 7.71 (t, 111, J=
2.4 Hz), 7.44 (m, 2H), 7.21 (m, 3H), 6.96 (dd, 111, J= 1.2 and 7.8 Hz), 6.86 (d, 1H, J=
3 Hz), 6.53 (m, 111), 4.64 (s, 211), 4.60 (s, 211), 3.79 (s, 611); LCMS: ret. time: 21.72 min.; purity: 87%;
MS (m/e): 457 (MH+).

7.3.28 N2,N4-Bis(3-acetyloxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926387) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-acetoxyaniline were reacted to yield N2,N4-bis[(3-acetoxypheny1]-5-fluoro-2,4-pyrimidinediamine.
Alternatively, N2,N4-bis[(3-acetoxypheny1]-5-fluoro-2,4-pyrimidinediamine can be prepared by acetylation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine with acetyl chloride in the presence of pyridine in CH2C12. NMR (CDC13): 6 8.00 (bs, 1H), 7.51-7.25(m, 8H), 2.32 (s, 3H), 2.28 (s, 3H); LCMS: ret. time: 22.14 min; purity: 100%; MS (m/e): 397 (MH+).
7.3.29 N2,N4-Bis(3-benzyloxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926394) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-primidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-benzyloxyaniline were reacted to yield N2,N4-bis(3-benzyloxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR
(CDC13): 8 7.98 (bs, 1H), 7.42-6.99 (m, 16H), 6.75 (d, 1H, J= 2.4 Hz), 6.71 (m, 1H), 6.60 (dd, 1H, J= 2.4 and 8.4 Hz), 6.32 (m, 1H), 4.97 (s, 2H), 4.94 (s, 2H); LCMS:
ret. time:
32.56 min.; purity: 98%; MS (m/e): 493 (MH+).
7.3.30 N2,N4-Bis(2-phenylpheny1)-5-fluoro-2,4-pyrimidinediamine (R926398) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-phenylaniline were reacted to yield N2,N4-bis[(2-phenylpheny1]-5-fluoro-2,4-pyrimidinediamine. 1H NMR
(CDC13):
8 8.35 (m, 1H), 8.0 (s, 1H), 7.85 (s, 1H), 7.45-7.00 (m, 18H); LCMS: ret.
time: 30.29 min.;
purity: 68%; MS (m/e): 433 (MHf).
7.3.31 (R926404) N2, N4-Bis(2-phenylpheny1)-5-methy1-2,4-pyrimidinediamine In like manner to the preparation of 5-fluoro-N2,N4-bis(3-hydroxypheny1)-2,4-pyrirnidinediamine, 2-aminobiphenyl and 2,4-dichloro-5-methylpyrimidine were reacted to provide N2, N4-bis(2-phenylpheny1)-5-methyl-2,4-pyrirnidinediamine. LCMS: ret.
time:
30.47 min.; purity: 91%; MS (m/e): 429 (MH4).

7.3.32 N2,N4-Bis[(4-methoxy-3-phenyl)pheny1]-5-fluoro-2,4-pyrimidinediamine (R926399) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-methoxy-3-phenylaniline were reacted to yield N2,N4-bis[(4-methoxy-3-phenyl)pheny1]-5-fluoro-2,4-pyrimidinediamine.
111 NMR (CD30D): 8 7.83 (d, 1H, J= 4.2 Hz), 7.57 (bd, 111, J= 8.7 Hz), 7.48 (d, 111, J= 2.7 Hz), 7.47-7.22 (m, 12H), 6.85 (d, 1H, J= 8.7 Hz), 6.78 (d, 111, 9.3 Hz), 3.72 (s, 3H), 3.69 (s, 3H); LCMS: ret. time: 29.97 min.; purity: 92%; MS (m/e): 493 (MIl+).
7.3.33 N2,N4-Bis[(2-methoxy-5-phenyl)pheny1]-5-fluoro-2,4-pyrimidinediamine (R926400) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-methoxy-5-phenylaniline were reacted to yield N2,N4-bis[(2-methoxy-5-phenyl)pheny1]-5-fluoro-2,4-pyrimidinediamine.
1H NMR (CD30D): 8 8.03 (d, 1H, J= 6.6 Hz), 7.76 (t, 1H, J= 2.4 Hz), 7.28-7.10 (m, 13H), 7.07 (d, 1H, J= 9 Hz), 7.01 (d, 1H, J= 8.1 Hz), 3.91 (s, 3H), 3.86 (s, 3H);
LCMS: ret. time:
18.58 min.; purity: 96%; MS (mile): MH+).
7.3.34 N2,N4-Bis[(2-methoxy-5-methy1-4-phenyl)pheny1]-5-fluoro-2,4-pyrimidinediamine (R926401) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-methoxy-5-methy1-4-phenylaniline were reacted to yield N2,N4-bis[(2-methoxy-5-methy1-4-phenyl)pheny1]-5-fluoro-2,4-pyrimidinediamine. 111 NMR (CD30D): 8 8.00 (d, 1H, J= 4.8 Hz), 7.73 (s, 1H), 7.66 (s, 1H), 7.43-7.24 (m, 9H), 6.91 (s, 1H), 6.82 (s, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 2.14 (s, 3H), 1.99 (s, 3H); LCMS: ret. time: 19.98 mm.; purity: 99%; MS (m/e): 521 (MH+).
7.3.35 N2,N4-Bis[(2-methy1-5-phenyl)pheny1]-5-fluoro-2,4-pyrimidinediamine (R926402) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-methyl-5-phenylaniline were reacted to yield N2,N4-bis[(2-methy1-5-phenyl)pheny1]-5-fluoro-2,4-pyrimidinediamine.
1H NMR (CD30D): 67.84 (bd, 1H), 7.51-7.20(m, 16H), 2.30 (s, 311), 2.24 (s, 3H); LCMS:
ret. time: 18.57 min.; purity: 87%; MS (m/e): 461 (MO.

7.3.36 N2,N4-Bis[(3-phenyl)pheny1]-5-fluoro-2,4-pyrimidinediamine (R926403) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-phenylaniline were reacted to yield N2,N4-bis[(3-phenyl)pheny1]-5-fluoro-2,4-pyrimidinediamine. 1H NMR
(CD30D): 8 8.02 (d, 1H, J= 5.1 Hz), 7.82 (t, 1H, J= 1.5 Hz), 7.67 (t, 1H, J= 1.8 Hz), 7.58 (dd, 111, J= 1.2 and 7.2 Hz), 7.42-7.24 (m, 15H); LCMS: ret. time: 32.06 min.; purity: 94%; MS
(m/e): 433 MO.
7.3.37 N2,N4-Bis(4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926405) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyriinidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-acetoxyaniline were reacted to yield N2,N4-bis[(4-hydroxypheny1]-5-fluoro-2,4-pyrimidinediamine. After the work up it was observed that the acetoxy group was hydrolyzed to afford the N2,N4-bis(4-hydroxypheny1)-5-fluoro-2,4-primidinediamine instead of the corresponding acetate derivative. 1H NMR (CD30D): 8 7.74 (d, 1H, J= 5.6 Hz), 7.43 (dd, 2H, J= 2.1 and 6.6 Hz), 7.28 (dd, 2H, J= 2.4 and 6.3 Hz), 6.74 (dd, 2H, J= 2.4 and 6.3 Hz), 6.66 (dd, 2H, J= 2.4 and 7.2 Hz); 19F NMR (CD30D): -48116 (d, 1F); LCMS: ret. time: 16.15 min; purity:
100%;
MS (m/e): 313 (MH4).
7.3.38 N2,N4'-Bis(4-hydroxy-3-methylpheny1)-5-fluoro-2,4-pyrimidinediamine (R926469) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-primidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-hydroxy-3-methylaniline were reacted to yield N2,N4-bis[(4-hydroxy-3-methylpheny1]-5-fluoro-2,4-pyrimidinediamine.
1H NMR (CD30D): 8 7.64 (d, 1H, J= 3.6 Hz), 7.11 (t, 2H, J= 9 Hz), 6.70-6.45 (m, 4H), 2.15 (s, 3H), 2.09 (s, 3H); 19F NMR (CD30D): - 46278; LCMS: ret. time: 15.53;
purity: 84%;
MS (rn/e): 341 (MH+).
7.3.39 N2,N4-Bis[4-(tert-butoxycarbonylmethyleneoxy)pheny11-5-fluoro-2,4-pyrimidinediamine (R926574) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and tert-butyl 4-aminophenoxyacetate were reacted to yield N2,N4-bis[4-(tert-butoxycarbonyhnethyleneoxy)pheny1]-5-fluoro-2,4-pyrimidinediamine 1H NMR (CDC13): 6 7.88 (s, 111), 7.48 (d, 2H, J= 8.4 Hz), 7.40 (d, 2H, J= 8.7 Hz), 6.86 (m, 411), 4.52 (s, 211), 4.48 (s, 211), 1.49 (s, 911), 1.48 (s, 9H); LCMS: ret.
time: 28.48 min.; purity: 95%; MS (m/e): 541 (MO.
7.3.40 N2,N4-Bis(indo1-5-y1)-5-fluoro-2,4-pyrimidinediamine (R926582) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 5-aminoindole were reacted to yield N2,N4-bis(indo1-5-y1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time:
20.26 min.;
purity: 99%; MS (m/e): 359 (MH+).
7.3.41 N2,N4-Bis(4-eyanomethylpheny1)-5-ethoxycarbony1-2,4-pyrimidinediamine (R926319) In like marmer to N2,N4-bis(3-hydroxypheny1)-5-ethoxycarbony1-2,4-pyrimidinediamine, 2,4-dichloro-5-ethoxycarbonylpyrimidine and 4-cyanomethylaniline were reacted to yield N2,N4-bis(4-cyanomethylpheny1)-5-ethoxycarbony1-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 8.72 (s, 1H), 7.64 (m, 411), 7.32 (d, 211, J= 8.7 Hz), 7.21 (d, 211, J= 8.4 Hz), 4.3 (q, 211, J= 7.0 Hz), 3.97 (s, 211,), 3.89 (s, 211), 1.32 (3H, J=
7 Hz); LCMS: ret. time: 30.83 min.; purity: 90 %; MS (m/e): 413 (MO.
7.3.42 N2,N4-Bis(3-indazol-6-y1)-5-ethoxycarbony1-2,4-pyrimidinediamine (R926320) In like manner to N2,N4-bis(3-hydroxypheny1)-5-ethoxycarbony1-2,4-pyrimidinediamine, 2,4-dichloro-5-ethoxycarbonylpyrimidine and 6-aminoindazole were reacted to yield N2,N4-bis(6-indazoly1)-5-ethoxycarbony1-2,4-pyrimidinediamine. 1H NMR
(DMSO-d6): 6 8.76 (s, 1H), 7.73(d, 2H J= 8.8), 7.54 (m, 411), 7.36 (d, 211, J=
9.5 Hz), 4.3 (q, 211, J= 7.0 Hz), 1.34 (311, J= 7 Hz); LCMS: ret. time 27.59 min.; purity:
95 %; MS
7.3.43 N2,N4-Bis(3-indazol-7-y1)-5-ethoxycarbony1-2,4-pyrimidinediamine (R926321) In like manner to N2,N4-bis(3-hydroxypheny1)-5-ethoxycarbony1-2,4-pyrimidinediamine, 2,4-dichloro-5-ethoxycarbonylpyrimidine and 7-aminoindazole were (DMSO-d6): 8 8.70 (s, 1H), 7.54 (d, 211 J.= 8.4 Hz), 7.37 (m, 611), 4.3 (q, 211, J= 7.0 Hz), 1.33 (3H, J= 7 Hz); LCMS: ret. time 23.61 min.; purity: 94 %; MS (m/e): 415 W).
7.3.44 N2,N4-Bis[6-(1,4-benzoxazine-3-ony1)]-5-ethoxycarbony1-2,4-pyrimidinediamine (R926325) In like marmer to to N2,N4-bis(3-hydroxypheny1)-5-ethoxycarbony1-2,4-pyrimidinediamine, 2,4-dichloro-5-ethoxycarbonylpyrimidine and 6-amino-1,4-benzoxazine-3-one were reacted to yield N2,N4-bis[6-(1,4-benzoxazine-3-ony1)]-ethoxycarbony1-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 8.66 (s, 1H), 7.21 (dd, 211 J= 8.8 and J= 2.2 Hz), 6.89 (d, 211 J= 8.4 Hz), 4.54 (s, 211) 4.49 (s, 211) 4.3 (q, 211, J= 7.0 7.3.45 N2,N4-Bis(4-ethoxycarbonylmethyleneaminopheny1)-5-ethoxycarbony1-2,4-pyrimidinediamine (R926331) In like manner to to N2,N4-bis(3-hydroxypheny1)-5-ethoxycarbony1-2,4-pyrimidinediamine, 2,4-dichloro-5-ethoxycarbonylpyrimidine and 4-20 7.3.46 N2,N4-Bis(4-ethoxypheny1)-6-methoxycarbony1-2,4-pyrimidinediamine (R926058) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-6-methoxycarbonylpyrimidine with 4-ethoxyaniline gave N2,N4-bis(4-ethoxypheny1)-6-methoxycarbony1-2,4-pyrimidinediamine.
7.3.47 N2,N4-Bis(4-ethoxypheny1)-5-methyl-2,4-pyrimidinediamine (R926068) 30 In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-methylpyrimidine with 4-ethoxyaniline gave N2,N4-bis(4-ethoxypheny1)-5-methyl-2,4-pyrimidinediamine.

(CD30D): 8 7.55 (s, 1H), 7.40 (d, 211), 7.21 (d, 2H, J= 8.7 Hz), 6.90 (dd, 4H, J= 8.7 Hz), 4.04 (q, 4H, J= 6.6 Hz), 2.17 (m, 6H); LCMS: ret. time: 26.51 min.; purity:
95%; MS (m/e):
365 (1V111+).
7.3.48 N2,N4-Bis(4-ethoxypheny1)-6-chloro-2,4-pyrimidinediamine (R926072) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4,6-trichloropyrimidine with 4-ethoxyaniline gave N2,N4-bis(4-ethoxypheny1)-6-chloro-2,4-pyrimidinediamine. 1H NMR (CDC13): 8 7.42 (d, 2H, J= 9 Hz), 7.18 (d, 211, J= 8.7 Hz), 6.89 (d, 211, J= 6.3 Hz), 6.84 (d, 2H, J= 8.7 Hz), 6.58 (bs, 111), 4.02 (m, 4H), 1.43 (m, 6H); LCMS: ret. time: 83.21 min.; purity:
87%; MS (m/e):
385 (MH+).
7.3.49 N2,N4-Bis(3,4-ethylenedioxypheny1)-5-methy1-2,4-pyrimidinediamine (R926242) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-methylpyrimidine with 3,4-ethyleneoxyaniline gave N2,N4-bis(3,4-ethylenedioxypheny1)-5-methy1-2,4-pyrimidinediamine. 111 NMR (CD30D): 8 7.75 (bs, 1H), 7.06 (d, 1H, J= 2.4 Hz), 6.96 (d, 111, J= 2.1 Hz), 6.94 (d, 1H, J= 2.1 Hz), 6.85-6.77 (m, 2H), 6.70 (d, 111, J=
9 Hz), 4.23 (s, 411), 4.19 (s, 411), 2.09 (s, 3I1); LCMS: ret. time: 22.01 min.; purity: 100%;
MS (m/e): 393 0110.
7.3.50 N2,N4-Bis(3,4-ethylenedioxypheny1)-2,4-pyrimidinediamine (R926243) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloropyrimidine with 3,4-ethyleneoxyaniline gave N2,N4-bis(3,4-ethylenedioxypheny1)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 10.95 (s, 111), 10.50 (s, 1H), 7.84 (bd, 211), 7.24 (bd, 2H), 6.79 (bd, 211), 6.40 (bd, 211), 4.24 (s, 811); LCMS: ret. time: 21.68 min.; purity: 100%; MS (m/e): 379 (MH+).

7.3.51 N2,N4-Bis(3-hydroxypheny1)-5-methyl-2,4-pyrimidinediamine (R926248) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-methylpyrimidine with 3-hydroxyaniline gave N2,N4-bis(3-hydroxypheny1)-5-methyl-2,4-pyrimidinediamine.
LCMS: ret. time: 16.76 min.; purity: 100%, MS (m/e): 309 (MO.
7.3.52 N2, N4-Bis(3-hydroxypheny1)-2,4-pyrimidinediamine (R926249) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloropyrimidine with 3-hydroxyaniline gave N2,N4-bis(3-hydroxypheny1)-2,4-pyrimidinediamine. LCMS: ret. time: 16.21 min.;
purity:
100%; MS (m/e): 295 (M1-14).
7.3.53 N2,N4-Bis[(4-methoxycarbonylmethyleneoxy)pheny1]-2,4-pyrimidinediamine (R926256) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloropyrimidine with methyl 4-aminophenoxyacetate gave N2,N4-bis[(4-methoxycarbonyhnethyleneoxy)pheny1]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 10.7 (bs, 1H), 10.28 (bs, 1H), 784 (d, 1H, 6.9 Hz), 7.48 (bd, 2H), 7.35 (d, 211, J=. 8.7 Hz), 6.95 (d, 2H, J 9 Hz), 6.90 (d, 2H, J.= 8.7 Hz), 6.35, (d, 111, J.=, 6.9 Hz), 4.81 (s, 211), 4.79 (s, 211), 3.69 (s, 3H), 3.68 (s, 3H); LCMS:
ret. time: 21.27 min.; purity: 98%; MS (m/e): 439 (MH4).
7.3.54 ( )-N2,N4-Bis[4-methoxyearbonyl(alpha-methyl)methyleneoxypheny1]-2,4-pyrimidinediamine (R926257) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloropyrimidine with ( )-methyl 2-(4-aminophenoxy)propionate gave ( )-N2,N4-bis[4-methoxycarbonyl(alpha-methypmethyleneoxyoxypheny1]-2,4-pyrimidinediamine. LCMS: ret. time: 24.09 min.;
purity: 90%; MS (m/e): 467 (MH4).

7.3.55 N2,N4-Bis(4-methoxycarbonylmethyleneoxypheny1)-5-methy1-2,4-pyrimidinediamine (R926258) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-methylpyrimidine with methyl-4-aminophenoxyacetate gave N2,N4-bis(4-methoxycarbonyhnethyleneoxypheny1)-5-methy1-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 10.21 (s, 1H), 9.65 (s, 1H), 7.78 (s, 111), 7.42 (dd, 2H), J= 2.7 and 8.7 Hz), 7.28 (dd, 2H, J= 8.1 Hz), 6.94 (d, 2H, J=
8.47 Hz), 6.85 (d, 2H, J= 8.7 Hz), 4.82 (s, 2H), 4.77 (s, 2H), 3.69 (s, 3H), 3.68 (s, 3H), 2.12 (s, 3H);
LCMS: ret. time: 21.76 min.; purity: 100%; MS (m/e): 453 (MH+).
7.3.56 ( )-N2,N4-Bis[4-ethoxyearbonyl(alpha-methyl)methyleneoxypheny11-5-methy1-2,4-pyrimidinediamine (R926259) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-methylpyrimidine with ( )-ethyl 2-(4-aminophenoxy)propionate gave ( )-N2,N4-bis[4-ethoxycarbonyl(alpha-methyl)methyleneoxypheny1]-5-methy1-2,4-pyrimidinediamine. 1H NMR (DM5O-d6): 8 9.9 (bs, 1H), 9.35 (bs, 1H), 7.79 (s, 1H), 7.43 (dd, 2H, J= 3.6 and 8.7 Hz), 7.32 (d, 2H, J=
7.5 Hz), 6.86 (d, 2H, J= 9 Hz), 6.78 (d, 2H, J= 8.7 Hz), 4.95 (q, 1H, J= 7.2 Hz), 4.90 (q, 1H, J=7.2 Hz), 4.12 (2q, 4H, J= 5.7 Hz), 2.10 (s, 3H), 1.51 (d, 3H, J= 6.3 Hz), 1.47 (d, 3H, J=
6.3 Hz), 1.16 (2t, 6H, J= 5.7 Hz); LCMS: ret. time: 27.41 mm.; purity: 96%; MS
(m/e): 509 (MIT).
7.3.57 N2,N4-Bis[2-(4-hydroxyphenyl)ethy1]-5-methyl-2,4-pyrimidinediamine (R926397) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-methylpyrimidine with 2-(4-hydroxyphenypethylamine gave N2,N4-bis[2-(4-hydroxyphenyl)ethyl]-5-methy1-2,4-pyrirnidinediamine. LCMS: ret. time: 19.94 mm.; purity: 100%; MS (m/e): 365 (ME).
7.3.58 N2,N4-Bis-(3,4-dimethoxypeny1)-5-nitro-2,4-pyrimidinediamine (R940089) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-nitropyrimidine with 3,4-dimethoxyaniline gave N2,N4-bis-(3,4-dimethoxypheny1)-5-nitro-2,4-pyrimidinediamine.

LCMS: ret. time: 28.30 mm.; purity: 100%; MS (m/e): 428 (ME); 111NMR (CDC13):
6 10.30 (1H, s), 9.14 (1H, s), 7.52 (111, s), 7.08 (311, m), 7.00 (1H, d, J=
8.4 Hz), 6.84 (1H, d, J= 8.4 Hz), 6.76 (1H, d, J= 8.4 Hz), 3.90 (311, s), 3.87 (311, s), 3.68 (311, s), 3.60 (3H, s).
7.3.59 N2,N4-Bis-(4-ethoxypeny1)-5-nitro-2,4-pyrimidinediamine (R940090) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-nitropyrimidine with 4-ethoxyaniline gave N2,N4-bis-(4-ethoxypheny1)-5-nitro-2,4-pyrimidinediamine. LCMS: ret.
time: 35.91 min.; purity: 100%; MS (m/e): 396 (Mife); 1H NMR (CDC13): 610.25(111, s), 9.11 (111, s), 7.44(211, d, J= 8.6 Hz), 7.37 (211, d, J= 9Hz), 6.88 (211, d, J= 8.6 Hz), 6.80 (2H, d, J= 8.6 Hz), 4.06 (211, q, J= 7.2 Hz), 4.02 (211, q, J= 7.2 Hz), 1.45 (3H, t, J= 7.2 Hz), 1.42 (311, t, J=
7.2 Hz).
7.3.60 N2,N4-Bis-(3,4-ethylenedioxypheny1)-5-nitro-2,4-pyrimidinediamine (R940095) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrirnidinediamine, the reaction of 2,4-dichloro-5-nitropyrimidine with 3,4-ethylenedioxyaniline gave N2,N4-bis-(3,4-ethylenedioxypheny1)-5-nitro-2,4-pyrimidinediamine. LCMS: ret. time: 30.78 mm.; purity: 100%; MS (m/e): 424 (MB); 111 NMR (CDC13): 6 10.21 (1H, s), 9.10(111, s), 7.40 (111, s), 7.11-6.71 (611, m), 4.29 (411, s), 4.25 (411, s).
7.3.61 N2,N4-Bis-[(4-ethoxyearbonylmethyleneoxy)pheny1]-5-nitro-2,4-pyrimidinediamine (R940096) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-nitropyrimidine with ethyl-4-aminophenoxyacetate gave N2,N4-bis-[(4-ethoxycarbonyhnethyleneoxy)pheny1]-5-nitro-2,4-pyrimidinediamine. LCMS: ret. time: 32.48 min.; purity: 94%; MS (m/e): 512 (MH+);
1H NMR (CDC13): 6 10.22 (1H, s), 9.13 (1H, s), 7.50 (1H, s), 7.45 (2H, d, J=
8.7 Hz), 7.38 (2H, d, J= 8.7 Hz), 6.93 (2H, d, J.= 8.7 Hz), 6.83 (2H, d, J= 8.7 Hz), 4.67 (2H, s), 4.63 (2H, s), 4.29 (211, q, J= 7.2 Hz, 4.28 (211, q, J= 7.2 Hz), 1.31 (311, t, J= 7.2 Hz), 1.30 (311, t, J=
7.2 Hz).

7.3.62 N2,N4-Bis-(2,2-difluoro-1,3-benzodioxo1-5-y1)-5-nitro-2,4-pyrimidinediamine (R940100) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-primidinediamine, the reaction of 2,4-dichloro-5-nitropyrimidine with 2,2-difluoro-5-amino-1,3-benzodioxole gave N2,N4-bis-(2,2-difluoro-1,3-benzodioxo1-5-y1)-5-nitro-2,4-pyrimidinediamine. LCMS: ret. time: 38.15 min.; purity: 96%; MS (m/e): 467 (M+); 1H
NMR (CDC13): 8 10.76 (1H, s), 10.49 (1H, s), 9.20 (1H, s), 7.74 (2H, s), 7.56 (1H, d, J=
11.4 Hz), 7.33 (2H, m), 7.20 (1H, m).
7.3.63 N2,N4-Bis-(3,5-dichloro-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R940215) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 3,5-dichloro-4-hydroxyaniline gave N2,N4-bis-(3,5-dichloro-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 21.26 min.; purity: 88%; MS (mile): 450 (M+); 111 NMR (DMSO-d6): 69.96 (1H, s), 9.59 (1H, s), 9.47 (1H, s), 9.37 (1H, s), 8.22 (1H, d, J=
3.6 Hz), 7.79 (2H, s), 7.74 (2H, s).
7.3.64 N2,N4-Bis-(3-chloro-4-hydroxy-5-methylpheny1)-5-fluoro-2,4-pyrimidinediamine (R940216) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-chloro-4-hydroxy-5-methylaniline gave N2,N4-bis-(3-chloro-4-hydroxy-5-methylpheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 20.55 min.; purity: 99%; MS (m/e): 410 (MH+);
1H NMR (DMSO-d6): 69.23 (1H, s), 9.07 (1H, s), 8.99 (1H, s), 8.66 (1H, s), 8.13 (1H, d, J= 3.6 Hz), 7.59 (2H, t, J= 3.1 Hz), 7.50 (1H, d, J= 2.3 Hz), 7.34 (1H, d, J=
2.3 Hz), 2.27 (3H, s), 2.18 (3H, s).
7.3.65 N2,N4-Bis-(2,3-dimethy1-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R940217) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 2,3-dimethy1-4-hydroxyaniline gave N2,N4-bis-(2,3-dimethy1-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 19.07 min.; purity: 99%; MS (mile): 369 (MH+); 1H
NMR (DMSO-d6): 8 9.21 (111, s), 8.99 (1H, s), 8.63 (111, s), 7.92 (1H, s), 7.84 (1H, d, J=

3.6 Hz), 6.94 (111, d, Jt= 8.5 Hz), 6.85 (111, d, J= 8.5 Hz), 6.70 (111, d, J=
8.5 Hz), 6.58 (111, d, J= 8.5 Hz), 2.12 (311, s), 2.06 (3H, s), 2.02 (3H, s), 1.94 (311, s).
7.3.66 N2,N4-Bis-(4-Acetamidopheny1)-5-fluoro-2,4-pyrimidinediamine (R940222) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-acetamidoaniline gave N2,N4-bis-(4-acetamidopheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret.
time:
14.82 min.; purity: 95%; MS (m/e): 395 (MH+); 111 NMR (DMSO-d6): 610.33 (1H, s), 10.14 (111, s), 10.07 (2H, s), 8.39 (111, d, J= 5.1 Hz), 7.64 (8H, m), 2.15 (311, s), 2.13 (311, s).
7.3.67 N2,N4-Bis(3-isopropylpheny1)-5-fluoro-2,4-pyrimidinediamine R940297 In like manner to the preparation of N2,N4-bis-(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoroprimidine and 3-isopropylaniline were reacted to give N2,N4-bis-(3-isopropylpheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret.
time:
29.58 min.; Purity: 98 %; MS (m/e): 365 (MH4); 1H NMR (DMSO-d6): 610.5 (111, s), 10.34 (111, s), 8.41 (111, d, J= 5.1 Hz), 7.62 (111, d, J= 8.1 Hz), 7.53 (1H, s), 7.43 (1H, d, J=
8.1 Hz), 7.37 (2H, m), 7.29 (1H, t, J= 8.1 Hz), 7.19 (111, d, J= 7.8 Hz), 7.08 (1H, d, J= 7.8 Hz), 2.88 (211, m), 1.25 (611, d, J= 7.2 Hz), 1.201 (6H, d, J= 7.2 Hz).
7.3.68 N2,N4-Bis(3,4,5-trimethoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926688) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3,4,5-trimethoxyaniline were reacted to yield N2,N4-bis(3,4,5-trimethoxypheny1)-5-fluoro-2,4-pyrimidinediamine.
LCMS: ret. time: 19.55 min.; purity: 99 %; MS (m/e): 461 (MO.
7.3.69 N2,N4-Bis(2-methy1-5-phenylpheny1)-5-bromo-2,4-pyrimidinediamine R925800 In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 5-bromo-2,4-dichloropyrimidine and 5-phenyl-ortho-toluidine were reacted to yield N2,N4-bis(2-methy1-5-phenylpheny1)-5-bromo-2,4-primidinediamine.
LCMS: ret. time: 19.54 min.; purity: 90 %; MS (m/e): 422 (Mir).

7.3.70 N2,N4-Bis(2-methoxy-5-methy1-4-phenylpheny1)-5-bromo-2,4-pyrimidinediamine (R925801) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 5-bromo-2,4-dichloropyrimidine 5-methyl-4-phenyl-ortho-anisidine were reacted to yield N2,N4-bis(2-methoxy-5-methy1-4-phenylpheny1)-5-bromo-2,4-pyrimidinediamine. LCMS: ret. time: 20.99 min.; purity: 85 %; MS (m/e): 583 (MH+).
7.3.71 N2,N4-Bis(indo1-6-y1)-5-fluoro-2,4-pyrimidinediamine (R926594) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 6-aminoindole were reacted to yield N2,N4-bis(indo1-6-y1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time:
22.39 min.;
purity: 85%; MS (m/e): 359 (MH+).
7.3.72 N2,N4-Bis(2-methoxycarbonyl benzofuran-5-y1)-5-fluoro-2,4-pyrimidinediamine (R926604) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-methoxycarbony1-5-aminobenzofuran were reacted to yield N2,N4-bis(2-methoxycarbonyl benzofuran-5-y1))-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 10.3 (bs, 1H), 10.05 (bs, 1H), 8.25 (d, 1H, J= 5.4 Hz), 8.06 (s, 1H), 7.94 (s, 1H), 7.77-7.49 (m, 5H), 7.36 (bs, 111), 3.89 (s, 3H), 3.87 (s, 3H).
7.3.73 N2,N4-Bis[4-(methovcarbonylmethyl)pheny1]-5-fluoro-2,4-pyrimidinediamine (R926605) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and ethyl 4-aminophenyl acetate were reacted to yield N2,N4-bis[4-(methoxycarbonyhnethyl)pheny1]-5-fluoro-2,4-pyrimidinediamine. The cross esterification reaction of ethyl ester to obtain the corresponding methyl ester was observed. 1H NMR (CDC13): 8 10.62 (s, 1H), 8.06 (s, 1H), 7.69 (d, 111, J= 4.5 Hz), 7.53 (d, 2H, J= 8.1 Hz), 7.43 (d, 211, J= 8.7 Hz), 7.30 (d, 2H, J= 8.4 Hz), 7.20 (d, 211, J= 8.4 Hz), 3.73 (s, 3H), 3.72 (s, 3H), 3.67 (s, 211), 3.63 (s, 2H).

7.3.74 N2,N4-Bis(2-ethoxycarbonylindo1-5-y1)-5-fluoro-2,4-pyrimidinediamine (R926616) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-ethoxycarbony1-5-indoleamine were reacted to yield N2,N4-bis(2-ethoxycarbonylindo1-5-y1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 611.83 (s, 111), 11.63 (s, 1H), 9.21 (s, 1H), 8.99 (s, 1H), 8.08 (s, 111), 8.01 (m, 211), 7.49-7.22 (m, 4H), 6.92 (s, 1H), 6.63 (s, 111), 4.29 (q, 411, J= 7.2 Hz), 1.32 (m, 611); LCMS: ret. time: 24.74 min.; purity: 99%; MS
(m/e): 503 (M11)-7.3.75 N2,N4-Bis(coumarin-6-y1)-5-fluoro-2,4-pyrimidinediamine (R926617) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 6-aminocournarin were reacted to yield N2,N4-bis(coumarin-6-y1)-5-fluoro-2,4-primidinediamine. 111 NMR (DMSO-d6):
8 8.17 (d, 211, J= 3.6 Hz), 7.97-7.74 (m, 511), 7.40 (111, d, J= 8.7 Hz), 7.30 (d, 111, J= 9Hz), 6.50 (d, 111, J= 10.2 Hz), 6.40 (d, 111, J= 9.3 Hz); LCMS: ret. time: 19.05 min.; purity: 94%;
MS (m/e): 417 (MH4).
7.3.76 N2,N4-Bis(4-methoxymethyl)coumarin-7-y1)-5-fluoro-2,4-pyrimidinediamine (R926620) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 7-amino-4-methoxymethylcoumarin were reacted to yield N2,N4-bis(coumarin-7-y1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR (DMSO-d6): 8 10.38 (s, 111), 8.42 (d, 111, J= 3 Hz), 8.28 (m, 111), 8.05-7.93 (m, 211), 7.77-7.50 (m, 411), 6.31 (s, 111), 6.29 (s, 111), 4.66 (s, 211), 4.65 (s, 2I1), 3.43 (s, 3H), 3,41 (s, 311); LCMS: MS (m/e): 505 (M114).
7.3.77 N2,N4-Bis(3-(hydroxymethyl)pheny1)-5-fluoro-2,4-pyrimidinediamine (R925757) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-aminobenzylalcohol were reacted to yield N2,N4-bis(3-(hydroxymethyl)pheny1)-5-fluoro-2,4-pyrimidinediamine. 1H
NMR (CD30D): 8 7.90 (d, 111, J= 3.3 Hz), 7.71 (m, 111), 7.61 (d, 111, J= 6.9 Hz), 7.50 (d, 1H, J= 6.0), 7.47 (s, 1H), 7.31 (t, 1H, J= 8.1 Hz), 7.22 (t, 1H, J= 8.1 Hz), 7.10 (d, 1H, J=
6.9), 6.97 (d, 1H, J= 7.5 Hz), 4.63 (s, 4H); LCMS: ret. time: 15.36 min.;
purity: 100%; MS
(m/e): 342 (MH+).
7.3.78 N2,N4-Bis[(2R)-hydroxy-(1S)-methy1-2-phenylethy11-5-fluoro-2,4-pyrimidinediamine (R925767) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrirnidine and (1R,2S)-(-)-norephedrine were reacted to yield N2,N4-bisR2R)-hydroxy-(1S)-methy1-2-phenylethyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (acetone-d6): 8 7.67 (s, 1H), 7.49-7.42 (m, 4H), 7.38-7.19 (m, 6H), 6.09 (d, 1H, J= 9.0 Hz), 5.73 (d, 1H, J= 7.5 Hz), 5.61 (d, 1H, J= 9.3 Hz), 5.04 (d, 1H, J= 3.6 Hz), 4.97 (d, 1H, J= 2.7 Hz), 4.74 (bs, 1H), 4.48 (bs, 1H), 4.30-4.25 (m, 1H), 1.09 (d, 1H, J= 6.9 Hz), 1.03 (d, 1H, J= 6.6 Hz); LCMS: ret. time: 21.56 min.; purity:
98%; MS
(m/e): 397(MH+).
7.3.79 N2,N4-Bis(2-hydroxy-2-phenylethyl)-5-fluoro-2,4-(R925768) In a marmer similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-amino-l-phenylethanol were reacted to yield N2,N4-bis(2-hydroxy-2-phenylethyl)-5-fluoro-2,4-pyrimidinediamine. 111 NMR (acetone-d6): 8 8.15 (s, 1H), 7.46-7.22 (m, 10H), 5.01 (dd, 1H), 4.91 (dd, 1H), 4.78 (dd, 111), 3.86-3.18 (m, 5H); LCMS: ret. time: 19.64 min.; purity: 89 %; MS
(mile): 369 NO.
7.3.80 N2,N4-Bis(furfury1)-5-fluoro-2,4-pyrimidinediamine (R925769) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and furfurylamine were reacted to yield N2,N4-bis(furfury1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR (CDC13): 8 7.72 (bs, 1H), 7.38 (dd, 2H, J= 1.8 and 7.5 Hz), 6.34-6.30 (m, 2H), 6.22 (dd, 2H, J= 2.4 and 9.9 Hz), 5.163 (bs, 211), 4.63 (d, 2H, J= 6.0), 4.54 (d, 211, J= 6.0).; 19F NMR
(CDC13): - 48621;
LCMS: ret. time: 97.27min.; purity: 97%; MS (m/e): 289 (MO.

7.3.81 N2,N4-Bis(piperony1)-5-fluoro-2,4-pyrimidineamine (R925770) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and pip eronylamine were reacted to yield N2,N4-bis(piperony1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13):
8 7.60 (bs, 1H), 6.78-6.69 (m, 6H), 5.93 (s, 211), 5.91 (s, 2H), 4.51 (d, 2H, J= 5.7 Hz), 4.43 (d, 211, J= 5.1 Hz); 19F NMR (CDC13): - 45257; LCMS: ret. time: 22.06 min.;
purity: 96%;
MS (m/e): 397 (MO.
7.3.82 N2,N4-Dibenzy1-5-fluoro-2,4-pyrimidinediamine (R925772) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and benzylamine were reacted to yield N2,N4-bis(benzy1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13): 67.69 (bs, 111), 7.35-7.24 (m, 1011), 5.63 (bs, 111), 5.27 (bs, 111), 4.61 (d, 2H, J= 6.0 Hz), 4.55 (d, 2H, J=
6.0 Hz); 19F NMR (CDC13): - 48580; LCMS: ret. time: 23.73 min.; purity: 100%;
MS (m/e):
309 (MH+).
7.3.83 N2,N4-Bis(3,4-methylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R925776) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3,4-methylenedioxyaniline were reacted to yield N2,N4-bis(3,4-methylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H
NMR (CDC13): 8 7.86 (bs, 111), 7.27 (m, 1H), 7.19 (m, 1H), 6.89 (dd, 2H, J=
2.1 and 8.1 Hz), 6.80 (dd, 2H, J= 1.8 and 8.1 Hz), 6.73 (t, 2H, J= 8.1 Hz), 5.97 (s, 211), 5.92 (s, 2H); 19F
NMR (CDC13): - 47591; LCMS: ret. time: 21.74 min.; purity: 97%; MS (m/e): 369 (MO.
7.3.84 N2,N4-Bis[2-(4-hydroxyphenybethy1]-5-fluoro-2,4-pyrimidinediamine (R925791) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and tyramine were reacted to yield N2,N4-bis[2-(4-hydroxyphenyl)ethyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR
(DMSO-d6): 8 9.17 (bs, 1H), 8.22 (bs, 111), 6.99 (d, 411, J= 8.1 Hz), 6.65 (d, 411, J= 8.1 Hz), 3.48-3.43 (m, 411), 2.72 (t, 4H, J= 7.7 Hz); LCMS: ret. time: 19.19 min.; purity:
100 %; MS
(m/e): 369 (M11+).

7.3.85 N2,N4-Bis(4-cyanopheny1)-5-fluoro-2,4-pyrimidinediamine (R945057) In like manner to the preparation of N2,N-4-bis(3-hydroxypheny1)-5-fluoro-4-pyrimidineamine, 4-aminobenzonitrile and 2,4-dichloro-5-fluoropyrimidine gave N2,N4-bis(4-cyanopheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 7.26 (d, J=
8.7 Hz, 2 H), 7.36 (d, J= 9.0 Hz, 2 H), 7.43 (d, J= 8.7 Hz, 2 H), 7.60 (d, J=
8.7 Hz, 2 H), 7.86 (d, J= 3.6 Hz, 1 H), 9.49 (br, 1 H, NH), 9.51 (br, 1 H, NH); 19F NMR (282 MHz, DMSO-d6): 8 - 161.48; LC: 27.15 min.; 100%; MS (m/e): 331.00 (MB+).
7.3.86 N2,N4-Bis(4-ethylpheny1)-5-fluoro-2,4-pyrimidinediamine (R926234) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-ethylaniline were reacted to yield N2,N4-bis(4-ethylpheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13):
8 8.83 (bs, 111), 7.77 (d, 1H. J= 3.9 Hz), 7.48 (d, 2H, J= 8.7 Hz), 7.40 (d, 2H, J=
8.7 Hz), 7.31 (bs, 1H), 7.18 (d, 2H, J= 8.7 Hz), 7.11 (d, 2H, J= 8.7 Hz), 2.68-2.61 (m, 4H), 1.28-1.21 (m, 6H);
LCMS: ret. time: 29.17 min.; purity: 100 %; MS (m/e): 337(MH+).
7.3.87 N2,N4-Bis(3-chloro-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926675) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-primidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-hydroxyaniline were reacted to yield N2,N4-bis(3-chloro-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H
NMR (CD30D): 8 7.83 (d, 1H, J= 4.2 Hz), 7.59 (d, 1H, J= 2.4 Hz), 7.53 (d, 1H, J= 2.4 Hz), 7.40 (dd, 1H, J= 2.4 and 8.7 Hz), 7.20 (dd, 1H, J= 2.4 and 8.7 Hz), 6.89 (d, 1H, J= 8.7 Hz), 6.81 (d, 1H, J= 8.7 Hz); 19F NMR (CD30D): - 47862; LCMS: ret. time: 17.89 min.; purity:
99 %; MS (mile): 382 (MO.
7.3.88 N2,N4-Bis[3-chloro-4-(ethoxycarbonylmethyleneoxy)pheny1]-5-fluoro-2,4-pyrimidinediamine (R926676) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-(ethoxycarbonylmethyleneoxy)aniline were reacted to yield N2,N4-bis[3-chloro-4-(ethoxycarbonylmethyleneoxy)pheny1]-5-fluoro-2,4-pyrimidinediamine. 1H NMR
(CDC13):
8 7.93 (bs, 111), 7.67-7.65 (m, 211), 7.41 (dd, 1H, J= 3.0 and 9.3 Hz), 7.26 (dd, 111, J= 2.7 and 9.3 Hz), 6.92-6.85 (m, 311), 6.69 (d, 1H, J= 2.4 Hz), 4.71 (s, 211), 4.66 (s, 211), 4.32-4.23 (m, 411), 1.33-1.27 (m, 6H); 19F NMR (CDC13): - 47274; LCMS: ret. time:
27.51 min.;
purity: 97 %; MS (m/e): 553 (M4).
7.3.89 N2,N4-Bis(3-fluoro-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926681) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-fluoro-4-hydroxyaniline were reacted to yield N2,N4-bis(3-fluoro-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H
NMR (CDC13): 8 7.83 (d, 1H), 7.53 (dd, 1H), 7.42 (dd, 1H), 7.22 (dq, 111), 7.03 (dq, 111), 6.89 (d, 1H), 6.83 (s, 111), 6.80 (s, 111), 6.78 (d, 111); 19F NMR (CDC13): -390060, - 39165, - 47835; LCMS: ret. time: 15.27 mm.; purity: 95 %; MS (m/e): 349 (ME).
7.3.90 N2,N4-Bis(3-acetamidopheny1)-5-fluoro-2,4-pyrimidinediamine (R926682) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-aminoacetanilide were reacted to yield N2,N4-bis(3-acetamidopheny1)-5-fluoro-2,4-pyrimidinediamine. 111NMR
(DMSO-d6): 5 10.24 (bs, 111), 10.03 (s, 1H), 9.94 (s, 111), 8.20 (d, 1H, J= 4.8 Hz), 7.91 (bs, 111), 7.68 (bs, 111), 7.43 (d, 111, J= 8.1 Hz), 7.35-7.30 (m, 2II), 7.24-7.19 (m, 2H), 7.11 (t, 1H, J=
8.1 Hz), 2.03 (s, 311), 2.01 (s, 3H); LCMS: ret. time: 15.10 min.; purity: 99 %; MS (m/e):
395 (MH+).
7.3.91 N2,N4-Bis(2-fluoro-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926683) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-fluoro-4-hydroxyaniline were reacted to yield N2,N4-bis(2-fluoro-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR (DMSO-d6): 8 9.78 (s, 1H), 9.50 (s, 1H), 8.75 (s, 111), 8.06 (s, 1H), 7.87 (d, 1H, J=
4.2 Hz), 7.25-7.18 (m, 2H), 6.61 (dd, 1H, J= 2.4 and 12.3 Hz), 6.56-6.47 (m, 211), 6.39 (dd, 111, J= 1.8 and 8.7 Hz); LCMS: ret. time: 15.52 mm.; purity: 99 %; MS (mile):
349 (M114).

7.3.92 N2,N4-Bis(4-isopropoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926701) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-isopropoxyaniline were reacted to yield N2,N4-bis(4-isopropoxy)pheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR
(CDC13): 6 7.89 (bs, 1H), 7.47 (d, 2H, J= 8.7 Hz), 7.38 (d, 2H, J= 9.0 Hz), 6.87 (d, 2H, J=
9.0 Hz), 6.83 (d, 2H, J= 8.7 Hz); LCMS: ret. time: 27.51 min.; purity: 98 %;
MS (m/e): 397 (MIT).
7.3.93 N2,N4-Bis(3,4-ethylenedioxypheny1)-5-bromo-2,4-pyrimidinediamine (R925771) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 5-bromo-2,4-dichloropyrimidine and 3,4-ethylenedioxyaniline were reacted to yield N2,N4-bis(3,4-ethylenedioxypheny1)-5-bromo-2,4-pyrimidinediamine. 111 NMR (CDC13): 6 8.07 (bs, 111), 7.16 (d, 111, J= 3.0 Hz), 7.10 (d, 1H, J= 2.7 Hz), 6.98-6.93 (m, 2H), 6.90-6.75 (m, 3H), 4.28-4.21 (m, 8H); LCMS: ret. time: 22.61 min.;
purity: 100%;
MS (m/e: 458 (MO.
7.3.94 N2,N4-Bis(3-hydroxypheny1)-5-bromo-2,4-pyrimidinediamine (R925778) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyriMidinediamine, 5-bromo-2,4-dichloropyrimidine and 3-aminophenol were reacted to yield N2,N4-bis(3-hydroxypheny1)-5-bromo-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 9.99 (bs, 1H), 9.34 (bs, 1H), 8.30 (s, 1H), 7.15 (t, 1H, J= 8.4 Hz), 7.06-6.97 (m, 2H), 6.94-6.92 (m, 2H), 6.80 (bs, 1H), 6.62 (s, 111, J= 8.1 Hz), 6.43 (d, 1H, J=
7.8 Hz); LCMS:
ret. time: 18.48 min.; purity: 97%; MS (m/e): 374 (MH+).
7.3.95 N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)pheny1]-5-bromo-2,4-pyrimidinediamine (R925779) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 5-bromo-2,4-dichloropyrimidine and ethyl 4-aminophenoxyacetate were reacted to yield N2,N4-bis[4-(ethoxycarbonylmethyleneoxy)pheny1]-5-bromo-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 9.12 (s, 111), 8.48 (s, 111), 8.11 (s, 111), 7.42 (d, 4H, J= 8.7 Hz), 6.89 (d, 2H, J= 9.0 Hz), 6.71 (d, 211, J= 9.3 Hz), 4.78 (s, 211), 4.66 (s.

211), 4.20-4.10 (m, 4H), 1.23-1.16 (m, 6H); LCMS: ret. time: 25.82 min.;
purity: 94%; MS
(m/e): 546 (MH+).
7.3.96 N2,N4-Bis[2-(4-hydroxyphenyl)ethy1]-5-bromo-2,4-pyrimidinediamine (R925792) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 5-bromo-2,4-dichloropyrimidine and tyramine were reacted to yield N2,N4-bis[2-(4-hydroxyphenyl)ethyl]-5-bromo-2,4-pyrimidinediamine. 1H NMR
(DMSO-d6): 8 7.83 (s, 1H), 6.96 (d, 411, J= 8.1 Hz), 6.63 (d, 4H, J= 8.1 Hz), 3.54-3.42 (m, 211), 2.74-2.66 (m, 2H), 2.74-2.66 (m, 4H); ret. time: 20.10 mm.; purity: 100 %; MS
(m/e): 430 KO.
7.3.97 N2,N4-Bis(2-phenylpheny1)-5-bromo-2,4-pyrimidinediamine (R925798) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 5-bromo-2,4-dichloropyrimidine and 2-aminobiphenyl were reacted to yield N2,N4-bis(2-phenylpheny1)-5-bromo-2,4-primidinediamine. 111 NMR (CDC13):

8.34 (d, 111, J= 8.1 Hz), 8.27 (d, 111, J= 8.1 Hz), 8.00 (s, 111), 7.51-7.18 (m, 1711), 6.95 (s, 111); LCMS: ret. time: 18.87 mm.; purity: 97 %; MS (m/e): 495 (MH4).
7.3.98 N2,N4-Bis(2-methoxy-5-phenylpheny1)-5-bromo-2,4-pyrimidinediamine (R925799) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 5-bromo-2,4-dichloroprimidine and 5-phenyl-ortho-anisidine were reacted to yield N2,N4-bis(2-methoxy-5-phenylpheny1)-5-bromo-2,4-pyrimidinediamine.
1H NMR (DMSO-d6): 8 8.26 (m, 2H), 8.05 (m, 211), 7.39-7.21 (m, 1211), 7.17 (dd, 111, J=
2.4 and 8.1 Hz), 7.11 (d, 111, J= 8.7 Hz), 7.05 (d, 111, J= 9.0 Hz), 3.88 (s, 311), 3.83 (s, 311);
LCMS: ret. time: 20.51 min.; purity: 98 %; MS (m/e): 554 (MO.
7.3.99 N2,N4-Bis(4-methoxy-3-phenylpheny1)-5-bromo-2,4-pyrimidinediamine (R925802) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, with the addition of triethylamine, 5-bromo-2,4-dichloropyrimidine and 3-phenyl-para-anisidine hydrochloride were reacted to yield N2,N4-bis(4-methoxy-3-phenylpheny1)-5-bromo-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 8.26 (m, 2H), 8.06 (m, 2H), 7.38-7.25 (m, 12H), 7.18 (dd, 1H, J= 2.4 and 8.1 Hz), 7.12 (d, 1H, J= 8.7 Hz), 7.05 (d, 1H, 8.7 Hz), 3.89 (s, 3H), 3.83 (s, 3H); LCMS: ret. time: 36.77 min.;
purity: 98 %;
MS (m/e): 554 (MH+).
7.3.100 N2,N4-Bis(3-phenylpheny1)-5-bromo-2,4-pyrimidinediamine (R925803) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 5-bromo-2,4-dichloropyrimidine and 3-aminobiphenyl were reacted to yield N2,N4-bis(3-phenylpheny1)-5-bromo-2,4-pyrimidinediamine. 1H NMR (DMSO-d6):
8 9.86 (bs, 1H), 9.20 (bs 1H), 8.33 (s, 1H), 7.79 (bs, 1H), 7.18 (bs, 1H), 7.61 (d, 1I1), 7.56-7.51 (m, 211), 7.48-7.23 (m, 11H), 7.17-7.04 (m, 2H); LCMS: ret. time: 19.52 mm.; purity:
80 %; MS (m/e): 494 (Mil).
7.3.101 N2,N4-Bis(3,4-ethylenedioxypheny1)-5-cyano-2,4-pyrimidinediamine (11925773) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-cyanopyrimidine and 3,4-ethylenedioxyaniline were reacted to yield N2,N4-bis(3,4-ethylenedioxypheny1)-5-cyano-2,4-pyrimidinediamine. 1H
NMR (DMSO-d6): 8 9.69 (bs, 1H), 9.28 (bs, 1H), 8.40 (s, 1H), 7.16-6.89 (m, 4H), 6.79 (d, 1H, J= 9.0 Hz), 6.65 (bs, 1H), 4.22 (s, 4H), 4.16 (s, 4H); LCMS: ret. time:
24.42 min.;
purity: 93 %; MS (m/e): 404 (MH4).
7.3.102 N2,N4-Bis(3-hydroxypheny1)-5-cyano-2,4-pyrimidinediamine (R925774) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-cyanopyrimidine and 3-hydroxyaniline were reacted to yield N2,N4-bis(3-hydroxypheny1-5-cyano-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 9.73 (bs, 111), 9.40 (s, 1H), 9.33 (bs, 111), 9.24 (s, 1H), 8.47 (s, 111), 7.20 (d, 1H, J= 7.5 Hz), 7.11 (t, 1H, J= 7.5 Hz), 7.09-7.02 (m, 2H), 6.99-6.89 (m, 3H), 6.54 (d, 1H, J=
7.2 Hz), 6.37 (dd, 1H, J= 1.8 and 8.4 Hz); LCMS: ret. time: 19.71 min.; purity: 97%; MS
(m/e): 320 7.3.103 N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)pheny1]-5-cyano-2,4-pyrimidinediamine (R925775) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-cyanopyrimidine and ethyl 4-aminophenoxyacetatewere reacted to yield N2,N4-bis[4-(ethoxycarbonylmethyleneoxy)pheny1]-5-cyano-2,4-pyrimidinediamine. 111NMR (CD30D): 67.80 (s, 1H), 7.40 (d, 4H, J= 8.7 Hz), 6.90 (4H, J= 9.0 Hz), 6.82-6.75 (m, 2H). 4.60 (bs, 4H), 4.29-4.25 (m, 4H), 1.32-1.26 (m, 511), LCMS:
ret. time: 28.50 min.; purity: 100 %; MS (m/e): 493 (MH+).
7.3.104 R935192: N2, N4-Bis(1-methyl-indazolin-5-y1)-5-fluoro-2,4-pyrimidinediamine:
In like manner to the preparation of N2, N4-bis (3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2-chloro-5-fluoropyrimidine and 1-methy1-5-aminoindazole were reacted to produce N2, N4-bis(1-methyl-indazolin-5-y1)-5-fluoro-2,4-pyrimidinediamine.
111NMR (DMSO-d6): 8 10.65 (s, 1H), 10.41 (s, 111), 8.29 (d, 1H, J= 5.3 Hz), 7.98 (s, 111), 7.79 (d, 2H, J= 9.4 Hz), 7.69-7.54 (m, 411), 7.35 (dd, 1H, J= 1.7 and 9.4 Hz), 4.03 (s, 3H), 4.01 (s, 3H). LCMS: ret. time: 16.86 min.; purity: 99%; MS (m/e): 389 (M1-14).
7.3.105 R935205: N2, N4-Bis[1-(methoxycarbonyl)methyl-indazoline-6-y11-5-fluoro-2,4-pyrimidinediamine In like manner to the preparation of 5-fluoro-N2, N4-bis (3-hydroxypheny1)-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrmidine and 6-amino-1-(methoxycarbonyl)methyl-indazoline were reacted to produce N2, N4-bis[1-(methoxycarbonyl)methyl-indazoline-6-y1]-5-fluoro-2,4-pyrimidinediamine. 1H
NMR
(DMSO-d6): 8 9.59 (s, 1H), 9.45 (s, 1H), 8.18 (d, 111, J= 3.5 Hz), 8.11 (s, 111), 8.04 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.69 (d, 111, J= 8.8 Hz), 7.58 (d, 1H, J= 8.8 Hz), 7.48 (dd, 1H, J=
1.7 and 8.8 Hz), 7.32 (d, 1H, J= 8.8 Hz), 5.17 (s, 211), 4.88 (s, 1H), 3.58 (s, 311), 3.58 (s, 311). LCMS: ret. time: 17.80 min.; purity: 99%; MS (m/e): 505 (MH+).
7.3.106 R935211: N2, N4-Bis[1-(methoxyearbonyl)methyl-indazoline-5-y1]-5-fluoro-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrmidine and 6-amino-1-(methoxycarbonyl)methyl-indazoline was reacted to produce N2, N4-bis[1-(methoxycarbonyl)methyl-indazoline-6-y1]-5-fluoro-2,4-pyrimidinediamine. 1H
NMR

(DMSO-d6): 8 9.37 (s, 111), 9.17 (s, 1H), 8.11-8.06 (m, 3H), 7.94 (s, 111), 7.70 (s, 1H), 7.63 (s, 2H), 7.46 (s, 2H), 5.40 (s, 2H), 5.31 (s, 2H), 3.67 (s, 3H), 3.64 (s, 3H).
LCMS: ret. time:
17.06 min.; purity: 96%; MS (m/e): 505 (MO.
7.3.107 R935188: N2,N4-Bis(indazolin-6-y1)-5-fluoro-2,4-pyrimidinediamine:
In like manner to the preparation of 5-fluoro-N2, N4-bis (3-hydroxypheny1)-2,4-pyrimidinediamine, 2,4-dichlro-5-fluoropyrimidine and 6-aminoindazoline were reacted to produce N2,N4-bis(indazolin-6-y1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6):
8 9.80 (s, 1H), 9.65 (s, 1H), 8.20 (d, 1H, J= 4.1 Hz), 8.01 (s, 1H), 7.96 (s, 1H), 7.93 (s, 1H), 7.89 (s, 1H), 7.69 (d, 111, J= 8.8 Hz), 7.57 (d, 1H, J= 8.3 Hz), 7.54 (dd, 1H, J= 1.7 and 8.8 Hz), 7.29 (dd, 1H, J= 1.7 and 8.8 Hz); LCMS: ret. time:15.17 min.; purity:
94%; MS (mile):
361 (MO.
7.3.108 R935189: N2, N4-Bis(indazolin-5-y1)-5-fluoro-2,4-pyrimidinediamine:
In like manner to the preparation of N2, N4-bis (3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 5-aminoindazole were reacted to produce N2, N4-bis(indazolin-5-y1)-5-fluoro-2,4-pyrimidinediamine.111 NMR
(DMSO-d6):
8 10.05 (s, 111), 9.76 (s, 111), 8.16 (d, 1H, J= 4.7 Hz), 8.05 (s, 111), 7.92 (s, 1H), 7.82 (s, 111), 7.68 (s, 1H), 7.52-7.52 (m, 211), 7.44 (d, 111, J= 8.8 Hz), 7.34 (dd, 1H, J= 1.7 and 8.8 Hz); LCMS: ret. time: 14.33 min.; purity: 100%; MS (m/e): 361 (MO.
7.3.109 N2,N4-Bis(1-ethoxycarbony1-2-methylpropy1)-5-cyano-2,4-pyrimidinediamine (R925814) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-cyanopyrimidine and valine ethyl ester were reacted to yield N2,N4-bis(1-ethoxycarbony1-2-methylpropy1)-5-cyano-2,4-pyrimidinediamine. 111 NMR (CDC13): 8 8.15 (s, 111), 6.10 (d, 1H, J= 8.4 Hz), 5.67 (d, 1H, J= 8.1 Hz), 4.66-4.62 (m, 111), 4.50-4.46 (m, 1H), 4.25-4.13 (m, 411), 2.27-2.14 (m, 211), 1.31-1.24 (m, 611), 1.00-0.94 (m, 1211); LCMS: ret. time: 30.41 min.; purity: 98 %; MS (m/e): 392 (M114).

7.3.110 N2,N4-Bis(1-methoxycarbony1-3-methylbuty1)-5-cyano-2,4-pyrimidinediamine (R925815) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-cyanopyrimidine and leucine methyl ester were reacted to yield N2,N4-bis(1-methoxycarbony1-3-methylbuty1)-5-cyano-2,4-pyrimidinediamine. 111 NMR (CDC13): mixture of rotamers 6 8.15 (s, 1H), 6.10 and 5.49 (2d, 111, J=
8.1 Hz), 5.53 (d, 111, J= 8.4 Hz), 4.80-4.67 (m, 111), 4.57-4.48 (m, 111), 3.73 (s, 3H), 3.71 (s, 3H), 1.78-1.60 (m, 6H), 0.97-0.89 (m, 12H); LCMS: ret. time: 30.33 min.; purity: 91 %;
MS (m/e):
392 (MH+).
7.3.111 N2,N4-Bis(methoxycarbonylbenzy1)-5-cyano-2,4-pyrimidinediamine (R925819) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-cyanopyrimidine and phenyl glycine methyl ester were reacted to yield N2,N4-bis(methoxycarbonylbenzy1)-5-cyano-2,4-pyrimidinediamine. 1H
NMR (CDC13): mixture of rotamers 8 8.15 (s, 1H), 7.69-7.60 (m, 1H), 7.42-7.32 (m, 1011), 6.20 and 5.73 (2d, 111, J= 6.6 Hz), 6.14 and 5.65 (2d, 1H, J= 6.3 Hz), 5.55 (d, 111, J= 6.3 Hz), 5.39 (t, 1H, J= 7.2 Hz), 3.79 and 3.78 (2s, 3H), 3.67 and 3.65 (2s, 3H);
LCMS: ret.
time: 30.22 min.; purity: 91 %; MS (m/e): 432 (MH+).
7.3.112 N2,N4-Bis[4-(ethoxycarbonylmethyl)pheny11-5-cyano-2,4-pyrimidinediamine (R926662) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-cyanopyrimidine and ethyl 4-aminophenylacetate were reacted to yield N2,N4-bis[4-(ethoxycarbonylmethyl)pheny1]-5-cyano-2,4-pyrimidinediamine. 111 NMER (CDC13): 8 8.29 (bs, 111), 7.46 (2d, 4H, J= 7.8 Hz), 7.28 (d, 2h, J= 8.1 Hz), 7.19 (d, 2H, J= 8.1 Hz), 4.16 (2q, 4H, J= 6.3 Hz), 3.64 (s, 211), 3.59 (s, 211), 1.30-1.23 (m, 6H); LCMS: ret. time: 29.29 min.; purity: 93%; MS (m/e): 461 (M10.
7.3.113 R935000: N2,N4-Bis(2-methoxy-5-phenylpheny1)-5-methy1-2,4-pyrimidinediamine In like manner to the preparation of 5-fluoro-N2,N4-bis(3-hydroxypheny1)-2,4-pyrimidinediamine, 5-phenyl-2-anisidine and 2,4-dichloro-5-methylpyrimidine were reacted to provide N2,N4-bis(2-methoxy-5-phenylpheny1)-5-methy1-2,4-pyrimidinediamine.

NMR (CDC13 + CD30D): 8 7.76 (d, 111, J= 2.3 Hz), 7.57 (s, 111), 7.56 (s, 111), 7.02-6.85 (m, 8H), 6.86-6.80 (m, 411), 6.72 (d, 211), 3.73 (s, 3H), 3.72 (s, 311), 2.07 (s, 311); LCMS:
ret. time: 31.53 min.; purity: 97%; MS (m/e): 489 (MH+).
7.3.114 11935001: N2,N4-Bis[(2-methy1-5-phenyl)pheny11-5-methy1-2,4-pyrimidinediamine In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 5-phenyl-2-toluidine and 2,4-dichloro-5-methylpyrimidine were reacted to produce N2,N4-bis[(2-methy1-5-phenyl)pheny1]-5-methyl-2,4-pyrimidinediamine. 1H
NMR (CDC13): 8 7.59-7.55 (m, 111), 7.45 (d, 2H, J= 3.6 Hz), 7.26-7.17 (m, 611), 7.09-6.98 (m, 811), 2.36 (s, 3H), 2.22 (s, 311), 2.21(s, 311); LCMS: ret. time: 32.44 min.; purity: 90%;
MS (m/e): 457 (MH+).
7.3.115 11935002: N2,N4-Bis[(4-methoxy-3-phenyl)pheny1]-5-methy1-2,4-pyrimidinediamine In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 3-phenyl-4-anisidine hydrochloride and 2,4-dichloro-5-methylpyrimidine with an added diisopropylethylamine were reacted to produce N2,N4-bis[(4-methoxy-3-phenyl)pheny1]-5-methy1-2,4-pyrimidinediamine. 111 NMR
(CDC13):.
8.15 8.15 (d, 1.11, J= 2.3 Hz), 7.76 (t, 1H, J= 2.3 Hz), 7.71 (s, 1 H), 7.59 (s, 1H), 7.16 ¨7.03 (m, 811), 6.98-6.81 (511), 3.96 (s, 311), 3.89 (s, 311), 2.21 (s, 311); LCMS: ret.
time: 32.01 min.;
purity: 90%; MS (m/e): 489 (MO.
7.3.116 11935003: N2,N4-Bis[(4-pheny1-2-methoxy-5-methyl)pheny1]-5-methy1-2,4-pyrimidinediamine In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 5-methyl-4-phenyl-2-anisidine and 2,4-dichloro-5-methylpyrimidine were reacted to produce N2,N4-bis[(4-pheny1-2-methoxy-5-methyl)pheny1]-5-methyl-2,4-pyrimidinediamine. 1H NMR (CDC13): 8 9.25 (br s,111), 8.17 (s, 111), 7.77 (t, 1H, J= 6.4 Hz), 7.66 (s, 211), 7.43-7.25 (m, 1011), 6.79 (s, 211), 3.91 (s, 311), 3.85 (s, 311), 2.20 (s, 3H), 2.09 (s, 311), 2.02 (s, 3H); LCMS: ret. time: 31.10 min.; purity: 100%; MS
(m/e): 517 (MH).

7.3.117 R935004: N2,N4-Bis[pi-(4-methoxyphenyl)Jmethy11-5-fluoro-2,4-pyrimidinediamine In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 1,1-di(4-anisyl)methylamine and 2,4-dichloro-5-fluoropyrimidine were reacted to produce N2,N4-bisffdi-(4-methoxyphenyl)]methyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13 + CD30D): 8 7.91 (d, 1H, J= 2.3 Hz), 7.18 (d, 8H, J=
9.0 Hz), 6.85 (d, 811, J= 9.0 Hz), 6.40 (d, 1H, J= 8.2 Hz), 5.39 (d, 1H, J=
7.1 Hz), 3.81 (s, 6H), 3.78 (s, 6H); LCMS: ret. time: 32.76 min.; purity: 95%; MS (m/e): 581 (MH+).
7.3.118 R935005: N2,N4-Bis(diphenylmethyl)-5-fluoro-2,4-pyrimidinediamine In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 1,1-diphenyl methylamine and 2,4-dichloro-5-fluoropyrimidine were reacted to produce N2, N4-bis(diphenylmethyl)-5-fluoro-2,4-primidinediamine.

(CDC13): 8 7.91 (d, 111, J= 2.3 Hz), 7.39-7.25 (m, 2011), 6.51 (d, 1H, J= 8.2 Hz), 5.77 (d, 111, J= 7.0 Hz); LCMS: ret. time: 33.46 min.; purity: 92%; MS (m/e): 461 (MH+).
7.3.119 R935006: N2,N4-Bis[di-(4-ehlorophenyl)methy1]-5-fluoro-2,4-pyrimidinediamine In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, benzhydrylamine and 2,4-dichloro-5-fluoropyrimidine were reacted to yield N2,N4-bis[di-(4-chlorophenyl)methyl]-5-fluoro-2,4-pyrimidinediamine. 1H
NMR
(CDC13 + CD30D): 67.94.(d, 111, J= 2.3 Hz), 7.40-7.20 (m, 1611), 6.46 (d, 111, J= 8.2 Hz), 5.69 (d, 111, J= 7.0 Hz); LCMS: ret. time: 32.83 min.; purity: 90%; MS (m/e):
599 (M11+).
7.3.120 R935016: N2,N4-Bis[1(R)-4-methoxyphenylethy1]-5-bromo-2,4-pyrimidineamine In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, (R)-(+)-1-(4-methoxyphenypethylamine and 5-bromo-2,4-dichloropyrimidine were reacted to produce N2,N4-bis[1(R)-4-methoxyphenylethy1]-5-bromo-2,4-pyrimidineamine. 111 NMR (CDC13): 67.81 (s, 1H), 7.25 (d, 411, J=
8.4 Hz), 6.86 (app t, 4H, J= 8.4 and 8.7 Hz), 5.27-5.20 m (211), 5.09 (dq, 111, J= 6.4 and 7.0 Hz), 4.89 (dq, 111, J= 6.4 and 7.0 Hz), 3.80 (s, 31I), 3.79 (s, 31I), 1.40 (d, 6H, J= 7.0 Hz).

7.3.121 R935075: N2, N4-Bis[3-(2-hydroxyethoxy)pheny11-5-fluoro-2,4-pyrimidinediamine In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-(3-aminophenoxy)ethanol were reacted to produce N2,N4-bis[3-(2-hydroxyethoxy)pheny1]-5-fluoro-2,4-pyrimidinediamine.
1H NMR (DMSO-d6): 8 9.50 (br s, 1H), 9.35 (br s, 1H), 8.13 (d, 1H, J= 4.1 Hz), 7.44 (d, 111, J= 7.6 Hz), 7.26-7.19 (m, 4H), 7.10 (t, 1H, J= 7.6 Hz), 6.65 (dd, 111, J=
2.3 and 8.2 Hz), 6.50 (dd, 1H, J= 2.3 and 8.2 Hz), 5.0 (br s, 2H), 3.91 (t, 2H, J= 5.2 Hz), 3.85 (t, 2H, J= 5.2 Hz), 3.68 (qt, 2H, J= 5.2 Hz), 3.66 (qt, 2H, J= 5.2 Hz); LCMS: ret. time:
15.76 min.; purity:
97%; MS (m/e): 401 (MO.
7.3.122 R935076: N2,N4-Bis[3-(2-methoxyethypoxypheny11-5-fluoro-2,4-pyrimidinediamine:
In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-(2-methoxyethoxy)aniline were reacted to produce N2,N4-bis[3-(2-methoxyethyl)oxypheny1]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13): 8 7.96 (d, 1H, J= 2.9 Hz), 7.36 (t, 1H, J=
1.7 Hz), 7.28 (t, 1H J= 1.7 Hz), 7.25-7.06 (m, 4H), 6.98 (br s, 1H), 6.75 (d, 1H, J=
2.3 Hz), 6.70 (dd, 1H, J= 1.7 and 8.2 Hz), 6.58 (dd, 111, J= 1.7 and 8.2 Hz), 4.08-4.03 (m, 4H), 3.74-3.69 (m, 4H), 3.44 (s, 3H), 3.43 (s, 3H); LCMS: ret. time: 21.01 min.; purity: 97%; MS
(m/e): 429 (MO.
7.3.123 R935077: N2,N4-Bis(5-hydroxy-2-isopropylpheny1)-5-fluoro-2,4-pyrimidinediamine In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 3-amino-4-isopropylphenol and 2,4-dichloro-5-fluoropyrimidine were reacted to produce N2,N4-bis(5-hydroxy-2-isopropylpheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13): 8 7.93 (d, 1H, J= 3.5 Hz), 7.79 (br s, 1H), 7.64 (br s, 1H), 7.13 (d, 1H, J= 8.7 Hz), 7.06 (d, 111, J= 2.3 Hz), 7.05 (d, 111, J= 8.7 Hz), 6.89 (d, 1H, J= 2.3 Hz), 6.66 (d, 1H, J= 2.3 and 8.7 Hz), 6.57 (d, 111, J= 2.3 and 8.7 Hz), 2.96 (m, 2H), 1.25 (d, 6H, J= 7.0 Hz), 1.13 (dd, 6E1, J= 7.0 Hz); LCMS: ret. time: 24.27 min.; purity: 97%;
MS (m/e): 397 (MH+).

7.3.124 R935114: N2,N4-Bis(3-methoxycarbonylmethylenepheny1)-5-fluoro-2,4-pyrimidinediamine In like 'Timmer to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-(methoxycarbonylmethylene)aniline were reacted to produce the desired N2,N4-bis(3-methoxycarbonyhnethylenepheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6):
8 10.23 (br s, 1H), 10.05 (br s, 1H), 8.26 (d, 111, J= 4.6 Hz), 7.64 (d, 1H, J= 8.2 Hz), 7.51 (br s, 111), 7.46 (d, 1H, J= 8.2 Hz), 7.33 (br s, 1H), 7.29 (t, 1H, J= 7.6 Hz), 7.20 (t, 111, J=
7.6 Hz), 7.06 (d, 1H, J= 7.6 Hz), 6.93 (d, 111, J= 7.6 Hz), 3.63 (s, 211), 3.58 (s, 3H), 3.57 (s, 311), 3.56 (s, 211); LCMS: ret. time: 21.74 min.; purity: 92%; MS (m/e): 425 (MH).
7.3.125 R935162: N2, N4-Bis(3,4-propylenedioxypheny1)- 5-fluoro-2,4-pyrimidinediamine:
In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-primidinediamine, 2,4-dichloro-5-fluoropyrimidine and (3,4-propylenedioxy)aniline were reacted to give N2,N4-bis(3,4-propylenedioxypheny1)-5-fluoro-2,4-ppimidinediamine. 1H
NMR (DMSO-d6): 8 9.18 (s, 1H), 9.07 (s, 1H), 8.03 (d, 1H, J= 3.5 Hz), 7.38 (dd, 1H, J= 2.3 and 8.2 Hz), 7.35 (d, 1.11, J= 2.3 Hz), 7.33 (d, 1H, J= 2.3 Hz), 7.18 (dd, 111, J= 2.3 and 8.8 Hz), 6.90 (d, 1H, J= 8.8 Hz), 6.80 (d, 1H, J= 8.2 Hz), 4.11-3.98 (m, 8H), 2.09-2.01 (m, 4H);
LCMS: ret. time: 21.40 min.; purity: 97%; MS (m/e): 425 (M114).
7.3.126 R935163: N2,N4-Bis(3-chloro-4-fluoropheny)-2,4-pyrimidinediamine:
In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-ppimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline were reacted to produce N2, N4-bis(3-chloro-4-fluoropheny)-2,4-pyrimidinediamine.

(DMSO-d6): 8 9.58 (s, 111), 9.48 (s, 113), 8.17 (d, 111, J= 4.1 Hz), 7.94-7.90 (m, 2H), 7.73-7.67 (m, 111), 7.51-7.45 (m, 111), 7.38 (t, 1H, J= 8.8 Hz), 7.26 (t, 111, J=
8.8 Hz); LCMS:
ret. time: 27.83 min.; purity: 99%; MS (m/e): 386 (MH+).
7.3.127 N2,N4-Bis(3-hydroxypheny1)-6-ethoxycarbony1-5-nitro-2,4-pyrimidinediamine (R925849) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-6-ethoxycarbony1-5-nitropyrimidine and 3-aminophenol were reacted to yield N2,N4-bis(3-hydroxypheny1)-6-ethoxycarbony1-5-nitro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 10.56 (bs, 1H), 10.32 (bs, 1H), 9.54 (s, 111), 9.32 (bs, 111), 7.22-7.15 (m, 2H), 7.02-6.96 (m, 1H), 6.93-6.82 (m, 2H), 6.81-6.74 (m,111), 6.67 (d, 1H, J= 9.3 Hz), 6.43 (d, 111, J= 8.1 Hz), 4.35 (q, 2H, J= 6.9 Hz), 1.30 (t, 3H, J= 6.9 Hz); LCMS: ret. time: 26.01 min.; purity: 96 %; MS (m/e): 412 (ME).
7.3.128 N2,N4-Bis(3,4-ethylendioxypheny1)-6-ethoxycarbony1-5-nitro-2,4-pyrimidinediamine (R925852) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-6-ethoxycarbony1-5-nitropyiimidine and 3,4-ethylenedioxyaniline were reacted to yield N2,N4-bis(3,4-ethylendioxypheny1)-6-ethoxycarbony1-5-nitro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 10.52 (s, 1H), 10.28 (s, 111), 7.07-7.01 (m, 211), 6.96 (dd, 111, J= 1.8 and 8.7 Hz), 6.90-6.84 (m, 211), 6.61 (d, 1H, J= 8.7 Hz), 4.33 (q, 211, J= 6.9 Hz), 4.24 (s, 4H), 4.17 (s, 411), 1.29 (t, 3H, J= 6.9 Hz); LCMS: ret. time: 30.40 min.; purity: 100 %; MS (m/e): 496 (ME).
7.3.129 N2,N4-Bis(ethoxycarbonylmethyl)-6-ethoxycarbony1-5-nitro-2,4-pyrimidinediamine (R925864) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, with the addition of triethylamine, 2,4-dichloro-6-ethoxycarbony1-5-nitropyrimidine and glycine ethyl ester hydrochloride were reacted to yield N2,N4-bis(ethoxycarbonylmethyl)-6-ethoxycarbony1-5-nitro-2,4-pyrimidinediamine. 1H
NMR.
(CDC13): mixture of rotamers 8 8.99 and 8.80 (2bs, 111), 6.22 and 6.00 (2bs, 111), 4.45 (t, 2H, J= 7.2 Hz), 4.31-4.21 (m, 611), 4.14 (d, 2H, J= 5.1 Hz), 1.39 (t, 311, J=
7.2 Hz), 1.34-1.28 (m, 6H); LCMS: ret. time: 26.06 mm.; purity: 99 %; MS (m/e): 400 (MH+).
7.3.130 N2,N4-Bis[2-(4-hydroxyphenyl)ethy1]-2,4-pyrimidinediamine (R925790) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and tyramine were reacted to yield N2,N4-bis[2-(4-hydroxyphenypethy1]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 11.56 (bs, 1H), 9.23 (s, 111), 8.89 (bs, 111), 7.92 (bs, 111), 7.60 (d, 111, J= 6.9 Hz), 6.99 (d, 4H, J= 8.1 Hz), 6.65 (d, 411, J= 8.1 Hz), 6.00 (d, 1H, J= 7.2 Hz), 3.59-3.42 (m, 4H), 2.76-2.67 (m, 4H);
LCMS: ret. time: 17.93 min.; purity: 95 %; MS (rn/e): 351 (MH+).

7.3.131 N2,N4-Bis(2-phenylpheny1)-2,4-pyrimidinediamine (R925804) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and 2-aminobiphenyl were reacted to yield N2,N4-bis(2-phenylpheny1)-2,4-pyrimidinediamine. 1H NMR (CDC13): 5 8.36 (d, 1H, J=
8.1 Hz), 7.97 (d, 1H, J= 5.7 Hz), 7.80 (d, 1H, J= 7.5 Hz), 7.50-7.21 (m, 15H), 7.12-7.05 (m, 1H), 6.91 (bs, 1H), 6.38 (bs, 1H), 6.07 (d, 1H, J= 6.0 Hz); LCMS: ret. time:
29.94 min.;
purity: 100 %; MS (m/e): 415 (MM.
7.3.132 N2,N4-Bis(2-methoxy-5-phenylpheny1)-2,4-pyrimidinediamine (R925805) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and 5-phenyl-ortho-anisidine were reacted to yield N2,N4-bis(2-methoxy-5-phenylpheny1)-2,4-pyrimidinediamine. 1H NMR
(CD30D): 5 7.88-7.84 (m, 2H), 7.82 (d, 1H, J= 6.9 Hz), 7.30-7.14 (m, 14H), 7.10 (dd, 2H, J= 3.0 and 8.1 Hz), 6.48 (d, 1H, J= 6.9 Hz), 3.93 (s, 3H), 3.92 (s, 311); LCMS: ret. time:
30.09 min.; purity:
94 %; MS (m/e): 476 (MH+).
7.3.133 N2,N4-Bis(3-carboxy-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (1R945041) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, from 5-amino-2-hydroxybenzoic acid (458 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave N2,N4-bis(3-carboxy-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (235 mg, 98%). 1H NMR (DMSO-d6):

6.76 (d, J= 9.0 Hz, 1 H), 6.88 (d, J= 9.6 Hz, 1 H), 7.75 (dd, J= 3.0, 9.0 Hz, 1 H), 7.90-7.94 (m, 3 H), 8.02 (d, J= 3.9 Hz, 1 11), 9.04 (s, 1 H, NH), 9.28 (s, 1 H, NH); 19F
NMR (282 MHz, DMSO-d6): 5 -165.79; LC: 16.02 min, 86.82%; MS (m/z): 400.94 (MH+).
7.3.134 N2,N4-Bis(4-methoxy-3-phenylpheny1)-2,4-pyrimidinediamine (R925806) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, with the addition of triethylamine, 2,4-dichloropyrimidine and 3-phenyl-para-anisidine hydrochloride were reacted to yield N2,N4-bis(4-methoxy-phenylpheny1)-2,4-pyrimidinediamine. 1H NMR (CD30D): 5 7.93 (d, 111, J= 2.4 Hz), 7.88 (d, 1H, J= 2.4 Hz), 7.29 (dd, 111, J= 1.8 and 9.0 Hz), 7.26-7.18 (m, 13H), 7.10 (d, 211, J= 8.7 Hz), 6.46 (d, 1H, J= 7.2 Hz), 3.93 (s, 3H), 3.92 (s, 3H); LCMS: ret. time:
29.99 min.; purity:
92%; MS (m/e): 476 (1V1-11+).
7.3.135 N2,N4-Bis(2-methyl-5-phenylpheny1)-2,4-pyrimidinediamine (R925807) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and 5-phenyl-ortho-toluidine were reacted to yield N2,N4-bis(2-methyl-5-phenylpheny1)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6):
8 10.45 (bs, 1H), 10.01 (bs, 1H), 7.86 (bs, 111), 7.69-7.22 (m, 1711), 2.28 (s, 611); LCMS:
ret. time: 18.69 mm.; purity: 98 %; MS (m/e): 443 (MO.
7.3.136 N2,N4-Bis(2-methoxy-5-methy1-4-phenylpheny1)-2,4-pyrimidinediamine (R925808) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and 5-methyl-4-phenyl-ortho-anisidine were reacted to yield N2,N4-bis(2-methoxy-5-methy1-4-phenylpheny1)-2,4-pyrimidinediamine.
1H NMR (DMSO-d6): 8 9.99 (bs, 111), 9.22 (bs, 1H), 7.98 (d, 111, J= 6.3 Hz), 7.75 (s, 1H), 7.59 (s, 111), 7.46-7.29 (m, 1011), 6.92 (s, 1H), 6.87 (s, 1H), 6.49 (d, 1H, J= 5.4 Hz), 3.82 (s, 3H), 3.81 (s, 311), 2.07 (s, 3H), 1.98 (s, 3H); LCMS: ret. time: 19.69 min.;
purity: 93 %; MS
(rn/e): 503 (MH+).
7.3.137 N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)pheny1]-5-trifluoromethy1-2,4-pyrimidinediamine (R925862) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-trifluoromethylpyrimidine and ethyl 4-aminophenoxyacetate were reacted to yield N2,N4-bis[4-(ethoxycarbonylmethyleneoxy)pheny1]-5-trifluoromethy1-2,4-pyrimidinediamine.

(DMSO-d6): 69.64 (bs, 111), 8.80 (bs, 111), 8.29 (s, 1H), 7.36 (d, 2H, J= 8.1 Hz), 7.31 (d, 211, J= 9.3 Hz), 6.93 (d, 211, J= 8.7 Hz), 6.70 (d, 2H, J= 9.0 Hz), 4.80 (s, 2H), 4.67 (s, 2H), 4.18 (q, 211, J= 6.9 Hz), 4.15 (q, 2H, J= 6.9 Hz), 1.20 (t, 311, J= 6.9 Hz), 1.19 (t, 3H, J= 6.9 Hz); 19F NMR (DMSO-d6): -16932; LCMS: ret. time: 26.33 min.; purity: 98 %; MS
(m/e):
535 (ME).

7.3.138 N2,N4-Bis(3-hydroxypheny1)-5-trifluoromethyl-2,4-pyrimidinediamine (R925863) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediarnine, 2,4-dichloro-5-trifluoromethylpyrimidine and 3-aminophenol were reacted to yield N2,N4-bis(3-hydroxypheny1)-5-trifluoromethy1-2,4-pyrimidinediamine. 111 NMR (DMSO-d6): 8 9.82 (bs, 111), 8.88 (bs, 1H), 8.36 (s, 1H), 7.18-7.11 (m, 2H), 6.96 (m, 411), 6.63 (dd, 1H, J= 2.4 and 8.1 Hz), 6.38 (d, 111, J= 8.1 Hz); 19F NMR
(DMSO-d6): -16979; LCMS: ret. time: 19.04 min.; purity: 95 %; MS (m/e): 363 (MO.
7.3.139 N2,N4-Bis[4-(ethoxycarbonylmethyl)pheny11-5-trifluoromethy1-2,4-pyrimidinediamine (R926663) In a manner similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-trifluoromethylppimidine and ethyl 4-aminophenylacetate were reacted to yield N2,N4-bis[4-(ethoxycarbonylmethyl)pheny1]-5-trifluoromethy1-2,4-pyrimidinediamine. 1H NMR (CDC13): 8 8.31 (s, 1H), 7.46 (d, 2H, J=
9.0 Hz), 7.45 (d, 211, J= 8.7 Hz), 7.30 (d, 2H, J= 9.0 Hz), 7.18 (d, 211, J=
8.7 Hz), 7.16 (bs, 111), 6.82 (bs, 1H), 4.16 (2q, 411, J= 7.8 Hz), 3.64 (s, 2H), 3.57 (s, 211), 1.27 (t, 3H, J= 7.8 Hz), 1.26 (t, 3H, J= 7.8 Hz); 19F NMR (CDC13): -17223; LCMS: ret. time: 28.07 min.;
purity: 99 %; MS (m/e): 504 (MO.
7.3.140 N2,N4-Bis(2,5-dimethy1-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926623) In like manner to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2,5-dimethy1-4-hydroxyaniline were reacted to yield N2,N4-bis(2,5-dimethy1-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD30D): 67.63.(d,111, J= 4.2 Hz), 7.05 (s, 111), 6.97 (s, 111), 6.64 (111), 6.54 (s, 1H), 2.12 (s, 611), 2.06 (s, 311), 2.03 (s, 311), 2.03 (s, 3H); 19F NMR
(CD30D): -48488; LCMS: ret. time: 18.28; purity; 94%; MS (m/e): 369 (MH+).
7.3.141 N2,N4-Bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine (R926461) The reaction of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine with equivalents of sodium methoxide in methanol followed by removal of solvent gave the requisite compound, N2,N4-bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine.

NMR (D20): 67.65 (bd, 1H), 7.00-6.90 (m, 211), 6.71 (m, 2H), 6.55 (dd, 1H, J=
1.2 and 6.3 Hz), 6.31 (bd, 1H, J= 8.1 Hz), 6.23 (bd, 1H, J= 8.7 Hz); 19F NMR (D20): -47016; LCMS:
ret. time: 15.68 min.; purity: 99%; MS (m/e): 313 (MEr).
7.3.142 N2,N4-Bis(3-eyanopheny1)-5-fluoro-2,4-pyrimidinediamine (R945051) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, 3-aminobenzonitrile (177 mg, 1.5 mmol) and 2,4-dichloro-fluoropyrimidine (50 mg, 0.3 mmol) gave N2,N4-bis(3-cyanopheny1)-5-fluoro-2,4-pyrimidinediamine (75 mg, 76%). 1H NMR (acetone-d6): 8 7.33 (dt, J= 1.8, 7.8 Hz, 1 H), 7.46-7.52 (m, 2 H), 7.59 (t, J= 7.8 Hz, 1 H), 7.90 (ddd, J= 0.9, 2.1 and 8.4 Hz, 1 H), 8.09 (ddd, J= 1.2, 2.4 and 8.4 Hz, 1 H), 8.17 (d, J= 3.3 Hz, 1 H), 8.31 (m, 1 H), 8.35 (t, J= 2.1 Hz, 1 H), 8.98 (br, 1 H, NH), 9.02 (br, 1 H, NH); 19F NMR (282 MHz, acetone-d6): 8 -165.80; LCMS: 24.64 min.; purity: 98.02%; MS (m/e): 331.01 (MH+).
7.3.143 N2,N4-Bis(benzothiophen-3-ylmethyl)-5-fluoro-2,4-pyrimidinediamine (R945145) Using procedure similar to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, benzothiophen-3-ylmethylamine and 2,4-dichloro-5-fluoropyrimidine gave N2,N4-bis(benzothiophen-3-yh-nethyl)-5-fluoro-2,4-pyrimidinediamine. 111NMR (CDC13): 64.82 (dd, J= 0.9 and 5.7 Hz, 2 H), 4.86 (dd, J= 0.9 and 5.7 Hz, 2 H), 5.14 (br, 2 H), 7.31-7.40 (m, 6 H), 7.75-7.89 (m, 5 H); 19F
NMR (282 MHz, CDC13): 8 -172.12; LCMS: 27.79 min.; purity: 96.47%; MS (m/e): 420.92 (MH+).
7.3.144 N2,N4-Bis[4-(N-benzylpiperazino)pheny1]-5-fluoro-2,4-pyrimidinediamine (R945152) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 4-(N-benzylpiperazino)aniline (400 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) resulted N2,N4-bis[4-(N-benzylpiperazino)pheny1]-5-fluoro-2,4-pyrimidinediamine (120 mg, 64%). 1H NMR
(CDC13): 8 2.63 (p, J= 2.4 Hz, 8.11), 3.14 (t, J= 4.8 Hz, 4 H), 3.19 (t, J=
4.8 Hz, 4 H), 3.58 (s, 4 H), 6.58 (d, 1 H, NH), 6.67 (br, [H, NH), 6.87 (d, J= 9.3 Hz, 2 H), 6.90 (d, J= 9.0 Hz, 2 H), 7.33-7.39 (m, 12 H), 7.46 (d, J= 9.0 Hz, 2 H), 7.87 (d, J= 3.3 Hz, 1 H);
19F NMR (282 MHz, CDC13): 6-169.06; LCMS: 16.82 min.; purity: 96.88%; MS (m/e): 629.12 (M11+).

7.3.145 N2,N4-Bis(3-hydroxy-2-methylpheny1)-5-fluoro-2,4-pyrimidinediamine (R945038) In a manner analogous to the preparation of N2,N4-bis(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 3-hydroxy-2-methylaniline (369 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave N2,N4-bis(3-hydroxy-2-methylpheny1)-5-fluoro-2,4-pyrimidinediamine (180 mg, 88%). 1H NMR (acetone-d6): 8 2.14 (s, 3 H), 2.22 (s, 3 H), 6.61 (d, J= 8.1 Hz, 1 H), 6.78 (t, J= 8.7 Hz, 1 H), 6.87 (d, J= 7.8 Hz, 1 H), 6.99 (d, J= 9.0 Hz, 1 H), 7.08 (t, J= 7.8 Hz, 1 H), 7.13 (dd, J=
3.9, 8.4 Hz, 1 H), 8.24 (d, J= 5.1 Hz, 1 H), 8.32 (br, 1 H, NH), 8.57 (br, 1 H, NH); LCMS: ret.
time: 16.51 min.; purity: 90.47%; MS (m/e): 341.07 (MO.
7.3.146 N2,N4-Bis(3-nitropheny1)-5-fluoro-2,4-pyrimidinediamine (R950160) 2,4-Dichloro-5-fluoropyrimidine (4.7 g, 28.1 mmol) was dissolved in a mixture of Me0H (150 ml) and H20 (15 ml). 3-nitroaniline (15.5 g, 112 mmol) was added and the mixture was refluxed for 20 hours (100 C oil-bath temperature). The mixture was cooled to 22 C and filtered. The residue was washed carefully with 200 ml Me0H-H20 (1:1;
v/v) and dried under vacuum to give 7.89 g (76%) of N2,N4-bis(3-nitropheny1)-5-fluoro-2,4-pyrimidinediamine as yellow crystals. 1H NMR (DMSO-d6 + D20): 8 8.63 (m, 2H), 8.21 (m, 1H), 8.08 (d, 1H, J= 8.41 Hz), 7.88 (d, 1H, J= 8.4 Hz), 7.79 (d, 1H, J=
8.4 Hz), 7.70 (d, 1H, J= 8.4 Hz), 7.57 (d, 1H, J= 8.4 Hz), 7.45 (t, 1H, J= 8.4 Hz); LCMS:
purity: 100%; MS
(m/e): 371.30 (1\4+, 100).
7.3.147 N2,N4-Bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine (R921302) N2,N4-Bis(3-nitropheny1)-5-fluoro-2,4-pyrimidinediamine (4.0 g, 10.8 mmol) and Pd/C 10% (1.2 g, 50% water content) were suspended in 300 ml Et0H-10% aqueous (1: 1) and hydrogenated in a Parr apparatus for 6 hours (22 C, 50 psi). The suspension was filtered over celite and carefully washed with 20 ml DIVIE-H20 (1:1; v/v) followed by 50 ml H20. The combined filtrates were concentrated under reduced pressure to give pale yellow oil, which was triturated with Me0H to give the product as fine white needles.
The precipitate was filtered off and washed with Me0H followed by Et20. The remaining crystals were dried under vacuum to give 4.00 g of pure material (100%) as determined by LCMS. The free amine was obtained by adding 10 ml 1 N NaOH to a solution of lg salt in 5 ml H20. The resulting precipitate was filtered, washed with H20 and dried under vacuum for 24 hours to give N2,N4-bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine (770 mg) as a white solid. 1H NMR (CD30D): 8 7.92 (d, 111, J= 3.6 Hz), 7.31 (t, 1H, J= 2.1 Hz), 7.21 (t, 111, J= 2.4 Hz), 7.08, (t, 1H, J.= 8.1 Hz), 6.99 (t, 1H, J= 8.1 Hz), 6.88 (m, 1H), 6.77 (m, 111), 6.47 (m, 1H), 6.34 (m, 11I); LCMS: purity: 100%; MS (m/e):
311.07 (M+, 100).
7.3.148 N2,N4-Bis(4-aminopheny1)-5-fluoro-2,4-pyrimidinediamine (R950122) In like manner to the preparation of N2,N4-bis(3-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 1,4-diaminobenzene were reacted to prepare N2,N4-bis(4-aminopheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret.
time:
11.15 mm.; purity: 100%; MS (m/e): 311.09 (MH+).
7.3.149 N2,N4-Bis[3-(dimethylamino)pheny1]-5-fluoro-2,4-pyrimidinediamine (R950182) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of Me0H (0.3 ml) and H20 (0.03 ml). N,N-3-dimethyldiaminoaniline (163 mg, 1.2 mmol) was added and the mixture was refluxed for 24 hours (70 C oil-bath temperature).
The mixture was cooled to 22 C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHC13¨Acetone, 2: 1) to give N2,N4-bis[3-(dimethylamino)pheny1]-5-fluoro-2,4-pyrimidinediarnine. LCMS purity: 99.0%; MS
(m/e):
367.13 (M+, 100).
7.3.150 N2,N4-Bis(3-amino-4-methylpheny1)-2,4-pyrimidinediamine (R950130) 2,4-Dichloropyrimidine (45 mg, 0.30 mmol) was dissolved in a mixture of Me0H
(1 ml) and 1120 (0.1 ml). 3-amino-4-methylaniline (146 mg, 1.2 mmol) was added and the mixture was refluxed for 20 hours (70 C oil-bath temperature). The mixture was cooled to 22 C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHC13¨Acetone, 2:1) to give N2,N4-bis(3-amino-4-methylpheny1)-2,4-pyrimidinediamine. 1H NMR (CD30D): 8 8.13 (s, 111), 6.95 (d, 2H, J=
7.5 Hz), 6.82 (d, 2H, J= 1.8 Hz), 6.60 (dd, 211, J= 1.8, 7.5 Hz), 6.17 (s, 1H), 2.12 (s, 6H);
LCMS purity: 97.3%; MS (m/e): 321.09 (M+, 100).

7.3.151 N2,N4-Bis(3-amino-4-methylpheny1)-5-fluoro-2,4-pyrimidinediamine (12950129) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of Me0H (1 ml) and 1120 (0.1 m1). 3-amino-4-methylaniline (146 mg, 1.2 mmol) was added and the mixture was refluxed for 20 hours (70 C oil-bath temperature). The mixture was cooled to 22 C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHC13¨Acetone, 2:1) to give N2,N4-bis(3-amino-4-methylpheny1)-5-fluoro-2,4-pyrimidinediamine. 111NMR (CD30D): 8 8.11 (d, 111, J= 5.1 Hz), 7.98 (bs, 1H) (7.68 (dd, 1H, J= 2.4, 8.1 Hz), 7.40-7.55 (m, 4H), 2.43 (s, 313), 2.42 (s, 3H); LCMS: purity: 95.0%; MS (m/e): 338.66 (M+, 70).
7.3.152 N2,N4-Bis[(4-methylsulfonylamino)pheny1]-5-fluoro-2,4-pyrimidinediamine (11950083) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of Me0H (1 ml) and 1120 (0.1 ml). 4-methylsulfonylaminoaniline (335 mg, 1.8 mmol) was, added and the mixture was refluxed for 24 hours (100 C oil-bath temperature).
The mixture was cooled to 22 C and filtered. The residue was washed carefully with Me0H-1120 (1:1) and dried under vacuum to give N2,N4-bis[(4-methylsulfonylamino)pheny1]-5-fluoro-2,4-pyrimidinediamine. 111 NMR (CDC13): 8 8.86 (s, 1H), 8.65 (s, 1H), 8.53 (bs, 111), 8.39 (bs, 1H), 7.32 (d, 111, J= 3.3 Hz), 7.12 (d, 111, J= 8.7 Hz), 6.98 (d, 1H, J= 8.7 Hz), 6.62 (d,111, J= 8.7 Hz), 6.52 (d, 1H, J= 8.7 Hz), 2.32 (s, 3H), 2.27 (s, 3H); LCMS: purity:
96.8%; MS
(m/e): 466.94 (M+, 100).
7.3.153 N2,N4-Bis(4-benzyloxy-3-trifluoromethylpheny1)-5-fluoro-2,4-pyrimidinediamine (11950090) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of Me0H (1 ml) and 1120 (0.1 ml). 4-benzyloxy-3-trifluoromethylaniline (481 mg, 1.8 mmol) was added and the mixture was refluxed for 2 days (70 C oil-bath temperature). The mixture was cooled to 22 C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHC13¨Acetone, 9:1) to give N2,N4-bis(4-benzyloxy-3-trifluoromethylpheny1)-5-fluoro-2,4-pyrimidinediamine. 111NMR
(CDC13):
8.51 (s, 111), 8.05 (s, 1H), 7.38-7.64 (m, 511), 6.94-7.14 (m, 1111), 6.44-6.73 (m, 411), 4.84 (s, 211), 4.79 (s, 2H); LCMS purity: 94.7%; MS (mile): 628.93 (M+, 100).

7.3.154 N2,N4-Bis(3-cyano-4-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R950092) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of Me0H (1 ml) and H20 (0.1 ml). 3-cyano-4-hydroxyaniline (241 mg, 1.8 mmol) was added and the mixture was refluxed for 2 days (70 C oil-bath temperature). The mixture was cooled to 22 C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHC13¨Acetone, 9:1) to give N2,N4-bis(4-hydroxy-cyanopheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13): 8 7.96 (d, 1H, J=
3.5 Hz), 7.82 (d, 1H, J= 3.0 Hz), 7.79 (d, 1H, J= 3.0 Hz), 7.71 (dd, 1H, J= 3.0, 8.8 Hz), 7.54 (dd, J= 3.0, 8.8 Hz), 6.94 (d, 1H, J= 8.8 Hz), 6.84 (d, 1H, J= 8.8 Hz); LCMS:
purity: 97.2%;
MS (m/e): 362.98 (M+, 100).
7.3.155 N2,N4-Bis[3-methylsulfonylamino)phenyI]-5-fluoro-2,4-pyrimidinediamine (R950100) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) was dissolved in a mixture of Me0H (1 ml) and H20 (0.1 ml). 3-methylsulfonylaminoaniline (300 mg, 1.5 mmol) was added and the mixture was refluxed for 24 hours (70 C oil-bath temperature).
The mixture was cooled to 22 C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHC13¨Acetone, 9:1) to give N2,N4-bis[3-methylsulfonylamino)pheny1]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6 +
CD30D): 8 8.01 (d, 1H, J= 3.5 Hz), 7.46-7.68 (m, 4H), 7.49 (t, 1H, J= 8.2 Hz), 7.13 (t, 1H, J= 8.2 Hz), 6.89 (dd, 111, J= 2.4, 8.2 Hz), 6.72 (m, 1H), 2.95 (s, 3H), 2.91 (s, 3H); LCMS:
purity: 97.2%; MS (m/e): 466.89 (M+, 100).
7.3.156 N2,N4-Bis[3-(tert-butoxycarbonylamino)pheny1]-5-fluoro-2,4-pyrimidinediamine (R950108) 2,4-Dichloro-5-fluoropyrimidine (75 mg, 0.45 mmol) was dissolved in a mixture of Me0H (2 ml) and H20 (0.2 ml). 3-tert-butoxycarbonylaminoaniline (374 mg, 1.8 mmol) was added and the mixture was refluxed for 40 hours (70 C oil-bath temperature). The mixture was cooled to 22 C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHC13¨Acetone, 9:1) to give N2,N4-bis[3-(tert-butoxycarbonylamino)pheny1]-5-fluoro-2,4-pyrimidinediamine. 111NMR (DM5O-d6 +
CD30D): 8 7.96 (d, 114, J= 4.1 Hz), 7.83 (m, 1H), 7.60 (m, 1H), 7.34-7.42 (m, 2H), 7.15-.183 7.19 (m, 211), 7.06 (t, 111, J= 8.2 Hz), 6.93 (d, 1H, J= 8.2 Hz), 1.43 (s, 911), 1.40 (s, 9H);
LCMS: purity: 93.2%; MS (m/e): 511.06 (M+, 100).
7.3.157 N2,N4-Bis[4-(tert-butoxycarbonylamino)pheny1]-5-fluoro-2,4-pyrimidinediamine (R950120) 2,4-Dichloro-5-fluoropyrimidine (75 mg, 0.45 mmol) was dissolved in a mixture of Me0H (2 ml) and H20 (0.2 ml). 4-tert-butoxycarbonylaminoaniline (374 mg, 1.8 mmol) was added and the mixture was refluxed for 24 hours (70 C oil-bath temperature). The mixture was cooled to 22 C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHC13¨Acetone, 9:1) to give N2,N4-bis[4-(tert-butoxycarbony1amino)pheny1]-5-fluoro-2,4-pyrimidinediamine. 111 NMR (DMSO-d6 +
CD30D): 8 7.96 (d, 111, J= 3.5 Hz), 7.63 (d, 211, J= 8.8 Hz), 7.49 (d, 2H, J=
8.8 Hz), 7.37 (d, 211, J= 8.8 Hz), 7.24 (d, 2H, J= 8.8 Hz), 1.45 (s, 911), 1.43 (s, 9H);
LCMS: purity:
97.9%; MS (m/e): 511.04 (M+, 100).
7.3.158 N2,N4-Bis[242-(methylamino)ethyleneaminocarbonyll-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine (R950170) N2,N4-Bis[2-(ethoxycarbony1)-benzofiirane-5-y1]-5-fluoro-2,4-pyrimidinediamine (10 mg, 0.02 mmol) was dissolved in Et0H. To this was added N-methyl-1,2-aminoethane (0.1 ml: 0.1 ml) and the mixture was refluxed for 3 days (70 C oil-bath temperature). The mixture was cooled to 22 C, diluted with water and filtered. The residue was subjected to column chromatography on silica gel (CHC13¨Acetone, 2:1) to give N2,N4-bis[242-(methylamino)ethyleneaminocarbonyli-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine.
1H NMR (DMSO-d6 + CD30D): 8 8.14 (s, 111), 8.02 (s, 111), 7.99 (d, 1H, J= 2.4 Hz), 7.35-7.68 (m, 511), 7.17 (s, 111), 3.41 (m, 211), 2.75 (m, 2H), 2.35 (s, 311);
LCMS: purity: 84.2%;
MS (m/e): 561.08 (I\e, 100).
7.3.159 N2,N4-Bis[2-(2-hydroxyethyleneamoinocarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine (R950167) In like manner to the preparation of N2,N4-bis[2[2-(methylamino)ethyleneamino carbonylFbenzofurane-5-y11-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis[2-(ethoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine and 2-amino ethanol ' were reacted to prepare N2,N4-bis[2-(2-hydroxyethyleneamoinocarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 14.22 min.; purity:
95.7%; MS (m/e):
535.01 (MH+).

7.3.160 N2,N4-Bis[2-(2-aminoethyleneamoinocarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine (R950168) In like manner to the preparation of N2,N4-bis[2-[2-(methylamino)ethyleneamino carbonyl]-benzofurane-5-y11-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis[2-(ethoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine and 1,2-diaminoethane were reacted to prepare N2,N4-bis[2-(2-aminoethyleneamoinocarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 13.15 min.; purity: 95.8%; MS
(m/e):
532.99 (MH+).
7.3.161 N2,N4-Bis[2-(2-(N-benzylamino)ethyleneamoinocarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine (R950169) In like manner to the preparation of N2,N4-bis[2-[2-(methylamino)ethyleneamino carbonyl]-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis[2-(ethoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine and N-benzy1-1,2-diaminoethane were reacted to prepare N2,N4-bis[2-(2-(N-benzylamino)ethyleneamoino carbonyl)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time:
13.15 min.;
purity: 95.8%; MS (m/e): 713.10 (MR).
7.3.162 N2,N4-Bis[2-(N-morpholinocarbonyl)benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine (R950172) In like manner to the preparation of N2,N4-bis[2-[2-(methylamino)ethyleneamino carbonyl]-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis[2-(ethoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine and morpholine were reacted to N2,N4-bis[2-(N-morpholinocarbonyl)benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine. 11-1NMR (DMSO-d6 + CD30D): 8 8.13 (d, 1H, J= 2.7 Hz), 8.06 (d, 1H, J= 2.4 Hz), 8.03 (d, 1H, J= 3.6 Hz), 7.63 (dd, 1H, J= 2.4, 8.8 Hz), 7.57 (d, 1H, J= 9.3 Hz), 7.49 (dd, 1H, J= 2.4, 8.4 Hz), 7.42 (d, 1H, J= 8.8 Hz), 7.25 (s, 1H), 7.05 (s, 1H), 4.09 (m, 4H), 3.65 (m, 4H); LCMS: ret. time: 18.04 min.; purity: 83.2%; MS (m/e):
587.04 (MH+).
7.3.163 N2,N4-Bis[2-(2-N-morpholinoethyleneamoinocarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine (R950173) In like marmer to the preparation of N2,N4-bis[2-[2-(methylamino)ethyleneamino carbonyl]-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis[2-(ethoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine and N-(2-aminoethyleneamino)morpholine were reacted to prepare N2,N4-bis[2-(2-N-morpholinoethyleneamoinocarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine.
1H NMR (DMSO-d6 + CD30D): 8 8.16 (d, 111, J= 2.4 Hz), 8.03-8.05 (m, 2H), 7.71 (dd, 111, J= 1.8, 8.8 Hz), 7.56 (d, 1H, J= 8.8Hz), 7.42 (d, 111, J= 8.8 Hz), 7.36 (s, 111), 7.19 (s, 111), 4.19 (m, 4H), 3.38 (m, 411), 3.16 (t, 211, J= 6.3 Hz), 2.28 (t, 211, J=
6.3 Hz); LCMS:
ret. time: 12.85 min.; purity: 93.8%; MS (m/e): 673.35 (MH+).
7.3.164 N2,N4-Bis(3-amino-4-nitrophenyI)-5-fluoro-2,4-pyrimidinediamine (R950135) 2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) was dissolved in a mixture of Me0H (1 ml) and 1120 (0.1 ml). 3-amino-4-nitroaniline (184 mg, 1.2 mmol) was added and the mixture was refluxed for 3 days (70 C oil-bath temperature). The mixture was cooled to 22 C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHC13¨Acetone, 2:1) to give N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6 + CD30D): 8 8.21 (d, 1H, J= 2.9 Hz), 7.89 (m, 311), 7.56 (d, 111, J= 2.3 Hz), 7.01 (m, 1H), 6.81 (dd, 1H, J= 2.3, 9.4 Hz); LCMS: purity: 91.1%; MS (m/e): 401.00 (M+, 100).
7.3.165 N2,N4-Bis(3-amino-2,4-difluoropheny1)-5-fluoro-2,4-pyrimidinediamine (R950138) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-amino-2,4-difluoroaniline were reacted to prepare N2,N4-bis(3-amino-2,4-difluoropheny1)-5-fluoro-2,4-pyrimidinediamine.
LCMS: ret. time: 16.98 mm.; purity: 91.7%; MS (m/e): 382.97 (MH+).
7.3.166 N2,N4-Bis(3-amino-4-ethoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R950139) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-amino-4-ethoxyaniline were reacted to prepare N2,N4-bis(3-amino-4-ethoxypheny1)-5-fluoro-2,4-pyrimidinediamine.
LCMS: ret. time: 14.29 mm.; purity: 93.4%; MS (m/e): 399.09 (MI-14).
7.3.167 N2,N4-Bis(3-amino-5-methoxycarbonylpheny1)-5-fluoro-2,4-pyrimidinediamine (R950134) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrirnidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-amino-5-methoxycarbonylaniline were reacted to prepare N2,N4-bis(3-amino-5-methoxycarbonylpheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 14.72 min.;
purity: 93.8%; MS (m/e): 427.02 (MB).
7.3.168 N2,N4-Bis(3-amino-5-trifluoromethylpheny1)-5-fluoro-2,4-pyrimidinediamine (R950140) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-ppimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-amino-5-trifluoromethylaniline were reacted to prepare N2,N4-bis(3-amino-5-trifluoromethylpheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 23.35 min.; purity: 100%; MS (m/e): 446.92 (Me).
7.3.169 N2,N4-Bis(3-amino-5-ehloropheny1)-5-fluoro-2,4-pyrimidinediamine (R950141) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-amino-5-chloroaniline were reacted to prepare N2,N4-bis(3-amino-5-chloropheny1)-5-fluoro-2,4-pyrimidinediamine.
LCMS: ret. time: 19.25 min.; purity: 99.3%; MS (m/e): 378.91 (MH+).
7.3.170 N2,N4-Bis(4-hydroxy-3-trifluoromethylpheny1)-5-fluoro-2,4-pyrimidinediamine (R950093) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-hydroxy-3-trifluoromethylaniline were reacted to prepare N2,N4-bis(4-hydroxy-3-trifluoromethylpheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 22.06 min.;
purity: 99.1%; MS (m/e): 448.88 (Miff).
7.3.171 N2,N4-Bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine Hydrogen Chloride salt (R950107) N2,N4-Bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine was treated with 2 equivalents of HC1 in dioxane. The volatiles were removed under reduced pressure to give N2,N4-bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine hydrogen chloride salt. LCMS:
ret. time: 9.74 min.; purity: 91.3%; MS (m/e): 311.06 (1Val+).

7.3.172 N2,N4-Bis(4-aminopheny1)-5-fluoro-2,4-pyrimidinediamine Hydrogen Chloride Salt (R950121) N2,N4-Bis(4-aminopheny1)-5-fluoro-2,4-pyrimidinediamine was treated with 2 equivalents of HC1 in dioxane. The volatiles were removed under reduced pressure to give N2,N4-bis(4-aminopheny1)-5-fluoro-2,4-pyrimidinediamine Hydrogen Chloride Salt.
LCMS: ret. time: 11.15 mm.; purity: 100%; MS (m/e): 311.09 (MH+).
7.3.173 N2,N4-Bis(3-aminopheny1)-2,4-pyrimidinediamine (R950109) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and 3-aminoaniline were reacted to prepare N2,N4-bis(3-aminopheny1)-2,4-pyrimidinediamine. LCMS: ret. time: 8.90 min.;
purity:
91%; MS (m/e): 293.06 (MR).
7.3.174 N2,N4-Bis(3-amino-2,4-difluoropheny1)-2,4-pyrimidinediamine (11950131) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine,.2,4-dichloropyrimidine and 3-amino-2,4-difluoroaniline were reacted to prepare N2,N4-bis(3-amino-2,4-difluoropheny1)-2,4-primidinediamine. LCMS: ret.
time:
16.62 min.; purity: 96.7%; MS (m/e): 364.99 (MH+).
7.3.175 N2,N4-Bis(3-amino-4-ethoxypheny1)-2,4-pyrimidinediamine (R950142) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and 3-amino-4-ethoxyaniline were reacted to prepare N2,N4-bis(3-amino-4-ethoxypheny1)-2,4-pyrimidinediamine. LCMS: ret.
time:
14.38 min.; purity: 99.7%; MS (m/e): 381.07 (MH+).
7.3.176 N2,N4-Bis(3-amino-5-methoxycarbonylpheny1)-2,4-pyrimidinediamine (11950132) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloroppimidine and 3-amino-5-methoxycarbonylaniline were reacted to prepare N2,N4-bis(3-amino-5-methoxycarbonylpheny1)-2,4-pyrimidinediamine.
LCMS: ret. time: 15.25 mm.; purity: 93.6%; MS (m/e): 409.02 (MH+).

7.3.177 N2,N4-Bis(3-amino-5-trifluoromethylpheny1)-2,4-pyrimidinediamine (R950143) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and 3-amino-5-trifluoromethylaniline were reacted to prepare N2,N4-bis(3-amino-5-trifluoromethylpheny1)-2,4-pyrimidinediamine.
LCMS: ret. time: 23.23 min.; purity: 99.1%; MS (m/e): 428.95 (MH-f).
7.3.178 N2,N4-Bis(3-amino-5-chloropheny1)-2,4-pyrimidinediamine (R950133) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and 3-amino-5-chloroaniline were reacted to prepare N2,N4-bis(3-amino-5-chloropheny1)-2,4-ppimidinediamine. LCMS: ret.
time:
19.45 min.; purity: 100%; MS (rn/e): 360.93 (MH+).
7.3.179 N2,N4-Bis[3-amino-4-(N-phenylamino)-pheny1]-5-fluoro-2,4-pyrimidinediamine (R950125) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-amino-4-(N-phenylamino)-aniline were reacted to prepare N2,N4-bis[3-amino-4-(N-phenylarnino)-pheny1]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 23.67 min.; purity: 100%; MS (m/e):
476.36 (WO.
7.3.180 N2,N4-Bis[3-amino-4-(N-phenylamino)-pheny1]-2,4-pyrimidinediamine (R950123) In like manner the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and 3-amino-4-(N-phenylamino)-aniline were reacted to prepare N2,N4-bis[3-amino-4-(N-phenylamino)-pheny1]-2,4-pyrimidinediamine.
LCMS: ret. time: 23.77 min.; purity: 77.8%; MS (m/e): 475.04 (MI-I+).
7.3.181 N2,N4-Bis(5-amino-2-methylpheny1)-5-fluoro-2,4-pyrimidinediamine (R950157) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediarnine, 2,4-dichloro-5-fluoropyrimidine and 5-amino-2-methylaniline were reacted to prepare N2,N4-bis(5-amino-2-methylpheny1)-5-fluoro-2,4-pyrimidinediamine.
LCMS: ret. time: 10.61 min.; purity: 83.4%; MS (m/e): 339.13 (MH+).

7.3.182 N2,N4-Bis(5-amino-2-fluoropheny1)-5-fluoro-2,4-pyrimidinediamine (1R950158) In like marmer to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 5-amino-2-fluoroaniline were reacted to prepare N2,N4-bis(5-amino-2-fluoropheny1)-5-fluoro-2,4-pyrimidinediarnine.
LCMS: ret. time: 11.48 min.; purity: 95.6%; MS (m/e): 347.04 (MO.
7.3.183 N2,N4-Bis(3-amino-4-fluoropheny1)-5-fluoro-2,4-pyrimidinediamine (R950159) In like manner to the preparation of N2,N4-bis(3-amino-4-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-amino-4-fluoroaniline were reacted to prepare N2,N4-bis(3-amino-4-fluoropheny1)-5-fluoro-2,4-ppimidinediamine.
LCMS: ret. time: 18.74 mm.; purity: 95.6%; MS (m/e): 347.29 W).
7.3.184 N2,N4-Bis(2-methy1-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine (R950146) 2,4-Dichloro-5-fluoropyrimidine (33 mg, 0.2 mmol) was dissolved in a mixture of Me0H (1 ml) and 1120(0.1 ml). 2-Methyl-5-nitroaniline (122 mg, 0.8 mmol) was added and the mixture was refluxed for 2 days (70 C oil-bath temperature). The mixture was cooled to 22 C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHC13¨Acetone, 9:1) to give N2,N4-bis(2-methy1-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR (DMSO-d6 + CD30D): 6 8.31 (d, 1H, J= 2.3 Hz), 8.20 (d, 111, J= 2.3 Hz), 8.06 (d, 1H, J= 3.5 Hz), 7.91 (dd, 111, J= 2.3, 8.2 Hz), 7.65 (dd, 111, J= 2.9, 8.8 Hz), 7.41 (m, 111), 7.28 (d, 1H, J= 8.2 Hz), 2.28 (s, 311), 2.24 (s, 311); LCMS purity: 87.4%; MS (m/e): 399.20 (M+, 100).
7.3.185 N2,N4-Bis(2-fluoro-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine (R950147) In like manner to the preparation of N2,N4-bis(2-methy1-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-fluoro-5-nitroaniline were reacted to prepare N2,N4-bis(2-fluoro-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine.
LCMS: ret. time: 31.07 min.; purity: 93.6%; MS (m/e): 407.14 (MB4).

7.3.186 N2,N4-Bis(4-fluoro-3-nitropheny1)-5-fluoro-2,4-pyrimidinediamine (12950148) In like manner to the preparation of N2,N4-bis(2-methy1-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-fluoro-3-nitroaniline were reacted to prepare N2,N4-bis(4-fluoro-3-nitropheny1)-5-fluoro-2,4-pyrimidinediamine.
LCMS: ret. time: 27.17 min.; purity: 94.3%; MS (m/e): 406.96 (MI14).
7.3.187 N2,N4-Bis(4-methy1-3-nitropheny1)-5-fluoro-2,4-pyrimidinediamine (12950144) In like manner to the preparation of N2,N4-bis(2-methy1-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-methyl-3-nitroaniline were reacted to prepare N2,N4-bis(4-methy1-3-nitropheny1)-5-fluoro-2,4-pyrimidinediamine.
LCMS: ret. time: 27.40 min.; purity: 96.6%; MS (rn/e): 399.00 (MEI+).
7.3.188 N2,N4-Bis(4-ehloro-3-nitropheny1)-5-fluoro-2,4-pyrimidinediamine (12950149) In like manner to the preparation of N2,N4-bis(2-methy1-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-chloro-3-nitroaniline were reacted to prepare N2,N4-bis(4-chloro-3-nitropheny1)-5-fluoro-2,4-pyrimidinediamine.
LCMS: ret. time: 35.63 min.; purity: 98.9%; MS (m/e): 439.09 (MI-14).
7.3.189 N2,N4-Bis(2-hydroxyethyleneamino-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine (12950150) In like manner to the preparation of N2,N4-bis(2-methy1-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-hydroxyethyleneamino-5-nitroaniline were reacted to prepare N2,N4-bis(2-hydroxyethyleneamino-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 17.90 min.; purity: 97.8%; MS
(m/e):
489.19 (MH).
7.3.190 N2,N4-Bis(2-methoxy-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine (12950151) In like manner to the preparation of N2,N4-bis(2-methy1-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 2-methoxy-5-nitroaniline were reacted to prepare N2,N4-bis(2-methoxy-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine.
LCMS: ret. time: 31.46 min.; purity: 95.9%; MS (m/e): 431.22 (M1I+).

7.3.191 N2,N4-Bis(4-fluoro-3-nitropheny1)-2,4-pyrimidinediamine (R950152) In like manner to the preparation of N2,N4-bis(2-methy1-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and 4-fluoro-3-nitroaniline were reacted to prepare N2,N4-bis(4-fluoro-3-nitropheny1)-2,4-pyrimidinediamine. LCMS: ret.
time: 30.92 min.; purity: 94.4%; MS (m/e): 389.31 (MR).
7.3.192 N2,N4-Bis(4-methyl-3-nitropheny1)-2,4-pyrimidinediamine (R950153) In like manner to the preparation of N2,N4-bis(2-methy1-5-nitropheny1)-5-fluoro-2,4-primidinediamine, 2,4-dichloropyrimidine and 4-methyl-3-nitroaniline were reacted to prepare N2,N4-bis(4-methyl-3-nitropheny1)-2,4-pyrimidinediamine. LCMS: ret.
time:
31.22 min.; purity: 99.6%; MS (m/e): 381.35 (MO.
7.3.193 N2,N4-Bis(4-ehloro-3-nitropheny1)-2,4-pyrimidinediamine (R950154) In like mariner to the preparation of N2,N4-bis(2-methy1-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and 4-chloro-3-nitroaniline were reacted to prepare N2,N4-bis(4-chloro-3-nitropheny1)-2,4-pyrimidinediamine. LCMS: ret.
time: 37.24 min.; purity: 99.1%; MS (m/e): 421.30 (MH+).
7.3.194 N2,N4-Bis(2-hydroxy-5-nitropheny1)-2,4-pyrimidinediamine (R950155) In like manner to the preparation of N2,N4-bis(2-methy1-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and 2-hydroxy-5-nitroaniline were reacted to prepare N2,N4-bis(2-hydroxy-5-nitropheny1)-2,4-pyrimidinediarnine. LCMS:
ret. time:
23.26 min.; purity: 100%; MS (mile): 385.33 (MO.
7.3.195 N2,N4-Bis(2-hydroxyethyleneamino-5-nitropheny1)-2,4-pyrimidinediamine (R950156) In like manner to the preparation of N2,N4-bis(2-methy1-5-nitropheny1)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloropyrimidine and 2-hydroxyethyleneamino-5-nitroaniline were reacted to prepare N2,N4-bis(2-hydroxyethyleneamino-5-nitropheny1)-2,4-pyrimidinediamine. LCMS: ret. time: 17.87 min.; purity: 97.2%; MS (mile):
470.99 (M1-14).

7.3.196 N2,N4-Bis[3-(N-isopropyl)aminopheny1]-5-fluoro-2,4-pyrimidinediamine (R950166) N2,N4-Bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine, acetone and sodiumcyanoborohydride were reacted together to give N2,N4-bis[3-(N-isopropyl)aminopheny1]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 14.07 mm.;
purity: 90.3%; MS (m/e): 395.14 (MO.
7.3.197 N2,N4-Bis[3-N-(2-hydroxy-1-methylethyl)aminopheny1]-5-fluoro-2,4-pyrimidinediamine (R950171) N2,N4-Bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine, 1-hydroxyacetone and sodiumcyanoborohydride were reacted to give N2,N4-bis[3-N-(2-hydroxy-1-methylethypaminophenyl]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 11.97 min.;
purity: 79.01%; MS (m/e): 427.12 (MH+).
7.3.198 N2,N4-Bis(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine (R950177) N2,N4-Bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine and tert-butyl bromoacetate were reacted together to give N2,N4-bis(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret.
time:
29.34 min.; purity: 97.2%; MS (m/e): 427.07 (MO.
7.3.199 N4-(3-Aminopheny1)-N2-(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine (R950178) In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine and tert-butyl bromo acetate were reacted together to give N4-(3-aminopheny1)-N2-(3-tert-butoxycarbonyh-nethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 18.33 min.; purity: 94.5%; MS
(m/e):
369.09 (MIT).
7.3.200 N2-(3-Aminopheny1)-N4-(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine (R950179) In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrhnidinediamine, N2,N4-bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine and tert-butyl bromoacetate were reacted together to give N2-(3-aminopheny1)-N4-(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 18.82 min.; purity: 85.8%; MS
(m/e):
369.11 (M11+).
7.3.201 N2,N4-Bis(3-ethoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine (R950184) In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine and ethyl bromoacetate were reacted together to give N2,N4-bis(3-ethoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 23.41 min.; purity: 96.3%; MS (mile):
483.08 (MH+).
7.3.202 N2,N4-Bis(3-ethoxycarbonylmethyleneaminopheny1)-N2-(ethoxycarbonylmethyl)-5-fluoro-2,4-pyrimidinediamine (R950183) In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine and ethyl bromoacetate were reacted together to give N2,N4-bis(3-ethoxycarbonylmethyleneaminopheny1)-N2-(ethoxycarbonylmethyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 25.65 min.;
purity: 92.5%; MS (mile): 569.08 (M1I+).
7.3.203 N2-(3-Aminopheny1)-N4-(3-hydroxyethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine and N4-(3-Aminopheny1)-N2-(3-hydroxyethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine (R950180) In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine and 1-bromo-2-hydroxyethane were reacted together to give a unseparable mixture of N2-(3-aminopheny1)-N4-(3-hydroxyethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine and N4-(3-aminophenyl)-LCMS: ret. time:
9.84 min.; purity: 89.5%; MS (mile): 355.10 (ME().

7.3.204 N2,N4-Bis(3-hydroxyethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine (R950181) In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimiclinediamine, N2,N4-bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine and 1-bromo-2-hydroxyethane were reacted together to give N2,N4-bis(3-hydroxyethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 11.46 min.; purity: 83.3%; MS (m/e):
399.12 (Min.
7.3.205 N2,N4-Bis[3-(N-benzyloxyethyleneamino)pheny1]-5-fluoro-2,4-pyrimidinediamine (R950174) In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine and 1-benzyloxy-2-bromoethane were reacted together to give N2,N4-bis[3-(N-benzyloxyethyleneamino)pheny1]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 32.92 min.; MS (m/e): 579.17 (MH+).
7.3.206 N2-(3-Aminopheny1)-N443-(N-benzyloxyethyleneamino)pheny1]-5-fluoro-2,4-pyrimidinediamine (R950175) In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-primidinediamine, N2,N4-bis(3-aminopheny1)-5-fluoro-2,4-pyrimidinediamine and 1-benzyloxy-2-bromoethane were reacted together to give N2-(3-aminopheny1)-N443-(N-benzyloxyethyleneamino)pheny1]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 23.79 min.; MS (m/e): 445.11 (MH+).
7.3.207 N4-(3-Aminopheny1)-N2-[3-(N-benzyloxyethyleneamino)pheny1]-5-fluoro-2,4-pyrimidinediamine (R950176) In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminopheny1)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminopheny1)-5-fluoro-2,4-pyrirnidinediamine and 1-benzyloxy-2-bromoethane were reacted together to give N4-(3-aminopheny1)-N243-(N-benzyloxyethyleneamino)pheny1]-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 23.64 min.; MS (m/e): 445.13 (M114).

7.3.208 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (R926210) To a solution of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine (0.028g, 0.1 mmol) in MeOH: H20 (1.8: 0.2 rnL) was added 3-hydroxyaniline (0.033g, 0.3 mmol) and heated in a sealed tube at 100 C for 24h. The resulting reaction was diluted with H20 (10 mL), acidified with 2N HC1 (pH
>2), saturated and the resulting solid was filtered to give the desired product, N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1))-2,4-pyrimidinediamine (R926210).
Purification can be done by filtration through a pad of silica gel using 1-5%
Me0H in CH2C12 or by crystallization using an appropriate solvent system. 1H NMR
(CDC13 +
CD30D): 8 7.76 (bs, 1H), 7.30 (d, 1H, J= 2.4 Hz), 7.10 (m, 1H), 7.03 (t, 1H, J= 8.1 Hz), 6.89 (dd, 211, J= 2.4 and 9 Hz), 6.78 (d, 1H, J= 8.7 Hz), 6.42 (dd, 1H, J= 2.4 and 9 Hz), 4.22 (m, 411); 19F NMR (CDC13 + CD30D): -.47196; LCMS: ret. time: 19.55 min.;
purity: 95%;
MS (m/e): 355 (MO.
Note: When the substrate has ethyl, butyl, benzyl etc. ester functions and the reaction is carried out in methanol as a solvent, the cross esterification to produce methyl ester was observed.
7.3.209 N2-(3,4-Ethylenedioxypheny1)-5-fluoro-N443-(hydroxymethyl)pheny11-2,4-pyrimidinediamine (1R925758) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N443-(hydroxymethyl)pheny1]-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N2-(3,4-ethylenedioxypheny1)-5-fluoro-N443-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine. 111 NMR (CDC13): 8 7.92 (d, 1H, J= 3.0 Hz), 7.78 (bs, 1H), 7.41-7.31 (m, 314), 7.12 (d, 111, J= 7.2 Hz), 6.94 (bs, 1H), 6.81-6.75 (m, 3H), 4.68 (s, 2H), 4.25 (s, 411); 19F NMR (CDC13): - 47438; LCMS: ret. time: 17.73 min.; purity: 100 %; MS
(m/e):
369 (MO.
7.3.210 N2-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-[4-(hydroxymethyl)pheny11-2,4-pyrimidinediamine (R925760) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N444-(hydroxymethyl)pheny1]-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N2-(3,4-ethylenedioxypheny1)-5-fluoro-N244-(hydroxymethyl)phenyl]-2,4-pyrimidinediarnine. 111 NMR (CDC13): 8 7.92 (bs, 1H), 7.62 (d, 2H, J= 8.7 Hz), 7.36 (d, 2H, J= 8.7 Hz), 7.19 (d, 111, J= 2.1), 6.87 (dd, 1H, J= 2.7 and 8.7 Hz), 6.79 (d, 1H, J= 8.7 Hz), 4.68 (s, 2H), 4.28-4.23 (m, 4H); 19F NMR (CDC13): - 4.7466; LCMS: ret.
time: 17.86 mm.; purity: 93 %; MS (m/e): 369 (M11+).
7.3.211 N2-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-(2-hydroxy-2-phenylethyl)-2,4-pyrimidinediamine (R925765) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-ppimidinediamine, 2-chloro-5-fluoro-N4-(2-hydroxy-2-phenylethyl)-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N2-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(2-hydroxy-2-phenylethyl)-2,4-pyrimidinediamine.
111 NMR (CDC13): 8 7.79 (s, 1H), 7.48 (m, 5H), 6.89-6.71 (m, 3H), 5.41-5.38, 4.97 (dd, 1H, J= 3.6 and 7.5 Hz), 4.28-4.22 (m, 4H), 3.88 (ddd, 1H, J= 4.2, 7.2, and 14.1), 3.64-3.55 (m, 1H); 19F NMR (CDC13): - 47910; LCMS: ret. time: 20.47 mm.; purity: 88 %; MS
(m/e): 383 (E).
7.3.212 N2-(3,4-Ethylendioxypheny1)-5-fluoro-N4-[(2R)-hydroxy-(1S)-methy1-2-phenylethyl)-2,4-pyrimidinediamine (R925766) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-[(2R)-hydroxy-(1S)-methy1-2-phenylethyl)-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N2-(3,4-ethylendioxypheny1)-5-fluoro-N4-[(2R)-hydroxy-(1S)-methy1-2-phenylethyl)-2,4-pyrimidinediamine. 111 NMR (CDC13): 67.80 (bs, 1H), 7.71 (bs, 1H), 7.36-7.23 (m, 6H), 6.91 (dd, 1H, J= 3.0 and 9.0 Hz), 6.80 (d, 111, J= 9.0 Hz), 5.17 (d, 1H, J=
8.1 Hz), 5.01 (d, 1H, J= 3.0 Hz), 4.56-4.50 (m, 1H), 4.24 (s, 4H), 1.10 (d, 3H, J= 6.3 Hz);
19F NMR (CDC13): - 47840; LCMS: ret. time: 21.43 min.; purity: 99 %; MS (m/e):

(M11).
7.3.213 N4-Cyclohexyl-N2-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R925794) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-cyclohexy1-5-fluoro-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N4-cyclohexyl-N2-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD30D):
67.62 (d, 1H, J= 4.2 Hz), 7.31 (d, 1H, J= 2.1 Hz), 6.86 (dd, 1H, J= 2.4 and 8.7 Hz), 6.68 (d, 1H, J=

8.7 Hz), 4.23-4.16 (m, 4H), 3.99-3.89 (m, 1H), 2.03 (dd, 211, J= 2.1 and 12.3 Hz), 1.80 (dt, 2H, J= 3.0 and 13.5 Hz), 1.72-1.65 (m, 111), 1.49-1.20 (m, 5H); 19F NMR
(CD30D): -48332; LCMS: ret. time: 24.54 min.; purity: 95 %; MS (m/e): 345 (M11+).
7.3.214 N4-(4-Carboxycyclohexyl)-N2-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R925795) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, N4-(4-carboxycyclohexyl)-2-chloro-fluoro-4-primidineamine and 3,4-ethylenedioxyaniline were reacted to yield N4-(4-carboxycyclohexyl)-N2-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H
NMR (CD30D): 8 7.62 (d, 111, J= 4.2 Hz), 7.31 (d, 111, 1=2.4 Hz), 6.84 (dd, 111, J= 2.4 and 8.7 Hz), 6.70 (d, 1H, J= 8.7 Hz), 4.23-4.18 (m, 4H), 3.99-4.08 (m, 1H), 2.59 (t, 111, J= 3.9 Hz), 2.16-2.09 (m, 211), 1.91-1.84 (m, 2H), 1.78-1.57 (m, 4H); 19F NMR
(CD30D): -48152;
LCMS: ret. time: 19.31 min.; purity: 96 %; MS (m/e): 389 (MO.
7.3.215 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (R925796) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine. 1H
NMR
(DMSO-d6): 8 9.30 (s, 1H), 9.12 (bs, 1H), 8.91 (bs, 111), 8.02 (d, 111, J= 3.3 Hz), 7.35-7.30 (m, 111), 7.24-7.21 (m, 1H), 7.12 (t, 111, J= 1.8 Hz), 7.09-7.04 (m, 211), 6.67 (d, 111, J= 9.0), 6.46 (dd, 1H, J= 1.8 and 8.4 Hz), 4.18-4.12 (m, 4H); 19F NMR (DMSO-d6): -46594;
LCMS: ret. time: 18.43 min.; purity: 97 %; MS (m/e): 355 (MO.
7.3.216 N2-Allyl-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R925823) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and allylamine were reacted to yield N2-allyl-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD30D): 67.71 (bs, 111), 7.37 (d, 111, J= 2.4 Hz), 7.07 (dd, 111, J= 2.4 and 8.7 Hz), 6.75 (d, 1H, J=
8.7 Hz), 5.98-5.85 (m, 1H), 5.19 (dq, 111, J= 1.8 and 16.8 Hz), 5.06 (dq, 1H, J= 1.8 and 10.5 Hz), 4.24-4.18 (m, 411), 3.92-3.68 (m, 211); 19F NMR (CD30D): - 48552; LCMS: ret. time: 19.36 mm.; purity:
95 %; MS (m/e): 303 (MH+).
7.3.217 N4-(3,4-Ethylenedioxypheny1)-N2-(4-ethylpheny1)-5-fluoro-2,4-pyrimidinediamine (R926237) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 4-ethylaniline were reacted to yield N4-(3,4-ethylenedioxypheny1)-N2-(4-ethylpheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR
(CDC13): 8 7.87 (bs, 1H), 7.42 (d, 211, J= 8.7 Hz), 7.26 (d, 1H, J= 3.0 Hz), 7.13-7.08 (m, 3H), 6.95 (dd, 111, J= 2.4 and 8.7 Hz), 6.82 (d, 111, J= 9.0 Hz), 6.60 (bs, 111), 4.23 (s, 411), 2.59 (q, 211, J= 7.5 Hz), 1.20 (t, 3H, J= 7.5 Hz); 19F NMR (CDC13): - 47549;
LCMS: ret.
time: 25.31min.; purity: 99 %; MS (m/e): 367 (MH+).
7.3.218 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N242-(methoxycarbonyl)benzofuran-5-y11-2,4-pyrimidinediamine (R926690) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 2-methoxycarbony1-5-aminobenzofuran were reacted to yield ,N4-(3,4-ethylenedioxypheny1)-5-fluoro-N242-(methoxycarbonyl)benzofuran-5-y1]-2,4-,pyrimidinediamine. 1H NMR (DMSO-d6): 69.68 (bs, 111), 8.13-8.10 (m, 2H)7.63-7.54 (m, 3H), 7.27 (bs, 111), 7.10 (d, 111, J= 8.7 Hz), 6.80 (d, 1H, J= 8.1 Hz), 4.21 (s, 4H), 3.88 (s, 3H); LCMS: ret. time: 23.22 mm.; purity: 95 %; MS (m/e): 437 (MH+).
7.3.219 5-Fluoro-N2-(2-methoxycarbonylbenzofuran-5-y1)-N4-(4-isopropoxypheny1)- 2,4-pyrimidinediamine (R926704) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N444-(isopropoxy)pheny1]-4-pyrimidineamine and 2-methoxycarbony1-5-aminobenzofuran were reacted to yield 5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-y1)-N4-(4-isopropoxypheny1)- 2,4-pyrimidinediamine. 1H NMR (CDC13): 8 8.04 (d, 1H, J=
1.8 Hz), 7.49-7.41 (m, 4H), 7.35 (dd, 1H, J= 2.4 and 8.7 Hz), 7.14 (bs, 111), 6.90 (d, 2H, J= 9.3 Hz), 6.70 (bs, 1H), 4.56 (2q, 111, J= 5.7 Hz), 3.98 (s, 3H), 1.37 (d, 6H, J= 5.7 Hz); LCMS: ret.
time: 25.52 min.; purity: 98 %; MS (m/e): 437 (MH+).

=

7.3.220 5-Fluoro-N4-( 3-hydroxypheny1)-N244-(2-hydroxyethyl)oxypheny11-2,4-pyrimidinediamine (11926376) In like manner to N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-( 3-hydroxypheny1)]-4-pyrimidineamine and 4-(2-hydroxyethyloxy)aniline were reacted to yield 5-fluoro-N4-( 3-hydroxypheny1)-N244-(2-hydroxyethypoxypheny1]-2,4-pyrimidinediamine. 1H NMR (D20): 5 8.40 (d, 1113= 4 Hz), 7.57 (m, 611), 7.12 (m, 2H), 6.90 (m, 2H), 4.40 (m, 4H) 2,2 (s, 311);
LCMS: ret. time:
13.61 min.; purity: 97 %; MS (mile): 357 (Mir).
7.3.221 N244-(2-N,N-Dimethylamino)ethoxypheny11-5-fluoro-N4-(3-hydroxyphenyI)-2,4-pyrimidinediamine (11909236) In like manner to N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-( 3-hydroxypheny1)]-4-pyrimidineamine and 4-(2-N,N-dimethylamino)ethoxyaniline were reacted to yield N2-[4-(2-N,N-dimethylamino)ethoxyphenyl]-5-fluoro-N4-( 3-hydroxypheny1)-2,4-pyrimidinediamine. 1H .
NMR (CD30D): 67.80 (d, 111 J= 4 Hz), 7.47 (dd, 1H, J= 6.8 Hz, 2.7 Hz), 7.44 (m, 111), 7.05 (m, 1H), 6.85 (m, 111), 6.78 (m, 211), 4.16 (m, 211), 3.03 (m, 2H), 2.55(s, 611); LCMS:
ret. time: 12.74 min.; purity: 98 %; MS (m/e): 384 (MET).
7.3.222 N2-(1,4-Benzoxazin-3-on-6-y1)- 5-fluoro-N4-( 3-hydroxypheny1)-2,4-pyrimidinediamine (11909238) In like manner to N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-( 3-hydroxypheny1)]-4-pyrimidineamine and 6-amino-1,4-benzoxazin-3-one were reacted to yield N2-(1,4-benzoxazin-3-on-6-y1)-5-fluoro-N4-( 3-hydroxypheny1)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 5 8.18 (d, 111 3= 4 Hz), 7.17 (m, 311), 7.09 (m, 1H), 7.06 (m, 111), 6.58 (m, 111) 4.52 (s, 311); LCMS:
ret. time: 17.18 min.; purity: 99 %; MS (m/e): 368 (M11).
7.3.223 N2-(1,4-Benzoxazin-6-y1)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (11909241) In like manner to N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-=
2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-( 3-hydroxypheny1)]
pyrimidineamine and 6-amino-1,4-benzoxazine were reacted to yield N2-(1,4-benzoxazin-6-y1)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine. 1H NMR (CD30D): 6 7.82 (d, 111, 3= 4 Hz), 7.15 (m, 311), 6.68 (m, 2H), 6.52 (m, 2H), 6.52 (m, 1H), 4.18 (m, 2H), 3.37 (m, 2H); LCMS: ret.
time 17.42 min.; purity: 95%; MS (m/e): 354 NH).
7.3.224 N4-(1,4-Benzoxazin-6-y1)-N2-[3-.
ethoxyocarbonylmethyleneoxypheny11-5-fluoro-2,4-pyrimidinediamine (R909242) In like manner to N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, N4-(1,4-benzoxazin-6-y1)-N2-chloro-5-fluoro-4-pyrimidineamine and 3-ethoxyocarbonylmethyleneoxyaniline were reacted to yield N4-(1,4-benzoxazin-6-y1)-N2-(3-ethoxyocarbonylmethyleneoxypheny1)-5-fluoro-2,4-pyrimidinediamine.
1.11 NMR (CD30D): 6 8.2 (d, 1H, J 4 Hz), 7.15 (m, 4H), 6.84 (m, 2H), 6.62 (m, 1H), 4.65 (s, 2H), 4.15 (m, 4H), 3.28 (m, 2H), 1.19 (t, 311. J= 7 Hz); LCMS: ret. time 22.6 min.; purity:
94%; MS (m/e): 439 (MO.
7.3.225 N2-(1,4-Benzoxazin-6-y1)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R909243) In like manner to N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-=
2,4-pyrimidinediamine, N4-(1,4-benzoxazin-6-y1)-N2-chloro-5-fluoro-4-pyrimidinearnine and 3-aminophenol were reacted to yield N4-(1,4-benzoxazin-6-y1)-5-fluoro-N2-(3- =
hydroxypheny1)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 6 7.83 (d, 1H, I= 4 Hz), 7.18 (m, 311), 6.68 (m, 2H), 6.45 (m, 211), 6.52 (m, 111), 4.22 (m, 2H), 3.31 (m, 211);
LCMS: ret. time: 17.24; purity: 96%; MS (m/e): 354 (MH+).
7.3.226 N4-(1,4-Benzoxazin-6-y1)-N2-(3,5-dimethoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R909245) In like manner to N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, N4-(1,4-benzoxazin-6-y1)-N2-chloro-5-fluoro-4-pyrimidineamine and 3,5-dimethoxyaniline were reacted to yield N4-(1,4-benzoxazin-6-y1)-N2-(3,5-dimethoxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1=H NMR (DMSO-d6): 6 8.12 (d, 1H, J= 4 Hz), 6.80 (m, 4H), 6.60 (m, 111), 6.05 (m, 1H), 4.02 (m, 2H), 3.65 (s, 6H), 3.31 (m, 2H); LCMS: ret. time: 22.38 min.; purity: 99 %; MS (m/e): 398 (MH+).
7.3.227 N4-(1,4-Benzoxazin-6-y1)-N2-(3-tert-butylpheny1)-5-fluoro-2,4-pyrimidinediamine (R909246) In like manner to N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, N4-(1,4-benzoxazin-6-y1)-N2-chloro-5-fluoro-4-pyrimidineamine and 3-tert-butylaniline were reacted to yield N4-(1,4-benzoxazin-6-y1)-N2-(3-tert-butylpheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR. (DMSO-d6): 8 8.3 (d, 1H, , 1-- 4 Hz), 7.5 (m, 1H), 7.4 (m, 1H), 7.18 (m, 1H), 7.02 (m, 1H), 6.80 (m, 2H), 6.60 (m, 1H), 4.02 (m, 2H), 3.31 (in, 2H), 1.2 (s, 9H); LCMS: ret. time: 26.64 min.; purity: 99 %; MS (m/e):
508 (Min.
73.228 N4-(1,4-Benzoxazin-6-y))-5-fluoro-N2-[4-(2-hydroxyethyl)oxypheny11-2,4-pyrimidinediamine (R909248) In like manner to N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, N4-(1,4-benzoxazin-6-y1)-N2-chloro-5-fluoro-4-pyrimidineamine and 4-(2-hydroxyethyDoxyaniline were reacted to yield N4-(1,4-benzoxazin-6-y1)-5-fluoro-N244-(2-hydroxyethyl)oxyphenyl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6):
8 7.98 (d, 1H, .1= 4 Hz), 7.52 (m, 1H), 7.4 (m, 3H), 6.90 (m, 2H), 6.68 (m, 1H), 4.56 (s, 2H), 4.02 (in, 2H), 3.75 (m, 2H), 3.31 (m, 4H); LCMS: ret. time: 26.67 min.;
purity: 93 %;
MS(m/e): 399 (M114).
7.3.229 N2-(2,3-Dihydrobenzofuran-5-y1)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R909250) In like manner to N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyriznidinediamine, 2-chloro-5-fluoro-N4-( 3-hydroxypheny1)]-4-pyrimidineamine and 5-amino-2,3-dihydrobenzofuran were reacted to yield N2-(2,3-dihydrobenzofuran-5-y1)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine. 1HNMR (DMSO-d6): 8 8.09 (d, 1H), 8.00 (m, 1H), 7.82 (m, 111), 7.57 (m, 1H), 7.22 (m, 1H), 7.08 (m, 1H), 6.99 (m, 1H), 6.82 (m, 1H), 6.70 (m, 1H), 6.42 (m, 1H), 4.49 (m, 2H), 3.15 (m, 2H); LCMS:
ret time:
19.39 min.; MS (m/e): 338 (MTV).
7.3.230 N4-(1,4-Benzoxazin-6-y1)-N2-(3-chloro-4-hydroxy-5-methylpheny1)-5-fluoro-2,4-pyrimidinediamine (R909255) In like manner to N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, N4-(1,4-benzoxazin-6-y1)-N2-chloro-5-fluoro-4-pyrimidinearnine and 3-chloro-4-hydroxy-5-methylaniline were reacted to yield N4-(1,4-benzoxazin-6-y1)-N2-(3-chloro-4-hydroxy-5-methylpheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR
(DMSO-d6): 8 7.89 (d, 1H,, J 4 Hz), 7.25 (m, 1H), 7.14 (m, 1H), 6.80 (m, 2H), 6.82 (m, 1H), 4.29 (s, 211), 3.35 (m, 2H), 2.20 (s, 3H); LCMS: ret. time: 17.05 min.;
purity: 99 %;
MS(m/e): 402 (MH*).

7.3.231 5-Fluoro-N2-(2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-y1)-N4-(4-isopropoxypheny1)-2,4-pyrimidinediamine (R926706) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(4-isopropoxypheny1)-4-pyrimidineamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzan-an were reacted to yield 5-fluoro-N2-(2,3-dihydro-2-(methoxycarbonyl)benzothran-5-y1)-N4-(4-isopropoxypheny1)-2,4-primidinediamine. 1H
NMR (CDC13): 5 7.87 (d, 1H, J= 3.0 Hz), 7.47-7.42 (m, 3H), 7.12 (dd, 1H, J=
2.4 and 8.4 Hz), 6.87 (d, 2H, J= 9.6 Hz), 6.80 (d, 1H, J= 8.7 Hz), 6.63 (d, 1H, J= 2.4 Hz), 5.21 (dd, 111, J= 6.3 and 10.5 Hz), 4.53 (2q, 1H, J= 5.7 Hz), 3.80 (s, 3H), 3.52 (dd, 111, J=
10.5 and 15.9 Hz), 3.35 (dd, 1H, J= 6.3 and 15.9 Hz), 1.34 (d, 611, J= 5.7 Hz); 19F NMR
(CDC13): -47664;
LCMS: ret. time: 23.78 min.; purity: 95 %; MS (m/e): 439 (Mu').
7.3.232 5-Fluoro-N4-(3-hydroxypheny1)-N24442-(N-morpholino)ethyleneoxylpheny11-2,4-pyrimidinediamine (R926699) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3-hydroxypheny1)-5-fluoro-4-pyrimidineamine and 4-[2-(N-morpholino)ethyleneoxy]aniline were reacted to yield 5-fluoro-N4-(3-hydroxypheny1)-N24442-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 6 9.34 (s, 111), 9.17 (bs, 111), 8.95 (bs, 111), 8.02 (d, 111, J= 3.3 Hz), 7.53 (d, 2H, J= 9.0 Hz), 7.28-7.23 (m, 1H), 7.12-7.04 (m, al, 6.79 (d, 2H, J= 9.0 Hz), 6.47 (dd, 111, J= 1.2 and 5.7 Hz), 4.00 (t, 211, J= 6.0 Hz), 3.56 (t, 411, J= 4.5 Hz), 2.64 (t, 2H, J= 6.0 Hz), 2.44 (t, 411, J= 4.5 Hz); 19F NMR (DMSO-d6): -46715;
LCMS: ret. time: 12.66 min.; purity: 95 %; MS (m/e): 426 (MO.
7.3.233 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N214-[2-(N-morpholino)ethyleneoxy]pheny1]-2,4-pyrimidinediamine (R926709) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 4-[2-(N-morpholino)ethyleneoxy]aniline were reacted to yield N4-(3,4-ethylenedioxypheny1)-5-fluoro-N24442-(N-morpholino)ethyleneoxy]pheny1]-2,4-pyriMidinediamine. 1H NMR (CD30D): 7.80 (d, 1H, J= 3.6 Hz), 7.72 (bs, 1H), 7.62 (bs, 1H), 7.41 (d, 1H, J= 9.3 Hz), 7.24 (d, 1H, J= 5.4 Hz), 7.05 (dd, 1H, J= 2.4 and 8.7 Hz), 6.84 (d, 2H, J= 8.7 Hz), 6.75 (d, 1H, J= 9.0 Hz), 4.24 (bs, 4H), 4.11 (t, 2H, J= 5.4 Hz), 3.74-3.69 (m, 4H), 2.80 (t, 2H, J= 5.4 Hz), 2.62-2.58 (m, 4H); 19F NMR (CD30D): - 47912; LCMS: ret. time: 15.16 mm.; purity: 91 %; MS
(m/e):
468 (MET).
7.3.234 5-Fluoro-N2-(3-hydroxypheny1)-N4-[442-(N-morpholino)ethyleneoxy]pheny11-2,4-pyrimidinediamine (R926710) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-[442-(N-morpholino)ethyleneoxy]pheny1]-4-pyrimidineamine and 3-aminophenol were reacted to yield 5-fluoro-N2-(3-hydroxypheny1)-N44442-(N-moipholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine. 1H NMR (CD30D): 67.84 (d, 1H, J= 4.2 Hz), 7.60 (d, 1H. J=
9.3 Hz), 7.09 (t, 1H, J= 2.4 Hz), 7.04-6.96 (m, 2H), 6.93 (d, 2H, J= 9.3 Hz), 6.40 (dt, 1H, J= 1.8 and 7.5 Hz), 4.15 (t, 2H, J= 5.4 Hz), 3.75-3.70 (m, 4H), 2.81 (t, 2H, J= 5.1 Hz), 2.63-2.59 (m, 4H); LCMS: ret. time: 14.16 mm.; purity: 98 %; MS (m/e): 426 (MET).
7.3.235 N2-(3,4-Ethylenedioxypheny1)-5-fluoro-N4-[442-(N-morpholino)ethyleneoxylphenyl]-2,4-pyrimidinediamine (R926711) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N44442-(N-morpholino)ethyleneoxy]pheny1]-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N2-(3,4-ethylenedioxypheny1)-5-fluoro-N44412-(N-morpholino)ethyleneoxy]pheny1]-2,4-pyrimidinediamine. 1H NMR (CD30D): 67.80 (d, 1H, J= 4.2 Hz), 7.56 (d, 2H, J= 8.7 Hz), 7.13 (d, 111, J= 2.4 Hz), 6.91 (d, 2H, J= 9.6 Hz), 6.86 (dd, 1H, J= 2.4 and 9.0 Hz), 6.67 (d, 1H, J= 9.0 Hz), 4.23-4.18 (m, 4H), 4.14 (t, 3H, J=
5.4 Hz), 3.74-3.70 (m, 411), 2.82 (t, 3H, J= 5.4 Hz), 2.64-2.59 (m, 4H); 19F
NMR (CDC13): -47914; LCMS: ret. time: 15.97 min.; purity: 94 %; MS (m/e): 468 (MH4).
7.3.236 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-[4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)pheny11-2,4-pyrimidinediamine (R926716) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)aniline were reacted to yield N4-(3,4-ethylenedioxypheny1)-5-fluoro-N244-(tetrahydro-(1H)-pyno1-1-ylsulfonyl)pheny1]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 10.11 (bs, 1H), 9.76 (bs, 1H), 8.19 (d, 1H, J= 3.9 Hz), 7.82 (d, 2H, J= 8.7 Hz), 7.62 (d, 2H, J=
8.7 Hz), 7.27 (d, 111, J= 2.4 Hz), 7.08 (dd, 1H, J= 2.4 and 8.7 Hz), 6.85 (d, 1H, J= 8.7 Hz), 4.23 (s, 4H), 3.10-3.06 (m, 4H), 1.64-1.58 (m, 411); LCMS: ret. time: 22.68 min.; purity: 93 %;
MS (m/e): 472 NO.
7.3.237 N24344-(2-Chloro-6-fluorobenzyl)piperazinolpropy1]-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926717) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-primidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 344-(2-chloro-6-fluorobenzyppiperazino]propylamine were reacted to yield N24344-(2-chloro-6-fluorobenzyppiperazino]propy1]-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13): 8 7.79 (d, 111, J= 3.0 Hz), 7.37 (d, 111, J= 2.4 Hz), 7.19-7.15 (m, 211), 7.00-6.93 (m, 211), 6.81 (d, 1H, J=
8.7 Hz), 6.56 (d, 1H, J= 2.7 Hz), 5.48 (bs, 111), 4.27-4.21 (m, 411), 3.70 (d, 211, J= 1.8 Hz), 3.36 (q, 2H, J= 6.3 Hz), 2.68-2.35 (m, 1011), 1.75 (q, 2H, J= 6.3 Hz); 19F NMR
(CDC13): -31693, - 48483; LCMS: ret. time: 18.20 min.; purity: 97 %; MS (m/e): 532 (MH).
7.3.238 N2-(4-tert-Butylpheny1)-5-fluoro-N242,3-dihydro-2-(methoxycarbonyl)benzofuran-5-y11- 2,4-pyrimidinediamine (R926719) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, N4-(4-tert -butylpheny1]-2-chloro-5-fluoro-4-pyrimidineamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to yield N2-(4-tert-butylpheny1)-5-fluoro-N242,3-dihydro-2-(methoxycarbonyl)benzofuran-5-y1]- 2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 10.16 (bs, 111), 9.84 (bs, 111), 8.16 (d, 111, J= 5.4 Hz), 7.56 (d, 211, J= 8.1 Hz), 7.49 (s, 111), 7.35 (d, 2H, J=
8.7 Hz), 7.13 (dd, 1H, J= 1.8 and 8.7 Hz), 6.78 (d, 111, J= 8.7 Hz), 5.35 (dd, 111, J= 6.6 and 10.5 Hz), 3.52 (dd, 1H, J= 10.5 and 16.5 Hz), 3.20 (dd, 111, J= 6.6 and 16.5 Hz), 1.27 (s, 911);
LCMS: ret. time:
26.52 min.; purity: 96 %; MS (m/e): 437 (MH).

7.3.239 N4-[(5-Chloro-1-benzothiophen-3-yl)methyl]-N2-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926721) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-[(5-chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N4-[(5-chloro-1-benzothiophen-3-yl)methyl]-N2-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1HW41 (DMSO-d6): 8 8.08 (d, 1H, J= 1.8 Hz), 8.02 (d, 1H, J=
8.7 Hz), 7.97 (d, 1H, J= 4.8 Hz), 7.63 (s, 1H), 7.42 (dd, 1H, J= 1.8 and 9.3 Hz), 7.07 (bs, 1H), 6.85 (dd, 1H, J= 2.4 and 8.7 Hz), 6.56 (d, 1H, J= 8.7 Hz), 4.77 (s, 1H), 4.75 (s, 1H), 4.14 (s, 4H); LCMS: ret. time: 25.89 min.; purity: 97 %; MS (m/e): 444 (MI1+).
7.3.240 N4-[(5-Chloro-1-benzothiophen-3-yl)methy1]-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (R926722) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-[(5-chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-4-pyrimidineamine and 3-aminophenol were reacted to yield N4-[(5-chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine. 111 NMR (DMSO-d6): 5 9.47 (bs, 1H), 9.33 (bs, 1H), 8.78 (bs, 1), 8.11 (d, 111, J= 2.1 Hz), 8.02 (d, 1H, J= J= 8.7 Hz), 7.98 (d, 1H, J= 4.5 Hz), 7.69 (s, 1H), 7.41 (dd, 1H, J= 1.8, 8.1 Hz), 7.07 (bs, 1H), 6.92 (d, 1H, J= 8.4 Hz), 6.82 (t, 1H, J= 8.1 Hz), 6.34 (d, 1H, J= 6.9 Hz), 4.80 (s, 1H), 4.78 (s, 1H); LCMS: ret. time: 23.32 min.;
purity: 93 %;
MS (m/e): 402 (MH+).
7.3.241 N4124(2-Chloro-6-fluorobenzyl)thiolethyll-N2-(3,4-ethylenedioxy)-5-fluoro-2,4-pyrimidinediamine (R926723) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N442-[(2-chloro-6-fluorobenzypthio]ethyl]-5-fluoro-4-pyrimidineamine and 1,4-benzodioxan-6-amine were reacted to yield N442-[(2-chloro-6-fluorobenzyl)thio]ethy1]-N2-(3,4-ethylenedioxy)-5-fluoro-2,4-pyrimidinediamine. 111NMR (DMSO-d6): 5 9.09 (bs, 111), 7.94 (bs, 111), 7.87 (d, 1H, J= 4.2 Hz), 7.34-7.30 (m, 2H), 7.24-7.18 (m, 2H), 7.01 (dd, 1H, J= 2.4 and 8.7 Hz), 6.68 (d, 111, J= 8.7 Hz), 4.11 (s, 4H), 3.83 (d, 2H, J= 1.2 Hz), 3.63-3.56 (m, 2H), 2.74 (t, 2H, J= 7.5 Hz); LCMS: ret. time: 25.17 min.; purity: 92 %; MS (m/e): 466 (MO.

7.3.242 N2-(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R945168) In a manner analogous to the preparation of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidineamine, 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrirnidineamine and 2,3-dihydro-1,4-benzodioxin-6-ylmethylamine gave N2-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine. 1H NMR (CDC13) 5 4.24 (s, 4 H), 4.45 (d, J= 6.0 Hz, 211), 6.55 (ddd, J= 0.9, 2.4 and 8.4 Hz, 1 H), 6.66 (d, 1 11), 6.84 (m, 4 H), 6.90 (m, 1 H), 7.14 (t, J= 8.1 Hz, 1 H), 7.30 (m, 1 H), 7.86 (d, J= 3.3 Hz, 1 H); 19F NMR (282 MHz, CDC13) 8 -170.44;
LCMS: ret. time: 18.33 min.; purity: 96.75%; MS (m/e): 369.03 (MO.
7.3.243 N442-[(2-Chloro-6-fluorobenzypthio]ethy1]-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (R926724) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N442-[(2-chloro-6-fluorobenzyl)thio]ethy1]-5-fluoro-4-pyrimidineamine and 3-aminophenol were reacted to yield N442-[(2-chloro-6-fluorobenzypthio]ethyl]-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine. 1H NMR (methyl sulfoxide-d6): 5 9.76 (bs, 1H), 9.42 (bs, 1H), 8.70 (bs, 1H), 8.02 (d, 111, J= 5.1 Hz), 7.33-7.30 (m, 211), 7.24-7.18 (m, 111), 7.08-6.96 (m, 211), 6.42 (d,111, J= 4.6 Hz), 3.82 (d, 211, J= 1.2 Hz), 3.68-3.61 (m, 211), 2.77 (t, 2H, J= 7.2 Hz);
LCMS: ret. time: 23.00 min.; purity: 93 %; MS (mile): 424 (M114).
7.3.244 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-(3-pheny1-5-methylisoxazol-4-y1)-2,4-pyrimidinediamine (R926743) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 5-methyl-3-phenyl-4-isoxazolamine were reacted to yield N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-pheny1-5-methylisoxazol-4-y1)-2,4-pyrimidinediamine. LCMS: ret. time: 20.90 min.; purity: 96 %; MS (m/e): 420 (MH+).
7.3.245 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-(3,5-dimethylisoxazol-4-y1)-2,4-pyrimidinediamine (R926744) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 3,5-dimethy1-4-isoxazolamine were reacted to yield N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3,5-dimethylisoxazol-4-y1)-2,4-pyrimidinediamine.
LCMS: ret. time: 18.89 min.; purity: 98 %; MS (m/e): 358 (MH+).
7.3.246 N2-[2-(Ethoxycarbony1methy1enethio)pyridin-5-y1l-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926727) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 5-amino-2-(ethoxycarbonylmethylenethio)pyridine were reacted to yield N2-[2-(ethoxycarbonylmethylenethio)pyridin-5-y1]-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR (DMSO-d6): 8 9.30 (s, 1H), 9.22 (s, 111), 8.62 (d, 1H, J= 2.4 Hz), 8.06-8.01 (m, 2H), 7.25 (d, 1H, J= 2.4 Hz), 7.18-7.14 (m, 2H), 6.80 (d, 1H, J= 6.0 Hz), 4.22 (bs, 4H), 4.07 (q, 2H, J= 6.9 Hz), 3.95 (s, 2H), 1.14 (t, 3H, J= 6.9 Hz); LCMS: ret. time: 21.60 min.; purity: 97 %; MS (m/e):
458(M1H+).
7.3.247 N242-(Ethoxycarbonylmethyleneoxy)pyridin-5-yll-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926740) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 5-amino-2-(ethoxycarbonylmethyleneoxy)pyridine were reacted to yield N242-(ethoxycarbonyhnethyleneoxy)pyridin-5-y1]-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR (DMSO-d6): 8 9.54 (bs, 1H), 9.14 (bs, 1H), 8.05 (s, 1H), 7.88 (d, 111, J= 2.4 Hz), 7.54 (dd, 1H, J=
2.7 and 10.2 Hz), 7.22 (d, 111, J= 1.8 Hz), 7.10 (dd, 1H, J= 1.8 and 8.7 Hz), 6.75 (d, 1H, J=
9.0 Hz), 6.40 (d, 111, J= 9.9 Hz), 4.55 (s, 211), 4.20 (bs, 4H), 4.10 (q, 2H, J= 7.2 Hz), 1.18 (t, 211, J= 7.2 Hz).
7.3.248 5-Bromo-N2-(3,4-ethylenedioxypheny1)-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R925797) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 5-bromo-2-chloro-N4-(3-hydroxypheny1)-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield 5-bromo-N2-(3,4-ethylenedioxypheny1)-N4-(3-hydroxypheny1)-2,4-pyrirnidinediamine. 1H NMR
(CDC13): 8 9.33 (s, 111), 9.06 (s, 111), 8.34 (s, 1H), 8.14 (s, 1H), 7.13-7.06-(m, 411), 6.94 (bs, 111), 6.61 (d, 111, J= 8.7 Hz), 6.54-6.50 (m, 111), 4.17-4.13 (m, 4H); LCMS: ret. time:
20.01 min.;
purity: 93 %; MS (m/e): 416 (MM.

7.3.249 N2-Ally1-5-bromo-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R925822) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 5-bromo-2-chloro-N4-(3-hydroxypheny1)-4-pyrimidineamine and allylamine were reacted to yield N2-ally1-5-bromo-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine. 1H NMR (CD30D): 8 8.08 (s, 114 7.21 (t, 1H, J=
8.1 Hz), 7.02-6.97 (m, 2H), 6.71 (dd, 1H, J= 2.4 and 8.7 Hz), 5.91-5.77 (m, 1H), 5.19-5.09 (m, 211), 3.94-3.89 (m, 2H); LCMS: ret. time: 18.33 min.; purity: 99 %; MS
(m/e): 322 MO-7.3.250 5-Cyano-N2-(3,4-ethylenedioxypheny1)-N4-(methoxycarbonylbenzy1)-2,4-pyrimidinediamine (R925820) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-cyano-N4-( methoxycarbonylbenzy1)-4-primidineamine and 3,4-ethylenedioxyaniline were reacted to ,yield 5-cyano-N2-(3,4-ethylenedioxypheny1)-N4-(methoxycarbonylbenzy1)-2,4-pyrimidinediamine. 111NMR (CDC13): 6 8.23 (s, 111), 7.41-7.32 (m, 514 7.01 (d, 111, J=
3.0 Hz), 6.86-6.71 (m, 311), 6.54 (bs, 111), 5.48 (d, 111, J= 6.3 Hz), 4.31 (bs, 4H), 3.68 (s, 311); LCMS: ret. time: 25.53 min.; purity: 97 %; MS (mile): 418 (MT{).
7.3.251 (R935172): N444-[Ethoxycarbonyl(dimethyl)methyllphenyl]-N2-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine In like marmer to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro -N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4[4-[ethoxycarbonyl(dimethyl )methyl]pheny1]-5-fluoro-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to produce N4-[4-[ethoxycarbonyl(dimethyl)methyl]pheny1]-N2-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 9.31 (s, 111), 8.97 (s, 111), 8.03 (d, 1H, J = 3.5 Hz), 7.70 (d, 211, J = 8.8 Hz), 7.29 (d, 111, J = 2.3 Hz), 7.23 (d, 211, J = 8.8 Hz), 6.98 (dd, 1H, J = 2.1 and 8.8 Hz), 6.66 (d, 111, J = 8.2 Hz), 4.19-4.15 (m, 411), 4.07 (qt, 211, J = 7.0 Hz), 1.48 (s, 611), 1.10 (t, 311, J = 7.0 Hz). LCMS: ret. time: 24.51 min.; purity:
100%; MS (m/e): 453 (MH+).

7.3.252 (R935173): N2-(3,4-Ethylenedioxypheny1)-5-fluoro-N444-(2-hydroxy-1,1-dimethylethyl)pheny1]-2,4-pyrimidinediamine In like manner to the preparation of N2-(3,4-ethylenedioxypheny1)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl] -pyrimidine-2,4-diamine, N4-[4-[ethoxycarbonyl(dimethyl)methyl]pheny1]-N2-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine was reduced with DMALH to give N2-(3,4-ethylenedioxypheny1)-fluoro-N444-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-ppimidinediamine. 1H NMR
(DMSO-d6): 5 9.23 (s, 1H), 8.94 (s, 1H), 8.01 (d, 111, J = 3.5 Hz), 7.63 (d, 2H, J = 8.8 Hz), 7.31-7.27 (m, 3H), 6.98 (dd, 1H, J= 2.9 and 8.8 Hz), 6.65 (d, 1H, J = 8.8 Hz), 4.65 (t, 1H, J
= 5.3 Hz), 4.17-4.16 (m, 4H), 3.39 (d, 2H, J = 5.2 Hz), 1.20 (s, 6H). 8.9 Hz), LCMS: ret.
time: 19.52 min.; purity: 100%; MS (m/e): 411 (MH+).
7.3.253 R935182: 5-Fluoro-N244-(methoxycarbonylmethyleneoxy)phenyll-N4-(3,4-propylenedioxypheny1)-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3,4-propylenedioxypheny1)-4-pyrimidineamine and 4-(methoxycarbonylmethyleneoxy)aniline were reacted to produce 5-fluoro-N244-(methoxycarbonylmethyleneoxy)pheny1]-N4-(3,4-propylenedioxypheny1)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 5 9.16 (s, 1H), 9.01 (s, 1H), 8.10 (d, 1H, J=
4.1 Hz), 7.51 (d, 2H, J= 8.8 Hz), 7.37 (d, 1H, J= 2.9 Hz), 7.32 (dd, 1H, J=
2.9 and 8.8 Hz), 6.98 (d, 1H, J= 8.3 Hz), 6.80 (d, 2H, J= 8.3 Hz), 4.70 (s, 2H), 4.12-4.05 (app qt, 4H, J= 5.3 Hz), 3.68 (s, 3H), 2.07 (q, 2H, J= 5.3 Hz); LCMS: ret. time: 20.51 min.;
purity: 97%; MS
(m/e): 441 (MT).
7.3.254 R935185: 5-Fluoro-N243-(methoxyearbonylmethyleneoxy)phenyll-N4-(3,4-propylenedioxypheny1)-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3,4-propylenedioxypheny1)-4-pyrimidineamine and 3-(methoxycarbonylmethyleneoxy)aniline were reacted to produce 5-fluoro-N243-(methoxycarbonylmethyleneoxy)phenylj-N4-(3,4-propylenedioxypheny1)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 5 9.22 (s, 111), 9.18 (s, 1H), 8.07 (d, 1H, J=
3.5 Hz), 7.41-7.35 (m, 2H), 7.32-7.28 (m, 211), 7.09 (t, 1H, J= 8.2 Hz), 6.90 (d, 1H, I= 8.2 Hz), 6.43 (dd, 111, J= 2.3 and 8.8 Hz), 4.65 (s, 211), 4.11-4.04 (app q, 4H, J= 5.3 Hz), 3.67 (s, 3H), 2.06 (q, 2H, J= 5.3 Hz); LCMS: ret. time: 20.57 min.; purity: 97%; MS
(m/e): 441 MO.
7.3.255 R935187: N443-(1-Bis(ethoxyearbonyl)ethoxy)pheny11-5-fluoro-N244-isopropoxypheny1)-2,4-pyrimidinediamine In like marmer to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(4-isopropoxypheny1)-pyrimidineamine and 3[1-bis(ethoxycarbonyl)ethoxy]aniline were reacted to provide N4-[3-(1-bis(ethyloxycarbonyl)ethoxy)pheny1]-5-fluoro-N244-isopropoxypheny1)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 6 10.08 (s, 1H), 9.98 (s, 111), 8.19 (d, 111, J= 4.7 Hz), 7.55 (d, 211, J= 8.8 Hz), 7.25 (d, 111, J= 8.8 Hz), 7.15 (d 111, J= 8.3 Hz), 7.13 (d, 111, J= 8.3 Hz), 6.91 (d, 2H, J= 8.8 Hz), 6.51 (dd, 111, J= 1.7 and 8.3 Hz), 4.56 (q, 111, J= 5.8 Hz), 4.19 (qt, 4H, J= 7.0 Hz), 1.61 (s, 3H), 1.23 (d, 6H, J= 5.8 Hz), 1.14 (t, 6H, J= 7.0 Hz);
LCMS: ret. time: 15.23 min.; purity: 94%; MS (m/e): 527 (MH+).
7.3.256 R935190: N4-(3,4-Ethylenedioxypheny1)-5-fluoro -N2-(indazolin-6-y1) - 2,4-pyrimidinediamine.
In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 6-aminoindazole were reacted to produce N4-(3,4-ethylenedioxypheny1)-5-fluoro -N2-(indazolin-6-y1)-2,4-pyrimidinediamine. 111 NMR
(DMSO-d6): 6 9.69 (s, 1H), 9.62 (s, 1H), 8.14 (d, 114, J= 4.7 Hz), 7.93 (s, 111), 7.92 (s, 111), 7.60 (d, 111, J= 8.8 Hz), 7.33-7.31 (m 1H), 7.24 (dd, 211, J= 1.7 and 8.8 Hz), 6.79 (d, J= 8.8 Hz), 4.20 (s, 4H); LCMS: ret. time: 17.66 min.; purity: 99%; MS (m/e): 379 (MH+) 7.3.257 R935191: 5-Fluoro-N4-(3-hydroxypheny1)-N2-(indazolin-6-y1)-2,4-pyrimidinediamine In like marmer to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3-hydroxypheny1)-4-pyrimidineamine and 5-aminoindazole were reacted to give 5-fluoro N4-(3-hydroxypheny1)-N2-(indazolin-6-y1)-2,4-pyrimidinediarnine. 111NMR (DMSO-d6):
69.74 (s, 1H), 9.66 (s, 111), 8.18 (d, 111, J= 4.1 Hz), 7.95 (s, 111), 7.93 (s, 111), 7.59 (d, 111, J= 8.8 Hz), 7.33-7.26 (m, 211), 7.12-7.07 (m, 211), 6.52 (dd, 111, J= 2.3 and 8.2 Hz); LCMS: ret.
time: 15.27 min.; purity: 99%; MS (m/e): 337 (MH+) 7.3.258 R935193: N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-(1-methyl-indazoline-5-y1)-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3,4-ethylenedioxypheny1)-4-pyrimidineamime and 1-methyl-5-aminoindazole were reacted to give N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(1-methyl-indazoline-5-y1)-2,4-pyrimidinediamine. 111 NMR (DMSO-d6): 8 10.42 (s, 211), 8.25 (d, 111, J= 5.2 Hz), 7.92 (s, 111), 7.86 (app s, 111), 7.61 (d, 1H, J= 8.8 Hz), 7.38 (dd, 1H, J= 2.3 and 9.3Hz), 7.21 (d, 111, J= 2.3 Hz), 7.09 (dd, 111, J= 2.3 and 8.8 Hz). 6.79 (d, 111, J= 8.8 Hz), 4.20 (s, 411), 4.02 (s, 3H); LCMS: ret. time:
19.09 min.; purity: 99%; MS (m/e): 393 (MH+).
7.3.259 R935194: 5-Fluoro-N4-(3-hydroxypheny1)-N2-(1-methy-indazoline-5-y1)-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3-hydroxypheny1)-4-pyrimidineamine was reacted with 1-methy1-5-aminoindazole to produce 5-fluoro-N4-(3-hydroxypheny1)-N2-(1-methy-indazoline-5-y1)-2,4-pyrimidinediamine. 111NMR
(DMSO-d6): 8 10.56 (s, 111), 10.49 (s, 111), 8.29 (d, 111, J= 5.2 Hz), 7.98 (d, 111, J= 1.7 Hz), 7.92 (s, 1H), 7.59 (d, 111, J= 8.8 Hz), 7.36 (dd, 111, J= 1.7 and 8.8 Hz), 7.10 (br m, 311), 6.66 (td,.
1H, J= 1.7 and 7.0 Hz), 4.01 (s, 311). LCMS: ret. time: 16.62 min.; purity:
98%; MS (m/e):
351 (M114).
7.3.260 R935197: 5-Fluoro-N2-(indazoline-5-y1)-N4-(4-isopropoxypheny1)-2,4-pyrimidinediamine:
In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(4-isopropoxypheny1)-pyrimidineamine was reacted with 5-aminoindazoline to produce 5-fluoro-N2-(indazoline-5-y1)-N4-(4-isopropoxypheny1)-2,4-pyrimidinediamine. 111 NMR (DMSO-d6): 8 9.96 (s, 111), 9.76 (s, 111), 8.12 (d, 111, J= 4.6 Hz), 7.94 (s, 111), 7.92 (s, 111), 7.53 (d, 211, J= 9.8 Hz), 7.46 (d, 111, J= 8.8 Hz), 7.34 (dd, 111, J= 1.7 and 9.8 Hz), 6.83 (d, 2H, J= 9.8 Hz), 4.55 (q, 111, J= 5.8 Hz), 1.24 (d, 611, J= 5.8 Hz). LCMS: ret. time: 18.96 min.;
purity: 100%; MS
(m/e): 379 (MH+).

7.3.261 R935198: N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-(indazoline-5-y1)-2,4-pyrimidinediamine In like marmer to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3,4-ethylenedioxypheny1)-4-pyrimidineamime and 5-aminoindazole were reacted to give N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(indazoline-5-y1)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 9.91 (s, 111), 9.82 (s, 1H), 8.13 (d, 1H, J= 4.6 Hz), 7.94 (app s, 2H), 7.47 (d,111, J=
8.8 Hz), 7;36 (dd, 111, J= 1.7 and 8.8 Hz), 7.23 (d, 111, J= 2.3 Hz), 7.13(dd, 1H, J= 2.3 and 8.8 Hz), 6.76 (d, 1H, J= 8.8 Hz), 4.20 (s, 411); LCMS: ret. time: 16.17 min.; purity: 99%;
MS (mile): 379 (MH+).
7.3.262 R935199: 5-Fluoro-N4-(3-hydroxypheny1)-N2-(indazoline-5-y1)-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3-hydroxypheny1)-4-pyrimidineamime and 5-aminoindazole were reacted to give 5-fluoro-N4-(3-hydroxypheny1)-N2-(indazoline-5-y1)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6):
.3 9.78 (s, 111), 9.68 (s, 111), 9.49 (br s, 1H), 8.13 (d, 1H, J= 4.6 Hz), 8.06 (s, 1H), 7.93 (s, 1H), 7.50 (d, 111, J= 8.8 Hz), 7.38 (dd, 1H, J= 1.7 and 8.8 Hz), 7.17 (d, 111, J= 8.2 Hz), 7.11-7.06 (m, 211), 6.57 (dd, 111, J= 1.1 and 8.2 Hz). LCMS: ret. time: 13.79 min.; purity:
96%; MS
(m/e): 337 (Mu').
7.3.263 R935203: 5-Fluoro-N2-(4-isopropoxypheny1)-N4-(1-methyl-indazoline-5-y1)-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(1-methyl-indazoline-5-y1)-4-pyrimidineamine and 4-isopropoxyaniline were reacted to produce 5-fluoro-N2-(4-isopropoxypheny1)-N4-(1-methyl-indazoline-5-y1)-2,4-pyrimidinediamine. 1H NMR
(DMSO-d6): 8 10.57 (s, 1H), 10.12 (s, 111), 8.24 (d, 1H, J= 5.3 Hz), 8.04 (s, 1H), 7.95 (s, 111), 7.63 (d, 111, J= 9.3 Hz), 7.55 (dd, 111, J= 1.7 and 8.8 Hz), 7.30 (d, 211, J= 9.4 Hz), 6.82 (d, 2H, J= 8.8 Hz), 4.53 (q, 111, J= 6.4 Hz), 4.02 (s, 3H), 1.22 (d, 6H, J=
6.4 Hz). LCMS:
ret. time: 20.56 min.; purity: 99%; MS (m/e): 393 (MH).

7.3.264 R935204: 5-Fluoro-N2-(3-hydroxypheny1)-N4-(1-methyl-indazoline-5-y1)-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediarnine, 2-chloro-5-fluoro-N-(1-methyl-indazoline-5-y1)-4-pyrimidineamine and 3-aminophenol were reacted to produce 5-fluoro-N2-(3-hydroxypheny1)-N4-(1-methyl-indazoline-5-y1)-2,4-pyrimidinediamine.. LCMS:
ret. time:
15.55 min.; purity: 98%; MS (m/e): 351 (MH+).
7.3.265 R935207: N4-(3,4-ethylenedioxypheny1)-5-fluoro-N243-(2-methoxycarbonyl-fur-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro- N-(3,4-ethylenedioxypheny1)-5-fluoro-4-ppimidineamine was reacted with 4-(4-aminophenoxymethyl)-2-methoxycarbony1.-furan to give N4-(3,4-ethylenedioxypheny1)-5-fluoro-N243-(2-methoxycarbonyl-fur-4-yl)methyleneoxypheny1]-2,4-pyrimidinediamine. 111 NMR (DMSO-d6): 8 9.48 (s, 111), 9.41 (s, 1H), 8.08 (d, 111, J= 3.4 Hz), 7.37-7.10 (m, 6H), 6.74 (d, 2H, J= 8.2 Hz), 6.61 (d, 1H, J=
8.2 Hz), 5.00 (s, 2H), 4.19 (br s, 4H), 3.79 (s, 3H). LCMS: ret. time: 22.85 min.; purity:
97%; MS (m/e): 493 (MH+).
7.3.266 R935208: N4-(3,4-ethylenedioxypheny1)-5-fluoro-N241-(methoxycarbonyl)methyl-indazoline-6-y11-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3,4-ethylenedioxypheny1)-4-pyrimidineamine was reacted with 6-amino-1-(methoxycarbonyl)methyl-indazoline to produce N4-(3,4-ethylenedioxypheny1)-5-fluoro-N241-(methoxycarbonyl)methyl-indazoline-6-y1]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 9.39 (s, 111), 9.19 (s, 1H), 8.08 (d, 1H, J= 3.5 Hz), 7.95 (s, 111), 7.91 (s, 1H), 7.56 (d, 111, J= 8.2 Hz), 7.32 (d, 2H, J=
8.9 Hz), 7.22 (dd, 111, J= 2.9 and 8.2 Hz), 6.78 (d, 1H, J= 8.8 Hz), 5.06 (s, 211), 4.21 (s, 411), 3.61 (s, 3H). LCMS: ret. time: 19.39 min.; purity: 93%; MS (m/e): 451 (MO.

7.3.267 R935209: 5-Fluoro-N244-(methoxycarbonylmethyleneoxy)phenyll-N4-(1-methyl-indazoline-5-y1)-2,4-pyrimidinediamine In like marmer to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(1-methyl-indazoline-5-y1)-4-pyrimidineamine and 4-(methoxycarbonylmethyleneoxy)aniline were reacted to provide 5-fluoro-N244-(methoxycarbonylmethyleneoxy)phenyll-N4-(1-methyl-indazoline-5-y1)-2,4-pyrimidinediamine. 111NMR (DMSO-d6): 8 9.31 (s, 1H), 8.99 (s, 111), 8.17 (s, 1H), 8.02 (d, 111, J= 3.5 Hz), 7.92 (s, 111), 7.59 (s, 211), 7.50 (d, 211, J= 8.8 Hz), 6.73 (d, 211, J= 8.8 Hz), 4.69 (s, 211), 4.03 (s, 3H), 3.68 (s, 3H). LCMS: ret. time: 17.60 min.;
purity: 99%; MS
(m/e): 423 (MR).
7.3.268 R935214: 5-Fluoro-N2-(3,5-dimethoxypheny1)-N4-(1-methyl-indazoline-5-y1)-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(1-methyl-indazoline-5-y1)-4-pyrimidineamine and 3,5-dimethoxyaniline were reacted to produce 5-fluoro-N2-(3,5-dimethoxypheny1)-N4-(1-methyl-indazoline-5-y1)-2,4-pyrimidinediamine. 111 NMR
(DMSO-d6): 8 9.34 (s, 1H), 9.09 (s, 111), 8.20 (d, 111, J= 5.3 Hz), 8.07 (d, 111, Jr= 3.5 Hz), 7.90 (s, 111), 7.63-7.55 (m, 211), 6.89 (d, 211, J= 1.7 Hz), 6.02 (t, 111, J=
2.3 Hz), 4.02 (s, 3I1), 3.54 (s, 611). LCMS: ret. time: 18.81 mm.; purity: 97%; MS (m/e): 395 (MH+).
7.3.269 R935215: 5-Fluoro-N4-(3-hydroxypheny1)-N241-(methoxycarbonyl)methyl-indazoline-6-y11-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3-hydroxypheny1)-4-pyrimidineamine was reacted with 6-amino-1-(methoxycarbonyl)methyl-indazoline to produce 5-fluoro-N4-(3-hydroxypheny1)-N241-(methoxycarbonyl)methyl-indazoline-6-yll-2,4-pyrimidinediamine. LCMS: ret. time: 16.08 min.; purity: 90%; MS (m/e): 408 (Mu).
7.3.270 R935218: 5-Fluoro-N2-(4-isopropoxypheny1)-N441-(methoxycarbonyl)methyl-indazoline-6-y1]-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N41-(methoxycarbonyl)methyl-indazoline-6-y1]-4-pyrimidineamine was reacted with 4-isopropoxyaniline to provide 5-fluoro-N244-isopropoxypheny1)-N441-(methoxycarbonyl)methyl-indazoline-6-y1]-2,4-pyrimidinediamine. 11-1 NMR (DMSO-d6): 8 9.47 (s, 111), 8.99 (s, 111), 8.10 (s, 111), 8.07 (d, 111, J= 4.1 Hz), 8.02 (s, 111), 7.68 (d, 111, J= 8.8 Hz), 7.50-7.46 (m, 3H), 6.74 (d, 2H, 8.8 Hz), 5.26 (s, 211), 4.47 (q, 1H, J= 5.8 Hz), 3.62 (s, 311), 1.21 (d, 6H, J=
5.8 Hz). LCMS: ret.
time: 21.76 min.; purity: 97%; MS (m/e): 451 (M114).
7.3.271 R935219: N2-(3,4-Ethylenedioxypheny1)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-6-y1]-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N41-(methoxycarbonyl)methyl-indazoline-6-y1]-4-pyrimidineamine was reacted with 3,4-ethylenedioxyaniline to provide N2-(3,4-ethylenedioxypheny1)-5-fluoro-N441-(methoxycarbonyl)methyl-indazoline-6-y1]-2,4-pyrimidinediamine. 111 NMR (DMSO-d6): 8 9.48 (s, 111), 9.01 (s, 1H), 8.10 (s, 1H), 8.09 (d, 1H, J= 3.5 Hz), 8.01 (s, 1H), 7.68 (d, 1H, J= 8.8 Hz), 7.48-7.43 (m, 1H), 7.29 (d, 1H, J.= 2.3 Hz), 6.99 (d, 1H, J= 2.3 and 8.2 Hz), 6.67 (dd, 1H, J= 2.3 and 8.8 Hz), 5.27 (s, 2H), 4.15 (s, 41I), 3.62 (s, 3H). LCMS: ret. time: 18.99 min.; purity: 93%; MS
(m/e): 451 MO.
7.3.272 R935220: 5-Fluoro-N2-(3-hydroxypheny1)-N441-(methoxycarbonyl)methyl-indazoline-6-y1]-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N41-(methoxycarbonyl)methyl-indazoline-6-y1]-4-pyrimidineamine was reacted with 3-aminophenol to provide 5-fluoro-N2-(3-hydroxypheny1)-N441-(methoxycarbonyl)methyl-indazoline-6-y1]-2,4-pyrimidinediamine. 111 NMR (DMSO-d6): 8 9.51 (s,111), 9.19 (s, 1I1), 9.10( s, 1I1), 8.21 (s, 111), 8.12 (d, 111, J= 3.5 Hz), 8.02 (s, 111), 7.68 (d, 1H, J= 8.8 Hz), 7.49-7.45 (m 111), 7.16 (s, 111), 7.09 (d,111, J= 7.6 Hz), 6.95 (app t,111, J= 7.6 and 8.2 Hz), 6.31 (dd, 111, 1.7 and 7.6 Hz), 5.29 (s, 2H), 3.62 (s, 3H). LCMS: ret. time: 16.16 min.;
purity: 97%; MS
(m/e): 409 (MH4).

7.3.273 N4-(3,4-Ethylenedioxypheny1)-N2-(3-furanylmethylene)-5-fluoro-2,4-pyrimidinediamine (R950203) In like manner to the preparation of N4-(3-aminopheny1)-N242-(methoxycarbony1)-benzofurane-5-y11-5-fluoro-2,4-primidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 3-aminomethylenefurane were reacted to give N4-(3,4-ethylenedioxypheny1)-N2-(3-furanylmethylene)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 19.99 min.; purity: 88.4%; MS (m/e):
343.07 (MO.
7.3.274 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-[(4-methoxyphenyloxy)ethy1]-2,4-pyrimidinediamine (R950204) In like manner to the preparation of N4-(3-aminopheny1)-N242-(methoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 2-(4-methoxyphenyloxy)ethyl amine were reacted to give N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-[(4-methoxyphenyloxy)ethyl]-2,4-pyrimidinediamine. LCMS: ret. time: 22.74 min.;
purity:
91.9%; MS (m/e): 413.05 (MH+).
7.3.275 N2-12,3-Dihydrobenzo[b]furan-5-ylmethyll-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R950205) In like manner to the preparation of N4-(3-aminopheny1)-N242-(methoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 2,3-dihydrobenzo[b]furan-5-ylmethylamine were reacted to give N2-12,3-dihydrobenzo[b]furan-5-yh-nethyl]-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 21.43 min.;
purity: 97.5%; MS (m/e): 395.05 (MI-1+).
7.3.276 N2-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R950206) In like manner to the preparation of N4-(3-aminopheny1)-N2-[2-(methoxycarbonyl)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to give N2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 22.49 min.; purity:
87.6%; MS (mile): 411.01 (M114).

7.3.277 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-[2-(methylthio)-1,3-benzothiaz-6-y1]-2,4-pyrimidinediamine (R950201) In like manner to the preparation of N4-(3-aminopheny1)-N2-[2-(methoxycarbonyl)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 2-(methylthio)-1,3-benzothiazol-6-amine were reacted to give N4-(3,4-ethylenedioxypheny1)-5-fluoro-N242-(methylthio)-1,3-benzothiaz-6-y1]-2,4-pyrimidinediarnine. LCMS: ret. time: 22.67 min.; purity:
76.9%; MS
(m/e): 441.91 (MM.
7.3.278 N242,3-Dihydrobenzo[b]furan-5-ylmethy11-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R950213) In like manner to the preparation of N4-(3-aminopheny1)-N242-(methoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine and 2,3-dihydrobenzo[b]furan-5-ylmethylamine were reacted to N242,3-dihydrobenzo[b]furan-5-ylmethy1]-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine. LCMS: ret. time: 17.80 min.; purity: 99.2%; MS (m/e):
353.08 (MH+).
7.3.279 N2-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R950214) In like manner to the preparation of N4-(3-aminopheny1)-N242-(methoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine and 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to give N2-(2,3-dihydro-1,4-benzodioxin-2-yhnethyl)-5-fluoro-N4-(3-hydroxypheny1)-2,4-ppimidinediamine. LCMS: ret. time: 19.26 min.; purity:
96.2%; MS
(m/e): 369.08 (MI-I ).
7.3.280 5-Fluoro-N4-(3-hydroxypheny1)-N242-(methylthio)-1,3-benzothiaz-6-y1)-2,4-pyrimidinediamine (R950212) In like manner to the preparation of N4-(3-aminopheny1)-N242-(methoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-primidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine and 2-(methylthio)-1,3-benzothiazol-6-amine were reacted to give ,3-benzothiaz-6-yl)-LCMS: ret. time: 19.83 min.; purity: 98.9%; MS (m/e): 399.98 (1\410.

7.3.281 N2-(3-Aminopheny1)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R950227) In like manner to the preparation of N4-(3-aminopheny1)-N242-(methoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-7.3.282 N2-(1,4-Benzoxazin-6-y1)1-5-fluoro-N4-(3-nitropheny1)-2,4-pyrimidinediamine (R950253) In like manner to the preparation of N4-(3-aminopheny1)-N242-(methoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine and 6-amino-1,4-benzoxazine were reacted to give N2-(1,4-benzoxazin-6-y1)]-5-fluoro-N4-(3-nitropheny1)-2,4-pyrimidinediamine.
LCMS: ret.
time: 18.52 min.; purity: 99.5%; MS (m/e): 382.93 (MI-14).
7.3.283 N2-(Ethoxycarbonylmethyleneaminopheny1)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R950215) In like manner to the preparation of N4-(3-aminopheny1)-N242-(methoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine and 3-ethoxycarbonylmethyleneaminophenylaniline 7.3.284 N2-(Ethoxycarbonylmethyleneaminopheny1)-5-fluoro-N443-(2-hydroxyethylamino)pheny1]-2,4-pyrimidinediamine (R950229) In like manner to the preparation of N4-(3-aminopheny1)-N242-(methoxycarbony1)-benzofurane-5-y1]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine and 3-ethoxycarbonylmethyleneaminophenylaniline were reacted to N2-(ethoxycarbonylmethylenearninopheny1)-5-fluoro-N443-(2-7.3.285 5-Cyano-N2-(3-hydroxypheny1)-N4-(methoxycarbonylbenzy1)-2,4-pyrimidinediamine (R925821) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-cyano-N4-( methoxycarbonylbenzy1)-4-pyrimidineamine and 3-hydroxyaniline were reacted to yield 5-cyano-N2-(3-hydroxypheny1)-N4-(methoxycarbonylbenzy1)-2,4-pyrimidinediamine.

NMR (CD30D): 8 8.27 (s, 111), 7.38-7.28 (m, 5H), 7.19-7.07 (m, 2H), 6.98-6.91 (m, 211), 6.64 (d, 111, J= 6.6 Hz), 3.55 (s, 3H); LCMS: ret. time: 24.18 min.; purity:
98 %; MS (m/e):
376 (Mle).
7.3.286 5-Fluoro-N412-fluoro-4-(methoxymethyleneoxy)phenyll-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (R926680) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(2-fluoro-4-methoxymethyleneoxypheny1)-4-pyrimidineamine and 3-hydroxyaniline were reacted to yield 5-fluoro-N4-(2-fluoro-4-methoxymethyleneoxypheny1)-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine.
7.3.287 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-[(1H)-indol-5-y11-2,4-pyrimidinediamine (R926748) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 5-aminoindole were reacted to yield N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-[(1H)-indol-5-y1]-2,4-pyrimidinediamine.
LCMS: ret.
time: 20.37 min.; purity: 97 %; MS (m/e): 378 (MH+).
7.3.288 5-Fluoro-N4-(3-hydroxypheny1)-N2-[(1H)-indol-5-y1]-2,4-pyrimidinediamine (R926749) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine and 5-aminoindole were reacted to yield 5-fluoro-N4-(3-hydroxypheny1)-N2-[(1H)-indol-5-y1]-2,4-pyrirnidinediamine. LCMS: ret. time: 17.31 min.;
purity: 94 %;
MS (m/e): 366 (MH+).

7.3.289 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-[(1H)-indo1-6-y11-2,4-pyrimidinediamine (R926750) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 6-aminoindole were reacted to yield N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-[(1H)-indo1-6-y1]-2,4-pyrimidinediamine.
LCMS: ret.
time: 20.80 min.; purity: 91 %; MS (m/e): 378 (MITE).
7.3.290 5-Fluoro-N4-(3-hydroxypheny1)-N2-[(1H)-indo1-6-y1]-2,4-pyrimidinediamine (R926751) In a manner similar to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-primidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine and 6-aminoindole were reacted to yield 5-fluoro-N4-(3-hydroxypheny1)-N2-[(1H)-indol-6-y1]-2,4-pyrimidinediamine. LCMS: ret. time: 18.13 mm.;
purity: 96 %;
MS (m/e): 336 (MO.
7.3.291 N444-(Aminocarbonylmethyleneoxy)pheny11-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (R945063) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 3-hydroxyaniline (110 mg, 1 mmol) and N444-(aminocarbonylrnethyleneoxy)pheny1]-2-chloro-5-fluoro-4-pyrimidineamine (80 mg, 0.27 mmol) gave N444-(aminocarbonylmethyleneoxy)pheny1]-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (75 mg, 76%). 1H NMR
(acetone-d6):
8 5 4.51 (s, 2 H), 6.64 (dm, J= 8.4 Hz, 1 H), 7.06-7.14 (m, 5 H), 7.70 (dd, J=
2.4 and 9.0 Hz, 2 H), 8.27 (d, J= 6.0 Hz, 1 H); 19F NMR (282 MHz, acetone-d6): 5 - 164.00;
LCMS: ret.
time: 14.66 min.; purity: 88.63%; MS (m/e): 370.00 (MH+).
7.3.292 N444-(Cyanomethyleneoxy)pheny11-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (R945071) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediarnine, 3-hydroxyaniline (94 mg, 0.86 mmol) and 2-chloro-N444-(cyanomethyleneoxy)pheny1]-5-fluoro-4-pyrimidineamine (80 mg, 0.29 mmol) gave N444-(cyanomethyleneoxy)pheny1]-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (65 mg, 64%) as a off-white solid. 1H NMR (acetone-d6): 8 5.16 (s, 2 H), 6.64 (ddd, J= 1.8, 2.4 and 7.5 Hz, 1 H), 7.03 (t, 1=2.1 Hz, 1 H), 7.08-7.16 (m, 2 H), 7.19 (d, J= 9.3 Hz, 2 H), 7.77 (d, J= 9.3 Hz, 2 H), 8.30 (d, J= 5.4 Hz, 1 H), 10.04 (s, 1 H, NH), 11.33 (s, 1 H, NH); 19F NMR (282 MHz, acetone-d6): 8 - 163.52; LCMS: ret.
time:
17.08 min.; purity: 100%; MS (m/e): 352.13 (MH4).
7.3.293 N4-(3-Cyanopheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (R945109) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 3-aminobenzonitrile (142 mg, 1.2 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave 2-chloro-N4-(3-cyanopheny1)-5-fluoro-4-pyrimidineamine (128 mg, 86%) as a white solid. The reaction of 2-chloro-N4-(3-cyanopheny1)-5-fluoro-4-pyrimidineamine (50 mg, 0.2 mmol) and 3-aminophenol (66 mg, 0.6 mmol) gave N4-(3-cyanopheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pylimidinediamine (40 mg, 62%). 1H NMR (acetone-d6): 8 6.48 (ddd, J= 0.9, 2.4 and 7.8 Hz, 1 H), 7.10 (t, J= 8.1 Hz, 1 H), 7.18 (ddd, J= 1.2, 2.1 and 8.1 Hz, 1 H), 7.33 (t, J= 2.1 Hz, 1 H), 7.45 (dt, J= 1.2 and 7.8 Hz, 1 H), 7.54 (t, J= 8.1 Hz, 1 H), 8.08 (d, J= 3.3 Hz, 1 H), 8.14 (ddd, J= 1.5, 2.7 and 8.4 Hz, 1 H), 8.39 (t, J= 2.1 Hz, 1 H), 8.58 (s, 1 H, NH), 8.84 (s, 1 H, NH); 19F NMR (282 MHz, acetone-d6): 8 - 167.41; LCMS: ret. time: 17.75 mm.;
purity:
92.39%; MS (m/e): 322.59 (MH+).
7.3.294 N4-(3-Cyanopheny1)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxypheny1)-2,4-pyrimidinediamine (R945110) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3-cyanopheny1)-5-fluoro-4-pyrimidineamine (50 mg, 0.2 mmol) and 4-(methoxycarbonyhnethyleneoxy)aniline (109 mg, 0.6 mmol) gave N4-(3-cyanopheny1)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxypheny1)-2,4-pyrimidinediamine (30 mg, 38%). 1H NMR
(acetone-d6): 8 3.74 (s, 3 H), 4.72 (s, 2 H), 6.93 (d, J= 9.0 Hz, 2 H), 7.46 (dt, J= 1.5 and 7.5 Hz, 1 H), 7.54 (t, J= 7.8 Hz, 1 H), 7.60 (dd, J= 1.8 and 9.0 Hz, 2 H), 8.03-8.07 (m, 2 H), 8.43 (m, 1 H), 8.48 (br, 1 H, NH), 8.80 (br, 1 H, NH); 19F NMR (282 MHz, acetone-d6): 8 -168.2; LCMS: ret. time: 20.24 min.; purity: 94.79%; MS (m/e): 393.98 (M114).

7.3.295 5-Fluoro-N4-(3-hydroxypheny1)-N242-(indo1-3-y1)ethyll-2,4-pyrimidinediamine (R945117) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine (50 mg, 0.21 mmol) and tryptamine (100 mg, 0.62 mmol) gave 5-fluoro-N4-(3-hydroxypheny1)-N242-(indol-3-ypethyl]-2,4-pyrimidinediamine (40 mg, 53%). 1H NMR (CD30D): 5 3.01 (t, J= 7.2 Hz, 2 H), 3.61 (t, J=
7.2 Hz, 2 H), 6.51 (ddd, J= 0.9, 2.1 and 8.1 Hz, 1 H), 6.96 (td, J= 0.9 and 7.2 Hz, 1 H), 7.03-7.09 (m, 3 H), 7.22 (d, J= 7.5 Hz, 1 H), 7.28-7.32 (m, 2 H), 7.53 (d, J= 7.8 Hz, 1 H), 7.72 (d, J= 4.5 Hz, 1 H); 19F NMR (282 MHz, CD30D): 8 - 171.72; LCMS: ret. time: 20.17 mm.;
95.66%; MS (m/e): 364.05 (MIH4).
7.3.296 5-Fluoro-N4-(3-hydroxypheny1)-N2-(3-methoxycarbonylmethyleneoxypheny1)-2,4-pyrimidinediamine (R945118) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine (80 mg, 0.33 mmol) and 3-methoxycarbonylmethyleneoxyaniline (180 mg, 0.99 mmol) gave 5-fluoro-N4-(3-hydroxypheny1)-N2-(3-methoxycarbonylmethyleneoxypheny1)-2,4-pyrimidinediamine (130 mg). 1H NMR (acetone-d6): 5 3.74 (s, 3 H), 4.64 (s, 2 H), 6.71 (m, 1 H), 6.80 (m, 1 H), 7.23-7.32 (m, 6 H), 8.32 (d, J= 5.1 Hz, 1 H); LCMS: ret. time: 18.37 min.;
purity: 100%;
MS (m/e): 384.70 (MO.
7.3.297 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxypheny1)-2,4-pyrimidinediamine (R945124) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine (80 mg, 0.28 mmol) and 3-methoxycarbonylmethyleneoxyaniline (154 mg, 0.85 mmol) gave N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-methoxycarbonyhnethyleneoxypheny1)-2,4-pyrimidinediamine (90 mg, 74%). 111 NMR (CDC13): 8 3.80 (s, 31I), 4.27 (q, J=
0.9 Hz, 4H), 4.58 (s, 2H), 6.54 (ddd, J= 0.9, 2.7 and 8.1 Hz, 1H), 6.65 (d, J= 2.7 Hz, 1H), 6.86 (d, J= 8.7 Hz, 111), 6.98 (dd, J= 2.4 and 8.4 Hz, 111), 6.98 (br, 1 H), 7.09 (ddd, J= 1.2, 2.1 and 8.1 Hz, 1H), 7.18 (t, J= 8.1 Hz, 1H), 7.24 (d, J= 2.4 Hz, 1H), 7.32 (t, J= 2.1 Hz, 1H), 7.92 (d, J= 3.3 Hz, 1H); 19F NMR (282 MHz, CDC13): 8 - 167.52; LCMS: ret. time:
21.64 min.;
purity: 98.07%; MS (m/e): 426.99 (MM.
7.3.298 5-Fluoro-N4-(4-isopropoxypheny1)-N2-(3-methoxycarbonylmethyleneoxypheny1)-2,4-pyrimidinediamine (R945125) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(4-isopropoxypheny1)-4-pyrimidineamine (80 mg, 0.28 mmol) and methyl 3-aminophenoxyacete (154 mg, 0.85 mmol) gave 5-fluoro-N4-(4-isopropoxypheny1)-N2-(3-methoxycarbonylmethyleneoxypheny1)-2,4-pyrimidinediamine (80 mg, 66%). 111 NMR

(CDC13) 8 1.33 (s, 3H), 1.35 (s, 311), 3.80 (s, 3H), 4.52 (p, J= 6.0 Hz, 1H), 4.55 (s, 2H), 6.53 (ddd, J= 0.9, 2.4 and 8.1 Hz, 1H), 6.69 (d, J= 2.4 Hz, 1H), 6.90 (d, J= 9.0 Hz, 2H), 7.04-7.08 (m, 2H), 7.16 (t, J= 8.1 Hz, 1H), 7.32 (t, J= 2.1 Hz, 1H), 7.47 (d, J=
8.7 Hz, 211), 7.92 (d, J= 3.0 Hz, 111); 19F NMR (282 MHz, CDC13): 8 - 167.64; LCMS: ret. time:
24.70 min.;
purity: 100%; MS (m/e): 427.00 (MH+).
7.3.299 N244-(Aminocarbonylmethyleneoxy)pheny1]-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R945064) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-N2-(3-hydroxypheny1))-5-fluoro-2,4-pyrimidinediamine, 4-(aminocarbonylmethyleneoxy)aniline (198 mg, 1.2 mmol) and 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine (95 mg, 0.4 mmol) gave N244-(aminocarbonyh-nethyleneoxy)pheny1]-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (60 mg, 41%). 111NMR (CD30D): 64.55 (s, 2H), 6.75 (dm, J= 7.5 Hz, 111), 7.08 (d, J= 9.3 Hz, 211), 7.18 (m, 211), 7.22 (d, J= 8.7 Hz, 1H), 7.46 (d, J= 9.0 Hz, 2H), 8.09 (d, 111); LCMS: ret. time: 14.38 min.; purity:
100%; MS
(m/e): 370.00 (M11+).
7.3.300 5-Fluoro-N2-(3-hydroxypheny1)-N443-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine (R945132) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 3-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxyaniline (490 mg, 2.4 mmol) and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) gave 2-chloro-5-fluoro-N443-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine. The reaction of 2-chloro-5-fluoro-N4-[3-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine (40 mg, 0.12 mmol) and 3-aminophenol (40 mg, 0.36 mmol) gave 5-fluoro-N2-(3-hydroxypheny1)-N443-(5-methyl-1,2,4-oxadiazol-3-y1)methyleneoxyphenyl]-2,4-pyrimidinediamine (30 mg, 62%).
1H NMR (CDC13): 6 2.61 (s, 3H), 5.21 (s, 2H), 6.50 (ddd, J= 0.9, 2.4 and 7.8 Hz, 1H), 6.76 (ddd, J= 0.6, 2.4 and 9.0 Hz, 1H), 6.80-6.85 (m, 311), 7.12 (t, J= 8.1 Hz, 1H), 7.23 (t, J= 7.8 Hz, 111), 7.50-7.52 (m, 211), 7.94 (d, J= 3.3 Hz, 1H), 7.98 (t, J= 2.4 Hz, 1H); 19F NMR (282 MHz, CDC13): 6 - 167.19; LCMS: ret. time: 18.88 min.; purity: 100%; MS (m/e):
408.97 (NIH+).
7.3.301 N2-14-(Aminocarbonylmethoxy)pheny11-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-y1)methyleneoxypheny11-2,4-pyrimidinediamine (R945133) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N443-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine (30 mg, 0.09 mmol) and 4-(aminocarbonylmethyleneoxy)aniline (45 mg, 0.27 mmol) gave N244-(aminocarbonylmethyleneoxy)pheny1]-5-fluoro-N443-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxypheny1]-2,4-pyrimidinediamine (10 mg, 24%). 1H NMR (acetone-d6): 6 2.62 (s, 3H), 4.43 (s, 211), 5.19 (s, 211), 6.77 (ddd, J= 1.2,2.4 and 8.1 Hz, 1H), 6.94 (d, J=
9.0 Hz, 211), 7.25 (t, J= 8.1 Hz, 111), 7.34 (ddd, J= 0.9, 1.8, 9.0 Hz, 1H), 7.68 (d, J= 9.0 Hz, 211), 7.81 (t, J= 2.1 Hz, 1H), 7.99 (d, J= 3.6 Hz, 111), 8.45 (br, 1H, NH), 8.57 (br, 111, NH);
19F NMR (282 MHz, acetone-d6): 6 - 168.20; LCMS: ret. time: 16.80 min.;
purity: 84.91%;
MS (m/e): 466.05 (MO.
7.3.302 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N243-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxypheny11-2,4-pyrimidinediamine (R945128) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine (40 mg, 0.14 mmol) and 3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline (87 mg, 0.42 mmol) gave N4-(3,4-ethylenedioxypheny1)-5-fluoro-N243-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxypheny1]-2,4-pyrimidinediamine (30 mg, 47%). 111 NMR (CDC13):
62.62 (s, 3H), 4.26 (q, J= 2.1 Hz, 411), 5.09 (s, 211), 6.63-6.67 (m, 2H), 6.85 (d, J= 8.4 Hz, 111), 6.95-6.99 (m, 2H), 7.09 (dt, J= 0.9 and 6.9 Hz, 111), 7.19 (t, J= 8.4 Hz, 1H), 7.23 (d, J= 2.4 Hz, 1H), 7.42 (t, J= 2.4 Hz, 111), 7.92 (d, J= 3.0 Hz, 1H); 19F NMR (282 MHz, CDC13): 8 -167.47; LCMS: ret. time: 21.26 mm.; purity: 96.72%; MS (m/e): 451.01 (MO.
7.3.303 5-Fluoro-N4-(4-isopropoxypheny1)-N243-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxypheny11-2,4-pyrimidinediamine (R945129) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(4-isopropoxypheny1)-4-pyrimidineamine (40 mg, 0.14 mmol) and 3-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxyaniline (87 mg, 0.42 mmol) gave 5-fluoro-N4-(4-isopropoxypheny1)-N243-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine (40 mg, 63%). 1H NMR (CDC13): 8 1.32 (s, 3I1), 1.34 (s, 311), 2.61 (s, 3H), 4.52 (p, J= 6.0 Hz, 1H), 5.08 (s, 211), 6.64 (ddd, J= 1.2, 2.7 and 8.1 Hz, 1 H), 6.70 (d, J= 2.4 Hz, 1H), 6.89 (d, J= 9.0 Hz, 2H), 7.07-7.11 (m, 211), 7.16 (t, J= 8.1 Hz, 111), 7.38 (t, J= 2.1 Hz, 111), 7.46 (d, J= 9.0 Hz, 2H), 7.91 (d, J= 3.3 Hz, 1H); 19F NMR
(282 MHz, CDC13): 8 - 167.55; LCMS: ret. time: 24.49 min.; 96.15%; MS (m/e): 451.08 (M11+).
7.3.304 N2-(3,4-Ethylenedioxypheny1)-5-fluoro-N443-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxypheny11-2,4-pyrimidinediamine (R945137) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-[3-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-4-pyrimidineamine (40 mg, 0.12 mmol) and 3,4-*
ethylenedioxyaniline (55 mg, 0.36 mmol) reacted to give N2-(3,4-ethylenedioxypheny1)-5-fluoro-N4-[3-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.
1H NMR (CDC13): 6.2.60 (s, 3H), 4.24 (q, J= 2.7 Hz, 411), 5.21 (s, 211), 6.74-6.78 (m, 211), 6.81 (d, J= 8.4 Hz, 111), 6.90 (dd, J= 1.2, 7.8 Hz, 111), 7.01 (dd, J= 2.4 and 8.4 Hz, 111), 7.22 (t, J= 8.4 Hz, 1H), 7.30 (d, J= 2.4 Hz, 111), 7.48 (br, 111), 7.94 (d, J= 3.3 Hz, 111), 7.98 (br, 111); 19F NMR (282 MHz, CDC13) 6-,168.23; LCMS: ret. time: 21.20 min.; purity:
91.09%;
MS (m/e): 450.99 (MH+).

7.3.305 5-Fluoro-N2-(4-isopropoxypheny1)-N443-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine (R945138) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N443-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxyphenyll-4-pyrimidineamine (40 mg, 0.12 mmol) and 4-isopropoxyaniline (55 mg, 0.36 mmol) gave 5-fluoro-N2-(4-isopropoxypheny1)-N4-[3-(5-methy1-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine.

(CDC13): 8 1.31 (s, 3H), 1.33 (s, 3H), 2.60 (s, 3H), 4.48 (p, J= 6.0 Hz, 1H), 5.20 (s, 2H), 6.74-6.78 (m, 2H), 6.87 (d, J= 9.0 Hz, 2H), 6.92 (dd, J= 1.2 and 8.4 Hz, 1H), 7.22 (t, J= 8.4 Hz, 111), 7.50 (m, 311), 7.94 (d, J= 3.0 Hz, 2H); 19F NMR (282 MHz, CDC13): 8 -168.46;
LCMS: ret. time: 24.95 min.; purity: 73.74%; MS (m/e): 451.06 (MO.
7.3.306 N4-(3,5-Dimethy1-4-hydroxypheny1)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxypheny1)-2,4-pyrimidinediamine (R945139) Using general hydrogenation conditions, 2,6-dimethy1-4-nitrophenol was reduced to 4-amino-2,6-dimethylphenol. In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 4-amino-2,6-dimethylphenol (823 mg, 6 mmol) and 2,4-dichloro-5-fluoropyrimidine (500 mg, 3 mmol) gave 2-chloro-N4-(3,5-dimethy1-4-hydroxypheny1)-5-fluoro-4-pyrimidineamine. Compound 2-chloro-N4-(3,5-dimethy1-4-hydroxypheny1)-5-fluoro-pyrimidineamine (500 mg, 1.87 mmol) and 3-(methoxycarbonylmethyleneoxy)aniline (500 mg, 2.76 mmol) reacted to give N4-(3,5-dimethy1-4-hydroxypheny1)-5-fluoro-N2-(3-methoxycarbonyhnethyleneoxypheny1)-2,4-pyrimidinediamine (500 mg, 65%). 1H NMR
(CD30D): 8 2.16 (s, 611), 3.76 (s, 3H), 4.51 (s, 2H), 6.79 (ddd, J= 0.9, 2.4 and 8.1 Hz, 1H), 7.01-7.06 (m, 211), 7.15 (s, 2H), 7.26 (t, J= 8.1 Hz, 1H), 7.93 (d, J= 5.7 Hz, 1H); 19F NMR
(282 MHz, CD30D): 8 - 163.31; LCMS: ret. time: 20.44 min.; purity: 84.25%; MS
(m/e):
413.03 (MO.
7.3.307 N4-(Benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (R945146) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of benzothiophen-3-ylmethylamine (244 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine. The reaction of N4-(benzothiophen-3-ylmethyl)-2-chloro-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-(benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine. (40 mg, 36%). 1H NMR (CDC13): 64.45 (br, 1H), 4.95 (dd, J= 1.2 and 5.4 Hz, 2H), 5.33 (br, 1H), 6.40 (ddd, J= 1.2, 2.4 and 8.1 Hz, 1H), 6.85 (ddd, J= 0.9, 2.1 and 8.1 Hz, 1H), 6.91 (br, 1H), 7.05 (t, J= 8.1 Hz, 1H), 7.26 (m, 1H), 7.39-7.47 (m, 3H), 7.81 (dd, J= 1.2 and 5.1 Hz, 111), 7.84 (d, J= 3.3 Hz, 1H), 7.92 (m, 1H); 19F
NMR (282 MHz, CDC13): 8 - 168.89; LCMS: ret. time: 21.91 min.; purity: 99.34%;
MS
(m/e): 366.96 (MH+).
7.3.308 5-Fluoro-N2-(3-hydroxypheny1)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine (12945147) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 3-pyridylmethylamine (162 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) were reacted to give 2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine. Then 2-chloro-5-fluoro-N4-(3-pyridylmethyl)-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) reacted to give 5-fluoro-N2-(3-hydroxypheny1)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine (40 mg, 43%). 1H NMR (CD30D): 64.71 (s, 2H), 6.38 (ddd, J= 0.9, 2.4 and 8.1 Hz, 111), 6.88 (ddd, J= 0.9, 2.1 and 8.1 Hz, 1H), 7.00 (t, J= 8.1 Hz, 1H), 7.14 (t, J= 2.4 Hz, 1H), 7.37 (dd, J= 4.8 and 7.8 Hz, 1H), 7.73 (d, J= 3.6 Hz, 111), 7.87 (dt, J= 2.1 and 7.5 Hz, 1H), 8.39 (dd, J= 1.2 and 7.8 Hz, 1H), 8.57 (d, J= 2.1 Hz, 111); 19F NMR (282 MHz, CD30D): 8 -170.99;
LCMS: ret. time: 8.82 mm.; purity: 92.90%; MS (rn/e): 312.05 (MH+).
7.3.309 N4-(3-Chloro-4-hydroxy-5-methylpheny1)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxypheny1)-2,4-pyrimidinediamine (12945148) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 4-amino-2-chloro-6-methylphenol and 2,4-dichloro-5-fluoropyrimidine resulted 2-chloro-N4-(3-chloro-4-hydroxy-5-methylpheny1)-5-fluoro-4-pyrimidineamine. The reaction of 2-chloro-N4-(3-chloro-4-hydroxy-5-methylpheny1)-5-fluoro-4-pyrimidineamine and 3-methoxycarbonylmethyleneoxyaniline (1.95 g, 11 mmol) gave N4-(3-chloro-4-hydroxy-5-methylpheny1)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxypheny1)-2,4-pyrimidinediamine (850 mg, 55%). 1H NMR

(CD30D): 8 2.22 (s, 3H), 3.76 (s, 311), 4.52 (s, 211), 6.50 (dt, J= 2.7 and 6.3 Hz, 111), 7.09-7.14 (m, 2H), 7.24 (t, J= 1.8 Hz, 111), 7.30 (t, J= 1.2 Hz, 111), 7.49 (d, J=
2.4 Hz, 111), 7.88 (d, J= 3.9 Hz, 1H); 19F NMR (282 MHz, CD30D): 8 - 168.70; LCMS: ret. time:
20.63 min.;
purity: 98.56%; MS (m/e): 432.96 (MO.
7.3.310 N4-[(2,5-Dimethy1-3-furyl)methyl]-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrinddinediamine (R945151) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of (2,5-dimethy1-3-furyl)methylamine (188 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave 2-chloro-N4-[(2,5-dimethy1-3-furyl)methy11-5-fluoro-4-pyrimidineamine. The reaction of 2-chloro-N4-[(2,5-dimethy1-3-furypmethyl]-5-fluoro-4-primidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-[(2,5-dimethy1-3-fiffyl)methyl]-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (50 mg, 51%). 1H NMR (CDC13): 8 2.22 (s, 311), 2.23 (s, 311), 4.39 (d, J= 5.1 Hz, 211), 5.24 (br, 1H), 5.90 (s,11-1), 6.52 (d, J= 6.6 Hz, 111), 6.99 (d, J= 8.1 Hz, 111), 7.13 (t, J= 8.1 Hz, 111), 7.29 (s, 1H), 7.71 (m, 211); 19F NMR (282 MHz, CDC13): 6- 167.84; LCMS: ret. time: 19.83 min.; purity: 96.32%; MS
(mile): 329.05 (M11+).
7.3.311 N4-(3,5-Dimethy1-4-methoxypheny1)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxypheny1)-2,4-pyrimidinediamine (11945153) In a manner analogous to the preparation of N2,N4-bis[3-methoxy-4-(methoxycarbonyl)pheny1]-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,6-dimethy1-4-nitrophenol (1.67 g, 10 mmol), potassium carbonate (13 g, 0.1 mol) and iodomethane (2.5 mL, 50 mmol) gave 2,6-dimethyl-1-methoxy-4-nitrobenzene. Hydrogenation of 2,6-dimethyl-l-methoxy-4-nitrobenzene gave 3,5-dimethy1-4-methoxyaniline.
In a marmer analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-N2-(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine, the reaction of 3,5-dimethy1-4-methoxyaniline (400 mg, 2.6 mmol) and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) gave 2-chloro-N4-(3,5-dimethy1-4-methoxypheny1)-5-fluoro-4-ppimidineamine.
The reaction of 2-chloro-N4-(3,5-dimethy1-4-methoxypheny1)-5-fluoro-4-pyrirnidineamine and 3-(methoxycarbonylmethyleneoxy)aniline (650 mg, 3.6 mmol) gave N4-(3,5-dimethy1-4-methoxypheny1)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (180 mg, 35%). 1H NMR (CD30D): 5 2.20 (s, 6H), 3.70 (s, 3H), 3.74 (s, 311), 4.52 (s, 211), 6.76 (ddd, J= 0.9, 2.4 and 8.4 Hz, 1H), 7.03-7.08 (m, 2H), 7.24 (m, 3H), 7.96 (d, J= 5.4 Hz, 111); 19F NMR (282 MHz, CD30D): 5 - 162.92; LCMS:
ret. time:
23.13 mm.; purity: 100%; MS (m/e): 427.04 (MM.
7.3.312 N444-(N-Benzylpiperazino)phenyll-N2-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R945155) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-N2-(3-hydroxypheny1)-5-fluoro-2,4-pyrimidineamine, the reaction of N4-[4-(N-benzylpiperazino)pheny1]-2-chloro-5-fluoro-4-pyrimidineamine (50 mg, 0.12 mmol) and 3,4-ethylenedioxyaniline (0.045 mL, 0.36 mmol) gave N444-(N-benzylpiperazino)pheny1)]-N2-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (40 mg, 63%). 111 NMR (CDC13): 5 2.64 (t, J= 4.8 Hz, 411), 3.20 (t, J= 4.8 Hz, 4I1), 3.59 (s, 211), 4.24 (m, 4H), 6.61 (d, 111, NH), 6.68 (br, 1H, NH), 6.76 (d, J= 8.7 Hz, 111), 6.88 (dd, J= 2.4 and 8.7 Hz, 1H), 6.93 (d, J= 8.7 Hz, 211), 7.19 (d, J= 2.4 Hz, 111), 7.28-7.36 (m, 511), 7.47 (d, J= 8.7 Hz, 21I), 7.87 (d, J= 3.3 Hz, 1H); 19F NMR (282 MHz, CDC13): 5 -168.66;
LCMS: ret. time: 18.05 min.; purity: 100%; MS (m/e): 513.10 (MO.
7.3.313 N2-[(2,5-Dimethy1-3-furyl)methyl]-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R945162) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine (50 mg, 0.21 mmol) and (2,5-dimethy1-3-furypmethylamine (80 mg, 0.63 mmol) gave N2-[(2,5-dimethy1-3-furypmethyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 59%). 1H NMR (acetone-d6):
62.14 (s, 611), 4.37 (d, J= 4.2 Hz, 211), 5.96 (s, 1H), 6.77 (d, J= 6.6 Hz, 111), 7.23-7.28 (m, 2H), 7.44 (s, 111), 8.11 (d, J= 4.8 Hz, 111), 9.05 (br, 1H), 9.75 (br, 111); 19F
NMR (282 MHz, acetone-d6): 5 - 165.77; LCMS: ret. time: 19.23 min.; purity: 94.89%; MS
(m/e): 329.08 7.3.314 N244-(N-Benzylpiperazino)phenyll-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R945163) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylendioxypheny1)-5-fluoro-4-pyrimidineamine (50 mg, 0.18 mmol) and 4-(4-benzylpiperazino)aniline (142 mg, 0.53 mmol) resulted N244-(N-benzylpiperazino)phenyli-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (30 mg, 33%). 111 NMR (CDC13): 8 2.63 (t, J= 4.8 Hz, 411), 3.16 (t, J= 4.8 Hz, 411), 3.58 (s, 211), 4.27 (m, 4H), 6.56 (d, 111, NH), 6.70 (br, 1H, NH), 6.82 (d, J= 8.7 Hz, 1H), 6.89 (d, J=
9.0 Hz, 211), 6.96 (dd, J= 2.7 and 8.7 Hz, 111), 7.28 (d, J= 2.7 Hz, 1H), 7.30-7.36 (m, 511), 7.39 (d, J= 8.7 Hz, 211), 7.88 (d, J= 3.3 Hz, 1H); 19F NMR (282 MHz, CDC13): 8 - 168.94;
LCMS: ret. time: 18.12 min.; purity: 98.42%; MS (m/e): 512.95 (M11+).
7.3.315 N2-(Benzothiophen-3-ylmethyl)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R945164) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine (50 mg, 0.21 mmol) and benzothiophen-3-ylmethylamine (100 mg, 0.61 mmol) gave N2-(benzothiophen-3-ylmethyl)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (40 mg, 53%). 111 NMR (CDC13): 64.82 (d, J= 6.0 Hz, 2H), 6.45 (dd, 7= 8.1 Hz, 1H), 6.70 (m, 1H), 6.80 (d, J= 8.4 Hz, 111), 7.03 (t, J= 8.1 Hz, 111), 7.22 (m, 111), 7.34 (s, 111), 7.39-7.46 (m, 211), 7.82 (m, 111), 7.89-7.92 (m, 211); 19F
NMR (282 MHz, CDC13): 8 - 170.02; LCMS: ret. time: 21.29 mm.; purity: 92.97%;
MS
(m/e): 367.03 (MH+).
7.3.316 5-Fluoro-N4-(3-hydroxypheny1)-N2-(3-pyridylmethyl)-2,4-pyrimidinediamine (R945165) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine (50 mg, 0.21 mmol) and 3-pyridyhnethylamine (68 mg, 0.63 mmol) gave 5-fluoro-N4-(3-hydroxypheny1)-N2-(3-pyridyhnethyl)-2,4-pyrimidinediamine (40 mg, 62%). 111 NMR. (CDC13): 64.40 (d, J= 6.3 Hz, 211), 5.60 (br, 1H), 6.62-6.70 (m, 311), 7.05 (br, 111), 7.14 (t, J= 8.1 Hz, 1H), 7.30 (dd, J=
5.1 and 7.8 Hz, 1H), 7.73 (d, J= 7.5 Hz, 1H), 7.80 (d, J= 3.3 Hz, 1H), 8.49 (d, J= 4.5 Hz, 1H), 8.66 (s, 1H);
19F NMR (282 MHz, CDC13): 6- 169.52; LCMS: ret. time: 9.41 min.; purity:
99.25%; MS
(m/e): 312.01 (MH+).
7.3.317 5-Fluoro-N4-(3-hydroxypheny1)-N2-(2-pyridylmethyl)-2,4-pyrimidinediamine (R945166) In a manner analogous to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine (50 mg, 0.21 mmol) and 2-pyridylmethylamine (68 mg, 0.63 rnmol) gave 5-fluoro-N4-(3-hydroxypheny1)-N2-(2-pyridylmethyl)-2,4-pyrimidinediamine (40 mg, 62%). 1H NMR (CDC13): 64.73 (d, J= 6.3 Hz, 211), 5.85 (t, J=
6.0 Hz, 111, NH), 6.48 (d, J= 6.9 Hz, 1H), 6.61 (dd, J= 2.7 and 8.1 Hz, 1H), 6.67 (s, 1H), 7.13 (t, J= 8.1 Hz, 111), 7.21 (dd, J= 5.1 and 7.5 Hz, 1H), 7.49 (d, J= 7.5 Hz, 111), 7.69 (td, J= 1.8 and 7.8 Hz, 111), 7.85 (d, J= 3.6 Hz, 111), 8.38 (br, 111), 8.56 (dd, J= 1.2 and 3.9 Hz, 111); 19F NMR (282 MHz, CDC13): 5 -170.49; LCMS: ret. time: 10.10 min.;
purity: 100%;
MS (m/e): 312.08 (Miff).
7.3.318 N4-(3,5-Dimethoxypheny1)-N2-(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926802) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,5-dimethoxypheny1)-5-fluoro-4-pyrimidineamine with 3-hydroxyaniline gave N4-(3,5-dimethoxypheny1)-N2-(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS:
ret.
time: 18.98 min.; purity: 90%; MS (m/e): 357 (M114).
7.3.319 N4-(3,5-Dimethoxypheny1)-N2-(2-ethoxycarbonylindo1-7-y1)-5-fluoro-2,4-pyrimidinediamine (R926803) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,5-dimethoxypheny1)-5-fluoro-4-pyrimidineamine with 2-ethoxycarbony1-7-aminoindole gave N4-(3,5-dimethoxypheny1)-N2-(2-ethoxycarbonylindo1-7-y1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 24.21 min.; purity: 91%; MS (m/e): 452 (ME1+).

7.3.320 N2-(3,4-Dimethoxypheny1)-N4-(4-ethoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926108) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(4-ethoxypheny1)-5-fluoro-4-pyrimidineamine with 3,4-dimethoxyaniline gave N2-(3,4-dimethoxypheny1)-N4-(4-ethoxypheny1)-5-fluoro-2,4-primidinediamine. 1H NMR (CDC13): 6 7.89 (d, 1H, J= 3 Hz), 7.45 (bd, 2H, J= 9 Hz), 7.20 (d, 111, J= 2.4 Hz), 6.96-6.77 (m, 511), 6.63 (bs, 1H), 4.03 (q, 211, J= 7.2 Hz), 3.86 (s, 3H), 3.72 (s, 311), 1.42 (t, 311, J= 7.2 Hz);
19F NMR (CDC13): -47473.
7.3.321 N4-(4-Ethoxypheny1)-N2-(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926146) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(4-ethoxypheny1)-5-fluoro-4-pyrimidineamine with 3-hydroxyaniline gave N4-(4-ethoxypheny1)-N2-(3-hydroxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD30D): 67.79 (d, 1H, J= 4.2 Hz), 7.54 (dd, 211, J= 2.4 and 7.2 Hz), 7.05-6.97 (m, 3I1), 6.87 (dd, 211, J=
2.4 and 4.2 Hz), 6.41 (m, 1H), 4.02 (q, 211, J= 6.6 Hz), 1.38 (t, 3H, J= 6.9 Hz); 19F NMR
(CD30D): - 47444;
LCMS: ret. time: 21.15 min.; purity: 98%; MS (m/e): 341 (M11+).
7.3.322 N4-(4-Ethoxypheny1)-N2-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926213) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(4-ethoxypheny1)-5-fluoro-4-pyrimidineamine with 3,4-ethylenedioxyaniline gave N4-(4-ethoxypheny1)-N2-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13): 8 7.87 (d, 1H, J= 3Hz), 7.47 (dd, 2H, J= 2.4 and 5.1 Hz), 7.18 (d, 111, J= 2.4 Hz), 6.91-6.85 (m, 3H), 6.79-6.73 (m, 211), 6.64 (bs, 111), 4.25 (bs, 411), 4.05 (q, 2H, J= 6.9 Hz), 1.43 (t, 311, J= 7.2 Hz); 19F NMR (CDC13): - 47467; LCMS: ret. time: 24.32 min.; purity: 90%; MS
(m/e): 383 NH).
7.3.323 N4-(3,4-Dimethoxypheny1)-N2-(4-ethoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926145) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-dimethoxypheny1)-5-fluoro-4-pyrimidineamine with 4-ethoxyaniline gave N4-(3,4-dimethoxypheny1)-N2-(4-ethoxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR
(CDC13): 8 7.90 (bs, 1H), 7.37 (dd, 2H, J= 2.4 and 6.3 Hz), 7.21 (d, 1H, J=
2.4 Hz), 7.03 (dd, 111, J= 2.4 and 8.1 Hz), 6.86-6.80 (m, 4H), 6.65 (bs, 1H), 4.00 (q, 2H, J= 7.2 Hz), 3.89 (s, 3H), 3.75 (s, 3H), 1.39 (t, 3H, J= 6.9 Hz); 19F NMR (CDC13): -47501; LCMS:
ret. time:
22.69 min.; purity: 98%; MS (m/e): 385 (Ma).
7.3.324 N4-(3,4-Dimethoxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (R926147) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-dimethoxypheny1)-5-fluoro-4-pyrimidineamine with 3-hydroxyaniline gave N4-(3,4-dimethoxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine. 1H NMR
(CD30D): 8 7.77 (d, 111, J= 3.3 Hz), 7.15 (d, 1H, J= 2.4 Hz), 7.05 (dd, 1H, J=
2.4 and 8.4 Hz), 7.00-6.90 (m, 4H), 6.80 (d, 1H, J= 8.1 Hz), 6.40 (m, 1H), 4.05 (q, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 1.20 (t, 3H); 19F NMR (CD30D): - 47223; LCMS: ret. time: 17.94 mm.;
purity: 99%; MS (rn/e): 357 (MO.
7.3.325 N2-(3,4-Dimethoxypheny1)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R926113) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine with 3,4-dimethoxyaniline gave N2-(3,4-dimethoxypheny1)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine. 1H NMR
(CDC13): 8 7.90 (d, 111, J= 6.6 Hz), 7.59 (bs, 1H), 7.30 (s, 1H), 7.20-7.10 (m, 2H), 7.00-6.75 (m, 4H), 6.59 (bd, 1H, J= 7.8 Hz), 3.87 (s, 3H), 3.84 (s, 3H); 19F NMR
(CDC13): - 47229;
LCMS: ret. time: 17.77 min.; purity: 78%; MS (m/e): 357 (M11+).
7.3.326 N2-(4-Ethoxycarbonylmethyleneoxypheny1)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R926395) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrirnidinediamin.e, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine with ethyl-4-aminophenoxyacetate gave N2-(4-ethoxycarbonyhnethyleneoxypheny1)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine. 111 NMR (CD30D): 8 7.90 (d, 1H, J= 5.1 Hz), 7.35 (dd, 2H, J= 2.1 and 7.2 Hz), 7.13 (t, 111, J= 7.2 Hz), 7.10 9d, 1H, J= 6.6 Hz), 6.96 (dd, 211, J=
2.4 and 7.2 Hz), 6.67 (m, 1H), 4.72 (s, 2H), 4.25 (q, 2H, j= 7.2 Hz), 1.29 (t, 3H, J= 7.2 Hz);

(CD30D): - 21885; LCMS: ret. time: 20.18 min.; purity: 92%; MS (m/e): 399 (MH+).
7.3.327 5-Bromo-N2-(4-ethoxyc arb onylmethyleneoxypheny1)-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R926396) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3-hydroxypheny1)-4-pyrimidineamine with ethyl 4-aminophenoxyacetate gave 5-bromo-N2-(4-ethoxycarbonylmethyleneoxypheny1)-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine.
LCMS: ret. time: 21.64 mm.; purity: 92%; MS (m/e): 459 W).
7.3.328 N2-(4-Ethoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926211) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 4-ethoxyaniline were reacted to yield N2-(4-ethoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13): 8 7.88 (bs, 1H), 7.40 (bd, 2H, J= 8.7 Hz), 7.27 (bd, 211, J= 6.3 Hz), 6.95 (dd, 111, J= 3 and 9 Hz), 6.86-6.77 (m, 3H), 6.58 (s, 111), 4.28 (bs, 4H), 4.01 (q, 2H, J= 6.9 Hz), 1.40 (t, 311, J= 6.9 Hz);
LCMS: ret. time: 24.46 mm.; purity: 90%; MS (rn/e): 383 (MH4).
7.3.329 N2-(3,4-Dimethoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926212) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 3,4-dimethoxyaniline were reacted to yield N2-(3,4-dimethoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine.
LCMS:
ret. time: 20.98 min.; purity: 74%; MS (mile): 399 (MO.
7.3.330 N2-(3-Chloro-4-fluoropheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926218) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 3-chloro-4-fluoroaniline were reacted to yield N2-(3-chloro-4-fluoropheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H
NMR

(CD30D): 8 7.75 (bd, 111), 7.70 (bd, 111), 7.18 (m, 111), 7.10 (m, 111), 6.90 (m, 211), 6.75 (m, 111), 4.20 (bs, 4H); LCMS: ret. time: 25.04 mm.; purity: 99%; MS (m/e):
392 (MH4).
7.3.331 N2-(4-tert-Butylpheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926219) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 4-tert-butylaniline were reacted to yield N2-(4-tert-butylpheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR (CDC13):
8 7.85 (d, 1H, J= 3.6 Hz), 7.44 (bdd, 211, J= 6.3 Hz), 7.35-7.31 (m, 311), 6.93 (dd, 111, J= 2.7 and 8.7 Hz), 6.83 (d, 111, J= 9 Hz), 6.80 (bs, 111), 4.23 (s, 411), 1.28 (s, 9H);
LCMS: ret. time:
27.67 min.; purity: 98%; MS (m/e): 395 (MH4).
7.3.332 N4-(3,4-Ethylenedioxypheny1)-N2-(4-fluoropheny1)-5-fluoro-2,4-pyrimidinediamine (R926220) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 4-fluoroaniline were reacted to yield N4-(3,4-ethylenedioxypheny1)-N2-(4-fluoropheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR (CDC13): 8 7.92 (bs, 111), 7.80 (bs, 111), 7.60 (bd, 2H), 6.90 (m, 2H), 6.80 (bs, 111), 6.65 (bs, 1H), 4.25 (s, 411);
LCMS: ret. time: 22.87 min.; purity: 97%; MS (mile): 357 (Mu).
7.3.333 N4-(3,4-Ethylenedioxypheny1)-N2-(3-fluoropheny1)-5-fluoro-2,4-pyrimidinediamine (R926221) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 3-fluoroaniline were reacted to yield N4-(3,4-ethylenedioxypheny1)-N2-(3-fluoropheny1)-5-fluoro-2,4-primidinediamine. 1H NMR (CDC13): 8 7.76 (d, 1H, J=
5.6 Hz), 7.39 (m, 211), 7.14 (d, 111, J= 2.4 Hz), 6.94-6.85 (m, 311), 6.75 (d, 1H, J= 9 Hz), 4.21 (s, 411); LCMS: ret. time: 22.60 min.; purity: 100%; MS (m/e): 357 (M114).
7.3.334 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-(2-methoxyethyl)-2,4-pyrimidinediamine (R926229) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrirnidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 2-methoxyethylamine were reacted to yield N4-(3,4-ethylenedioxypheny1)--5-fluoro -N2-(2-methoxyethyl)-2,4-pyrimidinediamine. 111 NMR
(CDC13): 5 7.81 (bs, 1H), 7.33 (d, 1H, J= 2.4 Hz), 6.93 (dd, 1H, J= 2.4 Hz and 9 Hz), 6.81 (d, 1H, J= 9 Hz), 6.53 (s, 1H), 4.25 (bs, 2H), 3.54 (bs, 2H), 3.36 (s, 3H);
LCMS: ret. time:
18.01 min.; purity: 100%; MS (rn/e): 321 (MH+).
7.3.335 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-(4-methoxybenzy1)-2,4-pyrimidinediamine (R926230) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 4-methoxybenzylamine were reacted to yield N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(4-methoxybenzy1)-2,4-pyrimidinediamine. 1H
NMR
(CDC13): 5 7.81 (d, 1H, J= 2.7 Hz), 7.27 (m, 3H), 6.86 (m, 3H), 6.52 (s, 1H).
5.14 (s, 1H), 4.46 (d, 2H, J= 5.4 Hz), 4.24 (s, 4H), 3.78 (s, 3H); LCMS: ret. time: 23.06 min.; purity:
94%; MS (m/e): 383 (MH+).
7.3.336 N2-(2,2-Difluorobenzodioxo1-5-y1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926386) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 2,2-difluoro-5-aminobenzodioxole were reacted to yield N2-(2,2-difluorobenzodioxo1-5-y1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine.
111 NMR (CDC13): 8 9.39 (s, 1H), 9.24 (s, 1H), 8.06 (d, 1H, J= 5.6 Hz), 7.87 (d, 1H, J= 1.8 Hz), 7.27-7.19 (m, 3H), 7.08 (dd, 1H, J= 2.4 and 8.7 Hz), 6.80 (d, 1H, J=
9Hz), 4.21 (bs, 4H); 19F NMR (CDC13): -14012 and - 46487; LCMS: ret. time: 25.32 min,;
purity:100%;
MS (m/e): 419 (ME-I4).
7.3.337 N2-(2-Ethoxycarbonylindo1-5-y1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926476) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 2-ethoxycarbony1-5-aminoindole were reacted to yield N2-(2-ethoxycarbonylindo1-5-y1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine.

114 NMR (CDC13): 8 7.84 (d, 1H, J= 5.4 Hz), 7.76 (d, 1H, J= 3.6 Hz), 7.50 (d, 111, J= 9 Hz), 7.23-7.15 (m, 3H), 7.03 (bd, 1H, J= 8.7 Hz), 6.78 (d, 1H, J= 8.7 Hz), 4.38 (q, 2H, J= 7.2 Hz), 4.22 (s, 4H), 1.41 (t, 3H, J= 6.9 Hz); LCMS: ret. time: 23.58 min;
purity: 100%; MS
(m/e): 451 (MH+).
7.3.338 N2-(4-Cyanomethyleneoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyritnidinediamine (R926480) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and 4-cyanomethyleneoxyaniline were reacted to yield N2-(4-cyanomethyleneoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine.
1H NMR (CDC13): 8 7.87 (d, 111, J= 3.6 Hz), 7.52 (d, 111, J= 8.7 Hz), 7.38 (bs, 1H), 7.28 (d, 1H, J= 2.4 Hz), 6.96-6.86 (m, 3H), 6.65 (bd, 1H), 4.73 (s, 211), 4.29 (m, 411); 19F NMR
(CDC13): - 47416; LCMS: ret. time: 20.49 min.; purity: 100%; MS (m/e): 394 (M11+).
7.3.339 N2-(3-Ethoxycarbonylmethyleneoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926482) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediarnine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine and ethyl-3-aminophenoxyacetate were reacted to yield N2-(3-ethoxycarbonylmethyleneoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13): 610.53 (s, 111), 8.18 (s, 111), 7.67 (d, 1H, J=4.8 Hz), 7.19-7.02 (m, 511), 6.86 (d, 1H, 9Hz), 6.71 (dd, 111, J= 1.8 and 9 Hz), 4.51 (s, 211), 4.25 (m, 611), 1.29 (t, 311, J= 7.5 Hz); 19F NMR (CDC13): - 45640; LCMS: ret.
time: 22.71 min.; purity: 99%; MS (m/e): 441 (Mil).
7.3.340 N2-(3-Ethoxycarbonylpheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R925745) In like manner to preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrirnidineamine and 3-ethoxycarbonylaniline gave N2-(3-ethoxycarbonylpheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDC13): 8 8.04 (bs, 1H), 7.94 (bs, 1H), 7.90 (bd, 111), 7.68 (bd, 1H, J= 7.5 Hz), 7.35 (t, 111, J=
8.1 Hz), 7.28 (d, 1H, J= 2.4 Hz), 7.07 (s, 111), 6.93 (dd, 1H, J= 3 and 8.7 Hz), 6.83 (d, 1H, J=
9 Hz), 6.64 (bs, 1H), 4.36 (q, 211, J= 7.2 Hz), 4.26 9s, 4H), 1.35 (t, 3H, J= 7.5 Hz); 19F NMR
(CDC13): -47247; LCMS: ret. time: 15.88.; purity: 100%; MS (m/e): 411 (MI-1+).
7.3.341 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-(2-hydroxyethyl)-2,4-pyrimidinediamine (R925746) In like marmer to preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamineand 2-hydroxyethylamine gave N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(2-hydroxyethyl)-2,4-pyrimidinediamine. 1H NMR (CD30D): 8 7.7 (bs, 1H), 7.32 (d, 111, J= 2.4 Hz), 7.05 (dd, 111, J= 2.4 and 9 Hz), 6.75 (d, 111, J= 8.9 Hz), 4.21 (s, 4H), 3.67 (t, 211, J= 5.7 Hz), 3.38 (t, 211, J= 5.4 Hz); 19F NMR (CD30D): - 48518; LCMD:
ret. time:
15.54 min.; purity: 100%; MS (mile): 307 (M114).
7.3.342 N2-(4-Ethoxycarbonylmethyleneoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R925747) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-primidinediamine, 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamineand ethyl-4-aminophenoxyacetate gave N2-(4-ethoxycarbonylmethyleneoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 111 NMR (CDC13): 67.88 (bs, 111), 7.42 (dd, 2H, J= 2.4 and 6.9 Hz), 7.28 (d, 111, J= 3 Hz), 6.95-6.81 (m, 411), 6.59 (s, 111), 4.59 (s, 4I1), 4.28 (q, 2H, J= 6.2 Hz), 1.30 (t, 311, J= 6.1 Hz); 19F NMR (CDC13): - 47570; LCMS: ret. time: 22.74 min.; purity:
100%; MS (mile): 441 (MH+).
7.3.343 N2-(3-Chloro-4-hydroxy-5-methylpheny1)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine (R940233) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrirnidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxypheny1)-4-pyrimidineamine with 3-chloro-4-hydroxy-5-methylaniline gave N2-(3-chloro-4-hydroxy-5-methylpheny1)-5-fluoro-N4-(3-hydroxypheny1)-2,4-pyrimidinediamine.
LCMS: retn, time: 19.20 min.; purity: 94%; MS (mile): 360 (M4); 1H NMR
(CDC13): 67.93 (111, d, J= 3.1 Hz), 7.54 (111, d, J= 2.6 Hz), 7.30 (111, t, J= 2.1 Hz), 7.21 (111, t, J= 7.9 Hz), 7.02 (311, m), 6.78 (11I, s), 6.61 (1H, dd, J= 7.9 Hz, J= 2.1 Hz), 2.26 (311, s).

. = r.

7.3.344 N4-(3-Chloro-4-hydroxy-5-methylpheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine (R940235) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-chloro-4-hydroxy-5-methylpheny1)-4-pyrimidineamine with 3-hydroxyaniline gave N4-(3-chloro-4-hydroxy-5-methylpheny1)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine.
LCMS:
rein, time: 18.20 min.; purity: 94%; MS (m/e): 360 (M4); I HNMR (DMSOLd6): 8 9.26 (1H, s), 9.23 (1H, s), 9.16 (1H, s), 8.89 (111, s), 8.14 (1H, d, J= 4.5 Hz), 7.66 (111, d, J= 2.1 Hz), 7.60(111, d, J= 2.1 Hz), 7.29 (1H, d, J= 8.4 Hz), 7.11 (1H, s), 7.06 (1H, t, J= 8.4 Hz), 6.41 (1H, d, J= 8.4 Hz), 2.30 (3H, s).
7.3.345 N2-(3,4-Dimethoxypheny1)-5-fluoro-N4-14-[3-(N-morpholinyl)propyl]oxypheny11-2,4-pyrimidinediamine (11940250) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N44443-(N-morpholinyl)propylioxypheny1]-4-pyrimidineamine with 3,4-dimethoxyaniline.
gave N2-(3,4-dimethoxypheny1)-5-fluoro-N44443-(N-morpholinyl)propylioxypheny1]-2,4-pyrimidinediamine. LCMS: rein, time: 14.72 min.; purity: 94%; MS (m/e): 484 (MH4);
NMR. (CDC13): 87.89 (1H, d, J= 3.3 Hz), 7.47 (2H, d, J= 9 Hz), 7.22 (1H, d, J=
2.2 Hz), 6.93-6.76 (5H, m), 6.64 (1H, d, J= 2.2 Hz), 4.01 (211, t, J= 5.6 Hz), 3.86 (3H, s), 3.72 (3H, s), 3.71 (41I, m), 2.58-2.44 (6H, m), 1.97 (2H, m).
7.3.346 N2-(3-Chloro-4-hydroxy-5-methylpheny1)-5-fluoro- N44443-(N-morpholinyl)propyll oxypheny1]-2,4-pyrimidinediamine (11940251) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyritnidinediamine, the reaction of 2-chloro-5-fluoro-N444-[3-(N-morpholinyl)propyl]oxypheny1]-4-pyrimidineamine with 2-chloro-4-hydroxy-5-methylaniline gave N2-(2-chloro-4-hydroxy-5-methylpheny1)-5-fluoro-N4-[443-(N-morpho1inyl)propy1ioxypheny1]-2,4-pyrimidinediamine. LCMS: rein, time: 15.19 min.;
purity: 94%; MS (m/e): 488 (MLII+); (CDC13): 37.89 (1H, d, J.= 3.3 Hz), 7.52 (1H, =
d, J= 2.5 Hz), 7.44 (2H, d, 8.7 Hz), 6.97 (1H, d, J= 2.5 Hz), 6.91 (2H, d, 9 Hz), 6.71 (1H, s), 6.64 (111,2.5 Hz), 4.03 (2H, t, J= 6.03 Hz), 3.74 (4H, t, J= 4.65 Hz), 2.60-2.43 (6H, m), 2.23 (3H, s), 1.49 (211, m).

=
7.3.347 N4-(3,5-Dimethy1-4-hydroxypheny1)-N2-(3-ethoxycarbonylmethyleneoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R940253) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,5-dimethy1-4-hydroxypheny1)-5-fluoro-4-pyrimidineamine with ethyl 3-aminophenoxyacetate gave N4-(3,5-dimethy1-4-hydroxypheny1)-N2-(3-ethoxycarbonylmethyleneoxypheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: retn, time: 21.79 min.; purity: 91 %; MS (m/e): 427 (MW); 1H
NMR (DMSO-d6): 8 9.80 (111, s), 8.30 (1H, s), 8.23 (1H, d, J= 4.5 Hz), 7.37-7.17 (5H, m), 6.66 (1H, d, J= 9 Hz), 4.73 (211, s), 4.25 (2H, q, J= 7.2 Hz), 2.23 (6H, s), 1.29 (3H, t, J= 7.0 Hz).
7.3.348 N2-(3-tert-Butylpheny1)-N4-(3-ethoxycarbonylmethyleneoxypheny1)-5-fluoro-4-pyrimidinediamine (R940266) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3-ethoxycarbonyhnethyleneoxypheny1)-5-fluoro-4-pyrimidineamine with 3-tert-butylaniline gave N2-(3-tert-butylpheny1)-N4-(3-ethoxycarbonylmethyleneoxypheny1)-5-fluoro-pyrimidinediamine. LCMS: retn, time: 28.17 min.; purity: 96 %; MS (m/e): 439 (AO, 440 (MO; 1H NMR (DMSO-d6): 69.40 (1H, s), 9.19 (1H, s), 8.21 (1H, d, J= 3.6 Hz), 7.78 (111, d, J= 8.5 Hz) 7.60 (2H, m), 7.48 (111, t, J= 2 Hz), 7.31 (111, t, J= 8.5 Hz), 7.25 (1H, t, J= 8.5 Hz), 7.02 (111, d, J= 8.5 Hz), 6.70 (1H, dd, J= 8.5 and 2 Hz), 4.79 (211, s), 4.26 (2H, q, J= 7.2 Hz), 1.33 (9H, s), 1.29 (311, t, J= 7.2 Hz).
7.3.349 5-Fluoro-N4-(3-isopropylpheny1)-N2-(2-methoxycarbonylbenzofur-5-y1)-2,4-pyrimidinediamine and 5-fluoro-N2-(2-ethoxoxycarbonylbenzofur-5-y1)-N4 -(3-isopropylpheny1)-2,4-pyrimidinediamine R940284 In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hyroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-isopropylpheny1)-pyrimidineamine and ethyl 3-aminophenoxyacetate were reacted to give the mixture of 5-fluoro-N4-(3-isopropylpheny1)-N2-(2-methoxycarbonylbenzofur-5-y1)-2,4-pyrimidinediamine and 5-fluoro-N2-(2-ethoxoxycarbonylbenzofur-5-y1)-N4 -(3-isopropylpheny1)-2,4-pyrimidinediamine. (R = CO2Me). LCMS: retn, time: 25.41 min.;
purity: 60.61 %; MS (rn/e): 411 (MO; 1H NMR (DMSO-d6): 6.9.38 (111, s), 9.29 (111, s), 8.20 (1H, d, J= 3.9 Hz), 7.85 (111, d, J= 9.3 Hz), 7.58 (111, t, J= 1.6 Hz), 7.43-7.33 (3H, m), 7.18 (1H, t, J= 8.2 Hz), 7.05 (11I, d, J= 7.8 Hz), 6.53 (111, dd, J= 8.4 Hz, J= 2.1 Hz), 4.72 (2H, s), 3.79 (311, s), 2.95 (11I, quint, J= 7.2 Hz), 1.26 (6H, d, J= 7.2 Hz) (R = CO2E0 LCMS: retn, time: 26.99 min.; purity: 39 %; MS (rn/e): 425 (MR); 1H NMR (DMSO-d6):
8 9.38 (1H, s), 9.29 (111, s), 8.20 (111, d, J= 3.9 Hz), 7.85 (1H, d, J= 9.3 Hz), 7.58 (111, t, J=
1.6 Hz), 7.43-7.33 (311, m), 7.18 (1H, t, J= 8.2 Hz), 7.05 (111, d, J= 7.8 Hz), 6.53 (1H, dd, J= 8.4 and 2.1 Hz), 4.71 (2H, s), 4.25 (2H, q, J= 7.2 Hz), 2.95 (111, quint, J= 7.2 Hz), 1.31 (3H, t, J= 7.2 Hz), 1.26 (6H, d, J= 7.2 Hz).
7.3.350 N4-(3-tert-Butylpheny1)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-y1)-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hyroxypheny1)-2,4-pyrimidinediamine, N4-(3-tert-butylpheny1)-2-chloro-5-fluoro-pyrimidineamine and 2-methoxycarbony1-5-aminobenzofuran were reacted to give N4-(3-tert-butylpheny1)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-y1)-2,4-pyrimidinediamine.
LCMS: retn, time: 26.76 min.; purity: 97 %; MS (m/e): 435 (M114); 111 NMR
(DMSO-d6):
8 9.41 (211, sl), 8.27 (111, s), 8.21 (111, d, J 3.9 Hz), 7.98 (111, m), 7.77-7.60 (311, m), 7.37 (1H, t, J 8.1 Hz), 7.22 (1H, d, J 8.1 Hz), 3.98 (311, s), 1.34 (9H, s).
7.3.351 5-fluoro-N4-(3-isopropylpheny1)-N2-(2-methoxycarbonylbenzofur-5-y1)-2,4-pyrimidinediamine In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hyroxypheny1)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-isopropylpheny1)-pyrimidineamine and 2-methoxycarbony1-5-aminobenzofuran were reacted to give 5-fluoro-N4-(3-isopropylpheny1)-N2-(2-methoxycarbonylbenzofur-5-y1)-2,4-pyrimidinediamine.
LCMS: retn, time: 26.05 mm.; purity: 99 %; MS (m/e): 420 (M), 422 (MO; 111 NMR

(DMSO-d6): 5 10.00 (111, s), 9.95 (1H, s), 8.31 (111, d, J= 4.8 Hz), 8.11 (111, s), 7.74 (311, m), 7.35 (111, s), 7.35 (111, t, J= 7.2 Hz), 7.12 (1H, d, J= 7.2 Hz), 3.99 (311, s), 2.83 (1H, sept, J= 6.9 Hz), 1.20 (611, d, J= 6.9 Hz).

7.3.352 N2-(1,1-Dihydroisobenzofuran-1-one-6-y1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926786) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine with 6-amino-1,1-dihydroisobenzofuran-1-one gave N2-(1,1-dihydroisobenzofuran-1-one-6-y1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 6 10.20 (s, 1H), 9.85 (s, 1H), 8.22 (d, 1H, J= 4.8 Hz), 8.10 (d, 1H, J= 1.2 Hz), 7.86 (dd, 1H, J= 2.4 and 8.7 Hz), 7.54 (d, 1H, J=
8.4 Hz), 7.22 (d, 1H, J= 2.4 Hz), 7.13 (dd, 1H, J= 2.1 and 9 Hz), 6.81 (d, 1H, J= 8.7 Hz), 5.34 (s, 2H), 4.20 (s, 4H); LCMS: ret. time: 17.40 min.; purity: 83%; MS
(m/e): 395 (MO.
7.3.353 N213-(3-Acetamidophenoxy)propyll-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926787) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine with 3-N-acetamidophenoxy-3-propylamine gave N243-(3-acetamidophenoxy)propy1]-N4-(3,4-ethylenedioxypheny1)-fluoro-2,4-pyrimidinediamine. 111 NMR (DMSO-d6): 8 10.45 (bs, 111), 10.07 (s, 1H), 8.42 (s, 111), 8.20 (s, 1H), 7.37 (d, 1H, J= 3 Hz), 7.31 (s, 1H), 7.20-7.05 (m, 3H), 6.83 (d, 1H, J=
9Hz), 6.53 (d, 1H, J= 6.6 Hz), 4.18 (s, 4H), 3.95 (t, 2H, J= 6 Hz), 2.48 (m, 2H), 2.07 (s, 3H), 1.96 (t, 3H, J= 7.8 Hz); LCMS: ret. time: 19.58 min.; purity: 99%; MS (m/e):
454 (MH+).
7.3.354 N244-(4,5-Dichloro-1H-imidazol-1-yl)phenyll-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (11926788) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine with 4,5-dichloro-1H-imidazoleamine gave N244-(4,5-dichloro-1H-imidazol-1-yl)phenyl]-N4-(3,4-ethylenedioxypheny1)-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): 8 10.10 (s, 1H), 9.85 (s, 111), 8.20 (d, 111, J= 4.2 Hz), 8.01 (s, 1H), 7.78 (d, 1H, J= 8.7 Hz), 7.36 (d, 1H, J= 9 Hz), 7.25 (d, 1H, J=
3 Hz), 7.14 (dd, 1H, J= 2.1 and 9 Hz), 6.85 (d, 1H, J= 8.7 Hz); LCMS: ret.
time: 23.59 min.;
purity: 95%; MS (m/e): 474 (MH+).

7.3.355 N2-(2,4-Dimethoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926789) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine with 2,4-dimethoxyaniline gave (2,4-dimethoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H
NMR (DMSO-d6): 5 10.35 (s, 1H), 8.14 (bd, 1H), 7.38 (d, 1H, J= 9 Hz), 7.23 (s, 1H), 7.09 (d, 1H, J.= 8.7 Hz), 6.79 (d, 1H, J= 8.7 Hz), 6.66 (d, 1H, J= 2.4 Hz), 6.49 (dd, 1H, J= 2.4 and 9 Hz), 4.22 (s, 4H), 3.77 (s, 6H); LCMS: ret. time: 20.93 min.; purity: 98%;
MS (rn/e): 399 (MO.
=
7.3.356 N4-(3,4-Ethylenedioxypheny1)-5-fluoro-N2-(4-isopropylpheny1)-2,4-pyrimidinediamine (R926790) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine with 4-isopropylaniline gave N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(4-isopropylpheny1)-2,4-pyiimidinediamine. 1H
NMR
(DMSO-d6): 5 10.30 (s, 111), 10.50 (s, 1H), 8.22 (d, 111, J= 5.4 Hz). 7.37 (d, 1H, J= 8.4 Hz), 7.26 (d, 1H, J= 3 Hz), 7.18 (s, 1H), 7.15 (s, 1H), 7.06 (dd, 1H, J= 3.3 and 8.7 Hz), 6.81 (d, 111, J= 8.7 Hz), 4.23 (s, 411), 2.85 (sept., 1H, J= 7.2 Hz), 1.17 (d, 611, J=
6.9 Hz); LCMS:
ret. time: 24.91 min.; purity: 95%; MS (rn/e): 381 (MH+).
7.3.357 N2-(3,5-Dimethoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926791) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidinearnine with 3,4-dimethoxyaniline gave N2-(3,5-dimethoxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H
NMR (DMSO-d6): 5 10.08 (s, 1H), 9.99 (s, 111), 8.19 (m, 1H), 7.21 (d, 1H, J=
2.4 Hz), 7.14 (dd, 1H, J= 2.1 and 8.7 Hz), 6.79 (d, 111, J= 9 Hz), 6.72 (s, 1H), 6.20 (d, 111, J= 1.8 Hz), 4.21 (s, 411); LCMS: ret. time: 21.19 min.; purity: 93%; MS (m/e): 399 (M}O.

7.3.358 N2-(2,5-Dimethy1-4-hydroxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926792) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine with 2,5-dimethy1-4-hydroxyaniline gave N2-(2,5-dimethy1-4-hydroxypheny1)-N4-(3,4-ethylenedioxypheny1)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD30D): 8 7.69 (d, 111, J-= 3.9 Hz), 7.16 (d, 111, J".= 2.4 Hz), 7.05 (d, 1H, J 2.4 Hz), 7.02 (d, 111, J-= 1.2 Hz), 6.66 (s, 1H), 6.63 (s, 1H), 6.62 (s, 1H), 4.19 (s, 411), 2.12 (s, 311), 2.10 (s, 311); LCMS: ret. time: 19.80 min.;
purity: 90%; MS
(m/e): 383 (MH+).
7.3.359 N4-(3,4-Ethylenedioxypheny0-5-fluoro-N2-(5-methyl-3-pheny1-4-oxazoly1)-2,4-pyrimidinediamine (R926793) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxypheny1)-5-fluoro-4-pyrimidineamine with 5-methy1-3-pheny1-4-oxazolylamine gave N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(5-methy1-3-phenyl-oxazoly1)-2,4-pyrirnidinediamine. 111NMR (CD30D): 8 7.80-7.65 (m, 2I1), 7.45 (bd, 111), 7.20 (m, 111), 7.00 (m, 111), 6.65 (bd, 111), 4.20 (s, 411), 2.35 (s, 311);
LCMS: ret. time:
20.61 min.; purity: 78%; MS (m/e): 420 (M11+).
7.3.360 N4-(3,5-Dimethoxypheny1)-N2-(3-ethoxycarbonylmethyleneoxypheny1)-5-fluoro-2,4-pyrimidinediamine (R926795) In like manner to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,5-dimethoxypheny1)-5-fluoro-4-pyrimidineamine with ethyl-3-aminophenoxyacetate gave N4-(3,5-dimethoxypheny1)-N2-(3-ethoxycarbonylmethyleneoxypheny1)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 21.02 min.; purity: 84%; MS (mile): 429 (M11+).
7.3.361 N4-(3,4-Ethylenedioxypheny1)-N2-(3-ethoxycarbonylmethyleneoxypheny1)-5-ethoxycarbony1-2,4-pyrimidinediamine (R926797) In like marmer to the preparation of N4-(3,4-ethylenedioxypheny1)-5-fluoro-N2-(3-hydroxypheny1)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.

NOTE. Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.
JUMBO APPLICATIONS / PATENTS
THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.

NOTE For additional volumes please contact the Canadian Patent Office.

Claims (99)

What is claimed is:
1. A 2,4-pyrimidinediamine compound according to structural formula (I):
and salts, hydrates, solvates, and N-oxides thereof, wherein:
R2 is selected from the group consisting of phenyl mono substituted at the 3-or 5-position with an R8 group, phenyl di- or tfi-substituted with one or more of the same or different R8 groups, and optionally substituted heteroaryl as defined below;
R4 is selected from the group consisting of phenyl substituted with one or more of the same or different R8 groups and optionally substituted heteroaryl as defined below;
R5 is selected from the group consisting of -CN, -NC, fluoro, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, -C(0)Ra, -C(0)0Ra, -C(0)CF3 and -C(0)0CF3;
R8 is selected from the group consisting of Re, Rb, Re substituted with one or more of the same or different Ra or Rb, -0Ra substituted with one or more of the same or different Ra or Rb, -B(ORa)2, -B(Nle102, -(C1-12)m-R1), -(CHRa)m-Rb, -0-(C112),,õ-Rb, -S-(CH2),õ-Rb, -0-CHRaRb, -0-CRa(Rb)2, -0- (CHRa)ni-Rb,-0-(CH2),,-CHRCH2),,Rb]Rb, -S-(CHRa),,-Rb, -C(0)NH-(CH2),n-Rb, -C(0)NH-(CHR1)õ,-Rb, -0-(CH2)õ,-C(0)NH-(CH2),õ-Rb, -S-(CH2),n-C(0)NH-(CH2)õ,-Rb, -0-(CHRa)m-C(0)NH-(CHRa),,-Rb, -NH-(CH2)õ,-Rb, -NH-(CHRa)m-Rb,-NRCH2),R12, -NH-C(0)-NH-(CH2)õ,-Rb, -NH-C(0)-(CH2)õ,-CHR1)Rb and -NH-(CH2),n-C(0)-NH
-(CH2),,-Rb;
each Ra is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each Rb is a suitable group independently selected from the group consisting of =0, -ORd, (C1-C3) haloalkyloxy, -0CF3, =S, -SRd, =NRd, =NORd, -NRaRc, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(0)Rd, -S(0)2Rd, -S(0)20Rd, -S(0)NleRc, -S(0)2NRcRc, -0S(0)Rd, -0S(0)2Rd, -0S(0)20Rd, -0S(0)2NfeRc, -C(0)Rd, -C(0)0Rd, -C(0)NRcRc, -C(NH)NRcRc, -C(NRa)NRcRc, -C(NOH)Ra, -C(NOH)NRcRc, -OC(O)R d - C(O)OR d, - C(O)NR c R c, -OC(NH)NR c R c, - OC(NR a)NR c R c, -[NHC(O)]R d, -[NR a C(O)]n R d, - [NHC(O)]n OR d, [NR a C(O)n OR d, - [NHC
(O)] n NR c R c, - [NR a C (O)] n NR c R c, - [NHC (NH)] n NR c R c and -[NR a C(NR a)]n NR c R
c ;
each R e is independently a protecting group or R a, or, alternatively, two R
c are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or. . different R a groups;
each R d is independently a protecting group or R a;
each R e is independently selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4- 11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each m is independently an integer from 1 to 3; and each n is independently an integer from 0 to 3;
wherein a protecting group for an amino group is selected from the group consisting of formyl, acetyl, trifluoroacetyl, benzyl, benzylcarbonyl, tert-butoxycarbonyl, trimethylsilyl, 2-trimethylsilyl-ethanesulfonyl, trityl, substituted trityl, allyloxycarbonyl, 9- fluorenylmethyloxycarbonyl and nitro-veratryloxycarbonyl;
or a protecting group for a hydroxyl group in which the hydroxyl group is acylated or alkylated to form a benzyl ether, trityl ether, alkyl ether, tetrahydro pyranylether, trialkylsilyl ether or allyl ether;
wherein for R2 and R4 each of said optionally substituted heteroaryl, independent of one another, is selected from the group consisting of:

wherein:
p is an integer from one to three;
each - - - independently represents a single bond or a double bond;
R35 is hydrogen or R8;
X is selected from the group consisting of CH, N and N-O;

each Y is independently selected from the group consisting of O, S and NH;
each Y1 is independently selected from the group consisting of O, S, SO, SO2, SONR36, NH and NR37;
each Y2 is independently selected from the group consisting of CH, CH2, O, S, N, NH and NR37;
R36 is hydrogen or alkyl;
R37 is selected from the group consisting of hydrogen and a progroup selected from the group consisting of aryl, arylalkyl, heteroaryl, R a, R b-CR a R b-O-C(O)R8, -CR a R b-O-PO(OR8)2, -CH2-O-PO(OR8)2, -CH2-PO(OR8)2, -C(O)-CR a R b-N(CH3)2, -CR a R b-O-C(O)-CR a R b-N(CH3)2, -C(O)R8, -C(O)CF3 and -C(O)-NR8-C(O)R8;
A is selected from the group consisting of O, NH and NR38;
R38 is selected from the group consisting of alkyl and aryl;
R9, R10, R11 and R12 are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R9 and R10 or R11 and R12, or R9 and R10 and R11 and R12 are taken together to form an oxo group;
each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester and carbamate;
Q is selected from the group consisting of -OH, -OR a, -NR c R c, -NR39-CHR40-R b, -NR39-(CH2)m-R b and -NR39-C(O)-CHR40-NR c R c;
R39 and R40 are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl and NHR8;
with the provisos that:
(1) when R2 is a substituted phenyl, then R5 is other than cyano;
(2) when R2 and R4 are each independently a substituted or unsubstituted indole, then the R2 and R4 are attached to the remainder of the molecule via a ring carbon atom; and (3) the compound is not N2,N4-bis(3-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (R092788);
N2,N4-bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R067962);

N2,N4-bis(2,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R067963);
N2,N4-bis(3,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R067964);
N2,N4-bis(2,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (R070791);
N2,N4-bis(3-bromophenyl)-5-fluoro-2,4-pyrimidinediamine (R008958); or N2 ,N4-bi s [(3 -chloro-4-methoxyphenyl)] -5 -fluoro-2,4-pyrimidinediamine.
2. The compound of claim 1 in which R2 is selected from the group consisting of benzodioxanyl, benzodioxolyl, benzoxazinyl, benzoxazolyl, benzopyranyl, 1,4-benzoxazinyl-2-one, 2H-1,4-benzoxazinyl-3(4H)-one, 2H-1,3-benzoxazinyl-2,4(3H)-dione, dihydrocoumarinyl, 1,2-benzopyronyl, benzofuranyl, benzo[b]furanyl, and indolyl, where R8 is as defined in claim 1.
3. The compound of claim 1 in which R2 and R4 are the same.
4. The compound of claim 1 in which each R35 is independently selected from the group consisting of hydrogen, -NR c R c, -(CH2)m-NR c R c, -C(O)NR c R c, -(CH2)m,-C(O)NR c R c, -C(O)OR d, -(CH2)-C(O)OR d and -(CH2)m-OR d, where m, R c and R d are as defined in claim 1.
5. The compound of claim 4 in which each m is one.
6. The compound of claim 1 in which R2 is the optionally substituted heteroaryl which is attached to the remainder of the molecule via a ring carbon atom.
7. The compound of claim 1 in which R4 is the optionally substituted heteroaryl which is attached to the remainder of the molecule via a ring carbon atom.
8. The compound of claim 1 in which one or both of R2 and R4 are, independently of one another, a phenyl substituted with one, two or three R8 groups, where R8 is as defined in claim 1.
9. The compound of claim 8 in which R2 and R4 are each the same or different substituted phenyl.
10. The compound of claim 8 in which the phenyl is mono substituted.
11. The compound of claim 10 in which the R4 phenyl is substituted at the ortho, meta or para position.
12. The compound of claim 11 in which R8 is selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, -OR d, -O-(CH2)m-NR c R c, -O-C(O)NR
c R c, -O-(CH2)m-C(O)NR c R c, -O-C(O)OR a, -O-(CH2)m-C(O)OR a, -O-C(NH)NR c R c, -O-(CH2)m-C(NH)NR c R c, -NH-(CH2)m-NR c R c, -NH-C(O)NR c R c and -NH-(CH2)m-C(O)NR c R
c, where m, R a, R c and R d are as defined in claim 1.
13. The compound of claim 8 in which the phenyl is disubstituted.
14. The compound of claim 13 in which the R8 substituents are positioned 2,3-; 2,4-;
2,5-; 2,6-; 3,4-; or 3,5-.
15. The compound of claim 13 in which each R8 is independently selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, -OR a optionally substituted with one or more of the same or different R a or R b groups, -O-(CH2)m-NR c R
c, -O-C(O)NR c R c, -O-(CH2)m-C(O)NR c R c, -O-C(O)OR a, -O-(CH2)m-C(O)OR a, -O-C(NH)NR c R c, -O-(CH2)m-C(NH)NR c R c, -NH-(CH2)m-NR c R c, -NH-C(O)NR c R c and -NH-(CH2)m-C(O)NR c R c, where m, R a, R b and R c are as defined in claim 1.
16. The compound of claim 8 in which the phenyl is trisubstituted.
17. The compound of claim 16 in which the R8 substituents are positioned 2,3,4-;
2,3,5-; 2,3,6-; 2,4,5-; 2,4,6-; 2,5,6-; or 3,4,5-.
18. The compound of claim 17 which each R8 is independently selected from the group consisting of (C1-C10) alkyl, (C1 -C10) branched alkyl, -OR a optionally substituted with one or more of the same or different R a or R b groups, -O-(CH2)m-NR c R
c, -O-C(O)NR c R c, -O-(CH2)m-C(O)NR c R c, -O-C(O)OR a, -O-C(NH)NR c R c, -O-(CH2)m-C(O)OR a, -O-(C112)m-C(NH)NR c R c, -NH-(CH2),-NR c R c, -NH-C(O)NR c R c and -NH-(CH2)m-C(O)NR c R c, where m, R a, R b and R c are as defined in claim 1.
19. The compound of claim 16 in which the phenyl has the formula:
wherein: R31 is (C1-C6) alkyl; R32 is hydrogen, or (C1-C6) alkyl; and R33 is a halo group.
20. The compound of claim 9 in which R2 and R4 are the same.
21. The compound of claim 1 which has a structure according to formula (Ib):
and salts, hydrates, solvates, and N-oxides thereof, wherein R11 and R14 are each, independently of one another, selected from the group consisting of hydroxy, (C1-C6) alkoxy and -NR c R c; and R5 and R c are as defined in claim 1.
22. The compound of claim 1 which has a structure according to formula (Ic):
and salts, hydrates, solvates, and N-oxides thereof, wherein:

R14 is phenyl substituted with from 1 to 3 of the same or different R8 groups, where R8 is defined in claim 1;
R5 is as defined in claim 1; and R18 is -O(CH2)m-R b, where m and R b are as defined in claim 1.
23. The compound of claim 22 in which R18 is -O-CH2-C(O)-NHCH3.
24. The compound of any one of claims 1 to 23 in which R5 is selected from the group consisting of fluoro, -CF3 and -OCF3.
25. The compound of claim 24 in which R5 is fluoro.
26. The compound of any one of claims 1 to 25 which inhibits mast or basophil cell degranulation with an IC50 of about 20µM or less as measured in an in vitro assay.
27. N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine and salts, hydrates, solvates, and/or N-oxides thereof.
28. N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine and salts, hydrates, solvates, and/or N-oxides thereof.
29. N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine and salts, hydrates, solvates, and/or N-oxides thereof.
30. N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine and salts, hydrates, solvates, and/or N-oxides thereof.
31. N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)- 2,4-pyrimidinediamine and salts, hydrates, solvates, and/or N-oxides thereof.
32. N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-yl]-5-fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and salts, hydrates, solvates, and/or N-oxides thereof.
33. A pharmaceutical composition comprising the compound as defined in any one of claims 1 to 32 and/or a salt, hydrate, solvate, or N-oxide thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient.
34. The composition of claim 33 in which the compound is in the form of a pharmaceutically acceptable salt.
35. The composition of claim 34 in which the salt is a hydrochloride salt, a hydrogen sulfate salt, a sulfate salt, a phosphate salt, an alkane sulfonate salt, a methane sulfonate salt, an ethane sulfonate salt or a p-toluene sulfonate salt.
36. A method of inhibiting degranulation of a cell in vitro, comprising contacting a cell capable of undergoing degranulation with an amount of the compound as defined in any one of claims 1 to 32 and/or a salt, hydrate, solvate, and/or N-oxide thereof, effective to inhibit degranulation of the cell.
37. The compound of any one of claims 1 to 32 and/or a salt, hydrate, solvate, and/or N-oxide thereof, for inhibiting degranulation of a cell in an animal capable of undergoing degranulation.
38. The method of claim 36 in which the cell is a human mast, basophil, neutrophil or eosinophil cell.
39. The compound of claim 37 in which the cell is a human mast, basophil, neutrophil or eosinophil cell.
40. A method of inhibiting a Syk kinase in vitro, comprising the step of contacting a Syk kinase or an active fragment thereof with an effective amount of the compound as defined in any one of claims 1 to 32 and/or a salt, hydrate, solvate, and/or N-oxide thereof.
41. The method of claim 40 which is practiced with an isolated or recombinant Syk kinase or a cell or cell population that expresses an endogenous or recombinant Syk kinase.
42. The compound as defined in any one of claims 1 to 32 and/or a salt, hydrate, solvate, and/or N-oxide thereof, for inhibiting a Syk kinase.
43. A method of inhibiting an Fc receptor signal transduction cascade in vitro, comprising the step of contacting a cell comprising an Fc receptor having a gamma homodimer with an amount of the compound as defined in any one of claims 1 to and/or a salt, hydrate, solvate, and/or N-oxide thereof, effective to inhibit its signal transduction cascade.
44. The compound of any one of claims 1 to 32 and/or a salt, hydrate, solvate, and/or N-oxide thereof, for inhibiting an Fc receptor signal transduction cascade.
45. The method of claim 43 in which the Fc receptor is selected from the group consisting of Fc.alpha.Rl, Fc.gamma.RI, Fc.gamma.RIII and Fc.epsilon.RI.
46. The compound of claim 44 in which the Fc receptor is selected from the group consisting of Fc.alpha.RI, Fc.gamma.RI, Fc.gamma.RIII and Fc.epsilon.RI.
47. The compound of any one of claims 1 to 32 and/or a salt, hydrate, solvate, and/or N-oxide thereof for the treatment of a disease characterized by, caused by or associated with mast or basophil cell degranulation, in an animal.
48. The compound of claim 47 in which the animal is a human.
49. The compound of claim 48 in which the disease is selected from the group consisting of allergic diseases, low grade scarring, diseases associated with tissue destruction, diseases associated with tissue inflammation, inflammation, and scarring.
50. The compound of claim 49 in which the allergic disease is selected from the group consisting of conjunctivitis, rhinitis, asthma, atopic dermatitis and food allergies.
51. The compound of claim 49 in which the low grade scarring is selected from the group consisting of scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury and post myocardial infarction.
52. The compound of claim 49 in which the disease associated with tissue destruction is selected from the group consisting of chronic obstructive pulmonary disease, cardiobronchitis and post myocardial infarction.
53. The compound of claim 49 in which the disease associated with tissue inflammation is selected from the group consisting of chronic obstructive pulmonary disease, irritable bowel, spastic colon and inflammatory colon disease.
54. The compound of claim 1 in which the compound is N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine and/or a salt, hydrate, solvate and/or N-oxide thereof
55. The compound of claim 1 in which the compound is N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyd- 2,4-pyrimidinediamine and/or a salt, hydrate, solvate and/or N-oxide thereof.
56. The compound of claim 47 in which the disease is an anaphylactic or hypersensitivity reaction.
57. The compound of claim 47 in which the disease is asthma.
58. The compound of claim 1 in which the compound is N4-[(2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine and/or a salt, hydrate, solvate and/or N-oxide thereof.
59. A 4-pyrimidinediamine compound according to structural formula (IV):
and salts, hydrates, solvates, and N-oxides thereof wherein:
R4 is selected from the group consisting of phenyl mono-substituted at the 3-position with an R8 group, phenyl di-substituted at the 3,4- or 3,5-positions with the same or different R8 groups, phenyl trisubstititued at the 2,3,4-, 2,3,5- or 3,4,5-positions with the same or different R8 groups, and optionally substituted heteroaryl as defined below;
R8 is defined in claim 1; and LG is a leaving group, in which LG is halo, methanesulfonyloxy, trifluoromethane-sulfonyloxy, p-toluenesulfonyloxy, benzene sulfonyloxy or metanitro benzene sulfonyloxy, wherein for R4, the optionally substituted heteroaryl is selected from the group consisting of:

wherein:
p is an integer from one to three;
each ~ independently represents a single bond or a double bond;
R35 is hydrogen or R8, where R8 is as defined in Claim 1;
X is selected from the group consisting of CH, N and N-O;
each Y is independently selected from the group consisting of O, S and NH;

each Y1 is independently selected from the group consisting of O, S, SO, SO2, SONR36, NH and NR37;
each Y2 is independently selected from the group consisting of CH, CH2, O, S, N, NH and NR37;
R36 is hydrogen or alkyl;
R37 is selected from the group consisting of hydrogen and a progroup selected from the group consisting of aryl, arylalkyl, heteroaryl, R a, Rb-CR a R b-O-C(O)R8, -CR a R b-O-PO(OR8)2, -CH2-O-PO(OR8)2, -CH2-PO(OR8)2, -C(O)-CR a R b-N(CH3)2, -CR a R b-O-C(O)-CR a R b-NCH3)2) -C(O)R8, -C(O)CF3 and -C(O)-NR8-C(O)R8;
A is selected from the group consisting of O, NH and NR38;
R38 is selected from the group consisting of alkyl and aryl;
R9, R10, R11 and R12 are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R9 and R10 or R11 and R12, or R9 and R10 and R11 and R12 are taken together form an oxo group;
each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester and carbamate;
Q is selected from the group consisting of -OH, -OR a, -NR c R c, -NR39-C(O)R
a, -NR39-C(O)OR a, -NR39-CHR40-R b, -NR39-(CH2)m-R b and -NR39-C(O)-CHR40-NR c R
c;
R39 and R40 are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl, arylalkyl and NHR8; and R a, R b and R c are as defined in claim 1.
60. The compound of claim 59 in which LG is chloro.
61. The compound of claim 59 in which LG is chloro and R4 is phenyl monosubstituted at the 3-position with -OR d, where R d is as defined in claim 1.
62. The compound of claim 61 in which R d is hydrogen, acetyl, ethyl, butyl, hexyl, trifluoromethyl or benzyl.
63. The compound of claim 62 which is selected from the group consisting of chloro-N4-(3 -hydroxyphenyl)-5-fluoro-4-pyrimidineamine, 2-Chloro-5-fluoro-N4-(3-trifluoromethoxyphenyl)-4-pyrimidineamine, and 2-chloro-N4-(3-benzyloxyphenyl)-fluoro-4-pyrimidineamine.
64. The compound of claim 59 which is 2-chloro-N4-(3-hydroxyphenyl)-5-fluoro-4-pyrimidineamine.
65. The compound of claim 59 in which LG is chloro and R4 is phenyl disubstituted at the 3,4- or 3,5-positions with the same or different R8 groups.
66. The compound of claim 65 which is selected from the group consisting of chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine, 2-chloro-N4-(4-chloro-3- methoxyphenyl)-5-fluoro-4-pyrimidineamine, N4-(3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-2-chloro-5-fluoro-pyrimidineamine, 2-chloro-5- fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine, 2-chloro-5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-pyrimidineamine, 2-chloro-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-4-pyrimidineamine, N4-(3-(N-tert-butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)- 2-chloro-5-fluoro-4-pyrimidineamine, 2-chloro-N4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine, 2-chloro-N4-(3- hydroxymethylen-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine, 2-chloro-5-fluoro-N4-(3-hydroxy-4-methoxycarbonylmethyleneoxyphenyl)-4-pyrimidineamine, and 2-chloro-N4-(3-amino-4-ethoxyphenyl)-5-fluoro-4-pyrimidineamine.
67. The compound of claim 59 in which LG is chloro and R4 is phenyl trisubstituted at the 2,3,4-, 2,3,5- or 3,4,5-positions with the same or different R8 groups.
68. The compound of claim 67 which is 2-chloro-N4-(2,3-dimethyl-4-hydroxyphenyl)-5- fluoro-4-pyrimidineamine.
69. A method of making a 2,4-pyrimidinediamine compound, comprising contacting the 4-pyrimidineamine compound as defined in any one of claims 59 to 68 with an amine of the formula H2N-R2, where R2 is as defined as claim 1 and is optionally protected, under conditions in which the amine and 4-pyrimidineamine compound react to yield a 2,4- pyrimidinediamine compound.
70. A method of making the 2,4-pyrimidinediamine compound according to claim 1, comprising contacting a 4-pyrimidineamine compound according to structural formula (V):
and salts, hydrates, solvates, and N-oxides thereof, wherein R4 and R5 are as defined in claim 1 and are optionally protected and LG is a leaving group, with an amine of the formula H2N-R2, where R2 is as defined in claim 1 and is optionally protected, under conditions in which the amine and the 4-pyrimidineamine react to yield the 2,4-pyrimidinediamine compound according to claim 1.
71. The compound of claim 1, wherein R5 is (C1-C3) perhaloalkyl.
72. The compound of claim 1, wherein R5 is (C1-C3) fluoroalkyl.
73. The compound of claim 1, wherein R5 is (C1-C3) perfluoroalkyl.
74. The compound of claim 1, wherein R5 is -CF3.
75. The compound of claim 1, wherein R5 is (C1-C3) perhaloalkoxy.
76. The compound of claim 1, wherein R5 is (C1-C3) fluoroalkoxy.
77. The compound of claim 1, wherein R5 is (C1-C3) perfluoroalkoxy.
78. The compound of claim 1, wherein R5 is -OCF3.
79. The compound of claim 1, wherein R a is cyclohexyl.
80. The compound of claim 1, wherein le is phenyl or benzyl.
81. The compound of claim 2, wherein the benzodioxanyl is 1,4-benzodioxan-(5 or 6)-yl.
82. The compound of claim 2, wherein the benzodioxolyl is 1,3-benzodioxol-(4 or 5)-yl.
83. The compound of claim 2, wherein the benzoxazinyl is 1,4-benzoxazin-(5,6,7 or 8)-yl.
84. The compound of claim 2, wherein the benzoxazolyl is 1,3-benzoxazol-(4,5,6 or 7)-yl.
85. The compound of claim 2, wherein the 1,4-benzoxazinyl-2-one is 1,4-benzoxazin-(5,6,7 or 8)-yl-2-one.
86. The compound of claim 2, wherein the 2H-1,4-benzoxazinyl-3(4H)-one is 211-1,4-benzoxazin-(5, 6, 7, or 8)-yl-3(4H)-one.
87. The compound of claim 2, wherein the 2H-1,3-benzoxazinyl-2,4(3H)-dione is 2H-1,3-benzoxazin-(5,6,7 or 8)-yl-2,4(3H)-dione.
88. The compound of claim 2, wherein the dihydrocoumarinyl is dihydrocoumarin-(5,6,7 or 8)-yl.
89. The compound of claim 2, wherein the 1,2-benzopyronyl is 1,2-benzopyron-(5,6,7 or 8)-yl.
90. The compound of claim 2, wherein the benzofuranyl is benzofuran-(4,5,6 or 7)-yl.
91. The compound of claim 2, wherein the benzo[b]furanyl is benzo[b]furan-(4,5,6 or 7)-yl.
92. The compound of claim 2, wherein the indolyl is indol-(4,5,6 or 7)-yl.
93. The compound of claim 19, wherein R31 is methyl.
94. The compound of claim 19, wherein R32 is methyl.
95. The compound of claim 1, wherein one of R a and R e is selected from the group consisting of morpholinyl, homopiperazinyl, piperidinyl and piperazinyl.
96. The compound of claim 1, wherein both R a and R e are selected from the group consisting of morpholinyl, homopiperazinyl, piperidinyl and piperazinyl.
97. The compound of claim 1, wherein R e is cyclohexyl.
98. The compound of claim 1 in which R2 is said optionally substituted heteroaryl.
99. The compound of claim 1, wherein R e is selected from the group consisting of phenyl and benzyl.
CA 2474277 2002-02-01 2003-01-31 2,4-pyrimidinediamine compounds and their uses Expired - Lifetime CA2474277C (en)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
US35326702P 2002-02-01 2002-02-01
US35333302P 2002-02-01 2002-02-01
US60/353,267 2002-02-01
US60/353,333 2002-02-01
US39967302P 2002-07-29 2002-07-29
US60/399,673 2002-07-29
US43427702P 2002-12-17 2002-12-17
US60/434,277 2002-12-17
PCT/US2003/003022 WO2003063794A2 (en) 2002-02-01 2003-01-31 2,4-pyrimidinediamine compounds and their uses

Publications (2)

Publication Number Publication Date
CA2474277A1 CA2474277A1 (en) 2003-08-07
CA2474277C true CA2474277C (en) 2013-09-24

Family

ID=32996332

Family Applications (1)

Application Number Title Priority Date Filing Date
CA 2474277 Expired - Lifetime CA2474277C (en) 2002-02-01 2003-01-31 2,4-pyrimidinediamine compounds and their uses

Country Status (25)

Country Link
US (41) US7557210B2 (en)
EP (2) EP2281563B1 (en)
JP (2) JP4658477B2 (en)
KR (1) KR101037856B1 (en)
CN (2) CN1625400B (en)
AT (1) ATE524184T1 (en)
AU (2) AU2003208931C1 (en)
BR (1) BRPI0307355C1 (en)
CA (1) CA2474277C (en)
CY (1) CY1112516T1 (en)
DK (2) DK1471915T3 (en)
ES (2) ES2373646T3 (en)
HK (2) HK1069538A1 (en)
HR (1) HRP20040684B1 (en)
IL (1) IL221381A (en)
MX (2) MXPA04007386A (en)
NO (1) NO328071B1 (en)
NZ (1) NZ534361A (en)
PL (1) PL214988B1 (en)
PT (2) PT2281563E (en)
RS (2) RS53367B (en)
SG (1) SG167664A1 (en)
SI (2) SI2281563T1 (en)
TW (1) TWI329105B (en)
WO (1) WO2003063794A2 (en)

Families Citing this family (353)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RS94703A (en) * 2001-05-29 2007-02-05 Schering Aktiengesellschaft, Cdk inhibiting pyrimidines, production thereof and their use as medicaments
CA2451128A1 (en) 2001-06-26 2003-01-09 Bristol-Myers Squibb Company N-heterocyclic inhibitors of tnf-alpha expression
US7638522B2 (en) * 2001-08-13 2009-12-29 Janssen Pharmaceutica N.V. Salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino] benzonitrile
US8101629B2 (en) * 2001-08-13 2012-01-24 Janssen Pharmaceutica N.V. Salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile
JO3429B1 (en) 2001-08-13 2019-10-20 Janssen Pharmaceutica Nv Hiv inhibiting pyrimidines derivatives
EP2090571B1 (en) * 2001-10-17 2012-05-16 Boehringer Ingelheim Pharma GmbH & Co. KG Pyrimidine derivates, medicaments comprising them, their use and process of their preparation
TWI329105B (en) 2002-02-01 2010-08-21 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds and their uses
AU2003209077A1 (en) * 2002-02-08 2003-09-02 Smithkline Beecham Corporation Pyrimidine compounds
GB0206215D0 (en) 2002-03-15 2002-05-01 Novartis Ag Organic compounds
CA2489648A1 (en) * 2002-06-17 2003-12-24 Smithkline Beecham Corporation Chemical process
EP2130541A3 (en) * 2002-07-29 2013-12-18 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
US7517886B2 (en) 2002-07-29 2009-04-14 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
CN101481356B (en) * 2002-08-09 2012-07-11 詹森药业有限公司 Processes for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile
EA200500721A1 (en) * 2002-11-28 2005-12-29 Шеринг Акциенгезельшафт Pyrimidines inhibiting CHK, PDK and ACT, THEIR RECEIVING AND USING AS MEDICINES
US7109337B2 (en) 2002-12-20 2006-09-19 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
WO2004056807A1 (en) 2002-12-20 2004-07-08 Pfizer Products Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
UA80767C2 (en) * 2002-12-20 2007-10-25 Pfizer Prod Inc Pyrimidine derivatives for the treatment of abnormal cell growth
CA2514612A1 (en) * 2003-01-30 2004-08-12 Boehringer Ingelheim Pharmaceuticals, Inc. 2,4-diaminopyrimidine derivatives useful as inhibitors of pkc-theta
CL2004000303A1 (en) * 2003-02-20 2005-04-08 Tibotec Pharm Ltd COMPOUNDS DERIVED FROM PYRIMIDINS AND TRIAZINES; PREPARATION PROCESS; PHARMACEUTICAL COMPOSITION; AND ITS USE TO INHIBIT HIV REPLICATION.
ES2325440T3 (en) 2003-02-20 2009-09-04 Smithkline Beecham Corporation PIRIMIDINE COMPOUNDS.
GB0305929D0 (en) * 2003-03-14 2003-04-23 Novartis Ag Organic compounds
US7504396B2 (en) 2003-06-24 2009-03-17 Amgen Inc. Substituted heterocyclic compounds and methods of use
DK1658302T3 (en) 2003-07-25 2010-11-22 Idenix Pharmaceuticals Inc Purine nucleoside analogues for the treatment of diseases caused by Flavirividae, including hepatitis C
AU2004261484A1 (en) * 2003-07-30 2005-02-10 Cyclacel Limited 2-aminophenyl-4-phenylpyrimidines as kinase inhibitors
CN102358738A (en) * 2003-07-30 2012-02-22 里格尔药品股份有限公司 2,4-pyrimidinediamine compounds and uses of treating or preventing autoimmune diseases thereof
PL1660458T3 (en) * 2003-08-15 2012-07-31 Novartis Ag 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders
GB0321710D0 (en) 2003-09-16 2003-10-15 Novartis Ag Organic compounds
KR20080042188A (en) 2003-11-05 2008-05-14 에프. 호프만-라 로슈 아게 Phenyl derivatives as ppar agonists
JP2007511641A (en) * 2003-11-14 2007-05-10 アシュランド・ライセンシング・アンド・インテレクチュアル・プロパティー・エルエルシー Binary curing reaction product of self-initiated polyfunctional acrylate and alicyclic epoxy compound
JPWO2005095382A1 (en) 2004-03-30 2007-08-16 協和醗酵工業株式会社 Antitumor agent
WO2005111016A1 (en) 2004-05-14 2005-11-24 Pfizer Products Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
BRPI0510980A (en) 2004-05-14 2007-11-27 Pfizer Prod Inc pyrimidine derivatives for the treatment of abnormal cell growth
BRPI0511132A (en) 2004-05-14 2007-11-27 Pfizer Prod Inc pyrimidine derivatives and pharmaceutical composition comprising the same
CA2566531A1 (en) 2004-05-18 2005-12-15 Rigel Pharmaceuticals, Inc. Cycloalkyl substituted pyrimidinediamine compounds and their uses
EP1598343A1 (en) * 2004-05-19 2005-11-23 Boehringer Ingelheim International GmbH 2-Arylaminopyrimidine derivatives as PLK inhibitors
WO2006004776A1 (en) * 2004-06-29 2006-01-12 Rigel Pharmaceuticals, Inc. 4-pyrimidineamine compounds and their uses as anti-proliferative agents
WO2006012502A2 (en) * 2004-07-23 2006-02-02 Rigel Pharmaceuticals, Inc. Formulation of insoluble small molecule therapeutics in lipid-based carriers
GB0419160D0 (en) * 2004-08-27 2004-09-29 Novartis Ag Organic compounds
CA2578349A1 (en) * 2004-09-01 2006-03-16 Rigel Pharmaceuticals, Inc. Synthesis of 2,4-pyrimidinediamine compounds
EP1796679A1 (en) * 2004-09-10 2007-06-20 Altana Pharma AG Ciclesonide and syk inhibitor combination and methods of use thereof
CA2579017A1 (en) * 2004-09-10 2006-03-16 Altana Pharma Ag Roflumilast and syk inhibitor combination and methods of use thereof
CA2579143A1 (en) 2004-09-13 2006-03-23 Amgen Inc. Vanilloid receptor ligands and their use in treatments
AU2005286593A1 (en) 2004-09-23 2006-03-30 Reddy Us Therapeutics, Inc. Novel pyridine compounds, process for their preparation and compositions containing them
AU2005289426A1 (en) * 2004-09-27 2006-04-06 Amgen Inc. Substituted heterocyclic compounds and methods of use
CN101027288B (en) 2004-09-30 2013-04-17 泰博特克药品有限公司 HIV inhibiting 5-substituted pyrimidines
TW200626574A (en) 2004-09-30 2006-08-01 Tibotec Pharm Ltd HIV inhibiting 5-heterocyclyl pyrimidines
EP1809290A2 (en) 2004-11-03 2007-07-25 Vertex Pharmaceuticals Incorporated Pyrimidine derivatives as ion channel modulators and methods of use
GB2420559B (en) * 2004-11-15 2008-08-06 Rigel Pharmaceuticals Inc Stereoisomerically enriched 3-aminocarbonyl bicycloheptene pyrimidinediamine compounds and their uses
CA2584295C (en) * 2004-11-24 2014-08-26 Rigel Pharmaceuticals, Inc. Spiro-2, 4-pyrimidinediamine compounds and their uses
MY169441A (en) * 2004-12-08 2019-04-11 Janssen Pharmaceutica Nv 2,4, (4,6) pyrimidine derivatives
US7555655B2 (en) * 2004-12-22 2009-06-30 5th Fleet, L.L.C. Apparatus, system, and method for generating and authenticating a computer password
DE602006010979D1 (en) 2005-01-19 2010-01-21 Rigel Pharmaceuticals Inc PRODRUGS FROM 2,4-PYRIMIDIN DIAMIN COMPOUNDS AND THEIR USES
CA2604551A1 (en) * 2005-05-03 2007-03-08 Rigel Pharmaceuticals, Inc. Jak kinase inhibitors and their uses
WO2006133426A2 (en) 2005-06-08 2006-12-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
US20070203161A1 (en) * 2006-02-24 2007-08-30 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
CA2607901C (en) * 2005-06-13 2016-08-16 Rigel Pharmaceuticals, Inc. Methods and compositions for treating degenerative bone disorders using a syk inhibitory 2,4-pyrimidinediamine
PT1734251E (en) * 2005-06-17 2007-03-30 Magneti Marelli Powertrain Spa Fuel injector
EP1746096A1 (en) * 2005-07-15 2007-01-24 4Sc Ag 2-Arylbenzothiazole analogues and uses thereof in the treatment of cancer
PE20070362A1 (en) * 2005-07-15 2007-04-23 Glaxo Group Ltd COMPOUNDS DERIVED FROM INDAZOLE-4-IL-2,4-PYRIMIDINDIAMINE AS INHIBITORS OF TYROSINE KINASE (KINASE Syk)
WO2007028445A1 (en) * 2005-07-15 2007-03-15 Glaxo Group Limited 6-indolyl-4-yl-amino-5-halogeno-2-pyrimidinyl-amino derivatives
CN101253159B (en) 2005-09-01 2011-12-07 弗·哈夫曼-拉罗切有限公司 Diaminopyrimidines as P2X3 and P2X2/3 modulators
WO2007042571A1 (en) 2005-10-14 2007-04-19 Neurosearch A/S Novel pyrimidine-2,4-diamine derivatives and their use as modulators of small-conductance calcium-activated potassium channels
US8604042B2 (en) * 2005-11-01 2013-12-10 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
US8133900B2 (en) * 2005-11-01 2012-03-13 Targegen, Inc. Use of bi-aryl meta-pyrimidine inhibitors of kinases
DK1951684T3 (en) * 2005-11-01 2016-10-24 Targegen Inc BIARYLMETAPYRIMIDIN kinase inhibitors
JP2009518443A (en) * 2005-12-06 2009-05-07 リゲル ファーマシューティカルズ インコーポレーティッド Formulation of an insoluble small molecule therapeutic agent enclosed in a carrier mainly composed of lipids
US7713987B2 (en) 2005-12-06 2010-05-11 Rigel Pharmaceuticals, Inc. Pyrimidine-2,4-diamines and their uses
ES2562428T3 (en) 2005-12-15 2016-03-04 Rigel Pharmaceuticals, Inc. Kinase inhibitors and their uses
JP2007186507A (en) * 2005-12-15 2007-07-26 Nippon Nohyaku Co Ltd Phthalamide derivative, agricultural and horticultural insecticide and method for using the same
AU2006327871A1 (en) * 2005-12-21 2007-06-28 Pfizer Products Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
WO2007085540A1 (en) * 2006-01-27 2007-08-02 Glaxo Group Limited 1h-indaz0l-4-yl-2 , 4-pyrimidinediamine derivatives
PT1984357E (en) * 2006-02-17 2013-12-23 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds for treating or preventing autoimmune diseases
CA2642229C (en) 2006-02-24 2015-05-12 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
EP2004632B1 (en) 2006-03-30 2014-03-12 Janssen R&D Ireland Hiv inhibiting 5-amido substituted pyrimidines
EP2046759A1 (en) * 2006-07-21 2009-04-15 Novartis AG 2, 4 -di (arylaminio) -pyrimidine-5-carboxamide compounds as jak kinases inhibitors
US8445437B2 (en) * 2006-07-27 2013-05-21 The Brigham And Women's Hospital, Inc. Treatment and prevention of cardiovascular disease using mast cell stabilizers
AR063946A1 (en) * 2006-09-11 2009-03-04 Cgi Pharmaceuticals Inc CERTAIN REPLACED PIRIMIDINS, THE USE OF THE SAME FOR THE TREATMENT OF DISEASES MEDIATED BY THE INHIBITION OF THE ACTIVITY OF BTK AND PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM.
WO2008049123A2 (en) 2006-10-19 2008-04-24 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine derivatives as inhibitors of jak kinases for the treatment of autoimmune diseases
TWI432427B (en) 2006-10-23 2014-04-01 Cephalon Inc Fused bicyclic derivatives of 2,4-diaminopyrimidine as alk and c-met inhibitors
EP2097378B1 (en) * 2006-11-03 2012-09-12 GlaxoSmithKline LLC Novel seh inhibitors and their use
EP2420505A1 (en) 2006-11-21 2012-02-22 Rigel Pharmaceuticals, Inc. Prodrug salts of 2, 4- pyrimidinediamine compounds and their uses
EP3012249A1 (en) 2006-12-08 2016-04-27 Novartis AG Compounds and composition as protein kinase inhibitors
EP2123654A4 (en) 2006-12-28 2011-05-11 Taisho Pharmaceutical Co Ltd Pyrazolopyrimidine compound
CA2674178C (en) 2006-12-29 2015-11-10 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 6-substituted pyrimidines
AU2007341228B2 (en) 2006-12-29 2013-04-18 Janssen Sciences Ireland Uc HIV inhibiting 5,6-substituted pyrimidines
US7947698B2 (en) 2007-03-23 2011-05-24 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
WO2008118823A2 (en) * 2007-03-26 2008-10-02 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
WO2008128231A1 (en) 2007-04-16 2008-10-23 Hutchison Medipharma Enterprises Limited Pyrimidine derivatives
MX2009011090A (en) 2007-04-18 2009-11-02 Pfizer Prod Inc Sulfonyl amide derivatives for the treatment of abnormal cell growth.
KR20100049068A (en) 2007-07-17 2010-05-11 리겔 파마슈티칼스, 인크. Cyclic amine substituted pyrimidinediamines as pkc inhibitors
CA2697495C (en) 2007-09-05 2013-02-05 Pfizer Limited Xinafoate salt of n4-[(2,2-difluoro-4h-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-n2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine
US8445435B2 (en) * 2007-09-28 2013-05-21 The Brigham And Women's Hospital, Inc. Mast cell stabilizers in the treatment of obesity
US20100210655A1 (en) * 2007-10-11 2010-08-19 Yun Ding NOVEL sEH INHIBITORS AND THEIR USE
JP5372943B2 (en) * 2007-10-11 2013-12-18 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー Novel sEH inhibitors and their use
JP5411867B2 (en) * 2007-10-11 2014-02-12 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー Novel sEH inhibitors and their use
AU2008323938B2 (en) * 2007-11-07 2014-04-10 Rigel Pharmaceuticals, Inc. Wet granulation using a water sequestering agent
WO2009071535A1 (en) * 2007-12-03 2009-06-11 Boehringer Ingelheim International Gmbh Diaminopyridines for the treatment of diseases which are characterised by excessive or anomal cell proliferation
EP2224928A4 (en) * 2007-12-06 2012-02-15 Glaxosmithkline Llc Novel seh inhibitors and their use
US20100311776A1 (en) * 2008-01-30 2010-12-09 Smithkline Beecham Corporation Novel sEH Inhibitors and their Use
US20100324076A1 (en) * 2008-01-30 2010-12-23 Joseph Paul Marino Novel sEH Inhibitors and their Use
NZ587589A (en) * 2008-02-15 2012-10-26 Rigel Pharmaceuticals Inc Pyrimidine-2-amine compounds and their use as inhibitors of jak kinases
US8138339B2 (en) 2008-04-16 2012-03-20 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
NZ589315A (en) 2008-04-16 2012-11-30 Portola Pharm Inc 2,6-diamino-pyrimidin-5-yl-carboxamides as Spleen tryosine kinase (syk) or Janus kinase (JAK) inhibitors
KR20170051521A (en) 2008-04-16 2017-05-11 포톨라 파마슈티컬스, 인코포레이티드 2,6-diamino-pyrimidin-5-yl-carboxamides as syk or jak kinases inhibitors
WO2009145856A1 (en) * 2008-04-16 2009-12-03 Portola Pharmaceuticals, Inc. 2, 6-diamino-pyrimidin- 5-yl-carboxamides as syk or jak kinases inhibitors
EP2271631B1 (en) * 2008-04-22 2018-07-04 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
US7829574B2 (en) 2008-05-09 2010-11-09 Hutchison Medipharma Enterprises Limited Substituted quinazoline compounds and their use in treating angiogenesis-related diseases
CN102066325A (en) 2008-06-16 2011-05-18 弗·哈夫曼-拉罗切有限公司 Heteroaromatic monoamides as orexinin receptor antagonists
BRPI0914682B8 (en) 2008-06-27 2021-05-25 Avila Therapeutics Inc heteroaryl compounds and compositions comprising said compounds
US8338439B2 (en) 2008-06-27 2012-12-25 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidines useful as kinase inhibitors
US11351168B1 (en) 2008-06-27 2022-06-07 Celgene Car Llc 2,4-disubstituted pyrimidines useful as kinase inhibitors
AU2013202496B2 (en) * 2008-06-27 2016-08-04 Celgene Car Llc Heteroaryl compounds and uses thereof
US8426430B2 (en) 2008-06-30 2013-04-23 Hutchison Medipharma Enterprises Limited Quinazoline derivatives
TW201008933A (en) 2008-08-29 2010-03-01 Hutchison Medipharma Entpr Ltd Pyrimidine compounds
EP2344476B1 (en) 2008-09-23 2015-04-29 Rigel Pharmaceuticals, Inc. Tricyclic carbamate jak inhibitors
TW201016676A (en) * 2008-10-03 2010-05-01 Astrazeneca Ab Heterocyclic derivatives and methods of use thereof
CA2746810C (en) 2008-12-30 2017-03-14 Rigel Pharmaceuticals, Inc. Pyrimidinediamine kinase inhibitors
WO2010083207A2 (en) * 2009-01-15 2010-07-22 Rigel Pharmaceuticals, Inc. Protein kinase c inhibitors and uses thereof
US8377924B2 (en) 2009-01-21 2013-02-19 Rigel Pharmaceuticals Inc. Protein kinase C inhibitors and uses thereof
JP5802136B2 (en) 2009-01-23 2015-10-28 ライジェル ファーマシューティカルズ， インコーポレイテッド Compositions and methods for inhibition of the JAK pathway
WO2010093808A1 (en) * 2009-02-11 2010-08-19 Reaction Biology Corp. Selective kinase inhibitors
CN102482277B (en) 2009-05-05 2017-09-19 达纳-法伯癌症研究所有限公司 Epidermal growth factor receptor inhibitor and the method for treating obstacle
US8367689B2 (en) 2009-05-06 2013-02-05 Portola Pharmaceuticals, Inc. Inhibitors of JAK
EP2440541A1 (en) 2009-06-09 2012-04-18 Takeda Pharmaceutical Company Limited Novel fused cyclic compound and use thereof
UA108077C2 (en) 2009-07-02 2015-03-25 SYNTHESIS OF DINODIUM SALT N4- (2,2-DIMETHYL-4 - $ (DYHYDROPHOPHONOXY) METHYL] -3-OXO-5-PYRIDO $ 1,4] OXAZIN-6-YL) -2-FLUORINE 5-TRIMETHOXYPHENYL) -2,4-PYRIMIDINDIAMINE
WO2011009075A2 (en) 2009-07-17 2011-01-20 Rigel Pharmaceuticals, Inc. Deuterated 2, 4-pyrimidinediamine compounds and prodrugs thereof and their uses
BR112012002001A2 (en) * 2009-07-28 2016-05-10 Rigel Pharmaceuticals Inc method for treating an eye disease and / or disorder, pharmaceutical formulation, and kit
WO2011050159A1 (en) * 2009-10-23 2011-04-28 Glaxo Wellcome Manufacturing Pte Ltd Compositions and processes
EP2501705B1 (en) * 2009-11-20 2014-08-27 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and prodrugs thereof and their uses
US20110130415A1 (en) * 2009-12-01 2011-06-02 Rajinder Singh Protein kinase c inhibitors and uses thereof
EP2512246B1 (en) 2009-12-17 2015-09-30 Merck Sharp & Dohme Corp. Aminopyrimidines as syk inhibitors
MA33926B1 (en) 2009-12-17 2013-01-02 Merck Sharp & Dohme AMINOPYRIMIDINES AS INHIBITORS OF SYK
ME02186B (en) 2009-12-23 2016-02-20 Takeda Pharmaceuticals Co Fused heteroaromatic pyrrolidinones as syk inhibitors
AT509266B1 (en) * 2009-12-28 2014-07-15 Tech Universität Wien SUBSTITUTED PYRIDINES AND PYRIMIDINES
US8367315B2 (en) 2010-03-05 2013-02-05 Adan Rios Inactivation of reverse transcriptases by azido-diarylpyrimidines
JP6196551B2 (en) 2010-04-12 2017-09-13 スパーナス ファーマシューティカルズ インコーポレイテッド Process for producing viloxazine salts and novel polymorphs thereof
CA2792278C (en) 2010-04-13 2019-05-14 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds and prodrugs thereof and their uses
AU2011254550B2 (en) 2010-05-21 2013-11-07 Noviga Research Ab Novel pyrimidine derivatives
EP2395001A1 (en) 2010-05-21 2011-12-14 Chemilia AB Novel pyrimidine derivatives
CA2797947C (en) 2010-06-04 2019-07-09 Charles Baker-Glenn Aminopyrimidine derivatives as lrrk2 modulators
US8710223B2 (en) 2010-07-21 2014-04-29 Rigel Pharmaceuticals, Inc. Protein kinase C inhibitors and uses thereof
AU2011282742B2 (en) 2010-07-28 2015-08-27 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
KR20130099040A (en) 2010-08-10 2013-09-05 셀진 아빌로믹스 리서치, 인코포레이티드 Besylate salt of a btk inhibitor
US8846928B2 (en) 2010-11-01 2014-09-30 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as Syk modulators
EP2635557A2 (en) 2010-11-01 2013-09-11 Portola Pharmaceuticals, Inc. Nicotinamides as jak kinase modulators
JP5956999B2 (en) 2010-11-01 2016-07-27 セルジーン アヴィロミクス リサーチ， インコーポレイテッド Heteroaryl compounds and uses thereof
US20130317029A1 (en) 2010-11-01 2013-11-28 Portola Pharmaceuticals, Inc. Oxypyrimidines as syk modulators
BR112013010564B1 (en) 2010-11-01 2021-09-21 Celgene Car Llc HETEROCYCLIC COMPOUNDS AND COMPOSITIONS COMPRISING THE SAME
WO2012060847A1 (en) 2010-11-07 2012-05-10 Targegen, Inc. Compositions and methods for treating myelofibrosis
ES2665013T3 (en) 2010-11-10 2018-04-24 Celgene Car Llc EGFR selective mutant inhibitors and uses thereof
HUE046617T2 (en) 2010-11-10 2020-03-30 Genentech Inc Pyrazole aminopyrimidine derivatives as lrrk2 modulators
US20140128276A1 (en) * 2011-01-13 2014-05-08 Oklahoma Medical Research Foundation Cytokine profiles as methods for diagnosis and prognosis of irritable bowel syndrome
EP2489663A1 (en) 2011-02-16 2012-08-22 Almirall, S.A. Compounds as syk kinase inhibitors
EP2502924A1 (en) 2011-03-24 2012-09-26 Chemilia AB Novel pyrimidine derivatives
CA2830129C (en) 2011-03-24 2016-07-19 Chemilia Ab Novel pyrimidine derivatives
US9249124B2 (en) 2011-03-30 2016-02-02 H. Lee Moffitt Cancer Center And Research Institute, Inc. Aurora kinase inhibitors and methods of making and using thereof
TWI681952B (en) 2011-04-22 2020-01-11 美商標誌製藥公司 Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
AU2016244228B2 (en) * 2011-04-22 2019-02-21 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
WO2012154518A1 (en) 2011-05-10 2012-11-15 Merck Sharp & Dohme Corp. Bipyridylaminopyridines as syk inhibitors
US9120785B2 (en) 2011-05-10 2015-09-01 Merck Sharp & Dohme Corp. Pyridyl aminopyridines as Syk inhibitors
CA2834604A1 (en) 2011-05-10 2012-11-15 Merck Sharp & Dohme Corp. Aminopyrimidines as syk inhibitors
WO2012167423A1 (en) 2011-06-08 2012-12-13 Hutchison Medipharma Limited Substituted pyridopyrazines as novel syk inhibitors
EP2723739B1 (en) 2011-06-22 2016-08-24 Takeda Pharmaceutical Company Limited Substituted 6-aza-isoindolin-1-one derivatives
UY34223A (en) 2011-07-28 2013-02-28 Astrazeneca Ab FORMULATIONS OF (NEW TRIMETOXIFENILAMINO) PYRIMIDINYL
CA2846463C (en) 2011-09-02 2017-10-24 Purdue Pharma L.P. Pyrimidines as sodium channel blockers
PE20142083A1 (en) * 2011-09-16 2014-12-30 Fovea Pharmaceuticals DERIVATIVES OF ANILINE, ITS PREPARATION AND ITS THERAPEUTIC APPLICATION
EP2763975B1 (en) 2011-10-05 2016-04-06 Merck Sharp & Dohme Corp. 3-pyridyl carboxamide-containing spleen tyrosine kinase (syk) inhibitors
WO2013052394A1 (en) 2011-10-05 2013-04-11 Merck Sharp & Dohme Corp. 2-pyridyl carboxamide-containing spleen tyrosine kinase (syk) inhibitors
WO2013052391A1 (en) 2011-10-05 2013-04-11 Merck Sharp & Dohme Corp. PHENYL CARBOXAMIDE-CONTAINING SPLEEN TYROSINE KINASE (Syk) INHIBITORS
WO2013059631A1 (en) 2011-10-21 2013-04-25 Rigel Pharmaceuticals, Inc. Method and device for administering xinafoate salt of n4-(2,2-difluoro-4h-benzo [1,4] oxazin-3-one) -6-yl] -5-fluoro-n2- [3- (methylaminocarbonylmethyleneoxy) phenyl] 2,4-pyrimidinediamine
US9364476B2 (en) 2011-10-28 2016-06-14 Celgene Avilomics Research, Inc. Methods of treating a Bruton's Tyrosine Kinase disease or disorder
IN2014CN04065A (en) 2011-11-23 2015-09-04 Portola Pharm Inc
JP6096807B2 (en) * 2012-01-13 2017-03-15 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Triazolyl-substituted pyridyl compounds useful as kinase inhibitors
EP2825042B1 (en) 2012-03-15 2018-08-01 Celgene CAR LLC Salts of an epidermal growth factor receptor kinase inhibitor
BR112014022789B1 (en) 2012-03-15 2022-04-19 Celgene Car Llc Solid forms of an epidermal growth factor receptor kinase inhibitor, pharmaceutical composition and uses thereof
CN104519907A (en) 2012-03-23 2015-04-15 昆士兰大学 Immunomodulatory agent and uses therefor
US9321763B2 (en) * 2012-04-04 2016-04-26 Rigel Pharmaceuticals, Inc. Protein kinase C inhibitors and uses thereof
CA2871926A1 (en) * 2012-05-03 2013-11-07 Saint Louis College Of Pharmacy Compositions and methods for increasing neurotrophic peptides
US20130310340A1 (en) 2012-05-16 2013-11-21 Rigel Pharmaceuticals, Inc. Method of treating muscular degradation
WO2013192128A1 (en) 2012-06-20 2013-12-27 Merck Sharp & Dohme Corp. Imidazolyl analogs as syk inhibitors
EP2863914B1 (en) 2012-06-20 2018-10-03 Merck Sharp & Dohme Corp. Pyrazolyl derivatives as syk inhibitors
EP2863916B1 (en) 2012-06-22 2018-07-18 Merck Sharp & Dohme Corp. Substituted pyridine spleen tyrosine kinase (syk) inhibitors
EP2863915B1 (en) 2012-06-22 2017-12-06 Merck Sharp & Dohme Corp. SUBSTITUTED DIAZINE AND TRIAZINE SPLEEN TYROSINE KINASE (Syk) INHIBITORS
KR101446742B1 (en) 2012-08-10 2014-10-01 한국화학연구원 N2,N4-bis(4-(piperazin-1-yl)phenyl)pyrimidine-2,4-diamine derivatives or pharmaceutically acceptable salt thereof, and pharmaceutical composition for the prevention or treatment of cancer containing the same as an active ingredient
EP2884982B1 (en) * 2012-08-20 2017-09-20 Merck Sharp & Dohme Corp. SUBSTITUTED PHENYL SPLEEN TYROSINE KINASE (Syk) INHIBITORS
EP2711365A1 (en) 2012-09-21 2014-03-26 Chemilia AB 4-Indazolylamino-2-(2-(indol-3-yl)ethyl)aminopyrimidines useful for the treatment of cancer
EP2711364A1 (en) 2012-09-21 2014-03-26 Chemilia AB 4-(Indolyl or benzimidazolyl)amino-2-(2-(indol-3-yl)ethyl)aminopyrimidines useful for the treatment of cancer
WO2014048065A1 (en) 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Triazolyl derivatives as syk inhibitors
WO2014058921A2 (en) 2012-10-08 2014-04-17 Portola Pharmaceuticals, Inc. Substituted pyrimidinyl kinase inhibitors
CA2892677A1 (en) 2012-12-04 2014-06-12 Rigel Pharmaceuticals, Inc. Protein kinase c inhibitors and uses thereof
WO2014093191A1 (en) 2012-12-12 2014-06-19 Merck Sharp & Dohme Corp. AMINO-PYRIMIDINE-CONTAINING SPLEEN TYROSINE KINASE (Syk) INHIBITORS
EP2934525B1 (en) 2012-12-21 2019-05-08 Merck Sharp & Dohme Corp. Thiazole-substituted aminopyridines as spleen tyrosine kinase inhibitors
WO2014100748A1 (en) 2012-12-21 2014-06-26 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US20140213555A1 (en) 2013-01-25 2014-07-31 Rigel Pharmaceuticals, Inc. Compounds and method for treating autoimmune diseases
US9145387B2 (en) 2013-02-08 2015-09-29 Celgene Avilomics Research, Inc. ERK inhibitors and uses thereof
US10202356B2 (en) * 2013-03-14 2019-02-12 Tolero Pharmaceuticals, Inc. JAK2 and ALK2 inhibitors and methods for their use
US9169249B2 (en) 2013-03-14 2015-10-27 Rigel Pharmaceuticals, Inc. Protein kinase C inhibitors and uses thereof
WO2014152716A1 (en) * 2013-03-15 2014-09-25 President And Fellows Of Harvard College Substituted heterocyclic compounds for treating or preventing viral infections
US9499534B2 (en) 2013-04-26 2016-11-22 Merck Sharp & Dohme Corp. Thiazole-substituted aminopyrimidines as spleen tyrosine kinase inhibitors
EP2988744A4 (en) 2013-04-26 2016-11-02 Merck Sharp & Dohme Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
CA2912918C (en) * 2013-06-24 2021-07-27 Merck Patent Gmbh Imidazole compounds as modulators of fshr and uses thereof
US9850216B2 (en) 2013-08-06 2017-12-26 H. Lee Moffitt Cancer Center And Research Institute, Inc. Inhibitors of ACK1/TNK2 tyrosine kinase
US9492471B2 (en) 2013-08-27 2016-11-15 Celgene Avilomics Research, Inc. Methods of treating a disease or disorder associated with Bruton'S Tyrosine Kinase
EP3083560B1 (en) 2013-12-20 2021-10-27 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
WO2015094997A1 (en) 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9822107B2 (en) 2013-12-20 2017-11-21 Merck Sharp & Dohme Corp. Thiazole-substituted aminoheteroaryls as spleen tyrosine kinase inhibitors
US9415049B2 (en) 2013-12-20 2016-08-16 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
NZ715903A (en) 2014-01-30 2017-06-30 Signal Pharm Llc Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US20150224078A1 (en) 2014-02-10 2015-08-13 Patara Pharma, LLC Methods for the Treatment of Lung Diseases with Mast Cell Stabilizers
SI3104853T1 (en) 2014-02-10 2020-03-31 Respivant Sciences Gmbh Mast cell stabilizers treatment for systemic disorders
CA2940666C (en) 2014-02-28 2022-08-23 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
EP3116506B1 (en) 2014-03-13 2019-04-17 Merck Sharp & Dohme Corp. 2-pyrazine carboxamides as spleen tyrosine kinase inhibitors
US9399637B2 (en) 2014-03-28 2016-07-26 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
US11311512B2 (en) 2014-08-12 2022-04-26 Monash University Lymph directing prodrugs
US10005760B2 (en) 2014-08-13 2018-06-26 Celgene Car Llc Forms and compositions of an ERK inhibitor
US10059689B2 (en) 2014-10-14 2018-08-28 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
ES2882954T3 (en) 2014-12-16 2021-12-03 Signal Pharm Llc Medical uses comprising methods for the measurement of inhibition of c-Jun N-terminal kinase in the skin
US9796685B2 (en) 2014-12-16 2017-10-24 Signal Pharmaceuticals, Llc Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-Methylcyclohexylamino)-pyrimidine-5-carboxamide
US20180022710A1 (en) 2015-01-29 2018-01-25 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
TWI788655B (en) 2015-02-27 2023-01-01 美商林伯士拉克許米公司 Tyk2 inhibitors and uses thereof
WO2017004134A1 (en) 2015-06-29 2017-01-05 Nimbus Iris, Inc. Irak inhibitors and uses thereof
KR20180041119A (en) * 2015-07-09 2018-04-23 메르크 파텐트 게엠베하 Pyrimidine Derivatives as BTK Inhibitors and Their Uses
CA2993173C (en) 2015-07-24 2023-10-03 Celgene Corporation Methods of synthesis of (1r,2r,5r)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein
US10238625B2 (en) 2015-08-07 2019-03-26 Respivant Sciences Gmbh Methods for the treatment of mast cell related disorders with mast cell stabilizers
WO2017027402A1 (en) 2015-08-07 2017-02-16 Patara Pharma, LLC Methods for the treatment of systemic disorders treatable with mast cell stabilizers, including mast cell related disorders
US10023571B2 (en) 2015-09-02 2018-07-17 Nimbus Lakshimi, Inc. TYK2 inhibitors and uses thereof
AU2016318229A1 (en) 2015-09-08 2018-03-29 Monash University Lymph directing prodrugs
WO2017044434A1 (en) 2015-09-11 2017-03-16 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use
US10683308B2 (en) 2015-09-11 2020-06-16 Navitor Pharmaceuticals, Inc. Rapamycin analogs and uses thereof
JP6800968B2 (en) 2015-10-23 2020-12-16 ナビター ファーマシューティカルズ， インコーポレイテッド Sestrin-GATOR2 interaction modulator and its use
US10045981B2 (en) 2015-11-24 2018-08-14 Jakpharm, Llc Selective kinase inhibitors
CN108367006B (en) 2015-12-04 2021-12-31 博尔托拉制药公司 Cerdulatinib for treating hematologic cancers
EP3389664A4 (en) 2015-12-14 2020-01-08 Raze Therapeutics Inc. Caffeine inhibitors of mthfd2 and uses thereof
CN105646371B (en) * 2016-01-19 2019-10-01 浙江大学 The 2,4- diaryl-amine yl pyrimidines analog derivative of the segment containing hydroxamic acid and preparation and application
PT3426243T (en) 2016-03-09 2021-08-19 Raze Therapeutics Inc 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
US11014882B2 (en) 2016-03-09 2021-05-25 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
WO2017156527A1 (en) * 2016-03-11 2017-09-14 H. Lee Moffitt Cancer Center And Research Institute, Inc. Aurora kinase and janus kinase inhibitors for prevention of graft versus host disease
JP2019510785A (en) 2016-04-08 2019-04-18 エックス４ ファーマシューティカルズ， インコーポレイテッド How to treat cancer
EP3471726A4 (en) 2016-06-21 2019-10-09 X4 Pharmaceuticals, Inc. Cxcr4 inhibitors and uses thereof
WO2017223243A1 (en) 2016-06-21 2017-12-28 X4 Pharmaceuticals, Inc. Cxcr4 inhibitors and uses thereof
US10759796B2 (en) 2016-06-21 2020-09-01 X4 Pharmaceuticals, Inc. CXCR4 inhibitors and uses thereof
CA3035528A1 (en) 2016-08-31 2018-03-08 Respivant Sciences Gmbh Cromolyn compositions for treatment of chronic cough due to idiopathic pulmonary fibrosis
EP3512519A1 (en) 2016-09-14 2019-07-24 Gilead Sciences, Inc. Syk inhibitors
TW201822764A (en) 2016-09-14 2018-07-01 美商基利科學股份有限公司 Syk inhibitors
EP3522983A4 (en) 2016-10-07 2020-06-03 Respivant Sciences GmbH Cromolyn compositions for treatment of pulmonary fibrosis
EP3526222B1 (en) 2016-10-14 2022-08-17 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
EP3528816A4 (en) 2016-10-21 2020-04-08 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
WO2018089499A1 (en) 2016-11-08 2018-05-17 Navitor Pharmaceuticals, Inc. PHENYL AMINO PIPERIDINE mTORC INHIBITORS AND USES THEREOF
CA3043768A1 (en) 2016-11-29 2018-06-07 PureTech Health LLC Exosomes for delivery of therapeutic agents
US11091451B2 (en) 2016-12-05 2021-08-17 Raze Therapeutics, Inc. SHMT inhibitors and uses thereof
JP2020502238A (en) 2016-12-23 2020-01-23 バイスクルアールディー・リミテッド Peptide derivatives having a novel linking structure
EP3565638B8 (en) 2017-01-06 2024-04-10 BicycleRD Limited Bicycle conjugate for treating cancer
CN108341835B (en) * 2017-01-22 2021-01-15 正大天晴药业集团股份有限公司 Boron-containing compounds as tyrosine kinase inhibitors
TWI783978B (en) 2017-03-08 2022-11-21 美商林伯士拉克許米公司 Tyk2 inhibitors, uses, and methods for production thereof
EP3375778A1 (en) 2017-03-14 2018-09-19 Artax Biopharma Inc. Aryl-piperidine derivatives
EP3375784A1 (en) 2017-03-14 2018-09-19 Artax Biopharma Inc. Aza-dihydro-acridone derivatives
EA201992215A1 (en) 2017-03-20 2020-02-06 Форма Терапьютикс, Инк. Pyrrolopyrrole Compositions as Pyruvate Kinase Activators (PKR)
WO2018191146A1 (en) 2017-04-10 2018-10-18 Navitor Pharmaceuticals, Inc. Heteroaryl rheb inhibitors and uses thereof
WO2018195471A1 (en) 2017-04-21 2018-10-25 Gilead Sciences, Inc. Syk inhibitors in combination with hypomethylating agents
WO2018200625A1 (en) 2017-04-26 2018-11-01 Navitor Pharmaceuticals, Inc. Modulators of sestrin-gator2 interaction and uses thereof
US10857196B2 (en) 2017-04-27 2020-12-08 Bicycletx Limited Bicyclic peptide ligands and uses thereof
WO2019002842A1 (en) 2017-06-26 2019-01-03 Bicyclerd Limited Bicyclic peptide ligands with detectable moieties and uses thereof
CN117343049A (en) * 2017-06-30 2024-01-05 北京泰德制药股份有限公司 Rho-related protein kinase inhibitor, pharmaceutical composition containing Rho-related protein kinase inhibitor, and preparation method and application of Rho-related protein kinase inhibitor
US20210085796A1 (en) * 2017-07-28 2021-03-25 Yale University Anticancer drugs and methods of making and using same
JP7216705B2 (en) 2017-07-28 2023-02-02 ニンバス ラクシュミ， インコーポレイテッド TYK2 inhibitors and methods of use thereof
EP3668887A1 (en) 2017-08-14 2020-06-24 Bicyclerd Limited Bicyclic peptide ligand sting conjugates and uses thereof
WO2019034868A1 (en) 2017-08-14 2019-02-21 Bicyclerd Limited Bicyclic peptide ligand prr-a conjugates and uses thereof
EP4306524A2 (en) 2017-08-29 2024-01-17 PureTech LYT, Inc. Lymphatic system-directing lipid prodrugs
US11883497B2 (en) 2017-08-29 2024-01-30 Puretech Lyt, Inc. Lymphatic system-directing lipid prodrugs
IL307995A (en) 2017-09-22 2023-12-01 Kymera Therapeutics Inc Protein degraders and uses thereof
US11358948B2 (en) 2017-09-22 2022-06-14 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
US10052326B1 (en) 2017-10-12 2018-08-21 King Saud University Antihepatotoxic agents
EP3665171A1 (en) 2017-10-19 2020-06-17 Bayer Animal Health GmbH Use of fused heteroaromatic pyrrolidones for treatment and prevention of diseases in animals
ES2925450T3 (en) 2017-11-06 2022-10-18 Bristol Myers Squibb Co Isofuranone compounds useful as HPK1 inhibitors
EP3710006A4 (en) 2017-11-19 2021-09-01 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use
GB201721265D0 (en) 2017-12-19 2018-01-31 Bicyclerd Ltd Bicyclic peptide ligands specific for EphA2
US11304954B2 (en) 2017-12-19 2022-04-19 Puretech Lyt, Inc. Lipid prodrugs of mycophenolic acid and uses thereof
WO2019126378A1 (en) 2017-12-19 2019-06-27 Ariya Therapeutics, Inc. Lipid prodrugs of mycophenolic acid and uses thereof
US11608345B1 (en) 2017-12-19 2023-03-21 Puretech Lyt, Inc. Lipid prodrugs of rapamycin and its analogs and uses thereof
TWI825046B (en) 2017-12-19 2023-12-11 英商拜西可泰克斯有限公司 Bicyclic peptide ligands specific for epha2
MX2020006812A (en) 2017-12-26 2020-11-06 Kymera Therapeutics Inc Irak degraders and uses thereof.
US11512080B2 (en) 2018-01-12 2022-11-29 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
EP3737666A4 (en) 2018-01-12 2022-01-05 Kymera Therapeutics, Inc. Protein degraders and uses thereof
EP3746075A4 (en) 2018-01-29 2021-09-08 Merck Patent GmbH Gcn2 inhibitors and uses thereof
KR20200115620A (en) 2018-01-29 2020-10-07 메르크 파텐트 게엠베하 GCN2 inhibitors and uses thereof
WO2019169001A1 (en) 2018-02-27 2019-09-06 Artax Biopharma Inc. Chromene derivatives as inhibitors of tcr-nck interaction
MX2020010437A (en) 2018-04-05 2021-01-29 Sumitomo Pharma Oncology Inc Axl kinase inhibitors and use of the same.
ES2919572T3 (en) 2018-04-24 2022-07-27 Merck Patent Gmbh Anti-proliferation compounds and uses thereof
CA3097774A1 (en) 2018-04-24 2019-10-31 Vertex Pharmaceuticals Incorporated Pteridinone compounds and uses thereof
WO2019213606A2 (en) 2018-05-04 2019-11-07 Portola Pharmaceuticals, Inc. Solid forms of cerdulatinib
JP7382353B2 (en) 2018-06-15 2023-11-16 ヤンセン ファーマシューティカ エヌ．ベー． Rapamycin analogs and their uses
GB201810316D0 (en) 2018-06-22 2018-08-08 Bicyclerd Ltd Peptide ligands for binding to EphA2
US11180531B2 (en) 2018-06-22 2021-11-23 Bicycletx Limited Bicyclic peptide ligands specific for Nectin-4
US10487057B1 (en) * 2018-07-05 2019-11-26 Landos Biopharma, Inc. NLRX1 ligands
WO2020010177A1 (en) 2018-07-06 2020-01-09 Kymera Therapeutics, Inc. Tricyclic crbn ligands and uses thereof
CA3103995A1 (en) 2018-07-26 2020-01-30 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal acvr1 expression and acvr1 inhibitors for use in the same
US10548889B1 (en) 2018-08-31 2020-02-04 X4 Pharmaceuticals, Inc. Compositions of CXCR4 inhibitors and methods of preparation and use
EP3846793B1 (en) 2018-09-07 2024-01-24 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
EP3852791A4 (en) 2018-09-19 2022-06-15 Forma Therapeutics, Inc. Activating pyruvate kinase r
US20220031671A1 (en) 2018-09-19 2022-02-03 Forma Therapeutics, Inc. Treating sickle cell disease with a pyruvate kinase r activating compound
WO2020081508A1 (en) 2018-10-15 2020-04-23 Nimbus Lakshmi, Inc. Tyk2 inhibitors and uses thereof
CN112955459A (en) 2018-10-23 2021-06-11 拜斯科技术开发有限公司 Bicyclic peptide ligands and uses thereof
AU2019364542A1 (en) 2018-10-24 2021-06-10 Navitor Pharmaceuticals, Inc. Polymorphic compounds and uses thereof
US11352350B2 (en) 2018-11-30 2022-06-07 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
AU2019389025A1 (en) 2018-11-30 2021-06-17 Takeda Pharmaceutical Company Limited TYK2 inhibitors and uses thereof
EP3670659A1 (en) 2018-12-20 2020-06-24 Abivax Biomarkers, and uses in treatment of viral infections, inflammations, or cancer
CN113348021A (en) 2019-01-23 2021-09-03 林伯士拉克许米公司 TYK2 inhibitors and uses thereof
WO2020165600A1 (en) 2019-02-14 2020-08-20 Bicycletx Limited Bicyclic peptide ligand sting conjugates and uses thereof
AU2020242287A1 (en) 2019-03-21 2021-09-02 INSERM (Institut National de la Santé et de la Recherche Médicale) A Dbait molecule in combination with kinase inhibitor for the treatment of cancer
JP2022528887A (en) 2019-04-02 2022-06-16 バイスクルテクス・リミテッド Bicycle toxin conjugates and their use
KR20220006139A (en) 2019-04-05 2022-01-14 카이메라 쎄라퓨틱스 인코포레이티드 STAT degradation agents and uses thereof
JP2022534425A (en) 2019-05-31 2022-07-29 イケナ オンコロジー， インコーポレイテッド TEAD inhibitors and uses thereof
WO2021003417A1 (en) 2019-07-03 2021-01-07 Sumitomo Dainippon Pharma Oncology, Inc. Tyrosine kinase non-receptor 1 (tnk1) inhibitors and uses thereof
CN114698370A (en) 2019-08-08 2022-07-01 里格尔药品股份有限公司 Compounds and methods for treating cytokine release syndrome
AU2020345962A1 (en) 2019-09-11 2022-03-31 Vincere Biosciences, Inc. USP30 inhibitors and uses thereof
JP2022547719A (en) 2019-09-13 2022-11-15 ニンバス サターン， インコーポレイテッド HPK1 antagonists and uses thereof
US11723890B2 (en) 2019-11-01 2023-08-15 Navitor Pharmaceuticals, Inc. Methods of treatment using an mTORC1 modulator
US20220401436A1 (en) 2019-11-08 2022-12-22 INSERM (Institute National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021094296A1 (en) 2019-11-12 2021-05-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of mast cell stabilizer for the treatment of heart failure with preserved ejection fraction
CN115209897A (en) 2019-12-05 2022-10-18 安纳库利亚治疗公司 Rapamycin analogs and uses thereof
IL293917A (en) 2019-12-17 2022-08-01 Kymera Therapeutics Inc Irak degraders and uses thereof
US11591332B2 (en) 2019-12-17 2023-02-28 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
CA3162502A1 (en) 2019-12-23 2021-07-01 Yi Zhang Smarca degraders and uses thereof
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
JP2023513016A (en) * 2020-01-30 2023-03-30 スミトモ ファーマ オンコロジー， インコーポレイテッド Aminopyrimidinyl aminobenzonitrile derivatives as NEK2 inhibitors
TW202146393A (en) 2020-03-03 2021-12-16 美商皮克醫療公司 Eif4e inhibitors and uses thereof
JP2023518356A (en) * 2020-03-12 2023-05-01 ライジェル ファーマシューティカルズ， インコーポレイテッド Methods for treatment of COVID-19 related conditions
EP4121043A1 (en) 2020-03-19 2023-01-25 Kymera Therapeutics, Inc. Mdm2 degraders and uses thereof
TW202210483A (en) 2020-06-03 2022-03-16 美商凱麥拉醫療公司 Crystalline forms of irak degraders
CN116234931A (en) 2020-08-17 2023-06-06 拜斯科技术开发有限公司 Bicyclic conjugates with specificity for NECTIN-4 and uses thereof
EP4255895A1 (en) 2020-12-02 2023-10-11 Ikena Oncology, Inc. Tead inhibitors and uses thereof
WO2022120353A1 (en) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Tead inhibitors and uses thereof
CN112920124B (en) * 2021-01-29 2024-03-01 安徽医科大学 Pyrimidine-2, 4-diamine compound, and preparation method and application thereof
US20230113202A1 (en) 2021-02-02 2023-04-13 Liminal Biosciences Limited Gpr84 antagonists and uses thereof
CN116888116A (en) 2021-02-02 2023-10-13 里米诺生物科学有限公司 GPR84 antagonists and uses thereof
TW202245789A (en) 2021-02-15 2022-12-01 美商凱麥拉醫療公司 Irak4 degraders and uses thereof
EP4301756A1 (en) 2021-03-05 2024-01-10 Nimbus Saturn, Inc. Hpk1 antagonists and uses thereof
AU2022258968A1 (en) 2021-04-16 2023-10-19 Ikena Oncology, Inc. Mek inhibitors and uses thereof
US20230134932A1 (en) 2021-08-25 2023-05-04 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
WO2023028235A1 (en) 2021-08-25 2023-03-02 PIC Therapeutics, Inc. Eif4e inhibitors and uses thereof
WO2023108536A1 (en) * 2021-12-16 2023-06-22 Lynk Pharmaceuticals Co. Ltd. Tyk2 inhibitors and compositions and methods thereof
WO2023114984A1 (en) 2021-12-17 2023-06-22 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11478464B1 (en) 2022-02-06 2022-10-25 King Faisal University Method for treating inflammation
WO2023173057A1 (en) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Mek inhibitors and uses thereof
WO2023173053A1 (en) 2022-03-10 2023-09-14 Ikena Oncology, Inc. Mek inhibitors and uses thereof
WO2023211889A1 (en) 2022-04-25 2023-11-02 Ikena Oncology, Inc. Polymorphic compounds and uses thereof
KR20230155351A (en) * 2022-05-03 2023-11-10 한국화학연구원 A kinase inhibitory compound containing 5-chloro-2,4-diaminopyrimidine, preparation therof and use thereof as anti-cancer agent comprising same
US20230357125A1 (en) * 2022-05-06 2023-11-09 AMPAC Fine Chemicals Process for Catalytic Reduction of Nitro Compounds to Amines
US11878958B2 (en) 2022-05-25 2024-01-23 Ikena Oncology, Inc. MEK inhibitors and uses thereof
WO2024028364A1 (en) 2022-08-02 2024-02-08 Liminal Biosciences Limited Aryl-triazolyl and related gpr84 antagonists and uses thereof
WO2024028365A1 (en) 2022-08-02 2024-02-08 Liminal Biosciences Limited Substituted pyridone gpr84 antagonists and uses thereof
WO2024028363A1 (en) 2022-08-02 2024-02-08 Liminal Biosciences Limited Heteroaryl carboxamide and related gpr84 antagonists and uses thereof
WO2024042361A1 (en) * 2022-08-24 2024-02-29 Sudo Biosciences Limited Tyk2 inhibitors and uses thereof

Family Cites Families (294)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US38243A (en) * 1863-04-21 Improvement in flasks for founders
US192301A (en) * 1877-06-19 Improvement in lemon-squeezers
US113398A (en) * 1871-04-04 Improvement in towel-brackets and sponge-holders
US80858A (en) * 1868-08-11 Ensmore
US3159547A (en) 1963-06-28 1964-12-01 Abbott Lab Method of lowering blood pressure with 4-(2-amino-4-pyrimidylamino)-benzene-sulfonamide
US3320256A (en) 1965-04-09 1967-05-16 Hoffmann La Roche Fluorinated imidazoo[1, 2-c]pyrimidines and pyrimido[1, 2-c]pyrimidines
US4166452A (en) 1976-05-03 1979-09-04 Generales Constantine D J Jr Apparatus for testing human responses to stimuli
US4256108A (en) 1977-04-07 1981-03-17 Alza Corporation Microporous-semipermeable laminated osmotic system
US4265874A (en) 1980-04-25 1981-05-05 Alza Corporation Method of delivering drug with aid of effervescent activity generated in environment of use
JPS59122899U (en) 1983-02-08 1984-08-18 松下電器産業株式会社 iron
US5087240A (en) 1983-08-18 1992-02-11 Drug Delivery Systems Inc. Transdermal drug patch with conductive fibers
US4921475A (en) 1983-08-18 1990-05-01 Drug Delivery Systems Inc. Transdermal drug patch with microtubes
GR80171B (en) 1983-08-29 1985-01-02 Ciba Geigy Ag N-(2-nitrophenyl)-4-aminopyrimidine derivatives process for the preparation thereof and use
HU192875B (en) 1984-10-05 1987-07-28 Richter Gedeon Vegyeszet Process for preparing 2-pyridinethiol derivatives
DE3666587D1 (en) 1985-08-02 1989-11-30 Leo Pharm Prod Ltd Novel vitamin d analogues
US4738851A (en) 1985-09-27 1988-04-19 University Of Iowa Research Foundation, Inc. Controlled release ophthalmic gel formulation
DE3618353A1 (en) * 1986-05-31 1987-12-03 Hoechst Ag PEST CONTROLS BASED ON AMINOPYRIMIDINE DERIVATIVES AND NEW AMINOPYRIMIDINE COMPOUNDS
JPS638387A (en) 1986-06-27 1988-01-14 Yoshitomi Pharmaceut Ind Ltd Cephem compound
JPH0696592B2 (en) * 1986-06-30 1994-11-30 株式会社クラレ Method for producing 17β-hydroxy-17α- (3-hydroxypropyl) androsta-4,6-dien-3-one
US5163899A (en) 1987-03-20 1992-11-17 Drug Delivery Systems Inc. Transdermal drug delivery system
US4968781A (en) 1987-04-02 1990-11-06 Ciba-Geigy Corporation Fiber-reactive dyes comprising a halopyrimidine for which a vinylsulfonyl or the like moiety is attached via a bridge member
US5312325A (en) 1987-05-28 1994-05-17 Drug Delivery Systems Inc Pulsating transdermal drug delivery system
SU1499883A1 (en) 1987-11-24 1991-10-23 Научно-исследовательский институт фармакологии АМН СССР Dichlorhydrate 2,4-bis-(p-tret-butylanilino)-5-oxi-6-methylpyrimidine possessing analsetyc and antiflammatory activity
GB8804164D0 (en) 1988-02-23 1988-03-23 Tucker J M Bandage for administering physiologically active compound
EP0412110B1 (en) 1988-04-21 1993-07-07 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) Novel vitamin d analogues
US4882150A (en) 1988-06-03 1989-11-21 Kaufman Herbert E Drug delivery system
US5008110A (en) 1988-11-10 1991-04-16 The Procter & Gamble Company Storage-stable transdermal patch
US5088977A (en) 1988-12-21 1992-02-18 Drug Delivery Systems Inc. Electrical transdermal drug applicator with counteractor and method of drug delivery
HU206337B (en) 1988-12-29 1992-10-28 Mitsui Petrochemical Ind Process for producing pyrimidine derivatives and pharmaceutical compositions
IE63502B1 (en) 1989-04-21 1995-05-03 Zeneca Ltd Aminopyrimidine derivatives useful for treating cardiovascular disorders
US4983608A (en) 1989-09-05 1991-01-08 Hoechst-Roussell Pharmaceuticals, Inc. N-substituted-4-pyrimidinamines and pyrimidinediamines
US5179204A (en) 1989-09-05 1993-01-12 Hoechst-Roussel Pharmaceuticals Incorporated N-substituted-4-pyrimidinamines and pyrimidinediamines
US5521222A (en) 1989-09-28 1996-05-28 Alcon Laboratories, Inc. Topical ophthalmic pharmaceutical vehicles
JPH03127790A (en) * 1989-10-11 1991-05-30 Morishita Pharmaceut Co Ltd N-(1h-tetrazol-5-yl)-2-anilino-5-pyrimidinecarboxamides and synthetic intermediate therefor
TW224941B (en) 1989-11-08 1994-06-11 Yamanouchi Pharma Co Ltd
DE69009946T2 (en) 1989-12-04 1994-11-03 Searle & Co System for transdermal albuterol application.
US5532228A (en) 1990-02-06 1996-07-02 Schering Aktiengesellschaft Side-chain homologous vitamin D derivatives, process for their production, pharmaceutical preparations containing these derivatives and their use as pharmaceutical agents
DE4011682A1 (en) 1990-04-06 1991-10-10 Schering Ag 24-OXA DERIVATIVES IN THE VITAMIN D SERIES
JPH03127790U (en) 1990-04-06 1991-12-24
GB9012592D0 (en) * 1990-06-06 1990-07-25 Smithkline Beecham Intercredit Compounds
US5077033A (en) 1990-08-07 1991-12-31 Mediventures Inc. Ophthalmic drug delivery with thermo-irreversible gels of polxoxyalkylene polymer and ionic polysaccharide
DE4029650A1 (en) * 1990-09-19 1992-03-26 Hoechst Ag New 2-aryl:amino-pyrimidine derivs. - contg. alkynyl gp., useful as fungicides
JPH04178385A (en) 1990-11-09 1992-06-25 Yamanouchi Pharmaceut Co Ltd Diketopyridopyrazine derivative
DE69212850T2 (en) 1991-01-15 1997-03-06 Alcon Lab Inc Use of carrageenan in topical ophthalmic compositions
DE69209576D1 (en) 1991-05-10 1996-05-09 Takeda Chemical Industries Ltd Pyridine derivatives, their production and use
US5200400A (en) 1991-07-12 1993-04-06 New England Deaconess Hospital Corporation Method for inhibiting allograft rejection using photoactivatable nucleotides or nucleosides
CA2074864A1 (en) 1991-07-30 1993-01-31 Carmen Almansa Tetralones with pharmacological activity
US5352456A (en) 1991-10-10 1994-10-04 Cygnus Therapeutic Systems Device for administering drug transdermally which provides an initial pulse of drug
US5728536A (en) 1993-07-29 1998-03-17 St. Jude Children's Research Hospital Jak kinases and regulation of Cytokine signal transduction
DE4141746A1 (en) 1991-12-13 1993-06-17 Schering Ag 20-METHYL-SUBSTITUTED VITAMIN D DERIVATIVES
EP0617665B1 (en) 1991-12-18 1999-03-31 Minnesota Mining And Manufacturing Company Multilayered barrier structures
ATE132381T1 (en) 1992-01-29 1996-01-15 Voelkl Franz Ski BALL GAME RACKETS, ESPECIALLY TENNIS RACKETS
US5521184A (en) 1992-04-03 1996-05-28 Ciba-Geigy Corporation Pyrimidine derivatives and processes for the preparation thereof
US5194431A (en) 1992-07-08 1993-03-16 Wisconsin Alumni Research Foundation 24-cyclopropane vitamin D derivatives
EP0593054B1 (en) * 1992-10-14 2000-08-02 Mitsubishi Chemical Corporation Process for preparing a thermoplastic resin composition
US5335501A (en) 1992-11-16 1994-08-09 General Electric Company Flow spreading diffuser
TW287160B (en) 1992-12-10 1996-10-01 Hoffmann La Roche
DE4308034A1 (en) * 1993-03-13 1994-09-15 Cassella Ag New heterocycles, their preparation and their use
BR9407799A (en) 1993-10-12 1997-05-06 Du Pont Merck Pharma Composition of matter treatment method and pharmaceutical composition
IL112290A (en) 1994-01-12 1999-01-26 Novartis Ag Substituted aryl and heteroaryl pyrimidines and herbicidal compositions containing them
CA2150609C (en) 1994-06-01 1998-12-08 Mikiro Yanaka Pyrimidine derivatives and pharmaceutical composition
IL114193A (en) 1994-06-20 2000-02-29 Teva Pharma Ophthalmic pharmaceutical compositions based on sodium alginate
ES2094688B1 (en) 1994-08-08 1997-08-01 Cusi Lab MANOEMULSION OF THE TYPE OF OIL IN WATER, USEFUL AS AN OPHTHALMIC VEHICLE AND PROCEDURE FOR ITS PREPARATION.
US5733932A (en) 1995-01-06 1998-03-31 The Picower Institute For Medical Research Compounds and methods of use to derivatize neighboring lysine residues in proteins under physiological conditions
US6242434B1 (en) 1997-08-08 2001-06-05 Bone Care International, Inc. 24-hydroxyvitamin D, analogs and uses thereof
US6316635B1 (en) 1995-06-07 2001-11-13 Sugen, Inc. 2-indolinone derivatives as modulators of protein kinase activity
US5700904A (en) 1995-06-07 1997-12-23 Eli Lilly And Company Preparation of an acylated protein powder
GB9516121D0 (en) 1995-08-05 1995-10-04 Pfizer Ltd Organometallic addition to ketones
GB9523675D0 (en) 1995-11-20 1996-01-24 Celltech Therapeutics Ltd Chemical compounds
IT1283911B1 (en) 1996-02-05 1998-05-07 Farmigea Spa VISCOSIZED OPHTHALMIC SOLUTIONS WITH TAMARIND GUM POLYSACCHARIDES
JP4058129B2 (en) 1996-03-18 2008-03-05 株式会社資生堂 Pyridine derivatives and anti-ulcer agents, antibacterial agents
TW440563B (en) 1996-05-23 2001-06-16 Hoffmann La Roche Aryl pyrimidine derivatives and a pharmaceutical composition thereof
US6696448B2 (en) 1996-06-05 2004-02-24 Sugen, Inc. 3-(piperazinylbenzylidenyl)-2-indolinone compounds and derivatives as protein tyrosine kinase inhibitors
GB9619284D0 (en) 1996-09-16 1996-10-30 Celltech Therapeutics Ltd Chemical compounds
US6004985A (en) 1996-10-09 1999-12-21 Berlex Laboratories, Inc. Thio acid derived monocylic N-heterocyclics as anticoagulants
US5800807A (en) 1997-01-29 1998-09-01 Bausch & Lomb Incorporated Ophthalmic compositions including glycerin and propylene glycol
GB9705361D0 (en) 1997-03-14 1997-04-30 Celltech Therapeutics Ltd Chemical compounds
US6316429B1 (en) 1997-05-07 2001-11-13 Sugen, Inc. Bicyclic protein kinase inhibitors
US6486185B1 (en) 1997-05-07 2002-11-26 Sugen, Inc. 3-heteroarylidene-2-indolinone protein kinase inhibitors
US6987113B2 (en) 1997-06-11 2006-01-17 Sugen, Inc. Tyrosine kinase inhibitors
SE9702401D0 (en) 1997-06-19 1997-06-19 Astra Ab Pharmaceutical use
GB9718913D0 (en) 1997-09-05 1997-11-12 Glaxo Group Ltd Substituted oxindole derivatives
US6133305A (en) 1997-09-26 2000-10-17 Sugen, Inc. 3-(substituted)-2-indolinones compounds and use thereof as inhibitors of protein kinase activity
US6093820A (en) 1997-10-02 2000-07-25 Taro Pharmaceutical Industries Ltd. Method and reagents for N-alkylating ureides
US6022884A (en) 1997-11-07 2000-02-08 Amgen Inc. Substituted pyridine compounds and methods of use
GB9723859D0 (en) 1997-11-12 1998-01-07 Zeneca Ltd Compound,composition and use
DE19750701A1 (en) 1997-11-15 1999-05-20 Dystar Textilfarben Gmbh & Co Reaction of F-substituted triazine and pyrimidine compounds with amino compounds
AU1507199A (en) * 1997-12-15 1999-07-05 Yamanouchi Pharmaceutical Co., Ltd. Novel pyrimidine-5-carboxamide derivatives
ATE261730T1 (en) 1997-12-31 2004-04-15 Univ Kansas WATER-SOLUBLE MEDICINAL PRECURSORS OF TERTIARY AMINES CONTAINING MEDICATIONS AND METHOD FOR THE PRODUCTION THEREOF
JP2002503655A (en) 1998-02-13 2002-02-05 ファルマシア・アンド・アップジョン・カンパニー Substituted aminophenyl isoxazoline derivatives useful as antibacterial agents
CA2321153A1 (en) 1998-02-17 1999-08-19 Timothy D. Cushing Anti-viral pyrimidine derivatives
WO1999050250A1 (en) * 1998-03-27 1999-10-07 Janssen Pharmaceutica N.V. Hiv inhibiting pyrimidine derivatives
DE69943247D1 (en) 1998-03-27 2011-04-14 Janssen Pharmaceutica Nv HIV-inhibiting pyrimidine derivatives
GB9806739D0 (en) 1998-03-28 1998-05-27 Univ Newcastle Ventures Ltd Cyclin dependent kinase inhibitors
EP1054871A2 (en) 1998-04-01 2000-11-29 Du Pont Pharmaceuticals Company Pyrimidines and triazines as integrin antagonists
US6261547B1 (en) 1998-04-07 2001-07-17 Alcon Manufacturing, Ltd. Gelling ophthalmic compositions containing xanthan gum
JP4472173B2 (en) 1998-04-15 2010-06-02 セローノ ジェネティクス インスティテュート ソシエテ アノニム Genomic sequence of 5-lipoxygenase activating protein (FLAP), polymorphic marker thereof, and method for detecting asthma
US6197934B1 (en) 1998-05-22 2001-03-06 Collagenesis, Inc. Compound delivery using rapidly dissolving collagen film
BR9910621A (en) 1998-05-22 2001-01-30 Smithkline Beecham Corp New 2-alkyl imidazole substituted compounds
AU4851599A (en) 1998-06-30 2000-01-17 Parker Hughes Institute Method for inhibiting c-jun expression using jak-3 inhibitors
WO2000010981A1 (en) 1998-08-21 2000-03-02 Parker Hughes Institute Quinazoline derivatives
DE69933680T2 (en) 1998-08-29 2007-08-23 Astrazeneca Ab PYRIMIDINE COMPOUNDS
CN1189166C (en) * 1998-09-11 2005-02-16 伊来克萨斯独资有限公司 FC receptor modulators and uses thereof
DE19851421A1 (en) 1998-11-07 2000-05-11 Boehringer Ingelheim Pharma New pyrimidines, their production and use
OA11674A (en) * 1998-11-10 2005-01-12 Janssen Pharmaceutica Nv HIV Replication inhibiting pyrimidines.
EP1129068A1 (en) 1998-11-12 2001-09-05 Ariad Pharmaceuticals, Inc. Bicyclic signal transduction inhibitors, composition containing them and uses thereof
US6127376A (en) 1998-12-04 2000-10-03 Berlex Laboratories, Inc. Aryl and heterocyclyl substituted pyrimidine derivatives as anti-coagulants
GB9828511D0 (en) 1998-12-24 1999-02-17 Zeneca Ltd Chemical compounds
US6841567B1 (en) 1999-02-12 2005-01-11 Cephalon, Inc. Cyclic substituted fused pyrrolocarbazoles and isoindolones
US6673908B1 (en) 1999-02-22 2004-01-06 Nuvelo, Inc. Tumor necrosis factor receptor 2
GB9904995D0 (en) 1999-03-04 1999-04-28 Glaxo Group Ltd Substituted aza-oxindole derivatives
US6624171B1 (en) 1999-03-04 2003-09-23 Smithkline Beecham Corporation Substituted aza-oxindole derivatives
US6080747A (en) 1999-03-05 2000-06-27 Hughes Institute JAK-3 inhibitors for treating allergic disorders
EP1165545A1 (en) * 1999-03-26 2002-01-02 AstraZeneca AB Novel compounds
EP1165522A1 (en) 1999-04-06 2002-01-02 Krenitsky Pharmaceuticals, Inc. Neurotrophic thio substituted pyrimidines
DE19917785A1 (en) 1999-04-20 2000-10-26 Bayer Ag New 2,4-diamino-pyrimidine derivatives useful as microbicides in protection of plants and materials and as herbicides
AU5108000A (en) 1999-06-10 2001-01-02 Yamanouchi Pharmaceutical Co., Ltd. Novel nitrogen-contaiing heterocyclic derivatives or salts thereof
GB9914258D0 (en) 1999-06-18 1999-08-18 Celltech Therapeutics Ltd Chemical compounds
TWI262914B (en) 1999-07-02 2006-10-01 Agouron Pharma Compounds and pharmaceutical compositions for inhibiting protein kinases
GB9918035D0 (en) 1999-07-30 1999-09-29 Novartis Ag Organic compounds
EA005423B1 (en) * 1999-09-24 2005-02-24 Янссен Фармацевтика Н.В. Antiviral compositions
DE19945982A1 (en) * 1999-09-24 2001-03-29 Knoll Ag Velocity-determined particles
EA200200424A1 (en) 1999-09-30 2002-12-26 Ньюроджен Корпорейшн Some heterocycles substituted by alkylene diamin
KR100317935B1 (en) 1999-10-20 2001-12-22 유승필 Pharmaceutical compositions and preparations for treatment of metabolic bone disease
AU1026901A (en) 1999-10-29 2001-05-08 Syngenta Participations Ag Novel herbicides
JP2003518023A (en) 1999-11-30 2003-06-03 パーカー ヒューズ インスティテュート Inhibitors of thrombin-induced platelet aggregation
DK1235830T3 (en) 1999-12-10 2004-03-29 Pfizer Prod Inc Pyrrolo [2,3-d] pyrimidine compounds as protein kinase inhibitors
ES2245955T3 (en) 1999-12-21 2006-02-01 Sugen, Inc. 7-AZA-INDOLIN-2-ONAS 4-SUBSTITUTES AND THEIR USE AS PROTEIN-KINASE INHIBITORS.
EP1246823A1 (en) * 1999-12-28 2002-10-09 Pharmacopeia, Inc. Pyrimidine and triazine kinase inhibitors
US20020065270A1 (en) 1999-12-28 2002-05-30 Moriarty Kevin Joseph N-heterocyclic inhibitors of TNF-alpha expression
US6362172B2 (en) 2000-01-20 2002-03-26 Bristol-Myers Squibb Company Water soluble prodrugs of azole compounds
CA2397774A1 (en) 2000-01-24 2001-07-26 Genzyme Corporation Jak/stat pathway inhibitors and the uses thereof
EP1200422A2 (en) 2000-02-05 2002-05-02 Vertex Pharmaceuticals Incorporated Pyrazole compositions useful as inhibitors of erk
CA2369076A1 (en) 2000-02-05 2001-08-09 Vertex Pharmaceuticals Incorporated Pyrazole compositions useful as inhibitors of erk
WO2001060816A1 (en) * 2000-02-17 2001-08-23 Amgen Inc. Kinase inhibitors
GB0004886D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004888D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004890D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004887D0 (en) * 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
US6525051B2 (en) 2000-03-27 2003-02-25 Schering Aktiengesellschaft N-heterocyclic derivatives as NOS inhibitors
US6608048B2 (en) 2000-03-28 2003-08-19 Wyeth Holdings Tricyclic protein kinase inhibitors
AR028261A1 (en) 2000-03-28 2003-04-30 Wyeth Corp TRICICLIC INHIBITORS OF PROTEIN QUINASA
ES2542326T3 (en) 2000-05-08 2015-08-04 Janssen Pharmaceutica Nv HIV replication inhibitors
DK1282607T3 (en) * 2000-05-08 2016-02-01 Janssen Pharmaceutica Nv Prodrugs of HIV replication inhibiting pyrimidines
EE200200711A (en) 2000-06-26 2004-06-15 Pfizer Products Inc. Pyrrolo [2,3-d] pyrimidine compounds as immunosuppressive agents
GB0016877D0 (en) * 2000-07-11 2000-08-30 Astrazeneca Ab Chemical compounds
US20050009876A1 (en) * 2000-07-31 2005-01-13 Bhagwat Shripad S. Indazole compounds, compositions thereof and methods of treatment therewith
AU2001292670A1 (en) 2000-09-15 2002-03-26 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US6777441B2 (en) 2000-10-02 2004-08-17 Emory University Triptolide analogs for the treatment of autoimmune and inflammatory disorders
US6448401B1 (en) 2000-11-20 2002-09-10 Bristol-Myers Squibb Company Process for water soluble azole compounds
WO2002043735A1 (en) 2000-11-29 2002-06-06 Parker Hughes Institute Inhibitors of thrombin induced platelet aggregation
US20020137755A1 (en) 2000-12-04 2002-09-26 Bilodeau Mark T. Tyrosine kinase inhibitors
US20020115173A1 (en) 2000-12-11 2002-08-22 Children's Medical Center Corporation Short peptides from the 'A-region' of protein kinases which selectively modulate protein kinase activity
JP2004518669A (en) 2000-12-20 2004-06-24 スージェン・インコーポレーテッド 4-Aryl substituted indolinone
ATE430742T1 (en) * 2000-12-21 2009-05-15 Smithkline Beecham Corp PYRIMIDINAMINES AS ANGIOGENESIS MODULATORS
BR0116411A (en) 2000-12-21 2003-11-11 Vertex Pharma Pyrazole compounds useful as protein kinase inhibitors
EP1363702A4 (en) 2001-01-30 2007-08-22 Cytopia Pty Ltd Methods of inhibiting kinases
AUPR279101A0 (en) 2001-01-30 2001-02-22 Cytopia Pty Ltd Protein kinase signalling
AU2002258400A1 (en) 2001-02-16 2002-08-28 Tularik Inc. Methods of using pyrimidine-based antiviral agents
GB0103926D0 (en) 2001-02-17 2001-04-04 Astrazeneca Ab Chemical compounds
JP4309657B2 (en) 2001-02-20 2009-08-05 アストラゼネカ・アクチエボラーグ 2-Allylamino-pyrimidine for the treatment of GSK-3-related disorders
GB2373186A (en) * 2001-02-23 2002-09-18 Astrazeneca Ab Pharmaceutical combinations of a CCR3 antagonist and a compound which is usefulreatment of asthma, allergic disease or inflammation
PL364625A1 (en) * 2001-02-23 2004-12-13 Merck & Co, Inc. N-substituted nonaryl-heterocyclic nmda/nr2b antagonists
ES2360205T3 (en) * 2001-03-02 2011-06-01 Agennix Ag THREE HYBRID TEST SYSTEM.
RS94703A (en) * 2001-05-29 2007-02-05 Schering Aktiengesellschaft, Cdk inhibiting pyrimidines, production thereof and their use as medicaments
MXPA03010961A (en) 2001-05-31 2004-02-27 Vertex Pharma Thiazole compounds useful as inhibitors of protein kinases.
US7301023B2 (en) 2001-05-31 2007-11-27 Pfizer Inc. Chiral salt resolution
EP1392684B1 (en) * 2001-06-01 2006-09-13 Vertex Pharmaceuticals Incorporated Thiazole compounds useful as inhibitors of protein kinases
CA2450769A1 (en) 2001-06-15 2002-12-27 Vertex Pharmaceuticals Incorporated 5-(2-aminopyrimidin-4-yl) benzisoxazoles as protein kinase inhibitors
JP2005500294A (en) 2001-06-19 2005-01-06 ブリストル−マイヤーズ　スクイブ　カンパニー Pyrimidine inhibitors for phosphodiesterase 7
WO2003000186A2 (en) 2001-06-21 2003-01-03 Ariad Pharmaceuticals, Inc. Novel phenylamino-pyrimidines and uses thereof
GB0115109D0 (en) 2001-06-21 2001-08-15 Aventis Pharma Ltd Chemical compounds
MXPA03011998A (en) * 2001-06-23 2005-07-01 Aventis Pharma Inc Pyrrolopyrimidines as protein kinase inhibitors.
CA2451128A1 (en) * 2001-06-26 2003-01-09 Bristol-Myers Squibb Company N-heterocyclic inhibitors of tnf-alpha expression
CZ294535B6 (en) 2001-08-02 2005-01-12 Ústav Experimentální Botaniky Avčr Heterocyclic compounds based on N6-substituted adenine, processes of their preparation, their use in the preparation of medicaments, cosmetic compositions and growth regulators, as well as pharmaceutical preparations, cosmetic compositions and growth regulators in which these compounds are comprised
JO3429B1 (en) 2001-08-13 2019-10-20 Janssen Pharmaceutica Nv Hiv inhibiting pyrimidines derivatives
US6939874B2 (en) 2001-08-22 2005-09-06 Amgen Inc. Substituted pyrimidinyl derivatives and methods of use
US7115617B2 (en) 2001-08-22 2006-10-03 Amgen Inc. Amino-substituted pyrimidinyl derivatives and methods of use
US7070996B2 (en) 2001-08-31 2006-07-04 Rigel Pharmaceuticals, Inc. Production of cultured human mast cells and basophils for high throughput small molecule drug discovery
US6433018B1 (en) 2001-08-31 2002-08-13 The Research Foundation Of State University Of New York Method for reducing hypertrophy and ischemia
US6952284B2 (en) * 2001-08-31 2005-10-04 International Business Machines Corporation Manually operated digital printing device
WO2003022815A1 (en) 2001-09-10 2003-03-20 Sugen, Inc. 3-(4,5,6,7-tetrahydroindol-2-ylmethylidiene)-2-indolinone derivatives as kinase inhibitors
WO2003030909A1 (en) * 2001-09-25 2003-04-17 Bayer Pharmaceuticals Corporation 2- and 4-aminopyrimidines n-substtituded by a bicyclic ring for use as kinase inhibitors in the treatment of cancer
WO2003026666A1 (en) 2001-09-26 2003-04-03 Bayer Pharmaceuticals Corporation 2-phenylamino-4- (5-pyrazolylamino)-pyrimidine derivatives as kinase inhibitors, in particular, as src kinase inhibitors
WO2003040141A1 (en) 2001-09-28 2003-05-15 Bayer Pharmaceuticals Corporation Oxazolyl-phenyl-2,4-diamino-pyrimidine compounds and methods for treating hyperproliferative disorders
EP1453516A2 (en) 2001-10-17 2004-09-08 Boehringer Ingelheim Pharma GmbH & Co.KG Novel tri-substituted pyrimidines, method for production and use thereof as medicament
EP2090571B1 (en) 2001-10-17 2012-05-16 Boehringer Ingelheim Pharma GmbH & Co. KG Pyrimidine derivates, medicaments comprising them, their use and process of their preparation
US6897208B2 (en) 2001-10-26 2005-05-24 Aventis Pharmaceuticals Inc. Benzimidazoles
CN100354267C (en) 2001-11-28 2007-12-12 英国技术集团国际有限公司 Preventives or remedies for alzheimer's disease or amyloid protein fibrosis inhibitors containing nitrogen-containing heteroaryl compounds
GT200200234A (en) 2001-12-06 2003-06-27 NEW CRYSTAL COMPOUNDS
SE0104140D0 (en) 2001-12-07 2001-12-07 Astrazeneca Ab Novel Compounds
AU2002367172A1 (en) 2001-12-21 2003-07-15 Bayer Pharmaceuticals Corporation 2,4-diamino-pyrimidine derivative compounds as inhibitors of prolylpeptidase, inducers of apoptosis and cancer treatment agents
CA2473510A1 (en) 2002-01-23 2003-07-31 Bayer Pharmaceuticals Corporation Pyrimidine derivatives as rho-kinase inhibitors
TWI329105B (en) * 2002-02-01 2010-08-21 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds and their uses
US6998391B2 (en) 2002-02-07 2006-02-14 Supergen.Inc. Method for treating diseases associated with abnormal kinase activity
AU2003209077A1 (en) 2002-02-08 2003-09-02 Smithkline Beecham Corporation Pyrimidine compounds
US7153245B2 (en) * 2002-02-14 2006-12-26 Kellion Corporation Golf exerciser
ES2290479T3 (en) 2002-03-01 2008-02-16 Smithkline Beecham Corporation DIAMINO-PYRIMIDINES AND ITS USE AS INHIBITORS OF ANGIOGENESIS.
US7288547B2 (en) * 2002-03-11 2007-10-30 Schering Ag CDK-inhibitory 2-heteroaryl-pyrimidines, their production and use as pharmaceutical agents
AU2003212282A1 (en) 2002-03-11 2003-09-22 Schering Aktiengesellschaft Cdk inhibiting 2-heteroaryl pyrimidine, the production thereof, and use thereof as a medicament
GB0206215D0 (en) 2002-03-15 2002-05-01 Novartis Ag Organic compounds
GEP20074230B (en) 2002-03-20 2007-11-12 Bristol Myers Squibb Co Phosphate prodrugs of fluorooxindoles
AU2003231231A1 (en) 2002-05-06 2003-11-11 Bayer Pharmaceuticals Corporation Pyridinyl amino pyrimidine derivatives useful for treating hyper-proliferative disorders
WO2004039359A2 (en) 2002-05-06 2004-05-13 Bayer Pharmaceuticals Corporation Use of pyrimidine derivates for the manifacture of a medicament for the treatment of hyper-proliferative disorders
AR039540A1 (en) 2002-05-13 2005-02-23 Tibotec Pharm Ltd MICROBICIDE COMPOUNDS WITH PIRIMIDINE OR TRIAZINE CONTENT
CN1665810A (en) 2002-05-30 2005-09-07 沃泰克斯药物股份有限公司 Inhibitors of JAK and CDK2 protein kinases
CA2489648A1 (en) 2002-06-17 2003-12-24 Smithkline Beecham Corporation Chemical process
EP1518855B1 (en) 2002-06-28 2011-10-26 Astellas Pharma Inc. Diaminopyrimidinecarboxa mide derivative
US7517886B2 (en) 2002-07-29 2009-04-14 Rigel Pharmaceuticals, Inc. Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
WO2004014384A2 (en) 2002-08-13 2004-02-19 Warner-Lambert Company Llc Cyclic compounds containing zinc binding groups as matrix metalloproteinase inhibitors
JP4741948B2 (en) * 2002-08-14 2011-08-10 バーテックス ファーマシューティカルズ インコーポレイテッド Protein kinase inhibitors and their use
ATE454378T1 (en) 2002-11-01 2010-01-15 Vertex Pharma COMPOUNDS ACTIVE AS INHIBITORS OF JAK AND OTHER PROTEIN KINASES
CA2506773A1 (en) 2002-11-04 2004-05-21 Vertex Pharmaceuticals Incorporated Heteroaryl-pyramidine derivatives as jak inhibitors
CA2507406A1 (en) 2002-11-05 2004-05-21 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of jak and other protein kinases
GB0226583D0 (en) 2002-11-14 2002-12-18 Cyclacel Ltd Compounds
GB0226582D0 (en) 2002-11-14 2002-12-18 Cyclacel Ltd Anti-viral compounds
AR042052A1 (en) 2002-11-15 2005-06-08 Vertex Pharma USEFUL DIAMINOTRIAZOLS AS INHIBITORS OF PROTEINQUINASES
KR100742012B1 (en) 2002-11-21 2007-07-23 화이자 프로덕츠 인코포레이티드 3-amino-piperidine derivatives and methods of manufacture
EP1572213A1 (en) 2002-11-26 2005-09-14 Pfizer Products Inc. Method of treatment of transplant rejection
EA200500721A1 (en) 2002-11-28 2005-12-29 Шеринг Акциенгезельшафт Pyrimidines inhibiting CHK, PDK and ACT, THEIR RECEIVING AND USING AS MEDICINES
AU2002350719A1 (en) 2002-11-29 2004-06-23 Janssen Pharmaceutica N.V. Pharmaceutical compositions comprising a basic respectively acidic drug compound, a surfactant and a physiologically tolerable water-soluble acid respectively base
AU2003289330A1 (en) 2002-12-13 2004-07-09 Kyowa Hakko Kogyo Co., Ltd. Preventives and/or remedies for central diseases
AU2003297160A1 (en) 2002-12-18 2004-07-22 Vertex Pharmaceuticals Incorporated Benzisoxazole derivatives useful as inhibitors of protein kinases
US7098332B2 (en) * 2002-12-20 2006-08-29 Hoffmann-La Roche Inc. 5,8-Dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones
UA80767C2 (en) 2002-12-20 2007-10-25 Pfizer Prod Inc Pyrimidine derivatives for the treatment of abnormal cell growth
EP1597237B1 (en) 2003-02-07 2016-07-27 Janssen Pharmaceutica NV Pyrimidine derivatives for the prevention of HIV infection
CL2004000303A1 (en) 2003-02-20 2005-04-08 Tibotec Pharm Ltd COMPOUNDS DERIVED FROM PYRIMIDINS AND TRIAZINES; PREPARATION PROCESS; PHARMACEUTICAL COMPOSITION; AND ITS USE TO INHIBIT HIV REPLICATION.
ES2325440T3 (en) 2003-02-20 2009-09-04 Smithkline Beecham Corporation PIRIMIDINE COMPOUNDS.
GB0305929D0 (en) 2003-03-14 2003-04-23 Novartis Ag Organic compounds
US7547794B2 (en) 2003-04-03 2009-06-16 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of protein kinases
MXPA05011523A (en) 2003-04-30 2006-01-23 Inst For Pharm Discovery Inc Substituted heteroaryls as inhibitors of protein tyrosine phosphatases.
GB0311274D0 (en) 2003-05-16 2003-06-18 Astrazeneca Ab Chemical compounds
GB0311276D0 (en) 2003-05-16 2003-06-18 Astrazeneca Ab Chemical compounds
US7915293B2 (en) 2003-05-30 2011-03-29 Rigel Pharmaceuticals, Inc. Ubiquitin ligase inhibitors
EP1651636A1 (en) 2003-07-10 2006-05-03 Neurogen Corporation Substituted heterocyclic diarylamine analogues
CA2531333A1 (en) 2003-07-16 2005-02-10 Janssen Pharmaceutica N.V. Triazolopyrimidine derivatives as glycogen synthase kinase 3 inhibitors
WO2005012304A2 (en) 2003-07-16 2005-02-10 Janssen Pharmaceutica N.V. Triazolopyrimidine derivatives as glycogen synthase kinase 3 inhibitors
AU2004259346A1 (en) 2003-07-22 2005-02-03 Neurogen Corporation Substituted pyridin-2-ylamine analogues
US7442698B2 (en) * 2003-07-24 2008-10-28 Amgen Inc. Substituted heterocyclic compounds and methods of use
EP1651599A4 (en) 2003-07-24 2008-09-24 Merck & Co Inc Tyrosine kinase inhibitors
AU2004261484A1 (en) 2003-07-30 2005-02-10 Cyclacel Limited 2-aminophenyl-4-phenylpyrimidines as kinase inhibitors
CN102358738A (en) 2003-07-30 2012-02-22 里格尔药品股份有限公司 2,4-pyrimidinediamine compounds and uses of treating or preventing autoimmune diseases thereof
DE602004032446D1 (en) 2003-08-07 2011-06-09 Rigel Pharmaceuticals Inc 2,4-PYRIMIDINDIAMIN COMPOUNDS AND USES AS ANTIPROLIFERATIVE AGENTS
EP1663234A1 (en) 2003-08-14 2006-06-07 Pfizer Limited Piperazine derivatives for the treatment of hiv infections
PL1660458T3 (en) 2003-08-15 2012-07-31 Novartis Ag 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders
AR045595A1 (en) 2003-09-04 2005-11-02 Vertex Pharma USEFUL COMPOSITIONS AS INHIBITORS OF KINASE PROTEINS
US7223759B2 (en) 2003-09-15 2007-05-29 Anadys Pharmaceuticals, Inc. Antibacterial 3,5-diaminopiperidine-substituted aromatic and heteroaromatic compounds
GB0321710D0 (en) 2003-09-16 2003-10-15 Novartis Ag Organic compounds
CA2538413A1 (en) 2003-09-18 2005-03-24 Novartis Ag 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders
WO2005027848A2 (en) 2003-09-19 2005-03-31 Barnes-Jewish Hospital Methods for screening osteogenic compounds targeting syk kinase and/or vav3 and uses of syk modulators and/or vav modulators
WO2005028479A2 (en) 2003-09-25 2005-03-31 Janssen Pharmaceutica N.V. Hiv replication inhibiting purine derivatives
ATE380813T1 (en) 2003-10-03 2007-12-15 Pfizer IMIDAZOPYRIDINE-SUBSTITUTED TROPANE DERIVATIVES WITH CCR5 RECEPTOR ANTAGONISTIC EFFECTS FOR THE TREATMENT OF HIV AND INFLAMMATION
DE10349423A1 (en) 2003-10-16 2005-06-16 Schering Ag Sulfoximine-substituted parimidines as CDK and / or VEGF inhibitors, their preparation and use as medicaments
US7235161B2 (en) * 2003-11-19 2007-06-26 Alcoa Inc. Stable anodes including iron oxide and use of such anodes in metal production cells
US20080312192A1 (en) 2003-11-28 2008-12-18 Guido Bold Diaryl Urea Derivatives in the Treatment of Protein Kinase Dependent Diseases
MY141255A (en) 2003-12-11 2010-03-31 Memory Pharm Corp Phosphodiesterase 4 inhibitors, including n-substituted diarylamine analogs
EP1694652A1 (en) 2003-12-19 2006-08-30 Rigel Pharmaceuticals, Inc. Stereoisomers and stereoisomeric mixtures of 1-(2,4-pyrimidinediamino)-2-cyclopentanecarboxamide synthetic intermediates
CA2545427C (en) 2004-01-12 2012-08-21 Cytopia Research Pty Ltd Selective kinase inhibitors
GB0402653D0 (en) 2004-02-06 2004-03-10 Cyclacel Ltd Compounds
EP1713806B1 (en) 2004-02-14 2013-05-08 Irm Llc Compounds and compositions as protein kinase inhibitors
US7745625B2 (en) * 2004-03-15 2010-06-29 Bristol-Myers Squibb Company Prodrugs of piperazine and substituted piperidine antiviral agents
WO2005107760A1 (en) 2004-04-30 2005-11-17 Irm Llc Compounds and compositions as inducers of keratinocyte differentiation
CA2566531A1 (en) * 2004-05-18 2005-12-15 Rigel Pharmaceuticals, Inc. Cycloalkyl substituted pyrimidinediamine compounds and their uses
GB0419161D0 (en) 2004-08-27 2004-09-29 Novartis Ag Organic compounds
US20060047135A1 (en) 2004-08-30 2006-03-02 Chadwick Scott T Process for preparing chloromethyl di-tert-butylphosphate
CA2578349A1 (en) * 2004-09-01 2006-03-16 Rigel Pharmaceuticals, Inc. Synthesis of 2,4-pyrimidinediamine compounds
EP1794134A1 (en) 2004-09-29 2007-06-13 Bayer Schering Pharma Aktiengesellschaft Substituted 2-anilinopyrimidines as cell cycle kinase inhibitors or receptor tyrosine kinase inhibitors, production of said substances and use of the latter as medicaments
EP1817303A2 (en) * 2004-10-29 2007-08-15 Rigel Pharmaceuticals, Inc. Substituted pyridines with activity on syk kinase
CA2584295C (en) * 2004-11-24 2014-08-26 Rigel Pharmaceuticals, Inc. Spiro-2, 4-pyrimidinediamine compounds and their uses
US7442716B2 (en) 2004-12-17 2008-10-28 Merck Frosst Canada Ltd. 2-(phenyl or heterocyclic)-1H-phenantrho[9,10-d]imidazoles as mPGES-1 inhibitors
EP1841760B1 (en) 2004-12-30 2011-08-10 Exelixis, Inc. Pyrimidine derivatives as kinase modulators and method of use
DE602006010979D1 (en) 2005-01-19 2010-01-21 Rigel Pharmaceuticals Inc PRODRUGS FROM 2,4-PYRIMIDIN DIAMIN COMPOUNDS AND THEIR USES
CA2604551A1 (en) 2005-05-03 2007-03-08 Rigel Pharmaceuticals, Inc. Jak kinase inhibitors and their uses
US20070203161A1 (en) 2006-02-24 2007-08-30 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
WO2006133426A2 (en) * 2005-06-08 2006-12-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
CA2607901C (en) * 2005-06-13 2016-08-16 Rigel Pharmaceuticals, Inc. Methods and compositions for treating degenerative bone disorders using a syk inhibitory 2,4-pyrimidinediamine
WO2007006926A2 (en) 2005-07-11 2007-01-18 Sanofi-Aventis Novel 2,4-dianilinopyrimidine derivatives, the preparation thereof, their use as medicaments, pharmaceutical compositions and, in particular, as ikk inhibitors
ES2344275T3 (en) 2005-07-28 2010-08-23 Intervet International Bv NEW (UNCLE) CARBAMATES FROM BENZIMIDAZOL WITH ANTIPARASITARY ACTIVITY AND SYNTHESIS OF THEM.
JP4981673B2 (en) 2005-09-13 2012-07-25 エーザイ・アール・アンド・ディー・マネジメント株式会社 Composition comprising chloromethyl phosphate derivative with improved stability and method for producing the same
US20070117775A1 (en) 2005-10-31 2007-05-24 Rigel Pharmaceuticals, Inc. Compositions and Methods For Treating Inflammatory Disorders
DK1951684T3 (en) * 2005-11-01 2016-10-24 Targegen Inc BIARYLMETAPYRIMIDIN kinase inhibitors
US7713987B2 (en) * 2005-12-06 2010-05-11 Rigel Pharmaceuticals, Inc. Pyrimidine-2,4-diamines and their uses
US7962290B1 (en) * 2006-01-09 2011-06-14 Rigel Pharmaceuticals, Inc. Identification of pharmacophores from co-crystals of spleen tyrosine kinase (SYK) and SYK ligands
TW200736232A (en) 2006-01-26 2007-10-01 Astrazeneca Ab Pyrimidine derivatives
WO2007085540A1 (en) 2006-01-27 2007-08-02 Glaxo Group Limited 1h-indaz0l-4-yl-2 , 4-pyrimidinediamine derivatives
PT1984357E (en) 2006-02-17 2013-12-23 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds for treating or preventing autoimmune diseases
CA2642229C (en) 2006-02-24 2015-05-12 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
US20090192158A1 (en) 2006-05-02 2009-07-30 Stacia Kargman Methods for Treating or Preventing Neoplasias
US7776855B2 (en) 2006-07-27 2010-08-17 Janssen Pharmaceutica N.V. Antimicrobial oxazolidinone prodrugs
WO2008049123A2 (en) 2006-10-19 2008-04-24 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine derivatives as inhibitors of jak kinases for the treatment of autoimmune diseases
US7947698B2 (en) 2007-03-23 2011-05-24 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the JAK pathway
WO2008118823A2 (en) 2007-03-26 2008-10-02 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
KR20100049068A (en) 2007-07-17 2010-05-11 리겔 파마슈티칼스, 인크. Cyclic amine substituted pyrimidinediamines as pkc inhibitors
DK2683385T3 (en) * 2011-03-10 2018-09-17 Rigel Pharmaceuticals Inc 2,4-SUBSTITUTED PYRIMIDINE DIAMINES FOR DISKOID LUPUS USE

Also Published As

Publication number Publication date
US20050038243A1 (en) 2005-02-17
US20100197918A1 (en) 2010-08-05
BRPI0307355B8 (en) 2019-08-06
US20060058292A1 (en) 2006-03-16
US20170081290A1 (en) 2017-03-23
AU2003208931C1 (en) 2009-04-02
US20050209230A1 (en) 2005-09-22
IL221381A (en) 2015-05-31
US8748597B2 (en) 2014-06-10
BRPI0307355C1 (en) 2021-05-25
US9499493B2 (en) 2016-11-22
PT2281563E (en) 2013-12-09
RS53367B (en) 2014-10-31
US9018204B1 (en) 2015-04-28
US10709703B2 (en) 2020-07-14
US9416112B2 (en) 2016-08-16
CN102174024A (en) 2011-09-07
US20090171085A1 (en) 2009-07-02
US20150158823A1 (en) 2015-06-11
US7906644B2 (en) 2011-03-15
JP4658477B2 (en) 2011-03-23
EP2281563A1 (en) 2011-02-09
JP5357116B2 (en) 2013-12-04
WO2003063794A2 (en) 2003-08-07
US9540334B2 (en) 2017-01-10
HRP20040684A2 (en) 2008-12-31
US11007193B2 (en) 2021-05-18
US7550460B2 (en) 2009-06-23
YU67404A (en) 2006-08-17
US9346765B2 (en) 2016-05-24
US20060035916A1 (en) 2006-02-16
US20070293523A1 (en) 2007-12-20
US20040029902A1 (en) 2004-02-12
NZ534361A (en) 2008-04-30
US10828301B2 (en) 2020-11-10
US20070293520A1 (en) 2007-12-20
HK1069538A1 (en) 2005-05-27
US7485724B2 (en) 2009-02-03
US20160009661A1 (en) 2016-01-14
KR20040101216A (en) 2004-12-02
US20120045454A1 (en) 2012-02-23
CN1625400A (en) 2005-06-08
US20090082567A1 (en) 2009-03-26
US7332484B2 (en) 2008-02-19
CN102174024B (en) 2015-02-11
US7498435B2 (en) 2009-03-03
US20140031350A1 (en) 2014-01-30
JP2005516046A (en) 2005-06-02
US7557210B2 (en) 2009-07-07
IL221381A0 (en) 2012-09-24
US8410266B2 (en) 2013-04-02
US20070225321A1 (en) 2007-09-27
RS20120098A1 (en) 2012-08-31
BRPI0307355B1 (en) 2018-11-13
US20060135543A1 (en) 2006-06-22
SG167664A1 (en) 2011-01-28
US20150126504A1 (en) 2015-05-07
US20090171086A1 (en) 2009-07-02
SI1471915T1 (en) 2012-03-30
AU2008252053A1 (en) 2009-01-08
US10369148B2 (en) 2019-08-06
US9913842B2 (en) 2018-03-13
MX341239B (en) 2016-08-12
ES2373646T3 (en) 2012-02-07
US20130317216A1 (en) 2013-11-28
US8835430B2 (en) 2014-09-16
US20200085820A1 (en) 2020-03-19
US20070293521A1 (en) 2007-12-20
DK2281563T3 (en) 2014-01-13
JP2010285441A (en) 2010-12-24
US20080039622A1 (en) 2008-02-14
US8188276B2 (en) 2012-05-29
US20170151239A1 (en) 2017-06-01
US20190358228A1 (en) 2019-11-28
US7655797B2 (en) 2010-02-02
US20060025410A1 (en) 2006-02-02
US20190255047A1 (en) 2019-08-22
CN1625400B (en) 2011-04-13
US7589200B2 (en) 2009-09-15
US20140330007A1 (en) 2014-11-06
EP2281563B1 (en) 2013-09-18
NO20043632L (en) 2004-10-26
US7060827B2 (en) 2006-06-13
AU2003208931B2 (en) 2008-09-04
EP1471915A4 (en) 2006-02-15
NO328071B1 (en) 2009-11-23
US20170246167A1 (en) 2017-08-31
PL373530A1 (en) 2005-09-05
US9040550B2 (en) 2015-05-26
US7803939B2 (en) 2010-09-28
CY1112516T1 (en) 2015-12-09
US20090156622A1 (en) 2009-06-18
ATE524184T1 (en) 2011-09-15
DK1471915T3 (en) 2012-01-09
US7329672B2 (en) 2008-02-12
ES2440283T3 (en) 2014-01-28
US20130150349A1 (en) 2013-06-13
US20070293524A1 (en) 2007-12-20
SI2281563T1 (en) 2014-02-28
TW200307547A (en) 2003-12-16
US20150005297A1 (en) 2015-01-01
HK1154216A1 (en) 2012-04-13
US20110144330A1 (en) 2011-06-16
US10314840B2 (en) 2019-06-11
PT1471915E (en) 2011-12-26
US20130324524A1 (en) 2013-12-05
US8822685B2 (en) 2014-09-02
US7329671B2 (en) 2008-02-12
US20210267971A1 (en) 2021-09-02
EP1471915A2 (en) 2004-11-03
US7642351B2 (en) 2010-01-05
US20150266828A1 (en) 2015-09-24
CA2474277A1 (en) 2003-08-07
EP1471915B1 (en) 2011-09-14
US7435814B2 (en) 2008-10-14
US20070293522A1 (en) 2007-12-20
US20160009660A1 (en) 2016-01-14
BR0307355A (en) 2006-04-11
US8148525B2 (en) 2012-04-03
US20140303154A1 (en) 2014-10-09
US9162989B2 (en) 2015-10-20
HRP20040684B1 (en) 2014-07-04
US9133133B2 (en) 2015-09-15
PL214988B1 (en) 2013-10-31
US20150329532A1 (en) 2015-11-19
US10682350B2 (en) 2020-06-16
MXPA04007386A (en) 2006-04-27
US8334296B2 (en) 2012-12-18
RS54105B1 (en) 2015-10-30
US8853397B2 (en) 2014-10-07
WO2003063794A3 (en) 2003-12-04
TWI329105B (en) 2010-08-21
US7820819B2 (en) 2010-10-26
US9586908B2 (en) 2017-03-07
KR101037856B1 (en) 2011-06-01

Similar Documents

Publication Publication Date Title
US10709703B2 (en) 2,4-pyrimidinediamine compounds and their uses
RU2659777C9 (en) Methods for treatment or prevention of autoimmune diseases with use of 2,4-pyrimidinediamine
AU2003208931A1 (en) 2,4-pyrimidinediamine compounds and their uses
JP2005516046A5 (en)

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry

Effective date: 20230131