CA2464214A1 - Protein kinase and phosphatase inhibitors, methods for designing them, and methods of using them - Google Patents

Protein kinase and phosphatase inhibitors, methods for designing them, and methods of using them Download PDF

Info

Publication number
CA2464214A1
CA2464214A1 CA002464214A CA2464214A CA2464214A1 CA 2464214 A1 CA2464214 A1 CA 2464214A1 CA 002464214 A CA002464214 A CA 002464214A CA 2464214 A CA2464214 A CA 2464214A CA 2464214 A1 CA2464214 A1 CA 2464214A1
Authority
CA
Canada
Prior art keywords
group
biaryl
heteroaryl
aryl
cyclic
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.)
Granted
Application number
CA002464214A
Other languages
French (fr)
Other versions
CA2464214C (en
Inventor
David G. Hangauer, Jr.
Moustafa E. El-Araby
Karen L. Milkiewicz
Thomas Nicotera
Donald Henderson
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.)
ROSWELL PARK CANCER INSTITUTE
Research Foundation of State University of New York
Original Assignee
Individual
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
Application filed by Individual filed Critical Individual
Publication of CA2464214A1 publication Critical patent/CA2464214A1/en
Application granted granted Critical
Publication of CA2464214C publication Critical patent/CA2464214C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61P17/06—Antipsoriatics
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • 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
    • 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
    • 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

Abstract

The present invention provides a method for identifying inhibitors of protein kinases and/or protein phosphatases. Methods are also provided for inhibiting protein kinase and/or protein phosphatase activity. Specific non-peptide protein tyrosine kinase and/or protein phosphatase inhibitors are provided.
The protein kinase or protein phosphatase inhibitors of the present invention may be used to treat a number of conditions in patients, including cancer, psoriasis, arthrosclerosis, immune system activity, diabetes, or obesity. In addition, the present invention provides a method for protecting against or treating hearing loss in a subject. This method involves administering an effective amount of a protein tyrosine kinase inhibitor to the subject to protect against or to treat hearing loss.

Claims (217)

1. A non-peptide protein tyrosine kinase inhibitor or protein phosphatase inhibitor having the formula:
wherein X is a halogen;
R1 through R6 may be the same or different, and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R
a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and a branched, cyclic, or unbranched alkyl;
wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl; or R5 and R6 together form a heterocyclic compound; and wherein any of R1 through R6 and R a through R c is substituted or unsubstituted.
2. The non-peptide inhibitor according to claim 1, wherein at least one of R5 or R6 is wherein R7* is the point of attachment and is (CH2)x, wherein X is from 0 to 10, CH2CHOH, CH(CH3)R, or CH(CH3)S, and each of R8 through R12 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R
b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR6, NR a P(O)OR b OR c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and a branched, cyclic, or unbranched alkyl, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl; and wherein any of R8 through R12 and R a through R c is substituted or unsubstituted.
3. The non-peptide inhibitor according to claim 1, wherein at least one of R5 or R6 is wherein the asterisk indicates the point of attachment to the nitrogen.
4. The non-peptide inhibitor according to claim 1, wherein X is fluorine.
5. The non-peptide inhibitor according to claim 1, wherein the non-peptide inhibitor inhibits the activity of pp60c-src tyrosine kinase.
6. The non-peptide inhibitor according to claim 1, wherein the non-peptide inhibitor inhibits the activity of protein tyrosine phosphatase 1B.
7. The non-peptide inhibitor according to claim 1, wherein the non-peptide inhibitor inhibits the activity of epidermal growth factor receptor tyrosine kinase.
8. The non-peptide inhibitor according to claim 1, wherein the non-peptide inhibitor inhibits the activity of p56 lck tyrosine kinase.
9. The non-peptide inhibitor according to claim 1, wherein the non-peptide inhibitor inhibits the activity of p55 fyn tyrosine kinase.
10. A non-peptide protein tyrosine kinase inhibitor or protein phosphatase inhibitor having the formula:
wherein X is a halogen, R1 is H, R2 is <IMGs>
R3 is H, and R4 is H.
11. The non-peptide inhibitor according to claim 10, wherein X is fluorine.
12. The non-peptide inhibitor according to claim 10, wherein the non-peptide inhibitor inhibits the activity of pp60c-src tyrosine kinase.
13. The non-peptide inhibitor according to claim 10, wherein the non-peptide inhibitor inhibits the activity of protein tyrosine phosphatase 1B.
14. The non-peptide inhibitor according to claim 10, wherein the non-peptide inhibitor inhibits the activity of epidermal growth factor receptor tyrosine kinase.
15. The non-peptide inhibitor according to claim 10, wherein the non-peptide inhibitor inhibits the activity of p56 lck tyrosine kinase.
16. The non-peptide inhibitor according to claim 10, wherein the non-peptide inhibitor inhibits the activity of p55 fyn tyrosine kinase.
17. A method for identifying inhibitors of protein kinases comprising:
providing at least one first module having one or more functional groups each capable of covalently or non-covalently binding to catalytic residues of the protein kinase, wherein at least one of the one or more functional groups is a halogen;

combining the at least one first module with at least one second module which provides a non-peptide scaffold to form one or more combinations of the first and second modules;
screening the one or more combinations of the first and second modules for protein kinase inhibition; and selecting combinations of the first and second modules which inhibit protein kinase activity.
18. The method according to claim 17, wherein said providing at least one first module comprises:
attaching the at least one first module to a peptide scaffold;
identifying one or more functional groups on the first module which preferentially bind to catalytic residues of the protein kinase; and wherein said combining the at least one first module with the at least one second module comprises:
substituting the at least one second module for the peptide scaffold.
19. The method according to claim 17, wherein the halogen is fluorine.
20. The method according to claim 17, wherein the at least one first module comprises two or more functional groups.
21. The method according to claim 20, wherein the at least one first module comprises a functional group selected from the group consisting of boronic acid, a hydroxyl group, phosphonic acid, sulfamic acid, a guanidino group, carboxylic acid, an aldehyde, an amide, and hydroxymethylphosphonic acid
22. The method according to claim 21, wherein the at least one first module comprises a boronic acid group.
23. The method according to claim 21, wherein the at least one first module comprises a hydroxyl group.
24. The method according to claim 21, wherein the at least one first module comprises a amide group.
25. The method according to claim 24, wherein the amide group is a vicinal tricarbonyl amide.
26. The method according to claim 17, wherein the at least one second module is selected from the group consisting of indole, naphthalene, biphenyl, isoquinoline, benzofuran, and benzothiophene.
27. The method according to claim 26, wherein the at least one second module comprises an indole.
28. The method according to claim 26, wherein the at least one second module comprises naphthalene.
29. The method according to claim 17, wherein the at least one first module further comprises a linear chain comprising between one and three carbon atoms which links the at least one first module to at least one second module.
30. The method according to claim 29, wherein one of the carbon atoms in the linear chain is substituted with a nitrogen, oxygen, or sulfur atom.
31. The method according to claim 17, wherein the protein kinase is a protein tyrosine kinase.
32. The method according to claim 31, wherein the protein tyrosine kinase is selected from the group consisting of pp60c-src, p56tck, p55fyn, ZAP
kinase, platelet derived growth factor receptor tyrosine kinase, Bcr-Abl, VEGF receptor tyrosine kinase, epidermal growth factor receptor tyrosine kinase, and epidermal growth factor receptor-like tyrosine kinases.
33. The method according to claim 32, wherein the protein tyrosine kinase is pp60c-src.
34. The method according to claim 17, wherein the protein kinase is a protein serine kinase.
35. The method according to claim 34, wherein the protein serine kinase is selected from the group consisting of MAP kinase, protein kinase C, and CDK
kinase.
36. The method according to claim 17, further comprising:
attaching one or more specificity side chain elements to the one or more combinations of the first and second modules.
37. A method for identifying improved protein kinase inhibitors, comprising:
providing a first inhibitor produced according to the method of claim 17, modifying the at least one first module, specificity side chain elements, or a combination thereof of the first inhibitor; and identifying modified inhibitors which have an increased ability to inhibit protein kinase activity when compared to the unmodified first inhibitor.
38. The method according to claim 17, wherein the protein kinase inhibitor inhibits protein kinase activity but does not inhibit ATP binding to the protein kinase.
39. A method for testing compounds for an ability to inhibit protein kinase activity comprising:
providing a protein kinase inhibitor according to the method of claim 17, measuring activity of the protein kinase in the presence of the inhibitor at a same temperature, pH, ionic strength, osmolarity, and free magnesium concentration as found in a cell which expresses the protein kinase; and comparing the protein kinase activity to activity from the protein kinase without the presence of the inhibitor.
40. A method of inhibiting a protein kinase comprising:
contacting the protein kinase with a compound comprising at least one first module having one or more functional groups each capable of covalently or non-covalently binding to catalytic residues of the protein kinase, wherein the one or more functional groups comprise a halogen, and a second module which provides a non-peptide scaffold, wherein the combination of the at least one first module and second module inhibits the protein kinase's activity.
41. The method according to claim 40, wherein the halogen is fluorine.
42. The method according to claim 40, wherein the first module comprises two or more functional groups.
43. The method according to claim 42, wherein the first module comprises a functional group selected from the group consisting of boronic acid, hydroxy, phosphoric acid, sulfamic acid, a guanidino group, carboxylic acid, an aldehyde, an amide, and hydroxymethylphosphonic acid.
44. The method according to claim 43, wherein the first module comprises a boronic acid group.
45. The method according to claim 43, wherein the first module comprises a hydroxyl group.
46. The method according to claim 40, wherein the second module is selected from the group consisting of indole, naphthalene, biphenyl, isoquinoline, benzofuran, and benzothiophene.
47. The method according to claim 46, wherein the second module comprises an indole.
48. The method according to claim 46, wherein the second module comprises naphthalene.
49. The method according to claim 40, wherein a linear chain comprising between one and three carbon atoms links the first module to the second module.
50. The method according to claim 49, wherein one of the carbon atoms in the linear chain is substituted with a nitrogen, oxygen, or sulfur atom.
51. The method according to claim 40, wherein the protein kinase is a protein tyrosine kinase.
52. The method according to claim 51, wherein the protein tyrosine kinase is selected from the group consisting of pp60c-src, p56lck, p55fyn, ZAP
kinase, platelet derived growth factor receptor tyrosine kinase, Bcr-Ab1, VEGF receptor tyrosine kinase, epidermal growth factor receptor tyrosine kinase and epidermal growth factor receptor-like tyrosine kinases.
53. The method according to claim 52, wherein the protein tyrosine kinase is pp60c-src.
54. The method according to claim 53, wherein the compound has the following formula:

wherein X is a halogen;
R1 through R6 may be the same or different, and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R
a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and a branched, cyclic, or unbranched alkyl, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl, or R5 and R6 together form a heterocyclic compound; and wherein any of R1 through R6 and R a through R c is substituted or unsubstituted.
55. The method according to claim 54, wherein at least one of R5 or R6 is wherein R7* is the point of attachment and is (CH2)x, wherein X is from 0 to 10, CH2CHOH, CH(CH3)R, or CH(CH3)S, and each of R8 through R12 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R
b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and a branched, cyclic, or unbranched alkyl, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl; and wherein any of R8 through R12 and R a through R c is substituted or unsubstituted.
56. The method according to claim 54, wherein at least one of R5 or R6 is wherein the asterisk indicates the point of attachment to the nitrogen.
57. The method according to claim 54, wherein X is fluorine.
58. The method according to claim 53, wherein the compound has the following formula:

wherein X is a halogen, R1 is H, R2 is R3 is H, and R4 is H.
59. The method according to claim 58, wherein X is fluorine.
60. The method according to claim 40, wherein the protein kinase is a protein serine kinase.
61. The method according to claim 60, wherein the protein serine kinase is selected from the group consisting of MAP kinase, protein kinase C, and CDK
kinase.
62. The method according to claim 40, wherein the compound further comprises one or more specificity side chain elements attached to the combination of the at least one first module and second module.
63. A method of treating a condition, responsive to a protein kinase inhibitor, in a subject comprising:
administering an effective dose of a protein kinase inhibitor to a subject wherein the protein kinase inhibitor comprises at least one first module having one or more functional groups each capable of covalently or non-covalently binding to catalytic residues of the protein kinase, wherein the one or more functional groups comprise a halogen, and a second module which provides a non-peptide scaffold, wherein the combination of the at least one first module and second module inhibits protein kinase activity.
64. The method according to claim 63, wherein the condition is selected from the group consisting of cancer, psoriasis, arthrosclerosis, or immune system activity.
65. The method according to claim 63, wherein the halogen is fluorine.
66. The method according to claim 63, wherein the first module comprises two or more functional groups.
67. The method according to claim 66, wherein the first module comprises a functional group selected from the group consisting of boronic acid, hydroxy, phosphonic acid, sulfamic acid, a guanidino group, carboxylic acid, an aldehyde, an amide, and hydroxymethylphosphonic acid.
68. The method according to claim 67, wherein the first module comprises a boronic acid group.
69. The method according to claim 67, wherein the first module comprises a hydroxyl group.
70. The method according to claim 63, wherein the second module is selected from the group consisting of indole, naphthalene, biphenyl, isoquinoline, benzofuran, and benzothiophene.
71. The method according to claim 70, wherein the second module comprises indole.
72. The method according to claim 70, wherein the second module comprises naphthalene.
73. The method according to claim 63, wherein a linear chain comprising between one and three carbon atoms links the at least one first module to the second module.
74. The method according to claim 73, wherein one of the carbon atoms in the linear chain is substituted with a nitrogen, oxygen, or sulfur atom.
75. The method according to claim 63, wherein the protein kinase is a protein tyrosine kinase.
76. The method according to claim 75, wherein the protein tyrosine kinase is selected from the group consisting of pp60c-src, p56lck, p55fyn, ZAP
kinase, platelet derived growth factor receptor tyrosine kinase, Bcr-Ab1, VEGF receptor tyrosine kinase, epidermal growth factor receptor tyrosine kinase, and epidermal growth factor receptor-like tyrosine kinases.
77. The method according to claim 76, wherein the protein tyrosine kinase is pp60c-src.
78. The method according to claim 77, wherein the compound has the following formula:

wherein X is a halogen;
R1 through R6 may be the same or different, and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R
a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and a branched, cyclic, or unbranched alkyl, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl, or R5 and R6 together form a heterocyclic compound; and wherein any of R1 through R6 and R a through R c is substituted or unsubstituted.
79. The method according to claim 78, wherein at least one of R5 or R6 is wherein R7* is the point of attachment and is (CH2)x, wherein X is from 0 to 10, CH2CHOH, CH(CH3)R, or CH(CH3)S, and each of R8 through R12 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R
b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and a branched, cyclic, or unbranched alkyl, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl; and wherein any of R8 through R12 and R a through R c is substituted or unsubstituted.
80. The method according to claim 78, wherein at least one of R5 or R6 is wherein the asterisk indicates the point of attachment to the nitrogen.
81. The method according to claim 78, wherein X is fluorine.
82. The method according to claim 77, wherein the compound has the following formula:

wherein X is a halogen, R1 is H, R2 is <IMGs>
R3 is H, and R4 is H.
83. The method according to claim 82, wherein X is fluorine.
84. The method according to claim 63, wherein the protein kinase is a protein serine kinase.
85. The method according to claim 84, wherein the protein serine kinase is selected from the group consisting of MAP kinase, protein kinase C, and CDK
kinase.
86. The method according to claim 63, wherein the compound further comprises one or more specificity side chain elements attached to the combination of the at least one first module and second module.
87. A method for identifying inhibitors of protein phosphatases comprising:
providing at least one first module having one or more functional groups each capable of covalently or non-covalently binding to catalytic residues of the protein phosphatase;

combining the at least one first module with at least one second module which provides a non-peptide scaffold to form one or more combinations of the first and second modules;
screening the one or more combinations of the first and second modules for protein phosphatase inhibition; and selecting combinations of the first and second modules which inhibit protein phosphatase activity.
88. The method according to claim 87, wherein said providing at least one first module comprises:
attaching the at least one first module to a peptide scaffold;
identifying one or more functional groups on the first module which preferentially bind to catalytic residues of the protein phosphatase; and wherein said combining the at least one first module with the at least one second module comprises:
substituting the at least one second module for the peptide scaffold.
89. The method according to claim 87, wherein the at least one first module comprises two or more functional groups.
90. The method according to claim 87, wherein the at least one first module comprises a functional group selected from the group consisting of a halogen, boronic acid, a hydroxyl group, phosphonic acid, sulfamic acid, a guanidino group, carboxylic acid, an aldehyde, an amide, and hydroxymethylphosphonic acid
91. The method according to claim 90, wherein the at least one first module comprises a halogen.
92. The method according to claim 90, wherein the at least one first module comprises a boronic acid group.
93. The method according to claim 90, wherein the at least one first module comprises a hydroxyl group.
94. The method according to claim 90, wherein the at least one first module comprises a amide group.
95. The method according to claim 94, wherein the amide group is a vicinal tricarbonyl amide.
96. The method according to claim 87, wherein the at least one second module is selected from the group consisting of indole, naphthalene, biphenyl, isoquinoline, benzofuran, and benzothiophene.
97. The method according to claim 96, wherein the at least one second module comprises an indole.
98. The method according to claim 96, wherein the at least one second module comprises naphthalene.
99. The method according to claim 87, wherein the at least one first module further comprises a linear chain comprising between one and three carbon atoms which links the at least one first module to at least one second module.
100. The method according to claim 99, wherein one of the carbon atoms in the linear chain is substituted with a nitrogen, oxygen, or sulfur atom.
101. The method according to claim 87, wherein the protein phosphatase is protein tyrosine phosphatase 1B.
102. The method according to claim 87, further comprising:
attaching one or more specificity side chain elements to the one or more combinations of the first and second modules.
103. A method for identifying improved protein phosphatase inhibitors, comprising:
providing a first inhibitor produced according to the method of claim 87, modifying the at least one first module, specificity side chain elements, or a combination thereof of the first inhibitor; and identifying modified inhibitors which have an increased ability to inhibit protein phosphatase activity when compared to the unmodified first inhibitor.
104. A method for testing compounds for an ability to inhibit protein phosphatase activity comprising:
providing a protein phosphatase inhibitor according to the method of claim 87, measuring activity of the protein phosphatase in the presence of the inhibitor at a same temperature, pH, ionic strength, osmolarity, and free magnesium concentration as found in a cell which expresses the protein phosphatase; and comparing the protein phosphatase activity to activity from the protein phosphatase without the presence of the inhibitor.
105. A method of inhibiting a protein phosphatase comprising:
contacting the protein phosphatase with a compound comprising at least one first module having one or more functional groups each capable of covalently or non-covalently binding to catalytic residues of the protein phosphatase, and a second module which provides a non-peptide scaffold, wherein the combination of the at least one first module and second module inhibits the protein phosphatase's activity.
106. The method according to claim 105, wherein the first module comprises two or more functional groups.
107. The method according to claim 105, wherein the first module comprises a functional group selected from the group consisting of a halogen, boronic acid, hydroxy, phosphonic acid, sulfamic acid, a guanidino group, carboxylic acid, an aldehyde, an amide, and hydroxymethylphosphonic acid.
108. The method according to claim 107, wherein the first module comprises a halogen.
109. The method according to claim 107, wherein the first module comprises a boronic acid group.
110. The method according to claim 107, wherein the first module comprises a hydroxyl group.
111. The method according to claim 105, wherein the second module is selected from the group consisting of indole, naphthalene, biphenyl, isoquinoline, benzofuran, and benzothiophene.
112. The method according to claim 111, wherein the second module comprises an indole.
113. The method according to claim 111, wherein the second module comprises naphthalene.
114. The method according to claim 105, wherein a linear chain comprising between one and three carbon atoms links the at least one first module to the second module.
115. The method according to claim 114, wherein one of the carbon atoms in the linear chain is substituted with a nitrogen, oxygen, or sulfur atom.
116. The method according to claim 105, wherein the protein phosphatase is protein tyrosine phosphatase 1B.
117. The method according to claim 105, wherein the compound has the following formula:

wherein R1 through R7 may be the same or different, and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and a branched, cyclic, or unbranched alkyl, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl, or R6 and R7 together form a heterocyclic compound; and wherein any of R1 through R7 and R a through R c is substituted or unsubstituted.
118. The method according to claim 117, wherein R3 is a halogen.
119. The method according to claim 118, wherein R3 is fluorine.
120. The method according to claim 117, wherein at least one of R6 or R7 is wherein R8* is the point of attachment and is (CH2)x, wherein X is from 0 to 10, CH2CHOH, CH(CH3)R, or CH(CH3)S, and each of R9 through R13 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R
b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and a branched, cyclic, or unbranched alkyl, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl; and wherein any of R9 through R13 and R a through R c is substituted or unsubstituted.
121. The method according to claim 117, wherein at least one of R6 or R7 is wherein the asterisk indicates the point of attachment to the nitrogen.
122. The method according to claim 105, wherein the compound has the formula wherein each of R1 through R7 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and a branched, cyclic, or unbranched alkyl, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl; and wherein any of R1 through R7 and R a through R c is substituted or unsubstituted; and X is 0 or 1.
123. The method according to claim 105, wherein the compound further comprises one or more specificity side chain elements attached to the combination of the at least one first module and second module.
124. A method of treating a condition, responsive to a protein phosphatase inhibitor, in a subject comprising:
administering an effective dose of a protein phosphatase inhibitor to a subject wherein the protein phosphatase inhibitor comprises at least one first module having one or more functional groups each capable of covalently or non-covalently binding to catalytic residues of the protein phosphatase, and a second module which provides a non-peptide scaffold, wherein the combination of the at least one first module and second module inhibits protein phosphatase activity.
125. The method according to claim 124, wherein the condition is selected from the group consisting of cancer, Type II diabetes, and obesity.
126. The method according to claim 124, wherein the first module comprises two or more functional groups.
127. The method according to claim 124, wherein the first module comprises a functional group selected from the group consisting of boronic acid, hydroxy, phosphonic acid, sulfamic acid, a guanidino group, carboxylic acid, an aldehyde, an amide, and hydroxymethylphosphonic acid.
128. The method according to claim 127, wherein the first module comprises a halogen.
129. The method according to claim 127, wherein the first module comprises a boronic acid group.
130. The method according to claim.127, wherein the first module comprises a hydroxyl group.
131. The method according to claim 124, wherein the second module is selected from the group consisting of indole, naphthalene, biphenyl, isoquinoline, benzofuran, and benzothiophene.
132. The method according to claim 131, wherein the second module comprises indole.
133. The method according to claim 131, wherein the second module comprises naphthalene.
134. The method according to claim 124, wherein a linear chain comprising between one and three carbon atoms links the at least one first module to the second module.
135. The method according to claim 134, wherein one of the carbon atoms in the linear chain is substituted with a nitrogen, oxygen, or sulfur atom.
136. The method according to claim 124, wherein the protein phosphatase is protein tyrosine phosphatase 1B.
137. The method according to claim 124, wherein the compound has the following formula:
wherein R1 through R7 may be the same or different, and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a , OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and a branched, cyclic, or unbranched alkyl, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl, or R6 and R7 together form a heterocyclic compound; and wherein any of R1 through R7 and R a through R c is substituted or unsubstituted.
138. The method according to claim 137, wherein R3 is a halogen.
139. The method according to claim 138, wherein R3 is fluorine.
140. The method according to claim 137, wherein at least one of R6 or R7 is wherein R8* is the point of attachment and is (CH2)x, wherein X is from 0 to 10, CH2CHOH, CH(CH3)R, or CH(CH3)S, and each of R9 through R13 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R
b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR c, NR a P(O)OR b, NR a P(O)OR
b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and a branched, cyclic, or unbranched alkyl, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl; and wherein any of R9 through R13 and R a through R c is substituted or unsubstituted.
141. The method according to claim 137, wherein at least one of R6 or R7 is wherein the asterisk indicates the point of attachment to the nitrogen.
142. The method according to claim 124, wherein the compound has the formula:
wherein each of R1 through R7 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)Ra, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and a branched, cyclic, or unbranched alkyl, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl; and wherein any of R1 through R7 and R a through R c is substituted or unsubstituted; and X is 0 or 1.
143. The method according to claim 124, wherein the compound further comprises one or more specificity side chain elements attached to the combination of the at least one first module and second module.
144. The method according to claim 40, wherein the compound has the following formula:
wherein R1 through R8 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R8 and R a through R c may be substituted or unsubstituted; provided that at least one of R1 through R8 is a halogen.
145. The method according to claim 40, wherein the compound has the following formula:
wherein R1 through R7 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R7 and R a through R c may be substituted or unsubstituted.
146. The method according to claim 40, wherein the compound has the following formula:
wherein R1 through R7 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R7 and R a through R c may be substituted or unsubstituted.
147. The method according to claim 40, wherein the compound has the following formula:
wherein R1 through R6 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R6 and R a through R c may be substituted or unsubstituted.
148. The method according to claim 40, wherein the compound has the following formula:
wherein R1 through R6 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b,R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R6 and R a through R c may be substituted or unsubstituted.
149. The method according to claim 40, wherein the compound has the following formula:
wherein R1 through R5 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R5 and R a through R c may be substituted or unsubstituted.
150. The method according to claim 40, wherein the compound has the following formula:
wherein R1 through R8 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R8 and R a through R c may be substituted or unsubstituted.
151. The method according to claim 40, wherein the compound has the following formula:
wherein R1 through R6 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R6 and R a through R c may be substituted or unsubstituted.
152. The method according to claim 40, wherein the compound has the following formula:

wherein R1 through R10 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R10 and R a through R c may be substituted or unsubstituted.
153. The method according to claim 63, wherein the compound has the following formula:
wherein R1 through R8 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R8 and R a through R c may be substituted or unsubstituted; provided that at least one of R1 through R8 is a halogen.
154. The method according to claim 63, wherein the compound has the following formula:
wherein R1 through R7 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R7 and R a through R c may be substituted or unsubstituted.
155. The method according to claim 63, wherein the compound has the following formula:
wherein R1 through R7 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR aR b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R C, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R7 and R a through R c may be substituted or unsubstituted.
156. The method according to claim 63, wherein the compound has the following formula:
wherein R1 through R6 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2 OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R6 and R a through R c may be substituted or unsubstituted.
157. The method according to claim 63, wherein the compound has the following formula:
wherein R1 through R6 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R6 and R a through R c may be substituted or unsubstituted.
158. The method according to claim 63, wherein the compound has the following formula:
wherein R1 through R5 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R5 and R a through R c may be substituted or unsubstituted.
159. The method according to claim 63, wherein the compound has the following formula:
wherein R 1 through R 8 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
b, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R8 and R a through R c may be substituted or unsubstituted.
160. The method according to claim 63, wherein the compound has the following formula:
wherein R1 through R6 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR a R b, NR a C(O)OR b, NR
aC(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2 OR b, NR a P(O)OR b OR
b, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R6 and R a through R c may be substituted or unsubstituted.
161. The method according to claim 63, wherein the compound has the following formula:
wherein R1 through R10 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR6, NR a P(O)OR b OR c, NR a P(O)OR b R c, NR a P(O)OR a OR b, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R10 and R a through R c may be substituted or unsubstituted.
162. The method according to claim 105, wherein the compound has the following formula:

wherein R1 through R8 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R8 and R a through R c may be substituted or unsubstituted; provided that at least one of R1 through R8 is a halogen.
163. The method according to claim 105, wherein the compound has the following formula:
wherein R1 through R7 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R7 and R a through R c may be substituted or unsubstituted.
164. The method according to claim 105, wherein the compound has the following formula:
wherein R1 through R7 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R7 and R a through R c may be substituted or unsubstituted.
165. The method according to claim 105, wherein the compound has the following formula:

wherein R1 through R6 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R6 and R a through R c may be substituted or unsubstituted.
166. The method according to claim 105, wherein the compound has the following formula:
wherein R1 through R b may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R6 and R a through R c may be substituted or unsubstituted.
167. The method according to claim 105, wherein the compound has the following formula:
wherein R1 through R5 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R5 and R a through R c may be substituted or unsubstituted.
168. The method according to claim 105, wherein the compound has the following formula:
wherein R1 through R8 may be the same or different and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R8 and R a through R c may be substituted or unsubstituted.
169. The method according to claim 105, wherein the compound has the following formula:
wherein R1 through R6 may be the same or different and are selected from the group consisting of H, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)SRa, OH, ORa, OC(O)Ra, OC(O)ORa, NH2, NRaRb, NRaC(O)Rb, NRaC(O)NRbRc, NRaC(O)ORb, NRaC(O)SRb, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)ORb, NRaS(O)2ORb, NRaP(O)ORbORc, NRaP(O)ORbR NRaP(O)ORbORc, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, S(O)NRaRb, S(O)2NRaRb, P(O)ORaORb, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein Ra, Rb, and Rc may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of Rl through R6 and Ra through Rc may be substituted or unsubstituted.
170. The method according to claim 105, wherein the compound has the following formula:
wherein Rl through R,10 may be the same or different and are selected from the group consisting of H, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)SRa, OH, ORa, OC(O)Ra, OC(O)ORa, NH2, NRaRb, NRaC(O)Rb, NRaC(O)NRbRc, NRaC(O)ORb, NRaC(O)SRb, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)ORb, NRaS(O)2ORb, NRaP(O)ORbORc, NRaP(O)ORbRc, NRaP(O)ORbORc, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, S(O)NRaRb, S(O)2NRaRb, P(O)ORaORb, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein Ra, Rb, and Rc may be the same or different and are selected from the group consisting of H,aryl,heteroaryl, biaryl, heterobiaryl, .a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R10 and Ra through Rc may be substituted or unsubstituted.
171. The method according to claim 124, wherein the compound has the following formula:
wherein R1 through R8 may be the same or different and are selected from the group consisting of H, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)SRa, OH, ORa, OC(O)Ra, OC(O)ORa, NH2, NRaRb, NRaC(O)Rb, NRaC(O)NRbRc, NRaC(O)ORb, NRaC(O)SRb, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)2ORb, NRaS(O)2Rb, NRaP(O)ORbORc, NRaP(O)ORbRc, NRaP(O)ORbORc, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, S(O)NRaRb, S(O)2NRaRb, P(O)ORaORb, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein Ra, Rb, and Rc may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1, through R8 and Ra through Rc may be substituted or unsubstituted; provided that at least one of R1, through R8 is a halogen.
172. The method according to claim 124, wherein the compound has the following formula:

wherein RI through R7 may be the same or different and are selected from the group consisting of H, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)SRa, OH, ORa, OC(O)Ra, OC(O)ORa, NH2, NRaRb, NRaC(O)Rb, NRaC(O)NRbRc, NRaC(O)ORb, NRaC(O)SRb, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)ORb, NRaS(O)2ORb, NRaP(O)ORbORc, NRaP(O)ORbRc, NRaP(O)ORbORc, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, S(O)NRaRb, S(O)2NRaRb, P(O)ORaORb, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein Ra, Rb, and Rc may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1, through R7 and Ra through Rc may be substituted or unsubstituted.
173. The method according to claim 124, wherein the compound has the following formula:

wherein R1 through R7 may be the same or different and are selected from the group consisting of H, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)SRa, OH, ORa, OC(O)Ra, OC(O)ORa, NH2, NRaRb, NRaC(O)Rb, NRaC(O)NRbRc, NRaC(O)ORb, NRaC(O)SRb, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)ORb, NRaS(O)2ORb, NRaP(O)ORbORc NRaP(O)ORbRc, NRaP(O)ORbORc, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, S(O)NRaRb, S(O)2NRaRb, P(O)ORaORb, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein Ra, Rb, and Rc may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R7 and Ra through Rc may be substituted or unsubstituted.
174. The method according to claim 124, wherein the compound has the following formula:

wherein R1, through R6 may be the same or different and are selected from the group consisting of H, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)SRa, OH, ORa, OC(O)Ra, OC(O)ORa, NH2, NRaRb, NRaC(O)Rb, NRaC(O)NRbRc, NRaC(O)ORb, NRaC(O)SRb, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)ORb, NRaS(O)2ORb, NRaP(O)ORbORc, NRaP(O)ORbRc,, NRaP(O)ORbORc, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, S(O)NRaRb, S(O)2NRaRb, P(O)ORaORb, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein Ra, Rb, and Rc may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R6 and Ra through Rc may be substituted or unsubstituted.
175. The method according to claim 124, wherein the compound has the following formula:

wherein R1 through R6 may be the same or different and are selected from the group consisting of H, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)SRa, OH, ORa, OC(O)Ra, OC(O)ORa, NH2, NRaRb, NRaC(O)Rb, NRaC(O)NRbRc, NRaC(O)ORb, NRaC(O)SRb, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)ORb, NRaS(O)2ORb, NRaP(O)ORbORc, NRaP(O)ORbRc, NRaP(O)ORbORc, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, S(O)NRaRb, S(O)2NRaRb, P(O)ORaORb, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein Ra, Rb, and Rc may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R6 and Ra through Rc may be substituted or unsubstituted.
176. The method according to claim 124, wherein the compound has the following formula:

wherein R1 through R5 may be the same or different and are selected from the group consisting of H, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)SRa, OH, ORa, OC(O)Ra, OC(O)ORa, NH2, NRaRb, NRaC(O)Rb, NRaC(O)NRbRc, NRaC(O)ORb, NRaC(O)SRb, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)ORb, NRaS(O)2ORb, NRaP(O)ORbORc, NRaP(O)ORbRc, NRaP(O)ORbORc, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, S(O)NRaRb, S(O)2NRaRb, P(O)ORaORb, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein Ra, Rb, and Rc may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R5 and Ra through Rc may be substituted or unsubstituted.
177. The method according to claim 124, wherein the compound has the following formula:

wherein Rl through R8 may be the same or different and are selected from the group consisting of H, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)SRa, OH, ORa, OC(O)Ra, OC(O)ORa, NH2, NRaRb, NRaC(O)Rb, NRaC(O)NRbRc, NRaC(O)ORb, NRaC(O)SRb, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)ORb, NRaS(O)2ORb, NRaP(O)ORbORc, NRaP(O)ORbRc, NRaP(O)ORbORc, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, S(O)NRaRb, S(O)2NRaRb, P(O)ORaORb, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein Ra, Rb, and Rc may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R8 and Ra through Rc may be substituted or unsubstituted.
178. The method according to claim 124, wherein the compound has the following formula:

wherein Rl through R6 may be the same or different and are selected from the group consisting of H, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)SRa, OH, ORa, OC(O)Ra, OC(O)ORa, NH2, NRaRb, NRaC(O)Rb, NRaC(O)NRbRc, NRaC(O)ORb, NRaC(O)SRb, NRaS(O)Rb, NRaS(O)2R6, NRaS(O)ORb, NRaS(O)20Rb, NRaP(O)ORbORc, NRaP(O)ORbRc, NRaP(O)ORbORc, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, S(O)NRaRb, S(O)2NRaRb, P(O)ORaORb, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein Ra, Rb, and Rc may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R6 and Ra through Rc may be substituted or unsubstituted.
179. The method according to claim 124, wherein the compound has the following formula:

wherein R1 through R10 may be the same or different and are selected from the group consisting of H, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)SRa, OH, ORa, OC(O)Ra, OC(O)ORa, NH2, NRaRb, NRaC(O)Rb, NRaC(O)NRbRc, NRaC(O)ORb, NRaC(O)SRb, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)ORb, NRaS(O)ZORb, NRaP(O)ORbORc, NRaP(O)ORbRc, NRaP(O)ORbORc, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, S(O)NRaRb, S(O)2NRaRb, P(O)ORaORb, B(OH)2, halogen, aryl, heteroaryl, biaryl, and a branched, cyclic, or unbranched alkyl group, wherein Ra, Rb, and Rc may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, a branched, cyclic, or unbranched alkyl group; and wherein any of R1 through R10 and Ra through Rc may be substituted or unsubstituted.
180. A method for protecting against or treating hearing loss in a subject comprising administering an effective amount of a protein tyrosine kinase inhibitor to the subject to protect against or to treat hearing loss.
181. The method according to claim 180, wherein the protein tyrosine kinase inhibitor is a non-peptide protein tyrosine kinase inhibitor.
182. The method according to claim 181, wherein the non-peptide protein tyrosine kinase inhibitor comprises at least one first module having one or more functional groups each capable of covalently or non-covalently binding to catalytic residues of the protein kinase and a second module which provides a non-peptide scaffold, wherein the combination of the at least one first module and second module inhibits protein kinase activity.
183. The method according to claim 182, wherein the at least one first module comprises two or more functional groups.
184. The method according to claim 182, wherein the at least one first module comprises a functional group selected from the group consisting of a halogen, a boronic acid, a hydroxyl group, phosphonic acid, sulfamic acid, a guanidino group, carboxylic acid, an aldehyde, an amide, and hydroxymethylphosphonic acid.
185. The method according to claim 184, wherein the at least one first module comprises a halogen.
186. The method according to claim 184, wherein the at least one first module comprises a boronic acid group.
187. The method according to claim 184, wherein the at least one first module comprises a hydroxyl group.
188. The method according to claim 184, wherein the at least one first module comprises an amide group.
189. The method according to claim 188, wherein the amide group is a vicinal tricarbonyl amide.
190. The method according to claim 182, wherein the second module comprises a group selected from the group consisting of indole, naphthalene, biphenyl, isoquinoline, benzofuran, and benzothiophene.
191. The method according to claim 190, wherein the second module comprises an indole.
192. The method according to claim 190, wherein the second module comprises naphthalene.
193. The method according to claim 182, wherein the at least one first module further comprises a linear chain comprising between one and three carbon atoms which links the at least one first module to the second module.
194. The method according to claim 193, wherein one of the carbon atoms in the linear chain is substituted with a nitrogen, oxygen, or sulfur atom.
195. The method according to claim 182, wherein the non-peptide protein kinase inhibitor comprises one or more specificity side chain elements attached to the combination of the at least one first module and second module.
196. The method according to claim 182, wherein the non-peptide protein tyrosine kinase inhibitor has the formula:

wherein R1, through R7 may be the same or different, and are selected from the group consisting of H, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)SRa, OH, ORa, OC(O)Ra, OC(O)ORa, NH2, NRaRb, NRaC(O)Rb, NRaC(O)NRbRc, NRaC(O)ORb, NRaC(O)SRb, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)ORb, NRaS(O)2ORb, NRaP(O)ORbORc, NRaP(O)ORbRc, NRaP(O)ORbORc, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, S(O)NRaRb, S(O)2NRaRb, P(O)ORaORb, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and branched, cyclic, or unbranched alkyl, wherein Ra, Rb, and Rc may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl; or R5 and R6 together form a heterocyclic compound; and wherein any of Rl through R7 and Ra through Rc is substituted or unsubstituted.

Z
197. The method according to claim 196, wherein R3 is a halogen.
198. The method according to claim 197, wherein R3 is fluorine.
199. The method according to claim 196, wherein at least one of R6 or R7 is wherein R8* is the point of attachment and is (CH2)x, wherein X is from 0 to 10, CH2CHOH, CH(CH3)R, or CH(CH3)S, and each of R9 through R13 may be the same or different, and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R
b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and branched, cyclic, or unbranched alkyl, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl; and wherein any of R9 through R13 and R a through R c is substituted or unsubstituted.
200. The method according to claim 196, wherein at least one of R6 or R7 is wherein the asterisk indicates the point of attachment to the nitrogen.
201. The method according to claim 182, wherein the non-peptide tyrosine kinase inhibitor has the formula:
wherein X is a halogen, R1 is H, R2 is R3 is H, and R4 is H.
202. The method according to claim 201, wherein X is fluorine.
203. The method according to claim 182, wherein the non-peptide tyrosine kinase inhibitor has the formula wherein R1 through R7 may be the same or different, and are selected from the group consisting of H, C(O)R a, C(O)NR a R b, C(O)OR a, C(O)SR a, OH, OR a, OC(O)R a, OC(O)OR a, NH2, NR a R b, NR a C(O)R b, NR a C(O)NR b R c, NR a C(O)OR b, NR a C(O)SR b, NR a S(O)R b, NR a S(O)2R b, NR a S(O)OR b, NR a S(O)2OR b, NR a P(O)OR b OR
c, NR a P(O)OR b R c, NR a P(O)OR b OR c, SR a, S(O)R a, S(O)2R a, S(O)OR a, S(O)2OR a, S(O)NR a R b, S(O)2NR a R b, P(O)OR a OR b, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and branched, cyclic, or unbranched alkyl, wherein R a, R b, and R c may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl;
wherein any of R1 through R7 and R a through R c is substituted or unsubstituted; and wherein X is 0 or 1.
204. The method according to claim 180, wherein the protein tyrosine kinase inhibitor is a peptide protein tyrosine kinase inhibitor.
205. The method according to claim 180, wherein the protein tyrosine kinase inhibitor inhibits protein tyrosine kinase activity but does not inhibit ATP
binding to the protein tyrosine kinase.
206. The method according to claim 205, wherein the protein tyrosine kinase inhibitor is a peptide substrate directed inhibitor.
207. The method according to claim 180, wherein the protein tyrosine kinase inhibitor is a SH2 inhibitor.
208. The method according to claim 180, wherein the protein tyrosine kinase inhibitor is a SH3 inhibitor.
209. The method according to claim 180, wherein the protein tyrosine kinase inhibitor is an allosteric inhibitor.
210. The method according to claim 180, wherein the protein tyrosine kinase inhibitor inhibits ATP binding to the protein tyrosine kinase.
211. The method according to claim 180, wherein the protein tyrosine kinase is a Src family protein tyrosine kinase.
212. The method according to claim 211, wherein the Src family protein tyrosine kinase is pp60c-src tyrosine kinase.
213. The method according to claim 180, wherein the protein tyrosine kinase is focal adhesion kinase.
214. The method according to claim 180, wherein the administering is carried out orally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraauditorily, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
215. The method according to claim 180, wherein protein tyrosine kinase inhibitor is administered with a pharmaceutically acceptable carrier.
216. The method according to claim 180, wherein the protein tyrosine kinase inhibitor is administered before initiation of hearing loss.
217. The method according to claim 180, wherein the protein tyrosine kinase inhibitor is administered after initiation of hearing loss.
CA2464214A 2001-10-22 2002-10-19 Protein kinase and phosphatase inhibitors, methods for designing them, and methods of using them Expired - Fee Related CA2464214C (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US33619101P 2001-10-22 2001-10-22
US60/336,191 2001-10-22
US41072602P 2002-09-13 2002-09-13
US60/410,726 2002-09-13
PCT/US2002/033660 WO2003035621A1 (en) 2001-10-22 2002-10-19 Protein kinase and phosphatase inhibitors, methods for designing them, and methods of using them

Publications (2)

Publication Number Publication Date
CA2464214A1 true CA2464214A1 (en) 2003-05-01
CA2464214C CA2464214C (en) 2011-02-08

Family

ID=26990085

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2464214A Expired - Fee Related CA2464214C (en) 2001-10-22 2002-10-19 Protein kinase and phosphatase inhibitors, methods for designing them, and methods of using them

Country Status (6)

Country Link
US (2) US7129225B2 (en)
EP (1) EP1444204A4 (en)
JP (2) JP4623962B2 (en)
CA (1) CA2464214C (en)
MX (1) MXPA04003758A (en)
WO (1) WO2003035621A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9522881B2 (en) 2013-04-26 2016-12-20 Indiana University Research And Technology Corporation Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)

Families Citing this family (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3208200A (en) * 1999-01-13 2000-08-01 Research Foundation Of The State University Of New York, The A novel method for designing protein kinase inhibitors
MXPA04003758A (en) * 2001-10-22 2005-06-20 Univ New York State Res Found Protein kinase and phosphatase inhibitors, methods for designing them, and methods of using them.
US7005445B2 (en) * 2001-10-22 2006-02-28 The Research Foundation Of State University Of New York Protein kinase and phosphatase inhibitors and methods for designing them
US7598418B2 (en) 2002-04-18 2009-10-06 Institute Of Medicinal Molecular Design, Inc. Amide derivatives
WO2004014300A2 (en) 2002-08-09 2004-02-19 Merck & Co., Inc. Tyrosine kinase inhibitors
AU2003261415C1 (en) 2002-08-09 2010-01-14 Merck Sharp & Dohme Corp. Tyrosine kinase inhibitors
ATE409484T1 (en) * 2002-12-17 2008-10-15 Centre Nat Rech Scient USE OF PURINE DERIVATIVES TO INDUCE DIFFERENTIATION OF EXCESS HAIR CELLS AND DEITER CELLS IN THE DEVELOPING ORGAN OF CORTI FOR THE TREATMENT OF DEAFNESS
TWI328009B (en) 2003-05-21 2010-08-01 Glaxo Group Ltd Quinoline derivatives as phosphodiesterase inhibitors
EP1643991B1 (en) * 2003-07-11 2014-03-12 Merck Patent GmbH Benzimidazole carboxamides as raf kinase inhibitors
US20050089936A1 (en) * 2003-10-23 2005-04-28 Jianping Cai Combinatorial library of 3-aryl-1H-indole-2-carboxylic acid amides
EP1532980A1 (en) 2003-11-24 2005-05-25 Novo Nordisk A/S N-heteroaryl indole carboxamides and analogues thereof, for use as glucokinase activators in the treatment of diabetes
US7736911B2 (en) 2004-04-15 2010-06-15 Albert Einstein College Of Medicine Of Yeshiva University Activity-based probes for protein tyrosine phosphatases
WO2006055463A2 (en) 2004-11-15 2006-05-26 Bristol-Myers Squibb Company 2-amino-3-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
US7223786B2 (en) * 2004-11-15 2007-05-29 Bristol-Myers Squibb Company 2-aminonaphthalene derivatives and related glycogen phosphorylase inhibitors
US7214704B2 (en) 2004-11-15 2007-05-08 Bristol-Myers Squibb Company 2-Amino-1-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
WO2006055462A1 (en) 2004-11-15 2006-05-26 Bristol-Myers Squibb Company 2-amino-4-functionalized tetralin derivatives and related glycogen phosphorylase inhibitors
GB0425919D0 (en) * 2004-11-25 2004-12-29 Prosidion Ltd Indole-2-carboxylic acid amides
FR2878849B1 (en) * 2004-12-06 2008-09-12 Aventis Pharma Sa SUBSTITUTED INDOLES, COMPOSITIONS CONTAINING SAME, METHOD OF MANUFACTURE AND USE
JP2008532926A (en) * 2004-12-06 2008-08-21 アバンテイス・フアルマ・エス・アー Substituted indole compounds, compositions containing them, methods for their preparation and uses thereof
CN101084209A (en) * 2004-12-21 2007-12-05 德福根有限公司 Compounds with Kv4 ion channel activity
EP2308839B1 (en) * 2005-04-20 2017-03-01 Takeda Pharmaceutical Company Limited Fused heterocyclic compounds
FR2884821B1 (en) * 2005-04-26 2007-07-06 Aventis Pharma Sa SUBSTITUTED PYRROLOPYRIDINES, COMPOSITIONS CONTAINING SAME, METHOD OF MANUFACTURE AND USE
MY148644A (en) 2005-07-18 2013-05-15 Orion Corp New pharmaceutical compounds
JP2009521427A (en) * 2005-12-23 2009-06-04 アストラゼネカ・アクチエボラーグ Pyrazole for the treatment of gastroesophageal reflux disease and irritable bowel syndrome
US7838542B2 (en) * 2006-06-29 2010-11-23 Kinex Pharmaceuticals, Llc Bicyclic compositions and methods for modulating a kinase cascade
US8178558B2 (en) 2006-09-15 2012-05-15 Pfizer Inc. Substituted pyridylmethyl bicycliccarboxyamide compounds
JP2010512305A (en) 2006-10-23 2010-04-22 ファイザー株式会社 Substituted phenylmethylbicyclocarboxamide compounds
EP2091944B1 (en) 2006-11-17 2011-05-18 Pfizer Inc. Substituted bicyclocarboxyamide compounds
EP2079687A1 (en) * 2006-12-18 2009-07-22 Ambrx, Inc. Compositions containing, methods involving, and uses of non-natural amino acids and polypeptides
US8663915B2 (en) 2007-04-13 2014-03-04 Agency For Science, Technology And Research Methods of controlling tumorigenesis and diagnosing the risk thereof
EP2173717B9 (en) 2007-07-27 2013-06-26 Bristol-Myers Squibb Company Novel glucokinase activators and methods of using same
JP5327051B2 (en) 2007-08-31 2013-10-30 アステラス製薬株式会社 Piperidine derivatives
BRPI0907797B8 (en) 2008-02-19 2021-05-25 Dsm Ip Assets Bv use of 3,3'-diindolylmethane, dairy products, sweets and/or confectionery for the prevention, treatment and/or delay of aging-related hearing loss
EP2306975A4 (en) 2008-07-21 2012-10-31 Otonomy Inc Controlled-release otic structure modulating and innate immune system modulating compositions and methods for the treatment of otic disorders
AU2009290474A1 (en) 2008-09-11 2010-03-18 Pfizer Inc. Heteroaryls amide derivatives and their use as glucokinase activators
CN102388038B (en) 2009-03-11 2014-04-23 辉瑞大药厂 Benzofuranyl derivatives used as glucokinase inhibitors
KR20150048759A (en) 2012-09-07 2015-05-07 노파르티스 아게 Indole carboxamide derivatives and uses thereof
CN103044311B (en) * 2012-12-26 2015-04-22 山东大学 Multi-substituted indole compounds and preparation method and application thereof
DK3125883T3 (en) * 2014-04-04 2020-10-19 Iomet Pharma Ltd CONTENTS DERIVATIVES FOR USE IN MEDICINE
CN104876851A (en) * 2015-05-15 2015-09-02 南京大学 Preparation method of piperazidine derivatives containing indolyl-3-carboxylic acid skeleton and application of piperazidine derivatives in anticancer drugs
PL3426243T3 (en) 2016-03-09 2021-10-04 Raze Therapeutics, Inc. 3-phosphoglycerate dehydrogenase inhibitors and uses thereof
ES2949357T3 (en) * 2016-03-09 2023-09-28 Raze Therapeutics Inc 3-Phosphoglycerate dehydrogenase inhibitors and uses thereof
MA51889A (en) 2018-01-31 2021-05-05 Heparegenix Gmbh KINASE MKK4 PROTEIN INHIBITORS TO PROMOTE HEPATIC REGENERATION OR TO REDUCE OR PREVENT HEPATOCYTE DEATH
EP3810139A1 (en) 2018-06-21 2021-04-28 HepaRegeniX GmbH Tricyclic protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
WO2020016243A1 (en) 2018-07-16 2020-01-23 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
US20230183810A1 (en) * 2020-05-04 2023-06-15 Dna-Seq, Inc. Methods and systems for determination of an effective therapeutic regimen and drug discovery
WO2022020114A2 (en) 2020-07-10 2022-01-27 Ting Therapeutics Llc Methods for the prevention and treatment of hearing loss

Family Cites Families (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01132579A (en) 1987-11-19 1989-05-25 Ss Pharmaceut Co Ltd Indole derivative
GB8827189D0 (en) * 1988-11-21 1988-12-29 Fujisawa Pharmaceutical Co 2(1h)-quinolinone compounds processes for preparation thereof & pharmaceutical composition comprising same
AU654808B2 (en) * 1989-12-28 1994-11-24 Pharmacia & Upjohn Company Diaromatic substituted anti-aids compounds
US5552534A (en) 1991-08-22 1996-09-03 The Trustees Of The University Of Pennsylvania Non-Peptide peptidomimetics
DE4307883A1 (en) * 1992-03-12 1993-09-23 Westarp Martin Egon Dr Med Use of anti-retroviral substances - to treat motor-neuronal diseases
US5705585A (en) 1993-06-30 1998-01-06 Arqule, Inc. Aminimide-containing molecules and materials as molecular recognition agents
SK283413B6 (en) 1992-08-06 2003-07-01 Warner-Lambert Company 2-Thioindoles, 2-indolinethiones and polysulfides, their analogues (2-indolineselenone) (selenide), and pharmaceutical compositions based on them
US6011175A (en) 1993-05-18 2000-01-04 University Of Pittsburgh Inhibition of farnesyltransferase
US5532167A (en) 1994-01-07 1996-07-02 Beth Israel Hospital Substrate specificity of protein kinases
US5712171A (en) 1995-01-20 1998-01-27 Arqule, Inc. Method of generating a plurality of chemical compounds in a spatially arranged array
FR2733995B1 (en) 1995-05-09 1997-07-25 Inst Nat Sante Rech Med INHIBITORS OF INACTIVATION OF ENDOGENOUS NEUROPEPTIDES IN PARTICULAR CHOLECYSTOKININ, METHODS OF PREPARING THEIR USE AS MEDICAMENTS AND METHOD OF SCREENING MEDICINAL PRODUCTS
DK0832065T3 (en) 1995-06-06 2001-11-19 Pfizer Substituted N- (indole-2-carbonyl) glycinamides and derivatives as glycogen phosphorylase inhibitors
ES2161291T3 (en) 1995-06-06 2001-12-01 Pfizer N- (INDOL-2-CARBONIL) AMIDAS AND DERIVATIVES AS INHIBITORS OF THE GLUCOGENO FOSFORILASA.
US5648378A (en) 1995-06-07 1997-07-15 Research Corporation Technologies, Inc. 2-iminochromene derivatives as inhibitors of protein tyrosine kinase
EP0850055B1 (en) 1995-09-11 2005-06-29 Osteoarthritis Sciences, Inc. Protein tyrosine kinase inhibitors for treating osteoarthritis
WO1998006715A1 (en) * 1996-08-09 1998-02-19 Smithkline Beecham Corporation Novel piperazine containing compounds
US5952322A (en) 1996-12-05 1999-09-14 Pfizer Inc. Method of reducing tissue damage associated with non-cardiac ischemia using glycogen phosphorylase inhibitors
WO1998027108A2 (en) * 1996-12-16 1998-06-25 Fujisawa Pharmaceutical Co., Ltd. New amide compounds and their use as nitric oxide synthase inhibitors
WO1998037070A1 (en) * 1997-02-21 1998-08-27 Takeda Chemical Industries, Ltd. Fused ring compounds, process for producing the same and use thereof
US6420338B1 (en) 1997-06-13 2002-07-16 New York University Medical Center Inhibition of the Src kinase family pathway as a method of treating HBV infection and hepatocellular carcinoma
GB9718913D0 (en) * 1997-09-05 1997-11-12 Glaxo Group Ltd Substituted oxindole derivatives
ATE293102T1 (en) * 1998-04-23 2005-04-15 Takeda Pharmaceutical NAPHTHALENE DERIVATIVES, THEIR PRODUCTION AND USE
AU9297998A (en) * 1998-05-15 1999-12-06 Guilford Pharmaceuticals Inc. Carboxamide compounds, compositions, and methods for inhibiting parp activity
AU763435B2 (en) * 1998-09-25 2003-07-24 Cephalon, Inc. Methods for preventing/treating damage to sensory hair cells and cochlear neurons
AU3208200A (en) * 1999-01-13 2000-08-01 Research Foundation Of The State University Of New York, The A novel method for designing protein kinase inhibitors
US7070936B1 (en) * 1999-01-13 2006-07-04 The Research Foundation Of State University Of New York Method for designing protein kinase inhibitors
CA2382789A1 (en) * 1999-08-27 2001-03-08 Sugen, Inc. Phosphate mimics and methods of treatment using phosphatase inhibitors
US6921763B2 (en) * 1999-09-17 2005-07-26 Abbott Laboratories Pyrazolopyrimidines as therapeutic agents
HN2001000008A (en) * 2000-01-21 2003-12-11 Inc Agouron Pharmaceuticals AMIDA COMPOSITE AND PHARMACEUTICAL COMPOSITIONS TO INHIBIT PROTEINKINASES, AND THE INSTRUCTIONS FOR USE
AU2868601A (en) * 2000-01-27 2001-08-07 Ribotargets Ltd Biaryl compounds, their preparation and their use in therapy
EP1255752B1 (en) * 2000-02-15 2007-08-08 Sugen, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors
KR100423899B1 (en) 2000-05-10 2004-03-24 주식회사 엘지생명과학 Indazoles substituted with 1,1-dioxoisothiazolidine useful as inhibitors of cell proliferation
OA12292A (en) * 2000-06-26 2003-11-11 Pfizer Prod Inc PyrroloÄ2,3-dÜpyrimidine compounds as immunosuppressive agents.
DE60118195T2 (en) * 2000-07-07 2006-12-14 Novo Nordisk A/S MODULATORS OF PROTEIN TYROSINE PHOSPHATASES (PTPASES)
JP4544820B2 (en) 2001-03-09 2010-09-15 オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド Heterocyclic compounds
KR100429841B1 (en) 2001-07-19 2004-05-04 삼성전자주식회사 Optical head providing GRIN lens
US7005445B2 (en) * 2001-10-22 2006-02-28 The Research Foundation Of State University Of New York Protein kinase and phosphatase inhibitors and methods for designing them
MXPA04003758A (en) * 2001-10-22 2005-06-20 Univ New York State Res Found Protein kinase and phosphatase inhibitors, methods for designing them, and methods of using them.
JP3975272B2 (en) 2002-02-21 2007-09-12 独立行政法人産業技術総合研究所 Ultrafine fluid jet device
EP1501514B1 (en) 2002-05-03 2012-12-19 Exelixis, Inc. Protein kinase modulators and methods of use
JP4539538B2 (en) * 2005-11-17 2010-09-08 トヨタ自動車株式会社 Energy recovery device
US7838542B2 (en) 2006-06-29 2010-11-23 Kinex Pharmaceuticals, Llc Bicyclic compositions and methods for modulating a kinase cascade

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9522881B2 (en) 2013-04-26 2016-12-20 Indiana University Research And Technology Corporation Hydroxyindole carboxylic acid based inhibitors for oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)

Also Published As

Publication number Publication date
JP2009263394A (en) 2009-11-12
EP1444204A1 (en) 2004-08-11
JP2005514339A (en) 2005-05-19
EP1444204A4 (en) 2009-11-04
JP4623962B2 (en) 2011-02-02
US7129225B2 (en) 2006-10-31
US20040019015A1 (en) 2004-01-29
MXPA04003758A (en) 2005-06-20
US20060172971A1 (en) 2006-08-03
WO2003035621A1 (en) 2003-05-01
CA2464214C (en) 2011-02-08
US7427608B2 (en) 2008-09-23

Similar Documents

Publication Publication Date Title
CA2464214A1 (en) Protein kinase and phosphatase inhibitors, methods for designing them, and methods of using them
Ferguson et al. Chain, sheet and framework structures in the adducts of phenylphosphonic acid with 4, 4'-bipyridyl (1/1), piperazine (2/1) and 1, 4-diazabicyclo [2.2. 2] octane (2/1)
Flacco et al. Different β‐adrenoceptor subtypes coupling to cAMP or NO/cGMP pathways: implications in the relaxant response of rat conductance and resistance vessels
RU2495044C2 (en) Protein tyrosine kinase activity inhibitors
Yamauchi et al. Structure-stability relationship in ternary copper (II) complexes involving aromatic amines and tyrosine or related amino acids. Intramolecular aromatic ring stacking and its regulation through tyrosine phosphorylation
Isaacs et al. Identification of ABR‐215050 as lead second generation quinoline‐3‐carboxamide anti‐angiogenic agent for the treatment of prostate cancer
DE69635737D1 (en) IBOGAMIN RELATED CONNECTIONS
RU98108602A (en) Succinimide and maleimide cytokine inhibitors
NO20060596L (en) Indazole Compounds and Pharmaceutical Compounds for Inhibition of Protein Kinases, and Methods for Using Them
CA2303428A1 (en) .alpha.-ketoamide multicatalytic protease inhibitors
RU2012123009A (en) APPLICATION OF BENZOHETEROCYCLIC DERIVATIVES FOR PREVENTION AND TREATMENT OF CANCER OR FOR INHIBITING CANCER METASTASIS
WO2003070894A2 (en) A non-invasive diagnostic test utilizing histone modification markers
ES2011919A6 (en) Substituted quinolines.
Klementyeva et al. Mono‐and Dinuclear Rare‐Earth Chlorides Ligated by a Mesityl‐Substituted β‐Diketiminate
BR9807851A (en) Olefin copolymers from bridged group 4 and bis (aryl starch) catalyst compounds
CO5261493A1 (en) PROCEDURE AND COMPOUNDS FOR THE INHIBITION OF MRP1
Blackburn et al. Synthesis of phosphonate analogues of 1, 3-bisphosphoglyceric acid and their binding to yeast phosphoglycerate kinase
de Leval et al. Extranodal T-and NK-cell lymphomas
ATE270308T1 (en) CATALYST SYSTEMS FOR ZIEGLER NATTA OLEFIN POLYMERIZATION
EA200900808A1 (en) ANTAGONISTS OF ANGIOTENSIN II RECEPTORS
KR890004700A (en) Synergistic Formulations Composed of Phosphodiesterase Inhibitors and Thromboxane A_2 Antagonists and Uses thereof and Methods of Making the Same
Auch-Schwelk et al. Vasomotor responses in cyclosporin A-treated rats after chronic angiotensin blockade.
ITRM20120060A1 (en) PEPTIDES ABLE TO RELEASE THE MDM2 / MDM4 HETERODYMER AND THEIR USE IN CANCER TREATMENT.
JP2007522247A5 (en)
WO2004094463A3 (en) Peptide inhibitors of autophosphorylation protein kinases

Legal Events

Date Code Title Description
EEER Examination request
MKLA Lapsed

Effective date: 20131021