WO2007117607A2 - Quinazolines for pdk1 inhibition - Google Patents

Quinazolines for pdk1 inhibition Download PDF

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Publication number
WO2007117607A2
WO2007117607A2 PCT/US2007/008592 US2007008592W WO2007117607A2 WO 2007117607 A2 WO2007117607 A2 WO 2007117607A2 US 2007008592 W US2007008592 W US 2007008592W WO 2007117607 A2 WO2007117607 A2 WO 2007117607A2
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WIPO (PCT)
Prior art keywords
substituted
alkyl
heteroaryl
amino
compound
Prior art date
Application number
PCT/US2007/008592
Other languages
French (fr)
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WO2007117607A9 (en
WO2007117607A3 (en
Inventor
Savithri Ramurthy
Xiaodong Lin
Sharadha Subramanian
Alice C. Rico
Xiaojing M. Wang
Rama Jain
Jeremy M. Murray
Steven E. Basham
Robert L. Warne
Wei Shu
Yasheen Zhou
Mina Aikawa
Payman Amiri
Johanna M. Jansen
Keith B. Pfister
Simon C. Ng
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Novartis Ag
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.)
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Publication date
Priority to JP2009504315A priority Critical patent/JP2009532486A/en
Priority to AU2007235339A priority patent/AU2007235339A1/en
Priority to EP07755008A priority patent/EP2004615A2/en
Priority to MX2008012852A priority patent/MX2008012852A/en
Priority to US12/295,967 priority patent/US7932262B2/en
Priority to EA200870415A priority patent/EA200870415A1/en
Priority to CA002648529A priority patent/CA2648529A1/en
Priority to BRPI0710521-5A priority patent/BRPI0710521A2/en
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to SM200800059T priority patent/SMP200800059B/en
Publication of WO2007117607A2 publication Critical patent/WO2007117607A2/en
Publication of WO2007117607A3 publication Critical patent/WO2007117607A3/en
Publication of WO2007117607A9 publication Critical patent/WO2007117607A9/en
Priority to TNP2008000375A priority patent/TNSN08375A1/en
Priority to NO20084665A priority patent/NO20084665L/en

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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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Definitions

  • the present invention generally relates to small molecule inhibitors of 3- phosphoinositide-dependent kinase (PDKl).
  • the compounds can be used as therapeutics in the treatment of cellular proliferative diseases.
  • PDKl (3-Phopsphoinositide-dependent kinase 1) is a serine/threonine kinase belonging to the AGC kinase super family. PDKl was first identified as the upstream kinase responsible for activating protein kinase B/AKT in the presence of phosphoinositide lipids (PIP3). PDKl activates AKT by phosphorylating a specific residue (threonine 308) located in the activation loop of this kinase.
  • PDKl is responsible for phosphorylating the activation-loop of many AGC kinases including p90 ribosomal S6 kinase (RSK), protein kinase C family members (PKC), p70 ribosomal S6 kinase (70S6K), and the serum and glucocorticoid-induced protein kinase (SGK).
  • RSK ribosomal S6 kinase
  • PLC protein kinase C family members
  • 70S6K p70 ribosomal S6 kinase
  • SGK serum and glucocorticoid-induced protein kinase
  • AKT is highly activated in a large percentage of common tumor types including melanoma, breast, lung, prostate and ovarian cancers.
  • RSK levels are elevated in prostate cancers, and an RSK-specif ⁇ c inhibitor (SLOlOl) has recently been shown to inhibit the proliferation of multiple prostate cancer cell lines.
  • SLOlOl RSK-specif ⁇ c inhibitor
  • PKC ⁇ has been shown to play an important role in regulating apoptosis and promoting survival of glioma cells.
  • the human PDKl gene encodes a 556 amino acid protein with an amino-terminal catalytic domain and a non-catalytic carboxy terminal containing a pleckstrin homology domain (PH).
  • PH pleckstrin homology domain
  • the PH domain of PDKl is required for the binding OfPIP 3 lipids produced by PI3kinase (PI3K). PDKl binding OfPIP 3 lipids results in membrane co-
  • PDKl activates AKT by phosphorylating tihreonine308.
  • PDKl can activate other AGC kinases independent of PIP3 lipids by binding directly to a conserved motif found on these targets. Because PDKl regulates two distinct classes of downstream signaling substrates (PI3K-de ⁇ endent and independent targets), inhibitors of this enzyme could have important therapeutic value in a variety of human cancers.
  • PDKl inhibitors could be efficacious in tumors in which the PI3K signaling pathway is upregulated due to activating mutations, amplification of PI3K itself or its upstream receptor tyrosine kinases, or deletion of PTEN, the phosphatase the counteracts PI3K activity.
  • the finding that mice expressing half the normal amount of PTEN are protected from developing a wide range of tumors by reducing PDKl expression levels supports this idea.
  • PDKl inhibitors could be useful in treating cancers driven by PHVindependent PDKl signaling pathways (e.g. K-ras or H-ras driven cancers).
  • PDKl is a central activator of several signaling pathways that are frequently altered in human cancers making it an attractive target for therapeutic intervention.
  • U.S. Patent No. 6,982,260 discloses quinazoline compounds for inhibition of cyclin- dependent kinases, and International Application PCT/IB2004/000091 discloses 2- aminopyridine substituted heterocycles as inhibitors for cellular proliferation.
  • This invention is directed to the discovery of novel compounds for PDKl inhibition and use of these compounds to treat a variety of diseases or disorders involving cellular proliferation.
  • the present invention provides PDKl, Cdkl, and/or Cdk2 inhibitors that are useful as therapeutic agents, for the treatment of diseases and disorders characterized by abnormal cellular proliferation, for example cancers of the prostate, lung, colon, breast, among others. jfr ⁇ z ⁇ zi ⁇ .u ⁇ z
  • the instant invention provides compounds that have the Formula I:
  • one of W 1 or W 2 is R 1 and the other is -L-A 1 ;
  • L is a covalent bond, carbonyl, carbonylamino, aminocarbonyl, -O-, -S-, -SO-, -SO 2 -, -NH-, C 1-3 alkyl, substituted C 1-3 alkyl, or an alkyl interrupted with -O-, -S-, -SO-, -SO 2 -, - NH-, carbonyl, carbonylamino, or aminocarbonyl;
  • a 1 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;
  • Y is H, C 1 - S alkyl, halo, cyano, nitro, or amino;
  • R 1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO 3 H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted ary
  • R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO 3 H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl,
  • R 4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; provided when R 4 is heteroaryl or substituted heteroaryl, W 2 is not aryl or heteroaryl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
  • the compounds of the invention have the Formula I:
  • one of W 1 or W 2 is R 1 and the other is -L-A 1 ;
  • L is a covalent bond, carbonyl, carbonylamino, aminocarbonyl, -O-, -S-, -SO-, -SO 2 -, -NH-, Ci-3 alkyl, substituted Ci -3 alkyl, or an alkyl interrupted with -O-, -S-, -SO-, -SO 2 -, - NH-, carbonyl, carbonylamino, or aminocarbonyl;
  • a 1 is hydroxyl, amino, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyclyl, or substituted cyclyl, heterocyclyl, or substituted heterocyclyl, provided whenW 2 is hydroxyl or methoxy, A 1 is not isopropyl or cyclopentyl;
  • Y is H, Ci-3 alkyl, halo, cyano, nitro, or amino;
  • R 1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted ary
  • R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, arninocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, arnidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO 3 H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio,
  • compounds of the invention have the Formula II:
  • X is O or NR 6 ;
  • Y is H, Ci . 3 alkyl, halo, cyano, nitro, or amino;
  • R 5a and R 5b are each independently H, halo, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, or substituted amino;
  • R 6 is H, acyl, substituted carbonyl, sulfonyl, alkyl, or substituted alkyl; or R 5a and R 6 are taken together to form a bridging alkylene moiety; or R 5a and R 5b are taken together to form a bridging alkylene moiety;
  • m and n are independently 0, 1 or 2;
  • R 1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl. substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO 3 H, sulfonyl, substituted sulfonyl, jrruz ⁇ .4 i ⁇ .uuuz
  • R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy
  • R 4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
  • the compounds of the invention have the Formula III:
  • X is O or NR 6 ;
  • Y is H, Ci- 3 alkyl, halo, cyano, nitro, or amino;
  • R 5a and R 5b are each independently H, halo, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, or substituted amino;
  • R 6 is H, acyl, substituted carbonyl, sulfonyl, alkyl, or substituted alkyl; or R 5a and R 6 are taken together to form a bridging alkylene moiety; or R 5a and R 5b are taken together to form abridging alkylene moiety;
  • m and n are independently 0, 1 or 2;
  • R 1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyl
  • R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl,
  • the invention provides compositions, preferably pharmaceutical compositions, that contain one or more compounds of the invention.
  • the invention provides methods of treating diseases or disorders that are characterized by, inter alia, abnormal cellular proliferation, for example cancer and/or precancerous lesions, that employ compounds of the invention.
  • the invention further provides methods of inhibiting tumor cell growth in a subject, that employ compounds of the invention.
  • the invention further provides methods of manufacturing compounds and compositions described herein, and method for the use of the quinazolines of the invention in methods for manufacturing medicaments for use in the methods of the invention.
  • compounds, such as those of Formula I can be used in the manufacture of a medicament for inhibiting PDKl . rr ⁇ z»zi». ⁇ uuz
  • the invention provides the use of the compounds of the invention, in the manufacture of medicament for PDKl inhibition, and/ or for treatment of one or more of the aforementioned diseases or disorders.
  • the present invention provides compounds that have the
  • one of W 1 or W 2 is R 1 and the other is -L-A 1 ;
  • L is a covalent bond, carbonyl, carbonylamino, aminocarbonyl, -O-, -S-, -SO-, -SO 2 - J -NH-, Ci-3 alkyl, substituted C 1 -3 alkyl, or an alkyl interrupted with -O-, -S-, -SO-, -SO 2 -, - NH-, carbonyl, carbonylamino, or aminocarbonyl;
  • a 1 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;
  • Y is H, C 1-3 alkyl, halo, cyano, nitro, or amino;
  • R 1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulforiylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted ary
  • R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO 3 H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl,
  • R 4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
  • the quinazoline compounds of this invention inhibit of PDKl activity or inhibit cell proliferation.
  • the quinazoline compounds have low IC 50 values with regard to inhibition of PDKl activity (i.e., the concention of a compound that is required for 50% inhibition of PDKl activity) or low EC50 with regard to inhibition of cell proliferation (i.e., the concentration of a compound which is required to induce inhibitory response against cell proliferation halfway between the baseline and maximum).
  • some quinazoline compounds exhibit IC50 or ECso valaues of about 25 ⁇ M or less, about 10 ⁇ M or less, about 1 ⁇ M or less, or about 0.1 ⁇ M or even less according to the PDKl kinase alpha screen assay and cell proliferation described herein.
  • -L-A 1 is a heterocyclyloxy group having the structure:
  • X is O or NR 6 ;
  • R 5a and R 515 are each independently H, halo, hydroxy, alkyl, substituted alkyl, alkoxy, 30 substituted alkoxy, amino, or substituted amino;
  • R 6 is H, acyl, substituted carbonyl, sulfonyl, alkyl, or substituted alkyl; or R 5a and R 6 are taken together to form a bridging alkylene moiety; or R 5a and R 5b are taken together to form a bridging alkylene moiety; m and n are independently 0, 1 or 2.
  • W 1 is -L-A 1 .
  • W 2 is -L-A 1 .
  • R 4 is substituted phenyl.
  • -N(RsOi)(RsO 2 ) forms -NH2, -NH-alkyl, -NH-alkyl substituted with alkoxy, -NH-cycloalkyl, morpholino, - NH-(alkyl)-pyrrolidinyl or piperizinyl optionally substituted with alkyl.
  • -N(RsOi)(RsO 2 ) forms -NH2, -NH-alkyl, -NH-alkyl substituted with alkoxy, -NH-cycloalkyl, morpholino, - NH-(alkyl)-pyrrolidinyl or piperizinyl optionally substituted with alkyl.
  • -N(R 5 Oi)(R 5 O 2 ) forms -NH 2 , -NH-CH(CH 3 ) 2 , -NH-(CH 2 ) 2 -O-CH 35 -NH-cyclopropyl, morpholin-4-yl, 4-methyl-piperizine-l-yI, or -NH-(CH 2 ) 2 -pyrrolidin-l-yl.
  • -N(R 5 Oi)(RsO 2 ) forms -NH 2 , -NH-alkyl, -NH-alkyl substituted with alkoxy, or - NH-cycloalkyl.
  • R 2 is H or halogen.
  • R 3 is H.
  • W 2 is H, halogen, cyano, heteroaryl, substituted heteroaryl, phenyl, substituted phenyl, or a group of formula:
  • each R 50I and each R 502 is independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyL
  • W 2 is H, halogen or cyano.
  • R 501 and R 502 are each independently selected from H and alkyl.
  • W 2 is a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently selected from O, S and N, that is optionally substituted with up to three substituents selected from alkyl, alkoxy and -N(R 501 )(R 502 ); wherein R 501 and R 5 02 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R 50 I and R 5025 taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from Ci. 3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.
  • W 2 is a heteroaryl group selected from pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, the heteroaryl group being optionally substituted with up to three substituents selected from alkyl, alkoxy and — N(R 501 )(R 502 ); wherein R 501 and R 502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R501 and Rso2, taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C 1-J alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino, hi some such embodiments, R 501 and R 502 are each independently selected from H and alkyl.
  • W 2 is a group of formula:
  • R 6 is H or alkyl.
  • W 1 is H, heteroaryl, substituted heteroaryl, or a group of formula:
  • W 1 is a group of formula:
  • X is NR 6 .
  • X is NR 6
  • R 5b is H
  • R 6 and R 5b together form an alkylene bridge, for example -(CHb) Z -.
  • X is NR 6 , and R 5a and R 5b together form an alkylene bridge, for example -(CHa) 2 -.
  • X is NR 6 , and R 6 is H or alkyl.
  • X is NR 6 , m and n are each 1 , and R 5a and R 5b are each H. In some such embodiments, R 6 is H or alkyl.
  • X is NR 6 , m is 1 and n is 0, and R 5a and R 5b are each H. In some such embodiments, R 6 is H or alkyl.
  • X is NR 6
  • m is 2 and n is 0, and R 5a and R 5b are each H.
  • R 6 is H or alkyl.
  • X is NR 6 , m and n are each 0, and R 5a and R 5b are each H. In some such embodiments, R 6 is H or alkyl.
  • Y is H or Cj. 3 alkyl. In other embodiments Y is H Or-CH 3 . In more particular embodiments, Y is H.
  • W 1 is heteroaryl or substituted heteroaryl.
  • W 1 is heteroaryl selected from pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, the heteroaryl group being optionally substituted with up to three substituents selected from alkyl, alkoxy, -N(R 50 ⁇ (R 502 ) and heterocyclyl; wherein R 501 and R 502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R501 and R5 0 2, taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from Ci -3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.
  • W 1 is pyridinyl optionally substituted with up to three substituents selected from alkyl, alkoxy, -N(R 501 )(R 502 ) and heterocyclyl; wherein Rso t and Rso 2 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or Rs 01 and Rso2 » taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C J-3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.
  • W 1 is pyridinyl optionally substituted with heterocyclyl, for example a group of formula:
  • R 6 is H or alkyl; and R5 01 and R 502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R 50I and R 502 , taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C1-3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.
  • W 1 is pyridinyl optionally substituted with up to three substituents selected from alkyl, alkoxy, -N(R 501 J(R 502 ) and heterocyclyl; or W 1 is a group of formula:
  • R 4 is substituted phenyl
  • W 2 is H, halogen, cyano, heteroaryl, substituted heteroaryl, phenyl, substituted phenyl, or a group of formula:
  • W 1 is H, heteroaryl, substituted heteroaryl, or a group of formula:
  • W 1 is a group of formula:
  • heteroaryl selected from pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, the heteroaryl group being optionally substituted with up to three substituents selected from alkyl, alkoxy, -N(R 501 )(R 502 ) and heterocyclyl; wherein each R 501 and each R 502 is independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl.
  • R 2 is H or halogen
  • R 3 is H.
  • compounds of the invention have the Formula II:
  • X is O or NR 6 ;
  • Y is H, Ci - 3 alkyl, halo, cyano, nitro, or amino;
  • R 5a and R 5b are each independently H, halo, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, or substituted amino;
  • R 6 is H, acyl, substituted carbonyl, sulfonyl, alkyl, or substituted alkyl; or R 5a and R 6 are taken together to form a bridging alkylene moiety; or R 5a and R 5b are taken together to form a bridging alkylene moiety;
  • m and n are independently 0, 1 or 2;
  • R 1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, arninothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO 3 H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substitute
  • R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester,
  • R 4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
  • R 4 is substituted phenyl.
  • X 1 is SO 2 -
  • -N(R 50 ')(R 502 ) forms -NH 2 , -NH- alkyl, -NH-alkyl substituted with alkoxy, -NH-cycloalkyl, morpholino, - NH-( alkyl)-pyrrolidinyl or piperizinyl optionally substituted with alkyl.
  • -N(R 501 )(R 502 ) forms -NH 2 , -NH-CH(CH 3 ) 2 , -NH-(CH 2 ) 2 -O-CH 3 , -NH- cyclopropyl, morpholin-4-yl, 4-rnethyl-piperizine- 1 -yl, or -NH-(CH 2 ) 2 -pyrrolidin- 1 -yl.
  • - N(R 501 )(R 502 ) forms -NH 2 , -NH-alkyl, -NH-alkyl substituted with alkoxy, or -NH-cycloalkyl.
  • Y is H or C 1 . 3 alkyl. In other embodiments Y is H Or-CH 3 . In more particular embodiments, Y is H. In some embodiments, R 2 is H or halogen. In some further embodiments, R 3 is H.
  • R 1 is selected from H, alkyl, and substituted alkyl.
  • compounds of the invention have the Formula HI:
  • X is O or NR 6 ;
  • Y is H, Ci . 3 alkyl, halo, cyano, nitro, or amino; rjruza_j ⁇ .uuuz
  • R 5a and R 5b are each independently H, halo, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, or substituted amino;
  • R 6 is H, acyl, substituted carbonyl, sulfonyl, alkyl, or substituted alkyl; or R 5a and R 6 are taken together to form a bridging alkylene moiety; or R 5a and R 5b are taken together to form a bridging alkylene moiety; m and n are independently 0, 1 or 2;
  • R 1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted ary
  • R 2 and R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO 3 H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl,
  • R 4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, hi some such embodiments, R 4 is substituted phenyl.
  • R 4 is phenyl substituted with a group of formula -Xi-N(R 501 )(R 502 ); wherein X 1 is SO 2 or C(O); and R 501 and R 502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R 501 and R 502 , taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from Cu 3 alkyl.
  • X 1 is SO 2 .
  • - N(R 501 )(R 502 ) forms -NH 2 , -NH-alkyl, -NH-alkyl substituted with alkoxy, -NH-cycloalkyl, morpholino, -NH-(alkyl)-pyrrolidinyl or piperizinyl optionally substituted with alkyl.
  • -N(R 501 )(R 502 ) forms -NH 2 , -NH-CH(CH 3 ) 2 , -NH-(CH 2 ) 2 -O-CH 3 , -NH-cyclopropyl, morpholin-4-yl, 4-methyl-piperizine-l-yl, or -NH-(CH 2 ) 2 -py ⁇ rolidin-l-yl.
  • -N(R 501 XR 502 ) forms -NH 2 , -NH-alkyl, -NH-alkyl substituted with alkoxy, or -NH-cycloalkyL
  • R 2 is H or halogen.
  • R 3 is H.
  • X is NR 6 .
  • X is NR 6 , R 5b is H, and R 6 and R 5b together form an alkylene bridge, for example -(CHa) 2 -.
  • X is NR 6
  • R 5a and R 5b together form an alkylene bridge, for example -(CHa) 2 -.
  • X is NR 6 , wherein R 6 is H or alkyl. Ih some embodiments, X is NR 6 , m and n are each 1 , and R 5a and R 5b are each H.
  • R 6 is H or alkyl.
  • X is NR 6
  • m is 1 and n is 0, and R 5a and R 5b are each H.
  • R 6 is H or alkyl.
  • X is NR 6
  • m is 2 and n is 0, and R 5a and R 5b are each H.
  • R 6 is H or alkyl.
  • X is NR 6 , m and n are each 0, and R 5a and R 5b are each H. hi some such embodiments, R 6 is H or alkyl.
  • Y is H or Ci . 3 alkyl. In other embodiments Y is H or -CH 3 . hi more particular embodiments, Y is H.
  • R 501 and R 502 are each independently selected from H and alkyl.
  • R 1 is H, halogen or cyano.
  • R 1 is a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently selected from O, S and N, that is optionally substituted with up to three substituents selected from alkyl, alkoxy and — N(R 501 )(R 502 ).
  • R 1 is a heteroaryl group selected from pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, the heteroaryl group being optionally substituted with up to three substituents selected from alkyl, alkoxy and — N(R 501 )(R 502 ).
  • R 501 and R 502 are each independently selected from H and alkyl.
  • R 4 is other than pyridinyl. In some of each of the foregoing embodiments, R 4 is other than pyridin-2-yl.
  • the columns labeled "PDKl IC 50 " "CPEC50 A2780,” “CPEC50 PC3,” and “CPEC50 PC3MM” indicates the compound's activity in the PDKl Kinase Alpha Screen Assay and the Cell Proliferation Assay described below.
  • the symbol “+” indicates IC 5O values or EC 50 values of 25 ⁇ M or greater (or compounds not evaluated)
  • the symbol “++” indicates IC 50 values or EC50 values between less than 25 ⁇ M and greater than 10 ⁇ M
  • the symbol “+++” indicates IC50 values or EC 50 values of 10 ⁇ M or less and greater than 5 ⁇ M
  • inventions provide methods for inhibiting PDKl in a subject. More particularly, the present invention provides a method of inhibitng PDKl comprising administering to a human or animal subject, a quinazoline compound as described herein. Such methods include administering a compound of Formula I, II or III to the subject.
  • compositions including: a compound of Formula I, II or III and a pharmaceutically acceptable carrier or excipient.
  • compositions described herein are used for the treatment of cancer and reduction of tumor growth.
  • the quinazoline compounds are useful in the treatment of human or animal (e.g., murine) cancers, including, for example, lung and bronchus; prostate; breast; pancreas; colon and rectum; thyroid; liver and intrahepatic bile duct; hepatocellular; gastric; glioma/glioblastoma; endometrial; melanoma; kidney and renal pelvis; urinary bladder; uterine corpus; uterine cervix; ovary; multiple myeloma; esophagus; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; non-Hodgkin lymphoma; melanoma; and villous colon a
  • human or animal e.g
  • the administration of the compound has an inhibiting effect upon tumor cell growth.
  • the composition is effective at inhibiting the growth of one or more mammalian tumor cells.
  • compositions that include the compounds described herein may include additives such as excipients.
  • suitable pharmaceutically acceptable excipients include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl- ⁇ -cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more of these.
  • processing agents and drug delivery modifiers and enhancers such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl- ⁇ -cyclodextrin, polyvinylpyrrolidinone, low melting wax
  • compositions that include the compounds of the invention may be in any form suitable for the intended method of administration, including, for example, as a solution, a suspension, or an emulsion.
  • Liquid carriers are typically used in preparing solutions, suspensions, and emulsions.
  • Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more of these.
  • the liquid carrier may include other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like.
  • Suitable organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols.
  • Suitable oils include, but are not limited to, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like.
  • the carrier may be an oily ester such as ethyl oleate, isopropyl myristate, and the like.
  • Compositions of the present invention may also be in the form PP028218.0002
  • microparticles are of microparticles, microcapsules, and the like, as well as combinations of any two or more of these.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form may include, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • Preferred lipids include phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods of forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. W., p. 33 et seq (1976).
  • Controlled release delivery systems may also be used, such as a diffusion controlled matrix system or an erod ⁇ ble system, as described for example in: Lee, "Diffusion-Controlled Matrix Systems", pp. 155-198 and Ron and Langer, “Erodible Systems", pp. 199-224, in
  • the matrix may be, for example, a biodegradable material that can degrade spontaneously in situ and in vivo for, example, by hydrolysis or enzymatic cleavage, e.g., by proteases.
  • the delivery system may be, for example, a naturally occurring or synthetic polymer or copolymer, for example in the form of a hydrogel.
  • Exemplary polymers with cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysaccharides, poly(phosphoesters), polyamides, polyurethanes, poly(imidocarbonates) and poly(phosphazenes).
  • the compounds of the invention may be administered enterally, orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations that include conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • suitable modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intramuscular, intraperitoneal, intranasal, subdermal, rectal, and the like.
  • Topical administration may also include the use of transdermal administration such as transdermal patches or ionophoresis devices.
  • parenteral as used PP028218.0002
  • herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will, therefore, melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will, therefore, melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
  • Such dosage forms may also include, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also include buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.
  • Effective amounts of the compounds of the invention generally include any amount sufficient to detectably treat the disorders described herein. PP028218.0002
  • Successful treatment of a subject in accordance with the invention may result in a reduction or alleviation of symptoms in a subject afflicted with a medical or biological disorder.
  • treatment may halt the further progression of the disorder, or may prevent or retard development of the disorder.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and severity of the particular disease undergoing therapy.
  • the therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
  • ICso value The concentration of an inhibitor that causes a 50 % reduction in a measured activity.
  • quinazolines (as pertaining to quinazolines of the present invention), indicates compounds having the general structure of Formula I, II or III as described herein.
  • the quinazolines include the compounds listed in Tables 1-5, infra.
  • Modeulating refers to inducing or suppressing.
  • a “disease associated with cellular proliferation” includes, but is not limited to cancers, for example cancers of the prostate, lung, colon and breast, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, proliferative diabetic PP028218.0002
  • PDR retinopathy
  • an effective amount of a compound to treat a disorder may be an amount necessary to cause reduction or alleviation of symptoms in a subject afflicted with a medical or biological disorder.
  • treatment may halt the further progression of the disorder, or may prevent or retard development of the disorder.
  • the effective amount may vary, depending, for example, upon the condition treated, weight of the subject and severity of the disease. One of skill in the art can readily determine the effective amount empirically without undue experimentation.
  • an effective amount for treatment refers to an amount sufficient to palliate, ameliorate, stabilize, reverse, slow or delay progression of a condition such as a disease state.
  • a “subject” or “patient” is meant to describe a human or vertebrate animal including a dog, cat, horse, cow, pig, sheep, goat, monkey, rat, mouse, and other mammals.
  • ester refers to esters, which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • Representative examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • the compounds of the present invention can be used in the form of salts as in "pharmaceutically acceptable salts" derived from inorganic or organic acids.
  • These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pe
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides such
  • Alkyl refers to saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH2-), »-propyl (CHaCH 2 CH 2 -), isopropyl ((CHa) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -) 5 sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), f-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), andneopentyl ((CH 3 ) 3 CCH 2 -).
  • Substituted alkyl refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio,
  • Alkyl interrupted with -O-, -S-, -SO-, -SO2-, -NH-, carbonyl, carbonylamino, or aminocarbonyl refers to a C2-10 alkyl group in which an -O-, -S-, -SO-, -SO2-, -NH-, carbonyl, carbonylamino, or aminocarbonyl is inserted between the carbon atoms of the alkyl group.
  • an ethylene radical interrupted with -O- is -C-O-C-.
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, byway of example, methoxy, ethoxy, w-propoxy, isopropoxy, «-butoxy, t-butoxy, sec-butoxy, and «-pentoxy.
  • Substituted alkoxy refers to the group -O-(substituted alkyl) wherein substituted alkyl is defined herein.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(OK cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(0)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, al
  • Acylamino refers to the groups -NRC(O)alkyl, -NRC(O)substituted alkyl, -NRC(O)cycloalkyl, -NRC(O)substituted cycloalkyl, -NRC(O)cycloalkenyl, -NRC(O)substituted cycloalkenyl, -NRC(O)alkenyl, -NRC(O)substituted alkenyl, -NRC(O)alkynyl, - NRC(O)substituted alkynyl, -NRC(O)aryl, -NRC(O)substituted aryl, -NRC(O)heteroaryl, -NRC(O)substituted heteroaryl, -NRC(0)hetero cyclic, and -NRC(O) substituted heterocyclic wherein R is hydrogen or alkyl
  • Acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O ⁇ , aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted PP028218.0002
  • Amino refers to the group -NH 2 .
  • Substituted amino refers to the group -NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -S ⁇ 2-alkyl, -SCh-substituted alkyl, -S ⁇ 2-alkenyl, -SCh-substituted alkenyl, -S ⁇ 2 -cycloalkyl, -SC> 2 -substituted cylcoalkyl, -S ⁇ 2 -cycloalkenyl, -SCh-substituted cylcoalkenyl,-SO 2
  • R' is hydrogen and R" is alkyl
  • the substituted amino group is sometimes referred to herein as alkylamino.
  • R' and R" are alkyl
  • the substituted amino group is sometimes referred to herein as dialkylamino.
  • a monosubstituted amino it is meant that either R' or R" is hydrogen but not both.
  • a disubstituted amino it is meant that neither R' nor R" are hydrogen.
  • Aminocarbonyl refers to the group -C(O)N R 10 R 11 where R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, PP028218.0002
  • substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Aminothiocarbonyl refers to the group -C(S)NR 10 R 11 where R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 1 ' are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted
  • Aminocarbonylamino refers to the group -NRC(O)NR 10 R 11 where R is hydrogen or alkyl and R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl
  • Aminothiocarbonylamino refers to the group -NRC(S)NR 10 R 11 where R is hydrogen or alkyl and R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloal
  • heteroaryl substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Aminocarbonyloxy refers to the group -0-C(O)NR 10 R 11 where R 10 and R n are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted
  • Aminosulfonyl refers to the group -SO 2 NR 10 R 11 where R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted substituted
  • Aminosulfonyloxy refers to the group -0-SO 2 NR 10 R 11 where R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted
  • Aminosulfonylamino refers to the group -NR-SO 2 NR 10 R 1 ' where R is hydrogen or alkyl and R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkyenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 10 and R 1 * are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
  • Aryl or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4- benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom.
  • Preferred aryl groups include phenyl and naphthyl.
  • Substituted aryl refers to aryl groups which are substituted with 1 to 5, preferably 1 to
  • substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, PP028218.0002
  • Aryloxy refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy . '
  • Substituted aryloxy refers to the group -O-(substituted aryl) where substituted aryl is as defined herein.
  • Arylthio refers to the group — S-aryl, where aryl is as defined herein.
  • Substituted arylthio refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
  • Alkenyl refers to alkenyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of alkenyl unsaturation. Such groups are exemplified, for example, by vinyl, allyl, and but-3-en-l-yl.
  • Substituted alkenyl refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio,
  • cycloalkenyloxy substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy substitution is not attached to a vinyl (unsaturated) carbon atom.
  • Alkynyl refers to alkynyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of alkynyl unsaturation.
  • Substituted alkynyl refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkyloxy
  • Carboxyl or “carboxy” refers to -COOH or salts thereof.
  • Carboxyl ester or “carboxy ester” refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, PP028218.0002
  • (Carboxyl ester)amino refers to the group -NR ⁇ C(O)O-alkyl, substituted -NR-C(O)O-alkyl, -NR-C(O)O-alkenyl, -NR-C(O)O-substituted alkenyl, -NR-C(O)O-alkynyl, ' -NR-C(O)O-substituted alkynyl, -NR-C(O)O-aryl, -NR-C(O)O-substituted aryl,
  • R is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
  • (Carboxyl ester)oxy refers to the group -O-C(O)O-alkyl, substituted -O-C(O)O-alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -0-C(0)0-cycloalkyl,
  • Cyano refers to the group -CN.
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable PP028218.0002
  • cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • Substituted cycloalkyl and “substituted cycloalkenyl” refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylarnino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl, carb
  • Cycloalkyloxy refers to -O-cycloalkyl.
  • Substituted cycloalkyloxy refers to -O-(substituted cycloalkyl).
  • Cycloalkylthio refers to -S-cycloalkyl.
  • Substituted cycloalkylthio refers to -S-(substituted cycloalkyl).
  • Cycloalkenyloxy refers to -O-cyeloalkenyl.
  • Substituted cycloalkenyloxy refers to -O-(substituted cycloalkenyl).
  • Cycloalkenylthio refers to — S-cycloalkenyl.
  • Substituted cycloalkenylthio refers to -S-(substituted cycloalkenyl).
  • Halo or halogen refers to fluoro, chloro, bromo and iodo.
  • Heteroaryl refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring.
  • Such heteroaryl groups can have a single ring (e.g. , pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N- »O), sulfinyl, or sulfonyl moieties.
  • Preferred heteroaryls include pyridinyl, py ⁇ rolyl, indolyl, thiophenyl, and furanyl.
  • Substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
  • Heteroaryloxy refers to -O-heteroaryl.
  • Substituted heteroaryloxy refers to the group — O-(substituted heteroaryl).
  • Heteroarylthio refers to the group — S-heteroaryl.
  • Substituted heteroarylthio refers to the group -S-(substituted heteroaryl).
  • Heterocycle or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more the rings can be cycloalkyl., aryl or heteroaryl provided that the point of attachment is through the non-aromatic ring.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, sulfonyl moieties.
  • Substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
  • Heterocyclyloxy refers to the group -O-heterocycyl.
  • Substituted heterocyclyloxy refers to the group -O-(substituted heterocycyl).
  • Heterocyclylth ⁇ o refers to the group — S-heterocycyl.
  • Substituted heterocyclylthio refers to the group — S-(substituted heterocycyl).
  • heterocycle and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4- tetrahydroisoquinoline, 4,5,6,
  • Niro refers to the group -NO 2 .
  • Oxo refers to the atom (O) or (-O " ).
  • “Spirocycloalkyl” refers to divalent cyclic groups from 3 to 10 carbon atoms having a cycloalkyl ring with a spiro union (the union formed by a single atom which is the only common member of the rings) as exemplified by the following structure:
  • Sulfonyl refers to the divalent group -S(O) 2 -.
  • Substituted sulfonyl refers to the group -S ⁇ 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 - alkenyl, -S ⁇ 2-substituted alkenyl, -SOa-cycloalkyl, -S ⁇ 2 -substituted cylcoalkyl, -SO 2 - cycloalkenyl, -S ⁇ 2-substituted cylcoalkenyl, -S ⁇ 2-aryl, -SO 2 -substituted aryl, -S ⁇ 2 -heteroaryl, -S ⁇ 2-substituted heteroaryl, -S0 2 -heterocyclic, -S ⁇ 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted
  • “Sulfonyloxy” refers to the group -OSO 2 -alkyl, -OSO 2 -substituted alkyl, -OSO 2 -alkenyl, -OSO 2 -substituted alkenyl, -OSO 2 -cycloalkyl, -OSO 2 -substituted cylcoalkyl, -OSO 2 - cycloalkenyl, -OSO 2 -substituted cylcoalkenyl.-OSO ⁇ -aryl, -OSO ⁇ -substituted aryl, -OSO 2 - heteroaryl, -OSOa-s ⁇ bstituted heteroaryl, -OSO 2 -heterocyclic, -OSO 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted al
  • Thioacyl refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted PP028218.0002
  • Thiol refers to the group -SH.
  • Alkylthio refers to the group -S-alkyl wherein alkyl is as defined herein.
  • Substituted alkylthio refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • the term "Ci-e alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl (propyl and isopropyl), C 4 alkyl, Cs alkyl, and Ce alkyl.
  • Stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • protected or a “protecting group” with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W., John Wiley & Sons, New York, NY, (1 st Edition, 1981) which can be added or removed using the procedures set forth therein.
  • Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t- butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
  • a reagent such as, but not limited to
  • protected amine groups include, but are not limited to, benzyl or dibenzyl, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others.
  • a protecting group for amines is a benzyl group.
  • protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • Quinazoline compounds of Formula I, II or III may exhibit the phenomenon of tautomerism, and the formula drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which possesses immunomodulatory activity and is not to be limited merely to any one tautomeric form utilized within the formula drawings.
  • Quinazolines of Formula I, II or III also may exist in solvated as well as unsolvated forms such as, for example, hydrated forms.
  • the invention encompasses both solvated and unsolvated forms which possess immunomodulatory activity.
  • the invention also includes isotopically-labeled quinazoline compounds, that are structurally identical to those disclosed above, except that one or more atom is/are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the PP028218.0002
  • isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively.
  • Compounds of the present invention, tautomers thereof, prodrugs thereof, and pharmaceutically acceptable salts of the compounds and of the prodrugs that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically- labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out known or referenced procedures and by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds of the invention are useful in pharmaceutical compositions for human or veterinary use where inhibition of PDKl is indicated, for example, in the treatment of cellular proliferative diseases such as tumor and/or cancerous cell growth mediated by PDKl .
  • the compounds are useful in the treatment of human or animal (e.g., murine) cancers, including, for example, lung and bronchus; prostate; breast; pancreas; colon and rectum; thyroid; liver and intrahepatic bile duct; hepatocellular; gastric; glioma/glioblastoma; endometrial; melanoma; kidney and renal pelvis; urinary bladder; uterine corpus; uterine cervix; ovary; multiple myeloma; esophagus; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx;
  • the invention provides methods for manufacture of PDKl inhibitor compounds. It is further contemplated that, in addition to the compounds of Formulas I-III, intermediates, and their corresponding methods of syntheses are included within the scope of the embodiments. PP028218.0Q02
  • the present invention provides for compounds of Formula I, II, or III for inhibition of Cdkl and/or Cdk2. Another embodiment provides a method of treating cancer responsive to inhibition of Cdkl, comprising administering a compound of Formula I, II, or III. Another embodiment provides a method of treating cancer responsive to inhibition of Cdk2, comprising administering a compound of Formula I, II, or III.
  • the invention provides methods of inhibiting phosphorylation of Akt comprising administering a compound of Formula I, II, or III to a human in need thereof. Another embodiment provides a method of treating cancer responsive to inhibition of phosphorylation of Akt, comprising administering a compound of Formula I, II, or III. Another embodiment provides a method of inhibiting phosphorylation of Akt comprising contacting a cell with a compound of Formula I, II, or III. hi further embodiments, the invention provides methods of inhibiting PDKl comprising orally administering a compound of Formula I, II, or III to a human in need thereof.
  • the human is suffering from cancer, hi a more particular embodiment the cancer is responsive to treatment with a compound that inhibits phosphorylation of PDKl .
  • the compound is orally bioavailable.
  • the IC 50 value of the compound is less than or equal to about 1 mM with respect to PDKl .
  • the IC 50 value is less than or equal to about 100 ⁇ M, is less than or equal to about 25 ⁇ M, is less than or equal to about 10 ⁇ M, is less than or equal to about 1 ⁇ M, is less than or equal to about 0.1 ⁇ M, is less than or equal to about 0.050 ⁇ M, or is less than or equal to about 0.010 ⁇ M.
  • a method of reducing PDKl activity in a human or animal subject is provided. In the method, a compound of the any of the aforementioned embodiments is administered in an amount effective to reduce PDKl activity.
  • the IC 50 value of the compound is between about 1 nM to about 10 nM. In other such embodiments, the IC50 value is between about 10 nM to about 50 nM, between about 50 nM to about 100 nM, between about 100 nM to about 1 ⁇ M, between about 1 ⁇ M to about 25 ⁇ M, or is between about 25 ⁇ M to about 100 ⁇ M.
  • Another embodiment provides methods of treating a PDKl -mediated disorder.
  • an effective amount of a PDKl inhibitor compound is administered to a patient (e.g., a human or animal subject) in need thereof to mediate (or modulate) PDKl activity.
  • the PDKl -mediated disorder is cancer.
  • Still another embodiment provides methods of treating diseases characterized by
  • abnormal cellular proliferation includes, for example, any disease or disorder characterized by excessive or pathologically elevated cell growth such as is characteristic of various cancers and non-cancer proliferative disorders.
  • Example cancers include, for example, lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular cancer, gastric cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvic cancer, urinary bladder cancer; uterine corpus cancer; uterine cervical cancer, ovarian cancer, multiple myeloma, esophageal cancer, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, brain cancer, oral cavity cancer, and pharyngeal cancer, laryngeal cancer, small intestinal cancer, non-Hodgkin lymphoma, and villous colon adenoma.
  • Example non-cancer proliferative disorders include neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, proliferative diabetic retinopathy (PDR), hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, angiogenesis, and endotoxic shock. . .
  • the invention provides pharmaceutical compositions including at least one compound of Formula I, II, or III, together with one or more pharmaceutically acceptable carriers suitable for administration to a human or animal subject, either alone or together with other agents, for example, anticancer agents.
  • the invention provides methods of treating human or animal subjects suffering from a cellular proliferative disease, such as cancer. Ih some such embodiments, the invention provides methods of treating a human or animal subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, II, or III, either alone or in combination with other anticancer agents.
  • compositions will either be formulated together as a combination PP028218.0002
  • Anticancer agents for use with the preferred embodiments include, but are not limited to, one or more of the following set forth below:
  • kinase inhibitors for use as anticancer agents in conjunction with the compositions of the preferred embodiments include inhibitors of Epidermal Growth Factor Receptor (EGFR) kinases such as small molecule quinazolines, for example gef ⁇ tinib (US 5457105, US 5616582, and US 5770599), ZD-6474 (WO 01/32651), erlotinib (Tarceva®, US 5,747,498 and WO 96/30347), and lapatinib (US 6,727,256 and WO 02/02552); Vascular Endothelial Growth Factor Receptor (VEGFR) kinase inhibitors, including SU-11248 (WO 01/60814), SU 5416 (US 5,883,113 and WO 99/61422), SU 6668 (US 5,883,113 and WO 99/61422), CHIR-258 (US 6,605,617 and US 6,774,237), vatalanib or PTK-787 (US 6,258,
  • Estrogen-targeting agents for use in anticancer therapy in conjunction with the compositions of the preferred embodiments include Selective Estrogen Receptor Modulators (SERMs) including tamoxifen, toremifene, raloxifene; aromatase inhibitors including Arimidex® or anastrozole; Estrogen Receptor Downregulators (ERDs) including Faslodex® or fulvestrant.
  • SERMs Selective Estrogen Receptor Modulators
  • ESDs Estrogen Receptor Downregulators
  • Androgen-targeti ⁇ g agents for use in anticancer therapy in conjunction with the compositions of the preferred embodiments include flutamide, bicalutamide, finasteride, aminoglutetharnide, ketoconazole, and corticosteroids.
  • flutamide bicalutamide
  • finasteride aminoglutetharnide
  • ketoconazole ketoconazole
  • corticosteroids corticosteroids
  • inhibitors for use as anticancer agents in conjunction with the compositions of the preferred embodiments include protein farnesyl transferase inhibitors including u ' pifarn ⁇ b or R- 115777 (US 2003134846 and WO 97/21701), BMS-214662, AZD-3409, and FTI-277; topoisomerase inhibitors including merbarone and difiomotecan (BN-80915); mitotic kinesin spindle protein (KSP) inhibitors including SB-743921 and MKI-833; proteasome modulators such as bortezomib or Velcade® (US 5,780,454), XL-784; and cyclooxygenase 2 (COX-2) inhibitors including non-steroidal antiinflammatory drugs I (NSAIDs).
  • protein farnesyl transferase inhibitors including u ' pifarn ⁇ b or R- 115777 (US 2003134846 and WO 97/21701), BMS-214662, AZ
  • cancer chemotherapeutic drugs for use as anticancer agents in conjunction with the compositions of the preferred embodiments include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukera ⁇ ®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCy
  • thioguanine, thiotepa, tirapazamine Terazone®
  • topotecan hydrochloride for injection Hycamptin®
  • vinblastine Velban®
  • vincristine Oncovin®
  • vinorelbine® vinorelbine
  • Alkylating agents for use in conjunction with the compositions of the preferred embodiments for anticancer therapeutics include VNP-40101M or cloretizine, oxaliplatin (US 4,169,846, WO 03/24978 and WO 03/04505), glufosfamide, mafosfamide, etopophos (US 5,041,424), prednimustine; treosulfan; busulfan, irofluven (acylfulvene), penclomedine, pyrazoloacridine (PD-115934); O6-benzylguanine, decitabine (5-aza-2-deoxycytidine), brostallicin, mitomycin C (MitoExtra), TLK-286 (Telcyta®), temozolomide, trabectedin (US 5,478,932), AP-5280 (Platinate formulation of Cisplatin), porfuromycin, and clearazide (meclorethamine) .
  • Chelating agents for use in conjunction with the compositions of the preferred embodiments for anticancer therapeutics include tetrathiomolybdate (WO 01/60814); RP-697, Chimeric T84.66 (cT84.66), gadofosveset (Vasovist®), deferoxamine, and bleomycin optionally in combination with electorporation (EPT).
  • Biological response modifiers such as immune modulators, for use in conjunction with the compositions of the preferred embodiments for anticancer therapeutics include staurosprine and macrocyclic analogs thereof, including UCN-Ol, CEP-701 and midostaurin (see WO
  • interleukins specifically IL-2 or aldesleukin as well as IL-I, IL-3, DL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-IO, IL-11, IL-12, and active biological variants thereof having amino acid sequences greater than 70% of the native human sequence; altretamine (Hexalen®); SU 101 or lefiunomide (WO 04/06834 and US 6,331,555); imidazoquinolines such as resiquimod and imiquimod (US 4,689,338, 5,389,640, 5,268,376,
  • Anticancer vaccines for use in conjunction with the compositions of the preferred embodiments include Avicine® ⁇ Tetrahedron Lett. 26:2269-70 (1974)); oregovomab
  • Theratope® (STn-KJLH); Melanoma Vaccines; GI-4000 series (GI-4014, GI-401S, and GI-4016), which are directed to five mutations in the Ras protein; GlioVax-1 ; MelaVax; Advexin® or INGN-201 (WO 95/12660); Sig/E7/LAMP-1, encoding HPV-16 E7; MAGE-3 Vaccine or M3TK (WO 94/05304); HER-2VAX; ACTIVE, which stimulates T-cells specific for tumors; GM-CSF cancer vaccine; and Listeria monocytogenes-based vaccines.
  • Anticancer agents for use in conjunction with the compositions of the preferred embodiments also include antisense compositions, such as AEG-35156 (GEM-640); AP-12009 and AP-11014 (TGF-beta2-specific antisense oligonucleotides); AVI-4126; AVI-4557; AVI- 4472; oblimersen (Genasense®); JFS2; aprinocarsen (WO 97/297S0); GTI-2040 (R2 ribonucleotide reductase mRNA antisense oligo) (WO 98/05769); GTI-2501 (WO 98/05769); liposome-encapsulated c-Raf antisense oligodeoxynucleotides (LErafAON) (WO 98/43095); and Sirna-027 (RNAi-based therapeutic targeting VEGFR-I mRNA).
  • AEG-35156 GEM-640
  • Example compounds and their analogs are easily synthesized by one skilled in the art from procedures described herein, as well as in patents or patent applications listed herein which are all hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein.
  • the compounds and/or intermediates were characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a 2695 Separation Module (Milford, MA).
  • HPLC high performance liquid chromatography
  • the analytical columns were reversed phase Phenomenex Luna Cl 8 -5 ⁇ , 4.6 x 50 mm, from Alltech (Deerf ⁇ eld, IL).
  • a gradient elution was PP028218.0002
  • TLC thin layer chromatography
  • glass or plastic backed silica gel plates such as, for example, Baker-Flex Silica Gel 1B2-F flexible sheets.
  • TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques.
  • Mass spectrometric analysis was performed on one of two LCMS instruments: a Waters
  • GCMS analysis is performed on a Hewlett Packard instrument (HP6890 Series gas chromatograph with a Mass Selective Detector 5973; injector volume: 1 ⁇ L; initial column temperature: 5O 0 C; final column temperature: 250 0 C; ramp time: 20 minutes; gas flow rate: 1 mL/min; column: 5% phenyl methyl siloxane, Model No. HP 190915-443, dimensions: 30.0 m x 25 m x 0.25 m).
  • NMR Nuclear magnetic resonance
  • Preparative separations are carried out using a Flash 40 chromatography system and KP-SiI, 6OA (Biotage, Charlottesville, VA), or by flash column chromatography using silica gel (230-400 mesh) packing material, or by HPLC using a Waters 2767 Sample Manager, C- 18 reversed phase column, 30X50 mm, flow 75 rnL/min.
  • Typical solvents employed for the Flash 40 Biotage system and flash column chromatography are dichloromethane, methanol, ethyl acetate, hexane, acetone, aqueous ammonia (or ammonium hydroxide), and triethyl amine.
  • Typical solvents employed for the reverse phase HPLC are varying concentrations of acetonitrile and water with 0.1% trifluoroacetic acid.
  • the reaction flask was washed out with water (3 x 100 mL) and EtOAc (4 x 50 mL). After stirring ca. 30 minutes, mixture was filtered to collect the light solid precipitate. The solid filter cake was washed with portions of water and EtOAc to give a white solid. The solid was dried on the frit and in vacuo to give the product in 99% purity and 95% yield (41 g, 233 mmole).
  • Step 3 Preparation of 2-chloro-8-methoxyquinazoline Neat POCI3 (400 mL) was added to 8-methoxyquinazolin-2-ol (5.0 g, 28.4 mmole) with stirring and cooling over an ice bath under argon. After ca. 1 minute, the reaction was removed from the ice bath and stirred at RT for ca. 20 minutes until a fine yellow suspension was formed. The reaction, fitted with a reflux condenser, was heated in an oil bath at 140-145 0 C. After about 1 hour, the reaction turned clear and colorless. LCMS showed that the reaction was complete. The POCI 3 was evaporated under reduced pressure, and dried in vacuo.
  • the product was extracted into CH 2 Cl 2 .
  • the emulsion that formed was filtered through celite, organic layer was washed with brine, dried over Na 2 SO ⁇ concentrated giving 12.0 g (98% yield) of the title compound.
  • Step 3 Preparation of 2-Hydroxy-7-methoxyquinazoline 2-Formyl-5-methoxyaniline (11.93 g, 79.5 mmol, 1.Oeq) and urea ( 38.Og, 0.636 mol, 8.0 eq) were mixed, ground into a fine powder and placed into a IL 2-neck flask equipped with a mechanical stirrer and an air condenser. The flask was placed into a preheated (160 0 C) oil bath. The reaction mixture melted and was stirred at 170-180 0 C for 1 hour until it solidified forming yellowish-brown solid.
  • the reaction mixture was cooled to RT, crushed, mixed with 70 mL of H 2 O and stirred for ⁇ 1 hour at RT.
  • the solid was filtered, washed with 150 mL of H 2 O and 20 mL of ice cold Et 2 O.
  • the yellow solid thus obtained was dried over P4O10 under high vacuum for several hours and the crude material (12.57 g) was used for the next step without purification.
  • Step 4 Preparation of 2-Chloro-7-methoxyquinazoline
  • the crude 2-Hydroxy-7-methoxyquinazoline (12.48 g) was mixed with 170 mL of POCI 3 , and the reaction mixture was stirred under reflux conditions for 6 hours. POCI 3 was removed using a PP028218.0002
  • Triphenylphosphine (0.49 g, 1.86 mmol), di-t-butylazodicarboxylate (0.42 g, 1.86 mmol) and 1- isoprpopylpiperidin-4-ol (0.54 g, 3.74 mmol) were mixed in anhydrous THF (6 mL) and stirred PP028218.0002
  • Step 1 To a suspension of 2-amino-3-fluorobenzoic acid (5 g, 32.2 mmol) in chloroform (200 mL) was added dropwise bromine (1.1 equiv.) in chloroform (125 mL) solution. The mixture was stirred at room temperature for 16 hrs. The resulting white solid was collected by filtration and washed thoroughly with methylene chloride until the filtrate was colorless. The solid was air-dried to give 9.6 g of white powder as HBr salt of 2-amino-5-bromo-3-fluorobenzoic acid (95% yield). ES/MS m/z 234/236 (MH 4 ). PP028218.0002
  • Step 2 To the above intermediate (30.6 mmol) in THF (100 mL) at 0 C was added boran tetrahydrofuran complex solution (1 M in THF, 129 mL, 4 equiv.). The mixture was stirred at room temperature for 40 hrs. The solvent was removed in vacuo and the excess reagent was quenched by addition of water (30 mL) slowly. The pH ( ⁇ 3) was adjusted by adding sodium bicarbonate (sat. aq.) to pH 7. Extracted with methylene chloride. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated to give a crude material as white solide. ES/MS m/z 220/222 (MH + ).
  • Step 3 To the above intermediate (30.6 mmol) in dichloromethane (450 mL) was added manganese dioxide (MnO 2 , 22 g, 258 mmol). The mixture was stirred at room temperature under argon for 18 hrs. The mixture was filtered through celite pad and washed thoroughly with dichloromethane. The filtrated was concentrated in vacuo to give crude product (2-amino-5- bromo-3-fluorophenyi)methanol (5.6 g) which was used for the next step without further purification. ES/MS m/z 218/220 (MH + ).
  • Step 4 A mixture of (2-amino-5-bromo-3-fluorophenyl)methanol (5.6 g, 23.7 mmol, obtained from step 3) and urea (21 g, 15 equiv.) was heated to 175 0 C with vigorous stirring for 15 min. The reaction was cooled to room temperature and water was added. The solid was collected by filtration. Air-dried to give 2-hydroxyquinazoline as a light brown solid.
  • Step 5 To the above crude material was added phosphooxychloride (POCI 3 , 20 mL) and heated to 110 0 C for 30 min. The resulting mixture was cooled to room temperature and concentrated in vacuo to nearly dryness. Ice water was added and pH was adjusted to ⁇ 6 using sodium bicarbonate. Extraction with dichloromethane followed by drying with sodium sulfate and concentrated in vacuo yielded desired product 6-bromo-2-chloro-8-fluoroquuiazoline as light brown powder (1.63 g).
  • phosphooxychloride POCI 3 , 20 mL
  • Step 1 To a suspension of 2-amino-3-chlorobenzoic acid (2 g, 11.6 mmol) in chloroform (120 mL) was added dropwise bromine (1.1 equiv.) in chloroform (12 mL) solution. The mixture was stirred at room temperature for 16 hrs. The resulting white solid was collected by filtration and washed thoroughly with methylene chloride until the filtrate was colorless. The solid was air- dried to give 3.35 g of white powder as HBr salt of 2-amino-5-bromo-3-chlorobenzoic acid (87% yield). ES/MS m/z 250/252 (MH + ).
  • Step 2 To the above intermediate (3.35 g, 10.1 mmol) in THF (40 mL) at 0 0 C was added borane tetrahydrofuran complex solution (1 M in THF, 40 mL, 4 equiv.). The mixture was stirred at room temperature for 18 hrs. Additional borane tetrahydrofuran (20 mL) was added and continued reaction for another 24 hrs until the complete conversion of the starting material. The solvent was removed in vacuo and the excess reagent was quenched by addition of ethanol (20 mL) slowly. Water was added and the pH ( ⁇ 3) was adjusted by adding sodium bicarbonate (sat. aq.) to pH 7. Extracted with methylene chloride. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated to give a crude material as white solide. ES/MS m/z 236/238 (MH + ).
  • Step 3 To the above intermediate (10.1 mmol) in dichloromethane (80 mL) was added manganese dioxide (MnO 2 , 6 g, 70 mmol). The mixture was stirred at room temperature under argon for 40 hrs. Additional manganese dioxide (6 g) was added and the reaction was continued for another 20 hrs until the complete conversion of the starting material. The mixture was filtered through celite pad and washed thoroughly with dichloromethane. The filtrated was concentrated in vacuo to give crude product (2-amino-5-bromo-3-chlorophenyl)methanol (3.3 g, orange solid) which was used for the next step without further purification. ES/MS m/z 234/236 (MH + ). PP028218.0002
  • Step 4 A mixture of (2-amino-5-bromo-3-chlorophenyl)methanol (3.3 g, obtained from step 3) and urea (10.5 g, 15 equiv.) was heated to 180 0 C with vigorous stirring for 1 hr. The reaction was cooled to room temperature and water was added. The solid was collected by filtration. Air-dried to give 2-hydroxyquinazoline as a yellow powder ( 2.18 g, crude). ES/MS m/z 259/261 (MH 4 ).
  • Step 5 To the above crude material was added phosphooxychloride (POCb 3 25 mL) and heated to 130 0 C for 30 min. The resulting mixture was cooled to room temperature and concentrated in vacuo to nearly dryness. Ice water was added and pH was adjusted to ⁇ 8 using sodium bicarbonate. Extraction with dichloromethane followed by drying with sodium sulfate and concentrated in vacuo yielded desired product 6-bromo-2,8-dichloroquinazoline as brown foam (1.4 g). This material was used in other chemical medications without further purification.
  • phosphooxychloride POCb 3 25 mL
  • Step 2 Preparation of 4-(8-isopropoxyquinazolin-2-ylamino)-N-methylbenzamide To a 0.30 M solution of the product from Step 1 in 2-propanol was added 4-amino-N- methylbenzamide (1.0 eq). The reaction was stirred at 100 °C for 14 h. The mixture was concentrated and purified by reverse-phase HPLC and lyophilized to give the desired product as the trifluoroacetic acid salt. ES/MS m/z 337 (MH + ).
  • Step 2 Preparation of 8-bromo-6-(trifluoromethyl)-l,4-dihydroquinazoline-2,4-diol 2-Amino-3-bromo-5-(trifluoromethyl)benzaldehyde (1.74 g, 6.49 mmol, 1.00 eq) and urea (5.85 g, 97.4 mmol, 15.0 eq) were stirred at 190 0 C for 3 h. The resulting solid was returned to ambient temperature, stirred in water (60 mL) for 20 min, and filtered. This was repeated for a total of three washes. The solid was dried in a desiccator to give 3.79 g of the desired product as an off-white solid. ES/MS m/z 311 ,313 (MH + ).
  • Phosphorus oxychloride (20 mL) was added. The mixture was stirred at 110 0 C for 1.5 h. Volatiles were removed under reduced pressure. Ice water was added, and the pH was adjusted to 6-7 with aqueous sodium hydroxide and sodium bicarbonate. The precipitate was filtered off, rinsed with water, and dried under high vacuum. The crude material was triturated with THF.
  • Step 4 Preparation of 4-(8-broino-6-(trifluoromethyl)q ⁇ inazolin-2-ylamino)benzenesulfonamide
  • sulfanilamide 1.0 eq
  • the reaction was stirred at 110 0 C for 14 h.
  • the hydrochloride was collected by vacuum filtration and then stirred in aqueous sodium bicarbonate.
  • the solid was collected by vacuum filtration and rinsed with water.
  • the light yellow solid was dried in a desiccator to give 343 mg of the desired product.
  • Step 1 Preparation of 2-Chloro-8-(l-isopropylpiperidin-4-yloxy)quinazoline
  • triphenylphosphine 1.5 eq
  • di-tert- butylazodicarboxylate 1.5 eq
  • 4- Hydroxy-1-isopropylpiperidine 4.0 eq
  • 2-Chloroquinazolin-8-ol 1.0 eq
  • the mixture was stirred an additional 2 h.
  • Step 3 Preparation of morpholino(4-(8-(piperidin-4-yloxy)quinazolm- 2-ylamino)phenyl)methanone
  • the product from Step 2 was dissolved in enough 1:1 DCM-.TFA to make a 0.20M solution. The mixture was stirred for 30 min at ambient temperature and concentrated. The crude product was purified by reverse-phase HPLC and lyophilized to give the desired product as its trifluoroacetic acid salt.
  • Step 2-3 Preparation of 6-ethynyl-8-(l-isopropylpiperidin-4-yloxy)-N-(3- morpholinophenyl)quinazolin-2-amine
  • step 1 The product of step 1 was subjected to subjected to Sonogashira and desilylation reaction (see the scheme above) to give the title compound.
  • Step 1 Preparation of 2,6-dibromo -8-(N-Boc-piperidin-4-yloxy)quinazoline
  • diethylazodicarboxylate 2.0 eq
  • diethylazodicarboxylate 2.0 eq
  • N-Tert-butyl-4-Hydroxy-l- piperidine carboxylate 4.0 eq
  • 2,6-Dibromo-8-hydroxyquinazoline 1.0 eq
  • the mixture was stirred an additional 24 h.
  • the crude mixture was concentrated, purified by flash chromatography (2:1 hexanes:EtOAc), and concentrated to give the desired product.
  • Step 3a Sonogashira & desilylation
  • the product from Step 2 was subjected to Sonogashira and desilylation reaction (see the scheme above) and carried on to Step 4 without purification.
  • Step 4 Preparation of 6-ethynyl-N-(4-morpholinophenyl)-8-(piperidin-4-yloxy)quinazolin-2- amine
  • the product from Step 3 was dissolved in enough 1 : 1 DCMrTFA to make a 0.20M solution. The mixture was stirred for 30 min at ambient temperature and concentrated. The crude product was purified by reverse-phase HPLC and lyophilized to give the desired product as its trifluoroacetic acid salt.
  • Step 1 To 2-Amino-5-fluorobenzoic acid (5 g, 32.2 mmol) in chloroform (90 mL) was added bromine (1.82 mL, 35.4 mmol) in chloroform (10 mL) solution dropwise via an additional funnel. The mixture was stirred at room temperature for 16 hrs. and LC/MS showed about 50% conversion of the starting material. Additional bromine (1.8 mL) was added to the reaction and continued stirring for another 24 hrs. The resulting white precipitate was collected by filtration, washed thoroughly with dichloromethane and air-dried to give 2-amino-3-bromo-5- fluorobenzoic acid as its HBr salt. ES/MS m/z 234/236 (MH + ).
  • Pd(dppf)2C12CH2C12 (0.05eq) was added to a 0.1 M mixture of 4-(8-bromo-6-fluoroquinazolin- 2-ylamino)benzensulfonamide (leq), 6-fluoropyridin-3-ylboronic acid (3eq), potassium carbonate/water (2.0M, 2eq) in DME.
  • the mixture was microwaved at 120 0 C for 20min. Reaction mixture was diluted with ethyl acetate and washed with water, brine, dried and PP028218.0002
  • Manganese (IV) oxide (4eq) was added to a 0.18M solution of (4-bromo-2-nitrophenyl)methanol in dichloromethane. The suspension was stirred at ambient temperature under Argon for 12 h. The reaction mixture was filtered through celite and filter cake was washed with dichloromethane. The combined filtrate was concentrated to give brown color solid in 78% yield.
  • Step 6 4-(7-Bromoquinazolm-2-ylarnino)-N-(3-(pyrrolidin-l-yl)propyl) benzenesulfonamide
  • a 0. IM suspension of 7-bromo-2-chloroquinazoline in isopropanol was added 4-amino-N-(3- (pyrrolidin-l-yl)propyl)benzenesulfonamide (l.leq), followed by the addition of 4.0M HCl in dioxane (1. leq) .
  • the reaction mixture was heated to 120 0 C in an oil bath for 1 h. LCMS showed that reaction was complete under the condition.
  • Step 7 Preparation of 4-(7-(l-isobutyl-lH-pyrazol-4 r yl)qumazolin-2-ylamino)-N-(3-Q)yi ⁇ olidin- 1 -yl)propyl)benzenesulfonamide
  • Pd(dppf)2C12CH2C12 (0.05eq) was added to a 0.05M mixture of 4-(7-bromoquinazolin-2- ylamino)-N-(3-(pyrrolidin-l-yl)propyl) benzenesulfonamide (leq), l-isobutyl-4-(4,4,5,5- PP028218.0002
  • Step 1 4-(6-Bromo-7-methoxyquinazolin-2-ylamino)-N-isopropylbenzamide
  • A- amino-N-isopropylbenzamide (l.Oeq).
  • the reaction mixture was heated to 100 0 C in an oil bath for 14 h.
  • Reaction mixture was diluted with ethyl acetate and filtered to collect desired product.
  • Step 2 4-(6-Bromo-7-hydroxyquinazolin-2-ylamino)-N-isopropylbenzamide
  • a 0.15M suspension of 4-(6-bromo-7-methoxyquinazolin-2-ylamino)-N-isopropylbenzarnide (1.Oeq) and sodium thiomethoxide (4.0eq) in DMF was heated to 80 0 C in an oil bath for 12 h. The mixture was partitioned between ethyl acetate and water. The pH of aqueous phase was adjusted to 5 by adding saturated ammonium hydrochloride.
  • Step 1 6-Bromo-7-methoxy-N-(4-morpholinophenyl)quinazolm-2-amine
  • 4-morpholinoaniline (1.Oeq)
  • the reaction mixture was heated to 120 0 C in an oil bath for 5 h.
  • LCMS showed that reaction was complete under the condition.
  • the reaction mixture was allowed to cool to room temperature and was filtered.
  • the filter cake was rinsed with ethyl acetate and allowed air dry. Desired product was a brown solid as HCl salt.
  • Boc-4-hydroxypiperidine (3.Oeq) was added, and the mixture was stirred at ambient temperature PP028218.0002
  • 6-Bromo-2-(4-moipholmophenylamino)quinazolin-7-ol (l.Oeq, a 0.12M solution in THF) was added to reaction flask. The mixture was stirred an additional 15 h at ambient temperature. Solvent was removed under reduced pressure and the residue was purified by Biotage using 2% methanol in dichloromethane to give tert-butyl 4-(6-bromo-2-(4- morpholinophenylamino)quinazolin-7-yloxy)piperidine-l-carboxy. ES/MS m/z 584/586 (MH + ).
  • Step 1 Preparation of tert-butyl 4-(2-chJoroquinazolin-8-yloxy)piperidine-l-carboxylate
  • triphenylphosphine (2 eq) in THF was added di-ethyl-azodicarboxylate (2 eq).
  • tert-butyl4-hydroxypiperidine-l- carboxylate (6 eq) was added.
  • the mixture was stirred 15 minutes at ambient temperature.
  • 4-(8- hydroxyquinazolin-2-ylamino)benzenesulfonamide (1.0 eq) was added. The mixture was stirred overnight at ambient temperature. The reaction goes to completion.
  • Step 3 Preparation of 4-(8-(l-isobutylpiperidine-4-yioxy)quinazolin- 2ylamino)b enzenesulfonamide
  • isobutyraldehyde (2eq) isobutyraldehyde (2eq) and a few drops of acetic acid.
  • the mixture was stirred for lOmins and to it was added sodiumtriacetoxyborohydride (1.5eq) and the mixture was stirred for Ih.
  • the reductive amination went to completion, by LC/MS.
  • Step 1 Preparation of 2-(4-sulfamoylphenylamino) quinazolin-7-yltrifluoromethane sulfonate
  • phenyltrifluoromethanesulfonate 1.2eq
  • DIEA 2.5eq
  • Step 2 Preparation of 4-(7-(6-fluoropyridin3-yl)quinazolin-2-ylamino)benzenesulfonaniide.
  • 2-(4-sulfanioylphenylainino)quinazolin-7-yltrifluoroniethane sulfonate (leq) in DME was added 2M sodium carbonate solution and 6-fluoropyridin-3ylboronic acid (3eq) and Pd(dppf) 2 Cl 2 .CH 2 Cl 2 (0.05eq) and the mixture was micro waved for 10 min at 120 0 C.
  • the reaction mixture was then partitioned between ethyl acetate and water.
  • the organic layer was concentrated to yield 4-(7-(6-fluoropyridin3-yl)quinazolin-2-ylamino)ben2enesulfonamide.
  • ES/MS m/z 396(MH + ).
  • Step 3 Preparation of 4-(7-(6-morpholinopyridin-3yl)quinazolin-2ylarnino-benzene sulfonamide
  • 4-(7-(6-fluoropyridin3-yl)qumazolin-2-ylamino)benzenesulfonamide was added morpholine.
  • the solution was heated at 80 0 C for 3h.
  • SNAR goes to completion and the product was purified on prep HPLC to yield 4-(7-(6-morpholinopyridin-3yl)quinazolin-2ylamino-benzene sulfonamide in 50% yield.
  • ES/MS m/z 463(MH + ). PP028218.0002
  • Step 4 Preparation of methyl 2-(4-sulfamoylphenylamino)quinazolin-7-carboxylate To methyl 2-chloroquinazoin-7-carboxylate (leq) was added sulfanilde (leq) and isopropanol and the mixture was heated to 90 0 C for 2h. The reaction went to completion. The reaction PP028218.0002
  • Step 5 Preparation of methyl 2-(4-sulfamoylphenylamino)quinazolin-7-carboxylic acid
  • 2-(4-sulfamoylphenyl amino)quinazolin-7-carboxylate was added 2N sodium hydroxide (4eq) and methanol and the mixture was heated to 80 0 C for lOmin. The saponification went to completion.
  • the reaction mixture was concentrated and IN HCl was added to precipitate methyl 2-(4-sulfamoylphenylamino)quinazolin-7-carboxylic acid as the HCl salt in quantitative yield.
  • ES/MS m/z 344(MH + ).
  • Step 2 Preparation of 5-chloro-2-(4-mo ⁇ holinophenylamino)quinazolin-8-ol
  • 2-dichloroquinazolin-8-ol leq
  • 4- morpholinoaniline leq
  • the SNAR went to completion by LC/MS and on concentration yielded 5-chloro-2-(4-morpholinophenylamino) quinazolin-8-ol in quantitative yield.
  • Step 3 The tert-butyl4-(methylsulfonyloxy)piperidine-l -carboxylate used in this step was made as follows:
  • Step 1 Preparation of l-(4-methoxy-2-aminophenyl)ethanone To a 1:1 mixture of ethanol and acetic acid was added l-(4-methoxy-2-nitrophenyl)ethanone (leq) and Fe dust (3eq)was added in portions. The reduction was complete in Ih. The reaction mixture was filtered and then concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate and dried and concentrated to give methyl l-(4-methoxy-2-aminophenyl)ethanone in 85 % yield. ES/MS m/z 196(MH + ).
  • Step 4 Preparation of 4-(7-methoxy-4-methylquinazolin-2-ylamino)benzenesulfonamide
  • 2-chloro-7-methoxy-4-methylquinazoline(l eq ) in isopropanol was added sulfanilide (1 eq) and the mixture was heated to 90 0 C for 16h. The solid that precipitated was filtered and collected to give 4-(7-methoxy-4-methylquinazolin-2-ylamino)benzene sulfonamide.
  • ES/MS m/z 345(MH + ).
  • Step 1 Preparation of 7-methoxy-N- (4-(morpholinosulfonyl) phenyl) quinazolin-2-amine
  • 2-chloro-7-methoxyquinazoline (leq) and 4-(M ⁇ holinosulfonyl) Aniline (leq) in 2-propanol was heated at 8O 0 C overnight.
  • Product was precipitated in the reaction mixture.
  • the precipitate was filtered, washed and dried under vacuum to provide 7-methoxy-N- (4- PP028218.0002
  • Step 2 Preparation of 2-(4-(mo ⁇ holinosulfonyl)phenylamino)quinazolin-7-ol
  • a mixture of 7-methoxy-N- (4-(morpholinosulfonyl) phenyl) quinazolin-2-amine (leq) and sodium thiomethoxide (4eq) in NMP was heated at 80 0 C for 4h.
  • Reaction mixture was diluted with water and acidified with IN HCl.
  • Compound was extracted with ethyl acetate.
  • the organic layer was washed with satd. NaHCOa, brine and dried over sodium sulfate.
  • Step 1 Preparation of 2-(4-(morpholinosulfonyl)phenylamino) quinazolin-7-yltrifluoromethane sulfonate For preparation see example 39 step 1.
  • Step 1 Preparation of N- (4-fluoro-3-methylphenyl)-7-methoxy quinazolin-2-amine See example 37, step 1 for synthesis.
  • Step 3 Preparation of tert-butyl 4-(2-(ethylsulfonyl) quinazolin-7-yloxy) piperidine-1 - carboxylate
  • a solution of tert -butyl 4-(2-(ethylthio) quinazolin-7-yloxy) piperidine-1- carboxylate (leq) in THF was added a solution of oxone in water (5ml) at 0 0 C.
  • the reaction mixture was stirred for 30min at 0 0 C then warmed to room temperature and stirred for 4h.
  • the reaction was quenched with satd. sodium thiosulfate solution and basified with IN NaOH.
  • Step 4 Preparation of tert-butyl 4-(2-(2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-ylamino) quinazolin-7-yloxy) piperidine-1- carboxylate
  • a solution of tert-butyl 4-(2-(ethylsulfonyl) quinazolin-7-yloxy) piperidine-1- carboxylate (leq) and 5-amino-l, 3-dihydro-benzimidazole-2-one (5eq) in acetonitrile was heated in sealed tube at 110 0 C for 48h. The product was filtered, washed and dried. A brown solid, yield 50%. ES/MS m/z All.5 (MH + ).
  • Step 1 Preparation of tert-butyl 2-(4-sulfamoylphenylamino) quinazolin-7-yl) carbamate
  • 2-(4-sulfamoylphenylamino) quinazoline-7-carboxylic acid (leq) in toluene was added diphenylphosphorylazide (1.2eq), tert-butanol (lOeq) and triethylamine (2eq).
  • the reaction mixture was heated at 70 0 C for 30min then 100 0 C for overnight.
  • the reaction mixture was concentrated and purified by semi-prep HPLC to provide pure product as a yellow solid in 35% yield.
  • Step 1 Preparation of 5-brorno-2-chloroquinazolin-8-ol Solid NBS (leq) was added to a stirred solution of 2-chloroquinazolin-8-ol (leq) (See example 1 for synthesis) in NMP at 0 0 C under argon. After stirring at 0 0 C for 30min, LCMS showed that the reaction was complete. The formation of both 5-bromo (Major) and 7-bromo (Minor) isomers PP028218.0002

Abstract

The invention provides quinazoline compounds that are inhibitors of PDKl. Also provided are pharmaceutical compositions including the compounds, and methods of treating proliferative diseases, such as cancers, with the compounds or compositions.

Description

rFUZ8.J18.UUU2 (20366-156WOl)
QUINAZOLINES FOR PDKl INHIBITION
FIELD OF THE INVENTION
The present invention generally relates to small molecule inhibitors of 3- phosphoinositide-dependent kinase (PDKl). In some embodiments, the compounds can be used as therapeutics in the treatment of cellular proliferative diseases.
BACKGROUND OF THE INVENTION PDKl (3-Phopsphoinositide-dependent kinase 1) is a serine/threonine kinase belonging to the AGC kinase super family. PDKl was first identified as the upstream kinase responsible for activating protein kinase B/AKT in the presence of phosphoinositide lipids (PIP3). PDKl activates AKT by phosphorylating a specific residue (threonine 308) located in the activation loop of this kinase. Subsequent research has shown that PDKl is responsible for phosphorylating the activation-loop of many AGC kinases including p90 ribosomal S6 kinase (RSK), protein kinase C family members (PKC), p70 ribosomal S6 kinase (70S6K), and the serum and glucocorticoid-induced protein kinase (SGK). Thus, PDKl is a central activator of multiple signaling pathways that are involved in cell proliferation, survival and control of apoptosis. Importantly, alterations in these signaling pathways are frequently observed in a variety of human cancers. For example, AKT is highly activated in a large percentage of common tumor types including melanoma, breast, lung, prostate and ovarian cancers. RSK levels are elevated in prostate cancers, and an RSK-specifϊc inhibitor (SLOlOl) has recently been shown to inhibit the proliferation of multiple prostate cancer cell lines. Similarly, PKCε has been shown to play an important role in regulating apoptosis and promoting survival of glioma cells.
The human PDKl gene encodes a 556 amino acid protein with an amino-terminal catalytic domain and a non-catalytic carboxy terminal containing a pleckstrin homology domain (PH). Recent studies suggest that PDKl is a constitutively active kinase, and that PDKl regulation occurs through the localization or conformational state of PDKl target proteins. For example, the PH domain of PDKl is required for the binding OfPIP3 lipids produced by PI3kinase (PI3K). PDKl binding OfPIP3 lipids results in membrane co-
- ] - localization with AKT, another PH domain containing protein. Once co-localized, PDKl activates AKT by phosphorylating tihreonine308. Alternatively, PDKl can activate other AGC kinases independent of PIP3 lipids by binding directly to a conserved motif found on these targets. Because PDKl regulates two distinct classes of downstream signaling substrates (PI3K-deρendent and independent targets), inhibitors of this enzyme could have important therapeutic value in a variety of human cancers. For instance, PDKl inhibitors could be efficacious in tumors in which the PI3K signaling pathway is upregulated due to activating mutations, amplification of PI3K itself or its upstream receptor tyrosine kinases, or deletion of PTEN, the phosphatase the counteracts PI3K activity. The finding that mice expressing half the normal amount of PTEN are protected from developing a wide range of tumors by reducing PDKl expression levels supports this idea. Alternatively, PDKl inhibitors could be useful in treating cancers driven by PHVindependent PDKl signaling pathways (e.g. K-ras or H-ras driven cancers). Finally, the recent identification of PDKl mutations (PDKl T354M, PDK1D527E) in human colorectal cancers suggests that inhibitors of this kinase may have therapeutic value by directly inhibiting either wild-type or mutant forms of this protein. See, Parsons et al, Nature 436, 792 (11 August 2005) "Colorectal cancer: Mutations in a signaling pathway."
In summary, PDKl is a central activator of several signaling pathways that are frequently altered in human cancers making it an attractive target for therapeutic intervention. U.S. Patent No. 6,982,260 discloses quinazoline compounds for inhibition of cyclin- dependent kinases, and International Application PCT/IB2004/000091 discloses 2- aminopyridine substituted heterocycles as inhibitors for cellular proliferation.
This invention is directed to the discovery of novel compounds for PDKl inhibition and use of these compounds to treat a variety of diseases or disorders involving cellular proliferation.
BRIEF SUMMARY OF THE INVENTION
In one aspect, the present invention provides PDKl, Cdkl, and/or Cdk2 inhibitors that are useful as therapeutic agents, for the treatment of diseases and disorders characterized by abnormal cellular proliferation, for example cancers of the prostate, lung, colon, breast, among others. jfrυzβziβ.uυϋz
In some embodiments, the instant invention provides compounds that have the Formula I:
Figure imgf000004_0001
wherein, one of W1 or W2 is R1 and the other is -L-A1;
L is a covalent bond, carbonyl, carbonylamino, aminocarbonyl, -O-, -S-, -SO-, -SO2-, -NH-, C1-3 alkyl, substituted C1-3 alkyl, or an alkyl interrupted with -O-, -S-, -SO-, -SO2-, - NH-, carbonyl, carbonylamino, or aminocarbonyl; A1 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;
Y is H, C1-S alkyl, halo, cyano, nitro, or amino;
R1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclyloxy, and substituted heterocyclyloxy;
R2 and R3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, Fl»U2»218.U002
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and
R4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; provided when R4 is heteroaryl or substituted heteroaryl, W2 is not aryl or heteroaryl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
In some further embodiments, the compounds of the invention have the Formula I:
Figure imgf000005_0001
wherein: one of W1 or W2 is R1 and the other is -L-A1;
L is a covalent bond, carbonyl, carbonylamino, aminocarbonyl, -O-, -S-, -SO-, -SO2-, -NH-, Ci-3 alkyl, substituted Ci-3 alkyl, or an alkyl interrupted with -O-, -S-, -SO-, -SO2-, - NH-, carbonyl, carbonylamino, or aminocarbonyl; A1 is hydroxyl, amino, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyclyl, or substituted cyclyl, heterocyclyl, or substituted heterocyclyl, provided whenW2 is hydroxyl or methoxy, A1 is not isopropyl or cyclopentyl; Y is H, Ci-3 alkyl, halo, cyano, nitro, or amino;
R1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclyloxy, and substituted heterocyclyloxy; -tτuz«zis.υυo2
R2 and R3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, arninocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, arnidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and R4 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
In some further embodiments, compounds of the invention have the Formula II:
Figure imgf000006_0001
wherein:
X is O or NR6;
Y is H, Ci .3 alkyl, halo, cyano, nitro, or amino;
R5a and R5b are each independently H, halo, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, or substituted amino; R6 is H, acyl, substituted carbonyl, sulfonyl, alkyl, or substituted alkyl; or R5a and R6 are taken together to form a bridging alkylene moiety; or R5a and R5b are taken together to form a bridging alkylene moiety; m and n are independently 0, 1 or 2;
R1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl. substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, jrruzβ.4 i β.uuuz
sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclyloxy, and substituted heterocyclyloxy; R2 and R3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and
R4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
In some further embodiments, the compounds of the invention have the Formula III:
Figure imgf000007_0001
wherein,
X is O or NR6;
Y is H, Ci-3 alkyl, halo, cyano, nitro, or amino;
R5a and R5b are each independently H, halo, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, or substituted amino; R6 is H, acyl, substituted carbonyl, sulfonyl, alkyl, or substituted alkyl; or R5a and R6 are taken together to form a bridging alkylene moiety; or R5a and R5b are taken together to form abridging alkylene moiety; m and n are independently 0, 1 or 2; R1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H5 sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclyloxy, and substituted heterocyclyloxy;
R2 and R3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and R4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. In some further embodiments, the invention provides compositions, preferably pharmaceutical compositions, that contain one or more compounds of the invention. In further embodiments, the invention provides methods of treating diseases or disorders that are characterized by, inter alia, abnormal cellular proliferation, for example cancer and/or precancerous lesions, that employ compounds of the invention. The invention further provides methods of inhibiting tumor cell growth in a subject, that employ compounds of the invention. The invention further provides methods of manufacturing compounds and compositions described herein, and method for the use of the quinazolines of the invention in methods for manufacturing medicaments for use in the methods of the invention. In each of the embodiments of the invention, compounds, such as those of Formula I, can be used in the manufacture of a medicament for inhibiting PDKl . rrυz»zi».υuuz
In further embodiments, the invention provides the use of the compounds of the invention, in the manufacture of medicament for PDKl inhibition, and/ or for treatment of one or more of the aforementioned diseases or disorders.
Further embodiments of the invention include those described in the detailed description.
DETAILED DESCRIPTION
In accordance with the present invention, Applicants have discovered novel quinazoline PDKl inhibitors that will provide effective treatments for disorders such as those described herein and those apparent to one skilled in the art. In some embodiments, the present invention provides compounds that have the
Formula I:
Figure imgf000009_0001
wherein, one of W1 or W2 is R1 and the other is -L-A1 ;
L is a covalent bond, carbonyl, carbonylamino, aminocarbonyl, -O-, -S-, -SO-, -SO2-J -NH-, Ci-3 alkyl, substituted C1-3 alkyl, or an alkyl interrupted with -O-, -S-, -SO-, -SO2-, - NH-, carbonyl, carbonylamino, or aminocarbonyl;
A1 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;
Y is H, C1-3 alkyl, halo, cyano, nitro, or amino;
R1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulforiylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclyloxy, and substituted heterocyclyloxy;
R2 and R3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and
R4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. The quinazoline compounds of this invention inhibit of PDKl activity or inhibit cell proliferation. In some embodiments, the quinazoline compounds have low IC50 values with regard to inhibition of PDKl activity (i.e., the concention of a compound that is required for 50% inhibition of PDKl activity) or low EC50 with regard to inhibition of cell proliferation (i.e., the concentration of a compound which is required to induce inhibitory response against cell proliferation halfway between the baseline and maximum). For example, some quinazoline compounds exhibit IC50 or ECso valaues of about 25 μM or less, about 10 μM or less, about 1 μM or less, or about 0.1 μM or even less according to the PDKl kinase alpha screen assay and cell proliferation described herein.
In more particular embodiments, -L-A1 is a heterocyclyloxy group having the structure:
Figure imgf000010_0001
wherein, X is O or NR6;
R5a and R515 are each independently H, halo, hydroxy, alkyl, substituted alkyl, alkoxy, 30 substituted alkoxy, amino, or substituted amino;
R6 is H, acyl, substituted carbonyl, sulfonyl, alkyl, or substituted alkyl; or R5a and R6 are taken together to form a bridging alkylene moiety; or R5a and R5b are taken together to form a bridging alkylene moiety; m and n are independently 0, 1 or 2.
In a more particular embodiment W1 is -L-A1. In another more particular embodiment W2 is -L-A1.
In some embodiments, R4 is substituted phenyl.
In some embodiments, R4 is phenyl substituted with a group of formula -X1- N(Rsoi)(R5O2); wherein X1 is SO2 or C(=O); and R501 and R502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R501 and R502, taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C1-3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino, hi some such embodiments, X1 is SO2. In some such embodiments, -N(RsOi)(RsO2) forms -NH2, -NH-alkyl, -NH-alkyl substituted with alkoxy, -NH-cycloalkyl, morpholino, - NH-(alkyl)-pyrrolidinyl or piperizinyl optionally substituted with alkyl. In some further such embodiments,
-N(R5Oi)(R5O2) forms -NH2, -NH-CH(CH3)2, -NH-(CH2)2-O-CH35 -NH-cyclopropyl, morpholin-4-yl, 4-methyl-piperizine-l-yI, or -NH-(CH2)2-pyrrolidin-l-yl.
Li some embodiments, R4 is substituted phenyl and X1 is C(=O). hi some such embodiments, -N(R5Oi)(RsO2) forms -NH2, -NH-alkyl, -NH-alkyl substituted with alkoxy, or - NH-cycloalkyl.
In some embodiments, R2 is H or halogen.
In some embodiments, R3 is H.
Li some further embodiments, W2 is H, halogen, cyano, heteroaryl, substituted heteroaryl, phenyl, substituted phenyl, or a group of formula:
Figure imgf000011_0001
Li some further embodiments, W2 is H, halogen, cyano; or phenyl optionally substituted with-C(=O) -N(R50I)(R502); or a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently selected from O, S and N, that is optionally substituted with up r MΓV AOΛ Λ a.uuυz
to three substituents selected from alkyl, alkoxy and -N(R501)(R502); or a group of formula:
Figure imgf000012_0001
wherein each R50I and each R502 is independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyL
In some embodiments, W2 is H, halogen or cyano. In some further embodiments, W2 is phenyl optionally substituted with-C(=O) -N(R501)(R502); wherein R50I and R502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R501 and R502, taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C1.3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino. In some such embodiments, R501 and R502 are each independently selected from H and alkyl.
In some embodiments, W2 is a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently selected from O, S and N, that is optionally substituted with up to three substituents selected from alkyl, alkoxy and -N(R501)(R502); wherein R501 and R502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R50I and R5025 taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from Ci.3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino. In some further embodiments, W2 is a heteroaryl group selected from pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, the heteroaryl group being optionally substituted with up to three substituents selected from alkyl, alkoxy and — N(R501)(R502); wherein R501 and R502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R501 and Rso2, taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C1-J alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino, hi some such embodiments, R501 and R502 are each independently selected from H and alkyl. In some embodiments, W2 is a group of formula:
Figure imgf000012_0002
30 wherein R6 is H or alkyl. In some embodiments, W1 is H, heteroaryl, substituted heteroaryl, or a group of formula:
Figure imgf000013_0001
In some such embodiments, W1 is a group of formula:
Figure imgf000013_0002
In some such embodiments, X is NR6. Li further such embodiments, X is NR6, R5b is H, and R6 and R5b together form an alkylene bridge, for example -(CHb)Z-.
In some embodiments, X is NR6, and R5a and R5b together form an alkylene bridge, for example -(CHa)2-. In some embodiments, X is NR6, and R6 is H or alkyl. In some embodiments, X is NR6, m and n are each 1 , and R5a and R5b are each H. In some such embodiments, R6 is H or alkyl. In some embodiments, X is NR6, m is 1 and n is 0, and R5a and R5b are each H. In some such embodiments, R6 is H or alkyl.
In some embodiments, X is NR6, m is 2 and n is 0, and R5a and R5b are each H. In some such embodiments, R6 is H or alkyl.
In some embodiments, X is NR6, m and n are each 0, and R5a and R5b are each H. In some such embodiments, R6 is H or alkyl.
In some embodiments, Y is H or Cj.3 alkyl. In other embodiments Y is H Or-CH3. In more particular embodiments, Y is H.
In some embodiments, W1 is heteroaryl or substituted heteroaryl. In some further embodiments, W1 is heteroaryl selected from pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, the heteroaryl group being optionally substituted with up to three substituents selected from alkyl, alkoxy, -N(R50 ^(R502) and heterocyclyl; wherein R501 and R502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R501 and R502, taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from Ci-3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.
In some embodiments, W1 is pyridinyl optionally substituted with up to three substituents selected from alkyl, alkoxy, -N(R501 )(R502) and heterocyclyl; wherein Rsot and Rso2 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or Rs01 and Rso2» taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from CJ-3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.
In some embodiments, W1 is pyridinyl optionally substituted with heterocyclyl, for example a group of formula:
Figure imgf000014_0001
In some embodiments, W2 is H, halogen, cyano, phenyl optionally substituted with- C(=O) - N(R501)(R502); or heteroaryl selected from pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, the heteroaryl group being optionally substituted with up to three substituents selected from alkyl, alkoxy and -N(R501)(R502); or a group of formula:
Figure imgf000014_0002
wherein R6 is H or alkyl; and R501 and R502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R50I and R502, taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C1-3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino. In some embodiments, W1 is pyridinyl optionally substituted with up to three substituents selected from alkyl, alkoxy, -N(R501J(R502) and heterocyclyl; or W1 is a group of formula:
Figure imgf000014_0003
r rυύOA±OMWZ.
In some further embodiments, R4 is substituted phenyl; W2 is H, halogen, cyano, heteroaryl, substituted heteroaryl, phenyl, substituted phenyl, or a group of formula:
Figure imgf000015_0001
W1 is H, heteroaryl, substituted heteroaryl, or a group of formula:
Figure imgf000015_0002
In some still further embodiments, R4 is phenyl substituted with a group of formula — Xi-N(R501)(R502); wherein X1 is SO2 or C(=O); and R501 and R502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and a group of formula — alkyl-heterocyclyl; or R501 and R502, taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from Cj .3 alkyl; W2 is H, halogen, cyano; or phenyl optionally substituted with~C(=O) -N(R501 )(R502); or a 5- or 6- membered heteroaryl group having 1 or 2 heteroatoms independently selected from O, S and N, that is optionally substituted with up to three substituents selected from alkyl, alkoxy and -N(R501XR502); or a group of formula:
W1 is a group of formula:
Figure imgf000015_0003
heteroaryl selected from pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, the heteroaryl group being optionally substituted with up to three substituents selected from alkyl, alkoxy, -N(R501)(R502) and heterocyclyl; wherein each R501 and each R502 is independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl. In some embodiments of each of the foregoing, R2 is H or halogen, and R3 is H. In some embodiments, compounds of the invention have the Formula II:
Figure imgf000016_0001
wherein:
X is O or NR6;
Y is H, Ci -3 alkyl, halo, cyano, nitro, or amino;
R5a and R5b are each independently H, halo, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, or substituted amino; R6 is H, acyl, substituted carbonyl, sulfonyl, alkyl, or substituted alkyl; or R5a and R6 are taken together to form a bridging alkylene moiety; or R5a and R5b are taken together to form a bridging alkylene moiety; m and n are independently 0, 1 or 2;
R1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, arninothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclyloxy, and substituted heterocyclyloxy;
R2 and R3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester,
(carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, 30 sulfonyl, substituted sulfonyl. sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and
R4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
In some embodiments, R4 is substituted phenyl. In some such embodiments, R4 is phenyl substituted with a group of formula -Xi-N(R50l)(R502); wherein Xi is SO2 or C(=O); and R501 and R502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R501 and R502, taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C1-3 alkyl. In some such embodiments, X1 is SO2- In some further such embodiments, -N(R50 ')(R502) forms -NH2, -NH- alkyl, -NH-alkyl substituted with alkoxy, -NH-cycloalkyl, morpholino, - NH-( alkyl)-pyrrolidinyl or piperizinyl optionally substituted with alkyl. In some further embodiments, -N(R501)(R502) forms -NH2, -NH-CH(CH3)2, -NH-(CH2)2-O-CH3, -NH- cyclopropyl, morpholin-4-yl, 4-rnethyl-piperizine- 1 -yl, or -NH-(CH2)2-pyrrolidin- 1 -yl.
In some of the foregoing embodiments, X1 is C(=O). In some such embodiments, - N(R501)(R502) forms -NH2, -NH-alkyl, -NH-alkyl substituted with alkoxy, or -NH-cycloalkyl.
In some embodiments, Y is H or C1.3 alkyl. In other embodiments Y is H Or-CH3. In more particular embodiments, Y is H. In some embodiments, R2 is H or halogen. In some further embodiments, R3 is H.
Ih some embodiments, R1 is selected from H, alkyl, and substituted alkyl.
In some embodiments, compounds of the invention have the Formula HI:
Figure imgf000017_0001
wherein,
X is O or NR6;
Y is H, Ci .3 alkyl, halo, cyano, nitro, or amino; rjruza_j±β.uuuz
R5a and R5b are each independently H, halo, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, or substituted amino;
R6 is H, acyl, substituted carbonyl, sulfonyl, alkyl, or substituted alkyl; or R5a and R6 are taken together to form a bridging alkylene moiety; or R5a and R5b are taken together to form a bridging alkylene moiety; m and n are independently 0, 1 or 2;
R1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclyloxy, and substituted heterocyclyloxy;
R2 and R3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and
R4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, hi some such embodiments, R4 is substituted phenyl. In some such embodiments, R4 is phenyl substituted with a group of formula -Xi-N(R501)(R502); wherein X1 is SO2 or C(O); and R501 and R502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R501 and R502, taken together, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from Cu3 alkyl. In some such embodiments, X1 is SO2. In some such embodiments, - N(R501)(R502) forms -NH2, -NH-alkyl, -NH-alkyl substituted with alkoxy, -NH-cycloalkyl, morpholino, -NH-(alkyl)-pyrrolidinyl or piperizinyl optionally substituted with alkyl. In some further embodiments, -N(R501)(R502) forms -NH2, -NH-CH(CH3)2, -NH-(CH2)2-O-CH3, -NH-cyclopropyl, morpholin-4-yl, 4-methyl-piperizine-l-yl, or -NH-(CH2)2-pyπrolidin-l-yl.
In of the foregoing some embodiments, X1 is C(=O). In some such embodiments, -N(R501XR502) forms -NH2, -NH-alkyl, -NH-alkyl substituted with alkoxy, or -NH-cycloalkyL In some embodiments, R2 is H or halogen. In some further embodiments, R3 is H. In some embodiments, X is NR6. In some embodiments, X is NR6, R5b is H, and R6 and R5b together form an alkylene bridge, for example -(CHa)2-.
In some embodiments, X is NR6, and R5a and R5b together form an alkylene bridge, for example -(CHa)2-.
In some embodiments, X is NR6, wherein R6 is H or alkyl. Ih some embodiments, X is NR6, m and n are each 1 , and R5a and R5b are each H.
In some such embodiments, R6 is H or alkyl. hi some embodiments, X is NR6, m is 1 and n is 0, and R5a and R5b are each H. In some such embodiments, R6 is H or alkyl.
In some embodiments, X is NR6, m is 2 and n is 0, and R5a and R5b are each H. In some such embodiments, R6 is H or alkyl.
In some embodiments, X is NR6, m and n are each 0, and R5a and R5b are each H. hi some such embodiments, R6 is H or alkyl.
In some embodiments, Y is H or Ci .3 alkyl. In other embodiments Y is H or -CH3. hi more particular embodiments, Y is H. In some embodiments of the compounds of Formula HI, R1 is selected from H, halogen, cyano, heteroaryl, substituted heteroary], phenyl, and substituted phenyl, hi some further embodiments, R1 is H, halogen, cyano; or phenyl optionally substituted with-C(=O) — N(R501)(R502); or a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently selected from O, S and N, that is optionally substituted with up to three substituents selected from alkyl, alkoxy and -N(R501 )(R502); wherein each R501 and each R502 is independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl. hi some such embodiments, R1 is phenyl optionally substituted with— rru-jβ^-i β.uυυz
C(=O) -N(R50I)(R502). In some such embodiments, R501 and R502 are each independently selected from H and alkyl.
In some further embodiments, R1 is H, halogen or cyano.
In some of the foregoing embodiments, R1 is a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently selected from O, S and N, that is optionally substituted with up to three substituents selected from alkyl, alkoxy and — N(R501)(R502).
Ih some of the foregoing embodiments, R1 is a heteroaryl group selected from pyridinyl, pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, the heteroaryl group being optionally substituted with up to three substituents selected from alkyl, alkoxy and — N(R501)(R502). In some such embodiments, R501 and R502 are each independently selected from H and alkyl.
In some of each of the foregoing embodiments, R4 is other than pyridinyl. In some of each of the foregoing embodiments, R4 is other than pyridin-2-yl.
Some compounds of the invention are shown in Tables 1-5 below. Physical data is provided in the column marked "MS (M+l)..." for each of the compounds, as is retention time data.
The columns labeled "PDKl IC50" "CPEC50 A2780," "CPEC50 PC3," and "CPEC50 PC3MM" indicates the compound's activity in the PDKl Kinase Alpha Screen Assay and the Cell Proliferation Assay described below. The symbol "+" indicates IC5O values or EC50 values of 25 μM or greater (or compounds not evaluated), the symbol "++" indicates IC50 values or EC50 values between less than 25 μM and greater than 10 μM, the symbol "+++" indicates IC50 values or EC50 values of 10 μM or less and greater than 5 μM, and the symbol
' indicates IC50 values or EC50 values less than 5 μM.
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Table 2
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
102
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
PP028218.0002 (20366-156WO1) Table 4
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
The Compounds in Tables 1-4 were named using AutoNom 2000 (Automatic Nomenclature) for ISIS/Base or ChemDraw v. 10, implementing IUPAC standardized nomenclature. Superscripted characters are denoted by asterisks (*) before and after the character. Further provided are compounds of Formula I and mixtures thereof where any asymmetric carbon atom(s) can have either the R or S configuration. Substituents at a double bond or a ring of the compounds of formula I may be present in either the cis (-Z-) or trans (-E-) configurations. The compounds may thus be present as mixtures of isomers, diastereomers, and enantiomers or may be present as pure isomers. In some embodiments, the compounds are enantiomerically pure where only one enantiomer is present. In other embodiments, the compound may be present as a mixture of enantiomers which includes more of one enantiomer than it does of the other.
Other embodiments provide methods for inhibiting PDKl in a subject. More particularly, the present invention provides a method of inhibitng PDKl comprising administering to a human or animal subject, a quinazoline compound as described herein. Such methods include administering a compound of Formula I, II or III to the subject.
The present invention further provides compositions including: a compound of Formula I, II or III and a pharmaceutically acceptable carrier or excipient.
Further methods of the invention are provided wherein compositions described herein are used for the treatment of cancer and reduction of tumor growth. In particular, the quinazoline compounds are useful in the treatment of human or animal (e.g., murine) cancers, including, for example, lung and bronchus; prostate; breast; pancreas; colon and rectum; thyroid; liver and intrahepatic bile duct; hepatocellular; gastric; glioma/glioblastoma; endometrial; melanoma; kidney and renal pelvis; urinary bladder; uterine corpus; uterine cervix; ovary; multiple myeloma; esophagus; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; non-Hodgkin lymphoma; melanoma; and villous colon adenoma. More particularly, the quinazoline compound of the invention is administered for the treatment of cancers of the prostate, lung, colon, or breast. In one such embodiment, the quinazoline compound is PP028218.0002
administered to a subject in need thereof. In some such embodiments, the administration of the compound has an inhibiting effect upon tumor cell growth.
In accordance with another embodiment of the present invention, a therapeutic composition for inhibiting tumor cell growth in a subject is provided. Such compositions include an effective amount of a compound of the invention (i.e., a compound of Formula I, II or III) and at least one pharmaceutically acceptable carrier. In such embodiments, the composition is effective at inhibiting the growth of one or more mammalian tumor cells.
Pharmaceutical compositions that include the compounds described herein may include additives such as excipients. Suitable pharmaceutically acceptable excipients include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as combinations of any two or more of these. Other suitable pharmaceutically acceptable excipients are described in Remington: The Science And Practice Of Pharmacy, Lippincott Williams & WilMns; Baltimore, MD, 21st ed. (May 28, 2005), which is hereby incorporated herein by reference in its entirety and for all purposes as if fully set forth herein.
Pharmaceutical compositions that include the compounds of the invention may be in any form suitable for the intended method of administration, including, for example, as a solution, a suspension, or an emulsion. Liquid carriers are typically used in preparing solutions, suspensions, and emulsions. Liquid carriers contemplated for use in the practice of the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils or fats, and the like, as well as mixtures of two or more of these. The liquid carrier may include other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity regulators, stabilizers, and the like. Suitable organic solvents include, for example, monohydric alcohols, such as ethanol, and polyhydric alcohols, such as glycols. Suitable oils include, but are not limited to, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, and the like. For parenteral administration, the carrier may be an oily ester such as ethyl oleate, isopropyl myristate, and the like. Compositions of the present invention may also be in the form PP028218.0002
of microparticles, microcapsules, and the like, as well as combinations of any two or more of these.
The compounds and combinations of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form may include, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids include phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods of forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. W., p. 33 et seq (1976).
Controlled release delivery systems may also be used, such as a diffusion controlled matrix system or an erodϊble system, as described for example in: Lee, "Diffusion-Controlled Matrix Systems", pp. 155-198 and Ron and Langer, "Erodible Systems", pp. 199-224, in
"Treatise on Controlled Drug Delivery", A. Kydonieus Ed., Marcel Dekker, Inc., New York 1992. The matrix may be, for example, a biodegradable material that can degrade spontaneously in situ and in vivo for, example, by hydrolysis or enzymatic cleavage, e.g., by proteases. The delivery system may be, for example, a naturally occurring or synthetic polymer or copolymer, for example in the form of a hydrogel. Exemplary polymers with cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysaccharides, poly(phosphoesters), polyamides, polyurethanes, poly(imidocarbonates) and poly(phosphazenes).
The compounds of the invention may be administered enterally, orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations that include conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. For example, suitable modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intramuscular, intraperitoneal, intranasal, subdermal, rectal, and the like. Topical administration may also include the use of transdermal administration such as transdermal patches or ionophoresis devices. The term parenteral as used PP028218.0002
herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. hi addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary temperatures but liquid at the rectal temperature and will, therefore, melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also include, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also include buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.
Effective amounts of the compounds of the invention generally include any amount sufficient to detectably treat the disorders described herein. PP028218.0002
Successful treatment of a subject in accordance with the invention may result in a reduction or alleviation of symptoms in a subject afflicted with a medical or biological disorder. For example, treatment may halt the further progression of the disorder, or may prevent or retard development of the disorder. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and severity of the particular disease undergoing therapy. The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
DEFIMTIONS As used above and elsewhere herein the following terms and abbreviations have the meanings defined below:
AcH Acetic Acid
ATP Adenosine triphosphate
BCG Mycobacterium bovis bacillus Calmette-Guerin Bn Benzyl
BSA Bovine Serum Albumin
DCM Dichloromethane
DIEA N,N-diisopropyl-ethylamine
EDC l-(3-Dimemylaminopropyl)3-ethylcarbodiimide hydrochloride FHA Filamentous haemaglutinin
GCMS Gas Chromatography / Mass Spectroscopy
H. Pylori Helicobacter Pylori
HBr Hydrogen Bromide
HPLC High Performance Liquid Chromatography PP028218.0002
ICso value The concentration of an inhibitor that causes a 50 % reduction in a measured activity.
IFN Interferon
IL Interleukin
IMS Immunomagnetic separation
IPV Inactivated polio virus
LCMS Liquid Chromatography / Mass Spectroscopy
LPS Lipid polysaccharide
MAb or mAb Monoclonal Antibody
MeOH Methanol
MW Molecular Weight
NMR Nuclear magnetic resonance
OMV Outer membrane vesicle
PBMC Peripheral blood mononuclear cells
Rt Room temperature (250C) tBOK Potassium Tertiary Butoxide
TEA Triethylamine
OTf Triflate
THF Tetrahydrofuran
TLC Thin Layer Chromatography and/or Tender Loving Care
TMS Trimethylsilyl
TNF- Tumour necrosis factor-alpha
Reference to "quinazolines" (as pertaining to quinazolines of the present invention), indicates compounds having the general structure of Formula I, II or III as described herein. In some embodiments, the quinazolines include the compounds listed in Tables 1-5, infra.
"Modulating" refers to inducing or suppressing.
A "disease associated with cellular proliferation" includes, but is not limited to cancers, for example cancers of the prostate, lung, colon and breast, neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, proliferative diabetic PP028218.0002
retinopathy (PDR), hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, angiogenesis, and endotoxic shock.
The term "effective amount" is an amount necessary or sufficient to realize a desired biological effect. For example, an effective amount of a compound to treat a disorder may be an amount necessary to cause reduction or alleviation of symptoms in a subject afflicted with a medical or biological disorder. For example, treatment may halt the further progression of the disorder, or may prevent or retard development of the disorder. The effective amount may vary, depending, for example, upon the condition treated, weight of the subject and severity of the disease. One of skill in the art can readily determine the effective amount empirically without undue experimentation.
As used herein "an effective amount for treatment" refers to an amount sufficient to palliate, ameliorate, stabilize, reverse, slow or delay progression of a condition such as a disease state.
A "subject" or "patient" is meant to describe a human or vertebrate animal including a dog, cat, horse, cow, pig, sheep, goat, monkey, rat, mouse, and other mammals.
As used herein, the term "pharmaceutically acceptable ester" refers to esters, which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Representative examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The compounds of the present invention can be used in the form of salts as in "pharmaceutically acceptable salts" derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate, sulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, PP028218.0002
tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained. The terms used in the claims are defined below.
"Alkyl" refers to saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), »-propyl (CHaCH2CH2-), isopropyl ((CHa)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-)5 sec-butyl ((CH3)(CH3CH2)CH-), f-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), andneopentyl ((CH3)3CCH2-).
"Substituted alkyl" refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
"Alkyl interrupted with -O-, -S-, -SO-, -SO2-, -NH-, carbonyl, carbonylamino, or aminocarbonyl" refers to a C2-10 alkyl group in which an -O-, -S-, -SO-, -SO2-, -NH-, carbonyl, carbonylamino, or aminocarbonyl is inserted between the carbon atoms of the alkyl group. For PP028218.0002
example, an ethylene radical interrupted with -O- is -C-O-C-. An ethylene radical interrupted with carbonyl is -C-C(=O)-C-.
"Alkoxy" refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, byway of example, methoxy, ethoxy, w-propoxy, isopropoxy, «-butoxy, t-butoxy, sec-butoxy, and «-pentoxy.
"Substituted alkoxy" refers to the group -O-(substituted alkyl) wherein substituted alkyl is defined herein.
"Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(OK cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(0)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Acyl includes the "acetyl" group CHsC(O)-.
"Acylamino" refers to the groups -NRC(O)alkyl, -NRC(O)substituted alkyl, -NRC(O)cycloalkyl, -NRC(O)substituted cycloalkyl, -NRC(O)cycloalkenyl, -NRC(O)substituted cycloalkenyl, -NRC(O)alkenyl, -NRC(O)substituted alkenyl, -NRC(O)alkynyl, - NRC(O)substituted alkynyl, -NRC(O)aryl, -NRC(O)substituted aryl, -NRC(O)heteroaryl, -NRC(O)substituted heteroaryl, -NRC(0)hetero cyclic, and -NRC(O) substituted heterocyclic wherein R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
"Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O~, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C(O)O-, substituted cycloalkenyl-C(O)O-, heteroaryl-C(O)O-, substituted PP028218.0002
heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(0)0- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkeήyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
"Amino" refers to the group -NH2.
"Substituted amino" refers to the group -NR'R" where R' and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -Sθ2-alkyl, -SCh-substituted alkyl, -Sθ2-alkenyl, -SCh-substituted alkenyl, -Sθ2-cycloalkyl, -SC>2-substituted cylcoalkyl, -Sθ2-cycloalkenyl, -SCh-substituted cylcoalkenyl,-SO2-aryl, -SCVsubstituted aryl, -SCh-heteroaryl, -SCVsubstituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic and wherein R' and R" are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R' and R" are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. When R' is hydrogen and R" is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R' and R" are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R' or R" is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R' nor R" are hydrogen.
"Aminocarbonyl" refers to the group -C(O)N R10R11 where R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, PP028218.0002
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
"Aminothiocarbonyl" refers to the group -C(S)NR10R11 where R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R1 ' are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
"Aminocarbonylamino" refers to the group -NRC(O)NR10R11 where R is hydrogen or alkyl and R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
"Aminothiocarbonylamino" refers to the group -NRC(S)NR10R11 where R is hydrogen or alkyl and R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, PP028218.0002
heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein..
"Aminocarbonyloxy" refers to the group -0-C(O)NR10R11 where R10 and Rn are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
"Aminosulfonyl" refers to the group -SO2NR10R11 where R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
"Aminosulfonyloxy" refers to the group -0-SO2NR10R11 where R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. PP028218.0002
"Aminosulfonylamino" refers to the group -NR-SO2NR10R1 ' where R is hydrogen or alkyl and R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkyenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R1 * are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkyenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
"Amidino" refers to the group -C(=NR12)R10Rn where R10, R11, and R12 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R10 and R11 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
"Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4- benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.
"Substituted aryl" refers to aryl groups which are substituted with 1 to 5, preferably 1 to
3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, PP028218.0002
arninosulfonyloxy, amnosirifonylami.no, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
"Aryloxy" refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy .'
"Substituted aryloxy" refers to the group -O-(substituted aryl) where substituted aryl is as defined herein.
"Arylthio" refers to the group — S-aryl, where aryl is as defined herein.
"Substituted arylthio" refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
"Alkenyl" refers to alkenyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of alkenyl unsaturation. Such groups are exemplified, for example, by vinyl, allyl, and but-3-en-l-yl.
"Substituted alkenyl" refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, PP028218.0002
cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy substitution is not attached to a vinyl (unsaturated) carbon atom.
"Alkynyl" refers to alkynyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of alkynyl unsaturation.
"Substituted alkynyl" refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy substitution is not attached to an acetylenic carbon atom.
"Carbonyl" refers to the divalent group -C(O)- which is equivalent to -C(=O)-.
"Carboxyl" or "carboxy" refers to -COOH or salts thereof.
"Carboxyl ester" or "carboxy ester" refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, PP028218.0002
-C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(0)0-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
"(Carboxyl ester)amino" refers to the group -NRτC(O)O-alkyl, substituted -NR-C(O)O-alkyl, -NR-C(O)O-alkenyl, -NR-C(O)O-substituted alkenyl, -NR-C(O)O-alkynyl, ' -NR-C(O)O-substituted alkynyl, -NR-C(O)O-aryl, -NR-C(O)O-substituted aryl,
-NR-C(O)O-cycloalkyl, -NR-C(O)O-substituted cycloalkyl, -NR-C(0)0-cyclo alkenyl, - NR-C(O)O-substituted cycloalkenyl, -NR-C(0)0-heteroaryl, -NR-C(O)O-substituted heteroaryl, -NR-C(O)O-heterocyclic, and -NR-C(O)O-substituted heterocyclic wherein R is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
"(Carboxyl ester)oxy" refers to the group -O-C(O)O-alkyl, substituted -O-C(O)O-alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -0-C(0)0-cycloalkyl,
-O-C(O)O-sύbstituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, -0-C(0)0-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocyclic, and -O-C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
"Cyano" refers to the group -CN.
"Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable PP028218.0002
cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
"Cycloalkenyl" refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings and having at least one >C=C< ring unsatuxation and preferably from 1 to 2 sites of >C=C< ring unsaturate on.
"Substituted cycloalkyl" and "substituted cycloalkenyl" refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylarnino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
"Cycloalkyloxy" refers to -O-cycloalkyl.
"Substituted cycloalkyloxy refers to -O-(substituted cycloalkyl).
"Cycloalkylthio" refers to -S-cycloalkyl.
"Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl).
"Cycloalkenyloxy" refers to -O-cyeloalkenyl.
"Substituted cycloalkenyloxy refers to -O-(substituted cycloalkenyl). PP028218.0002
"Cycloalkenylthio" refers to — S-cycloalkenyl.
"Substituted cycloalkenylthio" refers to -S-(substituted cycloalkenyl).
"Guanidino" refers to the group -NHC(^NH)NH2.
"Substituted guanidino" refers to -NR13CC=NR1 ^N(R13)2 where each R13 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl. substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and two R13 groups attached to a common guanidino nitrogen atom are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R13 is not hydrogen, and wherein said substituents are as defined herein.
"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
"Hydroxy" or "hydroxyl" refers to the group -OH.
"Heteroaryl" refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g. , pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N- »O), sulfinyl, or sulfonyl moieties. Preferred heteroaryls include pyridinyl, pyπrolyl, indolyl, thiophenyl, and furanyl.
"Substituted heteroaryl" refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
"Heteroaryloxy" refers to -O-heteroaryl.
"Substituted heteroaryloxy refers to the group — O-(substituted heteroaryl). PP028218.0002
"Heteroarylthio" refers to the group — S-heteroaryl.
"Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl).
"Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more the rings can be cycloalkyl., aryl or heteroaryl provided that the point of attachment is through the non-aromatic ring. In one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, sulfonyl moieties.
"Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
"Heterocyclyloxy" refers to the group -O-heterocycyl.
"Substituted heterocyclyloxy refers to the group -O-(substituted heterocycyl).
"Heterocyclylthϊo" refers to the group — S-heterocycyl.
"Substituted heterocyclylthio" refers to the group — S-(substituted heterocycyl).
Examples of heterocycle and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4- tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1- dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl. PP028218.0002
"Nitro" refers to the group -NO2.
"Oxo" refers to the atom (O) or (-O").
"Spirocycloalkyl" refers to divalent cyclic groups from 3 to 10 carbon atoms having a cycloalkyl ring with a spiro union (the union formed by a single atom which is the only common member of the rings) as exemplified by the following structure:
Figure imgf000295_0001
"Sulfonyl" refers to the divalent group -S(O)2-.
"Substituted sulfonyl" refers to the group -Sθ2-alkyl, -SO2-substituted alkyl, -SO2- alkenyl, -Sθ2-substituted alkenyl, -SOa-cycloalkyl, -Sθ2-substituted cylcoalkyl, -SO2- cycloalkenyl, -Sθ2-substituted cylcoalkenyl, -Sθ2-aryl, -SO2-substituted aryl, -Sθ2-heteroaryl, -Sθ2-substituted heteroaryl, -S02-heterocyclic, -Sθ2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Substituted sulfonyl includes groups such as methyl-SO∑-, phenyl-SO2~, and 4-methylphenyl-SO2-.
"Sulfonyloxy" refers to the group -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cylcoalkyl, -OSO2- cycloalkenyl, -OSO2-substituted cylcoalkenyl.-OSO∑-aryl, -OSO∑-substituted aryl, -OSO2- heteroaryl, -OSOa-sύbstituted heteroaryl, -OSO2-heterocyclic, -OSO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
"Thioacyl" refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted PP028218.0002
cycloalkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
"Thiol" refers to the group -SH.
"Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent to -C(=S)-.
"Thione" refers to the atom (=S).
"Alkylthio" refers to the group -S-alkyl wherein alkyl is as defined herein.
"Substituted alkylthio" refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.
At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci-e alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl (propyl and isopropyl), C4 alkyl, Cs alkyl, and Ce alkyl.
"Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
"Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moeity such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycabonyl" refers to the group (aryl)-(alkyl)-O-C(O)-. PP028218.0002
The term "protected" or a "protecting group" with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W., John Wiley & Sons, New York, NY, (1 st Edition, 1981) which can be added or removed using the procedures set forth therein. Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t- butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate. Examples of protected amine groups include, but are not limited to, benzyl or dibenzyl, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others. In some embodiments, a protecting group for amines is a benzyl group. Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
Quinazoline compounds of Formula I, II or III may exhibit the phenomenon of tautomerism, and the formula drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which possesses immunomodulatory activity and is not to be limited merely to any one tautomeric form utilized within the formula drawings.
Quinazolines of Formula I, II or III also may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. The invention encompasses both solvated and unsolvated forms which possess immunomodulatory activity.
The invention also includes isotopically-labeled quinazoline compounds, that are structurally identical to those disclosed above, except that one or more atom is/are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the PP028218.0002
invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F and 36Cl, respectively. Compounds of the present invention, tautomers thereof, prodrugs thereof, and pharmaceutically acceptable salts of the compounds and of the prodrugs that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically- labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out known or referenced procedures and by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. The compounds of the invention are useful in pharmaceutical compositions for human or veterinary use where inhibition of PDKl is indicated, for example, in the treatment of cellular proliferative diseases such as tumor and/or cancerous cell growth mediated by PDKl . In particular, the compounds are useful in the treatment of human or animal (e.g., murine) cancers, including, for example, lung and bronchus; prostate; breast; pancreas; colon and rectum; thyroid; liver and intrahepatic bile duct; hepatocellular; gastric; glioma/glioblastoma; endometrial; melanoma; kidney and renal pelvis; urinary bladder; uterine corpus; uterine cervix; ovary; multiple myeloma; esophagus; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine; non-Hodgkin lymphoma; melanoma; and villous colon adenoma. In some preferred embodiments, the compounds of the invention are used to treat cancers of the prostate, lung, colon, and breast.
In other aspects, the invention provides methods for manufacture of PDKl inhibitor compounds. It is further contemplated that, in addition to the compounds of Formulas I-III, intermediates, and their corresponding methods of syntheses are included within the scope of the embodiments. PP028218.0Q02
In further embodiments, the present invention provides for compounds of Formula I, II, or III for inhibition of Cdkl and/or Cdk2. Another embodiment provides a method of treating cancer responsive to inhibition of Cdkl, comprising administering a compound of Formula I, II, or III. Another embodiment provides a method of treating cancer responsive to inhibition of Cdk2, comprising administering a compound of Formula I, II, or III.
In further embodiment, the invention provides methods of inhibiting phosphorylation of Akt comprising administering a compound of Formula I, II, or III to a human in need thereof. Another embodiment provides a method of treating cancer responsive to inhibition of phosphorylation of Akt, comprising administering a compound of Formula I, II, or III. Another embodiment provides a method of inhibiting phosphorylation of Akt comprising contacting a cell with a compound of Formula I, II, or III. hi further embodiments, the invention provides methods of inhibiting PDKl comprising orally administering a compound of Formula I, II, or III to a human in need thereof. In a more particular embodiment the human is suffering from cancer, hi a more particular embodiment the cancer is responsive to treatment with a compound that inhibits phosphorylation of PDKl . In another embodiment the compound is orally bioavailable. hi some embodiments of the methods of inhibiting PDKl using a PDKl inhibitor- compound described herein, the IC50 value of the compound is less than or equal to about 1 mM with respect to PDKl . In other such embodiments, the IC50 value is less than or equal to about 100 μM, is less than or equal to about 25 μM, is less than or equal to about 10 μM, is less than or equal to about 1 μM, is less than or equal to about 0.1 μM, is less than or equal to about 0.050 μM, or is less than or equal to about 0.010 μM. hi one embodiment, a method of reducing PDKl activity in a human or animal subject is provided. In the method, a compound of the any of the aforementioned embodiments is administered in an amount effective to reduce PDKl activity.
In some embodiments of the method of inhibiting PDKl using a PDKl inhibitor compound of the embodiments, the IC50 value of the compound is between about 1 nM to about 10 nM. In other such embodiments, the IC50 value is between about 10 nM to about 50 nM, between about 50 nM to about 100 nM, between about 100 nM to about 1 μM, between about 1 μM to about 25 μM, or is between about 25 μM to about 100 μM. PP028218.0002
Another embodiment provides methods of treating a PDKl -mediated disorder. In one method, an effective amount of a PDKl inhibitor compound is administered to a patient (e.g., a human or animal subject) in need thereof to mediate (or modulate) PDKl activity. In other such embodiments the PDKl -mediated disorder is cancer. Still another embodiment provides methods of treating diseases characterized by
"abnormal cellular proliferation." The term "abnormal cellular proliferation" includes, for example, any disease or disorder characterized by excessive or pathologically elevated cell growth such as is characteristic of various cancers and non-cancer proliferative disorders.
Example cancers include, for example, lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular cancer, gastric cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvic cancer, urinary bladder cancer; uterine corpus cancer; uterine cervical cancer, ovarian cancer, multiple myeloma, esophageal cancer, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, brain cancer, oral cavity cancer, and pharyngeal cancer, laryngeal cancer, small intestinal cancer, non-Hodgkin lymphoma, and villous colon adenoma.
Example non-cancer proliferative disorders include neuro-fibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, proliferative diabetic retinopathy (PDR), hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, angiogenesis, and endotoxic shock. . .
In some embodiments, the invention provides pharmaceutical compositions including at least one compound of Formula I, II, or III, together with one or more pharmaceutically acceptable carriers suitable for administration to a human or animal subject, either alone or together with other agents, for example, anticancer agents. In further embodiments, the invention provides methods of treating human or animal subjects suffering from a cellular proliferative disease, such as cancer. Ih some such embodiments, the invention provides methods of treating a human or animal subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, II, or III, either alone or in combination with other anticancer agents. In particular, compositions will either be formulated together as a combination PP028218.0002
therapeutic or administered separately. Anticancer agents for use with the preferred embodiments include, but are not limited to, one or more of the following set forth below:
A. Kinase Inhibitors
Kinase inhibitors for use as anticancer agents in conjunction with the compositions of the preferred embodiments include inhibitors of Epidermal Growth Factor Receptor (EGFR) kinases such as small molecule quinazolines, for example gefϊtinib (US 5457105, US 5616582, and US 5770599), ZD-6474 (WO 01/32651), erlotinib (Tarceva®, US 5,747,498 and WO 96/30347), and lapatinib (US 6,727,256 and WO 02/02552); Vascular Endothelial Growth Factor Receptor (VEGFR) kinase inhibitors, including SU-11248 (WO 01/60814), SU 5416 (US 5,883,113 and WO 99/61422), SU 6668 (US 5,883,113 and WO 99/61422), CHIR-258 (US 6,605,617 and US 6,774,237), vatalanib or PTK-787 (US 6,258,812), VEGF-Trap (WO 02/57423), B43-Genistein (WO-09606116), fenretinide (retinoic acid p-hydroxyphenylamine) (US 4,323,581), IM-862 (WO 02/62826), bevacizumab or Avastin® (WO 94/10202), KRN-951, 3-[5- (methylsulfonylpiperadinemethyl)-indolyl]-quinolone, AG-13736 and AG-13925, pyrrolo[2,l- fj[l,2,4]triazines, ZK-304709, Veglin®, VMDA-3601, EG-004, CEP-701 (US 5,621,100), Cand5 (WO 04/09769); Erb2 tyrosine kinase inhibitors such as pertuzumab (WO 01/00245), trastuzumab, and rituximab; Akt protein kinase inhibitors, such as RX-0201; Protein Kinase C (PKC) inhibitors, such as LY-317615 (WO 95/17182), and perifosine (US 2003171303); Raf/Map/MEK/Ras kinase inhibitors including sorafenib (BAY 43-9006), ARQ-350RP, LErafAON, BMS-354825 AMG-548, and others disclosed in WO 03/82272; Fibroblast Growth Factor Receptor (FGFR) kinase inhibitors; Cell Dependent Kinase (CDK) inhibitors, including CYC-202 or roscovitine (WO 97/20842 and WO 99/02162); Platelet-Derived Growth Factor Receptor (PDGFR) kinase inhibitors such as CHIR-258, 3G3 mAb, AG-13736, SU-11248 and SU6668; and Bcr-Abl kinase inhibitors and fusion proteins such as STI-571 or Gleevec® (imatinib).
B. Anti-Estrogens
Estrogen-targeting agents for use in anticancer therapy in conjunction with the compositions of the preferred embodiments include Selective Estrogen Receptor Modulators (SERMs) including tamoxifen, toremifene, raloxifene; aromatase inhibitors including Arimidex® or anastrozole; Estrogen Receptor Downregulators (ERDs) including Faslodex® or fulvestrant. PP028218.0002
C. Anti-Androgens
Androgen-targetiπg agents for use in anticancer therapy in conjunction with the compositions of the preferred embodiments include flutamide, bicalutamide, finasteride, aminoglutetharnide, ketoconazole, and corticosteroids. D. Other Inhibitors
Other inhibitors for use as anticancer agents in conjunction with the compositions of the preferred embodiments include protein farnesyl transferase inhibitors including u'pifarnϊb or R- 115777 (US 2003134846 and WO 97/21701), BMS-214662, AZD-3409, and FTI-277; topoisomerase inhibitors including merbarone and difiomotecan (BN-80915); mitotic kinesin spindle protein (KSP) inhibitors including SB-743921 and MKI-833; proteasome modulators such as bortezomib or Velcade® (US 5,780,454), XL-784; and cyclooxygenase 2 (COX-2) inhibitors including non-steroidal antiinflammatory drugs I (NSAIDs).
E. Cancer Chemotherapeutic Drugs Particular cancer chemotherapeutic agents for use as anticancer agents in conjunction with the compositions of the preferred embodiments include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeraπ®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®, US 2004073044), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil® , Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (Gemzar® or difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6- mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6- PP028218.0002
thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).
F. Alkylating Agents
• Alkylating agents for use in conjunction with the compositions of the preferred embodiments for anticancer therapeutics include VNP-40101M or cloretizine, oxaliplatin (US 4,169,846, WO 03/24978 and WO 03/04505), glufosfamide, mafosfamide, etopophos (US 5,041,424), prednimustine; treosulfan; busulfan, irofluven (acylfulvene), penclomedine, pyrazoloacridine (PD-115934); O6-benzylguanine, decitabine (5-aza-2-deoxycytidine), brostallicin, mitomycin C (MitoExtra), TLK-286 (Telcyta®), temozolomide, trabectedin (US 5,478,932), AP-5280 (Platinate formulation of Cisplatin), porfuromycin, and clearazide (meclorethamine) .
G. Chelating Agents
Chelating agents for use in conjunction with the compositions of the preferred embodiments for anticancer therapeutics include tetrathiomolybdate (WO 01/60814); RP-697, Chimeric T84.66 (cT84.66), gadofosveset (Vasovist®), deferoxamine, and bleomycin optionally in combination with electorporation (EPT).
H. Biological Response Modifiers Biological response modifiers, such as immune modulators, for use in conjunction with the compositions of the preferred embodiments for anticancer therapeutics include staurosprine and macrocyclic analogs thereof, including UCN-Ol, CEP-701 and midostaurin (see WO
02/30941, WO 97/07081, WO 89/07105, US 5,621,100, WO 93/07153, WO 01/04125, WO
02/30941, WO 93/08809, WO 94/06799, WO 00/27422, WO 96/13506 and WO 88/07045); squalamine (WO 01/79255); DA-9601 (WO 98/04541 and US 6,025,387); alemtuzumab; interferons (e.g. IFN-a, IFN-b etc.); interleukins, specifically IL-2 or aldesleukin as well as IL-I, IL-3, DL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-IO, IL-11, IL-12, and active biological variants thereof having amino acid sequences greater than 70% of the native human sequence; altretamine (Hexalen®); SU 101 or lefiunomide (WO 04/06834 and US 6,331,555); imidazoquinolines such as resiquimod and imiquimod (US 4,689,338, 5,389,640, 5,268,376,
4,929,624, 5,266,575, 6,083,505, 5,352,784, 5,494,916, 5,482,936, 5,346,905, 5,395,937, 5,238,944, and 5,525,612) or 2,4-diaminoimidazoquinolines (WO 06/31878); and SMIPs, PP028218.0002
including benzazoles, anthraquinones, thiosemicarbazones, and tryptanthrins (WO 04/87153, WO 04/64759, and WO 04/60308). I. Cancer Vaccines:
Anticancer vaccines for use in conjunction with the compositions of the preferred embodiments include Avicine® {Tetrahedron Lett. 26:2269-70 (1974)); oregovomab
(OvaRex®); Theratope® (STn-KJLH); Melanoma Vaccines; GI-4000 series (GI-4014, GI-401S, and GI-4016), which are directed to five mutations in the Ras protein; GlioVax-1 ; MelaVax; Advexin® or INGN-201 (WO 95/12660); Sig/E7/LAMP-1, encoding HPV-16 E7; MAGE-3 Vaccine or M3TK (WO 94/05304); HER-2VAX; ACTIVE, which stimulates T-cells specific for tumors; GM-CSF cancer vaccine; and Listeria monocytogenes-based vaccines.
J. Antisense Therapy:
Anticancer agents for use in conjunction with the compositions of the preferred embodiments also include antisense compositions, such as AEG-35156 (GEM-640); AP-12009 and AP-11014 (TGF-beta2-specific antisense oligonucleotides); AVI-4126; AVI-4557; AVI- 4472; oblimersen (Genasense®); JFS2; aprinocarsen (WO 97/297S0); GTI-2040 (R2 ribonucleotide reductase mRNA antisense oligo) (WO 98/05769); GTI-2501 (WO 98/05769); liposome-encapsulated c-Raf antisense oligodeoxynucleotides (LErafAON) (WO 98/43095); and Sirna-027 (RNAi-based therapeutic targeting VEGFR-I mRNA).
The foregoing may be better understood by reference to the following Examples that are presented for illustration and not to limit the scope of the inventive concepts. The Example compounds and their analogs are easily synthesized by one skilled in the art from procedures described herein, as well as in patents or patent applications listed herein which are all hereby incorporated by reference in their entireties and for all purposes as if fully set forth herein.
EXAMPLES
Referring to the examples that follow, compounds of the preferred embodiments were synthesized using the methods described herein, or other methods, which are known in the art.
The compounds and/or intermediates were characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a 2695 Separation Module (Milford, MA). The analytical columns were reversed phase Phenomenex Luna Cl 8 -5 μ, 4.6 x 50 mm, from Alltech (Deerfϊeld, IL). A gradient elution was PP028218.0002
used (flow 2.5 mL/min), typically starting with 5% acetonitrile/95% water and progressing to 100% acetonitrile over a period of 10 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA). Compounds were detected by ultraviolet light (UV) absorption at either 220 or 254 nm. HPLC solvents were fromBurdick and Jackson (Muskegan, MI), or Fisher Scientific (Pittsburgh, PA).
In some instances, purity was assessed by thin layer chromatography (TLC) using glass or plastic backed silica gel plates, such as, for example, Baker-Flex Silica Gel 1B2-F flexible sheets. TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques. Mass spectrometric analysis was performed on one of two LCMS instruments: a Waters
System (Alliance HT HPLC and a Micromass ZQ mass spectrometer; Column: Eclipse XDB-C18, 2.1 x 50 mm; gradient: 5-95% (or 35-95%, or 65-95% or 95-95%) acetonitrile in water with 0.05% TFA over a 4 min period ; flow rate 0.8 mL/min; molecular weight range 200-1500; cone Voltage 20 V; column temperature 4O0C) or a Hewlett Packard System (Series 1100 HPLC; Column: Eclipse XDB-C 18, 2.1 x 50 mm; gradient: 5-95% acetonitrile in water with 0.05% TFA over a 4 min period ; flow rate 0.8 mL/min; molecular weight range 150-850; cone Voltage 50 V; column temperature 300C). All masses were reported as those of the protonated parent ions.
GCMS analysis is performed on a Hewlett Packard instrument (HP6890 Series gas chromatograph with a Mass Selective Detector 5973; injector volume: 1 μL; initial column temperature: 5O0C; final column temperature: 2500C; ramp time: 20 minutes; gas flow rate: 1 mL/min; column: 5% phenyl methyl siloxane, Model No. HP 190915-443, dimensions: 30.0 m x 25 m x 0.25 m).
Nuclear magnetic resonance (NMR) analysis was performed on some of the compounds with a Varian 300 MHz NMR (Palo Alto, CA). The spectral reference was either TMS or the known chemical shift of the solvent. Some compound samples were run at elevated . temperatures (e.g., 750C) to promote increased sample solubility.
The purity of some of the compounds is assessed by elemental analysis (Desert Analytics, Tucson, AZ). Melting points are determined on a Laboratory Devices Mel-Temp apparatus (Holliston,
MA). PP028218.0002
Preparative separations are carried out using a Flash 40 chromatography system and KP-SiI, 6OA (Biotage, Charlottesville, VA), or by flash column chromatography using silica gel (230-400 mesh) packing material, or by HPLC using a Waters 2767 Sample Manager, C- 18 reversed phase column, 30X50 mm, flow 75 rnL/min. Typical solvents employed for the Flash 40 Biotage system and flash column chromatography are dichloromethane, methanol, ethyl acetate, hexane, acetone, aqueous ammonia (or ammonium hydroxide), and triethyl amine. Typical solvents employed for the reverse phase HPLC are varying concentrations of acetonitrile and water with 0.1% trifluoroacetic acid.
Example 1
Preparation of 3-(8-( 1 -Methylpiperidin-4-yloxy)quinazolin-2-ylarnino)benzenesulfonamide
Figure imgf000306_0001
Step 1. Preparation of 2-Chloroquinazolin-8-ol To a 0.55M solution of 2-chloro-8-methoxyquinazoline in DCM was added boron tribromide
(2.2 eq. of a 1.0 M solution in DCM) over 5 minutes at 0 0C. The reaction mixture was stirred at ambient temperature for 22 hours, and then cooled to -5 0C for 30 minutes. The precipitate was collected by vacuum filtration and then stirred in ice water for 30 minutes. The solid was collected by vacuum filtration and rinsed with 2-propanol. The off-white solid was dried in a desiccator to give the desired product in 79% yield. ES/MS m/z 181 (MH+).
Step 2. Preparation of 3-(8-Hydroxyquinazolin-2-ylamino)benzenesulfonamide To a 0.3 M solution of 2-chloroquinazolin-8-ol in 2-propanol was added sulfanilamide (1.0 eq). The reaction was stirred at 90 0C for 14 hours. The hydrochloride was collected by vacuum filtration and then stirred in aqueous sodium bicarbonate. The solid was collected by vacuum filtration and rinsed with water. The off-white solid was dried in a desiccator to give the desired product in 93% yield. ESZMS wZz Sn (MH+). PP028218.0002
Step 3. Preparation of 3-(8-(l-Methylpiperidin-4-yloxy)quinazolin-2- ylamino)benzenesulfonamide
To a 0.3M solution of triphenylphosphine (1.5 eq) in THF was added di-tert- butylazodicarboxylate (1.5 eq). The mixture was stirred 15 minutes at ambient temperature. 4- Hydroxy-1-methylpiperidine (4.5 eq) was added. The mixture was stirred 15 minutes at ambient temperature. 3-(8-Hydroxyquinazolin-2-ylarnino)benzenesulfonamide (1.0 eq) was added. The mixture was stirred an additional 1 hour. The crude mixture was concentrated, purified by RPHPLC, and lyophilized to give the desired product in 24.2% yield. ES/MS m/z 414 (MH+).
Example 2 Step 1. Preparation of 2-chloro-8-methoxyquinazoline
Figure imgf000307_0001
Step 1. Preparation of 2-amino-3-methoxybenzaldehyde
Iron powder (40 g) was slowly added to a stirred solution of 3-methoxy-2-nitrobenzaldehyde (1) (70 g, 386 mmole) in AcOH gal. (100 mL) and EtOH abs. (400 mL). The reaction was cooled using an ice bath followed by addition of con. HCL (1 mL). The reaction became exothermic. After stabilization of the reaction temperature, the reaction was heated to reflux. The reaction reached completion after ca. 20 minutes according to LCMS. The reaction mixture was cooled to RT and filtered. The filtrate was evaporated to a thick brown syrup. The dark residue was dissolved in EtOAc (500 mL) and water (200 mL). The mixture was basified with NaOH 6M to ca. pH 10. The mixture was filtered over celite and the layers separated. The organic layer was washed with NaHCO3 (2 x 100 mL), water (2 x 100 mL), brine (100 mL), dried (Na2SO4), filtered and evaporated to a dark amber oil. The oil was dried in vacuo to give 95% pure product 2-amino-3-methoxybenzaldehyde in 64% yield (37.2 g, 246 mmole). PP028218.0002
Step 2. Preparation of 8-methoxyquinazolin-2-ol
Solid 2-amino-3-methoxybenzaldehyde (37.2 g, 0.246 mole), urea (158 g, 2.5 mole) and catalytic NEUOAc (1 g) were thoroughly mixed together in a roundbottom flask. The solid mixture was heated in a 160 0C bath. The solids quickly melted and stirring was commenced. After about 15 minutes, solids start to precipitate from the hot solution. After adding NMP (150 mL) to dissolve the solids, the reaction was heated with stirring for an additional 30-45 minutes until complete as judged by LCMS. The hot reaction mixture was poured into vigorously stirred water (400 mL). The reaction flask was washed out with water (3 x 100 mL) and EtOAc (4 x 50 mL). After stirring ca. 30 minutes, mixture was filtered to collect the light solid precipitate. The solid filter cake was washed with portions of water and EtOAc to give a white solid. The solid was dried on the frit and in vacuo to give the product in 99% purity and 95% yield (41 g, 233 mmole).
Step 3. Preparation of 2-chloro-8-methoxyquinazoline Neat POCI3 (400 mL) was added to 8-methoxyquinazolin-2-ol (5.0 g, 28.4 mmole) with stirring and cooling over an ice bath under argon. After ca. 1 minute, the reaction was removed from the ice bath and stirred at RT for ca. 20 minutes until a fine yellow suspension was formed. The reaction, fitted with a reflux condenser, was heated in an oil bath at 140-145 0C. After about 1 hour, the reaction turned clear and colorless. LCMS showed that the reaction was complete. The POCI3 was evaporated under reduced pressure, and dried in vacuo. After 12 hours, the residue was partitioned between EtOAc (300 mL) and sat. NaHCOa (200 mL). The mixture was stirred cautiously watching gas evolution until the pH reached ~8. The layers were separated and the organic layer was washed with NaHCO3 (2 x 100 mL), water with 5% brine (2 x 100 mL), brine (100 mL), dried (Na2SO4), filtered and evaporated to a yellow solid. The crude product was purified by flash chromatography eluting with 50% EtOAc/Hexane and finishing with 100% EtOAc to produce a white solid after evaporating the correct fractions. The pure 2-chloro-8- methoxyquinazoline was isolated in 89% yield (4.9 g, 25.3 mmole).
Example 3 Step 1. Preparation of 6-bromo-2-chloro-8-methoxyquinazoline PP028218.0002
Figure imgf000309_0001
Step 1. Preparation of 2-amino-5-bromo-3-methoxybenzoic acid
To a 0.24 M chloroform solution of 2-amino-3-methoxybenzoic acid (4, 11.87 g, 71.7 mmol) at 0 0C was added bromine (1.08 eq. 0.31 M) in chloroform dropwise. The mixture was warmed to room temperature and stirred under argon for 16 hours. The resulting precipitate was collected by filtration and washed thoroughly with chloroform. The crude material was dried in vacuo to give the title as an HBr salt in 99% yield. ES/MS m/z 248/250 (MH+).
Step 2. Preparation of (2-amino-5-brorno-3-rnethoxyphenyl)methanol
To a 0.24 M THF suspension 2-amino-5-bromo-3-methoxybenzoic acid (71.7 mmol) at 00C was added borane THF solution (I M, 220 mL, 220 mmol). The mixture was stirred under argon at room temperature for 66 hours. The reaction was quenched by adding ethanol (15 mL) at 00C and stirred for 15 minutes. The mixture was poured into water and extracted with dichloromethane. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo to give crude material as a white solid (10.16 g, 62% yield). ES/MS m/z 230/232 (MH+).
Step 3. Preparation of 2-amino-5-bromo-3-methoxybenzaldehyde
To a 0.15 M chloroform solution of (2-amino-5-bromo-3-methoxyphenyl)methanol (10.16 g, 43.96 mmol) was added manganese dioxide (19.9 g, 280.5 mmol). The mixture was stirred under argon at room temperature for 16 hours. The resulting mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated to dryness and used in next step. ES/MS m/z 228/230 (MH+). PP028218.0002
Step 4. Preparation of 6-bromo-8-methoxyquinazolin-2-ol
The mixture of 2-amino-5-bromo-3-methoxybenzaldehyde (43.96 mmol, crude material from step 3) and urea (35 g, 583 mmol) from the previous step was heated to 1800C under argon for 1 hour. Water (300 mL) was added after cooling to room temperature. The solid was collected by filtration and air dried to give 12.45 g of powder. ES/MS m/z 254/256 (MH+).
Step 5. Preparation of 6-bromo-2-chloro-8-methoxyquinazoline
A suspension of 6-bromo-8-methoxyquinazolin-2-ol (43.96 mmol) in POCI3 (120 mL) was heated to 110 0C for 30 minutes The mixture was cooled to room temperature, evaporated POCI3 and partitioned between water and dichloromethane. The organic portion was concentrated to give a crude material which was purified by column chromatography (silica gel, eluted with 2% MeOH in dichloromethane) to yield pure material as a yellow solid in 30% yield (3 steps, 3.62 g). ES/MS m/z 212121 A (MH4).
Example 4
Preparation of 3-(7-(l-Methylpiperidin-4-yloxy)quinazolin-2-ylarnino)benzenesulfonanτide
Figure imgf000310_0001
Step 1. Preparation of 4-methoxy-2-nitrobenzaldehyde
Compound 5 (20.43 g, 0.122 mol, 1.0 eq) was dissolved in 480 ml OfCCl4 under Ar. NBS (48.94 g, 0.275 mol, 2.2 eq) was added to the solution as a solid in one portion followed by addition of benzoyl peroxide (0.67 g, 2.76 mmol). The reaction mixture was stirred under reflux conditions for 4.5 hours. The 1H NMR of an aliquot showed ~ 90% conversion of starting material to dibromo derivative.
The reaction mixture was cooled to RT, and concentrated. CCI4 was chased twice with acetone. The residue was taken into acetone (IL) and Ag2COa (37.1 g, 0.135 mol, 1.1 eq) was added followed by addition of water (100 mL). The reaction mixture was left stirring at RT overnight. TLC ( EtOAc: Hexanes= 3:7) showed a new spot. The reaction mixture was filtered though PP028218.0002
celite, and the filter cake was washed with acetone and the filtrate was concentrated. 340 mL of H2O was added to the crude and the product was extracted with EtOAc (800 mL, 400 mL). The emulsion that formed was filtered through celite and the layers were separated. The organic layer was washed with hrine, dried over Na2SO4, and concentrated to give 8.27 g of crude material, which was purified by column chromatography (EtOAc/Hexanes) giving 14.7 g (67% yield) of pure compound.
Step 2. Preparation of 2-Formyl-5-methoxyaniline
A flask was charged with 4-methoxy-2-nitrobenzaldehyde (14.7 g, 81.2 mmol, l.Oeq), EtOH (270 mL), glacial AcOH (270 mL), H2O (135 mL), degassed and filled with argon. Then Fe powder (325 mesh) (27.2 g, 0.49 mol, 6.0 eq) was added followed by addition of concentrated HCl (12.24 mL, 0.148 mol, 1.8 eq). After stirring the reaction mixture for 1 hour at 60-650C (oil bath) TLC (EtO Ac/Hex = 4:6) showed that no starting material was left. The reaction mixture was cooled down to RT5 diluted with 200 mL of H2O and neutralized with Na2CO3 to pH= 7-8. The product was extracted into CH2Cl2. The emulsion that formed was filtered through celite, organic layer was washed with brine, dried over Na2SO^ concentrated giving 12.0 g (98% yield) of the title compound.
Step 3. Preparation of 2-Hydroxy-7-methoxyquinazoline 2-Formyl-5-methoxyaniline (11.93 g, 79.5 mmol, 1.Oeq) and urea ( 38.Og, 0.636 mol, 8.0 eq) were mixed, ground into a fine powder and placed into a IL 2-neck flask equipped with a mechanical stirrer and an air condenser. The flask was placed into a preheated (1600C) oil bath. The reaction mixture melted and was stirred at 170-1800C for 1 hour until it solidified forming yellowish-brown solid. The reaction mixture was cooled to RT, crushed, mixed with 70 mL of H2O and stirred for ~1 hour at RT. The solid was filtered, washed with 150 mL of H2O and 20 mL of ice cold Et2O. The yellow solid thus obtained was dried over P4O10 under high vacuum for several hours and the crude material (12.57 g) was used for the next step without purification.
Step 4. Preparation of 2-Chloro-7-methoxyquinazoline The crude 2-Hydroxy-7-methoxyquinazoline (12.48 g) was mixed with 170 mL of POCI3, and the reaction mixture was stirred under reflux conditions for 6 hours. POCI3 was removed using a PP028218.0002
rotovap. The crude was mixed with ~500 inL of CHCI3, stirred for 1 hour at RT, neutralized with Na2COa (pH 6-7) and the product was then extracted into chloroform. The emulsion that formed was filtered through celite, organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude was purified by column chromatography (EtOAc/Hex) followed by recrystallization from EtO Ac/Hex giving 4.4g of pure compound 6 (the combined yield for two last steps is 29%).
Step 5. Preparation of 3-(7-Methoxyquinazolin-2-ylamino)benzenesulfonamide To a 0.3 M solution of 2-chloro-7-methoxyquinazoline 6 in 2-propanol was added sulfanilamide (1.0 eq). The reaction was stirred at 90 0C for 20 hours. The hydrochloride was collected by vacuum filtration and then stirred in aqueous sodium bicarbonate. The solid was collected by vacuum filtration and rinsed with water. The off-white solid was dried in vacuum to give the desired product in 95% yield. ES/MS m/z 331 (MH+).
Step 6. Preparation of 3-(7-Hydroxyquinazolin-2-ylamino)benzenesulfonamide
To a 0.02M solution of 3-(7-Methoxyquinazolin-2-ylamino)benzenesulfonamide in NMP was added sodium thiomethoxide (5.0 eq) at ambient temperature. The reaction was stirred at 80 0C for 3 hours. The solid was collected by vacuum filtration and was partitioned between ethyl acetate and water. Saturated ammonium hydrochloride was added to aqueous phase until the PH = 6. Aqueous phase was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated to give desired product in 85% yield. ES/MS m/z 317 (MH+).
Step 7. 3-(7-(l-Methylpiperidin-4-yloxy)quinazolin-2-ylamino)benzenesulfonamide To a 0.2M solution of triphenylphosphine (1.5 eq) in THF was added di-tert- butylazodicarboxylate (1.5 eq). The mixture was stirred 15 minutes at ambient temperature. 4- Hydroxy-1-methylpiperidine (4.0 eq) was added, and the mixture was stirred 15 minutes at ambient temperature. 3-(7-Hydroxyquinazolin-2-ylamino)benzenesulfonamide (1.0 eq) was then added, and the mixture was stirred an additional 10 hours. The crude mixture was concentrated, purified by RPHPLC, and lyophilized to give the desired product 7 in 18% yield. ES/MS m/z 414 (MH*). PP028218.0002
Example 5
Preparation of 7-bromo-2-chloroquinazolin-8-ol
Figure imgf000313_0001
Solid NBS (1.09 g, 6.11 mmole) was added to a stirred solution of 2-chloroquinazolin-8-ol (1.10 g, 6.11 mmole) and diisopropyl amine (2.2 mL, 15.30 mmole) in CHCI3 (60 inL) at -5 0C under argon. After stirring at -5 to 0 0C for 1 hour, LCMS showed that the reaction was complete. The reaction was evaporated to a residue which was dissolved in DMSO (5 mL) and purified by prep. HPLC. The pure product was obtained as a white solid in 51% yield (800 mg, 3.08 mmole).
Example 6
Preparation of t erf-butyl 4-(7-bromo-2-chloroquinazolin-8-yloxy)piperidine- 1 -carboxylate
Figure imgf000313_0002
A solution of DEAD (404 mg, 2.32 mmole) in THF (0.5 mL) was added to a solution of 7- bromo-2-chloroquinazolin-8-ol (400 mg, 1.54 mmole), tert-butyl 4-hydroxypiperidine-l- carboxylate (621 mg, 3.09 mmole) and PPh3 (610 mg, 2.32 mmole) in THF (5.5 mL) at RT. After 1.5 hours, silica gel was added to the reaction which was evaporated to dryness and loaded onto a flash column. The product was eluted with 25% EtOAc/hexane to give tert-butyl 4-(7- bromo-2-chloroquinazolin-8-yloxy)piperidine-l -carboxylate in 80 % yield (545 mg, 1.23 mmole).
Example 7
Preparation of /ert-butyl 4-(7-bromo-2-(4-sulfamoylphenylamino)quinazolin-8-yloxy)piperidine- 1 -carboxylate PP028218.0002
Figure imgf000314_0001
Solid KOtBu (442 mg, 3.95 mmole) was added to a solution oftert-butyl 4-(7-bromo-2- chloroquinazolin-8-yloxy)piperidine-l-carboxylate (500 mg, 1.13 mmole) and 4- aminobenzenesulfonamide (777 mg, 4.62 mmole) in IPA (15 mL). The reaction was sealed and heated to 105 0C with stirring. After 2.5 hours, AcOH was added to the reaction to pH 4 and the reaction was evaporated to a solid. The crude product was dissolved in DMSO (15 mL) and purified by prep. HPLC to give 241 mg of product in 37 % yield (417 mmole).
Example 8
Preparation of 4-(7-(l-methyl-lH-pyrrol-3-yl)-8-(piperidin-4-yloxy)quinazolhi-2- ylamino)benzenesulfonamide
Figure imgf000314_0002
A 2M solution OfK2COj (180 μL) was added to a mixture of tert-bntyl 4-(7-bromo-2-(4- sulfamoylρhenylamino)quinazolin-8-yloxy)piperidine-l-carboxylate (18 mg, 0.031 mmole), 1- methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrole (20 mg, 0.093 mmole) and palladium (4 mg, 0.005 mmole) in DME (0.6 mL). The reaction was sparged with argon, sealed and heated at 90-95 0C with stirring. After 90 minutes, LCMS showed that the reaction had reached completion. The Boc group was removed by adding 4M HCl (1.5 mL) in dioxane to the PP028218.0002
cooled reaction mixture. After 2 hours, the reaction was complete by LCMS. The reaction was filtered, evaporated, dissolved in DMSO (1 mL) and purified by prep. HPLC to give 3.4 mg of the pure product as a TFA salt.
Example 9
Synthesis of 4-(6-ethynyl-8-(l -isopropylpiperidin-4-yloxy)quinazolin-2- ylamino)benzenesulfonamide (Compound 1015)
Step 1. Preparation of 6-bromo-2-chloroquinazolin-8-ol and 2,6-dibromoquinazolin-8-ol
Figure imgf000315_0001
To compound Ib (1.26 g, 4.6 mmol) suspended in dichloromethane (20 mL) at 0 °C was added dropwise a dichloromethane solution of borontribromide (1 M, 28 mL, 28 mmol). The mixture was heated to 45 0C for 18 hrs. The resulting suspension was cooled and concentrated to dryness. The residue was cooled in ice bath and saturated NaHCOβ aq. was added. The solid was collected and air dried to give desired product mixture. Without further purification, this was used in the next step.
Step 2. Preparation of 6-bromo-2-chloro-8-(l-isopropylpiperidin-4-yloxy)quinazoline and 2,6- dibromo-8-(l-isopropylpiperidin-4-yloxy)quinazoline
Figure imgf000315_0002
Triphenylphosphine (0.49 g, 1.86 mmol), di-t-butylazodicarboxylate (0.42 g, 1.86 mmol) and 1- isoprpopylpiperidin-4-ol (0.54 g, 3.74 mmol) were mixed in anhydrous THF (6 mL) and stirred PP028218.0002
at room temperature for 1.5 hrs. To this mixture was added the THF (5 mL) suspension of a mixture of 6-bromo-2-chloroquinazolin-8-ol and 2,6-dibromoquinazolin-8-ol (0.35 g). The reaction was stirred at room temperature for 2 hrs, worked up by pouring into water and extracted with EtOAc. The organic extracts were washed with brine, dried with sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromagraphy (silica gel, eluted with EtOAc/Hexanes 1:1 and DCM/MeOH 9:1) to give 0.25 g brown foam as desired product mixture. ES/MS m/z 384/386 (1:1) (MH+ for 6-bromo-2-chloro-8-(l-isopropylpiperidin- 4-yloxy)quinazoline) and 428/430/432 (1:2:1) (MH+ for 2,6-dibromo-8-(l-isopropylpiperidin-4- yloxy)quinazoline).
Step 3. Preparation of 4-(6-bromo-8-(l-isopropylpiperidin-4-yloxy)quinazolin-2- ylamino)benzenesulfonamide
Figure imgf000316_0001
To the mixture of 6-bromo-2-chloro-8-(l-isopropylpiperidin-4-yloxy)quinazoline and 2,6- dibromo-8-(l-isopropylpiperidin-4-yloxy)quinazoline (0.15 g) in 1.5 mL of isopropanol was added 4-aminobenzenesulfonamide (81 mg, 0.47 mmol) and HCl in dioxane ( 4M, 100 μL). The mixture was heated to 100 0C for 15 hrs. Additional amount of 4-aminobenzenesulfonamide (0.2 g) was added and heating was continued at 120 0C for 18 hrs. The reaction was cooled to room temperature, diluted with NaHCO3 (saturated aqueous) and extracted with EtOAc. The organic extracts were dried and concentrated to give a yellow foam containing desired product 4- (6-bromo-8-( 1 -isopropylpiperidm-4-yloxy)quinazolin-2-ylarnino)benzenesulfonamide. ES/MS m/z 520/522 (MH+).
Step 4. Preparation of 4-(6-ethynyl-8-(l-isopropylpiperidin-4-yloxy)quinazolin-2- ylamino)benzenesulfonamide PP028218.0002
Figure imgf000317_0001
A mixture of 4-(6-bromo-8-(l-isopropylpiperidin-4-yloxy)quinazolin-2- ylamino)benzenesulfonamide (crude, ~50% purity), trimethylsilylacetylene (0.2 mL), CuI (16 mg), PdCl2(dppf)2 (32 mg), triethylamine (0.8 mL) and dimethylforamide (0.8 mL) was microwaved at 120 0C for 10 min. The resulting dark brown mixture was diluted with THF (0.8 mL). Tetramethylammonium fluoride (30 mg) was added and the mixture was stirred at room temperature for 18 hrs. The resulting mixture was diluted with water and extracted with EtOAc. The organic extracts were dried with sodium sulfate and concentrated to give a residue which was purified by reverse phase HPLC. The pure fraction was collected and lyophilized to yield desired product as a TFA salt. ES/MS m/z 466 (MH+).
Example 10
Synthesis of ό-bromo^-chloro-S-fluoroquinazoline
Figure imgf000317_0002
Step 1. To a suspension of 2-amino-3-fluorobenzoic acid (5 g, 32.2 mmol) in chloroform (200 mL) was added dropwise bromine (1.1 equiv.) in chloroform (125 mL) solution. The mixture was stirred at room temperature for 16 hrs. The resulting white solid was collected by filtration and washed thoroughly with methylene chloride until the filtrate was colorless. The solid was air-dried to give 9.6 g of white powder as HBr salt of 2-amino-5-bromo-3-fluorobenzoic acid (95% yield). ES/MS m/z 234/236 (MH4). PP028218.0002
Step 2. To the above intermediate (30.6 mmol) in THF (100 mL) at 0 C was added boran tetrahydrofuran complex solution (1 M in THF, 129 mL, 4 equiv.). The mixture was stirred at room temperature for 40 hrs. The solvent was removed in vacuo and the excess reagent was quenched by addition of water (30 mL) slowly. The pH (~3) was adjusted by adding sodium bicarbonate (sat. aq.) to pH 7. Extracted with methylene chloride. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated to give a crude material as white solide. ES/MS m/z 220/222 (MH+).
Step 3. To the above intermediate (30.6 mmol) in dichloromethane (450 mL) was added manganese dioxide (MnO2, 22 g, 258 mmol). The mixture was stirred at room temperature under argon for 18 hrs. The mixture was filtered through celite pad and washed thoroughly with dichloromethane. The filtrated was concentrated in vacuo to give crude product (2-amino-5- bromo-3-fluorophenyi)methanol (5.6 g) which was used for the next step without further purification. ES/MS m/z 218/220 (MH+).
Step 4. A mixture of (2-amino-5-bromo-3-fluorophenyl)methanol (5.6 g, 23.7 mmol, obtained from step 3) and urea (21 g, 15 equiv.) was heated to 175 0C with vigorous stirring for 15 min. The reaction was cooled to room temperature and water was added. The solid was collected by filtration. Air-dried to give 2-hydroxyquinazoline as a light brown solid.
Step 5. To the above crude material was added phosphooxychloride (POCI3, 20 mL) and heated to 1100C for 30 min. The resulting mixture was cooled to room temperature and concentrated in vacuo to nearly dryness. Ice water was added and pH was adjusted to ~6 using sodium bicarbonate. Extraction with dichloromethane followed by drying with sodium sulfate and concentrated in vacuo yielded desired product 6-bromo-2-chloro-8-fluoroquuiazoline as light brown powder (1.63 g).
Example 11 Synthesis of 6-bromo-2,8-dichloroquinazoline PP028218.0002
Figure imgf000319_0001
Step 1. To a suspension of 2-amino-3-chlorobenzoic acid (2 g, 11.6 mmol) in chloroform (120 mL) was added dropwise bromine (1.1 equiv.) in chloroform (12 mL) solution. The mixture was stirred at room temperature for 16 hrs. The resulting white solid was collected by filtration and washed thoroughly with methylene chloride until the filtrate was colorless. The solid was air- dried to give 3.35 g of white powder as HBr salt of 2-amino-5-bromo-3-chlorobenzoic acid (87% yield). ES/MS m/z 250/252 (MH+).
Step 2. To the above intermediate (3.35 g, 10.1 mmol) in THF (40 mL) at 00C was added borane tetrahydrofuran complex solution (1 M in THF, 40 mL, 4 equiv.). The mixture was stirred at room temperature for 18 hrs. Additional borane tetrahydrofuran (20 mL) was added and continued reaction for another 24 hrs until the complete conversion of the starting material. The solvent was removed in vacuo and the excess reagent was quenched by addition of ethanol (20 mL) slowly. Water was added and the pH (~3) was adjusted by adding sodium bicarbonate (sat. aq.) to pH 7. Extracted with methylene chloride. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated to give a crude material as white solide. ES/MS m/z 236/238 (MH+).
Step 3. To the above intermediate (10.1 mmol) in dichloromethane (80 mL) was added manganese dioxide (MnO2, 6 g, 70 mmol). The mixture was stirred at room temperature under argon for 40 hrs. Additional manganese dioxide (6 g) was added and the reaction was continued for another 20 hrs until the complete conversion of the starting material. The mixture was filtered through celite pad and washed thoroughly with dichloromethane. The filtrated was concentrated in vacuo to give crude product (2-amino-5-bromo-3-chlorophenyl)methanol (3.3 g, orange solid) which was used for the next step without further purification. ES/MS m/z 234/236 (MH+). PP028218.0002
Step 4. A mixture of (2-amino-5-bromo-3-chlorophenyl)methanol (3.3 g, obtained from step 3) and urea (10.5 g, 15 equiv.) was heated to 1800C with vigorous stirring for 1 hr. The reaction was cooled to room temperature and water was added. The solid was collected by filtration. Air-dried to give 2-hydroxyquinazoline as a yellow powder ( 2.18 g, crude). ES/MS m/z 259/261 (MH4).
Step 5. To the above crude material was added phosphooxychloride (POCb3 25 mL) and heated to 1300C for 30 min. The resulting mixture was cooled to room temperature and concentrated in vacuo to nearly dryness. Ice water was added and pH was adjusted to ~8 using sodium bicarbonate. Extraction with dichloromethane followed by drying with sodium sulfate and concentrated in vacuo yielded desired product 6-bromo-2,8-dichloroquinazoline as brown foam (1.4 g). This material was used in other chemical medications without further purification.
Example 12 Preparation of 3-(8-methoxyquinazolin-2-ylamino)benzamide
Figure imgf000320_0001
To a 0.30 M solution of 2-chloro-8-methoxyquinazoline in 2-propanol was added 3- aminobenzamide (1.0 eq). The reaction was stirred at 90 0C for 14 h. The resulting solid was collected by vacuum filtration and triturated with additional 2-propanol. The yellow solid was dried in a desiccator to give the desired product as the hydrochloride. Alternatively, the product could be purified by reverse-phase HPLC and lyophilized to give the desired product as the trifluoroacetic acid salt. ES/MS m/z 295 (MH+).
Example 13
Preparation of N-(3 ,5-dimethoxyphenyl)-8-methoxyquinazolin-2-amine PP02821S.0002
Figure imgf000321_0001
To a 0.40 M suspension of sodium hydride (2.0 eq) in THF was added 3,5-dimethoxyaniline (2.0 eq). The mixture was stirred for 10 min. 2-Chloro-8-methoxyquinazolme was added. The reaction was stirred for 2 h at ambient temperature and. then quenched with water. The mixture was concentrated, and purified by reverse-phase HPLC and lyophilized to give the desired product as the trifluoroacetic acid salt. ES/MS m/z 312 (MH+).
Example 14
Preparation of 8 -(2-aminoethoxy)-N-phenylquinazolin-2-amine (Compound 507)
Figure imgf000321_0002
Step 1. Preparation of 8-O-alkylated intermediate
To a 0.20 M suspension of 2-chloroquinazolin-8-ol (1.0 eq) in THF was added cesium carbonate (4.0 eq). The mixture was stirred for 5 min at ambient temperature. N-(2- bromoethyl)phthalimide was added. The reaction was stirred for 24 h at 60 C. The mixture was diluted with THF and DCM, filtered, and concentrated. The crude material was purified by flash chromatography (1:1:1 hexanes : ethyl acetate : DCM) to give the desired product. ES/MS m/z 354 (MH4).
Step 2. Preparation of 2-anilino intermediate PP028218.0002
To a 0.20 M suspension of the product from Step 1 (1.0 eq) in 3:1 2-propanol:l,4-dioxane was added aniline (1.0 eq). The mixture was stirred at 90 C for 16 h and then concentrated to give the desired product as the hydrochloride salt. ES/MS m/z 411 (MH+).
Step 3. Preparation of 8-(2-aminoethoxy)-N-phenylquinazolin-2 -amine
To a 0.040 M suspension of the product from Step 2 (1.0 eq) in ethanol was added hydrazine (4.0 eq). The mixture was stirred at 70 C for 3 h and then concentrated. The residue was re- dissolved in chloroform and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated. The material could be purified by reverse-phase HPLC and lyophilized to give the desired product as the trifiuoroacetic acid salt. ES/MS m/z 281 (MH+).
Example 15
Preparation of 2,2-dimethyl-Nl -(2-(2-(phenylarrano)quinazolin-8-yloxy)ethyl)malonamide (Compound 508)
Figure imgf000322_0001
To a 0.1 IM solution of dimethylmalonyl dichloride (2.0 eq) in THF was added a 0.5 M solution of ammonia in dioxane (3.5 eq). The mixture was stirred for 15 min at ambient temperature. Crude 591475 was added. After stirring for 5 min, DIEA (4.0 eq) was added; and the mixture was stirred for 30 min. Volatiles were removed under reduced pressure, and the crude residue was purifed by reverse-phase HPLC and lyophilized to give the desired product as the trifiuoroacetic acid salt. ES/MS m/z 394 (MH+).
Example 16 -
Preparation of 4-(8-isopropoxyquinazolm-2-ylamino)-N-methylbenzamide (Compound 515) PP028218.0002
Figure imgf000323_0001
Step 1. Preparation of 8-O-alkylated intermediate
To a 0.30 M solution of triphenylphosphine (1.5 eq) in THF was added diethylazodicarboxyate (1.5 eq). The mixture was stirred 15 min at ambient temperature. 2-Propanol (4.0 eq) was added. The mixture was stirred 15 min at ambient temperature. 2-Chloroquinazolin-8-ol (1.0 eq) was added. The mixture was stirred an additional 4 h. The crude mixture was concentrated, purified by flash chromatography (3:1 hexanes : ethyl acetate) to give the desired product. ES/MS m/z 223 (MH+).
Step 2. Preparation of 4-(8-isopropoxyquinazolin-2-ylamino)-N-methylbenzamide To a 0.30 M solution of the product from Step 1 in 2-propanol was added 4-amino-N- methylbenzamide (1.0 eq). The reaction was stirred at 100 °C for 14 h. The mixture was concentrated and purified by reverse-phase HPLC and lyophilized to give the desired product as the trifluoroacetic acid salt. ES/MS m/z 337 (MH+).
Example 17
Preparation of 4-(S-(6-(2-(pyrrolidin- 1 -yl)ethylamino)pyridin-3-yl)-6- (irifluoromemyl)qumazolin-2-ylamino)benzenesulfonarnide (Compound 963)
Figure imgf000323_0002
Step 1. Preparation of 2-Amino-3-bromo-5-(trifluoromethyl)benzaldehyde 2,6-Dibromo-4-(trifluoromethyl)araline (3.19 g, 10.0 mmol, 1.00 eq) was dissolved in THF (50 mL) and cooled to -78 0C. A 2.5 M solution of n-butyllithium in hexanes (8.40 mL, 21.0 mmol, PP028218.0002
2.10 eq) was added dropwise over 15 min. The mixture was stirred at -78 0C for 1 h. A solution of DMF (1.03 mL, 14.0 mmol, 1.40 eq) in THF (5 mL) was added, and the mixture was stirred an additional 1 h at —78 0C. The reaction was allowed to come to —15 0C over 30 min and then quenched with brine. The mixture was diluted with ethyl acetate, washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated to give 1.74 g of the desired product as a pale yellow, crystalline solid. ES/MS m/z 268,270 (MH+).
Figure imgf000324_0001
Step 2. Preparation of 8-bromo-6-(trifluoromethyl)-l,4-dihydroquinazoline-2,4-diol 2-Amino-3-bromo-5-(trifluoromethyl)benzaldehyde (1.74 g, 6.49 mmol, 1.00 eq) and urea (5.85 g, 97.4 mmol, 15.0 eq) were stirred at 190 0C for 3 h. The resulting solid was returned to ambient temperature, stirred in water (60 mL) for 20 min, and filtered. This was repeated for a total of three washes. The solid was dried in a desiccator to give 3.79 g of the desired product as an off-white solid. ES/MS m/z 311 ,313 (MH+).
Figure imgf000324_0002
Step 3. Preparation of 8-Bromo-2-chloro-6-(trifluoromethyl)quinazoline
8-Bromo-6-(trifluoromethyl)-l,4-dihydroquinazoline-2,4-diol (3.79 g, 6.49 mmol, 1.00 eq).
Phosphorus oxychloride (20 mL) was added. The mixture was stirred at 110 0C for 1.5 h. Volatiles were removed under reduced pressure. Ice water was added, and the pH was adjusted to 6-7 with aqueous sodium hydroxide and sodium bicarbonate. The precipitate was filtered off, rinsed with water, and dried under high vacuum. The crude material was triturated with THF.
The mother liquor was concentrated to yield 332 mg of the desired product as an orange, crystalline solid. ES/MS m/z 313 (MH+). PP028218.0002
Figure imgf000325_0001
Step 4. Preparation of 4-(8-broino-6-(trifluoromethyl)qιιinazolin-2-ylamino)benzenesulfonamide To a 0.30 M solution of 8-bromo-2-chloro-6-(trifluoroniethyl)quinazoline in 2-propanol was added sulfanilamide (1.0 eq). The reaction was stirred at 110 0C for 14 h. The hydrochloride was collected by vacuum filtration and then stirred in aqueous sodium bicarbonate. The solid was collected by vacuum filtration and rinsed with water. The light yellow solid was dried in a desiccator to give 343 mg of the desired product. ES/MS m/z 44-1,449 (MH+).
Figure imgf000325_0002
Step 5. Preparation of 4-(8-(6-fluoropyridin-3-yl)-6-(trifluoromethyl)quinazolin-2- ylamino)benzenesulfonamide
To a 0.050 M solution of 4-(8-bromo-6-(trifiuoromethyl)quinazolin-2- ylamino)benzenesulfonamide (1.0 eq) in DME was added 2-fluoro-5-pyridineboronic acid (3.0 eq), (dppf)Pd(II)Cl2-CH2Cl2 (0.050 eq) and 2M aqueous potassium carbonate (8.0 eq). The mixture was microwaved at 120 0C for 10 min and then diluted with ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated to give the desired product which was used without further purification. ES/MS m/z 464 (MH+). PP028218.0002
Figure imgf000326_0001
4-(8-(6-(2-(pyrrolidin-1-yl)ethylamino)pyridin-3-yl)- 6-(trifluoromethyl)quinazolin-2-ylamino)benzβnesulfonamide
Step 6. Preparation of 4-(8-(6-(2-(pyrrolidin-l-yl)ethylamino)pyridm-3-yl)-6-
(trifluoromethyl)quinazolin-2-ylamino)benzenesulfonainide
To a 0.25M solution of 4-(8-(6-fluoropyridin-3-yl)-6-(trifluoromethyl)quinazoHn-2- ylamino)benzenesulfonamide (1.0 eq) in dioxane was added l-(2-aminoethyl)pyrrolidine (3.0 eq). The mixture was stirred at 1100C for 14 h and then concentrated and purified by reverse phase HPLC to give the desired compound as its TFA salt. ES/MS m/z 558 (MH+).
Example 18
Synthesis of 2-(4-(8-(l -isopropylpiperidin-4-yloxy)quinazolin-2-ylamhio)phenyl)-N- methylacetamide (Compound 969)
Figure imgf000326_0002
2-chloro-8-(1-isopropylpiperidin-4-yloxy)quinazoline
Step 1. Preparation of 2-Chloro-8-(l-isopropylpiperidin-4-yloxy)quinazoline To a 0.30M solution of triphenylphosphine (1.5 eq) in THF was added di-tert- butylazodicarboxylate (1.5 eq). The mixture was stirred 15 min at ambient temperature. 4- Hydroxy-1-isopropylpiperidine (4.0 eq) was added. The mixture was stirred 15 min at ambient temperature. 2-Chloroquinazolin-8-ol (1.0 eq) was added. The mixture was stirred an additional 2 h. The crude mixture was concentrated, purified by flash chromatography (EtOAc then 90:10:1 DCM:MeOH:NH4OH)5 and concentrated to give the desired product in 88% yield. ES/MS m/z 306 (MH+). PP028218.0002
Figure imgf000327_0001
Step 2. Preparation of 2-(4-(8-(l-isopropylpiperidin-4-yloxy)quinazolin-2-ylamino)phenyl)-N- methylacetamide To a 0.50M solution of 2-chloro-8-(l -isopropylpiperidin-4-yloxy)quinazoline in 2-propanol was added 2-(4-aminophenyl)-N-methylacetamide(1.0 eq). The reaction was stirred at 130 0C for 14 h. The crude mixture was concentrated, purified by reverse-phase HPLC, and lyophilized to give the desired product as a TFA salt. ES/MS m/z 434 (MH4).
Example 19
Preparation of 8-(l-isopropylpiperidin-4-yloxy)quinazolin-2-amine
Figure imgf000327_0002
Ammonia was bubbled into a 0.50M solution of 2-chloro-8-(l-isopropylpiperidin-4- yloxy)quinazoline (1.0 eq) in 2-propanol. The reaction was stirred at 140 0C for 4 d in a sealed vessel. The crude mixture was concentrated, purified by reverse-phase HPLC5 and lyophilized to give the desired product as its trifluoroacetic acid salt. ES/MS m/z 287 (MH+).
Example 20
Synthesis of morpholino(4-(8-(ρiperidin-4-yloxy)quinazolin- PP028218.0002
2-ylamino)phenyl)rnethanone (Compound 538)
Figure imgf000328_0001
Step 1. Preparation of 2-Chloro-8-(N-Boc-piperidin-4-yloxy)quinazoline
To a 0.30 M solution of triphenylphosphine (1.5 eq) in THF was added diethylazodicarboxylate
(1.5 eq). The mixture was stirred 15 min at ambient temperature. N-Tert-butyl-4-Hydroxy-l- piperidine carboxylate (4.0 eq) was added. The mixture was stirred 15 min at ambient temperature. 2-Chloroquinazolin-8-ol (1.0 eq) was added. The mixture was stirred an additional
4 h. The crude mixture was concentrated, purified by flash chromatography (3:2 hexanes: EtOAc), and concentrated to give the desired product. ES/MS m/z 364 (MH+).
Step 2. Displacement
To a 0.50M solution of 2-chloro-8-(l-isopropylpiperidin-4-yloxy)quinazoline in 2-propanol was added (4-aminophenyl)(morpholino)methanone (1.0 eq). The reaction was stirred at 130 0C for 14 h. The crude mixture was concentrated and used without further purification. ES/MS m/z 534 (MH+).
Step 3. Preparation of morpholino(4-(8-(piperidin-4-yloxy)quinazolm- 2-ylamino)phenyl)methanone The product from Step 2 was dissolved in enough 1:1 DCM-.TFA to make a 0.20M solution. The mixture was stirred for 30 min at ambient temperature and concentrated. The crude product was purified by reverse-phase HPLC and lyophilized to give the desired product as its trifluoroacetic acid salt. ES/MS m/z Λ2>A (MH+). PP028218.0002
Example 21
Preparation of 4-(8-( 1 -acetylpiperidin-4-yloxy)quinazolin- 2-ylamino)benzenesulfonamide (Compound 539)
Figure imgf000329_0001
To a 0.33M solution of 4-(8-(piperidin-4-yloxy)quinazolin-
2-ylamino)benzenesulfonamide in pyridine was added acetyl chloride (1.5 eq). The reaction was stirred for 2 h at ambient temperature and quenched with water. The crude mixture was concentrated, purified by reverse-phase HPLC, and lyophilized to give the desired product as its trifluoroacetic acid salt. ES/MS m/z 442 (MET+).
Example 22
Synthesis of 6-ethynyl-8-( 1 -isopropylpiperidin-4-yloxy)-N-(3-morpholinophenyl)quinazolin-2- amine (Compound 697)
Figure imgf000329_0002
Step 1. Displacement of 2-chloro
To a 0.25M solution of 3-morpholinoaniline in 2-propanol was added 6-bromo-2-chloro-8-(l- isopropylpiperidin-4-yloxy)quinazoline (prepared by following Example 9, step 2). The mixture PP028218.0002
was stirred at 1200C for 14 h, concentrated, and used without further purification. ES/MS m/z 526,528 (MH+).
Step 2-3. Preparation of 6-ethynyl-8-(l-isopropylpiperidin-4-yloxy)-N-(3- morpholinophenyl)quinazolin-2-amine
The product of step 1 was subjected to subjected to Sonogashira and desilylation reaction (see the scheme above) to give the title compound. ES/MS m/z 306 (MH+).
Example 23 Preparation of 6-ethynyl-N-(4-moφholinophenyl)-8-(piperidm-4-yloxy)quinazolin-2-arnine (Compound 700)
Figure imgf000330_0001
Step 1. Preparation of 2,6-dibromo -8-(N-Boc-piperidin-4-yloxy)quinazoline To a 0.30M solution of triphenylphosphine (2.0 eq) in THF was added diethylazodicarboxylate (2.0 eq). The mixture was stirred 15 min at ambient temperature. N-Tert-butyl-4-Hydroxy-l- piperidine carboxylate (4.0 eq) was added. The mixture was stirred 15 min at ambient temperature. 2,6-Dibromo-8-hydroxyquinazoline (1.0 eq) was added. The mixture was stirred an additional 24 h. The crude mixture was concentrated, purified by flash chromatography (2:1 hexanes:EtOAc), and concentrated to give the desired product. ES/MS m/z 488 (MH+).
Step 2. Displacement
To a 0.50M solution of 2,6-dibromo-8-(N-Boc-piperidin-4-yloxy)quinazoline in 2-proρanol was added 4-morpholinoaniline (1.0 eq). The reaction was stirred at 100 0C for 14 h. The crude mixture was concentrated and used without further purification. ES/MS m/z 584,586 (MH+). PP028218.0002
Step 3a. Sonogashira & desilylation The product from Step 2 was subjected to Sonogashira and desilylation reaction (see the scheme above) and carried on to Step 4 without purification. ES/MS m/z 530 (MH+).
Step 3b. Cyanation
The product from Step 2 was subjected to cyanation reaction (see the scheme above) and carried on to Step 4 without purification. ES/MS m/z 531 (MH+).
Step 3c. Negishi
The product from Step 2 was subjected to Negishi reaction (see the scheme above) and carried on to Step 4 without purification. ES/MS m/z 589 (MH+).
Step3d. Suzuki
To a 0.1 OM solution of the product from Step 2 (l.Oeq) in 1,4-dioxane was added cyclopropyl boronic acid pinacol ester (4.0 eq), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (0.20 eq), and 2.0M aqueous sodium carbonate (7.0 eq). The reaction was microwaved at 1400C for 10 min. The mixture was diluted with THF, filtered, concentrated, and carried on to Step 4 without purification. ES/MS m/z 488 (MH+).
Step 4. Preparation of 6-ethynyl-N-(4-morpholinophenyl)-8-(piperidin-4-yloxy)quinazolin-2- amine The product from Step 3 was dissolved in enough 1 : 1 DCMrTFA to make a 0.20M solution. The mixture was stirred for 30 min at ambient temperature and concentrated. The crude product was purified by reverse-phase HPLC and lyophilized to give the desired product as its trifluoroacetic acid salt. ES/MS m/z 430 (MH+). PP028218.0002
Example 24
Synthesis of 4-(6-fluoro-8-(6-fluoropyridin-3 -yl)quinazolm-2-ylarnmo)benzenesulfonarnide (Compound 633)
Figure imgf000332_0001
Step 1. To 2-Amino-5-fluorobenzoic acid (5 g, 32.2 mmol) in chloroform (90 mL) was added bromine (1.82 mL, 35.4 mmol) in chloroform (10 mL) solution dropwise via an additional funnel. The mixture was stirred at room temperature for 16 hrs. and LC/MS showed about 50% conversion of the starting material. Additional bromine (1.8 mL) was added to the reaction and continued stirring for another 24 hrs. The resulting white precipitate was collected by filtration, washed thoroughly with dichloromethane and air-dried to give 2-amino-3-bromo-5- fluorobenzoic acid as its HBr salt. ES/MS m/z 234/236 (MH+).
Step 2. (2-Amino-3-bromo-5-fluorophenyl)metanol
To a 0.5M suspension of 2-amino-3-bromo-5-fluorobenzoic acid in THF in an ice bath was slowly added borane (LOM /THF, 3eq). The reaction mixture was stirred at ambient temperature for 24 h. The mixture was recooled to 00C and quenched with methanol and concentrated to remove solvent. The residue was taken into ethyl acetate and organic phase was washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give yellow solid in 90% yield. ES/MS m/z 220/222 (MH+).
Step 3. 2-Amino-3-bromo-5-fluorobenzaldehyde
Manganese (IV) oxide (5eq) was added to a 0.2M solution of (2-amino-3-bromo-5- fluorophenyl)methanol in dichloromethane. The suspension was stirred at ambient temperature under Argon for 12 h. The reaction mixture was filtered through celite and filter cake was washed with dichloromethane. The combined filtrate was concentrated to give brown color solid. ES/MS m/z 218/220 (MH+). PP028218.0002
Step 4. 8-Bromo-6-fluoroquinazolin-2-ol
Solid 8-bromo-6-fluoroquinazolin-2-ol (leq) and urea (14eq) were thoroughly mixed together in a round bottom flask. The mixture was heated to 180 0C in an oil bath for 2.5 h. The reaction mixture was cooled to ambient temperature and water was added to the flask. Filtration gave yellow color solid, which was rinsed with ether and air dried. Yield: 62%. ES/MS m/z 243/245 (MH+).
Step 5. 8-Bromo-2-chloro-6-fluoroquinazoline
A 0.5M suspension of 8-bromo-6-fluoroquinazolin-2-ol in phosphorus oxychloride was heated to 110 0C in an oil bath. The suspension was turned to a brown color solution in 20min. LCMS data showed that the reaction was complete after 1 h. The phosphorus oxychloride was removed by concentration. The residue was mixed with ice water, and adjusted pH to 7 by adding sodium bicarbonate. Reaction mixture was extracted with ethyl acetate. Combined organic phase was washed with water, brine, dried over sodium sulfate and concentrated to give desired product in 89% yield. ES/MS m/z 261/263 (MH+).
Step 6. 4-(8-Bromo-6-fluoroqumazolin-2-ylarnino)benzensulfonamide To a 0.4M suspension of 8-bromo-2-chloro-6-fluoroquinazoline in isopropanol was added 4- aminobenzensulfonamide (leq). The reaction mixture was heated to 120 0C in an oil bath for 2days. LCMS showed that reaction was complete under the condition. Ethyl acetate was added to the reaction flask and the suspension was stirred at ambient temperature for 30 min and was filtered. Filter cake was rinsed with hexane and dried in vacuum to give product in 81% yield. ES/MS m/z 397/399 (MH+).
Step 7. Preparation of 4-(6-fluoro-8-(6-fluoropyridin-3-yl)quinazolin-2- ylamino)benzenesulfonamide
Pd(dppf)2C12CH2C12 (0.05eq) was added to a 0.1 M mixture of 4-(8-bromo-6-fluoroquinazolin- 2-ylamino)benzensulfonamide (leq), 6-fluoropyridin-3-ylboronic acid (3eq), potassium carbonate/water (2.0M, 2eq) in DME. The mixture was microwaved at 120 0C for 20min. Reaction mixture was diluted with ethyl acetate and washed with water, brine, dried and PP028218.0002
concentrated. The crude product was purified by RP HPLC. Lyophilization gave desired product 596148. ES/MS m/z 414 (MH4).
Example 25 Synthesis of 4-(7-( 1 -isobutyl- 1 H-pyrazol-4-yl)quinazolin-2-ylamino)-N-(3-(pyrrolidin- 1 - yl)propyl)benzenesulfonamide (Compound 709)
Figure imgf000334_0001
Stepl. (4-Bromo-2-nitrophenyl)methanol
To a 0.5M suspension of 4-bromo-2-nitrobenzoic acid in THF in an ice bath was slowly added borane (1.0M /THF, 4eq). The reaction mixture was stirred at ambient temperature for 48 h. LCMS showed the reaction was complete. The mixture was recooled to 00C and quenched with methanol and concentrated to remove solvent. The residue was taken into ethyl acetate and organic phase was washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give yellow solid in 95% yield.
Step 2. 4-Bromo-2-nitrobenzaldehyde
Manganese (IV) oxide (4eq) was added to a 0.18M solution of (4-bromo-2-nitrophenyl)methanol in dichloromethane. The suspension was stirred at ambient temperature under Argon for 12 h. The reaction mixture was filtered through celite and filter cake was washed with dichloromethane. The combined filtrate was concentrated to give brown color solid in 78% yield.
Step 3. 2-Amino-4-bromobenzaldehyde To a 0.2M solution of 4-bromo-2-nitrobenzaldehyde in acetic acid and ethanol (v/v 1:1) solvent system was added iron powder. The reaction mixture was stirred at ambient temperature under PP028218.0002
Argon for 1.5 h and LCMS showed the reaction was complete. Insoluble solid was filtered off and the filtrate was concentrated in vacuum. Residue was diluted with ethyl acetate and was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. Crude product was purified by Biotage using 15% ethyl acetate in hexane to give desired product in 38% yield. ES/MS m/z 200/202 (MH+).
Step 4. 7-Bromoquinazolin-2-ol
A mixture of 2-amino-4-bromobenzaldehyde (leq) and urea (14eq) was heated to 180 0C in an oil bath under Argon for 1 h. Water was added to after cooling to ambient temperature. The solid was collected by filtration and air dried to give product in 95% yield. ES/MS m/z 225/227 (MH+).
Step 5. 7-Bromo-2-chloroquinazoline
A 0.5M suspension of 7-bromoquinazolin-2-ol in phosphorus oxychloride was heated to 110 0C in an oil bath for 1 h. The mixture was cooled to room temperature. Volatiles were removed under reduced pressure. The residue was triturated with ice water. The solid was collected by filtration and air dried to give product in 65% yield. ES/MS m/z 243/245 (MH+).
Step 6. 4-(7-Bromoquinazolm-2-ylarnino)-N-(3-(pyrrolidin-l-yl)propyl) benzenesulfonamide To a 0. IM suspension of 7-bromo-2-chloroquinazoline in isopropanol was added 4-amino-N-(3- (pyrrolidin-l-yl)propyl)benzenesulfonamide (l.leq), followed by the addition of 4.0M HCl in dioxane (1. leq) . The reaction mixture was heated to 120 0C in an oil bath for 1 h. LCMS showed that reaction was complete under the condition. Ethyl acetate was added to the reaction flask and the mixture was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. Desired product was a yellow color solid. ES/MS m/z 490/492 (MH+).
Step 7. Preparation of 4-(7-(l-isobutyl-lH-pyrazol-4ryl)qumazolin-2-ylamino)-N-(3-Q)yiτolidin- 1 -yl)propyl)benzenesulfonamide
Pd(dppf)2C12CH2C12 (0.05eq) was added to a 0.05M mixture of 4-(7-bromoquinazolin-2- ylamino)-N-(3-(pyrrolidin-l-yl)propyl) benzenesulfonamide (leq), l-isobutyl-4-(4,4,5,5- PP028218.0002
tetxamemyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (3eq), 2.0M potassixim carbonate/water (2eq) in DME. The mixture was microwaved at 120 °C for lOmin.
Reaction mixture was diluted with ethyl acetate and washed with water, brine, dried and concentrated. The crude product was purified by RP HPLC. Lyophilization gave desired product. ES/MS m/z 534 (MH4).
Example 26
Synthesis of 4-(6-ethynyl-7-( 1 -oxo- 1 ,2, 3,4-tetrahydroisoquinolin-6-yl)quinazolin-2-ylamino)-N- isopropylbenzamide
Figure imgf000336_0001
Step 1. 4-(6-Bromo-7-methoxyquinazolin-2-ylamino)-N-isopropylbenzamide To a 0.25M suspension of 6-bromo-2-chloro-7-methoxyquinazoline in isopropanol was added A- amino-N-isopropylbenzamide (l.Oeq). The reaction mixture was heated to 100 0C in an oil bath for 14 h. Reaction mixture was diluted with ethyl acetate and filtered to collect desired product. ES/MS m/z 415/417 (MH").
Step 2. 4-(6-Bromo-7-hydroxyquinazolin-2-ylamino)-N-isopropylbenzamide A 0.15M suspension of 4-(6-bromo-7-methoxyquinazolin-2-ylamino)-N-isopropylbenzarnide (1.Oeq) and sodium thiomethoxide (4.0eq) in DMF was heated to 80 0C in an oil bath for 12 h. The mixture was partitioned between ethyl acetate and water. The pH of aqueous phase was adjusted to 5 by adding saturated ammonium hydrochloride. Aqueous phase was extracted with ethyl acetate, and combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to give desired product in 90% yield. ES/MS m/z 401/403 (MH+). PP028218.0002
Step 3. 4-(7-Hydroxy-6-((trimethylsilyl)ethynyl)quinazolin-2-ylamino)-N-isopropylbenzamide To a 0.09M mixture of 4-(6-bromo-7-hydroxyquinazolin-2-ylamino)-N-isopropylbenzarnide (0.17 mM), triethylamine ( 0.5ml), Pd(dppf)2C12CH2C12 ( O.leq), Copper(I) iodide (O.leq), in DMF was added trimethylsilylacetylene (10eq).The suspension was microwaved at 120 0C for 20min. Reaction mixture was diluted with ethyl acetate and was washed with water, brine, dried and concentrated to give crude product. ES/MS m/z 419 (MH+).
Step 4. 2-(4-(Isopropylcarbamoyl)phenylaiτuno)-6-((trimethylsilyl)ethnyl)quinazolin-7- yltrifluoromethanesulfonate To a 0.15M solution of 4-(7-hyojoxy-6-((1τimethylsilyl)ethynyl)quinazolin-2-ylarnino)-N- isopropylbenzamide in NMP were added N-phenyl-bis(trifluoromethanesulfonimide) (1.2eq), and N,N-diisopropylethylamine (2.5eq). The mixture was stirred at ambient temperature for 15 h. Solution was diluted with ethyl acetate and was washed with water, brine, dried over sodium sulfate and concentrated to give crude product. ES/MS m/z 551 (MH+).
Step 5. Preparation of 4-(6-ethynyl-7-(l-oxo-l,2,3,4-tetrahydroisoquinolin-6-yl)quinazolin-2- ylarnino)-N-isopropylbenzarnide
A 2.0M solution of potassium carbonate (0.8ml) was added to a mixture of 2-(4-
(isopropylcarbamoyl)phenylamino)-6-((trimethylsilyl)ethnyl)quinazolin-7- yltrifluoromethanesulfonate (0.13 mmol), 6-(4,4,5,5-tetramethyl-l ,3,2-dioxaboralan-2-yl)-3,4- dihydroisoquinolin-l(2H)-one (0.38 mmol), Pd(dppf)2C12Ch2C12 (0.01 mmol) in 1,2- dimethoxyethane (4ml). The mixture was microwaved at 120 0C for lOmin. LCMS indicated formation of Suzuki product. Mixture was diluted with ethyl acetate, and was washed with water, brine, dried and concentrated. The oil residue was treated with tetramethylammonium fluoride (30mg, 0.3 mmol) in THF (3ml) at ambient temperature for 1 h. Solvent was removed under reduced pressure, and residue was diluted with ethyl acetate. Organic phase was washed with water, brine, dried and concentrated. The crude product was purified by RP HPLC. Lyophilization gave desired product 623995. ES/MS m/z 476 (MH+). PP028218.0002
Example 27
Synthesi s of 6-Ethynyl-N-(4-moφholinophenyl)-7-(piperidin-4-yloxy)quinazolin-2-amine (Compound 646)
Figure imgf000338_0001
Step 1. 6-Bromo-7-methoxy-N-(4-morpholinophenyl)quinazolm-2-amine To a 0.12M suspension of 6-bromo-2-chloro-7-methoxyquinazoline (l.Oeq) in isopropanol was added 4-morpholinoaniline (1.Oeq). The reaction mixture was heated to 120 0C in an oil bath for 5 h. LCMS showed that reaction was complete under the condition. The reaction mixture was allowed to cool to room temperature and was filtered. The filter cake was rinsed with ethyl acetate and allowed air dry. Desired product was a brown solid as HCl salt. ES/MS m/z 415/417 (MH4).
Step 2. 6-Bromo-2-(4-morpholinophenylamino)quinazolin-7-ol
A 0.32M suspension of 6-bromo-7-methoxy-N-(4-morpholinophenyl)quinazolin-2-amine (l.Oeq) and sodium thiomethoxide (4.0eq) in DMF was heated to 80 0C in an oil bath for 12 h. LCMS data indicated the reaction was complete. The mixture was partitioned between ethyl acetate and water. The insoluble solid was filtered off and was rinsed with ether and air dried to give product. ES/MS m/z 401/403 (MH+).
Step 3. tert-butyl 4-(6-bromo-2-(4-moφholinophenylamino)quinazolin-7-yloxy)piperidine-l- carboxylate
To a 0.07M solution of triphenylphosphine (3.Oeq) in THF was added di-tert- butylazodicarboxylate (3.0eq). The mixture was stirred for 15 min at ambient temperature. N-
Boc-4-hydroxypiperidine (3.Oeq) was added, and the mixture was stirred at ambient temperature PP028218.0002
for another 15 min. 6-Bromo-2-(4-moipholmophenylamino)quinazolin-7-ol (l.Oeq, a 0.12M solution in THF) was added to reaction flask. The mixture was stirred an additional 15 h at ambient temperature. Solvent was removed under reduced pressure and the residue was purified by Biotage using 2% methanol in dichloromethane to give tert-butyl 4-(6-bromo-2-(4- morpholinophenylamino)quinazolin-7-yloxy)piperidine-l-carboxy. ES/MS m/z 584/586 (MH+).
Step 4. Preparation of 624175 - 6-Ethynyl-N-(4-morpholinophenyl)-7-(piperidin-4- yloxy)quinazolin-2-amine
To a 0.05M mixture of tert-butyl 4-(6-bromo-2-(4-morpholinophenylamino)quinazolin-7- yloxy)piperidine-l-carboxylate (0.1 mmol), triethylamine ( 0.5ml), Pd(dppf)2C12CH2C12 ( 0.1 eq), Copper(I) iodide (0.1 eq), in DMF was added trimethylsilylacetylene (10eq).The suspension was microwaved at 120 0C for 25 min. Reaction mixture was diluted with ethyl acetate and was washed with water, brine, dried and concentrated. The oil residue was treated with tetramethylammonium fluoride (2.0eq) in THF/methanol (1:1, 0.05M) at ambient temperature for 1 h. Solvent was removed under reduced pressure. The residue was taken into ethyl acetate and was washed with water, brine, dried and concentrated. The resulting dark oil was treated with 50%TFA in dichloromethane at ambient temperature for 1 h. LCMS indicated De-Boc was complete. Solvent was removed under reduced pressure. The crude product was purified by RP HPLC. Lyophilization gave desired product 624175. ES/MS m/z 430 (MH+).
Example 28
Preparation of 4-(8-( 1 -isobutylpiperidine-4-yloxy)quinazolin-2ylamino)benzene sulfonamide The subject compound was prepared according to the general Scheme below:
Figure imgf000339_0001
PP028218.0002
Step 1. Preparation of tert-butyl 4-(2-chJoroquinazolin-8-yloxy)piperidine-l-carboxylate To a solution of triphenylphosphine (2 eq) in THF was added di-ethyl-azodicarboxylate (2 eq). The mixture was stirred 15 minutes at ambient temperature. tert-butyl4-hydroxypiperidine-l- carboxylate (6 eq) was added. The mixture was stirred 15 minutes at ambient temperature. 4-(8- hydroxyquinazolin-2-ylamino)benzenesulfonamide (1.0 eq) was added. The mixture was stirred overnight at ambient temperature. The reaction goes to completion. The reaction mixture was concentrated and the oil was triturated the ether/hexane. A white solid crashed out. The solid was filtered to give tert-butyl 4-(2-chloroquinazolin-8-yloxy)piperidine-l-carboxylate in 90% yield ES/MS m/z 499 (MH+).
Step 2. Preparation of 4-(8-(piperidine-4-yloxy)quinazolin-2ylarnino)benzenesulfonarnide To a solution of tert-butyl-(2-chloroquinazolin-8-yloxy)piperidine-l-carboxylate in methylenechloride was added 30%TFA/ CH2CI2 and the mixture was stirred for Ih to give the TFA salt of 4-(8-(piperidine-4-yloxy)quinazolin-2ylamino)benzenesulfonamide. The reaction mixture was concentrated to a solid to give the product in quantitative yield. ES/MS m/z 399 (MH+)
Step 3. Preparation of 4-(8-(l-isobutylpiperidine-4-yioxy)quinazolin- 2ylamino)b enzenesulfonamide To a solution of the TFA salt of 4-(8-(piperidin-4-yloxy)quinazoloin-2- ylamino)benzenesulfonamide in DCM was added isobutyraldehyde (2eq) and a few drops of acetic acid. The mixture was stirred for lOmins and to it was added sodiumtriacetoxyborohydride (1.5eq) and the mixture was stirred for Ih. The reductive amination went to completion, by LC/MS. The crude mixture was concentrated and purified on prep HPLC to give the product 4-(8-(l-isobutylpiperidine-4-yloxy)quinazolin- 2ylamino)benzenesulfonamide in 80% yield. ES/MS m/z 456.2 (MH+).
Example 29
Preparation of 4-(7-(6-morpholinopyridin-3yl)quinazolin-2ylamino-benzene sulfonamide (Compound 881) The subject compound was prepared according to the general Scheme below: PP028218.0002
Figure imgf000341_0001
Step 1. Preparation of 2-(4-sulfamoylphenylamino) quinazolin-7-yltrifluoromethane sulfonate To a solution of 4-(7-hydroxyquinazolin-2-ylamino) benzenesulfonamide (leq) in NMP was added phenyltrifluoromethanesulfonate (1.2eq) and DIEA (2.5eq) and the reaction mixture was stirred over night at ambient temperature. The reaction mixture was then partitioned between ethyl acetate and water. The organic layers were washed with saturated sodium chloride and dried and concentrated. To the crude was added methylene chloride and few drops of methanol. The white solid hence formed was filtered to give 2-(4-sulfamoylphenylamino)quinazolin-7- yltrifluoromethane sulfonate in 80% yield. ES/MS m/z 447(MH4).
Step 2. Preparation of 4-(7-(6-fluoropyridin3-yl)quinazolin-2-ylamino)benzenesulfonaniide. To a solution of 2-(4-sulfanioylphenylainino)quinazolin-7-yltrifluoroniethane sulfonate (leq) in DME was added 2M sodium carbonate solution and 6-fluoropyridin-3ylboronic acid (3eq) and Pd(dppf)2Cl2.CH2Cl2 (0.05eq) and the mixture was micro waved for 10 min at 1200C. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was concentrated to yield 4-(7-(6-fluoropyridin3-yl)quinazolin-2-ylamino)ben2enesulfonamide. ES/MS m/z 396(MH+).
Step 3. Preparation of 4-(7-(6-morpholinopyridin-3yl)quinazolin-2ylarnino-benzene sulfonamide To 4-(7-(6-fluoropyridin3-yl)qumazolin-2-ylamino)benzenesulfonamide was added morpholine. The solution was heated at 800C for 3h. SNAR goes to completion and the product was purified on prep HPLC to yield 4-(7-(6-morpholinopyridin-3yl)quinazolin-2ylamino-benzene sulfonamide in 50% yield. ES/MS m/z 463(MH+). PP028218.0002
Example 30
Preparation ofN-methyl-2-(4-sulfamoylphenylaπiino)quiπazoline-7-carboxamide The subject compound was prepared according to the general Scheme below:
Figure imgf000342_0001
Step 1. Preparation of methyl 4-formyl-3-aminobenzoate
To a 1 : 1 mixture of ethanol and acetic acid was added methyl4-formyl-3-nitrobenzoate (leq) and Fe dust (3eq) was added in portions. The reduction was complete in Ih. The reaction mixture was filtered and then concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate and dried and concentrated to give methyl 4-formyl-3-aminobenzoate in 85 % yield. ES/MS m/z 180(MH+).
Step 2. Preparation of methyl 2-hydroxyquinazoin-7-carboxylate
To methyl 4-formyl-3-aminobenzoate(leq) was added urea (5eq) and the mixture was heated tol45°C for 16h. To the crude was added water and the precipitated solid was filtered to give methyl 2-hydroxyquinazoin-7-carboxylate in quantitative yield. ES/MS m/z 205(MH+).
Step 3. Preparation of methyl 2-chloroqumazoin-7-carboxylate
To 2-hydroxyquinazoin-7-carboxylate was added POCI3 and the mixture was added heated to 1000C for 20min when the reaction went to completion. To the reaction mixture was added ice and water and the precipitated solid was filtered and dried on the high vacuum overnight to give methyl 2-chloroquinazoin-7-carboxylate in 60% yield. ES/MS m/z 223(MH+).
Step 4. Preparation of methyl 2-(4-sulfamoylphenylamino)quinazolin-7-carboxylate To methyl 2-chloroquinazoin-7-carboxylate (leq) was added sulfanilde (leq) and isopropanol and the mixture was heated to 900C for 2h. The reaction went to completion. The reaction PP028218.0002
mixture was cooled to RT and filtered to give methyl 2-(4-sulfamoylphenyl amino)quinazolin-7- carboxylate in quantitative yield. ES/MS m/z 359(MH+).
Step 5. Preparation of methyl 2-(4-sulfamoylphenylamino)quinazolin-7-carboxylic acid To 2-(4-sulfamoylphenyl amino)quinazolin-7-carboxylate was added 2N sodium hydroxide (4eq) and methanol and the mixture was heated to 800C for lOmin. The saponification went to completion. The reaction mixture was concentrated and IN HCl was added to precipitate methyl 2-(4-sulfamoylphenylamino)quinazolin-7-carboxylic acid as the HCl salt in quantitative yield. ES/MS m/z 344(MH+).
Step 6. Preparation of N-methyl-2-(4-sulfamoylphenylamino)quinazoline-7-carboxamide To methyl 2-(4-sulfamoylphenylamino)quinazolin-7-carboxylic acid (leq) was added methylamine (2eq) and DIEA(4eq) and HBTU (2eq) and the mixture was stirred at RT overnight. The coupling went to completion and the mixture was concentrated and partitioned between ethyl acetate and water. The organic layers were concentrated and purified on the prep HPLC to give N-methyl-2-(4-sulfamoylphenylamino)quinazolme-7-carboxamide in 50% yield. ES/MS m/z 358(MH+).
Example 31 Preparation of 7-(piperidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinazolin-2-amine (Compound 569)
To tert-butyl 4-(2-(ethylsulfonyl)quinazolin-7-yloxy)piperidine-l-carboxylate (leq ) was added 3-trifluoromethylaniline and the mixture was heated to 1000C for 16h. The formation of the product was confirmed by LC/MS. The mixture was then partitioned between ethyl acetate and water. The organic layer was purified on prep HPLC to give tert-butyl 4-(2-
(ethylsulfonyl)quinazolin-7-yloxy)piperidine-l-carboxylate. To the concentrated pure fractions was added 30% TFA/DCM. and the mixture was stirred for 30 min. The deprotection went to completion and the 7-(piperidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinazolin-2 -amine was isolated. ES/MS m/z 389(MH+). PP028218.0002
Preparation of 7-(l-isopropylpiperidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl) quinazolin-2- amine (596754)
To 7-(piperi<Mn-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinazolin-2-amine in DCM was added acetone (lOeq), a few drops of acetic acid and sodium triacetoxy borohydride (4eq). The reaction mixture was stirred for 16h at ambient temperature. The reductive amination went to completion to give 7-(l-isopropylpiperidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl) quinazolin-2- amine. The mixture was then purified on prep HPLC to give 7-(l-isopropylpiperidin-4-yloxy)- N-(3-(trifluoromethyl)phenyl) quinazolin-2-amine. ES/MS m/z 431(MH+).
Example 32
Preparation of 5-chloro-N-(4-morpholinophenyl)-8-(piperidin-4-yloxy)quinazolin-2-amine (Compound 605) The subject compound was prepared according to the general Scheme below:
Figure imgf000344_0001
Step 1. Preparation of 2,5-dichloroquinazolin-8-ol
To a solution of 2-chloroquinazlin-8-ol (leq) in chloroform was added N-chlosuccinimide (leq) and the resulting mixture was heated to 400C for 2h. The chlorination goes to completion giving 2,5-dichloroquinazalin-8-ol in 65 % yield. 25% of the reaction was 2,7dichloroquinazolin-8-ol and 15% of the reaction mixture was 2,5,8-trichloro quinazolin-8-ol. The reaction mixture was concentrated and the crude was purified by silica gel. The structures of the isomers were confirmed by 1HNMR and by LC/MS. ES/MS m/z 215(MH+). PP028218.0002
Step 2. Preparation of 5-chloro-2-(4-moφholinophenylamino)quinazolin-8-ol To a solution of isolated 2,5-dichloroquinazolin-8-ol (leq) in isopropanol was added 4- morpholinoaniline (leq) and the mixture was heated to 9O0C for Ih. The SNAR went to completion by LC/MS and on concentration yielded 5-chloro-2-(4-morpholinophenylamino) quinazolin-8-ol in quantitative yield. ESZMS WZZ SST(MH+).
3. Preparation of tert-butyl 4-(5-chloto-2-(4-morpholinophenylamino)quinazolin-8- yloxy)piperidin- 1 -carboxylate.
Step 3. The tert-butyl4-(methylsulfonyloxy)piperidine-l -carboxylate used in this step was made as follows:
To tert-butyl 4-hydroxypiperidine-l -carboxylate (leq) in methylene chloride and triethyl amine (1.4eq) at 0°C was added methane sulfonyl chloride ( 1.4 eq) drop- wise. The reaction was brought to ambient temperature and was stirred for Ih. The reaction mixture was washed with water and saturated sodium chloride solution. The organic layer was then dried with sodium sulfate and concentrated to yield tert-butyl4-(methylsulfonyloxy)piperidine-l -carboxylate in quantitative yield. The product was confirmed by 1H NMR. and used without further purification.
To 5-cMoro-2-(4-moφholinophenylaomino)quinazolin-8-ol (leq) in DMF was added potassium carbonate (1.1 eq) and KHMDS (1.2eq) and tert-butyl4-(methylsulfonyloxy)piperidine-l- carboxylate ( 1.5eq). The reaction mixture was micro waved at 17O0C for lOmin. Formation of tert-butyl 4-(5-cUoto-2-(4-moipholinophenylamino)quinazolin-8-yloxy)piperidin-l-carboxylate was confirmed by LC/MS. ES/MS m/z 540(MH+).
Step 4. Preparation of 5-chloro-N-(4-morpholinophenyl)-8-(piperidin-4yloxy)quinazolin-2- amine
The crude reaction mixture of tert-butyl 4-(5-chloto-2-(4-morpholinophenylamino) quinazolin - 8-yloxy)piperidin-l -carboxylate was purified using prep HPLC and the purified fractions of the product was concentrated. To it was added a few drops of 30% TFA/ DCM and the mixture was stirred for 30 min. The deprotection went to completion yielding 5-chloro-N-(4- PP028218.0002
morpholinophenyl)-8-(piperidin-4yloxy)quinazolin-2-amine that was confirmed by LC/MS. ES/MS w/z 440(MH+).
Example 33 Preparation of 4-(7-methoxy-4-methylquinazolin-2-ylamino)eiizenesulfonamide (Compound 583)
The subject compound was prepared according to the general Scheme below:
Figure imgf000346_0001
Step 1. Preparation of l-(4-methoxy-2-aminophenyl)ethanone To a 1:1 mixture of ethanol and acetic acid was added l-(4-methoxy-2-nitrophenyl)ethanone (leq) and Fe dust (3eq)was added in portions. The reduction was complete in Ih. The reaction mixture was filtered and then concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate and dried and concentrated to give methyl l-(4-methoxy-2-aminophenyl)ethanone in 85 % yield. ES/MS m/z 196(MH+).
Step 2. Preparation of 7-methoxy-4-methylquinazolin-2-ol
To methyl l-(4-methoxy-2-aminophenyl)ethanone (leq) was added urea (5eq) and few mis of acetic acid the mixture was heated to 1000C for 16h. To the crude was added water and the precipitated solid was filtered to give methyl 7-methoxy-4-methylquinazolin-2-ol in quantitative yield. ES/MS m/z 191(MH+).
Step 3. Preparation of 2-chloro-7-methoxy-4-methylquinazoline
To 7-methoxy-4-methylquinazolin-2-ol was added POCI3 and the mixture was added heated to
1000C for 16h when the reaction went to completion. To the reaction mixture was added ice and PP028218.0002
water and the precipitated solid was filtered and dried on the high vacuum overnight to give 2- chloro-7-methoxy-4-methylquinazoline in 60% yield. ES/MS m/z 209(MH4).
Step 4. Preparation of 4-(7-methoxy-4-methylquinazolin-2-ylamino)benzenesulfonamide To 2-chloro-7-methoxy-4-methylquinazoline(l eq ) in isopropanol was added sulfanilide (1 eq) and the mixture was heated to 900C for 16h. The solid that precipitated was filtered and collected to give 4-(7-methoxy-4-methylquinazolin-2-ylamino)benzene sulfonamide. ES/MS m/z 345(MH+).
Step 5. Preparation of 4-(7-hydroxy-4-niemylqumazolin-2-ylarnino)benzenesulfonamide
To 2-chloro-7-methoxy-4-methylquinazoline in NMP was added sodium thiomethoxide (4eq) and the mixture was added heated to 800C for 16h when the reaction went to completion. To the reaction mixture was added water and ethyl acetate and ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic layer was concentrated to give 4-(7- hydroxy-4-methylquinazolin~2-ylamino)benzenesulfonamide. ES/MS m/z 330(MH+).
Step 6. Preparation of 4-(4-methyl-7-(2-(piperidin-4-yl)ethoxy)quinazolin-2-ylamino)benzene sulfonamide
To 4-(7-hydroxy-4-methylquinazolin-2-ylamino)benzenesulfonamide (leq) in DMF was added potassium carbonate (1.1 eq) and KHMDS (1.2eq) and tert-butyl 4-(2-
(methylsulfonyloxy)ethyl)piperidine-l-carboxylate (1.5eq). The reaction mixture was microwaved at 1700C for lOmin. Formation of tert-butyl 4-(2-(4-methyl-2-(4- sulfamoylphenylamino)quinazolin-7-yloxy)ethyl)piperidine-l-carboxylate was confirmed by 1HNMR and LC/MS. The crude reaction mixture of tert-butyl 4-(2-(4-methyl-2-(4-sulfamoylphenylamino) quinazolin-7-yloxy) ethyl) piperidine-1-carboxylate was purified using prep HPLC and the purified fractions of the product was concentrated. To it was added a few drops of 30% TFA/ DCM and the mixture was stirred for 30 min. The deprotection went to completion yielding 4- (4-methyl-7-(2-(piperidin-4-yl)ethoxy)quinazolin-2-ylamino)benzene sulfonamide that was confirmed by LC/MS. ES/MS m/z 442(MH+). PP028218.0002
Example 34
Preparation of (4-(5-chloro-8-methoxy-7-(l-methyl-lH-pyr.ιzol-4-yl)qιιinazolin-2- ylamino)phenyl)(moφholino)methanone
The subject compound was prepared according to the general Scheme below:
Figure imgf000348_0001
Step 1. Preparation of 7-bromo-2,5-dichloroquinazolin-8-ol
To 2,5-dichloroqumazolin-8-ol 91eq) in chloroform was added NBS (leq) and the formation of 7-bromo-2,5-dichloroquinazolin-8-ol was instantaneous. The mixture was concentrated and confirmed by LC/MS. ES/MS m/z 294(MH+).
Step 2. Preparation of 7-bromo-2,5-dichloro-8-methoxyquinazoline
To 7-bromo-2,5-dichloroquinazolin-8-ol (leq ) was added methyl iodide (leq) and potassium carbonate (leq) and the mixture was stirred for 16h at ambient temperature. Complete conversion to 7-bromo-2,5-dichloro-8-methoxyquinazoline was observed by HPLC. ES/MS m/z
308(MH+).
Step 3. Preparation of (4-(7-bromo-5-chloro-8-methoxyquinazolin-2:-ylamino)phenyl)
(morpholino)methanone
To 7-bromo-2,5-dichloro-8-methoxyquinazoline (leq) was added (4-aminophenyl)
(morpholino)methanone (leq) in isopropanol and the mixture was heated to 9O0C for 16h. The solid formed was filtered to give (4-(7-bromo-5-chloro-8-methoxyquinazolin-2-ylamino)phenyl)
(morpholino)methanone and was confirmed by LC/MS. ES/MS m/z 478(MH+). PP028218.0002
Step 4. Preparation pf N-(5-chloro-8-methoxy-7-(l-methyl-lH-pyrazol-4-yl)quinazolin-2- yl)morpholine-4-carboxatnide
To (4-(7-bromo-5-chloro-8-methoxyquinazolin-2-ylamino)phenyl) (morpholino)methanone (leq) in DME and 2M sodium carbonate solution was added l-methyl-3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-lH-pyrazole (3eq) and Pd^pPf)2Cl2-CH2Cl2 (0.05eq) and the mixture was micro waved for 10 min at 12O0C. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was concentrated and purifϊedon prep HPLC to yield N-(5- chloro-8-methoxy-7-( 1 -methyl- 1 H-pyrazol-4-yl) quinazolin-2-yl)moφholine-4-carboxamide. ES/MS m/z 479(MH+).
Example 35
Preparation of 2-chloro-8-methoxy-4-methylquinazolhie The subject compound was prepared according to the general Scheme below:
Figure imgf000349_0001
Step 1. Preparation of 3-methoxy-2-aminobenzaldehyde
To a 1 :1 mixture of ethanol and acetic acid was added 3-methoxy-2-nitrobenzaldehyde (leq) and Fe dust (3eq)was added in portions. The reduction was complete in 3h. The reaction mixture was filtered and then concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate and dried and concentrated to give 2- amino-3-methoxybenzaldehyde in 85 % yield. ES/MS m/z 151(MH+).
Step 2. Preparation of 8-methoxy-4-methylquinazolin-2-ol To methyl 2-anτino-3-methoxybenzaldehyde (leq) was added urea (5eq) and few ml of acetic acid the mixture was heated to 1000C for 16h. To the crude was added water and the precipitated solid was filtered to give methyl 8-methoxy-4-methylquinazolin-2-pl in quantitative yield. ES/MS m/z 191(MH+). PP028218.0002
Step 3. Preparation of 2-chloro-8-methoxy-4-methylquinazoline
To 8-methoxy-4-methylquinazolin-2-ol was added POCI3 and the mixture was added heated to 1000C for 16h when the reaction went to completion. To the reaction mixture was added ice and water and the precipitated solid was filtered and dried on the high vacuum overnight to give 2- chloro-8-methoxy-4-methylquinazoline. ES/MS m/z 209(MH+).
Example 36
Preparation of 4-(quinazolin-2-ylamino)benzenesulfonamide (Compound 618) To 2-(4-sulfamoylphenylamino)quinazolin-6-yltrifluoromethane sulfonate in DMF was added
Pd(Ph3)2Cl2 (0.02eq) and formic acid (2eq) followed by tributylamine( 3eq) and the mixture was heated to 11O0C for 3h. Formation of the product was observed by LC/MS. The crude was purified on the prep to give 4-(quinazolin-2-ylamino)benzenesulfonamide. ES/MS m/z
301(MH+).
Example 37
Synthesis of N- (4-(morpholinosulfonyl) phenyl-7- (pϊperidin-4-yloxy) quinazolin-2 -amine
(Compound 332)
Figure imgf000350_0001
Step 1. Preparation of 7-methoxy-N- (4-(morpholinosulfonyl) phenyl) quinazolin-2-amine A mixture of 2-chloro-7-methoxyquinazoline (leq) and 4-(Mθφholinosulfonyl) Aniline (leq) in 2-propanol was heated at 8O0C overnight. Product was precipitated in the reaction mixture. The precipitate was filtered, washed and dried under vacuum to provide 7-methoxy-N- (4- PP028218.0002
(morpholinosulfonyl) phenyl) quinazolin-2-amine as a yellow solid in 99% yield. ES/MS m/z 401.0(MH+).
Step 2. Preparation of 2-(4-(moφholinosulfonyl)phenylamino)quinazolin-7-ol A mixture of 7-methoxy-N- (4-(morpholinosulfonyl) phenyl) quinazolin-2-amine (leq) and sodium thiomethoxide (4eq) in NMP was heated at 800C for 4h. Reaction mixture was diluted with water and acidified with IN HCl. Compound was extracted with ethyl acetate. The organic layer was washed with satd. NaHCOa, brine and dried over sodium sulfate. Filtration, evaporation and drying under vacuum provide 2-(4-(morpholinosulfonyl) phenyl amino) quinazolin-7-ol as a light yellow viscous liquid in 99% yield. ES/MS m/z 387.0(MH+).
Step 3. Preparation of tert-butyl 4-(2-(4-(morpholinosulfonyl) phenylamino) quinazolin-7-yloxy) piperidine-1 -carboxylate
To a solution of triphenylphosphine (2eq) in THF was added di-terbutylazodicarboxylate (2eq). The mixture was stirred 15 minutes at ambient temperature under nitrogen atmosphere. To that was added tert.butyl-4-hydroxypiperidine-l -carboxylate (5eq). The mixture was stirred 15 minutes at ambient temperature followed by addition of 2-(morpholinosulfonyl phenylamino) quinazolin-7-ol (leq). The mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated and the residue was purified by flash column chromatography (50%EtOAc / Hexane) to provide product as a white solid in 80% yield. ES/MS m/z 570.1 (MH+).
Step 4. N- (4-(morpholinosulfonyl) phenyl-7- (piperidin-4-yloxy) quinazolin-2-amine A solution of tert-butyl 4-(2-(4-(morpholinosulfonyl) phenylamino) quinazolin-7-yloxy) piperidine-1 -carboxylate in 30%TFA / DCM was stirred for 30min at ambient temperature. The solvent was evaporated and residue was purified by semi-prep HPLC to provide N- (4- (morpholinosulfonyl) phenyl-7- (piperidin-4-yloxy) quinazolin-2-amine in 80% yield. ES/MS m/z 470.1 (MH+). PP028218.0002
Example 38
Synthesis of 7-(l -(2-fluoroethyl) piperidine-4-yloxy)-N- (4-(moφholinosulfonyl) phenyl)quinazolin-2-amine (Compound 333)
To a solution of N- (4-(morpholinosulfonyl) phenyl-7- (piperidin-4-yloxy) quinazolin-2-amine (leq) (See example 37, step 4) in DMF was added potassium carbonate (4eq) and l-fiuoro-2- iodoethane (1.2eq). The mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. Dried over sodium sulfate, filtered, evaporated and purified by semi-preparative HPLC to provide 7-(l-(2- fluoroethyl) piperidme-4-yloxy)-N- (4-(morpholinosulfonyl) phenyl) quinazolin-2-amine as a yellow solid in 50% yield. ES/MS m/z 516.1 (MH4).
Example 39
Synthesis of 7-(l-methyl-lH-pyrazol-4-yl) -N- (4-(morpholinosulfonyl) phenyl)quinazolin-2- amine (Compound 317)
Figure imgf000352_0001
Step 1. Preparation of 2-(4-(morpholinosulfonyl)phenylamino) quinazolin-7-yltrifluoromethane sulfonate
To a solution of 2-(4-(morpholinosulfonyl)phenylamino)quinazolin-7-ol (leq) (See example 37, step 2) in NMP was added phenyltrifluoromethanesulfonate (1.2eq) and DIEA (2.5eq) and the reaction mixture was stirred over night at ambient temperature. The reaction mixture was then partitioned between ethyl acetate and water. The organic layers were washed with saturated sodium chloride, dried and concentrated. The crude was purified by flash chromatography (60%EtOAc / Hexane) to provide product as a white solid in 70% yield. ES/MS m/z 519.0(MH+). PP028218.0002
Step 2. Preparation of 7-(l -methyl- lH-pyrazol-4-yl) -N- (4-(moτpholinosulfonyl) phenyl)quinazolin-2-amine
To a solution of 2-(4-(moφholinosulfonyl)phenylamino) quinazolin-7-yltrifluoromethane sulfonate (leq) in DME was added 2M sodium carbonate solution and l-methyl-4-(4,4,5,5,- tetramethyl-ls3,2-dioxaborolan-2-yl)-lH-pyrazole (3eq) and Pd (dppf)2Cl2.CH2Cl2 (0.05eq) and the mixture was micro waved for 10 min at 1200C. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, concentrated and purified by semi-preparative HPLC to provide 7-(l -methyl- lH-pyrazol-4-yl) -N- (4- (morpholinosulfonyl) phenyl) quinazolin-2-amine in 60%yield. ES/MS m/z 551.1(MH+).
Example 40
Synthesis of N7- (l-methylpiperidin-4-yl) -N2- (4-(morpholinosulfonyl) phenyl) quinazolin-2, 7- diamine (Compound 348)
Figure imgf000353_0001
Step 1. Preparation of 2-(4-(morpholinosulfonyl)phenylamino) quinazolin-7-yltrifluoromethane sulfonate For preparation see example 39 step 1.
Step 2. Preparation of N7- (l-methylpiperidin-4-yl) — N2- (4-(morpholinosulfonyl) phenyl) quinazolin-2, 7-diamine PP028218.0002
To a mixture OfPd(OAc)2 (O.leq), CS2CO3 (1.75eq) and BINAP (0.2eq) in THF was purged nitrogen for lOmin. Then added to it was 2-(4-(morpholinosulfonyl)phenylamino) quinazolin-7- yltrifluoromethane sulfonate (leq) and 4-amino-l-methylpiperidine (4eq). The reaction mixture was heated in sealed tube in oil bath for 3h at 1100C. The reaction mixture was concentrated and purified by semi-prep HPLC to provide N7- (l-methylpiperidin-4-yl) -N2- (4- (morpholinosulfonyl) phenyl) quinazolin-2, 7-diamine in 35% yield. ES/MS m/z 483.1 (MH+).
Example 41
Synthesis of Preparation of N- (4-fluoro-3-methylphenyl)-7-(l-isopropyl-piperidin-4-yloxy)- quinazolin-2-amine (Compound 327)
Figure imgf000354_0001
Step 1. Preparation of N- (4-fluoro-3-methylphenyl)-7-methoxy quinazolin-2-amine See example 37, step 1 for synthesis. ES/MS m/z 284.0 (MH+).
Step 2. Preparation of 2- (4-fluoro-3-methylphenylamino) quinazolin-7-ol See example 37, step 2 for synthesis. ES/MS m/z 270.1 (MH+).
Step 3. Preparation of N- (4-fluoro-3-methylphenyl)-7-(l-isopropyl-piperidin-4-yloxy)- quinazolin-2-amine
To a solution of triphenylphosphine (2eq) in THF was added di-terbutylazodicarboxylate (2eq). The mixture was stirred 15 minutes at ambient temperature under nitrogen atmosphere. To that PP028218.0002
was added l-isopropylpiperidine-4-ol (5eq). The mixture was stirred 15 minutes at ambient temperature followed by addition of 2-(4-fluoro-3-mrthylphenylarnino) quinazolin-7-ol (leq). The mixture was stirred overnight at ambient temperature. The LC —MS of reaction mixture shows the presence of two product (2: 1) with identical mass. The reaction mixture was concentrated and purified by semi-preparative HPLC to provide (N- (4-fluoro-3-methylphenyl)- 7-(l-isopropyl-piperidin-4-yloxy)-quinazolin-2-amine as a major product .ES/MS m/z 395.2 (MH+).
The other product was identified by NMR as 2-(4-fluoro-3-methylphenylamino)-8-(l-isopropyl- piperidin-4-yl)-quinazolin-7-ol). ES/MS m/z 395.2 (MH+).
Example 42
Synthesis of 5-(7-(piperidin-4-yloxy)-quinazolin-2-ylamino]- lH-benzo[d] imidazol-2 (3H)-one (Compound 330)
Figure imgf000355_0001
Step 1. Preparation of 2-(ethylthio) quinazolin-7-ol
To a solution of ethanthiol (30ml) in DCM (50ml) was added AICI3 (6eq). The reaction mixture was cooled to 00C and stirred for lOmin under N2 atmosphere. A solution of 2-chloro-7- methoxyquinazoline (leq) in DCM (20ml) was added dropwise to it. The reaction mixture was warmed to room temperature and stirred for 2h. The solvent was evaporated and residue was partitioned between EtOAc and satd. NaHCO3. The insoluble material was filtered, washed and dried to provide title product as a yellow solid (yield, 60%). The ethyl acetate layer was separated from basic layer, washed with brine and dried over sodium sulfate. Filtration, PP028218.0002
evaporation and drying under vacuum provide additional amount of product, (yield, 38%) . ES/MS m/z 207.0 (MH+).
Step 2. Preparation of tert -butyl 4-(2-(ethylthio) quinazolin-7-yloxy) piperidine-1- carboxylate To a solution of triphenylphosphiπe (2eq) in THF was added di-terbutylazodicarboxylate (2eq). The mixture was stirred 15 minutes at ambient temperature under nitrogen atmosphere. To that was added tert-butyl-4-hydroxypiperidine-l -carboxylate (5eq). The mixture was stirred 15 minutes at ambient temperature followed by addition of 2-(ethylthio) quinazolin-7-ol (leq). The mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated and purified by flash column chromatography (10%EtOAc / Hexane) to provide product as a white solid in 90% yield. ES/MS m/z 390.1 (MH+).
Step 3. Preparation of tert-butyl 4-(2-(ethylsulfonyl) quinazolin-7-yloxy) piperidine-1 - carboxylate To a solution of tert -butyl 4-(2-(ethylthio) quinazolin-7-yloxy) piperidine-1- carboxylate (leq) in THF (5ml) was added a solution of oxone in water (5ml) at 00C. The reaction mixture was stirred for 30min at 00C then warmed to room temperature and stirred for 4h. The reaction was quenched with satd. sodium thiosulfate solution and basified with IN NaOH. The product was extracted from basic layer with DCM. The DCM extracts were combined together, washed with brine and dried over sodium sulfate. The purification by flash column chromatography (70% EtOAc / Hexane) provide pure product in 60%yield. ES/MS m/z 422.0 (MH+).
Step 4. Preparation of tert-butyl 4-(2-(2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-ylamino) quinazolin-7-yloxy) piperidine-1- carboxylate A solution of tert-butyl 4-(2-(ethylsulfonyl) quinazolin-7-yloxy) piperidine-1- carboxylate (leq) and 5-amino-l, 3-dihydro-benzimidazole-2-one (5eq) in acetonitrile was heated in sealed tube at 1100C for 48h. The product was filtered, washed and dried. A brown solid, yield 50%. ES/MS m/z All.5 (MH+).
Step 5. Preparation of 5-(7-(piperidin-4-yloxy)-quinazolin-2-ylamino]- lH-benzo[d]imidazol- 2(3H)-one PP028218.0002
A solution of crude tert-butyl 4-(2-(2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-ylamino) quinazolin-7-yloxy) piperidine-1- carboxylate in 30%TFA / DCM was stirred at room temperature for 30min. The solvent was evaporated and crude was purified by semi-prep HPLC to provide pure product in 30% yield. ES/MS m/z 377.1 (MH+).
Example 43
Synthesis of 4-(7-aminoquinazolin-2-ylamino]- benzenesulfonamide (Compound 315)
Figure imgf000357_0001
Step 1. Preparation of tert-butyl 2-(4-sulfamoylphenylamino) quinazolin-7-yl) carbamate To 2-(4-sulfamoylphenylamino) quinazoline-7-carboxylic acid (leq) in toluene was added diphenylphosphorylazide (1.2eq), tert-butanol (lOeq) and triethylamine (2eq). The reaction mixture was heated at 700C for 30min then 1000C for overnight. The reaction mixture was concentrated and purified by semi-prep HPLC to provide pure product as a yellow solid in 35% yield. ES/MS m/z 416.0' (MH+).
Step 2. Preparation of 4-(7-aminoquinazolin-2-ylamino]- benzenesulfonamide
A solution of tert-butyl 2-(4-sulfamoylphenylamino) quinazolin-7-ylcarbamate in 30%TFA / DCM was stirred at room temperature for 30min. The solvent was evaporated and crude was purified by semi-prep HPLC to provide 4-(7-aminoquinazolin-2-ylamino]- benzenesulfonamide. ES/MS m/z 316.0 (MH+).
Example 45
Synthesis of N- (2-(4- sulfamoylphenylamino) quinazolin-7-yl) acetamide (Compound 316) PP028218.0002
\
Figure imgf000358_0001
To a solution of 4-(7-aminoqumazolin-2-ylamino]- benzenesulfonamide (leq) (For synthesis see example 43) in THF was added acetic acid (5eq), HBTU (4eq) and DIEA (lOeq). The reaction mixture was stirred at room temperature for 48h. The reaction does not go to completion. Diluted with ethyl acetate and washed with water, brine and dried over sodium sulfate. Filtered, concentrated and purified by semi-prep HPLC to provide N- (2-(4- sulfamoylphenylamino) quinazolin-7-yl) acetamide ES/MS m/z 358.0 (MH+).
Example 45 Synthesis 5-bromo-N- (3- chloro-4-morpholinophenyl)-8-(piperidine-4-yloxy) quinazolin-2- amine (Compound 338)
Figure imgf000358_0002
Step 1. Preparation of 5-brorno-2-chloroquinazolin-8-ol Solid NBS (leq) was added to a stirred solution of 2-chloroquinazolin-8-ol (leq) (See example 1 for synthesis) in NMP at 00C under argon. After stirring at 00C for 30min, LCMS showed that the reaction was complete. The formation of both 5-bromo (Major) and 7-bromo (Minor) isomers PP028218.0002
along with 5,7 dibromo product was observed. The reaction mixture was diluted with ethyl acetate and washed with satd. sodium bicarbonate, water and brine. Dried, filtered and concentrated. The crude was purified by flash chromatography (3-5% EtOAc / Hexane) to provide 5-bromo-2-chloroquinazolin-8-ol as a white solid in 60% yield. ES/MS m/z 259.2 (MH+).
Step 2. Preparation of tert-butyl 4-(5-bromo-2-chloroquinazolin-8-yloxy) piperidine-1- carboxylate
To a solution of triphenylphosphine (2eq) in THF was added di-terbutylazodicarboxylate (2eq). The mixture was stirred 15 minutes at ambient temperature under nitrogen atmosphere. To that was added tert.butyl-4-hydroxypiperidine-l-carboxylate (5eq). The mixture was stirred 15 minutes at ambient temperature followed by addition of 5-bromo-2-chloroquinazolin-8-ol (leq).
The mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated and the residue was purified by flash column chromatography (25%EtOAc / Hexane) to provide product as a white solid in 90% yield. ES/MS m/z 442.1 (MH+).
Step 3. Preparation of tert-butyl 4-(5-bromo-2-(3-chloro-4-moφholinophenylamino) quinazolin- 8-yloxy) piperidine-1-carboxylate
A mixture of tert-butyl 4-(5-bromo-2-chloroquinazolin-8-yloxy) piperidine-1-carboxylate (leq) and N- (4-amino-2-chlorophenyl) morpholine (leq) in isopropanol was heated in a sealed tube at 1100C for overnight. The reaction mixture was concentrated and proceeds for next step. ES/MS m/z 618.0 (MH+).
Step 4. Preparation of 5-bromo-N- (3- chloro-4-morpholinophenyl)-8-(piperidine-4-yloxy) quinazolin-2-amine
A solution of tert-butyl 4-(5-bromo-2-(3-chloro-4-moφholinophenylamino) quinazolin-8-yloxy) piperidine-1-carboxylate in 30%TFA / DCM was stirred at room temperature for 30min. The solvent was evaporated and crude was purified by semi-prep HPLC to provide 5-bromo-N- (3- chloro-4-morpholinophenyl)-8-(piperidine-4-yloxy) quinazolin-2-amine in 50% yield. ES/MS m/z 518.0 (MH+). PP028218.0002
Example 46
Synthesis of N-(3-chloro-4-morpholinophenyl)-5-methyl-8- (piperidine-4-yloxy) quinazolin-2- amine (Compound 602)
Figure imgf000360_0001
Step 1. Preparation of tert-butyl 4-(2- (3-chloro-4-morpholinophenylamino)-5-methylquinazolin-
8-yloxy) piperidine-1-carboxylate
To a solution of tert-butyl 4-(5-bromo-2- (3-chloro-4-moφholinophenylamino) quinazolin-8- yloxy) piperidine-1-carboxylate (See example 45 for synthesis)
(leq) in DMF was added 2M sodium carbonate solution, trimethylboroxine (3eq) and Pd (dppf)2Cl2.CH2Cl2 (0.05eq). The reaction mixture was micro waved for 10 min at 12O0C. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, concentrated and purified by semi-preparative HPLC to provide pure product . ES/MS m/z 554.1 (MH+).
Step 2. Preparation of N- (3- chloro-4-morpholinophenyl)-5-methyl-8- (piperidine-4-yloxy) quinazolin-2-amine
A solution of tert-butyl 4-(2- (3-chloro-4-morpholinophenylamino)-5-methylquinazolin-8-yloxy) piperidine-1-carboxylate in 30%TFA / DCM was stirred at room temperature for 30min. The solvent was evaporated and crude was purified by semi-prep HPLC to provide N- (3- chloro-4- moφholinophenyl)-5-methyl-8- (piperidine-4-yloxy) quinazolin-2-amine 50% yield. ES/MS m/z 454.1 (MH+). PP028218.0002
Example 47
Synthesis of 4-(5-bromo-8- (piperidin-4-yloxy) quinazolin-2-ylamino)-3-methoxy-N- (1- methylpiperidinyl)benzamide (Compound 371)
Figure imgf000361_0001
For preparation of the starting material, 4-(5-bromo-8- (piperidine-4-yloxy)quinazolin-2- ylamino)-3-methoxybenzoic acid see example 45. ES/MS m/z 473.0 (MH+).
Preparation of 4-(5-bromo-8- (piperidin-4-yloxy)quinazolin-2-ylamino)-3-methoxy-N-(l - methylpiperidinyl)benzamide
A mixture of 4-(5-bromo-8-(piperidine-4-yloxy)quinazolin-2-ylamino)-3-methoxybenzoic acid (leq), 4-amino-N-methylpiperidine (2eq), HATU (l-5eq) and DEEA (3eq) in NMP was stirred at room temperature for 4h. The reaction mixture was concentrated and purified by semi-prep HPLC to provide pure product in 45% yield. ES/MS m/z 569.1 (MH+).
Example 48
Synthesis (2-chloro-4- (5-chloro-8- (piperidin-4-yloxy) quinazolin-2-ylamino)phenyl) (morpholino)methanone (Compound 692) PP028218.0002
Figure imgf000362_0001
For preparation of the starting material, 2-chloro-4- (5-chloro-8- (piperidin-4-yloxy) quinazolin- 2-ylamino) benzoic acid, see example 32 for the synthesis. ES/MS m/z 433.0 (MEI+).
Preparation of (2-chloro-4- (5-chloro-8- (piperidin-4-yloxy) quinazolin-2-ylamino)phenyl)
(morpholino)methanone
A mixture of 2-chloro-4- (5-chloro-8- (piperidin-4-yloxy) quinazolin-2-ylamino) benzoic acid
(leq), morpholine (3eq), HATU (1.5eq) and DIEA (4eq) in NMP was stirred at room temperature for 4h. The reaction mixture was concentrated and purified by semi-prep HPLC to provide pure product in 50% yield. ES/MS m/z 502.3 (MH+).
Example 49
Synthesis N- (3-chloro-8-methoxyquinazolin-2-ylamino)-5-((dimethylamino)methyl) phenyl)acetamide (Compound 691)
Figure imgf000362_0002
Step 1. Preparation of 2,5 -dichloro-8-methoxyquinazoline PP028218.0002
To a solution of 2,5-dichloroquinazolin-8-ol (leq) (See example 32 for synthesis) in DMF was added iodomethane (3eq) and potassium carbonate (3eq). The reaction mixture was stirred at room temperature for overnight. Diluted with ethyl acetate and washed with water and brine and dried over sodium sulfate. Filtered, evaporated and dried to provide product as a yellow solid in quantitative yield. ES/MS m/z 229.0 (MH+). Proceed for next step.
Step 2. Preparation of (3-cUoro-8-methoxyquinazolin-2-ylarnino)-5-((dimethylamino) methyl) phenyl) acetamide
A mixture of 2,5 -dichloro-8-methoxyquinazoline (leq) and l-(3-amino-5- ((dimethylamino)methyl)phenyl)propan-2-one (leq) and 6NHC1 (l.leq) in isopropanol was heated at 1200C for overnight. The reaction mixture was concentrated and purified by semi-prep HPLC to provide pure product in 30% yield. ES/MS m/z 400.2 (MH4).
Example 50 Synthesis (4-(5-chloro-8- (l-methylpiperidin-4-ylamino) quinazolin-2-ylamino)phenyl) (morpholino)methanone (Compound 377)
Figure imgf000363_0001
Step 1. Preparation of (4-(5-chloro-8-hydroxyquinazolin-2-ylamino) phenyl) (morpholino)methanone See example 32 for synthesis. ES/MS m/z 385.0(MH+). PP028218.0002
Step 2. Preparation of 5-chloro-2- (4-(morpholino-4-carbonyl) phenylamino) quinazolin-8- yltrifluoromethane sulfonate
See example 39, stepl for synthesis. ES/MS m/z 517.0(MH+).
Step 3. Preparation of (4-(5-chloro-8- (l-methylpiperidin-4-ylamino) quinazolin-2- ylamino)phenyl)(morpholino)methanone
To a mixture of Pd (OAc)2 (O.leq), CS2CO3 (1.75eq) and BINAP (0.2eq) in THF was purged nitrogen for lOmin. Then added to it were 5-chloro-2- (4-(morpholino-4-carbonyl) phenylamino) quinazolin-8-yltrifluoromethane sulfonate (leq) and 4-amino-l-methylpiperidine (2eq). The reaction mixture was heated in sealed tube in oil bath for 16h atl 100C. The reaction mixture was concentrated and purified by semi-prep HPLC to provide (4-(5-chloro-8- (l-methylpiperidin-4- ylamino) quinazolin-2-ylamino) phenyl) (morpholino)methanone in 35% yield. ES/MS m/z 481.0 (MH+).
Example 51
Synthesis of 4-(8-methoxy-5- (trifluorornethyl) quinazolin-2-ylamino) phenyl)(moφholino)methanone (Compound 500)
Figure imgf000364_0001
PP028218.0002
Step 1. Preparation of 2-methoxy-5- (trifluoromethyl) aniline
A mixture of 4-methoxy-3-nitrobezotrifluoride and 10% of 10% Pd / C in methanol was stirred under Hfe atmosphere overnight at room temperature. The reaction mixture was filtered through celite, concentrated and dried under vacuum to provide product as an off white solid in 99%yield. ES/MS m/z 192.1 (MH+).
Step 2. Preparation of N- (2-methoxy-5-(trifluoromethyl) phenyl) pivalamide To a solution of 2-methoxy-5- (trifluoromethyl) aniline (leq) in DCM at 00C was added TEA (leq) followed by dropwise addition of pivaloyl chloride (leq). The reaction mixture was warmed to room temperature and left stirred overnight. Diluted with DCM and washed with satd. sodium bicarbonate, water, brine and dried over sodium sulfate. Filtered, evaporated and dried under vacuum to provide pure product as an off white solid in 95% yield. ES/MS m/z 276.1 (MH+).
Step 3. Preparation of 3-methoxy-2-pivalamido-6- (trifluoromethyl) benzoic acid
N- (2-methoxy-5- (trifluoromethyl) phenyl) pivalamide (leq) was azeotrope with toluene (x=3). Dissolved in THF, cooled to -500C and added n-BuLi (2eq, 2.5M solution in hexane) dropwise. . The reaction mixture was stirred at -500C for Ih then warmed to -100C in 30min. Stirred at this temperature for 30min then CO2 gas was passed through cylinder into the reaction mixture at -10 to 00C for Ih. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was poured to water and extracted with ethyl acetate. (EtOAc extracts contained starting material). The aq layer pH was adjusted to 1-2 and product was extracted with ethyl acetate (x=3). The ethyl acetate extracts were combined, washed with brine and dried over sodium sulfate. Filtered, evaporated and dried under vacuum to provide product as yellow solid in 65% yield. ES/MS m/z 320.1 (MH+). Proceeds for next step without any purification.
Step 4. Preparation of methyl-3-methoxy-2-pivalamido-6-(trifluoromethyl) benzoate A mixture of 3-methoxy-2-pivalamido-6- (trifluoromethyl) benzoic acid (leq), dimethyl sulfate (1 eq) and sodium bicarbonate (1.3eq) in acetone was refluxed for 4h. The reaction mixture was poured to water and extracted with ethyl acetate. The ethyl acetate extracts were combined, PP028218.0002
washed with brine and dried over sodium sulfate. Filtered, evaporated and dried under vacuum to provide product as yellow solid in 95% yield. ES/MS m/z 334.1 (MH+). Proceeds for next step without any purification.
Step 5. Preparation of methyl-2- (acetylacetamido)-3-methoxy-6-(trifluoromethyl) benzoate A solution of memyl-3-methoxy-2-pivalarnido-6- (trifluoromethyl) benzoate in acetic acid and acetic anhydride (1:2) was heated to reflux for 16h. The reaction mixture was concentrated and residue was partitioned between ether and water. Ether layer was separated and washed with water, satd.sodium bicarbonate and dried over sodium sulfate. Filtered, evaporated and dried. The residue was triturated with hexane and solid was collected by filtration and dried under vacuum to provide pure product as an off white solid in 60% yield. ES/MS m/z 334.1 (MH+).
Step 6. Preparation of 2-amino -3-methoxy-6- (trifluoromethyl) benzoic acid A solution of methyl-2- (acetylacetamido)-3-methoxy-6-(trifiuoromethyl) benzoate in 2N NaOH was heated to reflux for 4-5h. The reaction mixture was cooled and pH was adjusted to 2. The product was extracted in ethyl acetate. The ethyl acetate extracts were combined, washed with brine and dried over sodium sulfate. Filtered, evaporated and residue was triturated with hexane. The solid was collected by filtration and dried under vacuum to provide product as light brown solid in 85% yield. ES/MS m/z 236.0 (MH+).
Step 7. Preparation of 2-amino -3-methoxy-6- (trifluoromethyl) phenyl) methanol To 2-amino -3-methoxy-6- (trifluoromethyl) benzoic acid (leq) in THF at 00C was added boran tetrahydrofuran complex solution (6eq, 1 M in THF) at different time interval. The mixture was stirred at room temperature for 48 hrs. The solvent was removed in vacuo and residue was partitioned between water and ethyl acetate.The organic layer was separated, washed with brine, dried with sodium sulfate and concentrated to give product in 85% yield. ES/MS m/z 222.1 (MH+). PP028218.0002
Step 8. Preparation of 2-amino -3-methoxy-6- (trifluoromethyl) benzaldehyde To 2-amino -3-methoxy-6- (trifluoromethyl) phenyl) methanol (leq) in dichloromethane was added manganese dioxide (5eq). The mixture was stirred at room temperature under argon for 48 hrs. The mixture was filtered through celite pad and washed thoroughly with dichloromethane. The filtrated was concentrated in vacuo to give crude product in 90% yield, which was used for the next step without further purification. ES/MS m/z 220.0 (MH+). Step 9. Preparation of 8-methoxy-5-(trifluoromethyl) quinazolin-2-ol
A mixture of 2-amino -3-methoxy-6- (trifluoromethyl) benzaldehyde (leq) (obtained from step 7) and urea (15 equiv.) was heated to 175 0C with vigorous stirring for 2h. The reaction was cooled to room temperature and water was added. The solid was collected by filtration. Air- dried to give 8-methoxy-5- (trifluoromethyl) quinazolin-2-ol as yellow solid in 70%yield. ES/MS m/z 245.0 (MH+).
Step 10. Preparation of 2-chloro-8-methoxy-5- (trifluoromethyl) quinazoline The crude 8-methoxy-5-(trifluoromethyl) quinazolin-2-ol was heated in neat phosphooxychloride
(POCI3) at 1100C for 2h. The resulted mixture was cooled to room temperature and concentrated in vacuo to nearly dryness. Ice water was added and precipitate was filtered, washed and dried to provide 2-chloro-8-methoxy-5- (trifluoromethyl) quinazoline as a light pink solid in 70% yield. ES/MS m/z 263.0 (MH+).
Step 11. Preparation of 4-(8-methoxy-5- (trifluoromethyl) quinazolin-2-ylamino) phenyl)(moφholino)methanone
A mixture of 2-chloro-8-methoxy-5- (trifluoromethyl) quinazoline (leq) and 4-aτnino phenyl)(morpholino)methanone (leq) in isopropanol was heated in sealed tube at 1100C for 16h. The solvent was evaporated and residue was purified by semi-prep HPLC to provide pure product as yellow solid in 50% yield. ES/MS m/z 433.2 (MH+).
Example 52
Synthesis of morpholino(4-(8-piperidin-4-yloxy)-5-(trifluoromethyl) quinazolin-2-ylamino) phenyl) methanone (Compound 383) PP028218.0002
Figure imgf000368_0001
Step 1. Preparation of 2-chloro-5- (trifluoromethyl) quinazolin-8-ol
To a solution of 2-chloro-8-methoxy-5- (trifluoromethyl) quinazoline (leq) (See example 51 for synthesis) in DCM was added boron tribromide at 00C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated and residue was treated with ice cold water. Precipitate was filtered, washed and dried in vacuo to provide product as a yellow solid in 78% yield. ES/MS m/z 249.0 (MH+).
Step 2. Preparation of tert.butyl-4- (2-chloro-5- (trifluoromethyl) quinazolin-8-yloxy) piperidine- 1 -carboxylate See example 37, step 2 for the synthesis. ES/MS m/z 431.2 (MH4).
Step 3 - 4. Preparation of morpholino(4-(8-piperidin-4-yloxy)-5-(trifluoromethyl) quinazolin-2- ylamino) phenyl) methanone
See example 45, step 3 and 4 for the synthesis. ES/MS m/z 502.2 (MH+).
Example 53
Synthesis of N- (3-methoxy-5 (5 -methyl- lH-tetrazol-l-yl)phenyl)-7 -(piperidin-4-yloxy)-6- (thiazol-2-yl)quinazolin-2-amine (Compound 682) PP028218.0002
Figure imgf000369_0001
Step 1. Preparation of 6-bromo-2-(ethylthio) quinazolin-7-ol For preparation, see example 37, step 2. (yield, 60%). ES/MS m/z 270.9 (MH+).
Step 2. Preparation of tert -butyl 4-(6-bromo-2- (methylsulfonyl) quinazolin-7-yloxy) piperidine-
1- carboxylate
Step 2 &3. See example 42, step 2 and 3 for the synthesis, (yield, 70%) ES/MS m/z 454 / 456
(MH+).
Step 4. Preparation of tert -butyl 4-(6-bromo-2- (3-methoxy-5-(5-methyl-lH-tetrazol-l- yl)phenylamino)) quinazolin-7-yloxy) piperidine-1- carboxylate
A mixture of tert -butyl 4-(6-bromo-2- (methylsulfonyl) quinazolin-7-yloxy) piperidine-1- carboxylate (leq) and 3-Methoxy-5- (5-methyl-tetrazol-l-yl)-phenylamine (2eq) in dioxane was heated in sealed tube at 1200C for 48h. The product was purified by semi prep HPLC to provide pure product as a brown solid. ES/MS m/z 611.0 / 613.0 (MH+).
Step 5 & 6. Preparation of N- (3-methoxy-5- (5-methyl-lH-tetrazol-l-yl) phenyl)-7-(piperidin-4- yloxy) -ό-(thiazol-2-yl) quinazolin-2-amine
See example 27 for the synthesis. ES/MS m/z 516.1 (MH+). PP028218.0002
Example 54
Preparation of 4-(8-(((2-methoxyethyl)(methyl)amino)methyl)quinazolin-2- ylarmno)benzenesulfonamide (Compound 392)
The subject compound was prepared according to the general Scheme below: Step i
Figure imgf000370_0001
Step2
Figure imgf000370_0002
Step3
Figure imgf000370_0003
Step 1. Preparation of 2-(4-sulfamoylphenylamino)quinazolin-8-yl-trifluoromethanesulfonate To a solution of 4-(8-hydroxyqumazolin-2-ylarnino) benzenesulfonamide in NMP was added phenyltrifluoromethanesulfonate and DIEA and the reaction mixture was stirred over night at ambient temperature. The reaction mixture was then partitioned between ethyl acetate and PP028218.0002
water. The organic layers were washed with saturated sodium, chloride and dried and concentrated. To the crude was added methylene chloride and few drops of methanol. The white solid hence formed was filtered to give 2-(4-sulfamoylphenylamino)quinazolin-8- yltrifluoromeihane sulfonate.
Step 2. Preparation of 4-(8-foπnylquinazolin-2-ylamino)benzenesulfonarnide A mixture of 2-(4-sulfamoylphenylamino)quinazolin-8-yl trifluoromethanesulfonate (900 mg, 2 mmole), Pd(dppf)Cl2 (170 mg, 0.2 mmole), triethylamine (700 ul, 5 mmole) and triethylsilane (960 ul, 6 mmole) in DMF (20 ml) was placed in a stainless steel reactor. CO was bubbled into the mixture in the reactor. The reaction solution was stirred at 85°c under CO (420 psi) for overnight. The reaction mixture was poured into 80 ml of saturated NaHCO3 and extracted with ethyl acetate (2x250 ml). The combined organic layers were washed with water (2x60 ml) and brine (60 ml), then dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash column chromatography to give 4-(8-formylquinazolin-2-ylamino)benzenesulfonamide (274 mg, 0.83 mmole) as brown solid. ES/MS m/z 328.9(MH+).
Step 3, Preparation of 4-(8-(((2-methoxyethyl)(methyl)amino)methyl)quinazolin-2- ylamino)benzenesulfonamide
To the solution of 4-(8-foπnylquinazolin-2-ylamino)benzenesulfonamide (11 mg, 30 umole) and 2-methoxy-N-methylethanamine (37 ul, 30 umole) in 500 ul of NMP was added a few drops of acetic acid. The reaction solution was stirred at room temperature for overnight. Sodium triacetoxy borohydride (7 mg, 33 umole) was added. The reaction mixture was stirred for 2hr at ambient temperature. The reductive amination went to completion to give 4-(8-(((2- meΛoxyethyl)(rnemyl)arra^o)nαethyl)quinazolin-2-ylamino)benzenesulfonamide that was then purified on prep HPLC to give product as powder . ES/MS m/z 402.2 (MH+).
Example 55
Preparation of 4-(8-(6-(2-(pyrrolidin- 1 -yl)ethylamino)-5-(trifluoromethyl)pyridin-3- yl)quinazolin-2-ylamino)benzenesulfonamide The subject compound was prepared according to the general Scheme below: PP028218.0002
Figure imgf000372_0001
Figure imgf000372_0002
Figure imgf000372_0003
Figure imgf000372_0004
Stepl . Preparation of N-(2-(pyrrolidin-l -yl)ethyl)-3-(trifluoromethyl)pyridin-2-amine To the solution of 2-fluoro-3-(trifluoromethyl)pyridine (990 mg, 6 mmole) in 5 ml of NMP, 2- aminoethylpyrrolidine (1.13 ml, 9 mmole) and triethylamine (1 ml, 7.2 mmole) were added. The PP028218.0002
reaction solution was stirred at 85°c for overnight. The reaction mixture was poured into 40 ml of saturated NaHCO3 and extracted with ethyl acetate (2x80 ml). The combined organic layers were washed with water (2x30 ml) and brine (30 ml), then dried over Na2SO4 and evaporated in vacuo to give a brown oily N-(2-(pyπ-olidin-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2-arnine (1.6Ig). ES/MS m/z 260.1 (MH+).
Step 2. Preparation of 5-bromo-N-(2-(pyrrolidin-l-yl)emyl)-3-(trifluoromemyl)pyrioUn-2-arnine. To the solution of N-(2-(pyiτolidm-l-yl)ethyl)-3-(trifluoromethyl)pyridin-2-amine (1030 mg, 4 mmole) in 10 ml of acetic acid, bromine (203 ul, 4 mmole) was added. The reaction solution was stirred at room temperature for 1.5 hr and then concentrated under vacuo to give an orange solid. The crude product was dissolved with 40 ml of ethyl acetate to give a yellow milky mixture that was then filtered and washed to give an invory powder as HBr salt of 5-bromo-N-(2-(pyrrolidin- l-yl)ethyl)-3-(trifluoromethyl)pyridin-2-amine (963 mg). ES/MS m/z 335.9, 337.9 (MH+).
Step 3. Preparation of N-(2-(pyrrolidin-l -yl)ethyl)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-3 -(trifluoromethyl)pyridin-2-amine.
A mixture of 5-bromo-N-(2-(pvrrolidm-l-yl)ethyl)-3-(trifiuoromethyl)pyridin-2-amine as TFA salt (356 mg, 789 umole), 4,4,4',4',5,5,5l,5l-octamethyl-2s2'-bi(l,352-dioxaborolane) (219 mg, 862 umole) and potassium acetate (231 mg, 2.35 mmole) in 4 ml of dioxane, Pd(dppf)Cl2 (41 mg, 50 umole) was added into the reaction mixture that was stirred at 92°c for overnight. The reaction mixture was saved for future reaction and analyzed by LCMS to characterize the product as N-(2-(pyrrolidin-l-yl)ethyl)-5-(4,455,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-3- (trifluoromethyl)pyridin-2-amine.
Step 4. Preparation of 4-(8-(6-(2-(pyrrolidin-l-yl)ethylarnino)-5-(trifluoromethyl)pyridin-3- yl)quinazolin-2-ylamino)benzenesulfonamide.
To the reaction mixture of N-(2-(pyrrolidin-l-yl)ethyl)-5-(4J4,5,5-tetramethyl-l,352- dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (1.2 ml, 235 umole) in dioxane, 2-(4- sulfamoylphenylamino)quinazolin-8-yl trifluoromethanesulfonate (45 mg, 100 umole), Pd(dppf)Cl2 (9 mg, 11 umole) and 2M Na2CO3 (300 ul, 600 umole) were added. The reaction mixture was stirred at 92°c for 5hr. The reaction mixture was poured into 30 ml of saturated PP028218.0002
NaHCθ3 and extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with water (2x20 ml) and brine (30 ml), then dried over Na2SO4 and evaporated in vacuo to give a brown solid (150 mg) that then purified on prep HPLC to give 4-(8-(6-(2-(pyrrolidin-l- yl)emylainino)-5-(1riiluoromethyl)pyridm-3-yl)qumazolin-2-ylamino)benzenesulfonarnide. as powder (2.7 mg). ES/MS mJz 558 (MH+).
Example 56
Preparation of 4-(8-(2-memoxypyridm-4-yl)quinazoline-2-ylamino)benzenesulfonarnide
(Compound 418)
The subject compound was prepared according to the general Scheme below:
Figure imgf000374_0001
To a solution of 4-(8-(2-fluoroypyridin-4-yl)quinazoline-2-ylamino)benzenesulfonamide (9 mg, 0.0227 mMol) in NMP (0.4 ml) and MeOH (0.4mL) under argon was added (10eq.) NaH 60 % in oil. The reaction was sealed and heated at 65 0C for 5.5 hrs. The crude reaction mixture was concentrated under reduced pressure, purified on prep HPLC and lyophilized to give the desired product (1.2 mg) as TFA salt. ES/MS m/z 408 (MH+).
Example 57
Synthesis of 4-(8-(6-fluoropyridin-3-yloxy)quinazolin-2-ylamino)benzenesulfonamide (Compound 413) PP028218.0002
Figure imgf000375_0001
Step 1. To a 0.13 M solution of Ia in DCM was added boron tribromide (2.0 eq. of a 1.0 M solution in DCM) dropwise at -10 0C under a nitrogen atmosphere. The reaction was allowed to warm to room temperature (dark orange color) and stirred for 22 hours. The reaction was then cooled to 0 0C (red solution and precipitate formed) and the precipitate was collected by vacuum filtration and rinsed with cold DCM. The solid was stirred in ice water for one hour then filtered off, washed with water, cold 2-propanol and hexanes. The light tan solid was dried under vacuum to give the desired product in 82 % yield as a mixture of the 2-chloro and 2- bromoquinazolin-8-ol. ES/MS m/z 181.1 and 225.0/227.0 (MH+).
Step 2. To a 0.1 M solution of the 2-chloro and 2-bromoquinazolin-8-ol in DCM was added 4A MS followed by Cu(OACh1H2O (1.0 eq.). The solution was stirred at room temperature for 5 min. (brown color), then 2-fluorpyridine5-boronic acid was added (2.0 eq.), followed by Et3N (5 eq.). The solution turned dark green and it was allowed to stir for 24 hr. The reaction was then filtered, the filtrate was evaporated and passed through a plug of silica gel eluting with EtOAc. Upon concentration of the fractions, the desired product was obtained in 33% yield. ES/MS m/z 276.0 and 321.9/320.0 (MH+).
Step 3. To a 0.13 M solution of the 2-chloro-8-(6-fluoropyridin-3-yloxy)quinazoline and 2- bromo-8-(6-fluoropyridin-3-yloxy)quinazoline mixture in /-PrOH was added sulfanilamide (1.0 eq.) and the solution was heated to refluxed for 12 hr. Cooled to room temperature and the precipitate was filtered off and washed with z-PrOH to give the desired product in 61% yield.
The solid was 96% pure by HPLC. ES/MS m/z 412.0 (MH+) for 595644 - 4-(8-(6-fluoropyridin-
3-yloxy)quinazolin-2-ylamino)benzenesulfonamide. PP028218.0002
Example 58
Synthesis of 4-(7-(2-fluoropyridin-4-yloxy)quinaz»lin-2-ylainino)benzenesulfonainide (Compound 416)
Figure imgf000376_0001
Step 1. To a solution of DCM/ethanethiol (0.3 M, 1:1) was added AlCl3 (6 eq.) and the reaction was cooled to 0 0C under a nitrogen atmosphere. Compound 6 was dissolved in DCM and added dropwise to the above solution dropwise. The reaction was allowed to warm to room temperature and stirred for 36 hr. The solvent was removed under vacuum and the crude was dissolved in EtOAc. Saturated NaHCO3 was added slowly dropwise and the layers were separated. The organic layer was dried with brine and Na2SO4 and concentrated. The crude was triturated in DCM and the precipitate was filtered off to give the desired product as an off-white solid in 83% yield. ES/MS m/z 207.0 (MH+).
Step 2. To a 0.1 M solution of the 2-(ethylthio)quinazolin-7-ol in DCM was added 4A MS followed by Cu(OAc)2 H2O (1.0 eq.). The solution was stirred at room temperature for 5 min. (brown color), then 2-fluoropyridine-5-boronic acid was added (2.0 eq.), followed by Et3N (5 eq.). The solution turned dark green and it was allowed to stir for 24 hrs. The reaction was then filtered, the filtrate was evaporated and passed through a plug of silica gel eluting with EtOAc. Upon concentration of the fractions, the desired product was obtained in 41% yield. ES/MS m/z 302.0 (MH+).
Step 3. To a 0.2 M solution of the 2-(ethylthio)-7-(2-fluoropyidin-4-yloxy)quinazoline in DCM was added m-CPBA (3 eq.) and the solution was stirred for 30 min at room temperature. Quenched the reaction with IN NaHCO3 and extracted with DCM. The organic layer was dried PP028218.0002
with Na2SO4 and concentrated. Purification via SiO2 column chromatography eluting with EtOAc and Hexanes (50%) afforded the desired product in 53% yield. ES/MS m/z 334.0 (MET*).
Step 4. To a 0.06 M solution of the 2-(ethylsulfonyl)-7-(2-fluoropyridin-4-yloxy)quinazoline in dioxane was added sulfanilamide (2.0 eq.) and /J-TSA-H2O (0.8 eq.) and the reaction was heated to 100 0C for 15 hr. The solvent was removed under vacuum and the crude was purified via automated reverse phase HPLC. The pure fractions were lyophilized over 2 days to afford the desired product 4-(7-(2-fluoropyridm^-yloxy)quinazolin-2-ylamino)benzenesulfonamide in 31% yield as the TFA salt. ES/MS m/z 412.1 (MH4)-
BIOLOGICAL METHODS
I. PDKl Kinase Alpha Screen Assay
Reagents/Concentrations: The PDKl -4 peptide substrate, biotin-GGGGRTWTLCG- NH2, was purchased from the Tufts University Core Facility. The final concentration of PDKl- 4 peptide substrate was 50 nM The ATP substrate (Adenosine-5 '-triphosphate) was purchased from Roche Diagnostics. The final concentration of ATP substrate was lOuM. Phospho- (Ser/Thr) PKA substrate antibody was purchased from Cell Signaling Technology. The final concentration of antibody was 0.3 mg/ml. The Alpha Screen Protein A detection kit containing donor and acceptor beads was purchased from PerkinEkαer Life Sciences. The final concentration of both donor and acceptor beads was 25 μg/ml. Alpha Screen was used for detection. The biotinylated-PDKl-4 peptide was phosphorylated by PDKl kinase using the ATP substrate. The biotinylated-PDKl-4 peptide substrate was bound to the streptavidin coated donor bead. The antibody was bound to the protein A coated acceptor bead. The antibody bound to the phosphorylated form of the biotinylated PDK-I peptide substrate, bringing the donor and acceptor beads into close proximity. Laser irradiation of the donor bead at 680nm generated a flow of short-lived singlet oxygen molecules. When the donor and acceptor beads were in close proximity, the reactive oxygen generated by the irradiation of the donor beads initiated a luminescence/fluorescence cascade in the acceptor beads. This process led to a highly amplified signal with output in the 530-620 nm range. Assays were carried out in 50 mM Tris, pH=7.5, 10 mM MgCl2, 0.1% Bovine Serum Albumin, 0.01% Tween-20, 2 mM Dithiolthreitol, PP028218.0002
2.5% Dimethyl Sulfoxide. Reactions were stopped by adding 50 mM Tris, pH=7.5, 90 mM EDTA, 0.1% Bovine Serum Albumin, 0.01% Tween-20.
Procedure: To 10 μl of PDK1-4 peptide, 0.5 μl of test compound in dimethyl sulfoxide is added. PDKl kinase and ATP are mixed. 10 μl of the PDKl kinase/ATP mix is added to start the reaction. The reaction is allowed to proceed for 3-18 hours. The reactions are stopped by adding 10 μl of the EDTA-containing stop buffer. Beads are mixed with antibody. 25 μl of the bead/antibody mix is added to the stopped reactions. Plates are incubated at room temperature overnight to allow for detection development before being read. The assay is run is a 384- well format. Results: Each of the compounds listed in Tables 1 -5 was screened according the method above, and exhibited an ICso value of less than or equal to 25 μM, with respect to inhibition of PDKl. Additionally, many of the compounds exhibited an IC50 of less than 10 μM, or less than 1 μM, or less than 0.1 μM, or less than 0.01 μM. Accordingly, each of the compounds is preferred individually, and/or as a member of a group that includes the compounds of Formula I, or Formula II or Formula III.
II. CDKl (CDC2) Kinase Inhibition In Vitro Screen Assay
Reagents/Concentrations: Human full length Cdkl is purchased from Upstate (# 14-450) as a co-purification with Cyclin B. The final enzyme concentration in the assay is 0.8 nM. Histone Hl peptide substrate is purchased from Research Genetics. The peptide, with the sequence lcBiotin-GGCGPKTPKKAKKL[CONH2], is used in the assay at a final concentration 0.5 μM. The ATP substrate (Adenosine-5' -triphosphate) was purchased from Roche Diagnostics. The final concentration of ATP substrate is 1 μM. P33 γ-ATP is purchased from NEN. The biotinylated peptide substrate is phosphorylated by Cdkl/Cyclin B enzyme, in the presence of varying concentrations of compounds, using the ATP substrate. A fraction of ATP in the reaction is radiolabeled to provide a detectable phosphorylation signal. The phosphoryaltion reaction is stopped with the addition of 25 mM EDTA. The solutions are then transferred to White BioBind Streptavidin Coated Assay plates, purchased from Thermo Electron Corporation. After washing, Microscint 20 scintillation fluid, purchased from Perkin Elmer, is added to each well and counts per minute (cpm) is measured using a Packard TopCount PP028218.0002
Microscintillation Counter. The highest cpms measured indicates the maximum phosphorylation of the substrate possible under the assay conditions. Reactions run without enzyme present give cpms indicative of complete inhibition of the enzyme. Each concentration of compound produces a measurable percent inhibition from the maximum signal based on these values. Assays were carried out in 50 mM Tris-HCl pH7.55 10 mM MgCl2, 1 mM DTT, 1 mM EGTA, 25 mM β-glycerol phosphate, 1 mM NaF, 0.01% BSA/PBS, 0.5 uM peptide substrate, and 0.8 nM Cdkl.
Procedure: Distribute 100 uL of Reaction Buffer containing 50 mM Tris-HCl pH7.5, 10 mM MgCl2, 0.01% BSA/PBS, 1.5 mM DTT, 1.5 mM EGTA3 37.5 mM β-glycerol phosphate, 1.5 mM NaF, 0.75 uM peptide substrate, and 1.2 nM Cdkl to each well. 100% inhibition control wells contain no Cdkl . Add compounds to wells in desired 1 OX concentrations with 10% DMSO, 50 mM Tris-HCl pH7.5, 10 mM MgCl2, and 0.01% BSA/PBS. Start reactions by adding 15 uL of ATP concentrated at 10 uM, with P33 γ-ATP at < 10 nM as label. Run reactions for four hours at room temperature with shaking. Streptavidin coated plates are blocked for one hour with 1 % BSA in PBS. 100 uL 50 mM EDTA is added to each streptavidin well. 100 uL of each assay solution are transferred to corresponding streptavidin wells containing EDTA. Capture of radiolabeled substrate then takes place by shaking at room temperature for one hour. After binding the wells are washed 4 times with PBS, 200 uL Microscint 20 is added to each well, and cpms are measured. The assay is run in a 96-well format.
Results: Many of the compounds listed in Tables 1-5 were screened according to the " method above, and exhibited an ICso value of less than or equal to 25 μM, with respect to inhibition of Cdkl. Additionally, many of the compounds exhibited an ICso of less than 10 μM, or less than 1 μM, or less than 0.1 μM. Accordingly, each of the compounds is preferred individually, and/or as a member of a group that includes the compounds of Formula I, or Formula II or Formula III.
III. CDK2 Kinase Inhibition In Vitro Screen Assay
Reagents/Concentrations: Human full length Cdk2 is purchased from Upstate (# 14-407) as a co-purification with Cyclin A. The final enzyme concentration in the assay is 5 nM. PP028218.0002
Histone Hl peptide substrate is purchased from Research Genetics. The peptide, with the sequence lcBiotin-GGCGPKTPBCKAKKL[CONH2], is used in the assay at a final concentration 0.5 μM. The ATP substrate (Adenosine-5' -triphosphate) was purchased from Roche Diagnostics. The final concentration of ATP substrate is 1 μM. P33 γ-ATP is purchased from NEN. The biotinylated peptide substrate is phosphorylated by Cdk2/Cyclin A enzyme, in the presence of varying concentrations of compounds, using the ATP substrate. A fraction of ATP in the reaction is radiolabeled to provide a detectable phosphorylation signal. The phosphoryaltion reaction is stopped with the addition of 25 mM EDTA. The solutions are then transferred to White BioBind Streptavidin Coated Assay plates, purchased from Thermo Electron Corporation. After washing, Microscint 20 scintillation fluid, purchased from Perkin Elmer, is added to each well and counts per minute (cpm) is measured using a Packard TopCount Microscintillation Counter. The highest cpms measured indicates the maximum phosphorylation of the substrate possible under the assay conditions. Reactions run without enzyme present give cpms indicative of complete inhibition of the enzyme. Each concentration of compound produces a measurable percent inhibition from the maximum signal based on these values.
Assays were carried out in 50 mM Tris-HCl pH7.5, 10 mM MgCl2, 1 mM DTT, 1 mM EGTA, 25 mM β-glycerol phosphate, 1 mM NaF, 0.01% BSA/PBS, 0.5 uM peptide substrate, and 5 nM Cdkl.
Procedure: Distribute 100 uL of Reaction Buffer containing 50 mM Tris-HCl pH7.5, 10 mM MgCl2, 0.01% BSA/PBS, 1.5 mM DTT, 1.5 mM EGTA, 37.5 mM β-glycerol phosphate, 1.5 mM NaF, 0.75 uM peptide substrate, and 7.5 nM Cdk2 to each well. 100% inhibition control wells contain no Cdk2. Add compounds to wells in desired 1OX concentrations with 10% DMSO, 50 mM Tris-HCl pH7.5, 10 mM MgCl2, and 0.01% BSA/PBS. Start reactions by adding 15 uL of ATP concentrated at 10 uM, with P33 γ-ATP at < 10 nM as label. Run reactions for four hours at room temperature with shaking. Streptavidin coated plates are blocked for one hour with 1% BSA in PBS. 100 uL 50 mM EDTA is added to each streptavidin well. 100 uL of each assay solution are transferred to corresponding streptavidin wells containing EDTA. Capture of radiolabeled substrate then takes place by shaking at room temperature for one hour. After binding the wells are washed 4 times with PBS, 200 uL Microscint 20 is added to each well, and cpms are measured. The assay is run in a 96-well format. PP028218.0002
Results: Many of the compounds listed in Tables 1-5 were screened according to the method above, and exhibited an IC50 value of less than or equal to 25 μM, with respect to inhibition of Cdk2. Additionally, many of the compounds exhibited an IC50 of less than 10 μM, or less than 1 μM, or less than 0.1 μM. Accordingly, each of the compounds is preferred individually, and/or as a member of a group that includes the compounds of Formula I, Formula II or Formula III.
IV. Cell Proliferation Assay Protocol: A2780, PC-3, or PC3MM cells were seeded at 1000 cells/well in 100 μL/well (10.000 cells/mL) growth media in 96-well plates. Cells were allowed to adhere to the bottom of plates for 3-5 hours in a 37 0C 5% CO2 incubator. Compounds were dissolved in DMSO and then transferred to the cell plates. The cells were incubated with the compounds for 3 days in a 37 0C 5% CO2 incubator. The growth medium containing the compounds was then removed from the cells and fresh medium was added, followed by 100 μL of Cell Titer GIo assay reagent (Promega). This mixture was shaken for 1 minute and then incubated without shaking for 10 minutes. Activity determinations for the compounds were made by detection on a Trilux Instrument. Results: Many of the compounds listed in Tables 1-5 were screened according to the method above, and exhibited an EC50 value of less than or equal to 10 μM, with respect to inhibition of cell proliferation. Additionally, many of the compounds exhibited an IC50 of less than 5 μM, or less than 1 μM, or less than 0.1 μM.
V. Cell Proliferation Assay Protocol: PC-3 Cell Line PC-3 cells were seeded at 1000 cells/well in 100 μL/well (10.000 cells/mL) along with growth media into black-walled, clear bottom 96-well plates. The cells were allowed to adhere to the bottom of the plate for 3-5 hours in a 37 0C 5% CO2 incubator.
Test compounds were diluted to 50Ox in DMSO. The DMSO solutions of six of the compounds were transferred to the cells in the 96 well round bottom plate, column 2, row B-F. A 1 :3 serial dilution of each compound was carried out. The serial dilution comprised adding 20 μL of DMSO to the wells containing the compounds and doing a 1:3 dilution across the plate PP028218.0002
from columns 2-10. Column 11 contained only DMSO. The serial dilution was carried out using a BioMek 2000 protocol "CP Serial Dilution using 250 μL tips" or "Proliferation Compound" (if using 20 μL tips).
To a 96 deep well block, columns 2-11 rows B-F, was transferred 500 μL of growth medium. Using the FX protocol "HH_CellAssay_2μL to 500 μL", 2 μL of compound from each cell of the compound plate was transferred to the corresponding cell in the 96 deep well block containing 500 μL of growth medium. The instrument was programmed to dilute the compound in growth medium and then transfer 100 μL of that mixture to cell plates containing cells. The cell plates, to which test compounds had been added, were incubated for 3 days at 37 0C. Following the incubation, the medium was removed and replaced with fresh medium. Cell Titer GIo (100 μL) was added to each well and the plate was shaken for 1 minute and then incubated without shaking for 10 minutes. The plates were then read using a Trilux instrument.
VI. The pAktT308 ECL Assay Protocol On Day 1, PC-3 cells were seeded at 15,000 cells/well in 100 μL/well (10.000 cells/mL) growth media into black-walled, clear bottom, poly-L-lysine coated plates. The cells were incubated overnight in a 37 0C, 5% CO2 incubator.
On Day 2, a MSD ECL plate was blocked for two hours with 150 μL per well of 3%
MSD blocker A. Test compounds were diluted to 50Ox in DMSO and then were subjected to further serial dilution using a BioMek 2000 instrument. DMSO diluted compounds were then diluted into growth media and then added to the cell plates.
The cell plates incubated with compounds for six hours in a 37 0C, 5% CO2 incubator after which the growth medium was removed and 55 μl of MSD lysis buffer was added to cell plates on ice. The plates were lysed on ice for five minutes followed by 15 minutes of vigorous shaking on a plate shaker at 40C. The blocked MSD assay plates were washed twice with Ix
MSD wash buffer followed by the addition of cell lysate as follows: 30 μl of cell lysate was added to the pAkt308 plates and 13 μl of lysate + 12 μl lysis buffer was added to the tAkt plates.
The plates were then sealed and shaken at 4 0C overnight. PP028218.0002
On Day 3, the MSD plates were washed four times with Ix MSD wash buffer then, 25 μl/well of MSD SULFO-TAG antibodies diluted to 1OnM final concentration in 1% blocker. A buffer was added to the antibody diluent which was added to assay plates. The plates were then sealed and incubated at RT for 1.5 hour. The plates were then washed twice with Ix MSD wash buffer followed by the addition of 150μl/well of 1.5x MSD read buffer. The plates were read immediately after the addition of read buffer using a Trilux instrument.
Many of tested compounds demonstrated IC50 values of less than 5 μM, as shown in Table 1. Some of them even had IC50 values as low as less than 5 μM.
The contents of each of the patents, patent applications and journal articles cited above are hereby incorporated by reference herein and for all purposes as if fully set forth in their entireties.

Claims

What is claimed is:
1. A compound of Formula I:
Figure imgf000384_0001
wherein: one of W1 or W2 is R1 and the other is -L-A1;
L is a covalent bond, carbonyl, carbonylammo, aminocarbonyl, -O-, -S-, -SO-, -SO2-, -NH-, Ci-3 alkyl, substituted C1-3 alkyl, or an alkyl interrupted with -O-, -S-, -SO-, -SO2-, - NH-, carbonyl, carbonylamino, or aminocarbonyl;
A1 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;
Y is H, Cu alkyl, halo, cyano, nitro, or amino;
R1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,. alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfbnyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclyloxy, and substituted heterocyclyloxy;
R2 and R3 are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylainino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkyltihio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and
R4 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl, provided when R4 is heteroaryl or substituted heteroaryl, W2 is not aryl or heteroaryl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
2. A compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R4 is substituted phenyl.
3. A compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R4 is phenyl substituted with a group of formula -X^N(RsO1)(RsOa); wherein X1 is a covalent bond, SO2, or C(=O); and Rsoi and R502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R501 and R502, taken together with the nitrogen atom to which they are attached, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C1.3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.
4. A compound of claim 3, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein -N(R5oi)(R5O2) forms -NH2, -NH-CH(CH3)2, -NH-(CEb)2-O-CH3, -NH- cyclopropyl, morpholin-4-yl, 4-methyl-piperizine-l-yl, or -NH-(CH2)2-pyrrolidin-l-yl.
5. A compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein -L-A1 is a heterocyclyloxy group having the structure:
Figure imgf000385_0001
wherein, X is O or NR6;
R5a and R5b are each independently H, halo, hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, or substituted amino;
R6 is H, acyl, substituted carbonyl, sulfonyl, alkyl, or substituted alkyl; or R5a and R6 are taken together to form a bridging alkylene moiety; or RSa and R5b are taken together to form a bridging alkylene moiety; m and n are independently 0, 1 or 2.
6. A compound of claim 5, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein W1 is R1 and W2 is -L-A1.
7. A compound of claim 6, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R4 is phenyl substituted with a group of formula -X^N(RSOI)(RSO2); wherein X1 is a covalent bond, SO2, or C(=O); and R501 and R502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R501 and R502, taken together with the nitrogen atom to which they are attached, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C1-3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.
8. A compound of claim 7, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein -N(R50 i)(R»a) forms -NH2, -NH-CH(CH3)2, -NH-(CH2)2-O-CH3, -NH- cyclopropyl, morpholin-4-yl, 4-methyl-piperizine-l-yl, or -NH-(CH2)2-pyrrolidin-l-yl.
9. A compound of claim 8, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2 is heteroaryl or substituted heteroaryl.
10. A compound of claim 5, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein W1 is -L-A1 and W2 is R1.
11. A compound of claim 10, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R4 is phenyl substituted with a group of formula
Figure imgf000386_0001
wherein X1 is a covalent bond, SO2, or C(=O); and Rsoi and Rso2 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or Rs01 and Rso2, taken together with the nitrogen atom to which they are attached, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C1-3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.
12. A compound of claim 11 , a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein -N(R5Oi)(IW forms -NH2, -NH-CH(CH3)2, -NH-(CHa)2-O-CH3, -NH- cyclopropyl, morpholin-4-yl, 4-methyI-piperizine-l-yl, or -NH-(CH2)2-pyrrolidin-l-yl.
13. A compound of claim 12, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2 is heteroaryl or substituted heteroaryl.
14. A compound of claim 5, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is H, halogen, cyano; or phenyl optionally substituted with-C(=O) -N(R501)(R502); or a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms independently selected from O, S and N, that is optionally substituted with up to three substituents selected from alkyl, alkoxy and -N(RS0I)(R502); or a group of formula:
Figure imgf000387_0001
wherein each R501 and each R502 is independently selected from H, alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl.
15. A compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein W1 is heteroaryl or substituted heteroaryl.
16. A compound of claim 1 , a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein W2 is heteroaryl or substituted heteroaryl.
17. A compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2 is heteroaryl or substituted heteroaryl.
18. A compound of Formula I:
Figure imgf000388_0001
wherein: one of W1 or W2 is R1 and the other is -L-A1 ;
L is a covalent bond, carbonyl, carbonylamino, aminocarbonyl, -O-, -S-, -SO-, -SO2-, -NH-, Ci -3 alkyl, substituted C 1.3 alkyl, or an alkyl interrupted with -O-, -S-, -SO-, -SO2-, - NH-, carbonyl, carbonylamino, or aminocarbonyl;
A1 is hydroxyl, amino, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cyclyl, or substituted cyclyl, heterocyclyl, or substituted heterocyclyl, provided when W2 is hydroxyl or methoxy, A1 is not isopropyl or cyclopentyl;
Y is H, Ci -3 alkyl, halo, cyano, nitro, or amino;
R1 is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, cycloalkyloxy, substituted cycloalkyloxy, heterocyclyloxy, and substituted heterocyclyloxy;
R and R are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, halo, hydroxy, nitro, SO3H, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; and R4 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
19. A compound of claim 18, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein A1 is alkyl or substituted alkyl.
20. A compound of claim 18, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein A1 is hydroxyl or amino.
21. A compound of claim 18, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R4 is phenyl or substituted phenyl.
22. A compound of claim 21 , a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R4 is phenyl substituted with a group of formula -X1 -N(RsOi)(Rs(E); wherein X1 is a covalent bond, SO2, or C(=O); and RsO1 and R502 are independently selected from H, alkyl, substituted alkyl, alkoxyalkyl, cycloalkyl and heterocyclylalkyl; or R501 and Rso∑, taken together with the nitrogen atom to which they are attached, form a heterocyclyl group that is optionally substituted with up to three groups independently selected from C 1.3 alkyl, hydroxyl, halo, alkoxy, amino, and substituted amino.
23. A compound of claim 22, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein -N(R5Oi)(RsO2) forms -NH2, -NH-CH(CH3)2, -NH-(CH2)2-O-CH3, -NH- cyclopropyl, morpholin-4-yl, 4-methyl-piperizine-l-yl, or -NH-(CH2)2-pyrrolidin-l-yl.
24. A compound of claim 21, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein A1 is alkyl or substituted alkyl.
25. A compound of claim 21 , a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein A1 is hydroxyl or amino.
26. A compound of claim 18, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein one of R2 and R3 is heteroaryl or substituted heteroaryl.
27. A method of inhibiting PDKl comprising administering to a human or animal subject, a compound of any one of the previous claims.
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