Claims for Patent: 8,586,605

Summary for Patent: 8,586,605

Title:	Fused amino pyridine as HSP90 inhibitors
Abstract:	The present invention relates to HSP90 inhibitors containing fused amino pyridine core that are useful as inhibitors of HSP90 and their use in the treatment of HSP90 related diseases and disorders such as cancer, an autoimmune disease, or a neurodegenerative disease.
Inventor(s):	Cai; Xiong (Bedford, MA), Qian; Changgeng (Wayland, MA), Zhai; Haixiao (Bedford, MA)
Assignee:	Curis, Inc. (Lexington, MA)
Application Number:	13/424,780
Patent Claims:	1. A combination therapy comprising the administration of a compound represented by Formula I: ##STR00141## or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof, wherein U is N; W is hydrogen, halogen, amino, hydroxy, thiol, alkyl, substituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF.sub.3, NO.sub.2, CN, N.sub.3, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; X is O, S, S(O), S(O).sub.2, N(R.sub.8), or C(O); Y is independently hydrogen, halogen, NO.sub.2, CN, or lower alkyl; Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; Q is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or heterocycloalkyl; V is hydrogen, straight- or branched-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; wherein R.sub.8 is hydrogen, acyl, aliphatic or substituted aliphatic; and, a second compound that can modulate one or more protein kinases, histone deacetylase (HDAC), DNA methyltransferase (DNMT), heat shock proteins or proteasomes to a subject in need thereof. 2. The combination therapy according to claim 1, wherein said compound of Formula I is selected from: ##STR00142## or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof, wherein X.sub.2 and X.sub.5 are independently CH or N; R.sub.21-R.sub.23 are independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxyl, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF.sub.3, NO.sub.2, CN, N.sub.3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; R.sub.22 and R.sub.23 can be taken together from the carbon to which they are attached to form a saturated or unsaturated fused 5-8 membered cyclic ring optionally substituted with 0-3 heteroatom; M.sub.1 is absent, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl or heteroaryl; M.sub.2 is absent, O, S, SO, SO.sub.2, N(R.sub.8), or C.dbd.O; M.sub.3 is absent, C.dbd.O, O, S, SO, SO.sub.2 or N(R.sub.8); M.sub.4 is hydrogen, halogen, CN, N.sub.3, hydroxy, substituted hydroxy, amino, substituted amino, CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; X is O, S, S(O), S(O).sub.2, N(R.sub.8), or C(O); Y is independently hydrogen, halogen, NO.sub.2, CN, or lower alkyl; Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; and, R.sub.8 is hydrogen, acyl, aliphatic or substituted aliphatic. 3. The combination therapy according to claim 1, wherein said compound of Formula I is selected from: ##STR00143## or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, and solvates thereof, wherein X.sub.1-X.sub.5 are independently N or CR.sub.21; where R.sub.21 is independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF.sub.3, NO.sub.2, CN, N.sub.3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; M.sub.1 is absent, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl or heteroaryl; M.sub.2 is absent, O, S, SO, SO.sub.2, N(R.sub.8), or C.dbd.O; M.sub.3 is absent, C.dbd.O, O, S, SO, SO.sub.2 or N(R.sub.8); M.sub.4 is hydrogen, halogen, CN, N.sub.3, hydroxy, substituted hydroxy, amino, substituted amino, CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; X is O, S, S(O), S(O).sub.2, N(R.sub.8), or C(O); Y is independently hydrogen, halogen, NO.sub.2, CN, or lower alkyl; Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; and, R.sub.8 is hydrogen, acyl, aliphatic or substituted aliphatic. 4. The combination therapy according to claim 1, wherein said compound of Formula I is selected from: ##STR00144## or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof, wherein X.sub.2 and X.sub.5 are independently CH or N; R.sub.21 is independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF.sub.3, NO.sub.2, CN, N.sub.3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; Cy is a saturated or unsaturated fused 5-8 membered cyclic ring optionally substituted with 0-3 heteroatom; M.sub.1 is absent, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl or heteroaryl; M.sub.2 is absent, O, S, SO, SO.sub.2, N(R.sub.8), or C.dbd.O; M.sub.3 is absent, C.dbd.O, O, S, SO, SO.sub.2 or N(R.sub.8); M.sub.4 is hydrogen, halogen, CN, N.sub.3, hydroxy, substituted hydroxy, amino, substituted amino, CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; X is O, S, S(O), S(O).sub.2, N(R.sub.8), or C(O); Y is independently hydrogen, halogen, NO.sub.2, CN, or lower alkyl; Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; and, R.sub.8 is hydrogen, acyl, aliphatic or substituted aliphatic. 5. The combination therapy according to claim 1, wherein said compound of Formula I is selected from: ##STR00145## or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof, wherein X.sub.2 and X.sub.5 are independently CH or N; R.sub.21 is independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF.sub.3, NO.sub.2, CN, N.sub.3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; Y.sub.1 and Y.sub.3 are independently O, S, N(R.sub.8), CH(R.sub.21); n is 1, 2, or 3; M.sub.1 is absent, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl or heteroaryl; M.sub.2 is absent, O, S, SO, SO.sub.2, N(R.sub.8), or C.dbd.O; M.sub.3 is absent, C.dbd.O, O, S, SO, SO.sub.2 or N(R.sub.8); M.sub.4 is hydrogen, halogen, CN, N.sub.3, hydroxy, substituted hydroxy, amino, substituted amino, CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; R.sub.10 and R.sub.20 are independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; X is O, S, S(O), S(O).sub.2, N(R.sub.8), or C(O); Y is independently hydrogen, halogen, NO.sub.2, CN, or lower alkyl; Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; and, R.sub.8 is hydrogen, acyl, aliphatic or substituted aliphatic. 6. The combination therapy according to claim 1, wherein said compound of Formula I is selected from: TABLE-US-00003 TABLE A Com- pound # Structure 1 ##STR00146## 2 ##STR00147## 3 ##STR00148## 4 ##STR00149## 5 ##STR00150## 6 ##STR00151## 7 ##STR00152## 8 ##STR00153## 9 ##STR00154## 10 ##STR00155## 11 ##STR00156## 12 ##STR00157## 13 ##STR00158## 14 ##STR00159## 15 ##STR00160## 16 ##STR00161## 17 ##STR00162## 18 ##STR00163## 19 ##STR00164## 20 ##STR00165## 21 ##STR00166## 22 ##STR00167## 23 ##STR00168## 24 ##STR00169## 25 ##STR00170## 26 ##STR00171## 27 ##STR00172## 28 ##STR00173## 29 ##STR00174## 30 ##STR00175## 31 ##STR00176## 32 ##STR00177## 33 ##STR00178## 34 ##STR00179## 35 ##STR00180## 36 ##STR00181## 37 ##STR00182## 38 ##STR00183## 39 ##STR00184## 40 ##STR00185## 41 ##STR00186## 42 ##STR00187## 43 ##STR00188## 44 ##STR00189## 45 ##STR00190## 46 ##STR00191## 47 ##STR00192## 48 ##STR00193## 49 ##STR00194## 50 ##STR00195## 51 ##STR00196## 52 ##STR00197## 53 ##STR00198## 54 ##STR00199## 55 ##STR00200## 56 ##STR00201## 57 ##STR00202## 58 ##STR00203## 59 ##STR00204## 60 ##STR00205## 61 ##STR00206## 62 ##STR00207## 63 ##STR00208## 64 ##STR00209## 65 ##STR00210## 66 ##STR00211## 67 ##STR00212## 68 ##STR00213## 69 ##STR00214## 70 ##STR00215## 71 ##STR00216## 72 ##STR00217## 73 ##STR00218## 74 ##STR00219## 75 ##STR00220## 76 ##STR00221## 77 ##STR00222## 78 ##STR00223## 79 ##STR00224## 80 ##STR00225## 81 ##STR00226## 82 ##STR00227## 83 ##STR00228## 84 ##STR00229## 85 ##STR00230## 86 ##STR00231## 87 ##STR00232## 88 ##STR00233## 89 ##STR00234## 90 ##STR00235## 91 ##STR00236## 92 ##STR00237## 93 ##STR00238## 94 ##STR00239## 95 ##STR00240## 96 ##STR00241## 97 ##STR00242## 98 ##STR00243## 99 ##STR00244## 100 ##STR00245## 101 ##STR00246## 102 ##STR00247## 103 ##STR00248## 104 ##STR00249## 105 ##STR00250## 106 ##STR00251## 107 ##STR00252## 108 ##STR00253## 109 ##STR00254## 110 ##STR00255## 111 ##STR00256## 112 ##STR00257## 113 ##STR00258## 114 ##STR00259## 115 ##STR00260## 116 ##STR00261## 117 ##STR00262## 118 ##STR00263## 119 ##STR00264## 120 ##STR00265## 121 ##STR00266## 123 ##STR00267## 124 ##STR00268## 125 ##STR00269## 126 ##STR00270## 127 ##STR00271## 7. The combination therapy according to claim 1, wherein said protein kinase is a serine/threonine specific kinase, receptor tyrosine specific kinase or a non-receptor tyrosine specific kinase. 8. The combination therapy according to claim 7, wherein said serine/threonine kinase is selected from mitogen activated protein kinases (MAPK), meiosis specific kinase (MEK), RAF and aurora kinase. 9. The combination therapy according to claim 8, wherein said kinase is an epidermal growth factor receptor (EGFR), fibroblast growth factor (FGF) receptor, hepatocyte growth/scatter factor receptor, insulin receptor, Eph, platelet-derived growth factor receptor (PDGFR), BCR-ABL, BTK , CSK, FAK, FPS, JAK, SRC, BMX, FER, CDK or SYK. 10. A combination therapy comprising a compound represented by Formula I: ##STR00272## or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof, wherein U is N; W is hydrogen, halogen, amino, hydroxy, thiol, alkyl, substituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF.sub.3, NO.sub.2, CN, N.sub.3, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; X is O, S, S(O), S(O).sub.2, N(R.sub.8), or C(O); Y is independently hydrogen, halogen, NO.sub.2, CN, or lower alkyl; Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; Q is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or heterocycloalkyl; V is hydrogen, straight- or branched-, substituted or unsubstituted alkyl, Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; wherein R.sub.8 is hydrogen, acyl, aliphatic or substituted aliphatic; and, an antineoplastic agent or a chemoprotective agent. 11. The combination therapy according to claim 10, wherein said compound of Formula I is selected from: ##STR00273## or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof, wherein X.sub.2 and X.sub.5 are independently CH or N; R.sub.21-R.sub.23 are independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxyl, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF.sub.3, NO.sub.2, CN, N.sub.3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; R.sub.22 and R.sub.23 can be taken together from the carbon to which they are attached to form a saturated or unsaturated fused 5-8 membered cyclic ring optionally substituted with 0-3 heteroatom; M.sub.1 is absent, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl or heteroaryl; M.sub.2 is absent, O, S, SO, SO.sub.2, N(R.sub.8), or C.dbd.O; M.sub.3 is absent, C.dbd.O, O, S, SO, SO.sub.2 or N(R.sub.8); M.sub.4 is hydrogen, halogen, CN, N.sub.3, hydroxy, substituted hydroxy, amino, substituted amino, CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; X is O, S, S(O), S(O).sub.2, N(R.sub.8), or C(O); Y is independently hydrogen, halogen, NO.sub.2, CN, or lower alkyl; Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; and, R.sub.8 is hydrogen, acyl, aliphatic or substituted aliphatic. 12. The combination therapy according to claim 10, wherein said compound of Formula I is selected from: ##STR00274## or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, and solvates thereof, wherein X.sub.1-X.sub.5 are independently N or CR.sub.21, where R.sub.21 is independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF.sub.3, NO.sub.2, CN, N.sub.3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; M.sub.1 is absent, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl or heteroaryl; M.sub.2 is absent, O, S, SO, SO.sub.2, N(R.sub.8), or C.dbd.O; M.sub.3 is absent, C.dbd.O, O, S, SO, SO.sub.2 or N(R.sub.8); M.sub.4 is hydrogen, halogen, CN, N.sub.3, hydroxy, substituted hydroxy, amino, substituted amino, CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; X is O, S, S(O), S(O).sub.2, N(R.sub.8), or C(O); Y is independently hydrogen, halogen, NO.sub.2, CN, or lower alkyl; Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; and, R.sub.8 is hydrogen, acyl, aliphatic or substituted aliphatic. 13. The combination therapy according to claim 10, wherein said compound of Formula I is selected from: ##STR00275## or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof, wherein X.sub.2 and X.sub.5 are independently CH or N; R.sub.21 is independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF.sub.3, NO.sub.2, CN, N.sub.3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; Cy is a saturated or unsaturated fused 5-8 membered cyclic ring optionally substituted with 0-3 heteroatom; M.sub.1 is absent, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl or heteroaryl; M.sub.2 is absent, O, S, SO, SO.sub.2, N(R.sub.8), or C.dbd.O; M.sub.3 is absent, C.dbd.O, O, S, SO, SO.sub.2 or N(R.sub.8); M.sub.4 is hydrogen, halogen, CN, N.sub.3, hydroxy, substituted hydroxy, amino, substituted amino, CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; X is O, S, S(O), S(O).sub.2, N(R.sub.8), or C(O); Y is independently hydrogen, halogen, NO.sub.2, CN, or lower alkyl; Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; and, R.sub.8 is hydrogen, acyl, aliphatic or substituted aliphatic. 14. The combination therapy according to claim 10, wherein said compound of Formula I is selected from: ##STR00276## or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof, wherein X.sub.2 and X.sub.5 are independently CH or N; R.sub.21 is independently selected from the group consisting of hydrogen, halogen, amino, substituted amino, hydroxy, substituted hydroxy, thiol, substituted thiol, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF.sub.3, NO.sub.2, CN, N.sub.3, substituted carbonyl, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; Y.sub.1 and Y.sub.3 are independently O, S, N(R.sub.8), CH(R.sub.21); n is 1, 2, or 3; M.sub.1 is absent, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, aryl or heteroaryl; M.sub.2 is absent, O, S, SO, SO.sub.2, N(R.sub.8), or C.dbd.O; M.sub.3 is absent, C.dbd.O, O, S, SO, SO.sub.2 or N(R.sub.8); M.sub.4 is hydrogen, halogen, CN, N.sub.3, hydroxy, substituted hydroxy, amino, substituted amino, CF.sub.3, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; R.sub.10 and R.sub.20 are independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; X is O, S, S(O), S(O).sub.2, N(R.sub.8), or C(O); Y is independently hydrogen, halogen, NO.sub.2, CN, or lower alkyl; Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; and, R.sub.8 is hydrogen, acyl, aliphatic or substituted aliphatic. 15. The combination therapy according to claim 1, wherein said compound of Formula I is selected from: TABLE-US-00004 TABLE A Compound # Structure 1 ##STR00277## 2 ##STR00278## 3 ##STR00279## 4 ##STR00280## 5 ##STR00281## 6 ##STR00282## 7 ##STR00283## 8 ##STR00284## 9 ##STR00285## 10 ##STR00286## 11 ##STR00287## 12 ##STR00288## 13 ##STR00289## 14 ##STR00290## 15 ##STR00291## 16 ##STR00292## 17 ##STR00293## 18 ##STR00294## 19 ##STR00295## 20 ##STR00296## 21 ##STR00297## 22 ##STR00298## 23 ##STR00299## 24 ##STR00300## 25 ##STR00301## 26 ##STR00302## 27 ##STR00303## 28 ##STR00304## 29 ##STR00305## 30 ##STR00306## 31 ##STR00307## 32 ##STR00308## 33 ##STR00309## 34 ##STR00310## 35 ##STR00311## 36 ##STR00312## 37 ##STR00313## 38 ##STR00314## 39 ##STR00315## 40 ##STR00316## 41 ##STR00317## 42 ##STR00318## 43 ##STR00319## 44 ##STR00320## 45 ##STR00321## 46 ##STR00322## 47 ##STR00323## 48 ##STR00324## 49 ##STR00325## 50 ##STR00326## 51 ##STR00327## 52 ##STR00328## 53 ##STR00329## 54 ##STR00330## 55 ##STR00331## 56 ##STR00332## 57 ##STR00333## 58 ##STR00334## 59 ##STR00335## 60 ##STR00336## 61 ##STR00337## 62 ##STR00338## 63 ##STR00339## 64 ##STR00340## 65 ##STR00341## 66 ##STR00342## 67 ##STR00343## 68 ##STR00344## 69 ##STR00345## 70 ##STR00346## 71 ##STR00347## 72 ##STR00348## 73 ##STR00349## 74 ##STR00350## 75 ##STR00351## 76 ##STR00352## 77 ##STR00353## 78 ##STR00354## 79 ##STR00355## 80 ##STR00356## 81 ##STR00357## 82 ##STR00358## 83 ##STR00359## 84 ##STR00360## 85 ##STR00361## 86 ##STR00362## 87 ##STR00363## 88 ##STR00364## 89 ##STR00365## 90 ##STR00366## 91 ##STR00367## 92 ##STR00368## 93 ##STR00369## 94 ##STR00370## 95 ##STR00371## 96 ##STR00372## 97 ##STR00373## 98 ##STR00374## 99 ##STR00375## 100 ##STR00376## 101 ##STR00377## 102 ##STR00378## 103 ##STR00379## 104 ##STR00380## 105 ##STR00381## 106 ##STR00382## 107 ##STR00383## 108 ##STR00384## 109 ##STR00385## 110 ##STR00386## 111 ##STR00387## 112 ##STR00388## 113 ##STR00389## 114 ##STR00390## 115 ##STR00391## 116 ##STR00392## 117 ##STR00393## 118 ##STR00394## 119 ##STR00395## 120 ##STR00396## 121 ##STR00397## 123 ##STR00398## 124 ##STR00399## 125 ##STR00400## 126 ##STR00401## 127 ##STR00402## 16. The combination therapy according to claim 10, wherein said antineoplastic or chemoprotective agent is selected from Zolinza, Tarceva, Iressa, Tykerb, Gleevec, Sutent, Sprycel, Nexavar, Sorafinib, CNF2024, RG108, BMS387032, Affinitak, Avastin, Herceptin, Erbitux, AG24322, PD325901, ZD6474, PD184322, Obatodax, ABT737 and AEE788. 17. The combination therapy according to claim 10, wherein said antineoplastic agent or chemoprotective agent is selected from mechlorethamine, cylophosphamide, chlorambucil, melphalan, ifosfamide, ethylenimines, alkylsulfonates, hydrazines, triazines, nitrosoureas, ifosfamide, metal salts, alkaloids, taxanes, vinca alkaloids, camptothecan analogs, anti-tumor antibiotics, chromomycins, anthracyclines, pyrimidine antagonists, purine antagonists, adenosine deaminase inhibitors, topoisomerase inhibitors, topoisomerase II inhibitors, monoclonal antibodies, ribonucleotide reductase inhibitors, adrenocortical steroid inhibitor, and anti-microtubule agents. 18. The combination therapy according to claim 1, wherein said second compound is a compound that can modulate histone deacetylase. 19. The combination therapy according to claim 1, wherein said second compound is a compound that can modulate proteosomes. 20. The combination therapy according to claim 1, wherein said protein kinase is selected from EGFR, HER2/neu, HER3, HER4, ErB, ErB2, ErbB3, ErbB4, Xmrk, DER, Let23, FGF, FGF-R1,GFF-R2/BEK/CEK3, FGF-R3/ CEK2, FGF-R4/TKF, KGF-R, HGFR MET, RON, SEA, SEX, Axl, Mer/Nyk, Rse, RET, PDGFR, PDGF.beta.-R, PDG.DELTA.-R, CSF1-R/FMS, SCF-R/C-KIT, VEGF-R/FLT, NEK/FLK1, FLT3/FLK2/STK-1, BTK, ITK/EMT, TEC, FAK, JAK, SRC and SYK. 21. The combination therapy according to claim 1, wherein said compound of Formula I is: ##STR00403## or its pharmaceutically acceptable salts or solvate thereof. 22. The combination therapy according to claim 1, wherein said compound of Formula I is: ##STR00404## or its pharmaceutically acceptable salts or solvate thereof. 23. The combination therapy according to claim 10, wherein said compound of Formula I is: ##STR00405## or its pharmaceutically acceptable salts or solvate thereof. 24. The combination therapy according to claim 10, wherein said compound of Formula I is: ##STR00406## or its pharmaceutically acceptable salts or solvate thereof. 25. A combination therapy comprising the administration of a compound represented by Formula I: ##STR00407## or its geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof to a subject in need thereof, wherein U is N; W is hydrogen, halogen, amino, hydroxy, thiol, alkyl, substituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF.sub.3, NO.sub.2, CN, N.sub.3, sulfonyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, or substituted cycloalkyl; X is O, S, S(O), S(O).sub.2, N(R.sub.8), or C(O); Y is independently hydrogen, halogen, NO.sub.2, CN, or lower alkyl; Z is amino, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylcarbonylamino; Q is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or heterocycloalkyl; V is hydrogen, straight- or branched-, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; wherein R.sub.8 is hydrogen, acyl, aliphatic or substituted aliphatic; in combination with a non-drug therapy wherein said non-drug therapy is radiation treatment.

Details for Patent 8,586,605

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2027-03-20
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2027-03-20
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2027-03-20
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2027-03-20
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2027-03-20