Claims
- 1. A compound of formula (I):
- 2. The compound of claim 1, wherein Ar1 is selected from one of the following groups:
- 3. The compound of claim 2, wherein Ar1 is selected from phenyl, pyridyl, or pyrimidinyl
- 4. The compound of claim 1, wherein R1 is hydrogen, Ar1 is phenyl (a), and compounds have the formula I-A and I-A′:
- 5. The compound of claim 1, wherein R2 is -(T)nCy1 and Cy1 is selected from one of the following groups:
- 6. The compound of claim 5, wherein Cy1 is selected from one of the following groups:
- 7. The compound of claim 1, wherein R1 is hydrogen, Cy1 is cyclohexyl (v), tetrahydrofuranyl (ee), or cyclopropyl (ff), and compounds have one of the following formulas I-B, I-C, I-D, I-B′, I-C′, or I-D′:
- 8. The compound of claim 1, wherein R1 is hydrogen or C1-4alkyl.
- 9. The compound of claim 1, wherein R1 is hydrogen.
- 10. The compound of claim 1, wherein T groups, when present, include CH2 and —CH2CH2—.
- 11. The compound of claim 1, wherein n is 0 and T is absent.
- 12. The compound of claim 1, wherein x is 0-3, or x is 0 and Ar1 or Cy1 are unsubstituted.
- 13. The compound of claim 1, wherein QRX groups are each independently R′, halogen, CN, NO2—N(R′)2, —CH2N(R′)2, —OR′, —CH2OR′, —SR′, —CH2SR′, —COOR′, —NRCOR′, —CON(R′)2, —SO2N(R′)2, —CONR(CH2)2N(R′)2, —CONR(CH2)3N(R′)2, —CONR(CH2)4N(R′)2, —O(CH2)2OR′, O(CH2)3OR′, O(CH2)4OR′, —O(CH2)2N(R′)2, —O(CH2)3N(R′)2, or —O(CH2)4N(R′)2.
- 14. The compound of claim 1, wherein QRX groups are each independently Cl, Br, F, CF3, Me, Et, CN, —COOH, —N(CH3)2, —N(Et)2, —N(iPr)2, —O(CH2)2OCH3, —CONH2, —COOCH3, —OH, —CH2OH, —NHCOCH3, —SO2NH2, —O(CH2)2N-morpholino, —O(CH2)3N-morpholino, —O(CH2)4N-morpholino, —O(CH2)2N-piperazinyl, O(CH2)3N-piperizinyl, O(CH2)4N-piperizinyl, —NHCH(CH2OH)phenyl, —CONH(CH2)2N-morpholino, —CONH(CH2)2N-piperazinyl, —CONH(CH2)3N-morpholino, —CONH(CH2)3N-piperazinyl, —CONH(CH2)4N-morpholino, —CONH(CH2)4N-piperazinyl, —SO2NH(CH2)2N-morpholino, —SO2NH(CH2)2N-piperazinyl, —SO2NH(CH2)3N-morpholino, —SO2NH(CH2)3N-piperazinyl, —SO2NH(CH2)4N-morpholino, —SO2NH(CH2)4N-piperazinyl, methylenedioxy, ethylenedioxy, piperidinyl, piperizinyl, morpholino, or an optionally substituted group selected from C1-4alkoxy, phenyl, phenyloxy, benzyl, or benzyloxy
- 15. The compound of claim 1, wherein R4 and R5 are each hydrogen and compounds have the general formula II or II′
- 16. The compound of claim 15, wherein R1 is hydrogen, Ar1 is optionally substituted phenyl, and R3 is -(L)mAr2 or (L)mCy2, and compounds have the formula II-A-(i), II-A-(ii), II-A-(i)′ or II-A-(ii)′:
- 17. The compound of claim 15, wherein R1 is hydrogen, Cy1 is optionally substituted cyclohexyl, tetrahydrofuranyl, or cyclopropyl, and R3 is -(L)mAr2 or (L)mCy2, and compounds have the formula II-B-(i), II-B-(ii), II-C-(i), II-C-(ii), II-D-(i), II-D-(ii)′, II-B-(i)′, II-B-(ii)′, II-C-(i)′, II-C-(ii)′, II-D-(i)′ or II-D-(ii)′:
- 18. The compound of claim 16 or 17, wherein R3 is -(L)mAr2 and Ar2 is selected from one of the following groups:
- 19. The compound of claim 16 or 17, wherein Ar2 is selected from one of the following groups:
- 20. The compound of claim 16 or 17, wherein R3 is -(L)mCy2, and Cy2 is selected from one of the following groups:
- 21. The compound of claim 16 or 17, wherein Cy2 is selected from one of the following groups i-b or viii-b:
- 22. The compound of claim 15, wherein Ar2 is optionally substituted phenyl, 2-pyridyl, 2-thiazolyl, 2-pyrimidinyl, 6-pyrimidinyl, 4-pyridyl, benzothiazolyl, or 2-quinolinyl, and compounds have one of the structures II-E-(i), II-E-(ii), II-F-(i), II-F-(ii), II-G-(i), II-G-(ii), II-G′-(i), II-G′-(ii), II-H-(i), II-H-(ii), II-I-(i), II-I-(ii), II-I′-(i), II-I′-(ii), II-J-(i), or II-J-(ii), II-E-(i)′, II-E-(ii)′, II-F-(i)′, II-F-(ii)′, II-G-(i)′, II-G-(ii)′, II-G′-(i)′, II-G′-(ii)′, II-H-(i)′, II-H-(ii)′, II-I-(i)′, II-I-(ii)′, II-I′-(i)′, II-I′-(ii)′, II-J-(i)′, or II-J-(ii)′:
- 23. The compound of claim 15, wherein Cy2 is cyclohexyl and compounds have the formula II-K-(i), II-K-(ii), II-K-(i)′ or II-K-(ii)′:
- 24. The compound of claim 16 or 17, wherein Ar2 is phenyl, pyridyl, pyrimidinyl, quinolinyl, or thiazolyl each optionally substituted with 0-3 occurrences of ZRY, or Cy2 is cyclohexyl, optionally substituted with 0-3 occurrences of ZRY.
- 25. The compound of claim 24, wherein n is 0, or n is 1 and T is CH2; m is 0; x is 0-3; y is 0-3; and each occurrence of QRX or ZRY is independently R′, halogen, CN, NO2—N(R′)2, —CH2N(R′)2, —OR′, —CH2OR′, —SR′, —CH2SR′, —COOR′, —NRCOR′, —CON(R′)2, —SO2N(R′)2, —CONR(CH2)2N(R′)2, —CONR(CH2)3N(R′)2, —CONR(CH2)4N(R′)2, —O(CH2)2OR′, O(CH2)3OR′, O(CH2)4OR′, —O(CH2)2N(R′)2, —O(CH2)3N(R′)2, or —O(CH2)4N(R′)2.
- 26. The compound of claim 22 or 23, wherein Ar1 is an optionally substituted group selected from phenyl, or Cy1 is selected from cyclohexyl, furanyl, or cyclopropyl, optionally substituted with 0-3 occurrences of QRX.
- 27. The compound of claim 26, wherein n is 0, or n is 1 and T is CH2; x is 0-3; y is 0-3; and each occurrence of QRX or ZRY is independently Cl, Br, F, CF3, Me, Et, CN, —COOH, —N(CH3)2, —N(Et)2, —N(iPr)2, —O(CH2)2OCH3, —CONH2, —COOCH3, —OH, —CH2OH, —NHCOCH3, —SO2NH2, methylenedioxy, ethylenedioxy, —O(CH2)2N-morpholino, —O(CH2)3N-morpholino, —O(CH2)4N-morpholino, —O(CH2)2N-piperazinyl, O(CH2)3N-piperizinyl, O(CH2)4N-piperizinyl, —NHCH(CH2OH)phenyl, —CONH(CH2)2N-morpholino, —CONH(CH2)2N-piperazinyl, —CONH(CH2)3N-morpholino, —CONH(CH2)3N-piperazinyl, —CONH(CH2)4N-morpholino, —CONH(CH2)4N-piperazinyl, —SO2NH(CH2)2N-morpholino, —SO2NH(CH2)2N-piperazinyl, —SO2NH(CH2)3N-morpholino, —SO2NH(CH2)3N-piperazinyl, —SO2NH(CH2)4N-morpholino, —SO2NH(CH2)4N-piperazinyl, where each of the foregoing phenyl, morpholino, piperazinyl, or piperidinyl groups is optionally substituted, or an optionally substituted group selected from C1-4alkoxy, phenyl, phenyloxy, benzyl, piperidinyl, piperazinyl, morpholino, or benzyloxy.
- 28. The compound of claim 1, having one of the formulae:
- 29. The compound of claim 28, wherein x is 0-3; y is 0-3; and each occurrence of QRX or ZRY is independently R′, halogen, CN, NO2—N(R′)2, —CH2N(R′)2, —OR′, —CH2OR′, —SR′, —CH2SR′, —COOR′, —NRCOR′, —CON(R′)2, —SO2N(R′)2, —CONR(CH2)2N(R′)2, —CONR(CH2)3N(R′)2, —CONR(CH2)4N(R′)2, —O(CH2)2OR′, O(CH2)3OR′, O(CH2)4OR′, —O(CH2)2N(R′)2, —O(CH2)3N(R′)2, or —O(CH2)4N(R′)2.
- 30. The compound of claim 29, wherein QRX or ZRY groups are each independently Cl, Br, F, CF3, Me, Et, CN, —COOH, —N(CH3)2, —N(Et)2, —N(iPr)2, —O(CH2)2OCH3, —CONH2, —COOCH3, —OH, —CH2OH, —NHCOCH3, —SO2NH2, methylenedioxy, ethylenedioxy, —O(CH2)2N-morpholino, —O(CH2)3N-morpholino, —O(CH2)4N-morpholino, —O(CH2)2N-piperazinyl, O(CH2)3N-piperizinyl, O(CH2)4N-piperizinyl, —NHCH(CH2OH)phenyl, —CONH(CH2)2N-morpholino, —CONH(CH2)2N-piperazinyl, —CONH(CH2)3N-morpholino, —CONH(CH2)3N-piperazinyl, —CONH(CH2)4N-morpholino, —CONH(CH2)4N-piperazinyl, —SO2NH(CH2)2N-morpholino, —SO2NH(CH2)2N-piperazinyl, —SO2NH(CH2)3N-morpholino, —SO2NH(CH2)3N-piperazinyl, —SO2NH(CH2)4N-morpholino, —SO2NH(CH2)4N-piperazinyl, where each of the foregoing phenyl, morpholino, piperazinyl, or piperidinyl groups is optionally substituted, or an optionally substituted group selected from C1-4alkoxy, phenyl, phenyloxy, benzyl, piperidinyl, piperazinyl, morpholino, or benzyloxy.
- 31. The compound of claim 1, wherein
R4 is hydrogen or C1-6alkyl; R3 and R5, taken together form an optionally substituted group selected from a 5-7-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R3 and R5, taken together form an optionally substituted group selected from a 5-7-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and wherein any ring formed R3 and R5 taken together, is optionally substituted with up to five substituents selected from W—RW; wherein W is a bond or is a C1-C6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, or —POR—; and each occurrence of RW is independently R′, halogen, NO2, CN, OR′, SR′, N(R′)2, NR′COR′, NR′CONR′2, NR′CO2R′, COR′, CO2R′, OCOR′, CON(R′)2, OCON(R′)2, SOR′, SO2R′, SO2N(R′)2, NR′SO2R′, NR′SO2N(R′)2, COCOR′, or COCH2COR′.
- 32. The compound of claim 31, having one of the following formulae:
- 33. The compound of claim 32, wherein R1 is hydrogen and Ar1 is optionally substituted phenyl
- 34. The compound of claim 32, wherein R1 is hydrogen and Ar1 is optionally substituted pyridyl
- 35. The compound of claim 32, wherein R1 is hydrogen and Ar1 is optionally substituted cyclohexyl
- 36. The compound of claim 32, wherein R1 is hydrogen and Ar1 is optionally substituted tetrahydrofuryl
- 37. The compound of claim 32, wherein R1 is hydrogen and Ar1 is optionally substituted cyclopropyl
- 38. The compound of claim 32, wherein WRW groups are each independently R′, halogen, CN, NO2—N(R′)2, —CH2N(R′)2, —OR′, —CH2OR′, —SR′, —CH2SR′, —COOR′, —NRCOR′, —CON(R′)2, —SO2N(R′)2, —CONR(CH2)2N(R′)2, —CONR(CH2)3N(R′)2, —CONR(CH2)4N(R′)2, —O(CH2)2OR′, O(CH2)3OR′, O(CH2)4OR′, —O(CH2)2N(R′)2, —O(CH2)3N(R′)2, or —O(CH2)4N(R′)2.
- 39. The compound of claim 32, wherein n is 0, or n is 1 and T is CH2; p is 0-3; y is 0-3; and each occurrence of WRW or ZRY is independently Cl, Br, F, CF3, Me, Et, CN, —COOH, —N(CH3)2, —N(Et)2, —N(iPr)2, —O(CH2)2OCH3, —CONH2, —COOCH3, —OH, —CH2OH, —NHCOCH3, —SO2NH2, methylenedioxy, ethylenedioxy, —O(CH2)2N-morpholino, —O(CH2)3N-morpholino, —O(CH2)4N-morpholino, —O(CH2)2N-piperazinyl, O(CH2)3N-piperizinyl, O(CH2)4N-piperizinyl, —NHCH(CH2OH)phenyl, —CONH(CH2)2N-morpholino, —CONH(CH2)2N-piperazinyl, —CONH(CH2)3N-morpholino, —CONH(CH2)3N-piperazinyl, —CONH(CH2)4N-morpholino, —CONH(CH2)4N-piperazinyl, —SO2NH(CH2)2N-morpholino, —SO2NH(CH2)2N-piperazinyl, —SO2NH(CH2)3N-morpholino, —SO2NH(CH2)3N-piperazinyl, —SO2NH(CH2)4N-morpholino, —SO2NH(CH2)4N-piperazinyl, where each of the foregoing phenyl, morpholino, piperazinyl, or piperidinyl groups is optionally substituted, or an optionally substituted group selected from C1-4alkoxy, phenyl, phenyloxy, benzyl, piperidinyl, piperazinyl, morpholino, or benzyloxy.
- 40. The compound of claim 32, wherein R4 is hydrogen or C1-4alkyl.
- 41. A pharmaceutical composition composition comprising a compound having the structure:
- 42. The composition of claim 41, further comprising an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer's Disease, a treatment for Parkinson's Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an agent for treating schizophrenia, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder.
- 43. A method of inhibiting FLT-3, FMS, c-KIT, PDGFR, JAK, AGC sub-family of protein kinases (e.g., PKA, PDK, p70S6K-1 and -2, and PKB), CDK, GSK, SRC, ROCK, and/or SYK kinase activity in a biological sample or a patient, comprising the step of contacting said biological sample or said patient with:
a) a composition according to claim 41; or b) a compound having the structure: 1402or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or Y—R′, wherein Y is an optionally substituted C1-6alkylidene chain wherein up to two methylene units are optionally and independently replaced with —O—, —S—, —NR—, —OCO—, —COO—, or —CO—; each occurrence of R is independently hydrogen or an optionally substituted C1-6 aliphatic group; and each occurrence of R′ is independently hydrogen or an optionally substituted group selected from a C1-6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R2 is -(T)nAr1, or -(T)nCy1, wherein T is an optionally substituted C1-4 alkylidene chain wherein one methylene unit of T is optionally replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, or —POR—; n is 0 or 1; Ar1 is an optionally substituted aryl group selected from a 5-6 membered monocyclic or an 8-12 membered bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and Cy1 is an optionally substituted group selected from a 3-7-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12-membered saturated or partially unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R1 and R2, taken together with the nitrogen form an optionally substituted 5-8 membered monocyclic or 8-12 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein Ar1, Cy1, or any ring formed by R1 and R2 taken together, are each independently optionally substituted with x independent occurrences of Q-RX; wherein x is 0-5, Q is a bond or is a C1-C6 alkylidene chain wherein up to two methylene units of Q are optionally replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, or —POR—; and each occurrence of RX is independently R′, halogen, NO2, CN, OR′, SR′, N(R′)2, NR′COR′, NR′CONR′2, NR′CO2R′, COR′, CO2R′, OCOR′, CON(R′)2, OCON(R′)2, SOR′, SO2R′, SO2N(R′)2, NR′SO2R′, NR′SO2N(R′)2, COCOR′, or COCH2COR′; R3 is bonded to the nitrogen atom in either the 1- or 2-position of the ring and is (L)mAr2, or (L)mCy2; wherein L is an optionally substituted C1-4 alkylidene chain wherein one methylene unit of L is optionally replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, or —POR—; m is 0 or 1; Ar2 is an optionally substituted aryl group selected from a 5-6 membered monocyclic or an 8-12 membered bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and Cy2 is an optionally substituted group selected from a 3-7-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12-membered saturated or partially unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar2 and Cy2 are each independently optionally substituted with y occurrences of Z-RY; wherein y is 0-5, Z is a bond or is a C1-C6 alkylidene chain wherein up to two methylene units of Z are optionally replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, or —POR—; and each occurrence of RY is independently R′, halogen, NO2, CN, OR′, SR′, N(R′)2, NR′COR′, NR′CONR′2, NR′CO2R′, COR′, CO2R′, OCOR′, CON(R′)2, OCON(R′)2, SOR′, SO2R′, SO2N(R′)2, NR′SO2R′, NR′SO2N(R′)2, COCOR′, or COCH2COR′; R4 is hydrogen or C1-6alkyl, provided that when R5 is hydrogen, R4 is also hydrogen; R5 is hydrogen; or R3 and R5, taken together form an optionally substituted group selected from a 5-7-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and wherein any ring formed R3 and R5 taken together, is optionally substituted with up to five substituents selected from W—RW; wherein W is a bond or is a C1-C6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, or —POR—; and each occurrence of RW is independently R′, halogen, NO2, CN, OR′, SR′, N(R′)2, NR′COR′, NR′CONR′2, NR′CO2R′, COR′, CO2R′, OCOR′, CON(R′)2, OCON(R′)2, SOR′, SO2R′, SO2N(R′)2, NR′SO2R′, NR′SO2N(R′)2, COCOR′, or COCH2COR′.
- 44. The method of claim 43, wherein the method comprises inhibiting FLT-3 or c-KIT activity.
- 45. The method of claim 43, wherein the method comprises inhibiting JAK-3 activity.
- 46. The method of claim 43, wherein the method comprises inhibiting PDK-1 activity.
- 47. A method of treating or lessening the severity of a disease of condition selected from allergic disorders, proliferative disorders, autoimmune disorders, conditions associated with organ transplant, inflammatory disorders, immunologically mediated disorders, or destructive bone disorders, comprising the step of administering to said patient:
a) a composition according to claim 41; or b) a compound having the structure: 1403or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or Y—R′, wherein Y is an optionally substituted C1-6alkylidene chain wherein up to two methylene units are optionally and independently replaced with —O—, —S—, —NR—, —OCO—, —COO—, or —CO—; each occurrence of R is independently hydrogen or an optionally substituted C1-6 aliphatic group; and each occurrence of R′ is independently hydrogen or an optionally substituted group selected from a C1-6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R2 is -(T)nAr1, or -(T)nCy1, wherein T is an optionally substituted C1-4 alkylidene chain wherein one methylene unit of T is optionally replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, or —POR—; n is 0 or 1; Ar1 is an optionally substituted aryl group selected from a 5-6 membered monocyclic or an 8-12 membered bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and Cy1 is an optionally substituted group selected from a 3-7-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12-membered saturated or partially unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R1 and R2, taken together with the nitrogen form an optionally substituted 5-8 membered monocyclic or 8-12 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein Ar1, Cy1, or any ring formed by R1 and R2 taken together, are each independently optionally substituted with x independent occurrences of Q-RX; wherein x is 0-5, Q is a bond or is a C1-C6 alkylidene chain wherein up to two methylene units of Q are optionally replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, or —POR—; and each occurrence of RX is independently R′, halogen, NO2, CN, OR′, SR′, N(R′)2, NR′COR′, NR′CONR′2, NR′CO2R′, COR′, CO2R′, OCOR′, CON(R′)2, OCON(R′)2, SOR′, SO2R′, SO2N(R′)2, NR′SO2R′, NR′SO2N(R′)2, COCOR′, or COCH2COR′; R3 is bonded to the nitrogen atom in either the 1- or 2-position of the ring and is (L)mAr2, or (L)mCy2; wherein L is an optionally substituted C1-4 alkylidene chain wherein one methylene unit of L is optionally replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, or —POR—; m is 0 or 1; Ar2 is an optionally substituted aryl group selected from a 5-6 membered monocyclic or an 8-12 membered bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and Cy2 is an optionally substituted group selected from a 3-7-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12-membered saturated or partially unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar2 and Cy2 are each independently optionally substituted with y occurrences of Z-RY; wherein y is 0-5, Z is a bond or is a C1-C6 alkylidene chain wherein up to two methylene units of Z are optionally replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, or —POR—; and each occurrence of RY is independently R′, halogen, NO2, CN, OR′, SR′, N(R′)2, NR′COR′, NR′CONR′2, NR′CO2R′, COR′, CO2R′, OCOR′, CON(R′)2, OCON(R′)2, SOR′, SO2R′, SO2N(R′)2, NR′SO2R′, NR′SO2N(R′)2, COCOR′, or COCH2COR′; R4 is hydrogen or C1-6alkyl, provided that when R5 is hydrogen, R4 is also hydrogen; R5 is hydrogen; or R3 and R5, taken together form an optionally substituted group selected from a 5-7-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10-membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and wherein any ring formed R3 and R5 taken together, is optionally substituted with up to five substituents selected from W—RW; wherein W is a bond or is a C1-C6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO2—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO2—, —SO2NR—, —NRSO2—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO2NR—, —SO—, —SO2—, —PO—, —PO2—, or —POR—; and each occurrence of RW is independently R′, halogen, NO2, CN, OR′, SR′, N(R′)2, NR′COR′, NR′CONR′2, NR′CO2R′, COR′, CO2R′, OCOR′, CON(R′)2, OCON(R′)2, SOR′, SO2R′, SO2N(R′)2, NR′SO2R′, NR′SO2N(R′)2, COCOR′, or COCH2COR′.
- 48. The method of claim 47, comprising the further step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer's Disease, a treatment for Parkinson's Disease, an agent for treating, Multiple Sclerosis (MS), a treatment for asthma, an agent for treating schizophrenia, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder, wherein:
said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
- 49. The method of claim 47, wherein the disease is selected from cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, an autoimmune disease, a viral infection, a neurodegenerative disorder, a disorder associated with thymocyte apoptosis, or a proliferative disorder.
- 50. The method of claim 47, wherein the disease is selected from hematopoietic disorders, in particular, acute-myelogenous leukemia (AML), acute-promyelocytic leukemia (APL), and acute lymphocytic leukemia (ALL).
- 51. The method of claim 47, wherein the disease is selected from immune responses such as allergic or type I hypersensitivity reactions, asthma, autoimmune diseases such as transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis, neurodegenerative disorders such as Familial amyotrophic lateral sclerosis (FALS), as well as in solid and hematologic malignancies such as leukemias and lymphomas
- 52. The method of claim 47, wherein the disease is a proliferative disorder or cancer.
- 53. The method of claim 47, wherein the cancer is pancreatic, prostate, or ovarian cancer.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority under 35 U.S.C. §119 to U.S. Provisional Application No. 60/426,681, filed Nov. 15, 2002, entitled “Compositions Useful as Inhibitors of Protein Kinases, and 60/447,705, filed Feb. 11, 2003, entitled “Compositions Useful as Inhibitors of Protein Kinases”, and the entire contents of each of these applications is hereby incorporated by reference.
Provisional Applications (2)
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Number |
Date |
Country |
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60426681 |
Nov 2002 |
US |
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60447705 |
Feb 2003 |
US |
Patent Application
20040214817
