Claims
- 1. A compound of formula (I):
- 2. The compound of claim 1, wherein Ar1 are optionally substituted rings selected from:
(a) a phenyl, indanyl, or naphthyl ring; (b) a 5-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or (c) a 5-6 membered monocyclic or 9-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur.
- 3. The compound of claim 1, wherein Ar1 are optionally substituted rings selected from:
(a) a phenyl ring; (b) a 5-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or (c) a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur.
- 4. The compound of claim 1, wherein Ar1 is selected from any one of a-bb:
- 5. The compound of claim 1, wherein Ar1 is optionally substituted phenyl, pyrimidinyl, or pyridyl.
- 6. The compound of claim 1, wherein Ar1 is phenyl and is substituted with two (x=2) or three (x=3) occurrences of Q—R5 and Ar1 is:
- 7. The compound of claim 1, wherein Q is independently a bond or is an optionally substituted C1-C4 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally replaced by CO, CO2, CONR, OCONR, NRCO, NRCO2, NRSO2, SO2NR, O, S, or NR; and each occurrence of R5 is independently selected from R′, halogen, NO2, CN, OR′, SR′, N(R′)2, NR′C(O)R′, NR′C(O)N(R′)2, NR′CO2R′, C(O)R′, CO2R′, OC(O)R′, C(O)N(R′)2, OC(O)N(R′)2, SOR′, SO2R′, SO2N(R′)2, NR′SO2R′, NR′SO2N(R′)2, PO(OR′)2, C(O)C(O)R′, or C(O)CH2C(O)R′, and x is 0, 1, 2, or 3.
- 8. The compound of claim 1, wherein Q—R5 substituents on Ar1 are CH2halogen, halogen, CH2CN, CN, CH2CO2R′, CO2R′, CH2COR′, COR′, R′, CH2NO2, NO2, CH2OR′, OR′, CH2SR′, SR′, haloalkyl, CH2SO2N(R′)2, SO2N(R′)2, CH2N(R′)2, N(R′)2, NHCOR′, CH2NHCOR′, CH2PO(OR′)2, PO(OR′)2, or two adjacent occurrences of Q—R5, taken together with the atoms to which they are bound, form an optionally substituted saturated, partially unsaturated, or fully unsaturated 5-8-membered ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur.
- 9. The compound of claim 1, wherein Q—R5 substituents on Ar1 are fluoro, iodo, chloro, bromo, COCH3, CO2CH3, C1-4alkyl, NH2, CH2NH2, NHMe, CH2NHMe, N(Me)2, CH2N(Me)2, N(Et)2, CH2N(Et)2, NH(phenyl), CO(C1-4alkyl), CH2CO(C1-4alkyl), NHCO(C1-4alkyl), CH2NHCO(C1-4alkyl), CN, CH2CN, OH, C1-4alkoxy, optionally substituted benzyloxy, optionally substituted phenyloxy, CF3, SO2NH2, SO2NHMe, optionally substituted SO2(phenyl), SO2(C1-4alkyl), CONH2, CH2PO(OR′)2, or an optionally substituted group selected from a saturated, partially unsaturated, or fully unsaturated 5- or 6-membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- 10. The compound of claim 1, wherein R1 and R2 groups of formula I are each independently hydrogen, N(R)2, SR, OR, or TR, or R1 and R2, taken together form an optionally substituted saturated, partially unsaturated, or fully unsaturated 5-membered ring having 0-2 heteroatoms independently selected from N, O, or S.
- 11. The compound of claim 1, wherein R1 and R2 groups are each independently hydrogen, OH, CH3, CH2CH3, OCH3, CH2OH, CH2OCH3, CH2NH2, CH2NHCH3, NH2, or CH2NH2, or R1 and R2, taken together, form a fused optionally substituted pyrrolyl, pyrazolyl, or imidazolyl ring.
- 12. The compound of claim 1, wherein R3 and R4are each independently Z—R7 wherein Z is an optionally substituted C0-4 alkylidene chain wherein one methylene unit of Z is optionally replaced by O, NR, NRCO, NRCO2, NRSO2, CONR, C(O), C(O)O, and wherein R7 is selected from halogen, CN, N(R′)2, NHCOR′, or R′, or wherein R3 and R4, taken together form an optionally substituted saturated, partially unsaturated, or fully unsaturated 5- or 6-membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- 13. The compound of claim 1, wherein R3 and R4 are each independently hydrogen, CN, halogen, OH, SH, NH2, CO2H, COH, CONH2, SO2NH2, NO2, (CH2)nNRR7, wherein R and R7, taken together with the nitrogen atom to which they are bound form an optionally substituted 3-8-membered saturated or partially unsaturated ring having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, or R3 and R4, taken together with the atoms to which they are bound, form an optionally substituted saturated, partially unsaturated, or fully unsaturated 5- or 6-membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and n is 0, 1, 2, 3, 4, or 5.
- 14. The compound of claim 1, wherein one of R3 or R4 is hydrogen, and the other of R3 or R4 is (CH2)nhalogen, (CH2)nCN, (CH2)nOR7, (CH2)nNRR7, (CH2)nC(O)R7, (CH2)nC(O)R7 (CH2)nCH3, (CH2)nC(O)NRR7, (CH2)nSR7, wherein R7 is hydrogen, (CH2)mN(R′)2, C1-C4alkyl, an optionally substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or heteroaralkyl group, or R and R7, taken together with the nitrogen atom to which they are bound form an optionally substituted 3-8-membered saturated or partially unsaturated ring having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur.
- 15. The compound of claim 14, wherein R3is hydrogen.
- 16. The compound of claim 14, wherein R4is hydrogen.
- 17. The compound of claim 1, having one of formulas I-A-i, I-A-ii, I-B-i, I-B-ii, I-C-i, I-C-ii, I-D-i, or I-E-i:
- 18. The compound of claim 17, wherein Ar1 is:
(a) a phenyl, indanyl, or naphthyl ring; (b) a 5-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or (c) a 5-6 membered monocyclic or 9-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur.
- 19. The compound of claim 17, wherein Ar1 is:
(a) a phenyl ring; (b) a 5-6 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or (c) a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur.
- 20. The compound of claim 17, wherein Ar1 is any one of a-bb:
- 21. The compound of claim 17, wherein Ar1 is phenyl, pyrimidinyl, or pyridyl.
- 22. The compound of claim 17, wherein Ar1 is phenyl and is substituted with two (x=2) or three (x=3) occurrences of Q—R5 and Ar1 is:
- 23. The compound of claim 17, wherein Ar1 is optionally substituted phenyl and compounds have one of formulas II-A-i, II-A-ii, II-B-i, II-B-ii, II-C-i, II-C-ii, II-D-i, or II-E-i:
- 24. The compound of claim 23, wherein each occurrence of Q is independently a bond or is an optionally substituted C1-C4 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally replaced by CO, CO2, CONR, OCONR, NRCO, NRCO2, NRSO2, SO2NR, O, S, or NR; and each occurrence of R5 is independently selected from R′, halogen, NO2, CN, OR′, SR′, N(R′)2, NR′C(O)R′, NR′C(O)N(R′)2, NR′CO2R′, C(O)R′, CO2R′, OC(O)R′, C(O)N(R′)2, OC(O)N(R′)2, SOR′, SO2R′, SO2N(R′)2, NR′SO2R′, NR′SO2N(R′)2, PO(OR′)2, C(O)C(O)R′, or C(O)CH2C(O)R′, and x is 0, 1, 2, or 3.
- 25. The compound of claim 23, wherein each occurrence of Q—R5 is independently CH2halogen, halogen, CH2CN, CN, CH2CO2R′, CO2R′, CH2COR′, COR′, R′, CH2NO2, NO2, CH2OR′, OR′, CH2SR′, SR′, haloalkyl, CH2SO2N(R′)2, SO2N(R′)2, CH2N(R′)2, N(R′)2, NHCOR′, CH2NHCOR′, CH2PO(OR′)2, PO(OR′)2, or two adjacent occurrences of Q—R5, taken together with the atoms to which they are bound, form an optionally substituted saturated, partially unsaturated, or fully unsaturated 5-8-membered ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur.
- 26. The compound of claim 23, wherein each occurrence of Q—R5 is independently fluoro, iodo, chloro, bromo, COCH3, CO2CH3, C1-4alkyl, NH2, CH2NH2, NHMe, CH2NHMe, N(Me)2, CH2N(Me)2, N(Et)2, CH2N(Et)2, NH(phenyl), CO(C1-4alkyl), CH2CO(C1-4alkyl), NHCO(C1-4alkyl), CH2NHCO(C1-4alkyl), CN, CH2CN, OH, C1-4alkoxy, optionally substituted benzyloxy, optionally substituted phenyloxy, CF3, SO2NH2, SO2NHMe, optionally substituted SO2(phenyl), SO2(C1-4alkyl), CONH2, CH2PO(OR′)2, or an optionally substituted group selected from a saturated, partially unsaturated, or fully unsaturated 5- or 6-membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- 27. The compound of claim 23, wherein R1 and R2 are each independently hydrogen, N(R)2, SR, OR, or TR, or R1 and R2, taken together form an optionally substituted saturated, partially unsaturated, or fully unsaturated 5-membered ring having 0-2 heteroatoms independently selected from N, O, or S.
- 28. The compound of claim 27, wherein R1 and R2 are each independently hydrogen, OH, CH3, CH2CH3, OCH3, CH2OH, CH2OCH3, CH2NH2, CH2NHCH3, NH2, or CH2NH2, or R1 and R2, taken together, form a fused optionally substituted pyrrolyl, pyrazolyl, or imidazolyl ring.
- 29. The compound of claim 23, wherein R3 is Z—R , wherein Z is a bond or is an optionally substituted C0-4 alkylidene chain wherein one methylene unit of Z is optionally replaced by O, NR, NRCO, NRCO2, NRSO2, CONR, C(O), C(O)O, and wherein R7 is halogen, CN, N(R′)2, NHCOR′, or R′.
- 30. The compound of claim 23, wherein R3 is (CH2)nhalogen, (CH2)nCN, (CH2)nOR7, (CH2)nNRR7, (CH2)nC(O)R7, (CH2)nC(O)R7 (CH2)nCH3, (CH2)nC(O)NRR7, (CH2)nSR7, wherein R7 is (CH2)mN(R′)2, C1-C4alkyl, an optionally substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or heteroaralkyl group, or R and R7, taken together with the nitrogen atom to which they are bound form an optionally substituted 3-8-membered saturated or partially unsaturated ring having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n is 0 or 1, and m is 0 or 1.
- 31. The compound of claim 23, wherein R4 is Z—R7, wherein Z is a bond or is an optionally substituted C0-4 alkylidene chain wherein one methylene unit of Z is optionally replaced by O, NR, NRCO, NRCO2, NRSO2, CONR, C(O), C(O)O, and wherein R7 is selected from halogen, CN, N(R′)2, NHCOR′, or R′.
- 32. The compound of claim 23, wherein R4 is (CH2)nhalogen, (CH2)nCN, (CH2)nOR7, (CH2)nNRR7, (CH2)nC(O)R7, (CH2)nC(O)R7 (CH2)nCH3, (CH2)nC(O)NRR7, (CH2)nSR7, wherein R7 is (CH2)mN(R′)2, C1-C4alkyl, an optionally substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or heteroaralkyl group, or R and R7, taken together with the nitrogen atom to which they are bound form an optionally substituted 3-8-membered saturated or partially unsaturated ring having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n is 0 or 1, and m is 0 or 1.
- 33. The compound of claim 23, wherein compounds have one of formulas II-A-i, I-B-i, II-C-i, or II-F-i and the compound variables are defined as:
a) x is 0, 1, or 2, and Q—R5 is CH2halogen, halogen, CH2CN, CN, CH2CO2R′, CO2R′, CH2COR′, COR′, R′, CH2NO2, NO2, CH2OR′, OR′, CH2SR′, SR′, haloalkyl, CH2SO2N(R′)2, SO2N(R′)2, CH2N(R′)2, N(R′)2, NHCOR′, CH2NHCOR′, CH2PO(OR′)2, PO(OR′)2, or Q—R5, taken together with the atoms to which they are bound, form an optionally substituted saturated, partially unsaturated, or fully unsaturated 5-8-membered ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur; b) R1 and R2 are each independently hydrogen, N(R)2, SR, OR, or TR, or R1 and R2, taken together form an optionally substituted saturated, partially unsaturated, or fully unsaturated 5-membered ring having 0-2 heteroatoms independently selected from N, O, or S; and c) R3 is (CH2)nhalogen, (CH2)nCN, (CH2)nOR7, (CH2)nNRR7, (CH2)nC(O)R7, (CH2)nC(O)R7 (CH2)nCH3, (CH2)nC(O)NRR7, (CH2)nSR7, wherein R7 is (CH2)mN(R′)2, C1-C4alkyl, an optionally substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or heteroaralkyl group, or R and R7, taken together with the nitrogen atom to which they are bound form an optionally substituted 3-8-membered saturated or partially unsaturated ring having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n is 0 or 1, and m is 0 or 1.
- 34. The compound of claim 23, wherein compounds have one of formulas II-A-ii, II-B-ii, II-C-ii, or II-F-ii and one or more of the compound variables are defined as:
a) x is 0, 1, 2, or 3, and Q—R5 is CH2halogen, halogen, CH2CN, CN, CH2CO2R′, CO2R′, CH2COR′, COR′, R′, CH2NO2, NO2, CH2OR′, OR′, CH2SR′, SR′, haloalkyl, CH2SO2N(R′)2, SO2N(R′)2, CH2N(R′)2, N(R′)2, NHCOR′, CH2NHCOR′, CH2PO(OR′)2, PO(OR′)2, or Q—R5, taken together with the atoms to which they are bound, form an optionally substituted saturated, partially unsaturated, or fully unsaturated 5-8-membered ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur; b) R1 and R2 are each independently hydrogen, N(R)2, SR, OR, or TR, or R1 and R2, taken together form an optionally substituted saturated, partially unsaturated, or fully unsaturated 5-membered ring having 0-2 heteroatoms independently selected from N, O, or S; and c) R4 is (CH2)nhalogen, (CH2)nCN, (CH2)nOR7, (CH2)nNRR7, (CH2)nC(O)R7, (CH2)nC(O)R7 (CH2)nCH3, (CH2)nC(O)NRR7, (CH2)nSR7, wherein R7 is (CH2)mN(R′)2, C1-C4alkyl, an optionally substituted 5- or 6-membered aryl, aralkyl, heteroaryl, or heteroaralkyl group, or R and R7, taken together with the nitrogen atom to which they are bound form an optionally substituted 3-8-membered saturated or partially unsaturated ring having 1-3 heteroatoms selected from nitrogen, oxygen, or sulfur, n is 0 or 1, and m is 0 or 1.
- 35. The compound of claim 23, wherein compounds have formula I-F-i, and one or more of the compound variables are defined as:
a) x is 0, 1, 2, or 3, and Q—R5 is CH2halogen, halogen, CH2CN, CN, CH2CO2R′, CO2R′, CH2COR′, COR′, R′, CH2NO2, NO2, CH2OR′, OR′, CH2SR′, SR′, haloalkyl, CH2SO2N(R′)2, SO2N(R′)2, CH2N(R′)2, N(R′)2, NHCOR′, CH2NHCOR′, CH2PO(OR′)2, PO(OR′)2, or Q—R5, taken together with the atoms to which they are bound, form an optionally substituted saturated, partially unsaturated, or fully unsaturated 5-8-membered ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur; and b) R1 and R2 are each independently hydrogen, N(R)2, SR, OR, or TR, or R1 and R2, taken together form an optionally substituted saturated, partially unsaturated, or fully unsaturated 5-membered ring having 0-2 heteroatoms independently selected from N, O, or S.
- 36. The compound of claim 1, selected from:
- 37. A composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- 38. The composition of claim 37, wherein the compound is in an amount to detectably inhibit SYK, or ZAP-70 protein kinase activity.
- 39. The composition of claim 37, additionally comprising a therapeutic agent selected from an anti-inflammatory agent, an anti-proliferative agent, an immunomodulatory or immunosuppressive agent, or an agent for treating immunodeficiency disorders.
- 40. A method of inhibiting SYK or ZAP-70 kinase activity in:
(a) a patient; or (b) a biological sample; which method comprises administering to said patient, or contacting said biological sample with: a) a composition of claim 37; or b) a compound of claim 1.
- 41. A method of treating or lessening the severity of treatment or lessening the severity of an immunodeficiency disorder, inflammatory disease, allergic disease, autoimmune disease, proliferative disorder, immunologically-mediated disease, or respiratory disorder, comprising the step of administering to said patient:
a) a composition of claim 37; or b) a compound of claim 1.
- 42. The method according to claim 41, comprising the additional step of administering to said patient an additional therapeutic agent selected from an anti-inflammatory agent, an anti-proliferative agent, an immunomodulatory or immunosuppressive agent, or an agent for treating immunodeficiency disorders, 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.
- 43. The method according to claim 41, wherein the disease is an immune disorder.
- 44. The method according to claim 41, wherein the disease is asthma.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority under 35 U.S.C. §119 to U.S. Provisional Application No. 60/457,218, filed Mar. 25, 2003, entitled “Thiazoles Useful as Inhibitors of Protein Kinases”, the entire contents of which is hereby incorporated by reference.
Provisional Applications (1)
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Number |
Date |
Country |
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60457218 |
Mar 2003 |
US |