Tyrosine kinase inhibitors
View Patent ↗The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such as angiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy, inflammatory diseases, and the like in mammals.
1. A compound of Formula I
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
A and B are independently N or N + —O − ;
Y is O, S or N—R 4 ;
R 1 and R 2 are independently:
1) H,
2) O r (C 1 –C 6 )perfluoroalkyl,
3) OH,
4) CN,
5) halogen,
6) (C═O) r O s (C 1 –C 10 )alkyl,
7) (C═O) r O s (C 2 –C 10 )alkenyl,
8) (C═O) r O s (C 2 –C 10 )alkynyl,
9) (C═O) r O s aryl,
10) (C═O) r O s heterocyclyl,
11) (C 0 –C 6 )alkyl-NR a R b , or
12) (C 1 –C 6 )heterocyclyl,
wherein r and s are independently 0 or 1, and said alkyl, alkenyl, alkynyl, aryl, and heterocyclyl is optionally substituted with one or more substituents selected from R 7 ;
R 4 is H, aryl or (C 1 –C 6 )alkyl;
R 5 is:
1) H,
2) SO 2 R c ,
3) (C═O) r R c , wherein r is 0 or 1, or
4) CO 2 R c ;
R 6 is:
1) phenyl,
2) CN,
3) halogen, or
4) heterocyclyl,
wherein said phenyl and heterocyclyl are optionally substituted with one or more substituents selected from R 7 ;
R 7 is:
1) O r (C═O)SNR a R b ,
2) (C═O) r O s aryl,
3) (C═O) r O s -heterocyclyl,
4) halogen,
5) OH,
6) oxo,
7) O(C 1 –C 3 )perfluoroalkyl,
8) (C 1 –C 3 )perfluoroalkyl,
9) (C═O) r O s (C 1 –C 6 )alkyl,
10) CHO,
11) CO 2 H,
12) CN,
13) (C 1 –C 6 )alkyl-NR a R b , or
14) (C 1 –C 6 )alkyl-heterocyclyl,
wherein r and s are independently 0 or 1, and said aryl, heterocyclyl and alkyl are optionally substituted with one to three substituents selected from R d ;
R a and R b are taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5–7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R d ;
R c is (C 1 –C 6 )alkyl, aryl, or heterocyclyl; and
R d is:
1) (C═O) r O s (C 1 –C 10 )alkyl, wherein r and s are independently 0 or 1, optionally substituted with up to three substituents selected from OH, (C 1 –C 6 )alkoxy, halogen, heterocyclyl, CN, oxo, N(R e ) 2 and S(O) 2 R c ,
2) O r (C 1 –C 3 )perfluoroalkyl,
3) (C 0 –C 6 )alkylene-S(O) m R c , wherein m is 0, 1, or 2,
4) oxo,
5) OH,
6) halo,
7) CN,
8) (C 0 –C 6 )alkylene-aryl, optionally substituted with up to three substituents selected from R e ,
9) (C 0 –C 6 )alkylene-heterocyclyl, optionally substituted with up to three substituents selected from R e ,
10) C(O)R c ,
11) CO 2 R c ,
12) C(O)H,
13) N(R e ) 2 , or
14) CO 2 H;
R e is:
1) H,
2) (C 1 –C 6 )alkyl, optionally substituted with one or more substituents selected from OH, heterocyclyl, (C 1 –C 6 )alkoxy, halogen, CN, oxo, N(R f) 2 and S(O) 2 R c ,
3) aryl, optionally substituted with one or more substituents selected from OH, heterocyclyl, (C 1 –C 6 )alkoxy, halogen, CN, N(R f ) 2 and S(O) 2 R c ,
4) heterocyclyl, optionally substituted with one or more substituents selected from OH, heterocyclyl, (C 1 –C 6 )alkoxy, halogen, CN, oxo, N(R f ) 2 and S(O) 2 R c , or
6) S(O) 2 R c , or
if two R e 's are on a nitrogen atom, they can be taken together with the nitrogen to form a heterocycle with 5–7 atoms, optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said heterocycle optionally substituted with one or more substituents selected from OH, (C 1 –C 6 )alkoxy, halogen, CN, oxo, N(R f ) 2 and S(O) 2 R c ; and
R f is H, aryl or (C 1 –C 6 )alkyl.
2. The compound of claim 1 , wherein
Y is S;
R 1 is H, (C 1 –C 6 )alkyl, or O(C 1 –C 6 )alkyl;
R 2 is:
1) H, provided that both R 1 and R 2 are not H at the same time,
2) O r (C 1 –C 6 )perfluoroalkyl,
3) OH,
4) CN,
5) halogen,
6) (C═O) r O s (C 1 –C 10 )alkyl,
7) (C═O) r O s (C 2 –C 10 )alkenyl,
8) (C═O) r O s (C 2 –C 10 )alkynyl,
9) (C═O) r O s aryl,
10) (C═O) r O s heterocyclyl,
11) (C 0 –C 6 )alkyl-NR a R b , or
12) (C 1 –C 6 )heterocyclyl,
wherein r and s are independently 0 or 1, and said alkyl, alkenyl, alkynyl, aryl, and heterocyclyl is optionally substituted with one or more substituents selected from R 7 ;
R 6 is:
1) phenyl,
2) CN,
3) halogen, or
4) heterocyclyl,
wherein said phenyl and heterocyclyl are optionally substituted with one to three substituents selected from R 7 ;
R 7 is:
1) O r (C═O) s NR a R b ,
2) (C═O) r O s aryl,
3) (C═O) r O s -heterocyclyl,
4) halogen,
5) OH,
6) oxo,
7) O(C 1 –C 3 )perfluoroalkyl,
8) (C 1 –C 3 )perfluoroalkyl,
9) (C═O) r O s (C 1 –C 6 )alkyl,
10) CHO,
11) CO 2 H,
12) CN,
13) (C 1 –C 6 )alkyl-NR a R b , or
14) (C 1 –C 6 )alkyl-heterocyclyl,
wherein r and s are independently 0 or 1, and said aryl, heterocyclyl and alkyl are optionally substituted with one to three substituents selected from R d ;
R a and R b are taken together with the nitrogen to which they are attached to form a monocyclic 5–7 membered heterocycle optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said heterocycle optionally substituted with one to three substituents selected from R d ; and
R d is:
1) (C═O) r O s (C 1 –C 6 )alkyl, wherein r and s are independently 0 or 1, optionally substituted with up to three substituents selected from OH, (C 1 –C 6 )alkoxy, halogen, CN, oxo, N(R e ) 2 and S(O) 2 R c ,
2) O r (C 1 –C 3 )perfluoroalkyl,
3) (C 0 –C 6 )alkylene-S(O) m R c , wherein m is 0, 1, or 2,
4) oxo,
5) OH,
6) halo,
7) CN,
8) (C 0 –C 6 )alkylene-aryl, optionally substituted with up to three substituents selected from R e ,
9) (C 0 –C 6 )alkylene-heterocyclyl, optionally substituted with up to three substituents selected from R e ,
10) (C 0 –C 6 )alkylene-N(R e ) 2 ,
11) C(O)R c ,
12) CO 2 R c ,
13) C(O)H, or
14) CO 2 H.
3. The compound of claim 2 , wherein A and B are N; and R 6 is phenyl, halogen, CN, or pyridyl, said phenyl and pyridyl are optionally substituted with one to three substituents selected from R 7 .
4. The compound of claim 3 wherein R 1 is H and R 2 is O s (C 1 –C 6 )alkyl, wherein s is 0 or 1, optionally substituted with one to three substituents selected from R 7 , or (C 0 –C 6 )alkyl-NR a R b .
5. A compound selected from:
2-({6-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile;
2-({6-[4-(2-morpholin-4-yl-2-oxoethyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile;
N-(tert-butyl)-2-(4-{6-[(5-cyano-1,3-thiazol-2-yl)amino]pyrimidin-4-yl}piperazin-1-yl)acetamide;
2-({6-[4-(1,1-dioxidotetrahydrothien-3-yl)piperazin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile;
2-(4-{6-[(5-cyano-1,3-thiazol-2-yl)amino]pyrimidin-4-yl}piperazin-1-yl)-N-isopropylacetamide;
2-(1-{6-[(5-cyano-1,3-thiazol-2-yl)amino]pyrimidin-4-yl}piperidin-4-yl)-N-isopropylacetamide; and
2-({6-[4-(2-oxopiperidin-3-yl)piperazin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile;
or a pharmaceutically acceptable salt or stereoisomer thereof.
6. A compound which is 2-({6-[4-(1,1-dioxidotetrahydrothien-3-yl)piperazin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile
or a pharmaceutically acceptable salt or stereoisomer thereof.
7. A compound which is N-(tert-butyl)-2-(4-{6-[(5-cyano-1,3-thiazol-2-yl)amino]pyrimidin-4-yl}piperazin-1-yl)acetamide
or a pharmaceutically acceptable salt thereof.
8. A compound which is the (R) or (S) enantiomer of 2-({6-[4-(1,1-dioxidotetrahydrothien-3-yl)piperazin-1-yl]pyrimidin-4-yl}amino)-1,3-thiazole-5-carbonitrile in enantiomerically pure form as characterized by an enatiomeric excess of at least 98%, or a pharmaceutically acceptable salt thereof.
9. A compound which is 2-(4-{6-[(5-cyano-1,3-thiazol-2-yl)amino]pyrimidin-4-yl}piperazin-1-yl)-N-isopropylacetamide
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.
12. A process for making a pharmaceutical composition which comprises combining a compound of claim 1 with a pharmaceutically acceptable carrier.
13. The composition of claim 10 further comprising a second compound selected from:
1) an estrogen receptor modulator,
2) an androgen receptor modulator,
3) retinoid receptor modulator,
4) a cytotoxic agent,
5) an antiproliferative agent,
6) a prenyl-protein transferase inhibitor,
7) an HMG-CoA reductase inhibitor,
8) an HIV protease inhibitor,
9) a reverse transcriptase inhibitor,
10) another angiogenesis inhibitor, and
11) a PPAR-γ agonist.
14. The composition of claim 13 , wherein the second compound is another angiogenesis inhibitor selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP inhibitor, an integrin blocker, interferon-α, interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-(chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, and an antibody to VEGF.
15. The composition of claim 13 , wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene.
16. The composition of claim 10 further comprising a steroidal anti-inflammatory compound.
17. The composition of claim 10 further comprising an anti-hypertensive compound.
18. A method of treating cancer in a mammal in need of such treatment which is comprised of administering to said mammal a therapeutically effective amount of a compound of claim 1 , wherein said cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung.
19. A method of treating cancer in a mammal in need of such treatment which is comprised of administering to said mammal a therapeutically effective amount of a compound of claim 1 , wherein said cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, glioblastomas and breast carcinoma.
20. A method of treating cancer in a mammal in need of such treatment which is comprised of administering to said mammal a therapeutically effective amount of a compound of claim 1 , wherein said cancer is selected from colorectal cancer, prostate cancer, breast cancer, and lung cancer.
21. A method of treating a disease in which angiogenesis is implicated, said disease is an ocular disease, which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 .
22. A method of treating retinal vascularization which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of claim 1 .
23. A method of treating diabetic retinopathy which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of claim 1 .
24. The method of claim 21 further comprising the use of photodynamic therapy with a photosensitive drug.
25. The method of claim 24 wherein the photosensitive drug is verteoporfin.
26. A method of treating inflammatory diseases said diseases selected from rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 .
27. A method of treating bone associated pathologies selected from osteosarcoma, osteoarthritis, and rickets which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 .
28. A method of reducing tissue damage following a cerebral ischemic event which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 .
29. A method to treat endometrioses which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 .
30. A method of treating diabetic retinopathy which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 in combination with a PPAR-γ agonist.
31. A method of treating acute myeloid leukemia which comprises administering a therapeutically effective amount of a compound of claim 1 .