Claims for Patent: 7,109,204

Summary for Patent: 7,109,204

Title:	Tyrosine kinase inhibitors
Abstract:	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.
Inventor(s):	Fraley; Mark E. (North Wales, PA), Arrington; Kenneth L. (Philadelphia, PA), Hoffman; William F. (Lansdale, PA), Hartman; George D. (Lansdale, PA), Peckham; Jennifer P. (Cary, NC)
Assignee:	Merck & Co., Inc. (Rahway, NJ)
Application Number:	10/485,296
Patent Claims:	1. A compound of Formula I ##STR00069## wherein R.sup.1a is independently selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, (3) OR.sup.8, and (4) N(R.sup.8).sub.2; R.sup.1 is independently selected from: (1) H, (2) unsubstituted or substituted C.sup.1 C.sup.10 alkyl, (3) unsubstituted or substituted C.sub.3 C.sub.10 cycloalkyl, (4) unsubstituted or substituted aryl, (5) unsubstituted or substituted heterocycle, (6) halo, (7) CF.sub.3, (8) --(CH.sub.2).sub.tR.sup.9C(O)R.sup.8, (9) --C(O)R.sup.9, (10) --(CH.sub.2).sub.tOR.sup.8, (11) unsubstituted or substituted C.sub.2 C.sub.6 alkenyl, (12) unsubstituted or substituted C.sub.2 C.sub.6 alkynyl, (13) CN, (14) --(CH.sub.2).sub.tNR.sup.7R.sup.8, (15) --(CH.sub.2).sub.tC(O)NR.sup.7R.sup.8, (16) --C(O)OR.sup.8, and (17) --(CH.sub.2).sub.tS(O).sub.q(CH.sub.2).sub.tNR.sup.7R.sup.8; R.sup.2 is independently selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, (3) unsubstituted or substituted C.sub.3 C.sub.10 cycloalkyl, (4) unsubstituted or substituted aryl, (5) unsubstituted or substituted heterocycle, (6) halo, (7) CF.sub.3, (8) --(CH.sub.2).sub.tR.sup.9C(O)R.sup.8, (9) --C(O)R.sup.9, (10) --(CH.sub.2).sub.tOR.sup.8, (11) unsubstituted or substituted C.sub.2 C.sub.6 alkenyl, (12) unsubstituted or substituted C.sub.2 C.sub.6 alkynyl, (13) CN, (14) --(CH.sub.2).sub.tNR.sup.7R.sup.8, (15) --(CH.sub.2).sub.tC(O)NR.sup.7R.sup.8, (16) --C(O)OR.sup.8, and (17) --(CH.sub.2).sub.tS(O).sub.q(CH.sub.2).sub.tNR.sup.7R.sup.8; R.sup.3 is independently selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, (3) unsubstituted or substituted aralkyl, (4) CN, (5) halo, (6) N(R.sup.8).sub.2, (7) OR.sup.8, and (8) unsubstituted or substituted aryl; R.sup.7 is selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, and (3) unsubstituted or substituted aralkyl; R.sup.8 is independently selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, (3) unsubstituted or substituted aryl, (4) unsubstituted or substituted heterocycle, (5) unsubstituted or substituted C.sub.3 C.sub.10 cycloalkyl, and (6) unsubstituted or substituted aralkyl; R.sup.7 and R.sup.8, when attached to the same nitrogen atom may be joined to form a 5 7 membered heterocycle containing, in addition to the nitrogen, one or two more heteroatoms selected from N, O, or S, said heterocycle being optionally substituted with one to three R.sup.2 substituents; R.sup.9 is independently selected from: (1) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, (2) unsubstituted or substituted heterocycle, and (3) unsubstituted or substituted aryl; V is selected from: (1) a bond, (2) aryl, and (3) heterocycle; W is selected from: (1) aryl, and (2) heterocycle; m is 0, 1, or 2; n is independently 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, or 4; q is independently 0, 1, or 2; t is independently 0, 1, 2, 3, 4, 5, or 6; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. The compound, according to claim 1, as illustrated by Formula I: ##STR00070## wherein R.sup.1a is independently selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.6 alkyl, and (3) OR.sup.8; R.sup.1 is independently selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, (3) halo, (4) CF.sub.3, (5) --(CH.sub.2).sub.tR.sup.9C(O)R.sup.8, (6) --C(O)R.sup.9, (7) --(CH.sub.2).sub.tOR.sup.8, (8) --(CH.sub.2).sub.tC(O)NR.sup.7R.sup.8, (9) --C(O)OR.sup.8, (10) --(CH.sub.2).sub.tNR.sup.7R.sup.8, and (11) --(CH.sub.2).sub.tS(O).sub.q(CH.sub.2).sub.tNR.sup.7R.sup.8; R.sup.2 is independently selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, (3) unsubstituted or substituted aryl, (4) unsubstituted or substituted heterocycle, (5) unsubstituted or substituted C.sub.3 C.sub.10 cycloalkyl, (6) unsubstituted or substituted C.sub.2 C.sub.6 alkenyl, (7) unsubstituted or substituted C.sub.2 C.sub.6 alkynyl, (8) CN, (9) halo, (10) N(R.sup.8).sub.2, and (11) OR.sup.8; R.sup.3 is independently selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, and (3) unsubstituted or substituted aralkyl; R.sup.7 is selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, and (3) unsubstituted or substituted aralkyl; R.sup.8 is independently selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, and (3) unsubstituted or substituted aryl; R.sup.7 and R.sup.8, when attached to the same nitrogen atom may be joined to form a 5 7 membered heterocycle containing, in addition to the nitrogen, one or two more heteroatoms selected from N, O, or S, said heterocycle being optionally substituted with one to three R.sup.2 substituents; R.sup.9 is independently selected from (1) unsubstituted or substituted aryl, and (2) unsubstituted or substituted heterocycle; V is selected from: (1) a bond, (2) aryl, and (3) heterocycle; W is selected from: (1) aryl, and (2) heteroaryl, selected from pyridyl, pyrimidinyl, isoxazolyl, or pyrazinyl; m is 0, 1, or 2; n is independently 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, or 4; q is independently 0, 1, or 2; t is independently 0, 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt or stereoisomer thereof. 3. The compound, according to claim 1, as illustrated by Formula II: ##STR00071## wherein R.sup.1 is independently selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, (3) halo, (4) unsubstituted or substituted aryl, (5) unsubstituted or substituted heterocycle, (6) CF.sub.3, (7) --(CH.sub.2).sub.tR.sup.9C(O)R.sup.8, (8) --C(O)R.sup.9, and (9) --(CH.sub.2).sub.tOR.sup.8; R.sup.2 is independently selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, (3) unsubstituted or substituted aryl, (4) unsubstituted or substituted heterocycle, (5) unsubstituted or substituted C.sub.2 C.sub.6 alkenyl, (6) unsubstituted or substituted C.sub.2 C.sub.6 alkynyl, (7) OR.sup.8, (8) CN, and (9) unsubstituted or substituted C.sub.3 C.sub.10 cycloalkyl; R.sup.3 is independently selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, and (3) unsubstituted or substituted aralkyl; R.sup.8 is independently selected from: (1) H, (2) unsubstituted or substituted C.sub.1 C.sub.10 alkyl, and (3) unsubstituted or substituted aryl; R.sup.9 is independently selected from (1) unsubstituted or substituted aryl, and (2) unsubstituted or substituted heterocycle; V is selected from: (1) a bond, (2) aryl, and (3) heterocycle; m is 0, 1, or 2; n is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, or 4; t is independently 0, 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt or stereoisomer thereof. 4. A compound selected from: N-(3-chlorophenyl)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine; N-(3,5-dimethylphenyl)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine; 4-[1-(4-chlorophenyl)-1H-pyrazol-5-yl]-N-(3,5-dimethylphenyl)pyrimidin-2-- amine; 4-[1-(3-chlorophenyl)-1H-pyrazol-5-yl]-N-(3,5-dimethylphenyl)pyrimi- din-2-amine; N-(3,5-dimethylphenyl)-4-(1-phenyl-1H-pyrazol-3-yl)pyrimidin-2-amine; N-(3,5-dimethylphenyl)-4-[1-(3,4-dimethylphenyl)-1H-pyrazol-5-yl]pyrimidi- n-2-amine; 4-[1-(2,3-dihydro-1H-inden-5-yl)-1H-pyrazol-5-yl]-N-(3,5-dimeth- ylphenyl) pyrimidin-2-amine; N-(3,5-dimethylphenyl)-4-{1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl }pyrimidin-2-amine; N-(3,5-dimethylphenyl)-4-[1-(3-ethynylphenyl)-1H-pyrazol-5-yl]pyrimidin-2- -amine; N-(3,5-dimethylphenyl)-4-[1-(3,5-dimethylphenyl)-1H-pyrazol-5-yl]p- yrimidin-2-amine; N-(3,5-dimethylphenyl)-4-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]pyrimidin-2- -amine; N-(3,5-dimethylphenyl)-4-[1-(3-methoxyphenyl)-1H-pyrazol-5-yl]pyri- midin-2-amine; N-(3,5-dimethylphenyl)-4-[1-(3-fluorophenyl)-1H-pyrazol-5-yl]pyrimidin-2-- amine; 4-(1-phenyl-1H-pyrazol-5-yl)-N-(4-piperazin-1-ylphenyl)pyrimidin-2-- amine; 4-(1-phenyl-1H-pyrazol-5-yl)-N-(piperidin-4-ylmethyl)pyrimidin-2-am- ine; methyl 4-{[4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-yl]amino }benzoate; 4-{[4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-yl]amino }benzoic acid; N-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl }-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine; N-(3,5-dimethylphenyl)-4-(4-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine; 4-(4-cyano-1H-pyrazol-5-yl)-2-[(3,5-dimethylphenyl)amino]pyrimidine; or a pharmaceutically acceptable salt thereof. 5. The compound, according to claim 4, which is selected from: ##STR00072## N-(3-chlorophenyl)-4-(1-phenyl1H-pyrazol-5-yl)pyrimidin-2-amine; ##STR00073## N-(3,5-dimethylphenyl)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidin-2-amine; ##STR00074## 4-[1-(3-chlorophenyl)-1H-pyrazol-5-yl]-N-(3,5-dimethylphenyl)pyrimidin-2-- amine; ##STR00075## N-(3,5-dimethylphenyl)-4-[1-(3-ethynylphenyl)-1H-pyrazol-5-yl]pyrimidin-2- -amine; ##STR00076## N-(3,5-dimethylphenyl)-4-[1-(3-fluorophenyl)-1H-pyrazol-5-yl]pyrimidin-2-- amine or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier. 7. 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 the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. 8. 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 the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, glioblastoma and breast carcinoma. 9. A process for making a pharmaceutical composition which comprises combining a compound of claim 1 with a pharmaceutically acceptable carrier. 10. The composition of claim 6 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, and 10) another angiogenesis inhibitor. 11. The composition of claim 10, 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-.alpha., 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. 12. The composition of claim 10, wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene. 13. A method of treating cancer, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung, which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with radiation therapy. 14. A method of treating cancer, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung, which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with a 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, and 10) another angiogenesis inhibitor. 15. A method of treating cancer, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung, which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with radiation therapy and a 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, and 10) another angiogenesis inhibitor. 16. A method of treating cancer, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung, which comprises administering a therapeutically effective amount of a compound of claim 1 and paclitaxel or trastuzumab. 17. A method of treating cancer, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung, which comprises administering a therapeutically effective amount of a compound of claim 1 and a GPIIb/IIIa antagonist. 18. The method of claim 17 wherein the GPIIb/IIIa antagonist is tirofiban. 19. A method of treating cancer, wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung, which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with a COX-2 inhibitor.

Details for Patent 7,109,204

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2021-08-01
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2021-08-01
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2021-08-01