التفاصيل البيبلوغرافية
| العنوان: |
NOVEL INDAZOLE DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF AS PROTEIN KINASE INHIBITORS FOR PROLIFERATIVE DISEASES TREATMENT, AND A PHARMACEUTICAL COMPOSITION CONTAINING THE SAME AS AN ACTIVE INGREDIENT |
| Document Number: |
20120130069 |
| تاريخ النشر: |
May 24, 2012 |
| Appl. No: |
13/132772 |
| Application Filed: |
December 04, 2009 |
| مستخلص: |
Disclosed are novel indazole derivatives represented by the following Chemical Formula 1 or pharmaceutically acceptable salts, hydrates or solvates thereof, and pharmaceutical compositions for the prevention or treatment of proliferative diseases, containing the same as an active ingredient. Having potent inhibitory effect against protein kinase, such as b-raf, KDR, Fms, Tie2, SAPK2a and Ret, inducing diseases caused by abnormal cell proliferation, the novel indazole derivatives can be used for the prevention or treatment of diseases caused by abnormal cell proliferation. |
| Inventors: |
Sim, Tae Bo (Daegu, KR); Son, Jung Beom (Seoul, KR); Kim, Hwan (Gyeonggi-do, KR); Park, Dong Sik (Busan, KR); Choi, Hwan Geun (Seoul, KR); Ham, Young Jin (Seoul, KR); Hah, Jung Mi (Seoul, KR); Yoo, Kyung Ho (Seoul, KR); Oh, Chang Hyun (Seoul, KR); Lee, So Ha (Seoul, KR); Ha, Jae Du (Daejeon, KR); Cho, Sung Yun (Daejeon, KR); Kwon, Byoung Mog (Daejeon, KR); Han, Dong Cho (Daejeon, KR) |
| Claim: |
1. An indazole derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [chemical expression included] wherein, R1 is HOCH2— or [chemical expression included] R2 is hydrogen, hydroxy, C1-C3 alkoxy or R3—(CH2)n—NH—; R3 is hydrogen, dimethylamine, morpholin, phenyl, heteroaryl, phenyl which is substituted with CF3, or C3-C6 cycloalkyl; A is 5-6 membered aryl or heteroaryl which is substituted with R4 and LR5; R4 is hydrogen or C1-C3 alkyl; L is —NH— or —C(O)NH—; R5 is hydrogen, —C(O)—R6, —C(O)NH—R6 or —S(O)2—R6; R6 is one selected from a group consisting of phenyl, benzyl, 5 or 6 membered heteroaryl, naphthalenyl and benzothienyl, wherein each one substituted one or two substituents selected from a group consisting of hydrogen, —CH3, —CF3, —OCH3, —Br, —Cl, —NO2, [chemical expression included] and n is 0, 1 or 2. |
| Claim: |
2. The indazole derivative according to claim 1, wherein the R2 is hydrogen, hydroxy, methoxy, ethoxy or R3—(CH2)n—NH—. |
| Claim: |
3. The indazole derivative according to claim 1, wherein the R3 is hydrogen, dimethylamine, morpholin, phenyl, phenyl which is substituted with CF3, or cyclopropyl. |
| Claim: |
4. The indazole derivative according to claim 1, wherein the A is phenyl or thienyl which is substituted with R4 and —NHR6. |
| Claim: |
5. The indazole derivative according to claim 1, wherein the R4 is hydrogen or methyl. |
| Claim: |
6. The indazole derivative according to claim 1, wherein the 5 or 6 membered heteroaryl of R6 is thienyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, isothiazolyl, pyridyl, pyridazinyl or pyrazinyl. |
| Claim: |
7. The indazole derivative according to claim 1, wherein the R6 is phenyl, (trifluoromethyl)phenyl, 4-nitro-3-(trifluoromethyl)phenyl, 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenyl, 4-(1-methylpiperidine-4-yloxy)-3-(trifluoromethyl)phenyl, 3,4-dichlorophenyl, 4-chloro-3-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 3,4-dimethoxyphenyl, 3-morpholino-5-(trifluoromethyl)phenyl, 2,3-dichlorophenyl, 2,4-dimethylphenyl, 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl, 4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl, 3-(4-hydroxypiperadin-1-yl)-5-(trifluoromethyl)phenyl, 4-(1-methylpiperadin-4-yloxy)-3-(trifluoromethyl)phenyl, benzyl, 3,4-dimethoxybenzyl, thienyl, 5-bromothienyl, pyrazinyl, furanyl, 2,5-dimethylfuranyl, 5-(4-methoxypenyl)furanyl, 5-(2-chloro-5-(trifluoromethyl)phenyl)furanyl, isoxazolyl, 5-methyl isoxazolyl, pyrazolyl, 1-(4-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazolyl, pyridazinyl, pyridinyl, 3-chloropyridinyl, thiazolyl, 4-(2-(pyridin-4-yl)thiazolyl, naphthalenyl, 4,7-dimethoxynaphthalenyl, benzo[b]thiophenyl, pyrimidinyl, imidazolyl, pyrrolyl, dihydropyrrolyl, oxazolyl, triazolyl, thiadiazolyl, benzimidazolyl, quinolinyl, tetrahydroquinolinyl, benzothiazolyl, benzothiazophenyl, benzodioxolyl, indazolyl, indolyl, indylyl, dihydroindylyl or dihyrobenzofuranyl. |
| Claim: |
8. The indazole derivative according to claim 1, being selected from a group consisting of: 1) ethyl 6-(4-aminophenyl)-1H-indazole-3-carboxylate; 2) ethyl 6-(4-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylate; 3) ethyl 6-(4-(5-bromothiophene-2-carboxamido)phenyl)-1H-indazole-3-carboxylate; 4) ethyl 6-(4-(pyrazine-2-carboxamido)phenyl)-1H-indazole-3-carboxylate; 5) ethyl 6-(4-(benzo[b]thiophene-2-carboxamido)phenyl)-1H-indazole-3-carboxylate; 6) ethyl 6-(4-(2,5-dimethylfuran-3-carboxamido)phenyl)-1H-indazole-3-carboxylate; 7) ethyl 6-(4-(5-methylisoxazole-3-carboxamido)phenyl)-1H-indazole-3-carboxylate; 8) ethyl 6-(4-(1-(4-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenyl)-1H-indazole-3-carboxylate; 9) ethyl 6-(4-(4-nitro-3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylate; 10) ethyl 6-(4-(pyridazine-4-carboxamido)phenyl)-1H-indazole-3-carboxylate; 11) ethyl 6-(4-(2-(3,4-dimethoxyphenyl)acetamido)phenyl)-1H-indazole-3-carboxylate; 12) ethyl 6-(4-(5-(4-methoxyphenyl)furan-2-carboxamido)phenyl)-1H-indazole-3-carboxylate; 13) ethyl 6-(4-(3-chloroisonicotinamido)phenyl)-1H-indazole-3-carboxylate; 14) ethyl 6-(4-(thiazole-4-carboxamido)phenyl)-1H-indazole-3-carboxylate; 15) ethyl 6-(4-(4,7-dimethoxy-1-naphthamido)phenyl)-1H-indazole-3-carboxylate; 16) ethyl 6-(4-(5-(2-chloro-5-(trifluoromethyl)phenyl)furan-2-carboxamido)phenyl)-1H-indazole-3-carboxylate; 17) ethyl 6-(4-(2-(pyridin-4-yl)thiazole-4-carboxamido)phenyl)-1H-indazole-3-carboxylate; 18) ethyl 6-(4-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylate; 19) ethyl 6-(4-(4-(1-methylpiperidin-4-yloxy)-3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylate; 20) ethyl 6-(4-(3-(3,4-dichlorophenyl)ureido)phenyl)-1H-indazole-3-carboxylate; 21) ethyl 6-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-indazole-3-carboxylate; 22) ethyl 6-(4-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)phenyl)-1H-indazole-3-carboxylate; 23) ethyl 6-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-indazole-3-carboxylate; 24) N-methyl-6-(4-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxamide; 25) 6-(4-(5-(4-methoxyphenyl)furan-2-carboxamido)phenyl)-N-methyl-1H-indazole-3-carboxamide; 26) 6-(4-(5-bromothiophene-2-carboxamido)phenyl)-N-methyl-1H-indazole-3-carboxamide; 27) 6-(4-(benzo[b]thiophene-2-carboxamido)phenyl)-N-methyl-1H-indazole-3-carboxamide; 28) 6-(4-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)phenyl)-N-methyl-1H-indazole-3-carboxamide; 29) N-methyl-6-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-indazole-3-carboxamide; 30) N-(2-morpholinoethyl)-6-(4-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxamide; 31) 6-(4-(5-bromothiophene-2-carboxamido)phenyl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide; 32) 6-(4-(benzo[b]thiophene-2-carboxamido)phenyl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide; 33) 6-(4-(2,5-dimethylfuran-3-carboxamido)phenyl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide; 34) 6-(4-(1-(4-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenyl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide; 35) 6-(4-(5-bromothiophene-2-carboxamido)phenyl)-N-(3-(trifluoromethyl)phenyl)-1H-indazole-3-carboxamide; 36) 6-(4-(3-(3,4-dichlorophenyl)ureido)phenyl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide; 37) N-methyl-6-(4-(pyridazine-4-carboxamido)phenyl)-1H-indazole-3-carboxamide; 38)-5-methyl-N-(4-(3-(methylcarbamoyl)-1H-indazol-6-yl)phenyl)isoxazole-3-carboxamide; 39) N-methyl-6-(4-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxamide; 40) N-methyl-6-(4-(4-(1-methylpiperidin-4-yloxy)-3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxamide; 41)N-(4-(3-(methylcarbamoyl)-1H-indazol-6-yl)phenyl)thiazole-4-carboxamide; 42) methyl 5-(4-aminophenyl)-1H-indazole-3-carboxylate; 43) methyl 5-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-indazole-3-carboxylate; 44) ethyl 6-(3-aminophenyl)-1H-indazole-3-carboxylate; 45) ethyl 6-(3-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylate; 46) ethyl 6-(3-(5-methylisoxazole-3-carboxamido)phenyl)-1H-indazole-3-carboxylate; 47) ethyl 6-(3-(benzo[b]thiophene-2-carboxamido)phenyl)-1H-indazole-3-carboxylate; 48) ethyl 6-(3-(2-(3,4-dimethoxyphenyl)acetamido)phenyl)-1H-indazole-3-carboxylate; 49) ethyl 6-(3-(5-bromothiophene-2-carboxamido)phenyl)-1H-indazole-3-carboxylate; 50)N-(2-morpholinoethyl)-6-(3-(3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxamide; 51) methyl 6-(3-aminophenyl)-1H-indazole-3-carboxylate; 52) methyl 6-(3-(3-morpholino-5-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylate; 53) ethyl 6-(5-amino-2-methylphenyl)-1H-indazole-3-carboxylate; 54) ethyl 6-(3-(3-(2,3-dichlorophenyl)ureido)phenyl)-1H-indazole-3-carboxylate; 55) ethyl 6-(3-(3-(3,4-dichlorophenyl)ureido)phenyl)-1H-indazole-3-carboxylate; 56) methyl 6-(3-(3-(2,4-dimethyl phenyl)ureido)phenyl)-1H-indazole-3-carboxylate; 57) ethyl 6-(5-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-2-methylphenyl)-1H-indazole-3-carboxylate; 58) 6-3-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenyl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide; 59) 6-3-(3-morpholino-5-(trifluoromethyl)benzamido)phenyl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide; 60) 6-3-(3-(2,3-dichlorophenyl)ureido)phenyl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide; 61) 6-3-(3-(2,3-dichlorophenyl)ureido)phenyl)-N-ethyl-1H-indazole-3-carboxamide; 62) 6-3-(3-(3,4-dichlorophenyl)ureido)phenyl)-N-ethyl-1H-indazole-3-carboxamide; 63) 6-(3-(3-(2,4-dimethyl phenyl)ureido)phenyl)-N-ethyl-1H-indazole-3-carboxamide; 64) 6-(5-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-2-methylphenyl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide; 65) 6-(5-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-2-methylphenyl)-N-(2-(dimethylamino)ethyl)-1H-indazole-3-carboxamide; 66) 6-(5-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-2-methylphenyl)-N-cyclopropyl-1H-indazole-3-carboxamide; 67) 6-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide; 68) ethyl 6-(3-(3-(trifluoromethyl)phenylsulfonamido)phenyl)-1H-indazole-3-carboxylate; 69) ethyl 6-(3-(3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-indazole-3-carboxylate; 70) methyl 6-(3-(3-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-indazole-3-carboxylate; 71) ethyl 6-(2-methyl-5-(3-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)ureido)phenyl)-1H-indazole-3-carboxylate; 72) 5-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenyl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide; 73) N-methyl-6-(2-methyl-5-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxamide; 74) ethyl 6-(2-methyl-5-(3-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)ureido)phenyl)-1H-indazole-3-carboxylate; 75) N-methyl-6-(2-methyl-5-(3-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)ureido)phenyl)-1H-indazole-3-carboxamide; 76) ethyl 6-(3-(3-(4-hydroxypiperidin-1-yl)-5-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylate; 77) 6-3-(3-(4-hydroxypiperidin-1-yl)-5-(trifluoromethyl)benzamido)phenyl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide; 78) methyl 6-(3-(4-(1-methylpiperidin-4-yloxy)-3-(trifluoromethyl)benzamido)phenyl)-1H-indazole-3-carboxylate; 79) 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(3-(hydroxymethyl)-1H-indazol-6-yl)phenyl)urea; 80) ethyl-6-(5-(3-(trifluoromethyl)phenylcarbamoyl)thiophen-3-yl)-1H-indazole-3-carboxylate; or 81)6-(4-(2,5-dimethylfuran-3-carboxamido)phenyl)-N-(2-morpholinoethyl)-1H-indazole-3-carboxamide hydrochloride. |
| Claim: |
9. A pharmaceutical composition for the prevention or treatment of diseases caused by abnormal cell proliferation containing the indazole derivative represented by Chemical Formula 1 in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. |
| Claim: |
10. The pharmaceutical composition according to claim 9, wherein the indazole derivative inhibits protein kinase which is selected from a group consisting of b-raf, KDR, Fms, Tie2, SAPK2a and Ret. |
| Claim: |
11. The pharmaceutical composition according to claim 9, wherein the diseases caused by abnormal cell proliferation is selected from a group consisting of stomach cancer, lung cancer, liver cancer, colorectal cancer, pancreatic cancer, brain cancer, bone cancer, melanoma cancer, breast cancer, nodular sclerosing adenosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, Thyroid cancer, parathyroid cancer, renal cell cancer, osteosarcoma, prostatic carcinoma, urethra cancer, bladder cancer, blood cancer, lymphoma, psoriasis and fibroadenoma. |
| Claim: |
12. The pharmaceutical composition according to claim 11, wherein the blood cancer is s selected from a group consisting of leukemia, multiple myeloma and myelodysplastic syndrome. |
| Claim: |
13. The pharmaceutical composition according to claim 11, wherein the lymphoma is Hodgkin's disease or non-Hodgkin's lymphoma. |
| Current U.S. Class: |
544/80 |
| Current International Class: |
07; 07; 07; 07; 61; 07; 07; 07; 61; 61; 07; 07 |
| رقم الانضمام: |
edspap.20120130069 |
| قاعدة البيانات: |
USPTO Patent Applications |