Claims for Patent: 9,199,983

Summary for Patent: 9,199,983

Title:	3-aryl-6-aryl-[1,2,4]triazolo[4,3-.alpha.]pyridines as inhibitors of cell proliferation and the use thereof
Abstract:	Disclosed are 3-aryl-6-aryl-[1,2,4]triazolo[4,3-a]pyridines thereof, represented by the Formula (I) wherein Ar.sub.1, Ar.sub.2, R.sub.1-R.sub.3 are defined herein. Compounds having Formula (I) are inhibitors of cell proliferation. Therefore, compounds of the invention may be used to treat clinical conditions in which uncontrolled growth and spread of abnormal cells occurs. ##STR00001##
Inventor(s):	Cai; Suixiong (Jiangsu, CN), Tian; Ye Edward (Jiangsu, CN), Dong; Haijun (Shanghai, CN), Chen; Lei (Jiangsu, CN), Yu; Zenghui (Jiangsu, CN), Yin; Feng (Jiangsu, CN), Bi; Sheng (Jiangsu, CN), Liu; Lijun (Jiangsu, CN), Wu; Lizhen (Jiangsu, CN)
Assignee:
Application Number:	13/885,896
Patent Claims:	1. A compound of Formula II: ##STR00007## or a pharmaceutically acceptable salt thereof, wherein: R.sub.1-R.sub.3 independently are hydrogen or C.sub.1-6 alkyl; R.sub.4-R.sub.13 independently are hydrogen, halo, C.sub.1-6 alkoxy, C.sub.1-10 alkyl, halo C.sub.1-6 alkyl, nitro, hydroxy, primary amino (--NH.sub.2), secondary amino (--NHR), tertiary amino (--NRR), or aminosulfonyl; wherein each R is independently C.sub.1-6 alkyl; with the proviso that at least one R.sub.4-R.sub.13 is independently C.sub.1-6 alkoxy; or R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6, or R.sub.6 and R.sub.7, or R.sub.7 and R.sub.8, taken together with the atoms to which they are attached to form --OCH.sub.2O-- or --OCH.sub.2CH.sub.2O--. 2. The compound of claim 1, wherein said compound is selected from the group consisting of: 3-(2-Methoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine; 3-(2-Methoxyphenyl)-6-(3-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine; 3,6-Bis(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine; 6-(2-Fluoro-4-methylphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyr- idine; 6-(4-Methoxy-3-methylphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,- 3-a]pyridine; 6-(4-Isopropoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine- ; 6-(4-Ethylphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine; 6-(4-Methoxy-2-methylphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]py- ridine; 6-(3-Hydroxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyri- dine; 6-(4-Hydroxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridi- ne; 6-(Benzo[d][1,3]dioxol-5-yl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a- ]pyridine; 6-(4-Ethoxy-3-methylphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo- [4,3-a]pyridine; 6-(4-Dimethylaminophenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyrid- ine; 6-(3-Chloro-4-methylphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a- ]pyridine; 6-(3-Hydroxy-4-methoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazo- lo[4,3-a]pyridine; 3-(2-Methoxyphenyl)-6-(4-methylphenyl)-[1,2,4]triazolo[4,3-a]pyridine; 3-(2-Methoxyphenyl)-6-(3-methylphenyl)-[1,2,4]triazolo[4,3-a]pyridine; 3-(2-Methoxyphenyl)-6-phenyl-[1,2,4]triazolo[4,3-a]pyridine; 6-(2,4-Dimethylphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine- ; 6-(3-Chloro-4-methoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]p- yridine; 3-(2-Methoxyphenyl)-6-(4-trifluoromethylphenyl)-[1,2,4]triazolo[4- ,3-a]pyridine; 6-(3-Methoxy-4-methylphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]py- ridine; 3-(2-Methoxyphenyl)-6-(3,4,5-trimethoxyphenyl)-[1,2,4]triazolo[4,3- -a]pyridine; 6-(3,5-Dimethyl-4-methoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-- a]pyridine; 6-(3,4-Dimethoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin- e; 6-(3,4-Dimethylphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridi- ne; 6-(3-Fluoro-4-methylphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]- pyridine; 6-(4-Hexyloxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]p- yridine; 6-(3-Fluoro-4-methoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[- 4,3-a]pyridine; 6-(2,4-Dimethoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin- e; 6-(4-Ethoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine; 6-(4-Hydroxy-3-methylphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]py- ridine; 6-(4-Amino-3-methoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,- 3-a]pyridine; 6-(3-Amino-4-methylphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyri- dine; 6-(3-Aminophenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine hydrochloride; 6-(3-Amino-4-methoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyr- idine hydrochloride; 6-(4-Aminophenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine hydrochloride; 6-(4-Methylaminophenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin- e hydrochloride; 3-(4-Chloro-2-methoxyphenyl)-6-(3-fluoro-4-methoxyphenyl)-[1,2,4]triazolo- [4,3-a]pyridine; 6-(3-Amino-4-methoxyphenyl)-3-(4-chloro-2-methoxyphenyl)-[1,2,4]triazolo[- 4,3-a]pyridine; 6-(3-Hydroxy-4-methoxyphenyl)-3-(2-methoxy-4-methylphenyl)-[1,2,4]triazol- o[4,3-a]pyridine; 6-(3-Amino-4-methoxyphenyl)-3-(2-methoxy-4-methylphenyl)-[1,2,4]triazolo[- 4,3-a]pyridine; 6-(3-Fluoro-4-methoxyphenyl)-3-(2-methoxy-4-methylphenyl)-[1,2,4]triazolo- [4,3-a]pyridine; 3-(2-Methoxyphenyl)-6-(4-methoxyphenyl)-7-methyl-[1,2,4]triazolo[4,3-a]py- ridine; 3-(2-Methoxyphenyl)-6-(4-methoxyphenyl)-8-methyl-[1,2,4]triazolo[4- ,3-a]pyridine; 6-(4-Hydroxy-3-methoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]p- yridine; 3-(4-Chloro-2-methoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[- 4,3-a]pyridine; 3-(4-Fluoro-2-methoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]py- ridine; 3-(4-Bromo-2-methoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,- 3-a]pyridine; 3-(2-Methoxy-4-trifluoromethylphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo- [4,3-a]pyridine; 3-(2,6-Dimethoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin- e; 3-(2,5-Dimethoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyrid- ine; 3-(6-Fluoro-2-methoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-- a]pyridine; 3,6-Bis(4-methoxyphenyl)-[1,2,4]triazolo[4,3-.alpha.]pyridine; 3-(3-Bromo-2,6-dimethoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a- ]pyridine; 3-(2-Methoxy-4-methylphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazol- o[4,3-a]pyridine; 6-(4-Methoxyphenyl)-3-phenyl-[1,2,4]triazolo[4,3-a]pyridine; 6-(4-Methoxyphenyl)-3-(2,4,5-trimethoxyphenyl)-[1,2,4]triazolo[4,3-a]pyri- dine; 3-(2,4-Dimethoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]py- ridine; 6-(4-Methoxyphenyl)-3-(2,3,4-trimethoxyphenyl)-[1,2,4]triazolo[4,3- -a]pyridine; 3-(2,3-Dimethoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridin- e; 3-(2-Ethoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine; 6-(4-Methoxyphenyl)-3-(2-methoxy-5-sulfamoylphenyl)-[1,2,4]triazolo[4,3-a- ]pyridine; 3-(2-Methoxy-5-methylphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazol- o[4,3-a]pyridine; 3-(3-Methoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine; 6-(4-Methoxyphenyl)-3-(2-methylphenyl)-[1,2,4]triazolo[4,3-a]pyridine; 6-(4-methoxyphenyl)-3-(2-methylaminophenyl)-[1,2,4]triazolo[4,3-a]pyridin- e; 3-(2-dimethylaminophenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyr- idine; 6-(3-Amino-4-methoxyphenyl)-3-(4-chloro-2-methoxyphenyl)-[1,2,4]tri- azolo[4,3-a]pyridine hydrochloride; 6-(3-Amino-4-methoxyphenyl)-3-(2-methoxy-4-methylphenyl)-[1,2,4]triazolo[- 4,3-a]pyridine hydrochloride; 3-(4-Chloro-2-methoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]py- ridine hydrochloride; 3-(2-Methoxy-4-methylphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]py- ridine hydrochloride; 3-(4-Amino-2-methoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyr- idine hydrochloride; 3-(4-Chloro-2-methoxyphenyl)-6-(4-methylaminophenyl)-[1,2,4]triazolo[4,3-- a]pyridine; 3-(4-Chloro-2-methoxyphenyl)-6-(3-hydroxy-4-methoxyphenyl)-[1,2,4]triazol- o[4,3-a]pyridine; 6-(3-Amino-4-methylphenyl)-3-(4-chloro-2-methoxyphenyl)-[1,2,4]triazolo[4- ,3-a]pyridine; 6-(3-Amino-4-methylphenyl)-3-(4-methyl-2-methoxyphenyl)-[1,2,4]triazolo[4- ,3-a]pyridine; and 6-(4-Methylaminophenyl)-3-(4-methyl-2-methoxyphenyl)-[1,2,4]triazolo[4,3-- a]pyridine; or a pharmaceutically acceptable salt thereof. 3. A method of treating a disorder responsive to the inhibition of uncontrolled cell proliferation in a mammal suffering therefrom, comprising administering to the mammal in need of such treatment an effective amount of a compound of claim 1, wherein said disorder is cancer. 4. The method according to claim 3, wherein said cancer is Hodgkin's disease, non-Hodgkin's lymphomas, acute or chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoide, head or neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, or pro static carcinoma. 5. The method of claim 3, wherein said cancer is drug resistant cancer. 6. The method of claim 3, further comprising administering at least one known anticancer agent, or a pharmaceutically acceptable salt of said agent. 7. The method according to claim 3, wherein said compound is administered together with at least one compound selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, campath, Herceptin.RTM., Rituxan.RTM., arsenic trioxide, gemcitabine, letrozole, fulvestrant, bendamustine, pralatrexate, pemetrexed, nelarabine, temozolomide, zoledronic acid, irinotecan, ixabepilone, cabazitaxel, vinorelbine, Panitumumab, Ofatumumab, Avastin, imatinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, bortezomib, vorinostat, romidepsin, temsirolimus, everolimus, thalidomide, lenalidomide, and alanosine. 8. The method of claim 3, further comprising treating said mammal with radiation-therapy. 9. The method of claim 3, wherein said compound is administered after surgical treatment of said mammal for said cancer. 10. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 11. The pharmaceutical composition of claim 10, further comprising at least one known anticancer agent, or a pharmaceutically acceptable salt of said agent. 12. The pharmaceutical composition of claim 10, further comprising at least one compound selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, campath, Herceptin.RTM., Rituxan.RTM., arsenic trioxide, gemcitabine, letrozole, fulvestrant, bendamustine, pralatrexate, pemetrexed, nelarabine, temozolomide, zoledronic acid, irinotecan, ixabepilone, cabazitaxel, vinorelbine, Panitumumab, Ofatumumab, Avastin, imatinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, bortezomib, vorinostat, romidepsin, temsirolimus, everolimus, thalidomide, lenalidomide, and alanosine. 13. The pharmaceutical composition of claim 12, comprising the compound of claim 4 and a pharmaceutically acceptable carrier. 14. The pharmaceutical composition of claim 12, comprising the compound of claim 5 and a pharmaceutically acceptable carrier. 15. The compound of claim 1, wherein R.sub.4-R.sub.8 independently are hydrogen, halo, C.sub.1-6 alkoxy, C.sub.1-10 alkyl, halo C.sub.1-6 alkyl, hydroxy, secondary amino (--NHR), tertiary amino (--NRR); or aminosulfonyl; and wherein R.sub.9-R.sub.13 independently are hydrogen, halo, C.sub.1-6 alkoxy, C.sub.1-10 alkyl, halo C.sub.1-6 alkyl, hydroxy, secondary amino (--NHR), tertiary amino (--NRR), or aminosulfonyl; wherein each R is independently C.sub.1-6 alkyl. 16. The compound of claim 1, wherein R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6, or R.sub.6 and R.sub.7, or R.sub.7 and R.sub.8, taken together with the atoms to which they are attached to form --OCH.sub.2O-- or --OCH.sub.2CH.sub.2O--. 17. The compound of claim 1, wherein R.sub.4-R.sub.13 independently are C.sub.1-6alkoxy, hydroxy, secondary amino (--NHR), tertiary amino (--NRR), or aminosulfonyl; wherein each R is independently C.sub.1-6 alkyl. 18. The compound of claim 1, wherein R.sub.4-R.sub.13 independently is C.sub.1-6 alkoxy. 19. The compound of claim 1, wherein said compound is selected from the group consisting of: 6-(4-Methoxy-3-methylphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]py- ridine; 6-(4-Dimethylaminophenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-- a]pyridine; 6-(3-Hydroxy-4-methoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]p- yridine; 6-(3-Chloro-4-methoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[- 4,3-a]pyridine; 6-(3-Amino-4-methoxyphenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyr- idine hydrochloride; 3-(4-chloro-2-methoxyphenyl)-6-(3-fluoro-2-methoxyphenyl)-[1,2,4]triazolo- [4,3-a]pyridine; 6-(3-Amino-4-methoxyphenyl)-3-(4-chloro-2-methoxyphenyl)-[1,2,4]triazolo[- 4,3-a]pyridine; 6-(3-Hydroxy-4-methoxyphenyl)-3-(2-methoxy-4-methylphenyl)-[1,2,4]triazol- o[4,3-a]pyridine; 6-(3-Amino-4-methoxyphenyl)-3-(2-methoxy-4-methylphenyl)-[1,2,4]triazolo[- 4,3-a]pyridine; 6-(3-Fluoro-4-methoxyphenyl)-3-(2-methoxy-4-methylphenyl)-[1,2,4]triazolo- [4,3-a]pyridine; 3-(4-Chloro-2-methoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]py- ridine; 3-(4-Bromo-2-methoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,- 3-a]pyridine; 3-(2-Methoxy-4-methylphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]py- ridine; 3-(2,4-Dimethoxyphenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]- pyridine; 3-(4-Chloro-2-methoxyphenyl)-6-(4-methylaminophenyl)-[1,2,4]tria- zolo[4,3-a]pyridine; 3-(4-Chloro-2-methoxyphenyl)-6-(3-hydroxy-4-methoxyphenyl)-[1,2,4]triazol- o[4,3-a]pyridine; 6-(3-Amino-4-methylphenyl)-3-(4-chloro-2-methoxyphenyl)-[1,2,4]triazolo[4- ,3-a]pyridine; 6-(3-Amino-4-methylphenyl)-3-(4-methyl-2-methoxyphenyl)-[1,2,4]triazolo[4- ,3-a]pyridine; and 6-(4-Methylaminophenyl)-3-(4-methyl-2-methoxyphenyl)-[1,2,4]triazolo[4,3-- a]pyridine; or a pharmaceutically acceptable salt thereof.

Details for Patent 9,199,983

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2030-11-16
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	11/14/2014		2030-11-16
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	10/12/2004		2030-11-16
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2030-11-16
Amgen, Inc.	VECTIBIX	panitumumab	Injection	125147	09/27/2006		2030-11-16
Novartis Pharmaceuticals Corporation	ARZERRA	ofatumumab	Injection	125326	10/26/2009		2030-11-16