Triazolopyrazine derivatives

Abstract

The invention relates to compounds of the formula I or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and R 4 are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formula I and to methods of treating hyperproliferative disorders in a mammal by administering the compounds of formula I.

1 . A method of treating a mammal having a c-Met related disorder, comprising administering to the mammal a therapeutically effective amount of a compound of the formula I: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  is selected from hydrogen, Br, Cl, F, —O(CH 2 ) n CH 3 , —NR 10 C(O)OR 12 , —(CR 12 R 13 ) n NR 10 R 11 , —O(CH 2 ) n OR 10 , —(CH 2 ) n OR 10 , —C(O)R 10 , —C(O)OR 10 , —C(O)NR 10 R 11 , —NR 10 R 11 , —S(O) 2 R 10 , —S(O)R 10 , —S(O) 2 NR 10 R 11 , —CF 3 , —CF 2 H, —NR 10 C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —NR 10 S(O) 2 R 11 , —N(CH 2 ) n (C 3 -C 8  cycloalkyl), —CN, —NO 2 , C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, 3-8 membered heteroalicyclic, 3-8 membered heteroalicyclic-(3-8 membered heteroalicyclic), 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C 6 -C 10  aryl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl wherein C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, 3-8 membered heteroalicyclic, 8-10 membered heterobicyclic, 5-7 membered heteroaryl, C 6 -C 10  aryl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl are optionally substituted by one or more moieties selected from the group consisting of Br, Cl, F, —(CH 2 ) n CH(OR 10 )CH 3 , —(CH 2 ) n OR 10 , —(CH 2 ) n C(CH 3 ) 2 OR 10 , —C(O)R 10 , —C(O)OR 10 , —(CR 10 R 11 ) n C(O)OR 10 , —C(O)NR 10 R 11 , —(CR 10 R 11 ) n C(O)NR 10 R 11 , —(CH 2 ) n NR 10 R 11 , —S(O) 2 R 10 , —S(O)R 10 , —S(O) 2 NR 10 R 11 , —CF 3 , —CF 2 H, —(CH 2 ) n NR 10 C(O)NR 10 R 11 , —(CH 2 ) n NR 10 C(O)OR 11 , —NR 10 C(O)R 11 , —NR 10 C(O)OR 11 , —NR 10 S(O) 2 R 11 , —CN, —NO 2 , oxo, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, —(CH 2 ) n (3-8 membered heteroalicyclic), —(CH 2 ) n (5-7 membered heteroaryl), —(CH 2 ) n (C 6 -C 10  aryl), C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl; 
       R 2  is H; 
       R 3  is selected from 
     
     
       
         
         
             
             
         
       
       R 10  and R 11  are independently selected from H, —(CH 2 ) n OR 12 , (CH 2 ) n C(CH 3 ) 2 OR 12 , —CHR 12 (CH 2 ) n OR 13 , —C(O)OR 12 , —(CH 2 ) n CHR 12 OR 13 , —C(CH 3 ) 2 (CH 2 ) n OR 12 , —CH 2 CF 2 H, —(CH 2 ) n C(CH 3 ) 2 NR 12 R 13 , —(CH 2 ) n NR 12 R 13 , —(CH 2 ) n CHOR 12 (CH 2 ) n OR 13 , —(CH 2 ) n (NR 12 R 13 )C(O)NR 12 R 13 , —(CH 2 ) n S(O) 2 R 12 , —(CH 2 ) n C(O)NR 12 R 13 , —NR 12 (CH 2 ) n (5-7 membered heteroaryl), —NR 12 (CH 2 ) n (3-8 membered heterocycle), —(CH 2 ) n (8-10 membered heterobicyclic), —(CH 2 ) n (3-8 membered heteroalicyclic), C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, C 2 -C 6  alkenyl, 3-8 membered heteroalicyclic and C 2 -C 6  alkynyl, wherein said 5-7 membered heteroaryl, 3-8 membered heterocycle and 8-10 membered heterobicyclic are optionally substituted by one or more moieties selected from the group consisting of —(CH 2 ) n OR 12 , C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, C 2 -C 6  alkenyl, 3-8 membered heteroalicyclic and C 2 -C 6  alkynyl; or when R 10  and R 11  are attached to the same atom, R 10  and R 11  optionally combine to form a 3-8 membered heteroalicyclic ring; 
       R 12  and R 13  are independently selected from H, C 1 -C 6  alkyl, —C(O)CH 3 , C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, C 2 -C 6  alkenyl, 5-7 membered heteroaryl and C 2 -C 6  alkynyl, wherein said 5-7 membered heteroaryl is optionally substituted by one or more moieties selected from the group consisting of C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, C 2 -C 6  alkenyl, and C 2 -C 6  alkynyl; or when R 12  and R 13  are attached to the same atom, R 12  and R 13  optionally combine to form a 3-8 membered heteroalicyclic ring; 
       R 4  is selected from the group consisting of hydrogen, and C 1 -C 6  alkyl; and 
       each n is independently 0, 1, 2, 3 or 4; 
       wherein 3-8 membered heteroalicyclic and 3-8 membered heterocycle are independently selected from the group consisting of aziridinyl, oxetanyl, thiapanyl, azepanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, azepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thieazapanyl, 1,4-diazepanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2-dihydropyridyl, and imidazolidinyl; 
       wherein 8-10 membered heterobicyclic is selected from the group consisting of benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, isoindolyl, quinolinyl, isoquinoliinyl, quinazolinyl, quinaxolinyl, indazolyl, purinyl, indolininyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, 3H-indolyl, indolyl, isoindolinyl, 2,3-dihydrobenzofuranyl, 1,3-dihydrobenzofuranyl, 1H-isoindolyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,2-dihydroquinoxalinyl, 1,2-dihydroquinazolinyl, 3,4-dihydroquinazolinyl, 3,3a-dihydropyrazolo[1,5-a]pyrimidinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, octahydropyrrolo[1,2-a]pyrazine, 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinyl, and 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine; 
       wherein 5-7 membered heteroaryl is selected from the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, tetrazolyl, pyridinyl, pyridazinyl, and pyrimidinyl; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       2 . The method of  claim 1 , wherein the c-Met related disorder is cancer. 
   
   
       3 . The method of  claim 2 , wherein the cancer is selected from breast cancer, lung cancer, colorectal cancer, prostate cancer, pancreatic cancer, glioma, liver cancer, gastric cancer, head cancer, neck cancer, melanoma, renal cancer, leukemia, myeloma, and sarcoma.