Raf kinase modulators and methods of use

Abstract

The present invention comprises a new class of compounds capable of modulating the activity of Raf kinase and, accordingly, useful for treatment of Raf kinase mediated diseases, including melanomas, tumors and other cancer-related conditions. The compounds have a general Formula I wherein each of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , bond B, X, rings Z 1 and Z 2 , R 1 and R 3 are defined herein. The invention further comprises pharmaceutical compositions, methods for treatment of Raf kinase mediated diseases, and intermediates and processes useful for the preparation of compounds of the invention.

What is claimed is: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 A 1  is C, CR 2  or N, provided that when A 1  is CR 2  or N, then bond B is a single bond, and when A 1  is C then bond B is a double bond; 
 each of A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8  and A 9 , independently, is CR 2  or N, provided that (1) no more than two of A 3 , A 4 , A 5  and A 6  is N, and (2) no more than two of A 7 , A 8  and A 9  is N; 
 X is CR 2 R 2 , C(O), NR 2 , O or S(O) p  wherein p is 0, 1, or 2; 
 Z 1 , together with the carbon atoms or carbon and nitrogen atoms to which it is attached, is a fully saturated or partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and optionally substituted independently with 1-5 substituents of R 4 ; 
 Z 2  is 
 
       
       
         
           
           
               
               
           
         
         
           R 1  is H, halo, haloalkyl, NO 2 , CN, OR 7 , SR 7 , NR 7 R 7 , NR 7 R 8 , C(O)R 7 , C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl or C 3-6 -cycloalkyl; 
           each R 2  independently, is H, halo, haloalkyl, NO 2 , CN, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, NR 7 R 7 , NR 7 R 8 , OR 7 , SR 7 , C(O)R 7 , OC(O)R 7 , COOR 7 , C(O)NR 7 R 7 , C(S)NR 7 R 7 , NR 7 C(O)R 7 , NR 7 C(O)NR 7 R 7 , NR 7 (COOR 7 ), OC(O)NR 7 R 7 , S(O) 2 R 7 , S(O) 2 NR 7 R 7 , NR 7 S(O) 2 NR 7 R 7  or NR 7 S(O) 2 R 7 ; 
           R 3  is NR 5 R 5 , NR 5 R 6 , OR 5 , SR 5 , OR 6 , SR 6 , C(O)R 5 , C(S)R 5 , C(NCN)R 5 , C(O)R 6 , C(S)R 6 , C(NCN)R 6 , OC(O)R 5 , COOR 5 , C(O)NR 5 R 5 , C(O)NR 5 R 6 , NR 5 C(O)R 5 , NR 5 C(O)R 6 , NR 5 C(O)NR 5 R 5 , NR 5 C(O)NR 5 R 6 , NR 5 (COOR 5 ), NR 5 (COOR 6 ), S(O) 2 R 5 , S(O) 2 R 6 , S(O) 2 NR 5 R 5 , S(O) 2 NR 5 R 6 , NR 5 S(O) 2 NR 5 R 6 , NR 5 S(O) 2 R 5  or NR 5 S(O) 2 R 6 ; 
           each R 4 , independently, is H, halo, haloalkyl, oxo, OH, NO 2 , NH 2 , C 1-8 -alkyl, —O—C 1-8 -alkyl, —C 1-6 -alkyl-O—C 1-6 -alkyl, —S—C 1-8 -alkyl, —C 1-6 -alkyl-S—C 1-6 -alkyl, —NH—C 1-8 -alkyl, —N-di-C 1-8 -alkyl, —C 1-6 -alkyl-NH—C 1-6 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-6 -cycloalkyl, or a partially or fully saturated or unsaturated 5-8 membered monocyclic ring formed of carbon atoms optionally including 1-3 heteroatoms, wherein each of said C 1-8 -alkyl, C 1-8 -alkenyl, C 1-8 -alkynyl and ring is optionally substituted independently with 1-5 substituents of R 7 ; 
           each R 5  independently, is H, C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-6 -cycloalkyl or C 4-8 -cycloalkenyl, each of the C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl and C 4-10 -cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents of R 6  or R 7 , NR 6 R 7 , NR 7 R 7 , OR 6 , SR 6 , OR 7 , SR 6 , C(O)R 7 , OC(O)R 6 , COOR 6 , C(O)R 7 , OC(O)R 7 , COOR 7 , C(O)NR 6 R 7 , NR 7 C(O)R 6 , C(O)NR 7 R 7 , NR 7 C(O)R 7 , NR 7 C(O)NR 6 R 7 , NR 7 C(O)NR 7 R 7 , NR 7 (COOR 6 ), NR 7 (COOR 7 ), OC(O)NR 6 R 7 , OC(O)NR 7 R 7 , S(O) 2 R 6 , S(O) 2 R 7 , S(O) 2 NR 6 R 7 , S(O) 2 NR 7 R 7 , NR 7 S(O) 2 NR 6 R 7 , NR 7 S(O) 2 NR 7 R 7 , NR 7 S(O) 2 R 6 , NR 7 S(O) 2 R 7 , NR 7 S(O) 2 R 6  or NR 7 S(O) 2 R 7 ; 
           R 6  is a partially or fully saturated or unsaturated 5-8 membered monocyclic or 6-12 membered bicyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, and wherein each ring of said ring system is optionally substituted independently with 1-5 substituents of R 7 ; 
           alternatively, R 5  and R 6  taken together form a partially or fully saturated or unsaturated 5-6 membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-5 substituents of R 7 ; and 
           each R 7 , independently, is H, F, Cl, Br, I, haloalkyl, CN, OH, NO 2 , NH 2 , C 1-8 -alkyl, —O—C 1-8 -alkyl, —C 1-6 -alkyl-O—C 1-6 -alkyl, —S—C 1-8 -alkyl, —C 1-6 -alkyl-S—C 1-6 -alkyl, —NH—C 1-8 -alkyl, —N-di-C 1-8 -alkyl, —C 1-6 -alkyl-NH—C 1-6 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-6 -cycloalkyl, oxo, acetyl, benzyl or a partially or fully saturated or unsaturated 5-8 membered monocyclic or 6-12 membered bicyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each of said C 1-8 -alkyl, C 1-8 -alkenyl, C 1-8 -alkynyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, benzyl or phenyl, 
           provided the compound is not a compound wherein 
           Z 1  is an imidazole ring; 
           A 3  and A 4  are each CR 2 ; and 
           Z 2  is a pyridyl ring, and 
           provided the compound is not N-5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-yl)-6-methyl-N-1-(2-methyl-5-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine or 4-(5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile. 
         
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 1  is a ring selected from 
       
         
           
           
               
               
           
         
         wherein R 4  is as defined in  claim 1  and n is 1, 2 or 3. 
       
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1  is C, A 2  is N and bond B is a double bond. 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 2  is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of A 3 , A 4  and A 5 , independently, is CH and A 6  is N. 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of A 7 , A 8  and A 9 , independently, is CR 2  wherein each R 2 , independently, is H, halo, haloalkyl, NO 2 , CN, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, NR 7 R 7 , OR 7 , SR 7  or C(O)R 7  and R 7  is H, C 1-6 -alkyl or C 1-6 -haloalkyl. 
     
     
         7 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CH 2 , NH, O or S. 
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is NR 5 R 5 , NR 5 R 6 , NR 5 C(O)R 5 , NR 5 C(O)R 6 , NR 5 S(O) 2 R 6  or NR 5 S(O) 2 R 6 ;
 R 5  is H, C 1-6 -alkyl or C 3-6 -cycloalkyl optionally substituted with 1-3 substituents of R 7 ; and   R 6  is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl, indolyl, azaindolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl or piperazinyl, each of which is optionally substituted independently with 1-5 substituents of R 7 .   
     
     
         9 . The compound of  claim 1  having a Formula II 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 each of A 3  and A 4 , independently, is CR 2  or N, provided 
 
         that no more than one of A 3  and A 4  is N;
 X is CHR 2 , NH or O; 
 Z 1  is a ring selected from 
 
       
       
         
           
           
               
               
           
         
         
           Z 2  is a ring selected from 
         
       
       
         
           
           
               
               
           
         
         
           R 1  is H, halo, haloalkyl, CN, OR 7 , SR 7 , NR 7 R 7 , C(O)R 7  or C 1-6 -alkyl; 
           each R 2  independently, is H, halo, haloalkyl, CN, OR 7 , SR 7 , NR 7 R 7 , C(O)R 7  or C 1-6 -alkyl; 
           each R 4 , independently, is H, halo, haloalkyl, CN, OR 7 , SR 7 , NR 7 R 7 , C(O)R 7  or C 1-6 -alkyl; 
           R 5  is H, C 1-6 -alkyl or C 3-6 -cycloalkyl optionally substituted with 1-3 substituents of R 7 ; 
           R 6  is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, benzoisothiazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl, benzodioxolyl, benzodioxinyl, indolyl, 1,3-dihydroindol-2-one, quinolinone, azaindolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl or piperazinyl, each of which is optionally substituted independently with 1-5 substituents of R 7 ; and 
           each R 7 , independently, is H, F, Cl, Br, I, haloalkyl, CN, OH, NO 2 , NH 2 , C 1-8 -alkyl, —O—C 1-8 -alkyl, —C 1-6 -alkyl-O—C 1-6 -alkyl, —S—C 1-8 -alkyl, —C 1-6 -alkyl-S—C 1-6 -alkyl, —NH—C 1-8 -alkyl, —N-di-C 1-8 -alkyl, —C 1-6 -alkyl-NH—C 1-6 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-6 -cycloalkyl, oxo, acetyl, benzyl or a partially or fully saturated or unsaturated 5-8 membered monocyclic or 6-12 membered bicyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each of said C 1-8 -alkyl, C 1-8 -alkenyl, C 1-8 -alkynyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, benzyl or phenyl. 
         
       
     
     
         10 . The compound of  claim 9 , or a pharmaceutically acceptable salt thereof, wherein each R 2 , independently, is H, halo, haloalkyl or C 1-6 -alkyl; and
 each R 4 , independently, is H, halo, haloalkyl or C 1-6 -alkyl.   
     
     
         11 . The compound of  claim 9 , or a pharmaceutically acceptable salt thereof, wherein each of A 3  and A 4  is CR 2 . 
     
     
         12 . The compound of  claim 9 , or a pharmaceutically acceptable salt thereof, wherein at least one of the three R 2  substitutions is other than H. 
     
     
         13 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, selected from
 4-((6-methyl-5-((3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)amino)-1-isoquinolinyl)amino)benzonitrile;   6-methyl-N-1-(2-methyl-5-((trifluoromethyl)oxy)phenyl)-N-5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)-1,5-isoquinolinediamine;   N-1-(4-chlorophenyl)-6-methyl-N-5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)-1,5-isoquinolinediamine;   N-1-(3-ethynylphenyl)-6-methyl-N-5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)-1,5-isoquinolinediamine;   N-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-6-methyl-N-5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)-1,5-isoquinolinediamine;   3,3-difluoro-1-methyl-5-((6-methyl-5-((3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)amino)-1-isoquinolinyl)amino)-1,3-dihydro-2H-indol-2-one;   3,3-difluoro-5-((6-methyl-5-((3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)amino)-1-isoquinolinyl)amino)-1,3-dihydro-2H-indol-2-one;   (3R)-3-methyl-6-((6-methyl-5-((3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)amino)-1-isoquinolinyl)amino)-1,3-dihydro-2H-indol-2-one;   6-methyl-N-1-(3-methyl-1,2-benzisothiazol-5-yl)-N-5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)-1,5-isoquinolinediamine;   N-1-1,3-benzothiazol-6-yl-6-methyl-N-5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)-1,5-isoquinolinediamine;   6-((6-methyl-5-((3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)amino)-1-isoquinolinyl)amino)-1,3-dihydro-2H-indol-2-one;   3,3-dimethyl-6-((6-methyl-5-((3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)amino)-1-isoquinolinyl)amino)-1,3-dihydro-2H-indol-2-one;   4-methyl-7-((6-methyl-5-((3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)amino)-1-isoquinolinyl)amino)-2(1H)-quinolinone;   6-methyl-N-5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)-N-1-(4-(trifluoromethyl)phenyl)-1,5-isoquinolinediamine;   6-methyl-N-5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)-N-1-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)-1,5-isoquinolinediamine;   N-5-(2-chloro-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-pyrimidinyl)-6-methyl-N-1-(2-methyl-5-(trifluoromethyl)phenyl)-1,5-isoquinolinediamine;   4-((7-methyl-8-((3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-pyridinyl)amino)-4-quinazolinyl)amino)benzonitrile;   N-1-(4-chlorophenyl)-6-methyl-N-5-(3-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)-2-pyridinyl)-1,5-isoquinolinediamine;   4-((6-methyl-5-((3-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)-2-pyridinyl)amino)-1-isoquinolinyl)amino)benzonitrile;   N-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-6-methyl-N-5-(3-(5H-pyrrolo[3,2-d]pyrimidin-4-yl)-2-pyridinyl)-1,5-isoquinolinediamine;   6-methyl-N-5-(3-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-pyridinyl)-N˜1˜-(3-(trifluoromethyl)phenyl)-1,5-isoquinolinediamine;   N-5-(3-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-N1-(4-methoxy-3-(trifluoromethyl)phenyl)-6-methylisoquinoline-1,5-diamine;   N-5-(3-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-N1-(4-chlorophenyl)-6-methylisoquinoline-1,5-diamine; and   N-(4-chlorophenyl)-6-methyl-5-((3-(9H-purin-6-yl)-2-pyridinyl)oxy)-1-isoquinolinamine.   
     
     
         14 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any of  claims 1 - 13 . 
     
     
         15 . Use of a compound according to  claims 1 - 13  for the preparation of a medicament for the treatment of cancer. 
     
     
         16 . Use of a compound according to  claims 1 - 13  for the preparation of a medicament for the treatment of melanoma, solid tumor, ovarian cancer, pancreatic cancer, lung cancer, colon cancer or thyroid cancer or a combination thereof in a subject. 
     
     
         17 . A process for synthesizing a compound of any of  claims 1 - 13 , the process comprising the step of reacting a compound of Formula A 
       
         
           
           
               
               
           
         
         wherein X is a nucloephilic species selected from an amine, an alcohol, a thiol and a carbion nucleophile, and wherein A 7-9 , Z 2  and R 3  are as defined in  claim 1 , with a compound of Formula B 
       
       
         
           
           
               
               
           
         
         wherein LG is a leaving group selected from a halogen, a metallic species, a boronic acid and a Grignard reagent, and wherein A 1-6 , bond B, Z 1  and R 1  are as defined in  claim 1 , to synthesize the compound of  claim 1 .