Raf inhibitor compounds and methods

Abstract

Pyrazolyl compounds of Formulas Ia and Ib are useful for inhibiting Raf kinase and for treating disorders mediated thereby. Methods of using pyrazolyl compounds for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

1 . A compound selected from Formulas Ia and Ib: 
     
       
         
         
             
             
         
       
       and stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof, wherein: 
       the A-ring is a 5 or 6 membered heterocyclic ring having one or two heteroatoms independently selected from O, N, and S, wherein said heterocyclic, ring is optionally substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , NR 20 R 21 , —NR 20 C(═Y)R 21 , —NR 20 C(═Y)OR 21 , —NR 20 C(═Y)NR 20 R 21 , ═NOR 20 , ═NR 20 , ═N+(O)OR 20 , ═NNR 20 R 21 , ═O , —OR 20 , —OC(═Y)R 20 , —OC(═Y)OR 20 , —OC(═Y)NR 20 R 21 , —OS(O) 2 (OR 20 ), —OP(═Y)(OR 20 )(OR 21 ), —OP(OR 20 )(OR 21 ), —P(═Y)(OR 20 )(OR 21 ), —P(═Y)(OR 20 )NR 20 R 21 , ═S, —SRW, —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 NR 20 R 21 , —S(O)(OR 20 ), —S(O) 2 (OR 20 ), —SC(═Y)R 20 , —SC(═Y)OR 20 , —SC(═Y)NR 20 R 21 , C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 6 -C 20  aryl, C 3 -C 12  carbocyclyl, C 2 -C 20  heterocyclyl, and a protecting group, and wherein said alkyl, alkenyl, alkynyl, aryl, carbocyclyl and heterocyclyl are optionally and independently substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , NR 20 R 21 , —NR 20 C(═Y)R 21 , —NR 20 C(═Y)OR 21 , —NR 23 C(═Y)NR 20 R 21 , —OR 20 , —OC(═Y)R 20 , —OC(═Y)OR 20 , —OC(═Y)NR 20 R 21 , —OS(O) 2 (OR 20 ), —OP(═Y)(OR 20 )(OR 21 ), —OP(OR 20 )(OR 21 ), —P(═Y)(OR 20 )(OR 21 ), —P(═Y)(OR)NR 20 R 21 , —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 NR 20 R 21 , —S(O)(OR 20 ), —S(O) 2 (OR 20 ), —SC(═Y)R 20 , —SC(═Y)OR 20 , —SC(═Y)NR 20 R 21 , C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 6 -C 20  aryl, C 3 -C 12  carbocyclyl, C 2 -C 20  heterocyclyl; 
       X is a C 2 -C 20  heterocyclyl, wherein said heterocycle is optionally substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , —NR 20 R 21 , —NR 20 C(═Y)R 21 , —NR 20 C(═Y)OR 21 , —NR 23 C(═Y)NR 20 R 21 , —OR 20 , —OC(═Y)R 20 , —OC(═Y)OR 20 , —OC(═Y)NR 20 R 21 , —OS(O) 2 (OR 20 ), —OP(═Y)(OR 20 )(OR 21 ), —OP(OR 20 )(OR 21 ), —P(═Y)(OR 20 )(OR 21 ), —P(═Y)(OR 23 )NR 20 R 21 , —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 NR 20 R 21 , —S(O)(OR 20 ), —S(O) 2 (OR 20 ), —SC(═Y)R 20 , —SC(═Y)OR 20 , —SC(═Y)NR 20 R 21 , 5-7 membered ring lactam, 5-7 membered ring lactone, 5-7 membered ring sultam, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 12  carbocyclyl, C 6 -C 20  aryl, and C 2 -C 20  heterocyclyl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR 20 , NR 20 R 21 —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl; 
       R 1  is selected from H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, (C 1 -C 8  alkyl)NR 20 R 21 , a C 2 -C 20  heterocyclyl, a C 3 -C 12  carbocyclyl, and a C 6 -C 20  aryl, wherein said alkyl, alkenyl, alkynyl, heterocycle, carbocyclyl and aryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , —NR 20 R 21 , OR 20 , CN, C(═O)NR 20 R 21 , C(═O)OR 20 , alkyl, (C 1 -C 8  alkyl)NR 20 R 21 , and heterocyclyl; 
       R 2  is selected from H, F, Cl, Br, I, —C(═Y)R 20 , —C(═Y)OR 20 , —C(═Y)NR 20 R 21 , —OR 20 , —OC(═Y)R 20 , —OC(═Y)OR 20 , —OC(═Y)NR 20 R 21 , —OS(O) 2 (OR 20 ), —OP(═Y)(OR 20 )(OR 21 ), —OP(OR 20 )(OR 21 ), —P(═Y)(OR 20 )(OR 21 ), —P(═Y)(OR)NR 20 R 21 , —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , S(O) 2 NR 20 R 21 , —S(O)(OR 20 ), —S(O) 2 (OR 20 ), —SC(═Y)R 20 , —SC(═Y)OR 20 , —SC(═Y)NR 20 R 21 , 5-7 membered ring lactam, 5-7 membered ring lactone, 5-7 membered ring sultam, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 12  carbocyclyl, C 6 -C 20  aryl, and C 2 -C 20  heterocyclyl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR 20 , NR 20 R 21 —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl, 
       R 3 , R 4 , and R 5  are independently selected from H, F, Cl, Br, I, —C(═Y)R 20 , —C(═Y)OR 20 , C(═Y)NR 20 R 21 , —NR 20 R 21 , —NR 20 C(═Y)R 21 , —NR 20 C(═Y)OR 21 , —NR 23 C(═Y)NR 20 R 21 , —OR 20 , —OC(═Y)R 20 , —OC(═Y)OR 20 , —OC(═Y)NR 20 R 21 , —OS(O) 2 (OR 20 ), —OP(═Y)(OR 20 )(OR 21 ), —OP(OR 20 )(OR 21 ), —P(═Y)(OR 20 )(OR 21 ), —P(═Y)(OR 23 )NR 20 R 21 , —SR 20 , —S(O)R 20 , —S(O) 2 R 20 , —S(O) 2 NR 20 R 21 , —S(O)(OR 20 ), —S(O) 2 (OR 20 ), —SC(═Y)R 20 , —SC(═Y)OR 20 , —SC(═Y)NR 20 R 21 , 5-7 membered ring lactam, 5-7 membered ring lactone, 5-7 membered ring sultam, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 12  carbocyclyl, C 6 -C 20  aryl, and C 2 -C 20  heterocyclyl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, OR 20 , NR 20 R 21 —SR 20 , —S(O)R 20 , —S(O) 2 R 21 , alkyl, alkenyl, alkynyl, carbocyclyl, aryl, and heterocyclyl; 
       R 20  and R 21  are independently selected from H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 6 -C 20  aryl, C 2 -C 20  heterocyclyl, and a protecting group, wherein said alkyl, alkenyl, alkynyl, aryl, and heterocyclyl are optionally and independently substituted with one or more groups independently selected from F, Cl, Br, I, —C(═Y)R a , —C(═Y)OR a , —C(═Y)NR a R b , —OR a , —OC(═Y)R a , —OC(═Y)OR a , —OC(═Y)NR a R b , —OS(O) 2 (OR a ), —OP(═Y)(OR a )(OR b ), —OP(OR a )(OR b ), —P(═Y)(OR a )(OR b ), —P(═Y)(OR)NR a R b , —SR a , —S(O)R a , —S(O) 2 R a , S(O) 2 NR a R b , —S(O)(OR a ), —S(O) 2 (OR a ), —SC(═Y)R a , —SC(═Y)OR a , and —SC(═Y)NR a R b , 
       or R 20  and R 21  together with the atoms to which they are attached form a heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from F, Cl, Br, I, alkyl, alkenyl and alkynyl; 
       R 23  is H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 6 -C 20  aryl, C 2 -C 20  heterocyclyl, or a protecting group; 
       R a  and R b  are independently H, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 6 -C 20  aryl, or C 2 -C 20  heterocyclyl; 
       Y is independently O, S, NR 20 ,  + N(O)R 20 , N(OR 20 ),  + N(O)(OR 20 ), or N—NR 20 R 21 ; and 
       protecting group is selected from trialkylsilyl, dialkylphenylsilyl, benzoate, benzyl, benzyloxymethyl, methyl, methoxymethyl, triarylmethyl, phthalimido, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), 9-fluorenylmethylenoxycarbonyl (Fmoc), and tetrahydropyranyl. 
     
   
   
       2 . The compound of  claim 1  wherein R 1  is selected from H, methyl, CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NHCH 2 C(═O)OCH 3 , CH 2 CH 2 NHCH 2 CH 2 OH, CH 2 CH 2 OH, CH 2 CH(OH)CH 2 OH, CH 2 C(═O)OH, 
     
       
         
         
             
             
         
       
     
   
   
       3 - 22 . (canceled) 
   
   
       23 . The compound of  claim 2 , wherein X is an optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 2-oxazolyl, 4-oxazolyl, or 5-oxazolyl. 
   
   
       24 . The compound of  claim 23  wherein X is optionally substituted 4-pyridyl. 
   
   
       25 . The compound of  claim 1 , wherein the A-ring is an optionally substituted ring selected from tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, piperazinyl, pyrrolidinyl, pyridyl, pyrimidinyl, dihydrothiophenyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl. 
   
   
       26 . (canceled) 
   
   
       27 . (canceled) 
   
   
       28 . The compound of  claim 24 , wherein the A-ring is an optionally substituted ring selected from tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, piperazinyl, pyrrolidinyl, pyridyl, pyrimidinyl, dihydrothiophenyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl. 
   
   
       29 . The compound of  claim 1  selected from Formulas IIa-h and IIIa-f: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein Z is selected from NR 20 , O, and S. 
     
   
   
       30 . (canceled) 
   
   
       31 . The compound of  claim 29  wherein Z is O. 
   
   
       32 . The compound of  claim 29  wherein Y is O. 
   
   
       33 . The compound of  claim 29  wherein Y is N—OR 20 . 
   
   
       34 . The compound of  claim 33  wherein Y is N—OH. 
   
   
       35 . The compound of  claim 29  wherein Z is O, and Y is N—OR 2 —. 
   
   
       36 . (canceled) 
   
   
       37 . (canceled) 
   
   
       38 . (canceled) 
   
   
       39 . The compound of  claim 29  selected from Formulas IVa, IVb, Va and Vb: 
     
       
         
         
             
             
         
       
     
   
   
       40 - 57 . (canceled) 
   
   
       58 . The compound of  claim 1  selected from: 
     5-(1-methyl-3-pyridin-4-yl-1H-pyrazol-4-yl)-benzofuran-3(2H)-one oxime; 
     5-(1-methyl-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydrochromen-4-one oxime; 
     5-(1-methyl-3-pyridin-4-yl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one oxime; 
     5-(1-(2-hydroxyethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-indolin-2-one; 
     5-(1-(2-hydroxyethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-isoquinolin-1-ol; 
     5-(1-methyl-3-pyridin-4-yl-1H-pyrazol-4-yl)-indolin-2-one; 
     5-(1-(2-hydroxyethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydrophthalazine-1,4-dione; 
     5-(1-(2-hydroxyethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-6-1H-indole; 
     5-(1-(2-hydroxyethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-2-(2-methoxyethyl)isoindoline-1,3-dione; 
     5-(1-(2-hydroxyethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-benzo[d][1,3]dioxole; 
     5-(1-(2-hydroxyethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-quinazolin-4(3H)-one; 
     5-(1-(2-hydroxyethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-N-tert-butyloxycarbonyl-2,3-dihydro-1H-inden-1-amine; 
     5-(1-(2-hydroxyethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-5-1H-indole; 
     5-(1-(2-hydroxyethyl)-3-pyridin-4-yl-1H-pyrazol-4-yl)-5-isoindoline-1,3-dione;
 (Z)-5-(1-methyl-3-(pyridin-4-yl)-1H-pyrazol-4-yl)isoindolin-1-one oxime; 
 (Z)-5-(1-(1-methylpiperidin-4-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)isoindolin-1-one oxime; and 
 
     5-(1-(1-methylpiperidin-4-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)isoindolin-1-imine. 
   
   
       59 . A pharmaceutical composition comprised of a compound of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       60 . The composition according to  claim 59 , additionally comprising an additional therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders. 
   
   
       61 . A composition comprising the compound of  claim 1  in an amount to detectably inhibit Raf kinase activity and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
   
   
       62 - 76 . (canceled)