Methods of treating p38 kinase-associated conditions with pyrrolotriazine compounds

Abstract

Methods of treating one or more conditions associated with p38 kinase activity are disclosed comprising administering to a patient in need thereof at least one compound having the formula (I): or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein R 3 is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano, or NH 2 , preferably methyl, and X, R 1 through R 6 , and Z are as described in the specification. Advantageously the groups -ZR 4 R 5 taken together comprise an —NH-substituted aryl.

We claim:  
     
         1 . A method of treating one or more conditions associated with p38 kinase activity comprising administering to a patient in need thereof at least one compound having the formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: 
 R 3  is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano or NH 2 ;  
 X is selected from —O—, —OC(═O)—, —S—, —S(═O)—, —SO 2 —, —C(═O)—, —CO 2 —, —NR 10 —, —NR 10 C(═O)—, —NR 10 C(═O)NR 11 —, —NR 10 CO 2 —, —NR 10 SO 2 —, —NR 10 SO 2 NR 11 —, —SO 2 NR 10 —, —C(═O)NR 10 —, halogen, nitro, and cyano, or X is absent;  
 Z is selected from O, S, N, and CR 20 , wherein when Z is CR 20 , said carbon atom may form an optionally-substituted bicyclic aryl or heteroaryl with R 4  and R 5 ;  
 R 1  is hydrogen, —CH 3 , —OH, —OCH 3 , —SH, —SCH 3 , —OC(═O)R 21 , —S(═O)R 22 , —SO 2 R 22 , —SO 2 NR 24 R 25 , —CO 2 R 21 , —C(═O)NR 24 R 25 , —NH 2 , —NR 24 R 25 , —NR 21  SO 2 NR 24 R 25 , —NR 21 SO 2 R 22 , —NR 24 C(═O)R 25 , —NR 24 CO 2 R 25 , —NR 21 C(═O)NR 24 R 25 , halogen, nitro, or cyano;  
 R 2  is selected from: 
 a) hydrogen, provided that R 2  is not hydrogen when X is —S(═O)—, —SO 2 —, —NR 10 CO 2 —, or —NR 10 SO 2 —;  
 b) alkyl, alkenyl, and alkynyl optionally substituted with up to four R 26  or pentafluoroalkyl;  
 c) aryl and heteroaryl optionally substituted with up to three R 27 ; and  
 d) heterocyclo and cycloalkyl optionally substituted with keto (═O), up to three R 27 , and/or having a carbon-carbon bridge of 3 to 4 carbon atoms; or  
 e) R 2  is absent if X is halogen, nitro or cyano;  
 
 (i) R 4  is substituted aryl, aryl substituted with NHSO 2 alkyl, substituted heteroaryl, or an optionally-substituted bicyclic 7-11 membered saturated or unsaturated carbocyclic or heterocyclic ring, and  
 R 5  is hydrogen, alkyl, or substituted alkyl, except when Z is O or S, R 5  is absent, or alternatively,  
 (ii) R 4  and R 5  taken together with Z form an optionally-substituted bicyclic 7-11 membered aryl or heteroaryl;  
 R 6  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, —NR 7 R 8 , —OR 7 , or halogen;  
 R 10  and R 11  are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclo, and substituted heterocyclo;  
 R 7 , R 8 , R 21 , R 24 , and R 25  are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocylco, and substituted heterocyclo;  
 R 20  is hydrogen, lower alkyl, or substituted alkyl, or R 20  may be absent if the carbon atom to which it is attached together with R 4  and R 5  is part of an unsaturated bicyclic aryl or heteroaryl;  
 R 22  is alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, or substituted heterocyclo;  
 R 26  is selected from halogen, trifluoromethyl, haloalkoxy, keto (═O), nitro, cyano, —SR 28 , —OR 28 , —NR 28 R 29 , —NR 28 SO 2 , —NR 28 SO 2 R 29 , —SO 2 R 28 , —SO 2 NR 28 R 29 , —CO 2 R 28 , —C(═O)R 28 , —C(═O)NR 28 R 29 , —OC(═O)R 28 , —OC(═O)NR 28 R 29 , —NR 28 C(═O)R 29 , —NR 28 CO 2 R 29 , ═N—OH, ═N—O-alkyl; aryl optionally substituted with one to three R 27 ; cycloalkyl optionally substituted with keto(=O), one to three R 27 , or having a carbon-carbon bridge of 3 to 4 carbon atoms; and heterocyclo optionally substituted with keto (═O), one to three R 27 , or having a carbon-carbon bridge of 3 to 4 carbon atoms; wherein R 28  and R 29  are each independently selected from hydrogen, alkyl, alkenyl, aryl, aralkyl, C 3-7 cycloalkyl, and C 3-7 heterocycle, or may be taken together to form a C 3-7 heterocycle; and wherein each R 28  and R 29  in turn is optionally substituted with up to two of alkyl, alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, hydroxy, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy; and  
 R 27  is selected from alkyl, R 32 , and C 1-4 alkyl substituted with one to three R 32 , wherein each R 32  group is independently selected from halogen, haloalkyl, haloalkoxy, nitro, cyano, —SR 30 , —OR 30 , —NR 30 R 31 , —NR 30 SO 2 , —NR 30 SO 2 R 31 , —SO 2 R 30 , —SO 2 NR 30 R 31 , —CO 2 R 30 , —C(═O)R 30 , —C(═O)NR 30 R 31 , —OC(═O)R 30 , —OC(═O)NR 30 R 31 , —NR 30 C(═O)R 31 , —NR 30 CO 2 R 31 , and a 3 to 7 membered carbocyclic or heterocyclic ring optionally substituted with alkyl, halogen, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, amino, or cyano, wherein R 30  and R 31  are each independently selected from hydrogen, alkyl, alkenyl, aryl, aralkyl, C 3-7 cycloalkyl, and heterocycle, or may be taken together to form a C 3-7 heterocycle.  
 
     
     
         2 . The method of  claim 1  comprising administering to the patient at least one compound having the formula (I), or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
 R 3  is methyl, —CF 3 , or —OCH 3 ;  
 X is selected from —C(═O)—, —CO 2 —, —NR 10 —, —NR 10 C(═O)—, —NR 10 CO 2 —, —NR 10 SO 2 —, —SO 2 NR 10 —, and —C(═O)NR 10 —, or X is absent;  
 Z is N;  
 R 2  is hydrogen, C 2-6 alkyl, C 1-4 alkyl substituted with up to four R 26 , pentafluoroalkyl, or aryl or heteroaryl optionally substituted with up to two R 27 ;  
 R 4  is phenyl substituted with one R 12  and zero to three R 13 ;  
 R 5  and R 10  independently are selected from hydrogen and lower alkyl;  
 R 12  is carbamyl, sulfonamido, arylsulfonylamine, or ureido, each of which is optionally substituted with up to two of hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, and aralkyl, or alkylsulfonylamine;  
 R 13  at each occurrence is independently selected from alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, —OR 14 , —C(═O)alkyl, —OC(═O)alkyl, —NR 15 R 16 , —SR 15 , —NO 2 , —CN, —CO 2 R 15 , —CONH 2 , —SO 3 H, —S(═O)alkyl, —S(═O)aryl, —NHSO 2 -aryl-R 17 , —NHSO 2 -alkyl, —SO 2 NHR 17 , —CONHR 17 , and —NHC(═O)NHR 17 ;  
 R 14  is hydrogen, alkyl, or aryl;  
 R 15  is hydrogen or alkyl;  
 R 16  is hydrogen, alkyl, aralkyl, or alkanoyl; and  
 R 17  is hydrogen, hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, or aralkyl.  
 
     
     
         3 . A method of treating one or more conditions associated with p38 kinase activity comprising administering to a patient in need thereof at least one compound having the formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
 R 3  is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano or NH 2 ;  
 X is selected from —O—, —OC(═O)—, —S—, —S(═O)—, —SO 2 —, —C(═O)—, —CO 2 —, —NR 10 —, —NR 10 C(═O)—, —NR 10 C(═O)NR 11 —, —NR 10 CO 2 —, —NR 10 SO 2 —, —NR 10 SO 2 NR 11 —, —SO 2 NR 10 —, —C(═O)NR 10 —, halogen, nitro, and cyano, or X is absent;  
 Z is O, S, N, or CR 20 ;  
 R 1  is hydrogen, —CH 3 , —OH, —OCH 3 , —SH, —SCH 3 , —OC(═O)R 21 , —S(═O)R 22 , —SO 2 R 22 , —SO 2 NR 24 R 25 , —CO 2 R 21 , —C(═O)NR 24 R 25 , —NH 2 , —NR 21 SO 2 NR 24 R 25 , —NR 21 SO 2 R 22 , —NR 24 C(═O)R 25 , —NR 24 CO 2 R 25 , —NR 21 C(═O)NR 24 R 25 , halogen, nitro, or cyano;  
 R 2  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, aralkyl, substituted aralkyl, or heterocycloalkyl, or substituted heterocycloalkyl, or when X is halo, nitro or cyano, R 2  is absent, provided that R 2  is not hydrogen when X is —S(═O)—, —SO 2 —, —NR 10 CO 2 —, or —NR 10 SO 2 —;  
 R 4  is substituted aryl, aryl substituted with NHSO 2 alkyl, substituted heteroaryl, or an optionally-substituted bicyclic 7-11 membered saturated or unsaturated carbocyclic or heterocyclic ring system;  
 R 5  is hydrogen, alkyl, or substituted alkyl, except that when Z is O or S, R 5  is absent;  
 R 6  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, —NR 7 R 8 , —OR 7 , or halogen;  
 R 7 , R 8 , R 10 , R 11 , R 21 , R 24 , and R 25  are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, and substituted heterocyclo;  
 R 20  is hydrogen, lower alkyl, or substituted alkyl; and  
 R 22  is alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, or substituted heterocyclo.  
 
     
     
         4 . The method of  claim 3  comprising administering to the patient at least one compound of formula (I), in which R 4  and R 5  taken together with Z form:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
 R 12  is attached to any available carbon atom of phenyl ring A and is selected from carbamyl, sulfonamido, arylsulfonylamine, and ureido, each of which is optionally substituted with up to one of hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, and aralkyl, or C 1-4 alkylsulfonylamine;  
 R 13  is attached to any available carbon atom of phenyl ring A and at each occurrence is independently selected from alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, —OR 14 , —C(═O)alkyl, —OC(═O)alkyl, —NR 15 R 16 , —SR 15 , —NO 2 , —CN, —CO 2 R 15 , —CONH 2 , —SO 3 H, —S(═O)alkyl, —S(═O)aryl, —NHSO 2 -aryl-R 17 , —NHSO 2 C 1-4 alkyl, —SO 2 NHR 17 , —CONHR 17 , and —NHC(═O)NHR 17 ;  
 R 14  is hydrogen, alkyl, or aryl;  
 R 15  is hydrogen or alkyl;  
 R 16  is hydrogen, alkyl, aralkyl, or alkanoyl; and  
 R 17  is hydrogen, hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, or aralkyl; and  
 n is 0, 1, 2 or 3.  
 
     
     
         5 . The method of  claim 3  comprising administering to the patient at least one compound having the formula (II):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: 
 R 3  is methyl or CF 3 ;  
 X is —C(═O)NR 10 —, —NR 10 C(═O)—, —C(═O)—, or —CO 2 —;  
 R 1  is hydrogen, —CH 3 , —OH, —OCH 3 , halogen, nitro, or cyano;  
 Y is —C(═O)NH—, —NHC(═O)NH—, —NHSO 2 —, or —SO 2 NH—;  
 R 10  is hydrogen or lower alkyl;  
 R 18  is selected from hydrogen, alkyl, alkoxy, aryl, and aryl substituted with one to three R 19 , except that when Y is —NHSO 2 —, R 18  is C 1-4 alkyl, aryl or aryl substituted with R 19 ;  
 R 13  is attached to any available carbon atom of phenyl ring A and at each occurrence is independently selected from alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, —OR 14 , —C(═O)alkyl, —OC(═O)alkyl, —NR 15 R 16 , —SR 15 , —NO 2 , —CN, —CO 2 R 15 , —CONH 2 , —SO 3 H, —S(═O)alkyl, —S(═O)aryl, —NHSO 2 -aryl-R 17 , —NHSO 2 C 1-4 alkyl, —SO 2 NHR 17 , —CONHR 17 , and —NHC(═O)NHR 17 ;  
 R 14 , R 15 , R 16  and R 17  are hydrogen or alkyl;  
 R 19  at each occurrence is selected from alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, and aryloxy, wherein each group R 19  may be further substituted by hydroxy, alkyl, alkoxy, aryl, or aralkyl; and  
 n is 0, 1 or 2.  
 
     
     
         6 . The method of  claim 3 , comprising administering to the patient at least one compound having the formula (Ia), (Ib), or (Ic):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: 
 R 3  is methyl or CF 3 ;  
 R 2a  and R 2c  are independently selected from hydrogen, C 2-6 alkyl, substituted C 1-4 alkyl, aryl, substituted aryl, benzyl, and substituted benzyl;  
 R 2b  is heterocyclo or substituted heterocycle; and  
 R 10  is hydrogen or lower alkyl.  
 
     
     
         7 . The method according to  claim 1  wherein the one or more conditions associated with p38 kinase are selected from inflammatory disorders.  
     
     
         8 . The method of  claim 7 , in which the inflammatory disorder is selected from asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, diabetes, inflammatory bowel disease, osteoporosis, psoriasis, graft vs. host rejection, atherosclerosis, and arthritis including rhematoid arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, gouty arthritis and osteoarthritis.  
     
     
         9 . The method according to  claim 1  wherein the one or more conditions associated with p38 kinase are selected from autoimmune diseases, destructive bone disorders, proliferative disorders, angiogenic disorders, infectious diseases, neurodegenerative diseases, and viral diseases.  
     
     
         10 . The method according to  claim 1  wherein the one or more conditions associated with p38 kinase are selected from edema, analgesia, fever, and pain.  
     
     
         11 . The method according to  claim 10  wherein the pain is selected from neuromuscular pain, headache, pain caused by cancer, dental pain, and arthritis pain.