Pyrrolo-triazine aniline compounds useful as kinase inhibitors

Abstract

Compounds having the formula (I), and pharmaceutically acceptable salts, prodrugs, and solvates thereof, are useful as kinase inhibitors, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X and Z are as described in the specification.

1 . A compound having the formula (I) 
       
         
           
           
               
               
           
         
       
       enantiomers, diastereomers, salts, and solvates thereof, wherein
 X is selected from —O—, —OC(═O)—, —S—, —S(═O)—, —SO 2 —, —C(═O)—, —CO 2 —, —NR 8 —, —NR 8 C(═O)—, —NR 8 C(═O)NR 9 —, —NR 8 CO 2 —, —NR 8 SO 2 —, —NR 8 SO 2 NR 9 —, —SO 2 NR 8 —, —C(═O)NR 8 —, halogen, nitro, and cyano, or X is absent; 
 Z is —C(═O)NR 10 —B b , —(CH 2 )—C(═O)NR 10 —B c , —NR 10a  C(═O)—B a , —(CH 2 )—NR 10a C(═O)—B c , —NR 10a C(═O)NR 10 —B, —NR 10 SO 2 —B, —SO 2 NR 10 —B, —C(═O)—B a , —CO 2 —B e , —OC(═O)—B a , —C(═O)NR 10 —NR 10a —B d , —NR 10 CO 2 —B a  or —C(═O)NR 10 —(CH 2 )C(═O)B a ; 
 B is
 (a) optionally-substituted cycloalkyl, optionally-substituted heterocyclo, or optionally substituted heteroaryl; or 
 (b) aryl substituted with one R 11  and zero to two R 12 ; 
 
 B a  is optionally substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; 
 B b  is
 (a) optionally-substituted cycloalkyl, optionally-substituted heterocyclo, or optionally substituted heteroaryl; 
 (b) aryl substituted with one R 11  and zero to two R 12 ; or 
 (c) —C(═O)R 13 , —CO 2 R 13 , —C(═O)NR 13 R 13a ; 
 
 B c  is optionally substituted alkyl, optionally substituted alkoxy, optionally-substituted cycloalkyl, optionally-substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; 
 B d  is hydrogen, —C(═O)R 13 , or —CO 2 R 13 ; 
 B e  is hydrogen, optionally substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; 
 R 1  and R 5  are independently selected from hydrogen, alkyl, substituted alkyl, —OR 14 , —SR 14 , —OC(═O)R 14 , —CO 2 R 14 , —C(═O)NR 14 R 14a , —NR 14 R 14a , —S(═O)R 14 , —SO 2 R 14 , —SO 2 NR 14 R 14a , —NR 14 SO 2 NR 14a R 14b , —NR 14a SO 2 R 14 , —NR 14 C(═O)R 14a , —NR 14 CO 2 R 14a , —NR 14 C(═O)NR 14a R 14b , halogen, nitro, and cyano; 
 R 2  is hydrogen or C 1-4 alkyl; 
 R 3  is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano, NH 2 , or NH(CH 3 ); 
 R 4  is selected from:
 (a) hydrogen, provided that R 4  is not hydrogen if X is —S(═O)—, —SO 2 —, —NR 8 CO 2 —, or —NR 8 SO 2 —; 
 (b) alkyl, alkenyl, and alkynyl optionally independently substituted with keto and/or one to four R 17 ; 
 
 (c) aryl and heteroaryl either of which may be optionally independently substituted with one to three R 16 ; and 
 (d) heterocyclo and cycloalkyl either of which may be optionally independently substituted with keto and/or one to three R 16 ; or 
 (e) R 4  is absent if X is halogen, nitro, or cyano; 
 R 6  is attached to any available carbon atom of phenyl ring A and at each occurrence is independently selected from alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, alkylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, phenyl, benzyl, aryloxy, and benzyloxy, wherein each R 6  group in turn may be further substituted by one to two R 18 ; 
 R 8  and R 9  are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl; 
 R 10  and R 10a  are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, and aryl; 
 R 11  is selected from
 (a) alkyl, haloalkyl, alkoxy, haloalkoxy, —SO 2 alkyl, cycloalkyl, heterocyclo, and heteroaryl any of which may be optionally substituted; or 
 (b) halo, cyano, amino, alkylamino, and dialkylamino; 
 
 R 12  is selected from alkyl, R 17 , and C 1-4 alkyl substituted with keto (═O) and/or one to three R 17 ; 
 R 13  and R 13a  are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl and optionally substituted aryl; 
 R 14 , R 14a  and R 14b  are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl, except when R 14  is joined to a sulphonyl group as in —S(═O)R 14 , —SO 2 R 14 , and —NR 14a SO 2 R 14 , then R 14  is not hydrogen; 
 R 16  is selected from alkyl, R 17 , and C 1-4 alkyl substituted with keto (═O) and/or one to three R 17 ; 
 R 17  is selected from
 (a) halogen, haloalkyl, haloalkoxy, nitro, cyano, —SR 23 , —OR 23 , —NR 23 R 24 , —NR 23 SO 2 R 25 , —SO 2 R 25 , —SO 2 NR 23 R 24 , —CO 2 R 23 , —C(═O)R 23 , —C(═O)NR 23 R 24 , —OC(═O)R 23 , —OC(═O)NR 23 R 24 , —NR 23 C(═O)R 24 , —NR 23 CO 2 R 24 ; 
 (b) aryl or heteroaryl either of which may be optionally substituted with one to three R 26 ; or 
 (c) cycloalkyl or heterocyclo optionally substituted with keto(═O) and/or one to three R 26 ; 
 
 R 18  and R 26  are independently selected from C 1-6 alkyl, C 2-6 alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C 1-4 alkylamino, aminoC 1-4 alkyl, hydroxy, hydroxyC 1-4 alkyl, alkoxy, C 1-4 alkylthio, aryl, heterocyclo, (aryl)alkyl, aryloxy, and (aryl)alkoxy; 
 R 23  and R 24  are each independently selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heteroaryl, and heterocyclo; 
 R 25  is selected from alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl and heterocyclo; and 
 m is 0, 1, 2 or 3. 
 
     
     
         2 . A compound of  claim 1  having the formula (I*): 
       
         
           
           
               
               
           
         
       
       enantiomers, diastereomers, salts and solvates thereof wherein
 X is selected from —O—, —OC(═O)—, —S—, —S(═O)—, —SO 2 —, —C(═O)—, —CO 2 —, —NR 8 —, —NR 8 C(═O)—, —NR 8 C(═O)NR 9 —, —NR 8 CO 2 —, —NR 8 SO 2 —, —NR 8 SO 2 NR 9 —, —SO 2 NR 8 —, —C(═O)NR 8 —, halogen, nitro, and cyano, or X is absent; 
 Y is —C(═O)NR 10 —, —NR 10a C(═O)NR 10 —, —NR 10 SO 2 —, —SO 2 NR 10 —, —C(═O)—, —CO 2 — or —OC(═O)—; 
 B is optionally-substituted cycloalkyl, heterocyclo, or heteroaryl; or aryl substituted with one R 11  and zero to two R 12 ; or when Y is —C(═O)NR 10 —, B also may be selected from —C(═O)R 13 , —CO 2 R 13 , and —C(═O)NR 13 R 13a ; 
 R 1  and R 5  are independently selected from hydrogen, alkyl, substituted alkyl, —OR 14 , —SR 14 , —OC(═O)R 14 , —CO 2 R 14 , —C(═O)NR 14 R 14a , —NR 14 R 14a , —S(═O)R 14 , —SO 2 R 14 , —SO 2 NR 14 R 14a , —NR 14 SO 2 NR 14a R 14b , —NR 14a SO 2 R 14 , —NR 14 C(═O)R 14a , —NR 14 CO 2 R 14a , —NR 14 C(═O)NR 14a R 14b , halogen, nitro, and cyano; 
 R 2  is hydrogen or C 1-4 alkyl; 
 R 3  is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano, NH 2 , or NH(CH 3 ); 
 R 4  is selected from:
 a) hydrogen, provided that R 4  is not hydrogen if X is —S(═O)—, —SO 2 —, —NR 8 CO 2 —, or —NR 8 SO 2 —; 
 b) alkyl, alkenyl, and alkynyl optionally substituted with keto and/or one to four R 17 ; 
 c) aryl and heteroaryl optionally substituted with one to three R 16 ; and 
 d) heterocyclo and cycloalkyl optionally substituted with keto and/or one to three R 16 ; or 
 e) R 4  is absent if X is halogen, nitro, or cyano; 
 
 R 6  is attached to any available carbon atom of phenyl ring A and at each occurrence is independently selected from alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, alkylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, phenyl, benzyl, aryloxy, and benzyloxy, wherein each R 6  group in turn may be further substituted by one to two R 18 ; 
 R 8  and R 9  are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl; 
 R 10  and R 10a  are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, and aryl; 
 R 11  is selected from optionally-substituted cycloalkyl, heterocyclo, and heteroaryl; 
 R 12  is selected from alkyl, R 17 , and C 1-4 alkyl substituted with keto (═O) and/or one to three R 17 ; 
 R 13  and R 13a  are selected from hydrogen, alkyl, and substituted alkyl; 
 R 14 , R 14a  and R 14b  are independently selected from hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, heterocyclo, and heteroaryl, except when R 14  is joined to a sulphonyl group as in —S(═O)R 14 , —SO 2 R 14 , and —NR 14a SO 2 R 14 , then R 14  is not hydrogen; 
 R 16  is selected from alkyl, R 17 , and C 1-4 alkyl substituted with keto (═O) and/or one to three R 17 ; 
 R 17  is selected from halogen, haloalkyl, haloalkoxy, nitro, cyano, —SR 23 , —OR 23 , —NR 23 R 24 , —NR 23 SO 2 R 25 , —SO 2 R 25 , —SO 2 NR 23 R 24 , —CO 2 R 23 , —C(═O)R 23 , —C(═O)NR 23 R 24 , —OC(═O)R 23 , —OC(═O)NR 23 R 24 , —NR 23 C(═O)R 24 , —NR 23 CO 2 R 24 , aryl or heteroaryl optionally substituted with one to three R 26 ; or cycloalkyl or heterocyclo optionally substituted with keto(═O) and/or one to three R 26 ; 
 R 18  and R 26  are independently selected from C 1-6 alkyl, C 2-6 alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C 1-4 alkylamino, aminoC 1-4 alkyl, hydroxy, hydroxyC 1-4 alkyl, alkoxy, C 1-4 alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy; 
 R 23  and R 24  are each independently selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heteroaryl, and heterocyclo; 
 R 25  is selected from alkyl, substituted alkyl, aryl, heteroaryl, cyclo alkyl and heterocyclo; and 
 m is 0, 1, 2 or 3. 
 
     
     
         3 . A compound according to  claim 2 , or a pharmaceutically-acceptable salt, or an hydrate thereof, in which:
 B is a C 3-7 cycloalkyl optionally substituted with one to two R 7 , a five membered heteroaryl optionally substituted with one to two R 7 , a five or six membered heterocyclo optionally substituted with one to two R 7 , aryl substituted with one R 11  and zero to two R 12 ; or when Y is —C(═O)NR 10 —, B also may be selected from —C(═O)R 13 , —CO 2 R 13 , and —C(═O)NR 13 R 13a ;   R 7  is attached to any available carbon or nitrogen atom of ring B and at each occurrence is independently selected from keto (═O), alkyl, substituted alkyl, halogen, haloalkoxy, ureido, cyano, —SR 20 , —OR 20 , —NR 2 OR 21 , —NR 20 SO 2 R 21 , —SO 2 R 19 , —SO 2 NR 20 R 21 , —CO 2 R 20 , —C(═O)R 20 , —C(═O)NR 20 R 21 , —C(═O)R 20 , —OC(═O)NR 20 R 21 , —NR 20 C(═O)R 21 , —NR 20 CO 2 R 21 , aryl, cycloalkyl, heterocycle, and heteroaryl; and/or when B is cycloalkyl, two R 7  groups may join to form an optionally-substituted carbon-carbon bridge of three to four carbon atoms, or two R 7  groups may join to form a fused carbocyclic, heterocyclic or heteroaryl ring, said fused ring being in turn optionally substituted with one to three R 22 ;   R 20  and R 21  are selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, phenyl, C 3-7 cycloalkyl, and five-to-six membered heterocyclo or heteroaryl; and   R 12  and R 22  are independently selected from C 1-6 alkyl, C 2-6 alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C 1-4 alkylamino, aminoC 1-4 alkyl, hydroxy, hydroxyC 1-4 alkyl, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy.   
     
     
         4 . A compound according to  claim 2 , having the formula (Ia), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, prodrug, or solvate thereof, wherein:
 R 3  is methyl, —CF 3 , or —OCF 3 ; 
 X is —C(═O)—, —NR 8 C(═O)—, or —C(═O)NR 8 —, wherein R 8  is hydrogen or C 1-4 alkyl; 
 Y is —C(═O)NH—, —NHC(═O)NH—, or —NHSO 2 —; 
 R 4  is hydrogen, C 2-6 alkyl, C 1-4 alkyl optionally substituted with one to three R 17 , cycloalkyl or heterocycle optionally-substituted with keto (═O) and/or one to three R 16 ; or aryl or heteroaryl optionally substituted with one to three R 16 ; 
 R 6a  and R 6b , are independently selected from hydrogen, C 1-6 alkyl, substituted C 1-4 alkyl, halogen, trifluoromethoxy, trifluoromethyl, —OR 27 , —C(═O)alkyl, —OC(═O)alkyl, —NR 27 R 28 , —SR 27 , —NO 2 , —CN, —CO 2 R 27 , —CONH 2 , —SO 3 H, —S(═O)alkyl, —S(═O)aryl, —NHSO 2 -aryl-R 27 , —SO 2 NHR 27 , —CONHR 27 , and —NHC(═O)NHR 27 ; 
 R 16  is selected from C 1-4 alkyl, R 17 , and C 1-4 alkyl substituted with keto (═O) and/or one to two R 17 ; 
 R 17  is selected from halogen, hydroxy, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 3-7 cycloalkyl, or five or six membered heteroaryl or heterocycle; and 
 R 27  and R 28  are selected from hydrogen, C 1-4 alkyl, phenyl, C 3-7 cycloalkyl, and five-to-six membered heterocyclo or heteroaryl. 
 
     
     
         5 . A compound according to  claim 2 , or a pharmaceutically-acceptable salt, or solvate thereof, wherein:
 ring B is phenyl substituted with heterocycle and zero to one R 12 , or is a cycloalkyl, heteroaryl, or heterocyclo ring selected from:   
       
         
           
           
               
               
           
         
         wherein E, G, J and K are selected from O, S, NH and CH 2 , provided that when q is 0, then J and K are not simultaneously selected from O and S; and 
         M is N or CH; wherein each hydrogen atom of E, G, J, K and M may optionally be replaced with an R 7  group; 
         R 7  and R 12  are independently selected from C 1-6 alkyl, substituted C 1-4 alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, —C 1-4 alkoxy, —C(═O)alkyl, —OC(═O)alkyl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , —CN, —CO 2 alkyl, —CONH 2 , —CONH(CH 3 ), —CON(CH 3 ) 2 , phenyl, benzyl, C 3-7  cycloalkyl, and five-to-six membered heterocyclo or heteroaryl; 
         n is 0, 1 or 2; and 
         p and q are selected from 0, 1, 2, 3 and 4, provided that p and q taken together are not greater than 4. 
       
     
     
         6 . A compound according to  claim 5 , or a pharmaceutically acceptable salt, or solvate thereof, in which:
 X is —C(═O)—, —C(═O)NH— or —C(═O)N(C 1-4 alkyl)-;   Y is —C(═O)NH—;   R 4  is hydrogen, C 2-6 alkyl, C 1-4 alkyl optionally substituted with one to three R 17 , aryl or heteroaryl optionally substituted with one to three R 16 , or cycloalkyl or heterocycle optionally-substituted with keto (═O), and/or one to three R 16 ;   R 16  is selected from C 1-4 alkyl, R 17 , and C 1-4 alkyl substituted with keto and/or one to two R 17 ; and   R 17  is selected from halogen, hydroxy, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NH 2 , NH(C 1-4 alkyl), and N(C 1-4 alkyl) 2 .   
     
     
         7 . A compound according to  claim 2  or a pharmaceutically acceptable salt, or solvate thereof, in which R 1  and R 5  are independently hydrogen or CH 3 . 
     
     
         8 . A compound according to  claim 2 , or a pharmaceutically acceptable salt, or solvate thereof, in which R 2  is hydrogen. 
     
     
         9 . A compound according to  claim 2 , or a pharmaceutically acceptable salt, or solvate thereof, in which R 3  is methyl, —CF 3 , or —OCF 3 . 
     
     
         10 . A compound according to  claim 2 , or a pharmaceutically acceptable salt, or solvate thereof, in which X is —C(═O)— or —C(═O)NH—. 
     
     
         11 . A compound according to  claim 2 , or a pharmaceutically acceptable salt, prodrug or solvate thereof, in which Y is —C(═O)NH—. 
     
     
         12 . A compound according to  claim 2 , or a pharmaceutically acceptable salt, or solvate thereof, in which X is —C(═O)NH— and R 4  is C 2-6 alkyl, optionally-substituted benzyl, or a heterocyclic or heteroaryl ring selected from diazepinyl, morpholinyl, piperidinyl, and pyrrolidinyl, said heterocycle being optionally substituted with one to two of C 1-4 alkyl, hydroxy, C 1-4 alkoxy, phenyl, and/or benzyl. 
     
     
         13 . A compound according to  claim 2 , or a pharmaceutically acceptable salt, prodrug or solvate thereof, in which X is —C(═O)— and R 4  is phenyl, pyridyl, pyrimidinyl, or pyrazinyl optionally-substituted with one to two of C 1-4 alkyl, halogen, hydroxy, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2  and/or a C 1-4 alkyl substituted with one to two of halogen, hydroxy, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, phenyl, benzyl, phenyloxy, benzyloxy, NH 2 , NH(C 1-4 -alkyl), and/or N(C 1-4 alkyl) 2 . 
     
     
         14 . A compound according to  claim 2 , or a pharmaceutically acceptable salt, or solvate thereof, in which B is cyclopropyl or cyclobutyl optionally substituted with one to two R 7 , phenyl substituted with a five or six membered heterocycle and zero to two R 12 , or B is selected from one of: 
       
         
           
           
               
               
           
         
         R 7  and R 12  are independently selected from C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, amino, C 1-4 alkylalmino, hydroxy, C 1-4 -alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; and 
         n is 0, 1 or 2. 
       
     
     
         15 . A compound having the formula, 
       
         
           
           
               
               
           
         
       
       enantiomers, diastereomers, salts, and solvates thereof, wherein
 R 3  is methyl or CF 3 ; 
 X is —C(═O)— or —C(═O)NH—; 
 R 4  is straight or branched C 2-6 alkyl; cycloalkyl optionally substituted with keto and/or up to two R 16 ; heterocycle or heteroaryl optionally substituted with keto and/or up to two R 16 ; C 1-4 alkyl substituted with up to three of halogen, trifluoromethyl, cyano, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, phenyl, phenyloxy or benzyloxy, wherein said phenyl group is optionally substituted with one to two R 26 ; or phenyl optionally substituted with zero to two R 16 ; 
 R 6a  and R 6b  are selected from lower alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, C 1-4 alkoxy, nitro, amino, C 1-4 alkylamino, and cyano; 
 B is a C 3-7 cycloalkyl optionally substituted with one to two R 7 , a five membered heteroaryl optionally substituted with one to two R 7 , a five or six membered heterocyclo optionally substituted with one to two R 7 , phenyl substituted with R 11  and zero to two R 12 , —C(═O)R 13 , —CO 2 R 13 , and —C(═O)NR 13 R 13a ; 
 R 7  is attached to any available carbon or nitrogen atom of ring B and at each occurrence is independently selected from alkyl, substituted alkyl, halogen, haloalkoxy, ureido, cyano, trifluoromethoxy, trifluoromethyl, hydroxy, —C 1-4 alkoxy, —C(═O)alkyl, —OC(═O)alkyl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , —CN, —CO 2 alkyl, —CONH 2 , —CONH(CH 3 ), —CON(CH 3 ) 2 , phenyl, benzyl, C 3-7  cycloalkyl, and five-to-six membered heterocyclo or heteroaryl; and/or when B is cycloalkyl, two R 2  groups may join to form an optionally-substituted carbon-carbon bridge of three to four carbon atoms, or two R 7  groups may join to form a fused carbocyclic, heterocyclic or heteroaryl ring, said fused ring being in turn optionally substituted with one to three R 22 ; 
 R 11  is cycloalkyl, heterocyclo, or heteroaryl optionally substituted with one to two R 15 ; 
 R 13  and R 13a  are selected from hydrogen and C 1-4 alkyl; 
 R 12 , R 15 , and R 16  at each occurrence are independently selected from hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, C 1-4 alkylamino, aminoC 1-4 alkyl, haloC 1-4 alkyl, hydroxy, hydroxyC 1-4 alkyl, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; 
 R 20  and R 21  are selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heteroaryl, and heterocyclo; and 
 R 22  and R 26  are selected from C 1-6 alkyl, C 2-6 alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C 1-4 alkylamino, aminoC 1-4 alkyl, hydroxy, hydroxyC 1-4 alkyl, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy. 
 
     
     
         16 . A compound according to  claim 15 , or a pharmaceutically acceptable salt, or solvate thereof, in which B is phenyl substituted with heterocyclo and one to two R 12 ; cyclopropyl or cyclobutyl optionally substituted with one to two R 7 ; or B is selected from one of: 
       
         
           
           
               
               
           
         
         R 7  is C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, amino, C 1-4 alkylalmino, hydroxy, C 1-4 alkoxy, phenyl, benzyl, phenyloxy, or benzyloxy; and 
         n is 0, 1 or 2. 
       
     
     
         17 . A compound having the formula (2a) or (2b), 
       
         
           
           
               
               
           
         
         enantiomers diastereomers, salts and solvates thereof, wherein: 
         R 3  is methyl or CF 3 ; 
         R 4a  is phenyl or five or six membered heteroaryl optionally substituted with up to two R 16 ; 
         R 4b  is straight or branched C 2-6 alkyl; cycloalkyl optionally substituted with keto and/or up to two R 16 ; heterocycle optionally substituted with keto and/or up to two R 16 ; or C 1-4 alkyl substituted with up to three of halogen, trifluoromethyl, cyano, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, phenyl, phenyloxy or benzyloxy, wherein said phenyl or benzyl group in turn is optionally substituted with one to two R 26 ; 
         R 6a  is lower alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, C 1-4 alkoxy, amino, C 1-4 alkylalmino, or cyano; 
         B is selected from phenyl substituted with heterocyclo or heteroaryl and up to two R 12 , cyclopropyl or cyclobutyl either of which may be optionally substituted with one to two R 7 , or B is selected from one of: 
       
       
         
           
           
               
               
           
         
         R 7  is C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, C 1-4 alkylalmino, hydroxy, C 1-4 alkoxy, phenyl, benzyl, phenyloxy, or benzyloxy; 
         R 12 , R 16  and R 17  at each occurrence are independently selected from hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, C 1-4 alkylalmino, hydroxy, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; 
         R 26  is selected from C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, amino, C 1-4 alkylalmino, hydroxy, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; 
         n is 0 or 1. 
       
     
     
         18 . A compound according to  claim 17  or a pharmaceutically acceptable salt, prodrug or solvate thereof, in which B is cyclopropyl optionally substituted with one to two R 7 , or B is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         19 . A pharmaceutical composition comprising at least one compound according to  claim 1  and a pharmaceutically-acceptable carrier or diluent. 
     
     
         20 . A pharmaceutical composition comprising at least one compound according to  claim 15  and a pharmaceutically-acceptable carrier or diluent. 
     
     
         21 . A method of treating an inflammatory disorder comprising administering to a patient in need of such treatment a pharmaceutical composition according to  claim 19 . 
     
     
         22 . The method of  claim 21  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. 
     
     
         23 . A compound having the formula, 
       
         
           
           
               
               
           
         
       
       enantiomers, diastereomers, salts, and solvates thereof, wherein
 R 3  is methyl or CF 3 ; 
 X is —C(═O)— or —C(═O)NH—; 
 R 4  is straight or branched C 2-6 alkyl; cycloalkyl optionally substituted with keto and/or up to two R 16 ; heterocycle or heteroaryl optionally substituted with keto and/or up to two R 16 ; C 1-4 alkyl substituted with up to three of halogen, trifluoromethyl, cyano, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, phenyl, phenyloxy or benzyloxy, wherein said phenyl group is optionally substituted with one to two R 26 ; or phenyl optionally substituted with zero to two R 16 ; 
 R 6a  and R 6b  are selected from lower alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, C 1-4 alkoxy, nitro, amino, C 1-4 alkylamino, and cyano; 
 B is a C 3-7 cycloalkyl optionally substituted with one to two R 7 , a five membered heteroaryl optionally substituted with one to two R 7 , a five or six membered heterocyclo optionally substituted with one to two R 7 , phenyl substituted with R 11  and zero to two R 12 , —C(═O)R 13 , —CO 2 R 13 , and —C(═O)NR 13 R 13a ; 
 R 7  is attached to any available carbon or nitrogen atom of ring B and at each occurrence is independently selected from alkyl, substituted alkyl, halogen, haloalkoxy, ureido, cyano, trifluoromethoxy, trifluoromethyl, hydroxy, —C 1-4 alkoxy, —C(═O)alkyl, —OC(═O)alkyl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , —CN, —CO 2 alkyl, —CONH 2 , —CONH(CH 3 ), —CON(CH 3 ) 2 , phenyl, benzyl, C 3-7  cycloalkyl, and five-to-six membered heterocyclo or heteroaryl; and/or when B is cycloalkyl, two R 7  groups may join to form an optionally-substituted carbon-carbon bridge of three to four carbon atoms, or two R 7  groups may join to form a fused carbocyclic, heterocyclic or heteroaryl ring, said fused ring being in turn optionally substituted with one to three R 22 ; 
 R 11  is cycloalkyl, heterocyclo, or heteroaryl optionally substituted with one to two R 15 ; 
 R 13  and R 13a  are selected from hydrogen and C 1-4 alkyl; 
 R 12 , R 15 , and R 16  at each occurrence are independently selected from hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, C 1-4 alkylamino, aminoC 1-4 alkyl, haloC 1-4 alkyl, hydroxy, hydroxyC 1-4 alkyl, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; 
 R 20  and R 21  are selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heteroaryl, and heterocyclo; and 
 R 22  and R 26  are selected from C 1-6 alkyl, C 2-6 alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C 1-4 alkylamino, aminoC 1-4 alkyl, hydroxy, hydroxyC 1-4 alkyl, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy. 
 
     
     
         24 . A compound according to  claim 23 , or a pharmaceutically acceptable salt, or solvate thereof, in which B is phenyl substituted with heterocyclo and one to two R 12 ; cyclopropyl or cyclobutyl optionally substituted with one to two R 7 ; or B is selected from one of: 
       
         
           
           
               
               
           
         
         R 7  is C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, amino, C 1-4 alkylalmino, hydroxy, C 1-4 alkoxy, phenyl, benzyl, phenyloxy, or benzyloxy; and 
         n is 0, 1 or 2. 
       
     
     
         25 . A compound having the formula, 
       
         
           
           
               
               
           
         
       
       enantiomers, diastereomers, salts, and solvates thereof, wherein
 R 3  is methyl or CF 3 ; 
 X is —C(═O)— or —C(═O)NH—; 
 R 4  is straight or branched C 2-6 alkyl; cycloalkyl optionally substituted with keto and/or up to two R 16 ; heterocycle or heteroaryl optionally substituted with keto and/or up to two R 16 ; C 1-4 alkyl substituted with up to three of halogen, trifluoromethyl, cyano, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, phenyl, phenyloxy or benzyloxy, wherein said phenyl group is optionally substituted with one to two R 26 ; or phenyl optionally substituted with zero to two R 16 ; 
 R 6a  and R 6b  are selected from lower alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, C 1-4 alkoxy, nitro, amino, C 1-4 alkylamino, and cyano; 
 B is a C 3-7 cycloalkyl optionally substituted with one to two R 7 , a five membered heteroaryl optionally substituted with one to two R 7 , a five or six membered heterocyclo optionally substituted with one to two R 7 , phenyl substituted with R 11  and zero to two R 12 , —C(═O)R 13 , —CO 2 R 13 , and —C(═O)NR 13 R 13a ; 
 R 7  is attached to any available carbon or nitrogen atom of ring B and at each occurrence is independently selected from alkyl, substituted alkyl, halogen, haloalkoxy, ureido, cyano, trifluoromethoxy, trifluoromethyl, hydroxy, —C 1-4 alkoxy, —C(═O)alkyl, —OC(═O)alkyl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , —CN, —CO 2 alkyl, —CONH 2 , —CONH(CH 3 ), —CON(CH 3 ) 2 , phenyl, benzyl, C 3-7  cycloalkyl, and five-to-six membered heterocyclo or heteroaryl; and/or when B is cycloalkyl, two R 2  groups may join to form an optionally-substituted carbon-carbon bridge of three to four carbon atoms, or two R 7  groups may join to form a fused carbocyclic, heterocyclic or heteroaryl ring, said fused ring being in turn optionally substituted with one to three R 22 ; 
 R 11  is cycloalkyl, heterocyclo, or heteroaryl optionally substituted with one to two R 15 ; 
 R 13  and R 13a  are selected from hydrogen and C 1-4 alkyl; 
 R 12 , R 15 , and R 16  at each occurrence are independently selected from hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, C 1-4 alkylamino, aminoC 1-4 alkyl, haloC 1-4 alkyl, hydroxy, hydroxyC 1-4 alkyl, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy; 
 R 20  and R 21  are selected from hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, cycloalkyl, heteroaryl, and heterocyclo; and 
 R 22  and R 26  are selected from C 1-6 alkyl, C 2-6 alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C 1-4 alkylamino, aminoC 1-4 alkyl, hydroxy, hydroxyC 1-4 alkyl, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy. 
 
     
     
         26 . A compound according to  claim 25 , or a pharmaceutically acceptable salt, or solvate thereof, in which B is phenyl substituted with heterocyclo and one to two R 12 ; cyclopropyl or cyclobutyl optionally substituted with one to two R 7 ; or B is selected from one of: 
       
         
           
           
               
               
           
         
         R 7  is C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, amino, C 1-4 alkylalmino, hydroxy, C 1-4 alkoxy, phenyl, benzyl, phenyloxy, or benzyloxy; and 
         n is 0, 1 or 2. 
       
     
     
         27 . A compound of  claim 1  selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       salts and solvates thereof. 
     
     
         28 . A compound of  claim 1  selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       enantiomers, diasteriomers, salts and solvates thereof. 
     
     
         29 . A compound of  claim 1  selected from 
       
         
           
           
               
               
           
         
       
       enantiomers, diasteriomers, salts and solvates thereof.