Aryl-substituted pyrazole-amide compounds useful as kinase inhibitors

Abstract

The present invention relates to compounds having the formula, and pharmaceutically-acceptable salts, prodrugs, solvates, isomers, and/or hydrates thereof, wherein Q is an optionally-substituted phenyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl ring; R 2 is alkyl or an amino group as defined herein; and Z is optionally-substituted oxadiazolyl or —C(═O)NR 6 , wherein R 6 is lower alkyl or cyclopropyl. The compounds are surprisingly advantageous in preparing pharmaceutical compositions for treating p38 kinase related conditions and/or in methods of treating conditions associated with the activity of p38 kinase in a patient.

1 . A compound having the formula (I), 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, prodrug, solvate, isomer, and/or hydrate thereof, wherein:
 Q is an optionally-substituted phenyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl ring; 
 the bond between the oxygen atom O* and the adjacent carbon atom Cl either (i) is a double bond to define a carbonyl group [C(═O)], wherein R 6  is C 1-6 alkyl or cyclopropyl; or (ii) is a single bond, wherein when a single bond, said oxygen atom O* is further bonded to the group R 6  and taken together with R 6  and the adjacent nitrogen atom define an optionally-substituted oxadiazolyl ring, the bond between Cl and the adjacent nitrogen atom being a double bond; and 
 R 2  is selected from C 1-6 alkyl, amino, alkylamino, substituted alkylamino, cycloamino, substituted cycloamino, and C 1-6 alkyl substituted with one to two of amino, alkylamino, substituted alkylamino, cycloamino, and/or substituted cycloamino. 
 
     
     
         2 . A compound according to  claim 1 , wherein,
 R 2  is selected from C 1-6 alkyl, NR 7 R 8 , and C 1-6 alkyl substituted with a group NR 7 R 8 ;   R 7  and R 8  are independently selected from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl, wherein each of said groups R 7  and R 8  are in turn optionally substituted with one to two of OH, O(C 1-4 alkyl), imidazolyl, pyridyl, phenyl, tetrahydrofuryl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , and N-morpholinyl, or alternatively, R 7  and R 8  are taken together with the nitrogen atom to which they are attached to form a morpholinyl, piperidinyl, or piperazinyl ring; and/or pharmaceutically-acceptable salts, prodrugs, solvates, isomers, and/or hydrates thereof.   
     
     
         3 . A compound according to  claim 1 , having the formula, 
       
         
           
           
               
               
           
         
         wherein Q is a phenyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl ring, and R 9 , R 10 , and R 11  are each independently selected from hydrogen, C 1-4 alkyl, O(C 1-4 alkyl), halogen, haloC 1-4 alkyl, cyano, SO 2 (C 1-4 alkyl), and/or nitro; and/or pharmaceutically-acceptable salts, prodrugs, solvates, isomers, and/or hydrates thereof. 
       
     
     
         4 . A compound according to  claim 3 , wherein,
 R 2  is selected from C 1-4 alkyl, NR 7 R 8 , and C 1-4 alkyl substituted with a group NR 7 R 8 ;   R 7  and R 8  are independently selected from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl, wherein each of said groups R 7  and R 8  are in turn optionally substituted with one to two of OH, O(C 1-4 alkyl), imidazolyl, pyridyl, phenyl, tetrahydrofuryl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , and N-morpholinyl, or alternatively, R 7  and R 8  are taken together with the nitrogen atom to which they are attached to form a morpholinyl, piperidinyl, or piperazinyl ring; and/or pharmaceutically-acceptable salts, prodrugs, solvates, isomers, and/or hydrates thereof.   
     
     
         5 . A compound according to  claim 1 , wherein ring Q is a group 
       
         
           
           
               
               
           
         
       
       wherein R 10  is halogen, cyano, or trifluoromethyl, and X is CH or N, and/or a pharmaceutically-acceptable salt, prodrug, solvate, isomer, and/or hydrate thereof. 
     
     
         6 . A compound according to  claim 5 , wherein R 2  is NH 2  or CH 3 , and/or a pharmaceutically-acceptable salt, prodrug, solvate, isomer, or hydrate thereof. 
     
     
         7 . A compound according to  claim 1 , having the formula, 
       
         
           
           
               
               
           
         
         wherein R 6  is C 1-4 alkyl or cyclopropyl; Q is a phenyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl ring, and R 9 , R 10 , and R 11  are each independently selected from hydrogen, C 1-4 alkyl, O(C 1-4 alkyl), halogen, haloC 1-4 alkyl, cyano, SO 2 (C 1-4 alkyl), and/or nitro; and/or pharmaceutically-acceptable salts, prodrugs, solvates, isomers, and/or hydrates thereof. 
       
     
     
         8 . A compound according to  claim 7 , wherein R 6  is cyclopropyl. 
     
     
         9 . A compound according to  claim 7 , wherein R 2  is C 1-4 alkyl or NR 7 R 8 , wherein R 7  is hydrogen or C 1-4 alkyl, and R 8  is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or a C 1-4 alkyl substituted with OH, methoxy, pyridyl, tetrahydrofuryl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , imidazolyl, and N-morpholinyl; or alternatively, R 7  and R 8  combine to form morpholinyl, piperidinyl, or piperazinyl. 
     
     
         10 . A compound according to  claim 9 , wherein ring Q is a group 
       
         
           
           
               
               
           
         
       
       wherein R 10  is halogen, cyano, or trifluoromethyl, and X is CH or N, and/or a pharmaceutically-acceptable salt, prodrug, solvate, isomer, and/or hydrate thereof. 
     
     
         11 . A compound according to  claim 1 , having the formula, 
       
         
           
           
               
               
           
         
         wherein Q is a phenyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl ring, and R 9 , R 10 , and R 11  are each independently selected from hydrogen, C 1-4 alkyl, O(C 1-4 alkyl), halogen, haloC 1-4 alkyl, cyano, SO 2 (C 1-4 alkyl), and/or nitro; and/or pharmaceutically-acceptable salts, prodrugs, solvates, isomers, and/or hydrates thereof. 
       
     
     
         12 . A compound according to  claim 11 , wherein R 2  is C 1-4 alkyl or NR 7 R 8 , wherein R 7  is hydrogen or C 1-4 alkyl, and R 8  is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or a C 1-4 alkyl substituted with OH, methoxy, pyridyl, tetrahydrofuryl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , imidazolyl, and N-morpholinyl; or alternatively, R 7  and R 8  combine to form morpholinyl, piperidinyl, or piperazinyl. 
     
     
         13 . A compound according to  claim 11 , wherein ring Q is a group 
       
         
           
           
               
               
           
         
       
       wherein R 10  is halogen, cyano, or trifluoromethyl, and X is CH or N, and/or a pharmaceutically-acceptable salt, prodrug, solvate, isomer, and/or hydrate thereof, 
     
     
         14 . A pharmaceutical composition comprising at least one compound according to  claim 1  and a pharmaceutically-acceptable carrier or diluent. 
     
     
         15 . A pharmaceutical composition comprising at least one compound according to  claim 4  and a pharmaceutically-acceptable carrier or diluent. 
     
     
         16 . A compound according to  claim 1  which is selective for inhibiting p38 kinase. 
     
     
         17 . A compound according to  claim 1  which is highly selective for inhibiting p38 kinase. 
     
     
         18 . A method of treating an inflammatory disorder comprising administering to a patient a pharmaceutical composition according to  claim 14 . 
     
     
         19 . The method of  claim 18  in which the inflammatory disorder is selected from the group consisting of asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, diabetes, inflammatory bowel disease, osteoporosis, psoriasis, graft vs. host rejection, atherosclerosis, pain, and arthritis including rhematoid arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, gouty arthritis and osteoarthritis. 
     
     
         20 . A method of modulating p38 kinase activity in a mammal comprising administering to the mammal a compound according to  claim 1  that is selective for p38 kinase. 
     
     
         21 . A method of modulating p38 kinase activity in a mammal comprising administering to the mammal a compound according to  claim 4  that is selective for p38 kinase. 
     
     
         22 . A process of making compounds having the formula (Ie), 
       
         
           
           
               
               
           
         
       
       wherein R 6  is alkyl or cyclopropyl, Q is as defined in  claim 1 , and R 2  is alkyl or aminoalkyl, comprising:
 reacting an acetoacetate compound, such as ethyl 3-oxobutanoate with a methanamine, such as dimethoxy-N—N-dimethylmethanamine, in the presence of solvent and appropriate hydrazine having the formula QNHNH 2 , wherein Q is as defined in  claim 1 , followed by addition of NaOH, to provide a sodium salt compound having the formula, 
 
       
         
           
           
               
               
           
         
         reaction the sodium salt (7-4) with acid to provide a carboxylic acid having the formula (7-5), 
       
       
         
           
           
               
               
           
         
         then converting said carboxylic acid to acid chloride upon reaction with thionyl chloride to provide a compound (7-6), 
       
       
         
           
           
               
               
           
         
         then reacting the acid chloride with benzamide hydrochloride having the formula (I-4), 
       
       
         
           
           
               
               
           
         
         to provide compounds having the formula (Ie). 
       
     
     
         23 . A process for making compounds having the formula (Ih), 
       
         
           
           
               
               
           
         
       
       wherein Q is as defined in  claim 1 , and R 6  is alkyl or cyclopropyl, and R 2a  is hydrogen, alkyl, cycloamino, or aminoalkyl, comprising
 reacting diketene having the formula, 
 
       
         
           
           
               
               
           
         
         with benzamide hydrochloride compound having the formula (8-2), 
       
       
         
           
           
               
               
           
         
         with DIPEA in solvent to provide compounds having the formula (8-3), 
       
       
         
           
           
               
               
           
         
         then adding DMF-DMA and removing DCM to provide compounds having the formula (8-4), 
       
       
         
           
           
               
               
           
         
         which upon reaction with hydrazine (QNHNH 2 ), such as phenylhydrazine, in solvent such as EtOH, provides compounds of formula (Ih).