Indazole derivatives as CRF antagonists

Abstract

This invention relates to compounds which are generally CRF-1 receptor antagonists and which are represented by Formula I or Formula II: wherein R 3 is optionally substituted aryl or heteroaryl, R 1 and R 2 are as defined in the specification; or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts thereof. The invention further relates to processes for preparing such compounds, to pharmaceutical compositions containing such compounds, and to methods for their use as therapeutic agents.

1 . A method for treating a subject having a disease state, wherein the disease state is selected from the group consisting of phobias, stress-related illnesses, mood disorders, eating disorders, generalized anxiety disorders, stress-induced gastrointestinal dysfunctions, neurodegenerative diseases, and neuropsychiatric disorders which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I wherein:  
     
       
         
         
             
             
         
       
       R 1  is —NR a R b , —CR c R d R e , CO 2 R a , or —C(O)NR a R b ; or R 1  is hydrogen, cycloalkenyl, aryl, or heteroaryl, where each aryl or heteroaryl is optionally substituted with one or more substituents independently selected from C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 1-6  alkylsulfonyl, halogen, haloalkyl, cyano, nitro, —C(O)NR a′ R b′ , and —NR a′ R b′ , where R a′ and R b′  are each independently selected from the group consisting of hydrogen, C 1-9  alkyl, and C 1-9 alkylcarbonyl;  
       R 2  is hydrogen, C 1-6  alkyl, C 3-6  cycloalkyl, C 3-6  cycloalkyl-C 1-3  alkyl, C 1-6  alkylcarbonyl, C 1-6  alkylsulfonyl, aryl, or arylalkyl, wherein said aryl or arylalkyl is optionally substituted with one or more substituents independently selected from C 1-6  alkyl, haloalkyl, C 1-6  alkoxy, and halogen;  
       R 3  is aryl or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylthio, C 1-6  alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and —NR a″ R b″ , where R a″  and R b″  are each independently selected from the group consisting of hydrogen, C 1-9  alkyl, and C 1-9  alkylcarbonyl;  
       R a  and R b  are each independently selected from the group consisting of hydrogen, C 1-9  alkyl, hydroxyalkyl, C 1-6  alkoxyalkyl, C 1-6  alkylthioalkyl, carboxyalkyl, acyl, C 3-6  cycloalkyl, C 3-6  cycloalkyl-C 1-3  alkyl, di-C 3-6  cycloalkyl, C 1-3  alkyl, C 1-6  heteroalkyl, aminoalkyl, aminocarbonylalkyl, cyanoalkyl, C 5-8  heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl, diphenylalkyl, and C 1-3  alkyl substituted with both a C 3-6  cycloalkyl and a phenyl group, wherein each of said cycloalkyl, phenyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C 1-6  alkyl, haloalkyl, C 1-6  alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl; or  
       R a  and R b  are taken together with the nitrogen to which they are attached form an heterocyclyl or heteroaryl ring selected from the group consisting of pyrrolidine, piperidine, homopiperidine, tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine, hexahydropyrimidine, pyrazolidine, piperazine, morpholine, imidazoline, pyrrole, pyrazole, and imidazole, where each of said rings is optionally substituted with one or more substituents selected from the group consisting of hydroxy, oxo, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, acyl, acylamino, aminocarbonyl, aminocarbonylalkyl, aminocarbonylamino, aminosulfonyl, alkylsulfonylamino, aminosulfonylamino, and phenyl, wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from C 1-6  alkyl, haloalkyl, C 1-6  alkoxy, amino, alkylamino, dialkylamino, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl, or is contained in a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl group;  
       R c  is hydrogen, hydroxy, C 1-6  alkoxy, or —NR a′″ R b′″ ;  
       R d  and R e  are each independently selected from the group consisting of hydrogen, C 1-9  alkyl, hydroxyalkyl, C 1-6  alkoxyalkyl, C 1-6  alkylthioalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, C 3-6  cycloalkyl, C 3-6  cycloalkyl-C 1-3  alkyl, di-C 3-6  cycloalkyl-C 1-3  alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl, diphenyl-C 1-3 alkyl, and C 1-3  alkyl substituted with both a C 3-6  cycloalkyl and a phenyl group, wherein each of said cycloalkyl, phenyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C 1-6  alkyl, haloalkyl, C 1-6  alkoxy, amino, alkylamino, dialkylamino, and halogen; or  
       R c  and R d  are taken together to form a divalent group selected from C 1-6  alkylidenyl, C 1-6  heteroalkylidenyl, C 3-6  cycloalkylidenyl, C 3-6  cycloalkyl-alkylidenyl, C 3-6  cycloalkyl-C 1-3  alkyl-alkylidenyl, C 3-6  heterocyclylidenyl, C 3-6  heterocyclyl-C 1-3  alkylidenyl, C 3-6  heterocyclylalkyl-C 1-3  alkylidenyl, aryl-C 1-3  alkylidenyl, aryl-C 1-3 alkyl-alkylidenyl, heteroaryl-C 1-3 alkylidenyl, and heteroarylalkyl-C 1-3  alkylidenyl, wherein each of said cycloalkyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from C 1-6  alkyl, haloalkyl, C 1-6  alkoxy, amino, alkylamino, dialkylamino, and halogen; or  
       R d  and R e  are taken together with the carbon to which they are attached to form a cycloalkyl or heterocyclyl ring;  
       R a′″  and R b′″  are each independently selected from the group consisting of hydrogen, C 1-9  alkyl, hydroxyalkyl, C 1-6  alkoxyalkyl, C 1-6  alkylthioalkyl, carboxyalkyl, acyl, C 3-6  cycloalkyl, C 3-6  cycloalkyl-C 1-3  alkyl, di-C 3-6  cycloalkyl-C 1-3  alkyl, C 1-6  heteroalkyl, aminoalkyl, aminocarbonylalkyl, cyanoalkyl, C 5-8  heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl, diphenyl-C 1-3  alkyl, and C 1-3  alkyl substituted with both a C 3-6  cycloalkyl and a phenyl group, wherein each of said cycloalkyl, phenyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of C 1-6  alkyl, haloalkyl, C 1-6  alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl; or  
       R a′″  and R b′″  are taken together with the nitrogen to which they are attached form an heterocyclyl or heteroaryl ring selected from the group consisting of pyrrolidine, piperidine, homopiperidine, tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, tetrahydropyrimidine, hexahydropyrimidine, pyrazolidine, piperazine, morpholine, imidazoline, pyrrole, pyrazole, and imidazole, where each of said rings is optionally substituted with one or more substituents selected from the group consisting of hydroxy, oxo, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, acyl, acylamino, aminocarbonyl, aminocarbonylalkyl, aminocarbonylamino, aminosulfonyl, alkylsulfonylamino, aminosulfonylamino, and phenyl, wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from C 1-6  alkyl, haloalkyl, C 1-6  alkoxy, amino, alkylamino, dialkylamino, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl, or is contained in a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl group;  
       or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts thereof.