Ring fused pyrazole derivatives as CRF antagonists

A compound of Formula I or Formula II:

• 176
• wherein:
• R1 is —ORa, —NRaRb, —CRcRdRe, CO2Ra, or —C(O)NRaRb;
• or R1 is hydrogen, halogen, cycloalkenyl, aryl, or heteroaryl, where each aryl or heteroaryl is optionally substituted with one or more substituents independently selected from C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, halogen, haloalkyl, cyano, nitro, —C(O)NRa′Rb′, and —NRa′Rb′, where Ra′ and Rb′ are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl;
• R2 is hydrogen, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, C1-6alkylcarbonyl, C1-6alkylsulfonyl, aryl, or arylalkyl, wherein said aryl or arylalkyl is optionally substituted with one or more substituents independently selected from C1-6alkyl, haloalkyl, C1-6alkoxy, and halogen;
• R3 and R4 are each independently selected from hydrogen and C1-6alkyl, or R3 and R4 are taken together with the carbon to which they are attached to form a C3-6cycloalkyl ring;
• Ar is aryl or heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulfonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, halogen, haloalkyl, cyano, nitro, and —NRa″Rb″, where Ra″ and Rb″ are each independently selected from the group consisting of hydrogen, C1-9alkyl, and C1-9alkylcarbonyl;
• Ra and Rb are each independently selected from the group consisting of hydrogen, C1-9alkyl, hydroxyalkyl, C1-6alkoxyalkyl, C1-6alkylthioalkyl, carboxyalkyl, C1-6-alkoxycarbonyl, C1-6-alkoxyC1-3-alkylcarbonyl, acyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, di-C3-6cycloalkylC1-3alkyl, C1-6heteroalkyl, aminoalkyl, aminocarbonylalkyl, cyanoalkyl, C5-8heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl, diphenylalkyl, phenylsulfonyl optionally substituted as described for phenyl below, and C1-3alkyl substituted with both a C3-6cycloalkyl 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 C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl;
• or
• Ra and Rb 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 C1-6alkyl, haloalkyl, C1-6alkoxy, 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;
• Rc is hydrogen, hydroxy, C1-6alkoxy, or —NRa′″Rb′″;
• Rd and Re are each independently selected from the group consisting of hydrogen, C1-9alkyl, hydroxyalkyl, C1-6alkoxyalkyl, C1-6alkylthioalkyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, di-C3-6cycloalkyl-C1-3alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl, diphenyl-C1-3alkyl, and C1-3alkyl substituted with both a C3-6cycloalkyl 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 C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, and halogen;
• or Rc and Rd are taken together to form a divalent group selected from C1-6alkylidenyl, C1-6heteroalkylidenyl, C3-6cycloalkylidenyl, C3-6cycloalkyl-alkylidenyl, C3-6cycloalkylalkyl-alkylidenyl, C3-6heterocyclylidenyl, C3-6heterocyclyl-C1-3alkylidenyl, C3-6heterocyclylalkyl-C1-3alkylidenyl, aryl-C1-3alkylidenyl, aryl-C1-3alkyl-alkylidenyl, heteroaryl-C1-3alkylidenyl, and heteroarylalkyl-C1-3alkylidenyl, wherein each of said cycloalkyl, aryl, or heteroaryl groups is optionally substituted with one or more substituents independently selected from C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, and halogen;
• or
• Rd and Re are taken together with the carbon to which they are attached to form a cycloalkyl or heterocyclyl ring;
• Ra′″ and Rb′″ are each independently selected from the group consisting of hydrogen, C1-9alkyl, hydroxyalkyl, C1-6alkoxyalkyl, C1-6alkylthioalkyl, carboxyalkyl, C1-6-alkoxycarbonyl, C1-6-alkoxyC1-3-alkylcarbonyl, acyl, C3-6cycloalkyl, C3-6cycloalkylalkyl, di-C3-6cycloalkyl-C1-3alkyl, C1-6heteroalkyl, aminoalkyl, aminocarbonylalkyl, cyanoalkyl, C5-8heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, phenylalkyl, diphenyl-C1-3alkyl, and C1-3alkyl substituted with both a C3-6cycloalkyl 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 C1-6alkyl, haloalkyl, C1-6alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, cyano, acylamino, alkylsulfonyl, alkylsulfonyloxy, and halogen, and each of said amino groups is optionally monosubstituted or disubstituted with alkyl;
• or, Ra′″ and Rb″ 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 C1-6alkyl, haloalkyl, C1-6alkoxy, 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;
• n is an integer selected from 0, 1 and 2;
• a is a single or double bond;
• providing that (i) when n is 0, R1 is not hydrogen;
• (ii) when n is 0 and a is a double bond, R4 is absent;
• and (iii) when n is 1 or 2, a is a single bond;
• or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts thereof.