1H-imidazo[4,5-d]pyridazin-7-ones, 3H-imidazo-[4,5-c]pyridin-4-ones and corresponding thiones as corticotropin releasing factor (CRF) receptor ligands

A method of antagonizing a CRF receptor in a mammal comprising contacting the receptor with a compound of the formula:

• and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein:
• X is O or S;
• A=CR9;
• Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R4 groups and each Ar is attached via an unsaturated carbon atom;
• R1 is independently selected at each occurrence from H, C1-C4†alkyl, C2-C4†alkenyl, C2-C4†alkynyl, halo, CN, C1-C4†haloalkyl, C1-C12 hydroxyalkyl, C2-C12 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9R10, C1-C4 alkyl-NR9R10, NR9COR10, OR11, SH or S(O)nR12;
• R2 is selected from:
• —H, aryl, heteroaryl and heterocyclyl, or
• —C1-C10†alkyl, C2-C10†alkenyl, C2-C10†alkynyl, C3-C8\cycloalkyl, C5-C8 cycloalkenyl, C4-C12\cycloalkylalkyl or C6-C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6†alkyl, C1-6 alkyloxy C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C6\cycloalkyl, halo, C1-C4†haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl and heterocyclyl;
• R3 is selected from H, C1-C4†alkyl, C3-C6\alkenyl, C3-C6†alkynyl, C3-C6\cycloalkyl, C4-C10 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6†alkyl, C3-C6\cycloalkyl, halo, C1-C4†haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl and heterocyclyl;
• R4 is independently selected at each occurrence from:
• C1-C10†alkyl, C2-C10†alkenyl, C2-C10†alkynyl, C3-C6 cycloalkyl, C4-C12\cycloalkylalkyl, NO2, halo, CN, C1-C4†haloalkyl, NR6R7, NR6COR7, NR6CO2R7, COR7, OR7, CONR6R7, CO(NOR9)R7, CO2R7, or S(O)nR7, where each such C1-C10†alkyl, C2-C10†alkenyl, C2-C10†alkynyl, C3-C6 cycloalkyl and C4-C12\cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NO2, halo, CN, NR6R7, NR6COR7, NR6CO2R7, COR7 OR7, CONR6R7, CO2R7, CO(NOR9)R7, or S(O)nR7;
• R6 and R7 are independently selected at each occurrence from:
• —H,
• —C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6\cycloalkyl, C4-C12\cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6†alkyl, C3-C6\cycloalkyl, halo, C1-C4†haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl,
• -aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
• alternatively, NR6R7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups;
• R8 is independently selected at each occurrence from H or C1-C4 alkyl optionally substituted by halogen, C1-C4 alkoxy or C1-C4 halo-alkoxy (1 to 4 halogens);
• R9 and R10 are independently selected at each occurrence from H, C1-C4 alkyl, or C3-C6 cycloalkyl;
• R11 is selected from H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;
• R12 is C1-C4 alkyl or C1-C4 haloalkyl;
• R13 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6\cycloalkyl, C4-C12\cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl)-;
• R15 and R16 are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C4-C16 cycloalkylalkyl, except that for S(O)nR15, R15 cannot be H;
• aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6†alkyl, C3-C6\cycloalkyl, halo, C1-C4†haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and CONR16R15;
• heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6†alkyl, C3-C6\cycloalkyl, halo, C1-C4†haloalkyl, cyano, OR15, SH, S(O)nR15, —COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and CONR16R15;
• heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6†alkyl, C3-C6\cycloalkyl, halo, C1-C4†haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR15R16, and CONR16R15;
• n is independently at each occurrence 0, 1 or 2.