Substituted pyrazinones, pyridines and pyrimidines as corticotropin releasing factor ligands

A compound of Formula (I) or (II):

• 113
• or a pharmaceutically acceptable salt form thereof, wherein:
• X is N or CR1;
• provided that when X is N, R1 can not be either —NR9R10 or —NR9COR9;
• W is ═O, ═S, —H or (—H, —H);
• Y is —C(═O)—, —C(RY)2—, —C(RY)2CH2—, —OCH2—, —SOnCH2—, —N═, —NRY—, —O—, or —CH═;
• RY is independently, at each occurrence, selected from H, methyl, ethyl, and C1-C2 haloalkyl;
• B is R3, NHR3, NR3R1, OR3, or SOnR3;
• R1 is independently, at each occurrence, selected from H, halogen, —CN, C1-C4 haloalkyl, —NR9R10, —NR9COR9, —COR10, —OR10, SH, —S(°)nR12, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and C4-C8 cycloalkylalkyl;
• wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C4-C8 cycloalkylalkyl is each optionally substituted with halogen, CN, C1-C4 haloalkyl, —NR9R10, —NR9COR9, —COR10, —OR10, SH or —S(O)nR12;
• R2 is H, halogen, CN, C1-C4 haloalkyl, —NR9R10, NR9COR9, —COR10, —OR10, SH, —S(O)nR12, C1-C4 alkyl, C3-C6 cycloalkyl, or C4-C8 cycloalkylalkyl;
• wherein each C1-C4 alkyl, C3-C6 cycloalkyl, or C4-C8 cycloalkylalkyl is optionally substituted with halogen, —CN, C1-C4 haloalkyl, —NR9R10, —NR9COR9, —COR10, —OR10, SH or —S(O)nR12;
• R2a is H, F, Cl, Br, —CN, —OH, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, C1-C3 alkoxy, cyclopropyloxy-, —OCF3, —CF3, —CO2CH3, —CO2CH2CH3, —C(O)CH3, —C(O)CH2CH3, —CH2OH, —CH2OCH3, —CH2OCH2CH3, —C(O)NH2, —C(O)N(H)CH3, —C(O)N (H)CH2CH3, —C(O)N(CH3)2, —C(O)N(CH3)CH2CH3, —C(O)N(CH2CH3)2, —S(O)2N(CH3)2, —S(O)2N(CH3)CH2CH3, —S(O)2N(CH2CH3)2, —S(O)2CH3, —S(O)2CH2CH3, —NH2, —N(H)CH3, —N(H)CH2CH3, —N(CH3)2, —N(CH3)CH2CH3, —N(CH2CH3)2, or —N(H)CF3;
• R3 is C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, C2-C10 alkoxyalkyl, C5-C10 cycloalkenyl, or C6-C10 cycloalkenylalkyl;
• wherein one carbon in any cycloalkyl ring may be replaced with O, S or NR9;
• and
• wherein each C1-C10 alkyl, C3-C10 alkenyl, C3-C8 alkynyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, C2-C10 alkoxyalkyl, C5-C10 cycloalkenyl, or C6-C10 cycloalkenylalkyl is optionally substituted with 1, 2 or 3 substituents independently selected at each occurrence from C1-C6 alkyl, C2-C6 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, halogen, C1-C4 haloalkyl, cyano, —OR7, SH, —S(O)nR11, —COR6, —NHR6SO2R8, —OC(O)NR6R7, —N3, —OC(O)OR7, —CO2R8, —OC(O)R6, —NR7COR6, —N(COR6)2, —NR7CONR6R7, —NR7CO2R8, —NR6R7, —CONR6R7, —CO2H, aryl, heteroaryl and heterocyclyl;
• alternatively, R3 is —OR3a, —NR3aR3b, NHR3a, —SOnR3a, —SO2NHR3a, —SO2NR3aR3b, —COR3a, —CONHR3a, or —CONR3aR3b;
• R3a and R3b are independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, C2-C10 alkoxyalkyl, C5-C10 cycloalkenyl, and C6-C10 cycloalkenylalkyl;
• wherein one carbon in any cycloalkyl may be replaced with O, S or NR9;
• and
• wherein each C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, C2-C10 alkoxyalkyl, C5-C10 cycloalkenyl, and C6-C10 cycloalkenylalkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C2-C6 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, halogen, C1-C4 haloalkyl, cyano, —OR7, —SH, —S(O)nR11, —COR6, —CO2R8, —OC(O)R6, —NR7COR6, —N(COR6)2, —NR7CONR6R7, —NR7CO2R8, —NR6R7, —NHR6SO2R8, —OC(O)NR6R7, —N3, —OC(O) OR7, —CONR6R7, —CO2H, aryl, heteroaryl and heterocyclyl;
• R4 is independently selected in each occurrence from —H, —OR10, —COR9, —CO2R8, —CONR9R10, —CN, —NR9R10, —S(O)nR12, —S(O)2NR9R10, —NO2, halogen, C1-C6 alkyl, C1-C4 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl and heteroaryl;
• wherein C1-C6 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl, are optionally substituted with —OR10, —COR9, —CO2R8, —CONR9R10, —CN, —NR9R10, —S(O)nR12, or halogen;
• A1 is CR5 or N;
• A2 is CR5 or N;
• R5 is independently selected at each occurrence from —H, C1-C10 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, —NO2, halogen, —CN, —NR6R7, —NR6COR7, —NR6CO2R8, —COR6—OR7, —CONR6R7, —CO(NOR9)R11, —CO2R8, —S(O)2NR9R10, and —S(O)nR11;
• wherein 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, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C1-C4 haloalkyl, —NO2, halogen, —CN, —NR6R7, —NR6COR7, NR6CO2R8, —COR6—OR7, —CONR6R7, —CO2R8, —CO(NOR9)R7, and —S(O)nR11;
• alternatively, two R5 groups on adjacent atoms can form a 5-7 membered fused ring, partially saturated or unsaturated, optionally containing 1-2 —O— or —SOn— or 1-3 N heteroatoms provided the ring does not contain any S—S, O—O, S—O or N—S bonds;
• said 5-7 membered fused ring optionally substituted with C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C8 cycloalkylalkyl, C1-C4 haloalkyl, —NO2, halogen, —CN, —NR6R7, NR6COR7, NR6CO2R8, —COR6—OR7, —CONR6R7, —CO2R8, —CO(NOR9)R7, or —S(O)nR11;
• R6 and R7 are independently at each occurrence H, C1-C6 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C12 bis(alkoxy)alkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl);
• alternatively NR6R7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;
• R8 is independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl);
• R9 and R10 are independently at each occurrence selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C2-C6 alkoxyalkyl, and C4-C7 cycloalkylalkyl;
• R11 is independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl), or —NR6R7;
• R12 is independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl;
• 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, C4-C7 cycloalkylalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C4 haloalkyl, cyano, —OR30, —SH, —S(O)nR32, —COR32, —CO2R28, —OC(O)R32, —NR29COR29, —N(COR32)2, —NR29CONR29R30, —NR29CO2R28, —NR29R30, and —CONR29R30;
• heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C4 haloalkyl, cyano, —OR30, —SH, —S(O)nR32, —COR32, —CO2R28, —OC(O)R32, —NR29COR29, —N(COR32)2, —NR29CONR29R30, —NR29CO2R28, —NR29R30, and —CONR29R30;
• heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C4 haloalkyl, cyano, —OR30, SH, —S(O)nR32 -COR32, —CO2R32, —OC(O)R32, —NR29COR29, —N(COR32)2, —NR29CONR29R30, —NR29CO2R32, —NR29R30, and —CONR29R30;
• R28 is independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, phenyl, or phenyl(C1-C4 alkyl)-;
• R29 and R30 are independently at each occurrence selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C2-C6 alkoxyalkyl, and C4-C7 cycloalkylalkyl;
• R32 is independently at each occurrence C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl;
• and n is 0, 1, or 2.