3,7-dihydro-purine-2,6-dione derivatives as CRF receptor ligands

A method of treating a mammal afflicted with a disorder selected from affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis and hypoglycemia, which method comprises administering to the mammal a therapeutically effective amount of a compound of formula (I):

• 7
• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is selected from the group consisting of H, C1-4 alkyl, C3-8 cycloalkyl, C2-4 alkenyl and C2-4 alkynyl, wherein each is optionally substituted with 0-3 substituents independently selected from the group consisting of —CN, hydroxy, halo and C1-4 alkoxy;
• alternatively R1 is selected from the group consisting of —CN, —CF3, —C2F5, H, C1-C6 alkyl-NR1aR1b, —NR1aC(O)R1b, —C(O)NR1aR1b, —OR1a, S(O)nR1a and —OC(O)R1a, wherein R1a and R1b are independently selected from the group consisting of H, C1-C4 alkyl and C3-C6 cycloalkyl, and wherein R1a and R1b are each optionally substituted with 0-3 substituents independently selected from the group consisting of —CN, hydroxy, halo and C1-4 alkoxy;
• n is 0, 1 or 2;
• R2 is selected from the group consisting of H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C6-cycloalkyl-C1-C6 alkyl, C3-C6-alkenyl, C3-C6-alkynyl, aryl, heteroaryl and C5-C8 cycloalkenyl, wherein each is optionally substituted with 0 to 4 substituents independently selected at each occurrence from the group consisting of halogen, —OH, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 cycloalkyl, C1-C4 haloalkyl, —CO2R5—OC(O)R5, —COR5, —OC(O)OR5, —CO2H, —OR5, —NR6R7, —NR5COR7, —NHR5SO2R7, —OC(O)NR5R6, —N(COR5)2, —NR5CONR6R7, —NR5CO2R7, —CONR5R7, —S(O)nR5, —SO2NR5R7, —SH, —CN, aryl, heteroaryl and heterocyclyl;
• R3 is selected from the group consisting of aryl and heteroaryl;
• R4 is selected from the group consisting of C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-4 alkoxy-C1-4 alkyl, aryl, heteroaryl, heterocyclyl and benzyl;
• R4 is optionally substituted with 0-1 substituents selected from the group consisting of —CN, —S(O)nR9, —COR10, —CO2R10, —NR11COR10, —N(COR10)2, —NR11CONR1OR12, —NR11CO2R9, —CONR10R12, 1-naphthalenyl, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C3-8 cycloalkyl is replaced by a group selected from the group consisting of —S(O)n—, —NR10—, —NCO2R9—, —NCOR9— and —NSO2R9—, and wherein N4 in 1-piperazinyl is optionally substituted with 0-1 substituents selected from the group consisting of R10, CO2R9, COR9 and SO2R9;
• alternatively R4 is optionally substituted with 0-3 substituents independently selected at each occurrence from the group consisting of aryl, heteroaryl, heterocyclyl, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, —OR10, —NR1OR12, C1-4 alkoxy-C1-4 alkyl and C3-8 cycloalkyl which is optionally substituted with 0-1 R8 and wherein 0-1 carbon atoms in the C3-8 cycloalkyl is replaced by —O—;
• R5 is selected from the group consisting of H, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C4 alkenyl, C3-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkyloxy-C1-C4 alkyl and C3-C6 cycloalkyl-C1-C4 alkyl, wherein one carbon atom in any cycloalkyl ring may be replaced with O, S or NR6, and wherein C1-C4 alkyl, C3-C6 cycloalkyl, C3-C4 alkenyl, C3-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkyloxy-C1-C4 alkyl and C3-C6 cycloalkyl-C1-C4 alkyl are each optionally substituted with 0 to 2 substituents independently selected at each occurrence from the group consisting of —OH, C1-C4 alkoxy and halogen;
• R6 is selected from the group consisting of H, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C4 alkyl and C1-C4 haloalkyl;
• R7 is selected from the group consisting of H, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C4 alkenyl, C3-C4 alkynyl, C1-C4 haloalkyl, aryl, C1-C4 alkyloxy-C1-C4 alkyl and C3-C6 cycloalkyl-C1-C4 alkyl, wherein one carbon in any cycloalkyl ring may be replaced with O, S or NR6, and wherein C1-C4 alkyl, C3-C6 cycloalkyl, C3-C4 alkenyl, C3-C4 alkynyl, C1-C4 haloalkyl, aryl, C1-C4 alkyloxy-C1-C4 alkyl and C3-C6 cycloalkyl-C1-C4 alkyl are each optionally substituted with 0 to 2 substituents independently selected at each occurrence from the group consisting of C1-C4 alkoxy and halogen;
• R8 is selected from the group consisting of H, C1-4 alkyl, C3-6 cycloalkyl-C1-4 alkyl and C3-8 cycloalkyl;
• R9 is selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl and C3-6 cycloalkyl-C1-6 alkyl;
• R10 is selected from the group consisting of H, benzyl, aryl, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl and C3-6 cycloalkyl-C1-6 alkyl;
• R11 is selected from the group consisting of H, C1-4 alkyl, C3-7 cycloalkyl and C3-6 cycloalkyl-C1-6 alkyl;
• R12 is selected from the group consisting of H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl and C3-6 cycloalkyl-C1-6 alkyl;
• R13 is selected from the group consisting of H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-4 alkyl, C1-4 haloalkyl, R16S(O)n—C1-4 alkyl and R9R1ON—C2-4 alkyl;
• R14 and R15 are independently selected at each occurrence from the group consisting of H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl and C1-4 haloalkyl;
• alternatively, in an —NR13R14 moiety, R13 and R15 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is optionally substituted with 0-1 substituents selected from the group consisting of R17, CO2R16, COR16 and SO2R16;
• R16 is selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl, heteroaryl(C1-4 alkyl)- and benzyl, wherein each benzyl being optionally substituted on the aryl moiety with 0-1 substituents selected from the group consisting of C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy C1-4 haloalkoxy and dimethylamino;
• R17 is selected from the group consisting of H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl and heteroaryl(C1-4 alkyl)-;
• R18 is selected from the group consisting of H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being optionally substituted on the aryl moiety with 0-3 groups chosen from the group consisting of C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy and dimethylamino;
• R19 is selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and benzyl, each benzyl being optionally substituted on the aryl moiety with 0-1 substituents selected from the group consisting of C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy and dimethylamino;
• aryl is selected from the group consisting of phenyl, naphthyl, indanyl and indenyl, each aryl optionally substituted with 0-5 substituents independently selected at each occurrence from the group consisting of phenyl, C1-6 alkyl, C3-6 cycloalkyl, methylenedioxy, C1-4 alkoxy-C1-4 alkoxy, —OR13, Br, Cl, F, I, C1-4 haloalkyl, —CN, —NO2, SH, —S(O)nRl4, —COR13, —CO2R13, —OC(O)R14, —NR18COR13, —N(COR13)2, —NR18CONR13R15, —NR18CO2R14, —NR13R15 and —CONR13R15;
• heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being optionally substituted with 0-4 substituents independently selected at each occurrence from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, —CN, nitro, —OR13, SH, —S(O)nR14, —COR13, —CO2R13, —OC(O)R14, —NR18COR13, —N(COR13)2, —NR18CONR13R15, —NR18CO2R14, —NR13R15 and —CONR13R15, and wherein each heteroaryl is optionally substituted on any nitrogen atom with 0-1 substituents selected from the group consisting of R18, CO2R19, COR19 and SO2R19;
• and
• heterocyclyl is saturated or partially saturated heteroaryl, morpholinyl, thiomorpholinyl, piperazinyl, each optionally substituted with 1-3 substituents independently selected at each occurrence from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C4 haloalkyl, —CN, —OR5, —SH, —NO2, —OCF3, —S(O)nR5, —COR5, —CO2R5, —OC(O)R5, —NR5COR6, —N(COR5)2, —NR5CONR5R6, —NR5CO2R6, —NR5R6 and —CONR5R6.