Substituted 6,5-hetero-bicyclic derivatives

Abstract

This invention relates to compounds of the formula wherein A, B, D, E K, I, G, R 3 and R 5 are defined as in the specification, and to the pharmaceutically acceptable salts of such compounds.

1 . A compound of the formula  
                   
       or a pharmaceutically acceptable salt thereof, wherein 
 the dashed lines represent optional double bonds;  
 A is nitrogen or CR 7 ;  
 B is —NR 1 R 2 , —CR 1 R 2 R 10  —C(═CR 2 R 11 )R 1 , —NHCR 1 R 2 R 10 , —OCR 1 R 2 R 10 , —SCR 1 R 2 R 10 , —CR 2 R 10 NHR 1 , —CR 2 R 10 R 1 , —CR 2 R 10 SR 1  or —COR 2 ;  
 J and K are each independently nitrogen or carbon and both J and K are not nitrogens;  
 D and E are each selected, independently, from nitrogen, CR 4 , C═O, C═S, sulfur, oxygen, CR 4 R 6  and NR 8 ;  
 G is nitrogen or carbon;  
 the ring containing D, E, G, K, and J in formula I may be a saturated or unsaturated 5-membered ring and may optionally contain one or two double bonds and may optionally contain from one to three heteroatoms in the ring and may optionally have one or two C═O or C═S groups;  
 R 1  is C 1 -C 6  alkyl optionally substituted with one or two substituents independently selected from hydroxy, fluoro, chloro, bromo, iodo, —O—(C 1 -C 4  alkyl), CF 3 , —C(═O)O—(C 1 -C 4 alkyl), —OC(═O)(C 1 -C 4  alkyl), —OC(═O)N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —NHCO(C 1 -C 4  alkyl), —COOH, —COO(C 1 -C 4  alkyl), —CONH(C 1 -C 4  alkyl), —CON(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —S(C 1 -C 4  alkyl), —CN, —NO 2 , —SO(C 1 -C 4  alkyl), —SO 2 (C 1 -C 4  alkyl), —SO 2 NH(C 1 -C 4  alkyl) and —SO 2 N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), wherein each of the C 1 -C 4  alkyl groups in the foregoing R 1  groups may optionally contain one or two double or triple bonds;  
 R 2  is C 1 -C 12  alkyl which may optionally contain from one to three double or triple bonds, aryl or (C 1 -C 4  alkylene)aryl, wherein said aryl and the aryl moiety of said (C 1 -C 4  alkylene)aryl is selected from phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidinyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl and benzoxazolyl; C 3 -C 8  cycloalkyl or (C 1 -C 6  alkylene)(C 3 -C 8  cycloalkyl), wherein one or two of the carbon atoms of said cycloalkyl and the 5 to 8 membered cycloalkyl moieties of said (C 1 -C 6  alkylene)(C 3 -C 8  cycloalkyl) may optionally and independently be replaced by an oxygen or sulfur atom or by NZ 2  wherein Z 2  is selected from hydrogen, C 1 -C 4  alkyl, benzyl and C 1 -C 4  alkanoyl, and wherein each of the foregoing R 2  groups may optionally be substituted with from one to three substituents independently selected from chloro, fluoro, hydroxy and C 1 -C 4  alkyl, or with one substituent selected from bromo, iodo, C 1 -C 6  alkoxy, —OC(═O)(C 1 -C 6  alkyl), —OC(═O)N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —S(C 1 -C 6  alkyl), amino, —NH(C 1 -C 2  alkyl), —N(C 1 -C 2  alkyl)(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)—CO—(C 1 -C 4  alkyl), —NHCO(C 1 -C 4  alkyl), —COOH, —COO(C 1 -C 4  alkyl), —CONH(C 1 -C 4  alkyl), —CON(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —SH, —CN, —NO 2 , —SO(C 1 -C 4  alkyl), —SO 2 (C 1 -C 4  alkyl), —SO 2 NH (C 1 -C 4  alkyl) and —SO 2 N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl);  
 —NR 1 R 2  or CR 1 R 2 R 10  may form a saturated 3 to 8 membered carbocyclic ring which may optionally contain from one to three double bonds and wherein one or two of the ring carbon atoms of such 5 to 8 membered rings may optionally and independently be replaced by an oxygen or sulfur atom or by NZ 3  wherein Z 3  is hydrogen, C 1 -C 4  alkyl, benzyl or C 1 -C 4  alkanoyl;  
 R 3  is hydrogen, C 1 -C 4  alkyl, —O(C 1 -C 4  alkyl), chloro, fluoro, bromo, iodo, (C 1 -C 2  alkylene)—O—(C 1 -C 2  alkyl), (C 1 -C 2  alkylene)-OH, or —S(C 1 -C 4  alkyl);  
 each R 4  is, independently, hydrogen, (C 1 -C 6  alkyl), fluoro, chloro, bromo, iodo, hydroxy, cyano, amino, (C 1 -C 2  alkylene)—OH, CF 3 , CH 2 SCH 3 , nitro, —O(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl)(C 1 -C 2  alkyl), —S(C 1 -C 4  alkyl), —CO(C 1 -C alkyl), —C(═O)H or —C(═O)O(C 1  -C 4 alkyl);  
 R 6  is hydrogen, methyl or ethyl;  
 R 8  is hydrogen or C 1 -C 4  alkyl;  
 R 5  is phenyl, pyndyl, pyrazinyl, pyrimidyl, pyridazinyl and wherein each of the foregoing R 5  groups is substituted with from one to four substituents R 13  wherein one to three of said substituents may be selected, independently, from fluoro, chloro, C 1 -C 6  alkyl and —O(C 1 -C 6  alkyl) and one of said substituents may be selected from bromo, iodo, formyl, OH, (C 1 -C 4  alkylene)—OH, (C 1 -C 4 alkylene)—O—(C 1 -C 2  alkyl), —CN, —CF 3 , —NO 2 , —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 2  alkyl)(C 1 -C. alkyl), —OCO(C 1 -C 4  alkyl), (C 1 -C 4  alkylene)—O—(C 1 -C 4  alkyl), —S(C 1 -C 6  alkyl), (Cl -C 4  alkylene)—S—(C 1 -C 4  alkyl), —C(═O)O(C 1 -C 4  alkyl), —C(═O)(C 1 -C 4  alkyl), —COOH, —SO 2 NH(C 1 -C 4  alkyl), —SO 2 N(C 1 -C 2  alkyl)(C 1 -C 4  alkyl), —SO 2 NH 2 , —NHSO 2 (C 1 -C 4  alkyl), —S(C 1 -C 6  alkyl) and —SO 2 (C 1 -C 6  alkyl), and wherein each of the C 1 -C 4  alkyl and C 1 -C 6  alkyl moieties in the foregoing R 5  groups may optionally have one or two double bonds;  
 R 7  is hydrogen, C 1 -C 4  alkyl, halo (e.g., chloro, fluoro, iodo or bromo), hydroxy, —O(C 1 -C 4  alkyl), —C(═O)(C 1 -C 4  alkyl), —C(═O)O(C 1 -C 4  alkyl), —OCF 3 , —CF 3 , —CH 2 OH or —CH 2 O(C 1 -C 2  alkyl);  
 R 10  is hydrogen, hydroxy, methoxy or fluoro;  
 R 11  is hydrogen or C 1 -C 4  alkyl; and  
 with the proviso that: a) when both J and K are carbons and D is CR 4  and E is nitrogen, then G can not be nitrogen; (b) when both J and K are carbons and D and G are nitrogens, then E can not be CR 4  or C═O or C═S; (c) when both J and K are carbons and D and E are carbons, then G can not be nitrogen; (d) when G is carbon, it must be double banded to E; and (e) in the ring containing J, K, D, E and G, there can not be two double bonds adjacent to each other;  
 and the pharmaceutically acceptable salts of such compounds.  
 
     
     
         2 . Compounds according to    claim 1    wherein B is —NR 1 R 2 , —NHCHR 1 R 2 , —OCHR 1  R 2  and R 1  is C 1 -C 6  alkyl, which may optionally be substituted with one fluoro, or C 1 -C 4  alkoxy group and which may optionally contain one double or triple bond; and R 2  is C 1 -C 4  alkyl or (C 1 -C 2  alkyl)—CO—(C 1 -C 2  alkyl) which may optionally contain one double or triple bond.  
     
     
         3 . Compounds according to    claim 1   , wherein B is —CHR 1 R 2 , —NR 1 R 2 , —NHCHR 1 R 2 , —OCHR 1 R 2   1  —SCHR 1 R 2 ; and R 1  is C 1 -C 6  alkyl, which may optionally be substituted with one hydroxy, fluoro, CF 3 , cyclopropyl or C 1 -C 4  alkoxy group and which may optionally contain one double or triple bond; and R 2  is benzyl or C 1 -C 6  alkyl, which may optionally contain one double or triple bond, wherein said C 1 -C 6  alkyl and the phenyl moiety of said benzyl may optionally be substituted with one fluoro, hydroxy, CF 3 , cyclopropyl, C 1 -C 2  alkyl, C 1 -C 2  alkoxy or chloro group.  
     
     
         4 . Compounds according to    claim 1    wherein R 3  is methyl.  
     
     
         5 . Compounds according to    claim 1    wherein R 4,  R 6 , R 8 , R 9 , and R 12  are hydrogen or methyl.  
     
     
         6 . Compounds according to    claim 1    wherein R 5  is di- or tri-substituted phenyl in which the two or three substitutents are independently selected from C 1 -C 4  alkyl, O—(C 1 -C 4  alkyl), (C 1 -C 4  alkylene)—O—(C 1 -C 4 alkyl), CF 3 , OCF 3 , CHO, (C 1 -C 4 alkylene)—OH, cyano, chloro, fluoro, bromo and iodo, wherein each of the forgoing (C 1 -C 4 ) alkyl groups may optionally contain one double or triple bond.  
     
     
         7 . Compounds 1 wherein R 3  is methyl, ethyl, chloro or methoxy; and each of R 4 , R 6 , R 8 , R 9 , and R 12  is, independently, hydrogen, methyl or ethyl.  
     
     
         8 . Compounds wherein R 5  is di- or tri-substituted pyridyl, or pyrimidyl in which the two or three substitutents are independently selected from C 1 -C 4  alkyl, O—(C 1 —C 4  alkyl), (C 1 -C 4  alkylene)—O—(C 1 -C, alkyl), CF 3 , OCF 3 , CHO, (C 1 -C 4  alkylene)—OH, cyano, chloro, fluoro, bromo and iodo, wherein each of the forgoing (C 1 -C 4 ) alkyl groups may optionally contain one double or triple bond.  
     
     
         9 . Compounds according to    claim 1    wherein A is N, CH or CCH 3 .  
     
     
         10 . Compounds according to    claim 1    wherein A is CH, J and K are carbon and D, E, and G are nitrogen.  
     
     
         11 . Compounds according to    claim 1    wherein J and D are nitrogen, and K and G are carbon, and E is CH, CCH, or CC 2 H 5 .  
     
     
         12 . Compounds according to    claim 1    wherein J and K are carbon, and D—EG is O—C(CH 3 )═C, 0—CH═C, S—C(CH 3 )═C, S—CH═C, N(CH 3 )—C(CH 3 )═C, NHC(CH 3 )═C, NHC(CH 3 CH 2 )═C, N(CH 3 )—CH═C, O—N═C, S—N═C, N(CH 3 )—N═C, O—CH 2 N or S—CH 2 N.  
     
     
         13 . A compound according to    claim 1    wherein B is —CHR 1 R 2 , —NCHR 1 R 2  or —OCHR 1 R 2 , and the CHR 1 R 2  group of B is a cyclopentane ring, a tetrahydrofuran ring or a tetrahydrothienyl ring.  
     
     
         14 . A compound according to    claim 1    wherein the NR 1  R 2  group of B is a five membered saturated or unsaturated heterocyclic ring.  
     
     
         15 . A compound according to    claim 14    wherein the NR 1 R 2  is a pyrrolo ring, a pyrrolidino ring, a thiazolidino ring or a morpholino ring.  
     
     
         16 . A pharmaceutical composition for the treatment, prevention or inhibition of (a) a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or (b) a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent, depression, child abuse induced depression, mood disorders associated with premenstrual syndrome, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-induced headache; cancer; irritable bowel syndrome, Crohn's disease; spastic colon; post operative ileus; ulcer; diarrhea; stress-induced fever; human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; hypertension; tachycardia; congestive heart failure; osteoporosis; premature birth; and hypoglycemia in a mammal, comprising an amount of a compound according to    claim 1    that is effective in the treatment of such disorder, and a pharmaceutically acceptable carrier.  
     
     
         17 . A method for the treatment, prevention or inhibition of (a) a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or (b) a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent premenstrual syndrome, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-induced headache; cancer; irritable bowel syndrome, Crohn's disease; spastic colon; post operative ileus; ulcer; diarrhea; stress-induced fever; human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Aizheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; hypertension; tachycardia; congestive heart failure; osteoporosis; premature birth; and hypoglycemia in a mammal, comprising administering to a subject in need of said treatment an amount of a compound according to    claim 1   , that is effective in treating such disorder.  
     
     
         18 . A method of treating or preventing a disorder or condition, the treatment or prevention of which can be effected or facilitated by inhibiting CRH binding protein in a mammal, comprising administering to said mammal a CRH binding protein inhibiting amount of a compound according to    claim 1   .  
     
     
         19 . A pharmaceutical composition for treating or preventing a disorder or condition, the treatment or prevention of which can be effected or facilitated by inhibiting CRH binding protein in a mammal, comprising a CRH binding protein inhibiting amount of a compound according to    claim 1    and a pharmaceutically acceptable carrier.  
     
     
         20 . A compound according to    claim 11    or    12    wherein A is N or CH, R 3  is methyl and each R 4 , R 6 , R 8 , R 9  and R 12  is, independently, hydrogen or methyl.  
     
     
         21 . A compound according to    claim 20   , wherein R 5  is di- or tri-substituted phenyl, wherein the two or three substitutents are independently selected from C 1 - 4  alkyl, O—(C 1 -C 4  alkyl), (C 1 -C 4  alkylene)—O—(C 1 -C 4 alkyl), CF 3 , OCF 3 , CHO, (C 1 -C 4 alkylene)—OH, cyano, chloro, fluoro, bromo and iodo, wherein each of the forgoing (C 1 -C 4 ) alkyl groups may optionally contain one double or triple bond.  
     
     
         22 . A compound of the formula  
                   
       wherein R 3′ is C 1 -C 4  alkyl, R 7′ is hydrogen, methyl, chloro, bromo, —COOH or —COO(C 1 -C 4  alkyl), T is chloro, bromo, iodo or triflate, R 8  is hydrogen or C 1 -C 4  alkyl and R  4  is hydrogen, (C 1 -C 6  alkyl), fluoro, chloro, bromo, iodo, hydroxy, cyano, amino, (C 1 -C 2  alkylene)—OH, CF 3 , CH 2 SCH 3 , nitro, —O(C 1 -C 4  alkyl), —N(Ci-C 4  alkyl)(C 1 -C 2  alkyl), —S(C 1 -C 4  alkyl), —CO(C 1 -C 4  alkyl), —C(═O)H or —C(═O)O(C 1 -C 4 alkyl).  
     
     
         23 . A compound according to    claim 1    wherein said compound is: 
 7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine;  
 [2,5-Dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-(1-ethyl-propyl)-amine;  
 (1-Ethyl-propyl)-[5-methyl-3-(2,4,6trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine;  
 7-(1-Ethyl-propoxy)-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine;  
 [2,5-Dimethyl-3-(2,4,6trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-ethyl-propyl-amine;  
 [6-Bromo-5-bromomethyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo [4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;  
 (1-Ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-amine;  
 [6-Bromo-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5b]pyridin-7-yl]-(1-ethyl-propyl)-methyl-amine;  
 7-(1-Ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo [4,5-b]pyridine;  
 4-(1 -Ethyl-propoxy)-2,5-dimethyl-7-(2,4,6-trimethyi-phenyl)-5H-pyrrolo [3,2-d]pyrimidine;  
 (±)-2,5-Dimethyl-4-(tetrahydro-furan-3-yloxy)-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo-[3,2-d]pyrimidine;  
 2,5-Dimethyl-4-(S)-(tetrahydro-furan-3-yloxy)-7-(2,4,6-trimethyt-phenyl)-5H-pyrrolo-[3,2-d]pyrimidine;  
 2,5-Dimethyl-4-(1-propyl-butoxy)-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo [3,2-d]pyrimidine; or  
 4-sec-Butylsulfanyl-2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine;  
 or a pharmaceutically acceptable salt of such compound.