BACKGROUND OF THE INVENTION

[0001] This invention relates to certain pharmaceutically active substituted 6,5-hetero-bicyclic derivatives, pharmaceutical compositions containing them and methods of administering them to subjects in need of their corticotropin releasing factor antagonist activity.

[0002] The substituted heterocyclic derivatives claimed in this case exhibit activity as corticotropin releasing factor (hormone) CRF (CRH) antagonists.

[0003] CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and 5,063,245 referring to peptides and pyrazolinones, respectively. They are also referred to in the following: PCT Patent Application PCT/IB95/00439, which designates the United States and was filed on Jun. 6, 1995 and published on Dec. 14, 1995; PCT Patent Application PCT/IB95/00373, which designates the United States and was filed on May 18, 1995 and published on Dec. 21, 1995; U.S. patent application Ser. No.08/448,539, which was filed in the PCT on Nov. 12, 1993 and entered the U.S. national phase on Jun. 14, 1995; PCT Patent Application WO 95/10506, which was filed on Oct. 12, 1993 and published on Apr. 20, 1995, and U.S. patent application Ser. No. 08/481,413, which was filed in the PCT on Nov. 26, 1993 and entered the U.S. national phase on Jul. 24, 1995; U.S. patent application Ser. No. 08/254,820, which was filed on Apr. 19, 1995; Provisional U.S. Patent Application 60/008,396, which was filed on Dec. 8, 1995; and Provisional U.S. Patent Application 60/006,333, which was filed on Nov. 8, 1995. All the foregoing patent applications are incorporated herein by reference in their entireties.

[0004] The importance of CRF antagonists is set out in the literature, e.q., P. Black, Scientific American SCIENCE &MEDICINE,1995, p. 1 625; T. Lovenberg et al., Current Pharmaceutical Design, 1995, 1, 305-316; and U.S. Pat. No. 5,063,245, which is referred to above. A recent outline of the different activities possessed by CRF antagonists is found in M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991), also incorporated herein by reference. Based on the research described in these two and other references, CRF antagonists are effective in the treatment of a wide range of stress-related illnesses, mood disorders such as depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, dysthemia, bipolar disorders and cyclothymia; chronic fatigue syndrome; eating disorders such as anorexia and bulimia nervosa; generalized anxiety disorder; panic disorder; phobias; obsessive-compulsive disorder, post-traumatic stress disorder, pain perception such as fibromyalgia; headache; gastrointestinal diseases; hemorrhagic stress; ulcers; stress-induced psychotic episodes; fever; diarrhea; post-operative ileus, colonic hypersensitivity; irritable bowel syndrome; Crohn's disease; spastic colon; inflammatory disorders such as rheumatoid arthritis and osteoarthritis; pain; asthma; psoriasis; allergies; osteoporosis; premature birth; hypertension, congestive heart failure; sleep disorders; neurodegenerative diseases such as Alzheimer's disease, senile dementia of the Alzheimer's type, muitiinfarct dementia, Parkinson's disease, and Huntington's disease; head trauma; ischemic neuronal damage; excitotoxic neuronal damage; epilepsy; stroke; spinal cord trauma; psychosocial dwarfism; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone, obesity; chemical dependencies and addictions; drug and alcohol withdrawal symptoms; infertility, cancer; infertility; muscular spasms; urinary incontinence; hypoglycemia and immune dysfunctions including stress induced immune dysfunctions, immune suppression and human immunodeficiency virus infections; and stress-induced infections in humans and animals.

[0005] The compounds of this invention are also believed to be inhibitors of CRH binding protein and therefore useful in the treatment of disorders the treatment of which can be effected or facilitated by inhibiting such protein. Examples of such disorders are Alzheimer's disease and obesity.

SUMMARY OF THE INVENTION

[0006] The present invention relates to compounds of the formula 2

[0007] or a pharmaceutically acceptable salt thereof, wherein

[0008] the dashed lines represent optional double bonds;

[0009] A is nitrogen or CR⁷;

[0010] B is —NR¹R², —CR¹R²R¹⁰, —C(═CR²R¹¹)R¹, —NHCR¹R²R¹⁰, —OCR¹R²R¹⁰, —SCR¹R²R¹⁰, —CR²R¹⁰ONHR¹, —CR²R¹⁰R¹, —CR²R¹⁰SR¹ or —COR²;

[0011] J and K are each independently nitrogen or carbon and both J and K are not nitrogens;

[0012] D and E are each selected, independently, from nitrogen, CR⁴, C═O, C═S, sulfur, oxygen, CR⁴R⁶ and NR⁸;

[0013] G is nitrogen or carbon;

[0014] 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;

[0015] R¹ is C₁-C₆ alkyl optionally substituted with one or two substituents independently selected from hydroxy, fluoro, chloro, bromo, iodo, —O—(C₁-C₄ alkyl), CF₃, —C(═O)O—(C₁-C₄alkyl), —OC(═O)(C₁-C₄ alkyl), —OC(═O)N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —NHCO(C₁-C₄ alkyl), —COOH, —COO(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CON(C₁-C₄ akyl)(C₁-C₂ alkyl), —S(C₁-C₄ alkyl), —CN, —NO₂, —SO(C₁-C₄ alkyl), —SO₂(C₁-C₄ alkyl), —SO₂NH(C₁-C₄ alkyl) and —SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), wherein each of the C₁-C₄ alkyl groups in the foregoing R¹ groups may optionally contain one or two double or triple bonds;

[0016] R² is C₁-C₁₂ alkyl which may optionally contain from one to three double or triple bonds, aryl or (C₁-C₄ alkylene)aryl, wherein said aryl and the aryl moiety of said (C₁-C₄ 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; C₃-C₈ cycloalkyl or (C₁-C₆ alkylene)(C₃-C₈ cycloalkyl), wherein one or two of the carbon atoms of said cycloalkyl and the 5 to 8 membered cycloalkyl moieties of said (C₁-C₆ alkylene)(C₃-C₈ cycloalkyl) may optionally and independently be replaced by an oxygen or sulfur atom or by NZ² wherein Z² is selected from hydrogen, C₁-C₄ alkyl, benzyl and C₁-C₄ alkanoyl, and wherein each of the foregoing R² groups may optionally be substituted with from one to three substituents independently selected from chloro, fluoro, hydroxy and C₁-C₄ alkyl, or with one substituent selected from bromo, iodo, C₁-C₆ alkoxy, —OC(═O)(C₁-C₆ alkyl), —OC(═O)N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —S(C₁-C₆alkyl), amino, —NH(C₁-C₂ alkyl), —N(C₁-C₂ alkyl)(C₁-C₄ alkyl), —N(C-C₄ alkyl)—CO—(C₁-C₄ alkyl), —NHCO(C₁-C₄ alkyl), —COOH, —COO(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl), —SH, —CN, —NO₂, —SO(C₁-C₄ alkyl), —SO₂(CI-C₄ alkyl), —SO₂NH(C₁-C₄ alkyl) and —SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl);

[0017] —NR¹R² or —CR¹R²R¹⁰ 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 NZ³ wherein Z³ is hydrogen, C₁-C₄ alkyl, benzyl or C₁-C₄ alkanoyl;

[0018] R³ is hydrogen, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), chloro, fluoro, bromo, iodo, (C₁-C₂ alkylene)—O—(C₁-C₂ alkyl), (C₁-C₂ alkylene)—OH, or —S(C₁-C₄ alkyl);

[0019] each R⁴ is, independently, hydrogen, (C₁-C₆ alkyl), fluoro, chloro, bromo, iodo, hydroxy, cyano, amino, (C₁-C₂ alkylene)—OH, CF₃, CH₂SCH₃, nitro, —O(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —S(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —C(═O)H or —C(═O)O(C₁-C₄alkyl);

[0020] R⁶ is hydrogen, methyl or ethyl;

[0021] R⁸ is hydrogen or C₁-C₄ alkyl;

[0022] R⁵ is phenyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl and wherein each of the foregoing R⁵ groups is substituted with from one to four substituents R¹³ wherein one to three of said substltuents may be selected, independently, from fluoro, chloro, C₁-C₆, alkyl and —O(C₁-C₆ alkyl) and one of said substituents may be selected from bromo, iodo, formyl, OH, (C₁-C₄ alkylene)—OH, (C₁-C₄alkylene)—O—(C₁-C₂ alkyl), —CN, —CF₃, —NO₂, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₂ alkyl)(C₁-C₆ alkyl), —OCO(C₁-C₄ alkyl), (C₁-C₄ alkylene)—O—(C₁-C₄ alkyl), —S(C₁-C₆ alkyl), (C₁-C₄alkylene)—S—(C₁-C₄alkyl), —C(═O)O(C₁-C₄ alkyl), —C(═O)(C₁-C₄ alkyl), —COOH, —SO₂NH(C₁-C₄ alkyl), —SO₂N(C₁-C₂ alkyl)(C₁-C₄ alkyl), —SO₂NH₂, —NHSO₂(C₁-C₄ alkyl), —S(C₁-C₆ alkyl) and —SO₂(C₁-C₆ alkyl), and wherein each of the C₁-C₄ alkyl and C₁-C₆ alkyl moieties in the foregoing R⁵ groups may optionally have one or two double bonds;

[0023] R⁷ is hydrogen, C₁-C₄ alkyl, halo (e.g., chloro, fluoro, iodo or bromo), hydroxy, —O(C₁-C₄ alkyl), —C(═O)(C₁-C₄ alkyl), —C(═O)O(C₁-C₄ alkyl), —OCF₃, —CF₃, —CH₂OH or —CH₂O(C₁-C₂ alkyl);

[0024] R¹⁰ is hydrogen, hydroxy, methoxy or fluoro;

[0025] R¹¹ is hydrogen or C₁-C₄ alkyl; and

[0026] with the proviso that: a) when both J and K are carbon and D is CR⁴ 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 CR⁴ 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 bonded 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.

[0027] and the pharmaceutically acceptable salts of such compounds.

[0028] When the ring containing D, E, G, K and J is a 5-membered heteroaromatic ring, it may be, e.g., pyrazolo, imidazolo, thieno, furano, thiazolo, oxazolo, triazolo or thiadiazolo.

[0029] The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight branched or cyclic moieties or combinations thereof.

[0030] The term “alkoxy”, as used herein, unless otherwise indicated, means —O-alkyl, where “alkyl” is defined as above.

[0031] Examples of more specific embodiments of formula I are the following, wherein (R)_n represents from zero to two substituents, wherein such substitutents are as defined above in the definition of formula I. 3

[0032] More specific embodiments of this invention include compounds of the above formula I wherein B is —CHR¹R², —NR¹R², —NHCHR¹R², —OCHR¹R² or —SCHR¹R² and R¹ is C₁-C₆ alkyl, which may optionally be substituted with one hydroxy, fluoro, CF₃ or C₁-C₄ alkoxy group and which may optionally contain one double or triple bond; and R² is benzyl or C₁-C₆ alkyl, which may optionally contain one double or triple bond, wherein said C₁-C₆ alkyl and the phenyl moiety of said benzyl may optionally be substituted with one fluoro, CF₃, C₁-C₂ alkyl, C₁-C₂ alkoxy or chloro group.

[0033] Other more specific embodiments of this invention include compounds of formula I wherein R³ is methyl, ethyl, chloro or methoxy; R⁴ and R⁶ are selected from hydrogen, methyl and ethyl; R5 is di- or tri-substituted phenyl, pyridyl, or pyrimidyl, in which the two or three substitutents on said phenyl, pyridyl or pyrimidyl are selected, independently, from C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), (C₁-C₂ alkyl)—O—(C₁-C₄ alkyl), —CF₃, —OCF₃, —CHO, —(C₁-C₄ alkyl)—OH, cyano, chloro, fluoro, bromo and iodo, wherein each of the forgoing C₁-C₄ alkyl groups may optionally contain one double or triple bond;

[0034] Other more specific embodiments of this invention include compounds of the formula I wherein B is or contains an NR¹R² or CR¹R²R¹⁰ moiety which forms a saturated or unsaturated 5-membered carbocyclic ring wherein one of the ring carbons may optionally be replaced by a sulfur or oxygen atom.

[0035] Other more specific embodiments of this invention include compounds of the formula I wherein A is nitrogen or CR⁷ and R⁷ is hydrogen or methyl.

[0036] Other more specific embodiments of this invention include compounds of the formula I wherein B is —CR¹R²R¹⁰, —C(═CR²R¹¹)R¹, —OCR¹R²R¹⁰, —SCR¹R²R¹⁰, —CR²R¹⁰NHR¹, CR²R¹⁰OR¹₁, —CR²R¹⁰SR¹ or —COR².

[0037] Other more specific embodiments of this invention include compounds of the formula I wherein A is CH, J and K are carbon and D, E, and G are nitrogen;

[0038] Other more specific embodiments of this invention include compounds of the formula I wherein J and D are nitrogen, K and G are carbon, and E is CH, CCH₃, or CC₂H₅.

[0039] Other more specific embodiments of this invention include compounds of the formula I wherein B contains a —NR¹R² or —CR¹R²R¹⁰ moiety that is a saturated or unsaturated three to five membered ring.

[0040] Other more specific embodiments of this invention include compounds of the formula I wherein J and K are carbon, and D—E—G is O—C(CH₃)═C, O—CH═C, S—C(CH₃)═C, S—CH═C, N(CH₃)—C(CH₃)═C, N(CH₃)—CH═C, O—N═C, S—N═C, N(CH_{3)—N═C, O—CH2}N, S—CH₂N, or NH—C(C₁-C₂alkyl)═C.

[0041] Examples of preferred compounds of the formula I:

[0042] 7-(1 -ethyl-propoxy)5methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo [1,5-a]pyrimidine;

[0043] [2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-(1-ethyl-propyl)-amine;

[0044] (1-ethyl-propyl)-[5-methyl-3-(2,4,6trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine;

[0045] 7-(1-ethyl-propoxy)-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine;

[0046] [2,5-dimethyl-3(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-ethyl-propylamine;

[0047] [6-bromo-5-bromomethyl3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]-pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0048] (1-ethyl-propyl)-[5methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1 ,2,3]triazolo[4,5-b]-pyridin-7-yl]-amine;

[0049] [6-bromo-5-methyl-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-(1-ethylpropyl)-methyl-amine; and

[0050] 7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]-pyridine.

[0051] Other compounds of formula I include the following:

[0052] 4-(1-ethyl-propoxy)-2,7-dimethyl-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-a]-pyrimidine;

[0053] (1-ethyl-propyl)-[5-methyl-3-(2,4,6bimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine;

[0054] [3(4-bromo-2,6-dimethyl-phenyl)-5-methyl-pyrazolo[1,5a]pyrimidin-7-yl]-(1ethyl-propyl)-amine;

[0055] butyl-ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1 ,5-a]pyrimidin-7-yl]-amine;

[0056] 3(4-bromo-2,6-dimethyl-phenyl)-7-(1-ethyl-propoxy)-5methyl-pyrazolo[1,5-a]-pyrimidine;

[0057] [2,7-dimethyl-8-(2,4,6trimethyl-phenyl)-pyrrolo[1,2a]pyrimidin-4-yl]-diethyl-amine;

[0058] [2,7-dimethyl-8-(2,4,-trimethyl-phenyl)-pyrrolo [1,2-a]pyrimidin4-yl]-ethyl-propyl-amine;

[0059] [8-(4-chloro-2,6-dimethyl-phenyl)-2,7-dimethyl-pyrrolo[1,2-a]pyrimidin4-yl]-ethyl-propyl-amine;

[0060] [8-(4-chloro-2,6-dimethyl-phenyl)-2,7-dimethyl-pyrrolo[1,2-a]pyrimidin4-yl]-diethyl-amine;

[0061] [8-(4-chloro-2,6-dimethyl-phenyl)-2,6-dimethyl-pyrrolo[1,2-a]pyrimidin4-yl]-diethyl-amine;

[0062] [2,6-dimethyl-8-(2,4,6trimethyl-phenyl)-pyrrolo[1,2-a]pyrimidin4yl]-diethyl-amine;

[0063] [2,6dimethyl-(2,4,6trimethyl-phenyl)-pyrrolo[1,2-a]pyrimidin4-yl]-ethyl-propyl-amine;

[0064] butyl-[2,6-dimethyl-8-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-a]pyrimidin4-yl]-ethyl-amine;

[0065] [2,6-dimethyl-8-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-alpyrimidin4yl]-(1-ethyl-propyl)-amine;

[0066] [8-(4-chloro-2,6-dimethyl-phenyl)-2,6-dimethyl-pyrrolo[1,2-a]pyrimidin4-yl]-(1-ethyl-propyl)-amine;

[0067] 8(4chloro-2,6-dimethyl-phenyl)4-(1-ethyl-propoxy)-2,6dimethyl-pyrrolo[1,2-a]-pyrimidine;

[0068] 4-(1-ethyl-propoxy)-2,6-dimethyl-8-(2,4,6trimethyl-phenyl)-pyrrolo [1,2-a]-pyrimidine;

[0069] 4(1ethyl-propoxy)-2-methyl-8-(2,4,6-trimethyl-phenyl)-pyrrolo [1,2-a]pyrimidine;

[0070] (1ethyl-propyl)-[2-methyl-8-(2,4,6-trimethyl-phenyl)-pyrrolo [1,2-a]pyrimidin-4-yl]-amine;

[0071] butyl-ethyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-a]pyrimidin-4-yl]-amine;

[0072] butyl-ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-2H-isothiazolo[2,3-a]-pyrimidin-7-yl]-amine;

[0073] (1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-2H-isothiazolo[2,3-a]-pyrimidin-7-yl]-amine;

[0074] 7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-2H-isothiazolo [2,3-a]-pyrimidine;

[0075] 4-(1-ethyl-propoxy)-2-methyl-8-(2,4,6-trimethyl-phenyl)-imidazo [1,5-a]-pyrimidine;

[0076] (1-ethyl-propyl)-[2-methyl-(2,4,6-trimethyl-phenyl)-imidazo[1,5-a]pyrimidin4-yl]-amine;

[0077] [2,6-dimethyl-8-(2,4,6-trimethyl-phenyl)-imidazo[1,5-a]pyrimidin4-yl]-(1-ethyl-propyl)-amine;

[0078] 4-(1-ethyl-propoxy)-2,6-dimethyl-8-(2,4,6-trimethyl-phenyl)-imidazo[1,5-a]-pyrimidine;

[0079] 4-(1-ethyl-propoxy)-2,6-dimethyl-8-(2,4,6-trimethyl-phenyl)-6,7-dihydro-imidazo[1,5-a]pyrimidine;

[0080] 4-(1-ethyl-propoxy)-2,6-dimethyl-8-(2,4,6-trimethyl-phenyl)-thiazolo[3,4-a]-pyrimidine;

[0081] 4(1-ethyl-propoxy)-2-methyl-7-(2,4,6-trimethyl-phenyl)-pyrrolo[12-b]pyridazine;

[0082] 4-(1-ethyl-propoxy)-2,-dimethyl-7-(2,4,6-trimethyl-phenyl)-pyrrolo 8 1,2-b]-pyridazine;

[0083] 4-(1-ethyl-propoxy)-2,6-dimethyl-7-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-b]; pyridazine;

[0084] 4-(1-ethyl-propoxy)-2,5,6-timethyl-7-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-b]-pyridazine;

[0085] [2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-b]pyrdazin-4-yl]-(1-ethyl-propyl)-amine;

[0086] (1-ethyl-propyt)-[2-methyl-7-(2,4,-trimethyl-phenyl)-pyrrolo[1,2-b]pyridazin-4-yl]-amine;

[0087] [2,6-dimethyl-3-(2,4,6-trimethyl-phenyl)-imidazo[1,2-b]pyridazin-8yl]-(1-ethyl-propyl)-amine;

[0088] 8-(1-ethyl-propoxy)-2,6-dimethyl-3-(2,4,6-trimethyl-phenyl)-imidazo[1,2-b]-pyridazine;

[0089] 8(1-ethyl-propoxy)-6-methyl-3-(2,4,6trimethyl-phenyl)-imidazo [1,2-b]pyridazine;

[0090] (1-ethyl-propyl)-[6-methyl-3-(2,4,6-trimethyl-phenyl)-imidazo[1,2-b]pyridazin-8-yl]-amine;

[0091] (1-ethyl-propyl)-[2-methyl-7-(2,4,6trimethyl-phenyl)-imidazo[1,5-b]pyridazin-yl]-amine;

[0092] [2,5dimethyl-7-(2,4,6-trimethyl-phenyl)-imidazo[1,5b]pyridazin-4yl]-(1 -ethyl-propyl)-amine;

[0093] 4-(1-ethyl-propoxy)-2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-imidazo[1,5-b]-pyridazine-b]pyridazine;

[0094] butyl-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-imidazo[1,5-b]pyridazin-4-yl]-ethyl-amine;

[0095] [2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-imidazo[1,5b]pyridazin-4-yl]-ethyl-propyl-amine;

[0096] [2,5-dimethyl-7-(2,4,6trimethyl-phenyl)-imidazo[1,5-b]pyridazin-4-yl]-diethyl-amine;

[0097] diethyl-[6-methyl-3-(2,4,6-trimethyl-phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-amine;

[0098] ethyl-[6-methyl-3-(2,4,6-trimethyl-phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-propyl-amine;

[0099] butyl-ethyl-[6-methyl-3-(2,4,6-trimethyl-phenyl)-[1 ,2,4]triazolo[4,3-b]pyridazin-8-yl]-amine;

[0100] (1-ethyl-propyl)-[6methyl-3-(2,4,6-trimethyl-phenyl)-[1,2,4]triazolo[4,3-b]-pyridazin-8yl]-amine;

[0101] 8-(1-ethyl-propoxy)-6-methyl-3-(2,4,6-trimethyl-phenyl)-[1 ,2,4]triazolo [4,3-b]-pyridazine;

[0102] 7-(1-ethyl-propoxy)-1,5-dimethyl-3-(2,4,6trimethyl-phenyl)-1H-pyrrolo [3,2-b]-pyridine;

[0103] 7-(1-ethyl-propoxy)-1,2,5-trimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo [3,2-b]-pyridine;

[0104] (1-ethyl-propyl)-[1,2,5trimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo [3,2-b]-pyridin-7-yl]-amine;

[0105] [1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0106] butyl-[1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-ethyl-amine;

[0107] [1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-ethyl-propyl-amine;

[0108] [1,5dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo [3,2-b]pyridin-7-yl]-diethyl-amine;

[0109] ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-propyl-amine;

[0110] butyl-ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1 ,2 ,3]triazolo [4,5-b]pyridin-7-yl]-amine;

[0111] diethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazoio[4,5-b]pyridin-7-yl]-amine;

[0112] [3-(4-bromo-2,6-dimethyl-phenyl)-5-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0113] [3-(4-chloro-2,6-dimethyl-phenyl)-5-methyl-3H-[1,2,3]triazolo[4,5b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0114] 3-(4-chloro-2,6-dimethyl-phenyl)-7-(1-ethyl-propoxy)-5-methyl-3H-[1,2,3]triazolo[4,5-b]pyridine;

[0115] 3-(4-bromo-2,6-dimethyl-phenyl)-7-(1-ethyl-propoxy)-5-methyl-3H-[1,2,3]triazolo[4,5-b]pyridine;

[0116] 7-(1ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-isothiazolo[4,5-b]pyridine;

[0117] (1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-isothiazolo[4,5-b]pyridin-7-yl]-amine;

[0118] (1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-isoxazolo[4,5-b]pyridin-7-yl]-amine;

[0119] 7-(1-ethyl-propoxy)-5methyl-3-(2,4,6-trimethyl-phenyl)-isoxazolo[4,5-b]pyridine;

[0120] 7-(1-ethyl-propoxy)-5-methyl-3-(2,4,-trimethyl-phenyl)-thieno[3,2-b]pyridine;

[0121] 7-(1-ethyl-propoxy)-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-thieno[3,2-b]pyridine;

[0122] [2,5-dimethyl-3(2,4,6-trimethy-phenyl)-thieno[3,2-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0123] (1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-thieno[3,2-b]pyridin-7-yl]-amine;

[0124] (1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-furo[3,2-b]pyridin-7-yl]-amine;

[0125] [2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-furo[3,2-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0126] 7-(1-ethyl-propoxy)-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-turo[3,2-b]pyridine;

[0127] 7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-furo[3,2-b]pyridine;

[0128] 4-(1-ethyl-propoxy)-2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-6H-pyrrolo[3,4-b]-pyridine;

[0129] 4-(1 -ethyl-propoxy)-2,5,-trimethyl-7-(2,4,6-trimethyl-phenyl)-6H-pyrrolo [3,4-b]-pyridine;

[0130] (1-ethyl-propyl)-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-6H-pyrrolo[3,4-b]pyridin-4-yl]-amine;

[0131] [1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-2-thia4-aza-inden-7-yl]-(1-ethyl-propyl)-amine;

[0132] 7-(1-ethyl-propoxy)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-2-thia-4-aza-indene;

[0133] 4-(1-ethyl-propoxy)-2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-furo[3,4-b]pyridine;

[0134] [2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-furo[3,4-b]pyridin-4-yl]-(1-ethyl-propyl)-amine;

[0135] [2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-2H-pyrazolo[4,3-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0136] 7-(1-ethyl-propoxy)-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-2H-pyrazolo[4,3-b]-pyridine;

[0137] 7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-isothiazolo[4,3-b]pyridine;

[0138] (1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)isothiazolo[4,3-b]pyridin-7-yl]-amine;

[0139] (1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyt)-3H-[1,2,3]triazolo[4,5-d]-pyrimidin-7-yl]-amine;

[0140] diethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5d]pyrimidin-7-yl]-amine;

[0141] ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-propyl-amine;

[0142] butyl-ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]-pyrimidin-7-yl]-amine;

[0143] [2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-diethyl-amine;

[0144] butyl-[2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-ethyl-amine;

[0145] butyl-ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine;

[0146] ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-propyl-amine;

[0147] diethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine;

[0148] [3-(4-chloro-2,6-dimethyl-phenyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-(1-ethyl-propyl)-amine;

[0149] [3-(4-chloro-2,6-dimethyl-phenyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-(1 -ethyl-propyl)-amine;

[0150] 3-(4-chloro-2,6-dimethyl-phenyl)-7-(1-ethyl-propoxy)-5-methyl-pyrazolo[1,5-a]-pyrimidine;

[0151] 8(4-chloro-2,6-dimethyl-phenyl)4-(1-ethyl-propoxy)-2-methyl-pyrazolo[1,5-a]-[1,3,5]triazine;

[0152] (1-ethyl-propyl)-[2-methyl-8-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-amine;

[0153] 4-(1-ethyl-propoxy)-2-methyl-8-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a][1,3,5]-triazine;

[0154] 4-(1ethyl-propoxy)-2,7-dimethyl(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a][1,3,5]-triazine;

[0155] [2,7-dimethyl-(2,4,6trimethyl-phenyl)-pyrazolo[1,5-a][1,3,5]triazinryl]-(1-ethyl-propyl)-amine;

[0156] [1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0157] 7-(1-ethyl-propoxy)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrazolo[4,3-b]-pyridine;

[0158] 7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-isothiazolo[4,5-b]-pyridine;

[0159] (1-ethyl-propyl)-[5-methyl-3-(2,4,6trimethyl-phenyl)isothiazolo[4,5-b]pyridin-7-yl]-amine;

[0160] 1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-7-(1-ethyl-propoxy)-1H-pyrrolo [3,2-b]pyridine;

[0161] 1,5-dimethyl-3-(2,6-dimethyl-4-chloro-phenyl)-7-(1-ethyl-propoxy)-1H-pyrrolo[3,2-b]pyridine;

[0162] 2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-7-(1-ethyl-propoxy)-1H-pyrrolo[3,2-b]pyridine;

[0163] 2,5-dimethyl-3-(2,6-dimethyl-4-chloro-phenyl)-7-(1-ethyl-propoxy)-1H-pyrrolo[3,2-b]pyridine;

[0164] 7-(1-cyclopropylmethyl-propoxy)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine;

[0165] 7-(1-cyclopropylmethyl-propoxy)-1,5-dimethyl-3-(2,6dimethyl-4-chloro-phenyl)-1H-pyrrolo[3,2-b]pyridine;

[0166] 1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-7-(tetrahydro-furan-3-yloxy)-1H-pyrrolo[3,2-b]pyridine;

[0167] 1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-7-(S)-(tetrahydro-furan-3-yloxy)-1H-pyrrolo[3,2-b]pyridine;

[0168] 1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-7-(1-propyl-butoxy)-1H-pyrrolo[3,2-b]pyridine;

[0169] 7-sec-butylsulfanyl-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine;

[0170] cyclopropylmethyl-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-b]pyrimidin-4-yl]-propyl-amine;

[0171] 2-[1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-7-ylamino]-butan-1-ol;

[0172] 1,5-dimethyl-7-thiazolidin-3-yl-3-(2,4,6trimethyl-phenyl)-1H-pyrrolo[3,2b]pyridine;

[0173] [1,5-dimethyl4(2,4,1trimethylphenyl)-1H-pyrrolo [3,2-b]pyridin-7-yl]-ethyl-(2,2,2-trifluoro-ethyl)-amine;

[0174] cyclopropylmethyl-[1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-propyl-amine;

[0175] (1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-isoxazolo[4,5-b]pyridin-7-yl]-amine; and

[0176] 7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-isoxazolo [4,5-b]-pyridine.

[0177] This invention also relates to 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, nicotine, 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 (ea., 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; multiinfract dementia; amyotrophic lateral sclerosis; hypertension; tachycardia; congestive heart failure; osteoporosis; premature birth; and hypoglycemia in a mammal, including a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in the treatment of such disorder, and a pharmaceutically acceptable carrier.

[0178] The invention also relates to 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 facilitator 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; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (g, cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions including stress induced immune dysfunctions (e, 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; chemical dependencies and addictions (e.g., dependencies on alcohol, nicotine, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; hypertension; tachycardia; congestive heart failure; osteoporosis; premature birth; and hypoglycemia in a mammal, including a human, comprising administering to a subject in need of said treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.

[0179] This invention also relates to 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, including a human, comprising administering to said mammal a CRH binding protein inhibiting amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.

[0180] This invention also relates to a pharmaceutical composition for treating or preventing a disorder or conditon, the treatment or prevention of which can be effected or facilitated by inhibiting CRH binding protein in a mammal, including a human, comprising a CRH binding protein inhibiting amount of a compound of the formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0181] This invention includes all optical isomers and other stereoisomers of compounds of the formula I. When such compounds contain one or more chiral centers, it is understood that the invention includes the racemic mixtures as well as all individual enantiomers and diastereomers of such compounds, and mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0182] The following compounds having the formulas II, III, IV and V are useful as intermediates in the synthesis of compounds of the formula I. 4

[0183] wherein T is chioro, bromo, iodo or —OSO₂CF₃; W is cyano, formyl, or —COO(C₀-C₄ alkyl) and A, J, K, D, E, G, R³, and R⁵ are as defined above with reference to formula I.

[0184] Compounds of the formula I may be prepared as described below. In the reaction schemes and discussion that follow, A, B, D, E, G, J, K, R³, R⁵ and structural formulae I, II, III, IV, and V are defined as above. 5 6 7 8 9 10 11 12 13

[0185] Compounds of the formula I wherein B is —NR¹R² or —NHCR¹R²R¹¹ may be prepared by reacting a compound of the formula II wherein T is chloro, bromo, or iodo with a compound of the formula BH, in the presence of a base, with or without an organometallic compound such as Cu(I)X, wherein X is chloro, bromo or iodo, or an acid (such as p-TsOH (Ts═Tosyl) or another sterically hindered phenol) or an equivalent agent known to those of skill in the art. Suitable solvents for this reaction include DMSO, NMP, dimethylacetamide and THF. An excess of BH may be used as both the reagent and the base. Other bases such as potassium or sodium carbonate, a trialkylamine, a potassium or sodium (C₁-C₄ alkoxide) and sodium hydride may also be used. When R⁷ is an electron withdrawing group such as —COO(C₁-C₄alkyl) or CN, the reaction generally is carried out at a temperature between about room temperature and about 100° C. When R⁷ is a non-electron withdrawing group, the reaction temperature can generally range from about 50° C. to about 270° C. and the pressure can generally range from about 4 psi to about 300 psi. A pressure reactor may be used.

[0186] Alternatively, the compounds of formula I may be prepared by reacting a compound of the formula II wherein T is bromo or iodo with 1 equivalent or an excess of BH and a base such as sodium or potassium carbonate or a sodium or potassium (C₁-C₄ alkoxide), in the presence of a palladium (II) or a palladium (0) catalyst such as Pd(OAc)₂ or Pd(PPh₃)₄, together with a racemic or chiral phosphino agent such as 2,2-bis(diphenylphosphino)-1,1-binaphthyl (BINAP). Alternatively, premade Pd(II)(BINAP) may be used in an appropriate inert (i.e., inert with respect to the reaction at hand) solvent such as toluene, xylene, dioxane or sulfolane, at a temperature from about room temperature to about 180° C., preferably at about reflux temperature.

[0187] Compounds of the formula I wherein B is —OCR¹R²R¹¹, —SCR¹R²R¹¹, or —NHCR¹R²R¹¹ may be prepared by reacting compounds in the formula II wherein T is chloro, bromo or iodo with a compound of the formula BH in the presence of a base which is capable of deprotonation of BH (e.g., sodium or potassium hydride, or an organometallic base such as sodium diisopropylamide, sodium bis(trimethylsilyl)amide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, a sodium C₁-C₄ alkoxide or n-butyllithium), in an inert organic solvent such as tetrahydrofuran, acetonitrile, dimethylsulfoxide, acetone, a C₂-C₅ alcohol, chloroform, benzene, xylene, toluene, N,N-dimethylformamide (DMF), methylene chloride, 1-methyl-2-pyrrolidinone or a mixture of two or more of the above solvents (e.g., DMSO and THF), at a temperature from about 0° C. to about 180° C., preferably from about 50° C. to about 180° C.

[0188] Compounds of the formula I wherein B is —CR¹R²R¹¹, —C(C═CR²R¹²)R¹, —CR²R¹¹NHR¹, —CR²R¹¹OR¹, —CR²R¹¹SR¹, or —C(O)R² may be prepared from compounds of the formula III wherein W is cyano, formyl or carboxy, as described below.

[0189] Reacting compounds of formula III wherein W is cyano with a Grignard reagent containing the group R² in an inert solvent such as THF, glyme, ether or dioxane, will yield corresponding compounds of formula I wherein B is —COR². Further reaction of the compounds of formula I wherein B is COR² with a Grignard reagent containing R¹, using a solvent such as those referred to above, will yield the corresponding the compounds of formula I wherein B is —CR¹R²OH. Reacting compounds of formula III wherein W is formyl with a Grignard reagent containing the group R², in an ethereal solvent such as those referred to above, will yield the corresponding compounds of formula I wherein B is —CHR²OH.

[0190] Compounds of formula I wherein B is —CR¹R²R¹¹ or —C(C═CR²R¹¹)R¹ may be prepared by conventional methods. Thus, reaction of a compound of the formula I wherein B is —CR^1′R^2′OH, (wherein R^1′and R^2′are defined as R¹ and R², respectively, except that R^1′may not be R¹ and R^2′may not be R²), with an acid such as concentrated sulfuric acid in acetic acid, or a Burgess inner salt such as (carboxysulfamoyl)triethylammonium hydroxide methyl ester, will yield a compound of the formula I wherein B is —C(═CR²R¹¹)R¹. Hydrogenation of a compound of formula I wherein B is —C(═CR²R¹¹)R¹ using palladium on carbon (Pd/C) or a platinum dioxide catalyst in a (C₁-C₄)alkanol solvent will yield a compound of the formula I wherein B is —CHR¹R². Reaction of a compound of the formula I wherein B is —CR¹R²OH with diethylaminosulfur trifluoride or triphenylphosphinelcarbon tetrachloride in an inert solvent such as carbon tetrachloride will afford a compound of the formula I wherein B is —CR¹R²F or —CR¹R²Cl, respectively.

[0191] Reduction of a compound of formula I wherein B is —COR² with sodium borohydride, in an inert solvent such as a (C₁-C₄)alkanol, will yield a compound of the formula I wherein B is —CHR²OH. Alkylation of a compound of the formula I wherein B is —CHR²OH with an alkyl halide (such as alkyl iodide) in the presence of a base such as sodium hydride (NaH) at room temperature, in an inert solvent such as toluene, THF, dioxane or ether, will yield the corresponding compound of the formula I wherein B is —CHR²OR¹.

[0192] Compounds of the formula I wherein B is —CR²R¹⁰NHR¹ may be prepared by conventional methods such as reductive amination of the corresponding compounds of the formula I wherein B is —C(O)R² with an appropriate amine and reducing agent (such as sodium cyanoborohydride, sodium triacetoxyborohydride, or lithium aluminum tetrahydride) in an appropriate inert solvent such as a C₁-C₄ alkanol or acetic acid.

[0193] Conversion of compounds in formula I wherein B is —C(O)R² into compounds in formula I wherein B is —C(S)R² can be accomplished using standard methods well known in the art (e.g., using Lawesson's Reagent or diphosphorus pentasulfide (P₂S₅)). Reduction of compounds of the formula I wherein B is —C(S)R² with a reducing agent such as sodium borohydride or lithium aluminum tetrahydride gives the corresponding compounds of the formula I wherein B is —CHR²SH. Alkylation of compounds of the formula I wherein B is —CHR²SH with alkyl halide (such as alkyl iodide) in the presence of a base such as sodium hydride in an inert solvent such as THF, DMF or toluene at about room temperature will afford the corresponding compounds of the formula I wherein B is —CHR²SR¹.

[0194] Compounds in formula II may be prepared from compounds of the formula IV or V as described below.

[0195] Compounds of formula II wherein T is chloro, bromo or iodo can be prepared by reacting compounds of the formula IV with from one equivalent to an excess of POT₃ (wherein T is chloro, bromo or iodo) in the presence or absence of a di(C₁-C₄ alkyl)aniline, preferably diethylaniline, with or without a solvent (such as dichloroethane, DMF, dimethylsulfoxide (DMSO) or acetarnide), at a -temperature from about room temperature to about 180° C., preferably from about 100° C. to about 150° C. Alternatively, compounds of formula II wherein T is chloro, bromo or iodo can be prepared by reacting the corresponding compounds of formula II wherein T is —O— SO₂CF₃ with a sodium or potassium halide, in an appropriate inert solvent such as THF, sulfolane, DMSO, DMF or acetonitrile, at a temperature from about 60° C. to about 180° C. Compounds of formula II wherein T is —OSO₂CF₃ can be prepared by reacting compounds of formula IV with Tf₂O in the presence of a base such as triethylamine or pyridine, in an appropriate inert solvent such as THF, methylene chloride, dioxane, ether or toluene, at an temperature from about 0° C. to about 50° C., preferably from about 0° C. to about room temperature.

[0196] Alternatively, compounds of formula II wherein T is chloro, bromo or iodo may be prepared by reacting compounds of formula V with a (C₁-C₇ alkyl)-nitrite and Cu(I)T₂ (wherein T is chloro, bromo or iodo) in an appropriate inert solvent such as acetonitrile, acetone, methylene chloride, THF, dioxane, benzene, toluene, dichloroethane, DMF, DMSO or N-methylpyrrolidinone (NMP) at a temperature from about room temperature to about 150° C., preferably from about 40° C. to about 100° C.

[0197] Compounds of the formula IV may be prepared by reacting the appropriate compounds of formula V with sodium nitrite (NaNO₂) in an aqueous acid such as sulfuric acid, acetic acid or phosporic acid, with or wtthout an organic solvent, preferably in acetonitrite (CH₃CN) or acetone.

[0198] Compounds of formula III wherein W is cyano can be prepared by reacting the corresponding compounds of formula II wherein T is chloro, bromo or iodo with potassium cyanide, copper cyanide, sodium cyanide or a di(C₁-C₄alkyl)aluminum cyanide in an appropriate inert solvent such as dimethylsulfoxide, DMF, toluene or xylene, at temperature from about room temperature to about 180° C., preferably from about 60° C. to about 150° C., with or without Pd(II)OAc or Pd(0)(PPh₃)₄.

[0199] Compounds of formula III wherein W is —CHO or —COOH may be prepared by reacting compounds in formula II wherein T is bromo or iodo with an organolithium reagent such as t-BuLi, s-BuLi, or n-BuLi in an appropriate inert solvent such as THF, dioxane, ether, benzene or methylene chloride, at temperature from about −120° C. to about room temperature, preferably from about −110° C. to about −60° C., followed by quenching with an appropriate electrophile such as DMF or CO₂ (gas or dry ice), to give compounds of formula III wherein W is —CHO and —COOH, respectively.

[0200] It is understood that the general organic chemistry knowledge can be applied to change the steps of the reaction sequences described herein depending on the feasibility of the reaction. For example, a protecting group may be used at any stage of the various syntheses described above at which it is workable, or an ester group may be reduced to the corresponding C₁-C₄ alkyl group at any convenient stage. Compounds of formulas I - XVIII, wherein R³ is chloro, bromo, —COO(C₁-C₄ alkyl) or —COOH, can be converted to the corresponding compounds wherein R³ is (C₁-C₄ alkyl), —O(C₁-C₄ alkyl), fluoro, —S(C₁-C₄ alkyl) at any convenient stage, as appropriate, in the syntheses referred to above using methods described in the literature. Compounds of formula I - XVIII, wherein R³ is —O(C₁-C₄ alkyl) or —S(C₁-C₄ alkyl) can be prepared by reacting the corresponding compounds wherein R³ is chloro, bromo or iodo, with a nucleophile such as a C₁-C₄ alkanol or a C₁-C₄ alkanethiol, in the presence of an organic or inorganic base. Suitable bases for such a reaction include sodium and sodium hydride. Compounds of formulas I - XVIII wherein R³ is fluoro can be prepared by reacting the corresponding compounds wherein R³ is chloro with tetrabutylammonium fluoride in a suitable inert solvent such as DMSO, methylene chloride, or tetrahydrofuran. Tetrahydrofuran is preferred.

[0201] Reduction of an ester or carboxylic acid using lithium aluminum tetrahydride/aluminum trichloride (LiAlH₄AlCl₃) in an appropriate inert solvent such as THF, ether, or dioxane, at temperature from about 1000C to about room temperature, will afford the corresponding compound wherein R³ is CH₃. Conversion of compounds wherein B is —COOH to the corresponding compounds wherein B is —CO(C₁-C₃ alkyl) may be accomplished using standard alkylation methods well known in art. Reduction of compounds wherein B is —CO(C₁-C₃ alkyl) using standard methods well known in the art will afford the corresponding compounds wherein R³ is one of various (C₁-C₄ alkyl) derivatives.

[0202] Compounds of the formula IV-a wherein A is CR⁷and G, J, and K are carbon may be prepared by heating compounds of formula VI-a with an appropriate compound of the formula R³C(O)CR⁷COO(C₁-C₄ alkyl) under acid or Lewis acid conditions with or without a solvent, as shown in Scheme 1. Examples of such reaction conditions are: a) heating in polyphosphoric acid; b) heating in toluene, benzene or xylene in the presence of acid catalyst (such as p-TsOH, sulfuric acid or HCl(g)) using a Dean-Stark trap; or c) heating in an appropriate solvent such as dichloroethane, diphenylether (Ph₂O) or Dowtherm A in the presence of a Lewis acid such as SnCl₄, ZnCl₂/HCl or AlCl₃.

[0203] Compounds of formula VI-a may be prepared using methods described in the scientific literature. (See Gazz. Chim. Ital.; 111, p167-172(1981); Chem. Pharm. Bull.; 24, 3001-3010 (1976); J. Org. Chem., 38, 1777-1780 (1973); Chem. Abstr. 68, 68982f (1968); Aust. J. Chem.; 22, 563-572(1969); J. Chem. Soc. Perkin Trans.2, p1954, p1957 (1972); J. Heterocycl. Chem.; FR, 19, 443-445(1982); J. Heterocycl. Chem., 22, 1496-1502 (1985); Tetrahedron, 47, 46394644 (1991); J. Heterocycl. Chem., 28, 2053-2055 (1991); J. Heterocycl. Chem., 29, 251-153 (1992).

[0204] Compounds of formula V-a and IV-a′, wherein R is C₁-C₄alkyl can be prepared by heating compounds of formula VI wherein W is —CN and —COO(C₁-C₄ alkyl), respectively, with an appropriate R³C(O)CH₂COO(C₁-C₄ alkyl) in the presence of a Lewis acid such as SnCl₄, AlCl₃, TiCl₃ or ZnCl₂, in a inert solvent such as dichloroethane, at about the reflux temperature, as shown in Scheme 2. Base hydrolysis of a compound of the formula V-a or IV-a′ with sodium hydroxide in H₂O/(C₁-C₄ alcohol) at reflux, or with lithium hydroxide in water/THF or water/dioxane at temperature from about room temperature to about the reflux temperature, followed by decarboxylation by heating in a oil bath at atemperature from about 140-180° C. will give a compound of formula V-b or IV-b, respectively. Compounds of the formulas V-a and IV-a′ may be converted into compounds of the formula II-a, and compounds of the formulas Vb and IVb may be converted into compounds of the formula IIb by the procedures described above. The conversion of compounds of the formula Il-a into those of the formula II-c can be accomplished using procedures analogous to those described above for converting compounds wherein R³ is —COO(C₁-C₄ alkyl) into those wherein R³ is C₁-C₄ alkyl.

[0205] Compounds of formula VI may be prepared using methods described in the literature. (See Liebigs Ann Chem., 1534-1546,1979; Gazz. Chim. Ital. 97, 25-33,1967; Gazz. Chim. Ital., 120, 725-730, 1990; Eur. J. Med. Chem. Chim. Ther., 26, 143-158, 1991; J. Heterocycl. Che., Fr. 19, 443445, 1982; J. Heterocycl. Chem., 22, 1496-1502, 1985; J. Heterocycl. Chem., 31, 305-312, 1994; J. Heterocycl. Chem., 24, 243-245, 1987; J. Org. Chem. 57, 3713-3716,1992; Liebigs Ann Chem., 1702-1710,1984; Chem. Pharm. Bull., 34, 701-702,1986; Pharmazie, 48, 849-853, 1993; Bull. Soc. Chim. Belg., 103, 181-184, 1994; and Indian. J. Chem. Sect. B, 33, 436-440, 1994).

[0206] Compounds of formula IV-c wherein A is N and G, J, and K are carbon may be prepared, as shown in Scheme 3, by reacting compounds of formula VI with (R³CO)₂O, R³COOH or R³CO(OC₁-C₂ alkyl)₃, in acetic acid or an appropriate inert organic solvent such as toluene, dioxane, acetonitrile, methylene chloride or chloroform, at a temperature from about 25° C. to about 150° C., preferably at about the reflux temperature, followed by heating in 85% phosphoric acid or an aqueous acid such as acetic acid, hydrochloric acid or sulfuric acid, preferably in 50-85% phosphoric acid. Compounds of formula V-b may be prepared, as shown in Scheme 3, by heating the corresponding compounds of formula VI with excess of the appropriate compound of the formula R³CONH₂.

[0207] Compounds of formula IV-d may be prepared, as shown in Scheme 4, by reacting compounds of formula IX with an appropriate reagent having the formula R³C(O)CHR⁷COO(C₁-C₄alkyl) in an R³COC)H solvent at temperature from about 60° C. to about 180° C., preferably at about the reflux temperature.

[0208] Compounds of formula I-N may be prepared, as shown in Scheme 5, by reacting the corresponding compounds of formula X with a (C₁-C₇ alkyl)nitrite, with or without CuBr₂, CuCl₂, or Cul₂, in an appropriate inert solvent such as acetonitrile, acetone, methylene chloride, chloroform, benzene or toluene, preferably acetonitrile at a temperature from about 25° C. to about 150° C., preferably from about 60° C. to 100° C.

[0209] Compounds of formula I-L and I-M may be prepared, as shown in Scheme 6, by reacting compounds of formula Xi wherein X is S or O with a compound of the formula R⁴CHO or R⁴CH(OC₁-C₂ alkyl)₂ and an acid catalyst such as p-TsOH, HCl, HBr, H₂SO₄, or HCl, in toluene, xylene or benzene, preferably toluene, with from one to ten equivalents of water, at temperature from about 70° C. to about 160° C., using a Dean-Stark trap or in the presence of anhydrous sodium sulfate.

[0210] Compounds of formula I-K and I-U may be prepared by reacting the corresponding compounds of formula XI with triphosgene and thiophosgene, respectively, and a base such as triethylamine or pyridine in an appropriate inert solvent such as methylene chloride, THF, dioxane, ether, benzene or chloroform, preferably methylene chloride or dry THF, at temperature from about 0° C. to about 25° C.

[0211] Compounds of formula I-V, I-W, and I-X may be prepared, as illustrated in Scheme 7, starting from compounds of formula XII. Compounds of formula XIII may be prepared by reacting the corresponding compounds of formula XII with hydroxylamine in acidic (e.g., in trifluoroacetic acid) or basic (e.g., in NaOAc or NaOH and hydroxylamine hydrochloride in a C₁-C₄ alcohol/water mixture) conditions at temperatures from about 25° C. to about 150° C., preferably at about the reflux temperature. Compounds of formula XIV can be prepared by heating the corresponding compounds of formula XIII in acetic anhydride, trifluoroacetic anhydride or Tf₂O, with or without a solvent such as acetic acid or methylene chloride, in the presence of an appropriate amine base such as triethylamine or pyridine. Compounds of formula I-V, I-W and I-X may be prepared by heating the corresponding compounds of formula XIV and pyridine in an inert solvent such as DMF, DMSO, NMP, sulfolane or acetamide at a temperature from about 80° C. to about 180° C.

[0212] Compounds of formula I-G may be prepared, as illustrated in Scheme 8, by reducing the corresponding compounds of formula XVII. This reduction can be performed using standard methods known in literature for reduction of a nitro group to an amino group. Such methods include hydrogenation or reduction by iron in acetic acid. Cyclization may occur upon reduction or heating in an appropriate solvent such as a C₁-C₄ alcohol, acetonitrile, toluene, THF, methylene chloride or acetic acid.

[0213] The conversion of compounds of formula XVI into those of formula XVII can be accomplished using methods analogous to those described above for the conversion of compounds of formula V wherein W is cyano into compounds of formula I wherein B is a group having a carbon atom directly attached to the bicyclic ring. The best method for conversion of a cyano group to a —COOH group is acid hydrolysis, for example, heating the cyano compound in 50-85% phosphoric acid or 50-90% acetic acid, preferably phosphoric acid. The best method for converting a cyano group into a —CO(C₁-C₄ alkyl) is reacting the cyano compound with a Grignard reagent at a temperature from about 0° C. to about 25° C. in ether, THF or dioxane. The best method for converting a cyano group into a —CHO group is a diisobutylaluminum hydride reduction in THF, dioxane, or ether at a temperature from about −78° C. to about 25° C., preferably from about −78° C. to about −40° C.

[0214] Compounds of the formula XVI may be prepared by reacting compounds of formula XV, wherein Hal is chloro, bromo or lodo, with a sodium, potassium, or lithium salt of R⁵CH₂CN in an appropriate inert solvent such as toluene, benzene, a C₁-C₅ alcohol, THF, DMSO, dioxane, or pyridine, with or without a Pd(II) or Pd(0) catalyst, at a temperature from about −78° C. to about 130° C.

[0215] Alternatively, compounds of formula XVII may be prepared by subjecting compounds of the formula XV to halogen-metal exchange (e.g., using an organo lithium agent such as tBuLi, s-BuLi or BuLi at −78° C. in ether, THF, or dioxane), followed by quenching with an electorphile such as R⁵CHO, to give compounds of formula XVIII. Compounds of formula XIX-a may be prepared by reacting the corresponding compounds of formula XVIII with thionyl chloride, followed by reduction. Reacting compounds of formula XIX-a with a base (such as organolithium agent (e.g., lithium diisopropylamide or BuLi), followed by quenching with an electrophile (such as carbon dioxide) will yield the corresponding compounds of formula XIX-b wherein R²¹ is —COOH. Compounds of formula XIX-c wherein R²¹ is —C(OH)R⁴ may be prepared in a similar fashion by quenching the appropriate compound of formula XIX-a with an electrophile of the formula C₁-C₃ alkyl-CHO. Compounds of formula XVII can be prepared by reacting compounds of formula XlX-C with PCC (pyridinium chlorochromate) using standard PCC oxidation methods that are well known in the art.

[0216] Compounds of formula II-d, II-e and II-f, wherein T is chloro, bromo or iodo and D, E, R³, R⁵ and R⁷ are as defined to those in formula I may be prepared, as shown in Scheme 9, by methods analogous to those described in Scheme 2. Alternatively, Compounds of formula II-d to II-f may be prepared using procedures analogous to those described in the literature (See: Pharm. Bull, 5, 229-231, 1957; Monatsh Chem, 100, 671-678, 1969; J. Heterocycl. Chem., 3, 218-220, 1966, Chem. Pharm. Bull, 23, 2891-2895, 1975; J. Heterocycl. Chem., 8, 1-6 1971; Justus Liebigs Ann. Chem, 735, 3544, 1970; Tetrahedron Lett, 1479, 1968; and Chem. Abstr., 1939, 4988.).

[0217] The acid addition salts of compounds of the formula can be prepared in a conventional manner by treating a solution or suspension of the corresponding free base with one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration or crystallization techniques can be employed to isolate the salts. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzene sulfonic, p-toluenesulfonic, and related acids.

[0218] The compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to, collectively, as “the active compounds of this invention”) may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions, oils (e.g., sesame oil, peanut oil) and various organic solvents. The pharmaceutical compositions formed by combining the novel compounds of formula I and pharmaceutically acceptable carriers can then be readily administered in a variety of dosage forms such as tablets, oil gel, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, methylcellulose, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.

[0219] For parenteral administration, solutions containing an active compound of this invention or a pharmaceutically acceptable salt thereof in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

[0220] The effective dosages for the active compounds of this invention will depend on the intended route of administration and factors such as the age and weight of the patient, as generally known to a physician. The dosages will also depend on the particular illness to be treated. For instance, the daily dosage for stress-induced illnesses, inflammatory disorders, Ajzheimses disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress and drug and alcohol withdrawal symptoms will generally range from about 0.1 to about 50 mg/kg body weight of the patient to be treated.

[0221] Methods that may be used to determine the CRF antagonist activity of the active compounds of this invention and their pharmaceutically acceptable salts are described in Endocrinology, 116, 1653-1659 (1985) and Peptides, 10, 179-188 (1985). The binding activities for compounds of the formula I, expressed as IC₅₀ values, generally range from about 0.5 nanomolar to about 10 micromolar. Methods that can be used to determine the CRF binding protein inhibiting activity of compounds of the formula I are described in Brain Research, (1 997), 745 (1,2),248-255.

[0222] The present invention is illustrated by the following examples. It will be understood, however, that the invention is not limited to the specific details of these examples. Melting points are uncorrected. Proton nuclear magnetic resonance spectra (¹H NMR) and C¹³ nuclear magnetic resonance spectra (C¹³ NMR) were measured for solutions in deuterochloroform (CDCl₃) and peak positions are expressed in parts per million (ppm) downfieldS from tetramethylsilane (TMS). The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad.

[0223] The following abbreviations are used in the Examples: Ph=phenyl; iPr=isopropyl.