CRF receptor antagonists and methods relating thereto

A method for treating depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, abnormal aggression, unstable angina, reactive hypertension, anorexia nervosa, bulimia, irritable bowel syndrome, stress-induced immune suppression, inflammation, Cushing's disease, substance abuse or withdrawal, infantile spasms, or epilepsy in a warm-blooded animal in need thereof, comprising administering to the animal an effective amount of a compound having the following structure:

• or a stereoisomer or pharmaceutically acceptable salt thereof,
• wherein:
• n is 1;
• m is 0, 1, 2 or 3;
• X is N or CR′;
• R′ is hydrogen, halogen or C1-6 alkyl;
• R is an optional substituent which, at each occurrence, is independently C1-6alkyl, C3-6alkenyl, C1-6alkylidenyl or C1-6alkylAr;
• R1 is —C(H)0,1(R3)(R4);
• R2 is hydrogen or C1-6alkyl;
• R3 is hydrogen, keto, C1-6alkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6cycloalkyl, C3-6alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, or C1-6alkyloxyC1-6alkyl, and
• R4 is hydrogen, Ar1, Ar1C1-6alkyl, OAr1C1-8alkyl, C1-6alkyloxy, C3-6cycloalkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6alkenyl, C1-6alkynyl, C1-6alkyloxyC1-6alkyl, C1-6alkoxyAr1, hydroxyC1-6alkyl, thienylC1-6alkyl, furanylC1-6alkyl, C1-6alkylthioC1-6alkyl, morpholinyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, (C1-6alkylAr1)amino, (C1-6alkyl)(Ar1)amino, C1-6alkylcarbonylC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, sulfonyl(C1-8alkyl), C(═O)C1-6alkyl, C1-8alkyl substituted with phthalimide, Ar1, OAr1, NHAr1, C(═O)Ar1, C(═O)NHAr1 or —C(═O)NH2, or a radical of the formula —(C1-6alkanediyl)-Y—(CO)0,1—Ar1 where Y is O, NH or a direct bond, or
• R3 and R4 taken together with the carbon atom to which they are attached form a C3-8cycloalkyl, a C5-8cycloalkenyl, a C3-12heterocycle, phenyl, naphthyl, or a C5-8cycloalkyl fused to Ar1, each of which being optionally substituted with one or more substituents independently selected from C1-6alkyl;
• Ar is phenyl, naphthyl or an aromatic C3-12heterocycle, each being optionally substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, trifluoromethyl, O(trifluoromethyl), hydroxy, cyano, C1-6alkyloxy, phenyoxy, benzoxy, C1-6alkylthio, nitro, amino, mono- or di(C1-6alkyl)amino, (C1-6alkyl)(C1-6alkanoyl)amino, or piperidinyl, or wherein two substituents taken together are a C1-6alkylidinyl or a C1-6alkylidenyl having one, two or three carbon atoms replaced with a heteroatom individually selected from oxygen, nitrogen or sulfur;
• and
• Ar1 is phenyl, naphthyl or an aromatic C3-12heterocycle, each of which being optionally substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, C1-6alkyloxy, di(C1-6alkyl)amino, di(C1-6alkyl)aminoC1-6alkyl, trifluoromethyl, sulfonyl(C1-6alkyl), and C1-6alkyl substituted with morpholinyl.