Patent ID: 6107300
Filing Date: 2000-08-22
Classification: A61P,C07D

Abstract:
A CRF antagonist compound of formula I: ##STR38## or a pharmaceutically acceptable salt or pro-drug form thereof, wherein: X is N;Y is N or CR.sup.2 ;Z is NR.sup.3, O, or S(O)n;Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl, each optionally substituted with 1 to 5 R.sup.5 groups;R.sup.1 is independently at each occurrence H, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.2 -C.sub.4 alkynyl, halo, CN, C.sub.1 -C.sub.4 haloalkyl, --NR.sup.9 R.sup.10, NR.sup.9 COR.sup.10, --OR.sup.11, SH or --S(O).sub.n R.sup.12 ;R.sup.2 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.6 cycloalkyl, halo, CN, --NR.sup.6 R.sup.7, NR.sup.9 COR.sup.10, C.sub.1 -C.sub.4 haloalkyl, --OR.sup.7, SH or --S(O).sub.n R.sup.12 ;R.sup.3 is H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.8 cycloalkyl or C.sub.4 -C.sub.12 cycloalkylalkyl each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, --CONR.sup.6 R.sup.7, aryl, heteroaryl and heterocyclyl, where the aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1-C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ;R.sup.4 is H, C.sub.1 -C.sub.4 alkyl, allyl, or propargyl, where C.sub.1 -C.sub.4 alkyl, allyl, or propargyl is optionally substituted with C.sub.3 -C.sub.6 cycloalkyl and where C.sub.1 -C.sub.4 alkyl is optionally substituted with, --OR.sup.7, --S(O).sub.n R.sup.12 or --CO.sub.2 R.sup.7 ;R.sup.5 is independently at each occurrence C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, --NO.sub.2, halo, --CN, C.sub.1 -C.sub.4 haloalkyl, --NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, --COR.sup.7 --OR.sup.7, --CONR.sup.6 R.sup.7, --CO(NOR.sup.9)R.sup.7, CO.sub.2 R.sup.7, or --S(O).sub.n R.sup.7, where C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl and C.sub.4 -C.sub.12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.4 alkyl, --NO.sub.2, halo, --CN, --NR.sup.6 R.sup.7, --NR.sup.6 R.sup.7, NR.sup.8 COR.sup.7, NR.sup.8 CO.sub.2 R.sup.7, --COR.sup.7 --OR.sup.7, --CONR.sup.6 R.sup.7, CO.sub.2 R.sup.7, --CO(NOR.sup.9)R.sup.7, or --S(O).sub.n R.sup.7 ;R.sup.6 and R.sup.7 are independently at each occurrence H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.2 -C.sub.8 alkoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.4 -C.sub.12 cycloalkylalkyl, aryl, aryl(C.sub.1 -C.sub.4 alkyl)-, heteroaryl or heteroaryl(C.sub.1 -C.sub.4 alkyl)-; or NR.sup.6 R.sup.7 is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine orthiomorpholine;R.sup.8 is independently at each occurrence H or C.sub.1 -C.sub.4 alkyl;R.sup.9 and R.sup.10 are independently at each occurrence selected from H, C.sub.1 -C.sub.4 alkyl, or C.sub.3 -C.sub.6 cycloalkyl;R.sup.11 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 haloalkyl, or C.sub.3 -C.sub.6 cycloalkyl;R.sup.12 is C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 haloalkyl;aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ;heteroaryl is pyridyl, pyrimidinyl, 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 C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, --NR.sup.8 CONR.sup.6 R.sup.7, --NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ;heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, halo, C.sub.1 -C.sub.4 haloalkyl, cyano, --OR.sup.7, SH, --S(O).sub.n R.sup.13, --COR.sup.7, --CO.sub.2 R.sup.7, --OC(O)R.sup.13, --NR.sup.8 COR.sup.7, --N(COR.sup.7).sub.2, NR.sup.8 CO.sub.2 R.sup.13, --NR.sup.6 R.sup.7, and --CONR.sup.6 R.sup.7 ;n is independently at each occurrence 0, 1 or 2;provided that R.sup.4 in formula I is not H:(a) when Y is N, Z is NR.sup.3, R.sup.1 is H, R.sup.3 is H or benzyl, and Ar is p-methylphenyl;(b) when Y is N, Z is NR.sup.3, R.sup.1 is butyl, R.sup.3 is benzyl, and Ar is phenyl;(c) when is CH, Z is NR.sup.3, R.sup.3 is methyl, R.sup.1 is H, and Ar is phenyl or 2-fluorophenyl;(d) when Y is CH, Z is NR.sup.3, R.sup.3 is methyl, R.sup.1 is Cl and Ar is phenyl;(e) when Y is CH, Z is NR.sup.3, R.sup.1 is Cl, R.sup.3 is benzyl, and Ar is phenyl or substituted phenyl;(f) when Y is CH, Z is NR.sup.3, R.sup.3 is p-methylbenzyl, and Ar is phenyl;(g) when Y is CR.sup.2, Z is NR.sup.3, R.sup.2 is CH.sub.3, R.sup.3 is H, and Ar is phenyl or phenyl substituted with methyl, ethyl, isopropyl, fluoro or chloro;(h) when Y is N, Z is NR.sup.3, R.sup.3 is cyclopropylmethyl, R1 is H, and Ar is 2-bromo-4-isopropylphenyl, or(i) when Y is N, Z is S, R.sup.1 is H, and Ar is 2-bromo-4-isopropylphenyl.