Amino-substituted pyrazoles having CRF antagonistic activity

A compound of the formula ##STR49## or a pharmaceutically acceptable acid addition salt thereof, wherein

• A is CH.sub.2 ;
• X.sub.1 is a covalent bond, CH.sub.2, NR, wherein R is hydrogen, linear C.sub.1 -C.sub.6 alkyl or branched C.sub.3 -C.sub.8 alkyl, O, or S;
• R.sub.1, R.sub.2 and R.sub.3 are each independently linear C.sub.1 -C.sub.6 alkyl, branched C.sub.3 -C.sub.8 alkyl, C.sub.3 -C.sub.8 alkenyl wherein the double bond is not adjacent to the N or X.sub.1 when X.sub.1 is oxygen or sulfur, or C.sub.3 -C.sub.7 cycloalkyl (CH.sub.2).sub.n wherein n is 0, 1, 2, 3 or 4;
• or R.sub.1 and R.sub.2 when taken together with the nitrogen form a saturated four, five or six membered ring optionally condensed with benzo;
• and R.sub.3 may also be (CH.sub.2).sub.q Q.sub.1 R.sub.19 wherein q is 0, 1 or 2, Q.sub.1 is O, S, NH, N(C.sub.1 -C.sub.6 alkyl) or a covalent bond when X is not a covalent bond, and R.sub.19 is hydrogen, linear C.sub.1 -C.sub.6 alkyl, branched C.sub.3 -C.sub.8 alkyl, C.sub.3 -C.sub.8 alkenyl, or C.sub.3 -C.sub.6 cycloalkyl (CH.sub.2).sub.n wherein n is 0 to 4;
• Y is phenyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, isoxazolyl, benzisoxazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, oxazolyl, benzoxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, or piperidinyl, each of which may be substituted by one to three of any one of fluoro, chloro, bromo, or methyl, or one of trifluoromethyl;
• with the proviso that Y is not unsubstituted phenyl;
• and
• Z is
• (a) ##STR50## wherein the B ring is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazilyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thienyl, or indolyl, each of which may be substituted by methyl, methoxy, fluoro, chloro, bromo or iodo;
• or a saturated 5- or 6-membered carbocyclic ring or a partially unsaturated ring having one or two double bonds;
• R.sub.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or hydroxy, fluoro, chloro, bromo, iodo, or trifluoromethyl;
• R.sub.5 is hydrogen, linear C.sub.1 -C.sub.6 alkyl, branched C.sub.3 -C.sub.8 alkyl, C.sub.3 -C.sub.8 alkenyl, or (CH.sub.2).sub.o --X.sub.2 --(CH.sub.2).sub.r --Q.sub.2 --R.sub.6 ;
• R.sub.6 is hydrogen, linear C.sub.1 -C.sub.6 alkyl, branched C.sub.3 -C.sub.8 alkyl, or C.sub.3 -C.sub.8 alkenyl;
• X.sub.2 and Q.sub.2 are each independently O, S, NH, N(C.sub.1 -C.sub.6 alkyl), or one of X.sub.2 and Q may be a covalent bond;
• m is 0 or 1;
• o is 1 or 2;
• p is 1 or 2;
• r is 0, 1, or 2;
• (b) ##STR51## wherein R.sub.4 and R.sub.5 are as defined above, and t and u are each independently 1 or 2;
• (c) --NR.sub.7 R.sub.8 wherein R.sub.7 and R.sub.8 are each independently hydrogen, C.sub.1 -C.sub.6 linear alkyl, branched C.sub.3 -C.sub.8 alkyl, C.sub.3 -C.sub.8 alkenyl, (CH.sub.2).sub.v CH.sub.2 OH,(CH.sub.2).sub.v NR.sub.9 R.sub.10, wherein v is 0 to 3, and R.sub.9 and R.sub.10 are each independently hydrogen, or linear C.sub.1 -C.sub.6 alkyl;
• C.sub.1 -C.sub.12 cycloalkyl, (C.sub.3 -C.sub.12 cycloalkyl) (CH.sub.2).sub.n, (C.sub.6 -C.sub.10 bicycloalkyl) (CH.sub.2).sub.n, wherein n is 0 to 4, benzofused C.sub.3 -C.sub.6 cycloalkyl, C.sub.1 -C.sub.6 hydroxyalkyl, phenyl, phenyl (C.sub.1 -C.sub.3 alkylene), each of which may be substituted by one or two of hydroxy, fluoro, chloro, bromo, C.sub.1 -C.sub.5 alkyl, or C.sub.1 -C.sub.5 alkoxy;
• or R.sub.7 and R.sub.8 may be taken together with the nitrogen to form a saturated or partially unsaturated 5- to 7-membered ring which may contain one of O, S, NH or N(C.sub.1 -C.sub.6 alkyl) and which may be substituted by C.sub.1 -C.sub.6 alkyl, hydroxy or phenyl wherein any double bond(s) are not adjacent to any heteroatoms;
• (d) ##STR52## wherein B, R.sub.4 and R.sub.5 are as defined above, w, x, y and z are each independently 1 or 2, and W is (CH.sub.2).sub.q wherein q is as defined above, N(C.sub.1 -C.sub.6 alkyl), or oxygen;
• (e) ##STR53## wherein B, R.sub.4, m and p are as defined above;
• (f) ##STR54## wherein B and R.sub.4 are as defined above;
• (g) O(CH.sub.2).sub.v R.sub.11
• wherein v is 0 to 3 and R.sub.11 is linear C.sub.1 -C.sub.6 alkyl, branched C.sub.3 -C.sub.8 alkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, isoxazolyl, benzisoxazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, oxazolyl, benzoxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, piperidinyl, or thienyl, each of which may be substituted by one or two of any one of fluoro, chloro, bromo, methyl, or trifluoromethyl;
• (h) ##STR55## wherein A is defined above and is linked to position 1 or 2 while R.sub.14 is attached to position 2 or 1, respectively;
• F, G, H, I, J and K are independently C or N, provided that not more than three of H, I, J and K are N with not more than two adjacent nitrogens;
• R.sub.12 and R.sub.13 each independently are hydrogen, linear C.sub.1 -C.sub.6 alkyl, branched C.sub.3 -C.sub.8 alkyl, C.sub.3 -C.sub.8 alkenyl, fluoro, chloro, bromo, trifluoromethyl, hydroxy, thiol, C.sub.1 -C.sub.12 alkoxy, C.sub.1 -C.sub.12 thioalkanyl, C.sub.3 -C.sub.12 alkenoxy or C.sub.3 -C.sub.12 thioalkenyl wherein the double bond is not adjacent to the oxygen or sulfur, and R.sub.14 is hydroxy, C.sub.1 -C.sub.12 alkoxy, C.sub.3 -C.sub.12 alkenoxy wherein the double bond is not adjacent to the oxygen, or --X.sub.2 --(CH.sub.2).sub.r Q.sub.2 R.sub.6 wherein X.sub.2, r, Q.sub.2 and R.sub.6 are as defined above in paragraph (a) except that Q.sub.2 is not sulfur, or R.sub.14 is NR.sub.15 R.sub.16 wherein R.sub.15 and R.sub.16 are each independently hydrogen, linear C.sub.1 -C.sub.6 alkyl, branched C.sub.3 -C.sub.8 alkyl, C.sub.3 -C.sub.8 alkenyl wherein the double bond is not adjacent to the nitrogen, or C.sub.3 -C.sub.7 cycloalkyl-(CH.sub.2).sub.n wherein n is as defined above, or R.sub.15 and R.sub.16 together with the nitrogen form a saturated five or six membered ring optionally condensed with benzo;
• or
• (i) ##STR56## wherein D,E,F and G are independently C or N, provided that not more than two of D,E,F and G are N, and R.sub.12 and R.sub.14 are as defined in paragraph (h), A, defined above, is linked to a carbon in formula XV;
• and R.sub.14 is linked to a carbon located adjacent to the carbon to which A is linked.