Monocyclic anilide spirolactam CGRP receptor antagonists
View Patent ↗The present invention is directed to compounds of Formula I: (where variables A 1 , A 2 , B, J, K, m, n, R 4 , R 5a , R 5b and R 5c are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
1. A compound of the formula I:
wherein:
B is a heterocycle selected from the group consisting of:
wherein X 1 , X 2 , X 3 and X 4 are each carbon, and one of X 1 , X 2 , X 3 and X 4 present on B is spirally substituted to form a ring or ring system selected from:
indanyl, azaindanyl, 1,2,3,4-tetrahydronaphthalenyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 2,3-dihydro-1-benzofuranyl, chromanyl, 3,4-dihydro-1H-isochromenyl, 2,3-dihydro-1-benzothiophenyl, thiochromanyl, 3,4-dihydro-1H-isothiochromenyl, 6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, 2,3,4,5-tetrahydro-1-benzoxepinyl, 2,3,4,5-tetrahydro-1H-1-benzazepinyl, 2,3,4,5-tetrahydro-1-benzothiepinyl, 1,3,4,5-tetrahydro-2-benzoxepinyl, 2,3,4,5-tetrahydro-1H-2-benzazepinyl, 1,3,4,5-tetrahydro-2-benzothiepinyl, 1,2,4,5-tetrahydro-3-benzoxepinyl, 2,3,4,5-tetrahydro-1H-3-benzazepinyl, 1,2,4,5-tetrahydro-3-benzothiepinyl, cycloheptyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, thiepanyl, oxepanyl and azepanyl,
which ring or ring system is unsubstituted or substituted with one or more substituents each independently selected from:
(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, —OC 1-6 alkyl, —C 3-6 cycloalkyl, —CO 2 R 9 , —NR 10 R 11 , —SO 2 R 12 , —CONR 10a R 11a , phenyl and heterocycle, wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, and morpholinyl,
(b) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, hydroxy, —CN, —C 3-6 cycloalkyl, —C 1-6 alkyl (which is unsubstituted or substituted with 1-6 fluoro), and —OC 1-6 alkyl (which is unsubstituted or substituted with 1-6 fluoro, halo, or hydroxyl),
(c) —SO 2 R 12 ,
(d) hydroxy,
(e) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(f) —COR 12 ,
(g) —NR 10 R 11 ,
(h) halo,
(i) —CN,
(j) —CONR 10a R 11a ,
(k) oxo, and
(l) —C 3-6 cycloalkyl,
and wherein the remaining members of the group X 1 , X 2 , X 3 and X 4 present on B are each independently unsubstituted or substituted with one or two substituents selected from R 1 and R 2 , where:
R 1 and R 2 are each independently selected from:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl,
(e) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: —C 1-6 alkyl, —OC 1-6 alkyl, halo, hydroxy, trifluoromethyl, —CN, and —OCF 3 ,
(f) —CO 2 R 9 , and
(g) —CONR 10a R 11a ;
(2) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from: halo, hydroxy, —OC 1-6 alkyl, trifluoromethyl and phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(b) halo,
(c) hydroxy,
(d) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(e) —C 3-6 cycloalkyl,
(f) phenyl which is unsubstituted or substituted with 1-5 substituents each independently selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halo, hydroxyl and trifluoromethyl,
(g) —CO 2 R 9 ,
(h) —NR 10 R 11 ;
(i) —CONR 10a R 11a , and
(j) —SO 2 R 12 ;
(4) halo,
(5) hydroxy,
(6) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(7) —CN,
(8) —CO 2 R 9 ,
(9) —NR 10 R 11 ;
(10) —SO 2 R 12 , and
(11) —CONR 10a R 11a ;
or, wherein X 1 , X 2 , X 3 and X 4 are each carbon, and one of X 1 , X 2 , X 3 and X 4 present on B is —(C═O)—,
wherein another one of the members of the group X 1 , X 2 , X 3 and X 4 present on B is optionally spirally substituted to form a ring or ring system selected from:
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azaindanyl, 1,2,3,4-tetrahydronaphthalenyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 2,3-dihydro-1-benzofuranyl, chromanyl, 3,4-dihydro-1H-isochromenyl, 2,3-dihydro-1-benzothiophenyl, thiochromanyl, 3,4-dihydro-1H-isothiochromenyl, 6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, 2,3,4,5-tetrahydro-1-benzoxepinyl, 2,3,4,5-tetrahydro-1H-1-benzazepinyl, 2,3,4,5-tetrahydro-1-benzothiepinyl, 1,3,4,5-tetrahydro-2-benzoxepinyl, 2,3,4,5-tetrahydro-1H-2-benzazepinyl, 1,3,4,5-tetrahydro-2-benzothiepinyl, 1,2,4,5-tetrahydro-3-benzoxepinyl, 2,3,4,5-tetrahydro-1H-3-benzazepinyl, 1,2,4,5-tetrahydro-3-benzothiepinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, thiepanyl, oxepanyl and azepanyl,
which ring or ring system is unsubstituted or substituted with one or more substituents each independently selected from:
(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, —OC 1-6 alkyl, —C 3-6 cycloalkyl, —CO 2 R 9 , —NR 10 R 11 , —SO 2 R 12 , —CONR 10a R 11a phenyl and heterocycle, wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, and morpholinyl,
(b) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, hydroxy, —CN, —C 3-6 cycloalkyl, —C 1-6 alkyl (which is unsubstituted or substituted with 1-6 fluoro), and —OC 1-6 alkyl (which is unsubstituted or substituted with 1-6 fluoro, halo, or hydroxyl),
(c) —SO 2 R 12 ,
(d) hydroxy,
(e) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(f) —COR 12 ,
(g) —NR 10 R 11 ,
(h) halo,
(i) —CN,
(j) —CONR 10a R 11a ,
(k) oxo, and
(l) —C 3-6 cycloalkyl,
and wherein the remaining members of the group X 1 , X 2 , X 3 and X 4 present on B are each independently unsubstituted or substituted with one or more substituents selected from R 1 and R 2 as defined,
A 1 and A 2 are each independently selected from:
(1) a bond, and
(2) —CR 13 R 14 —,
wherein one of A 1 and A 2 is optionally absent;
G 1 , G 2 , and G 3 are each independently selected from:
(1) —C(R 5 )═,
(2) —N═, and
(3) —(N + —O − )═,
wherein at least two of G 1 , G 2 and G 3 are —C(R 5 )═;
J is independently selected from:
(1) ═C(R 6a )—,
(2) —CR 13 R 14 —,
(3) —N(R 15 )—, and
(4) —C(═O)—;
Y is independently selected from:
(1) ═C(R 6b )—,
(2) —CR 13 R 14 —,
(3) —C(═O)—,
(4) —SO 2 —,
(5) ═N—, and
(6) —N(R 6b )—;
R 4 is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —C 3-6 cycloalkyl,
(c) —CF 3 , and
(d) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(3) —C 3-6 cycloalkyl,
(4) benzyl, and
(5) phenyl;
R 5 is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —OC 1-6 alkyl,
(d) —C 3-6 cycloalkyl,
(e) phenyl,
(f) —CONR 10a R 11a ,
(g) —CO 2 R 9 , and
(h) —NR 10 R 11 ,
(3) —C 3-6 cycloalkyl,
(4) phenyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) —C 1-4 -alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(b) halo,
(c) hydroxy, and
(d) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(5) halo,
(6) hydroxy,
(7) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(8) —CN,
(9) —CO 2 R 9 ,
(10) —NR 10 R 11 ,
(11) —SO 2 R 12 ,
(12) —CONR 10a R 11a ,
(13) —OCO 2 R 9 , and
(14) —(NR 10a )CO 2 R 9 ;
R 6a and R 6b are each independently selected from:
(1) hydrogen;
(2) —C 1-4 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —O—C 1-6 alkyl,
(c) —C 3-6 cycloalkyl, and
(d) phenyl or heterocycle, wherein heterocycle is selected from: imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halo, hydroxy, trifluoromethyl and —OCF 3 ,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, azetidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrahydrofuryl, piperidinyl, and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) —C 1-4 alkyl which is unsubstituted or substituted with 1-5 fluoro,
(b) halo,
(c) hydroxy,
(d) —O—C 1-4 alkyl which is unsubstituted or substituted with 1-5 fluoro,
(e) —C 3-6 cycloalkyl, and
(f) phenyl,
(4) halo,
(5) hydroxy,
(6) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(7) —CN,
(8) —CO 2 R 9 ,
(9) —NR 10 R 11 , and
(10) —CONR 10a R 11a ;
or where R 6a and R 6b and the atom(s) to which they are attached are joined to form a ring selected from cyclopentenyl, cyclohexenyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, dihydrofuranyl, dihydropyranyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thienyl, dihydrothienyl and dihydrothiopyranyl, which ring is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-6 alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) hydroxy,
(iii) —O—C 1-6 alkyl,
(iv) —C 3-6 cycloalkyl,
(v) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, or morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halo, hydroxy, trifluoromethyl and —OCF 3 ,
(vi) —CO 2 R 9 ,
(vii) —NR 10 R 11 ,
(viii) —SO 2 R 12 ,
(ix) —CONR 10a R 11a , and
(x) —(NR 10a )CO 2 R 9 ,
(b) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents are each independently selected from: —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, halo, hydroxy, —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro and —C 3-6 cycloalkyl,
(c) halo,
(d) —SO 2 R 12 ,
(e) hydroxy,
(f) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(g) —CN,
(h) —COR 12 ,
(i) —NR10R 11 ,
(j) —CONR 10a R 11a ,
(k) —CO 2 R 9 ,
(l) —(NR 10a )CO 2 R 9 ,
(m) —O(CO)NR 10a R 11a ,
(n) —(NR 9 )(CO)NR 10a R 11a , and
(o) oxo;
R 7 is selected from:
(1) hydrogen;
(2) —C 1-4 alkyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are each independently selected from:
(a) halo,
(b) —OC 1-6 alkyl,
(c) —C 3-6 cycloalkyl,
(d) phenyl or heterocycle, wherein heterocycle is selected from: imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: —CN, —C 1-6 alkyl, —OC 1-6 alkyl, halo, hydroxy, trifluoromethyl and —OCF 3 ,
(e) —COR 12 ,
(f) —NR 10 R 11 ,
(g) —CONR 10a R 11a ,
(h) —CO 2 R 9 ,
(i) —(NR 10a )CO 2 R 9 ,
(j) —O(CO)NR 10a R 11a ,
(k) —(NR 9 )(CO)NR 10a R 11a ,
(l) —CN, and
(m) hydroxy,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, azetidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrahydrofuryl, piperidinyl, and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) —C 1-4 alkyl which is unsubstituted or substituted with 1-5 fluoro,
(b) halo,
(c) hydroxy,
(d) —OC 1-6 alkyl which is unsubstituted or substituted with 1-5 fluoro,
(e) —C 3-6 cycloalkyl, and
(f) phenyl, and
(g) —CN,
(4) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from: halo, hydroxy, —OC 1-6 alkyl, trifluoromethyl and phenyl;
R 9 is independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 substituents, substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —C 3-6 cycloalkyl, and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) —C 1-4 alkyl,
(ii) —OC 1-6 alkyl,
(iii) halo,
(iv) trifluoromethyl, and
(v) —OCF 3 ,
(3) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 substituents, substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo, and
(e) phenyl,
(4) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydrofuryl, quinoxalinyl, piperidinyl, piperazinyl, and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo
(c) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo
(d) —C 3-6 cycloalkyl,
(e) oxo,
(f) —CN,
(g) hydroxy, and
(h) phenyl;
R 10 and R 11 are each independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —OCF 3 ,
(d) —C 3-6 cycloalkyl, and
(e) phenyl,
(3) —C 4-6 cycloalkyl,
(4) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(b) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(c) halo,
(d) hydroxy,
(e) trifluoromethyl,
(f) —OCF 3 , and
(g) —CN,
(5) benzyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(b) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(c) halo, and
(d) trifluoromethyl,
(6) —COR 9 , and
(7) —SO 2 R 12 ;
R 10a and R 11a are each independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 substituents each independently selected from:
(a) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(b) halo,
(c) hydroxy,
(d) —OCF 3 ,
(e) —C 3-6 cycloalkyl, and
(f) phenyl,
(3) —C 5-6 cycloalkyl, which is unsubstituted or substituted with 1-5 halo,
(4) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(b) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(c) halo,
(d) hydroxy,
(e) trifluoromethyl,
(f) —OCF 3 , and
(g) —CN,
(5) benzyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(b) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(c) halo, and
(d) trifluoromethyl,
or where R 10a and R 11a join to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl and morpholinyl, which ring is unsubstituted or substituted with 1-5 substituents each independently selected from:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(2) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(3) halo
(4) hydroxy
(5) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo,
(b) —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo, and
(c) halo,
(6) benzyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo,
(b) —OC 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo, and
(c) halo,
(7) —COR 9 , and
(8) —SO 2 R 12 ;
R 12 is selected from:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(2) —C 3-6 cycloalkyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(b) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(c) halo,
(d) hydroxy,
(e) trifluoromethyl,
(f) —OCF 3 ,
(g) —CN, and
(h) benzyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(ii) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(iii) halo, and
(iv) trifluoromethyl;
R 13 and R 14 are each independently selected from:
(1) hydrogen,
(2) C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 3-6 cycloalkyl,
(b) —OC 1-6 alkyl,
(c) halo,
(d) hydroxy, and
(e) phenyl,
(3) hydroxy, and
(4) halo;
R 15 is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl which is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl,
(e) phenyl, and
(f) —NR 10 R 11 ;
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, or thienyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C 1-6 alkyl,
(b) —O—C 1-6 alkyl,
(c) halo,
(d) hydroxy, and
(e) trifluoromethyl;
m is 1; and
n is 1;
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
2. A compound of claim 1 of the formula Ia:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
3. A compound of claim 1 of the formula Ic:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
4. A compound of claim 1 of the formula If:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
5. A compound of claim 1 of the formula Ig:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
6. A compound of claim 1 of the formula Ih:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
7. A compound of claim 1 of the formula Ii:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
8. The compound of claim 1 wherein B is selected from the group consisting of:
X 1 , X 2 , and X 3 are each carbon, and one of X 1 , X 2 , and X 3 present on B is spirally substituted to form a ring or ring system selected from:
indanyl, azaindanyl, 1,2,3,4-tetrahydronaphthalenyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 2,3-dihydro-1-benzofuranyl, chromanyl, 3,4-dihydro-1H-isochromenyl, 2,3-dihydro-1-benzothiophenyl, thiochromanyl, 3,4-dihydro-1H-isothiochromenyl, 6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, cycloheptyl, morpholinyl and tetrahydropyranyl,
which ring or ring system is unsubstituted or substituted with one or more substituents each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, —OC 1-6 alkyl, and —C 3-6 cycloalkyl,
(b) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, hydroxy, —CN, —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro0, and —OC 1-6 alkyl (which is unsubstituted or substituted with 1-6 fluoro, halo, or hydroxyl),
(c) hydroxy,
(d) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(e) halo,
(f) —CN, and
(g) —C 3-6 cycloalkyl,
and wherein the remaining members of the group X 1 , X 2 , and X 3 present on B are each independently unsubstituted or substituted with one or more substituents selected from R 1 and R 2 , where:
R 1 and R 2 are each independently selected from:
(1) —C 1-4 alkyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl, and
(e) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl,
which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: —C 1-6 alkyl, —OC 1-6 alkyl, halo, hydroxy, trifluoromethyl, —CN, and —OCF 3 ,
(2) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from: halo, hydroxy, —OC 1-6 alkyl, trifluoromethyl and phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-4 fluoro,
(b) halo,
(c) hydroxy,
(d) —OC 1-3 alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(e) —C 3-6 cycloalkyl,
(4) halo,
(5) hydroxy,
(6) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(7) —CN,
(8) —CO 2 R 9 ,
(9) —NR 10 R 11 ,
(10) —SO 2 R 12 , and
(11) —CONR 10a R 11a
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
9. The compound of claim 1 wherein B is:
X 1 , X 2 , and X 3 are each carbon, and one of X 1 , X 2 , and X 3 present on B is spirally substituted to form a ring or ring system selected from:
indanyl, azaindanyl, 1,2,3,4-tetrahydronaphthalenyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 2,3-dihydro-1-benzofuranyl, chromanyl, 3,4-dihydro-1H-isochromenyl, thiochromanyl, 6,7,8,9-tetrahydro-5H-benzo[7]annulenyl and cycloheptyl,
which ring or ring system is unsubstituted or substituted with one to five substituents each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from: halo, hydroxy, —OC 1-6 alkyl, and —C 3-6 cycloalkyl,
(b) hydroxy,
(c) —OC 1-4 alkyl, which is unsubstituted or substituted with 1-4 halo,
(d) halo, and
(e) —CN,
and wherein the remaining members of the group X 1 , X 2 and X 3 present on B are each independently unsubstituted or substituted with one or more substituents selected from R 1 and R 2 , where:
R 1 and R 2 are each independently selected from:
(1) —C 1-4 alkyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl, and
(e) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: —C 1-6 alkyl, —OC 1-6 alkyl, halo, hydroxy, trifluoromethyl, —CN, and —OCF 3 ,
(2) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from: halo, hydroxy, —OC 1-6 alkyl, trifluoromethyl and phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-4 fluoro,
(b) halo,
(c) hydroxy,
(d) —OC 1-3 alkyl, which is unsubstituted or substituted with 1-3 fluoro, and
(e) —C 3-6 cycloalkyl,
(4) halo,
(5) hydroxy,
(6) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo, and
(7) —CN
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
10. The compound of claim 1 wherein B is selected from the group consisting of:
X 1 , X 2 and X 3 are each carbon, and one of X 1 , X 2 and X 3 present on B is —(C═O)—,
wherein another one of the members of the group X 1 , X 2 , X 3 and X 4 present on B is optionally spirally substituted to form a ring or ring system selected from:
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, indanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azaindanyl, 1,2,3,4-tetrahydronaphthalenyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 2,3-dihydro-1-benzofuranyl, chromanyl, 3,4-dihydro-1H-isochromenyl, 2,3-dihydro-1-benzothiophenyl, thiochromanyl, 3,4-dihydro-1H-isothiochromenyl, 6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, thiepanyl, oxepanyl and azepanyl,
which ring or ring system is unsubstituted or substituted with one to seven substituents each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are independently selected from: halo, hydroxy, —OC 1-6 alkyl, —C 3-6 cycloalkyl phenyl and heterocycle, wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, and morpholinyl,
(b) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, hydroxy, —CN, —C 3-6 cycloalkyl, —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, and —OC 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, halo, or hydroxyl,
(c) hydroxy,
(d) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(e) halo,
(f) —CN, and
(g) —C 3-6 cycloalkyl,
and wherein the remaining members of the group X 1 , X 2 and X 3 present on B are each independently unsubstituted or substituted with one or more substituents selected from R 1 and R 2 , where
R 1 and R 2 are each independently selected from:
(1) —C 1-4 alkyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl, and
(e) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: —C 1-6 alkyl, —OC 1-6 alkyl, halo, hydroxy, trifluoromethyl, —CN, and —OCF 3 ,
(2) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from: halo, hydroxy, —OC 1-6 alkyl, trifluoromethyl and phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-4 fluoro,
(b) halo,
(c) hydroxy,
(d) —OC 1-3 alkyl, which is unsubstituted or substituted with 1-3 fluoro, and
(e) —C 3-6 cycloalkyl,
(4) halo,
(5) hydroxy,
(6) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(7) —CN,
(8) —CO 2 R 9 ,
(9) —NR 10 R 11 ,
(10) —SO 2 R 12 , and
(11) —CONR 10a R 11a
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
11. The compound of claim 1 wherein B is:
X 1 , X 2 and X 3 are each carbon, and one of X 1 , X 2 and X 3 present on B is —(C═O)—,
wherein another one of the members of the group X 1 , X 2 and X 3 present on B is optionally spirally substituted to form a ring or ring system selected from:
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azaindanyl, 1,2,3,4-tetrahydronaphthalenyl, 5,6,7,8-tetrahydroquinolinyl, chromanyl, thiochromanyl, 6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, morpholinyl, tetrahydropyranyl, thiepanyl, oxepanyl and azepanyl
which ring or ring system is unsubstituted or substituted with one to five substituents each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-4 substituents where the substituents are independently selected from: halo, hydroxy, —OC 1-6 alkyl, or —C 3-6 cycloalkyl,
(b) hydroxy,
(c) —OC 1-4 alkyl, which is unsubstituted or substituted with 1-4 halo,
(d) halo, and
(e) —CN,
and wherein the remaining members of the group X 1 , X 2 and X 3 present on B are each independently unsubstituted or substituted with one or more substituents selected from R 1 and R 2 , where:
R 1 and R 2 are each independently selected from:
(1) —C 1-4 alkyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl, and
(e) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: —C 1-6 alkyl, —OC 1-6 alkyl, halo, hydroxy, trifluoromethyl, —CN, and —OCF 3 ,
(2) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from: halo, hydroxy, —OC 1-6 alkyl, trifluoromethyl and phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-4 fluoro,
(b) halo,
(c) hydroxy,
(d) —OC 1-3 alkyl, which is unsubstituted or substituted with 1-3 fluoro, and
(e) —C 3-6 cycloalkyl,
(4) halo,
(5) hydroxy,
(6) —OC 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo, and
(7) —CN
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
12. The compound of claim 1 wherein B is 2-oxo-imidazolinyl, 2,4-dioxo-imidazolyl, or 2,4-dioxo-dihydropyrimidinyl, or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
13. The compound of claim 1 , wherein G 1 , G 2 , and G 3 are each independently selected from: —C(R 5 )═ and —N═, or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
14. The compound of claim 1 , wherein J is ═C(R 6a )—, —N(R 15 )—, or —CH 2 —, or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
15. The compound of claim 1 , wherein Y is ═C(R 6b )—, —CH 2 — or —C(═O)—, or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
16. The compound of claim 1 , wherein R 5 is hydrogen, C 1-6 alkyl or halo, or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
17. A compound selected from:
or a pharmaceutically acceptable salt thereof and individual diastereomers thereof.
18. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
19. A method for treating migraine or cluster headache in a mammalian patient, which method comprises the step administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.