Substituted monocyclic CGRP receptor antagonists
View Patent ↗Compounds of formula I: (wherein variables A 1 , A 2 , A 3 , A 4 , m, n, J, Q, R 4 , E a , E b , E c , R 6 , R 7 , R e , R f , R PG and Y are as described herein) which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. 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:
A 1 is selected from:
(1) —O—,
(2) —S(O) v —,
(3) —Si(OR a )—C 1-4 -alkyl-, where alkyl is unsubstituted or substituted with 1-5 halo,
(4) —Si(C 1-4 alkyl) 2 , where each alkyl is independently unsubstituted or substituted with 1-5 halo-,
(5) —CR 6 R 7 —,
(6) —N(R 8 )—,
(7) —(C═O)—,
(8) —C(R 8 )(R a )—,
(9) —C(N(R b )—SO 2 R d )(R a )—,
(10) —C(N(R b )(C═O)R a )(R a )—,
(11) —C(N(R b )(C═O)OR a )(R a )—,
(12) —CR 10 R 11 —, and
(13) —N(R 11 )—;
A 2 is selected from:
(1) —CR 6 R 7 —,
(2) —CR 10 R 11 —, and
(3) —(C═O)—;
A 3 is selected from:
(1) —CR 6 R 7 —,
(2) —N(R 8 )—,
(3) —CR 10 R 11 —, and
(4) —N(R 11 )—;
A 4 is
(6) a bond between A 2 and A 3 ;
E a is selected from:
(1) —C(R 5a )═,
(2) —N═, and
(3) —(N + —O − )═;
E b is selected from:
(1) —C(R 5b )═,
(2) —N═, and
(3) —(N + —O − )═;
E c is selected from:
(1) —C(R 5c )═,
(2) —N═, and
(3) —(N + —O − )═;
Q is —C(R a ) 2 —;
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) —O—R a ,
(3) —C 3-6 cycloalkyl,
(4) benzyl, and
(5) phenyl;
R 5a , R 5b and R 5c are each independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(3) halo,
(4) —OR a , and
(5) —CN;
R 6 and R 7 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) halo,
(b) —OR a ,
(c) —C 3-6 cycloalkyl,
(d) phenyl or heterocycle, wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl, indolyl, indazolyl, benzimidazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(iii) —OR a ,
(iv) —NR b R c ,
(v) —CN, and
(vi) oxo;
(e) —CO 2 R a ,
(f) —C(═O)NR b R c ,
(g) —S(O) v R d ,
(h) —CN,
(i) —NR b R c ,
(j) —N(R b )C(═O)R a ,
(k) —N(R b )SO 2 R d ,
(l) —CF 3 ,
(m) —O—CO 2 R d ,
(n) —O—(C═O)—NR b R c ,
(o) —NR b —(C═O)—NR b R c , and
(p) —C(═O)R a ,
(3) —C 3-8 cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —CN,
(c) —C 1-4 -alkyl, which is unsubstituted or substituted with 1-3 halo, and
(d) —OR a ,
(4) phenyl or heterocycle, wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 3-6 cycloalkyl,
(d) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iii) —OR a ,
(e) —CO 2 R a ,
(f) —C(═O)NR b R c ,
(g) —S(O) v R d ,
(h) —CN,
(i) —NR b R c ,
(j) —N(R b )C(═O)R a ,
(k) —N(R b )SO 2 R d ,
(l) —O—CO 2 R d ,
(m) —O—(C═O)—NR b R c ,
(n) —NR b —(C═O)—NR b R c ,
(o) —C(═O)R a ,
(p) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(q) oxo;
(5) halo,
(6) —OR a ,
(7) —CN,
(8) —CO 2 R a
(9) —N(R b )C(═O)R a
(10) —NR b R c ,
(11) —C(═O)NR b R c , and
(12) —O(C═O)R a ;
or R 6 and R 7 and the carbon atom or atoms to which they are attached join to form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, dioxolanyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiapyranyl, oxetanyl, thietanyl and tetrahydrothienyl, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, 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) —OR a ,
(iii) —C 3-6 cycloalkyl,
(iv) —CO 2 R a ,
(v) —NR b R c ,
(vi) —S(O) v R d ,
(vii) —C(═O)NR b R c , and
(viii) phenyl,
(b) —C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl group is optionally fused to the ring, and which C 3-6 cycloalkyl group is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —OR a ,
(iii) —C 3-6 cycloalkyl,
(iv) —CO 2 R a ,
(v) —NR b R c ,
(vi) —-S(O) v R d ,
(vii) —C(═O)NR b R c , and
(viii) phenyl,
(c) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, imidazolyl, furanyl, tetrahydrofuranyl, thiazolyl and oxazolyl, wherein the phenyl or heterocycle is optionally fused to the ring, and which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(iii) —OR a ,
(iv) —CO 2 R a ,
(v) —O(C═O)R a ,
(vi) —CN,
(vii) —NR b R c ,
(viii) oxo,
(ix) —C(═O)NR b R c ,
(x) —N(R b )C(═O)R a ,
(xi) —N(R b )CO 2 R a ,
(xii) —O(C═O)NR b R c , and
(xiii) —S(O) v R d ,
(d) —OR a ,
(e) —CO 2 R a ,
(f) —C(═O)NR b R c ,
(g) —S(O) v R d ,
(h) —CN,
(i) halo,
(j) —NR b R c ,
(k) —N(R b )C(═O)R a ,
(l) —N(R b )SO 2 R d ,
(m) —O—CO 2 R d ,
(n) —O—(C═O)—NR b R c ,
(o) —NR b —(C═O)—NR b R c ,
(p) —C(═O)R a , and
(q) oxo;
R 8 is independently selected from:
(1) hydrogen,
(2) —C(═O)R a ,
(3) —CO 2 R a ,
(4) —S(═O)R d ,
(5) —SO 2 R d ,
(6) —C(═O)NR b R c ,
(7) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 3-6 cycloalkyl,
(d) phenyl or heterocycle, wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo, and
(iii) —OR a ,
(iv) —NR b R c ,
(v) —C(═O)R a ,
(vi) —CO 2 R a , and
(vii) oxo,
(e) —CO 2 R a ,
(f) —C(═O)NR b R c ,
(g) —S(O) v R d ,
(h) —CN,
(i) —NR b R c ,
(j) —N(R b )C(═O)R a ,
(k) —N(R b )SO 2 R d ,
(l) —CF 3 ,
(m) —O—CO 2 R d ,
(n) —O—(C═O)—NR b R c ,
(o) —NR b —(C═O)—NR b R c and
(p) —C(═O)R a ,
(8) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 substituents each independently selected from:
(a) halo,
(b) —CN,
(c) —OR a , and
(d) C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo;
or R 7 and R 8 and the atoms to which they are attached join to form a 4-, 5-, 6- or 7-membered alkyl- or heteroalkyl-ring optionally containing an additional heteroatom selected from N, O, and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) phenyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, OR a , CN, and —C(═O)OR a ,
(c) —OR a , and
(d) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo;
R 10 is independently 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) —OR a ,
(c) —CN,
(d) phenyl, and
(e) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(3) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo;
R 11 is independently selected from the group consisting of:
phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, azepinyl, azepanyl, azetidinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, 1,3-benzodioxolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, chromanyl, cinnolinyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl, piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, triazolyl, isoxazolyl, tetrahydrothienyl, tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, and thietanyl, where R 11 is unsubstituted or substituted with 1-5 substituents each independently selected from R 12 , R 13 , R 14 , R 15a and R 15b ;
R 12 , R 13 , R 14 , R 15a and R 15b are each independently selected from:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 3-6 cycloalkyl,
(d) phenyl or heterocycle, wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo, and
(iii) —OR a ,
(e) —CO 2 R a ,
(f) —C(═O)NR b R c ,
(g) —S(O) v R d ,
(h) —CN,
(i) —NR b R c ,
(j) —N(R b )C(═O)R a ,
(k) —N(R b )SO 2 R d ,
(l) —CF 3 ,
(m) —O—CO 2 R d ,
(n) —O—(C═O)—NR b R c ,
(o) —NR b —(C═O)—NR b R c and
(p) —C(═O)R a ,
(2) —C 1-6 cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —CN,
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —OR a , and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are each independently selected from:
(i) —OR a ,
(ii) halo,
(iii) —CN, and
(iv) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(3) phenyl or heterocycle, wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 3-6 cycloalkyl,
(d) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iii) —OR a ,
(e) —CO 2 R a ,
(f) —C(═O)NR b R c ,
(g) —S(O) v R d ,
(h) —CN,
(i) —NR b R c ,
(j) —N(R b )C(═O)R a ,
(k) —N(R b )SO 2 R d ,
(l) —O—CO 2 R d ,
(m) —O—(C═O)—NR b R c ,
(n) —NR b —(C═O)—NR b R c ,
(o) —C(═O)R a , and
(p) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(4) halo,
(5) oxo,
(6) —OR a ,
(7) —CN,
(8) —CO 2 R a ,
(9) —C(═O)R a ,
(10) —NR b R c ,
(11) —S(O) v R d ,
(12) —C(═O)NR b R c ,
(13) —O—CO 2 R d ,
(14) —N(R b )CO 2 R d ,
(15) —O—(C═O)—NR b R c ,
(16) —NR b —(C═O)—NR b R c ,
(17) —SO 2 NR b R c ,
(18) —N(R b )SO 2 R d ,
or R 15a and R 15b and the atom(s) to which they are attached join to form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thietanyl and tetrahydrothienyl, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, 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) —OR a ,
(iii) —C 3-6 cycloalkyl,
(iv) —CO 2 R a ,
(v) —NR b R c ,
(vi) —S(O) v R d ,
(vii) —C(═O)NR b R c , and
(viii) phenyl,
(b) phenyl or heterocycle, wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo, and
(iii) —OR a ,
(c) —OR a ,
(d) halo,
(e) —CO 2 R a ,
(f) —C(═O)NR b R c ,
(g) —S(O) v R d ,
(h) —CN,
(i) —NR b R c ,
(j) —N(R b )C(═O)R a ,
(k) —N(R b )SO 2 R d ,
(l) —O—CO 2 R d ,
(m) —O—(C═O)—NR b R c ,
(n) —NR b —(C═O)—NR b R c and
(o) —C(═O)R a ;
R PG is independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl which is unsubstituted or substituted with 1-5 halo,
(3) —CH 2 OR a ,
(4) —CH 2 —O—CH 2 CH 2 Si(CH 3 ) 3 ,
(5) —CH 2 OP(═O)(OR c ) 2 ,
(6) —(CH 2 ) k -phenyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —CN, and
(d) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo;
J is independently selected from:
(1) ═C(R 16a )—,
(2) —CR 17 R 18 —,
(3) —C(═O)—, and
(4) —N(R b )—;
Y is independently selected from:
(1) ═C(R 16b )—,
(2) —CR 17 R 18 —,
(3) —C(═O)—,
(4) ═N—, and
(5) —N(R 16b )—;
R 17 and R 18 are each independently selected from:
(1) hydrogen,
(2) halo,
(3) —OR a ,
(4) —C 1-6 alkyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —CN,
(d) phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) —OR a ,
(ii) halo,
(iii) —CN,
(iv) —C 1-6 alkyl which is unsubstituted or substituted with 1-6 halo,
(5) phenyl or heterocycle wherein heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —CN,
(c) —OR a ,
(d) nitro,
(e) —C 1-6 alkyl which is unsubstituted or substituted with 1-6 halo;
or R 17 and R 18 and the atom to which they are attached join to form a 4-, 5-, or 6-membered ring optionally containing a heteroatom selected from N, O, and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(d) phenyl;
R 16a and R 16b 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) —OR a ,
(c) —C 3-6 cycloalkyl,
(d) phenyl or heterocycle, wherein said heterocycle is selected from: imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, isoxazolyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —OR a ,
(iii) —CN, and
(iv) C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(3) phenyl or heterocycle, wherein heterocycle is selected from: imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydrofuryl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, thiazolyl, thienyl, triazolyl, isoxazolyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 3-6 cycloalkyl,
(d) —C 1-4 -alkyl which is unsubstituted or substituted with 1-6 halo, and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iii) —OR a ,
(4) halo,
(5) —OR a ,
(6) —CN,
(7) —CO 2 R a ,
(8) —NR b R c , and
(9) —C(═O)NR b R c ;
or R 16a and R 16b and the atom(s) to which they are attached join 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) —OR a ,
(iii) —C 3-6 cycloalkyl,
(iv) 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:
(I) —OR a ,
(II) halo,
(III) —CN, and
(IV) —C 1-6 alkyl which is unsubstituted or substituted with 1-6 halo,
(v) —CO 2 R a ,
(vi) —NR b R c ,
(vii) —S(O) v R d ,
(viii) —C(═O)NR b R c ,
(ix) —N(R b )CO 2 R a , and
(x) —N(R b )SO 2 R d ,
(b) phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —OR a ,
(iii) —CN, and
(iv) —C 1-6 alkyl which is unsubstituted or substituted with 1-6 halo,
(c) halo,
(d) —S(O) v R d ,
(e) —OR a ,
(f) —CN,
(g) —C(═O)R a ,
(h) —NR b R c ,
(i) —C(═O)NR b R c ,
(j) —CO 2 R a ,
(k) —(NR b )CO 2 R a ,
(l) —O—(C═O)—NR b R c ,
(m) —(NR b )—(C═O)—NR b R c ,
(n) oxido,
(o) oxo, and
(p) —(NR b )SO 2 R d ;
R a is independently 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) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(c) hydroxyl,
(d) —CN, and
(e) phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(iii) —CN,
(iv) nitro,
(v) hydroxyl, and
(vi) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(3) phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —CN,
(c) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(d) nitro,
(e) hydroxyl, and
(f) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(4) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo;
R b and R c are independently 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) —OR a ,
(c) —CN,
(d) —CO 2 R a ,
(e) phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —OR a ,
(iii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iv) nitro,
(3) phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(d) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(e) —CN, and
(f) —CO 2 R a ,
(4) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo;
or R b and R c and the nitrogen to which they are attached join to form a 4-, 5-, or 6-membered ring optionally containing an additional heteroatom selected from N, O, and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) —OR a , and
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(d) phenyl;
R d is independently selected from:
(1) C 1-6 alkyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —CO 2 R a ,
(d) —CN, and
(e) phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —OR a ,
(iii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iv) nitro,
(2) phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(d) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo
(e) —CN, and
(f) —CO 2 R a , and
(3) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo;
R e and R f are independently selected from:
(1) hydrogen,
(2) —C 1-4 -alkyl, which is unsubstituted or substituted with 1-6 halo,
(3) phenyl, and
(4) benzyl;
or where R e and R f and the atom to which they are attached join to form a 3-, 4-, 5-, or 6-membered ring optionally containing a heteroatom selected from N, O, and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(d) phenyl;
m is 1;
n is 1;
v is 0, 1, or 2;
k is 0, 1, or 2;
or a pharmaceutically acceptable salt, individual enantiomer or diastereomer thereof.
2. The compound of claim 1 having the formula Ia:
or a pharmaceutically acceptable salt, individual enantiomer or diastereomer thereof.
3. The compound of claim 1 , wherein A 1 is independently selected from:
(1) —O—,
(2) —S(O)—,
(3) —Si(OR a )(C 1-4 alkyl), which alkyl is unsubstituted or substituted with 1-5 halo,
(4) —Si(C 1-4 alkyl) 2 , —Si(C 1-4 alkyl) 2 , where each alkyl is independently unsubstituted or substituted with 1-5 halo-,
(5) —CR 6 R 7 —,
(6) —N(R 8 )—,
(7) —(C═O)—,
(8) —C(R 8 )(R a )—,
(9) —C(N(R b )—SO 2 R d )(R a )—,
(10) —C(N(R b )(C═O)R a )(R a )—,
(11) —C(N(R b )(C═O)OR a )(R a )—,
(12) —CR 10 R 11 —, and
(13) —N(R 11 )—.
4. The compound of claim 1 , wherein A 2 is independently selected from:
(1) —CR 6 R 7 —,
(2) —CR 10 R 11 —, and
(3) —(C═O)—.
5. The compound of claim 1 , wherein A 3 is independently selected from:
(1) —CR 6 R 7 —,
(2) —CR 10 R 11 —, and
(3) —N(R 11 )—.
6. The compound of claim 1 , wherein E a is independently selected from:
(1) —C(R 5a )═,
(2) —N═, and
(3) —(N + —O − )═.
7. The compound of claim 1 , wherein E b is independently selected from:
(1) —C(R 5b )═,
(2) —N═, and
(3) —(N + —O − )═.
8. The compound of claim 1 , wherein E c is independently selected from:
(1) —C(R 5c )═,
(2) —N═, and
(3) —(N + —O − )═.
9. The compound of claim 1 , wherein R 4 is selected from: hydrogen and —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 fluoro.
10. The compound of claim 1 , wherein R 5a , R 5b and R 5c are independently selected from hydrogen, halo, and —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 fluoro.
11. The compound of claim 1 , wherein R 6 and R 7 are independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents where the substitutents are each independently selected from: halo, phenyl, and —OR a ,
(3) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-5 fluoro,
(4) phenyl or heterocycle, which is unsubstituted or substituted with 1-5 halo,
(5) halo,
(6) —OR a ,
(7) —NR b R c , and
(8) —O(C═O)R a .
12. The compound of claim 1 , wherein R 6 and R 7 and the carbon atom or atoms to which they are attached join to form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, dioxolanyl, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl, which ring is unsubstituted or substituted with 1-6 substituents each independently selected from:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 substituents where the substitutents are each independently selected from: halo, —OR a , and phenyl,
(2) —C 3-6 cycloalkyl, wherein the C 3-6 cycloalkyl group is optionally fused to the ring, and which C 3-6 cycloalkyl group is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, —OR a , and phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, wherein the phenyl or heterocycle is optionally fused to the ring, and which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, —OR a , and —C 1-4 -alkyl, which is unsubstituted or substituted with 1-5 fluoro,
(4) halo,
(5) oxo,
(6) —CO 2 R a , and
(7) —C(═O)R a .
13. The compound of claim 1 , wherein R 8 is selected from: hydrogen, —C(═O)R a , —CO 2 R a , —SO 2 R d , and —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 fluoro.
14. The compound of claim 1 , wherein R 8 and R 7 and the atoms to which they are attached join to form a 4-, 5-, 6- or 7-membered alkyl- or heteroalkyl-ring optionally containing an additional heteroatom selected from N, O, and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is unsubstituted or substituted with 1-4 substituents each independently selected from:
(1) halo,
(2) phenyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, OR a , CN, and —C(═O)OR a ,
(3) —OR a , and
(4) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo.
15. The compound of claim 1 , wherein R 10 is selected from: hydrogen, and —C 1-6 alkyl, which is unsubstituted or substituted with fluoro.
16. The compound of claim 1 , wherein R 11 is independently selected from the group consisting of:
phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, azepinyl, azepanyl, azetidinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, chromanyl, cinnolinyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl, piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, triazolyl, isoxazolyl, tetrahydrothienyl, tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, and thietanyl, where R 11 is unsubstituted or substituted with 1-5 substituents each independently selected from R 12 , R 13 , R 14 , R 15a and R 15b .
17. The compound of claim 1 , wherein R PG is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 halo,
(3) —CH 2 OR a ,
(4) —CH 2 —O—CH 2 CH 2 Si(CH 3 ) 3 , and
(5) CH 2 OP(═O)(OR c ) 2
wherein R a is defined herein.
18. The compound of claim 1 , wherein J is ═C(R 16a )—, —CR 17 R 18 — or —N(R b )—.
19. The compound of claim 1 , wherein Y is ═C(R 16b )—, —CR 17 R 18 — or —C(═O)—.
20. The compound of claim 1 , wherein R 16a and R 16b are independently selected from:
(1) hydrogen,
(2) —C 1-4 -alkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, —OR a , —C 3-6 cycloalkyl, and phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, triazolyl, isoxazolyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: —C 1-4 -alkyl which is unsubstituted or substituted with 1-3 halo, —OR a , and halo,
(4) halo,
(5) OR a , and
(6) —NR b R c .
21. The compound of claim 1 , wherein R 16a and R 16b and the atom(s) to which they are attached join to form a ring selected from cyclohexenyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, oxazolyl, isoxazolyl, imidazolyl, and thienyl, which ring is unsubstituted or substituted with 1-3 substituents each independently selected from:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, OR a , —CO 2 R a , —NR b R c and CONR b R c ,
(2) phenyl or heterocycle, wherein heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, OR a and —C 1-4 -alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(3) halo,
(4) OR a ,
(5) —CN,
(6) —NR b R c ,
(7) CONR b R c , and
(8) oxo.
22. A compound which is:
or a pharmaceutically acceptable salt, individual enantiomer or diastereomer thereof.
23. A compound which is:
or a pharmaceutically acceptable salt, individual enantiomer or diastereomer thereof.
24. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 or a pharmaceutically acceptable salt thereof.
25. A method for treating headache, migraine or cluster headache in a mammalian patient in need of such which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
26. A method of treating migraine headaches, cluster headaches, and headaches, said method comprising the co-administration, to a person in need of such treatment, of:
a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and
a therapeutically effective amount of a second agent selected from serotonin agonists, analgesics, anti-inflamatory agents, anti-hypertensives and anticonvulsants.