Spirolactam aryl CGRP receptor antagonists
View Patent ↗Compounds of formula I: (wherein variables A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , E 1 , E 2 , E 3 , E 4 , E 5 , G 1 , G 2 , J and K 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:
B is a selected from:
C 3 - 10 cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, azepanyl, azepinyl, 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, indazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, isothiazolidinyl, isothiazolyl, morpholinyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, oxazolidinyl, 2-oxoazepinyl, 4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, phthalazinyl, piperidyl, piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, triazolyl and triazolinyl,
where B is linked to A 1 via a carbon atom in B and
where B is unsubstituted or substituted with 1-5 substituents independently selected from R 1 , R 2 , R 3a and R 3b , wherein
R 1 , R 2 , R 3a and R 3b 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, which is unsubstituted or substituted with 1-5 halo,
(d) —C 3-6 cycloalkyl,
(e) phenyl or heterocycle, wherein heterocycle is selected from: azetidinyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azepanyl, azepinyl, piperazinyl, pyrazolyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, tetrazolyl, tetrahydrofuryl and morpholinyl, which phenyl or heterocycle 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,
(iv) hydroxy,
(v) trifluoromethyl,
(vi) —OCF 3 ,
(vii) oxo,
(viii) amino,
(ix) phenyl, and
(x) benzyl,
(f) —CO 2 R 9 , wherein R 9 is independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 substituents, substituents each independently selected from:
(I) halo,
(II) hydroxy,
(III) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(IV) —C 3-6 cycloalkyl,
(V) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(1) —C 1-4 alkyl,
(2) —O—C 1-6 alkyl,
(3) halo,
(4) trifluoromethyl, and
(5) —OCF 3 ,
(iii) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 substituents, substituents each independently selected from:
(I) halo,
(II) hydroxy,
(III) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(IV) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo, and
(V) phenyl, and
(iv) 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:
(I) halo,
(II) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo
(III) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo
(IV) —C 3-6 cycloalkyl,
(V) oxo,
(VI) —CN,
(VII) hydroxy, and
(VIII) phenyl,
(g) —NR 10 R 11 , wherein R 10 and R 11 are each independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 substituents each independently selected from:
(I) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(II) halo,
(III) hydroxy,
(IV) —OCF 3 ,
(V) —C 3-6 cycloalkyl, and
(VI) phenyl,
(iii) —C 4-6 cycloalkyl,
(iv) phenyl, 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,
(IV) hydroxy,
(V) trifluoromethyl,
(VI) —OCF 3 , and
(VII) CN, and
(v) 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,
(vi) —COR 9 , and
(vii) —SO 2 R 12 ,
(h) —SO 2 R 12 , wherein R 12 is selected from:
(i) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(ii) —C 3-6 cycloalkyl,
(iii) 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:
(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,
(IV) hydroxy,
(V) trifluoromethyl,
(VI) —OCF 3 , and
(VII) CN, and
(iv) 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,
(i) —CONR 10a R 11a , wherein R 10a and R 11a are each independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 substituents each independently selected from:
(I) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(II) halo,
(III) hydroxy,
(IV) —OCF 3 ,
(V) —C 3-6 cycloalkyl, and
(VI) phenyl,
(iii) —C 5-6 cycloalkyl, which is unsubstituted or substituted with 1-5 halo,
(iv) phenyl, 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,
(IV) hydroxy,
(V) trifluoromethyl,
(VI) —OCF 3 , and
(VII) CN, and
(v) 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,
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:
(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
(IV) hydroxy
(V) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(1) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo,
(2) —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo, and
(3) halo,
(VI) benzyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(1) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo,
(2) —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo, and
(3) halo,
(VII) —COR 9 , and
(VIII) —SO 2 R 12 ,
(j) trifluoromethyl,
(k) —OCO 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 ,
(o) —SO 2 NR 10a R 11a , and
(p) —O—C 3-6 cycloalkyl,
(2) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(e) phenyl, 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,
(iv) hydroxy, and
(v) trifluoromethyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, azepanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepinyl, benzimidazolyl, benzopyranyl, benzofuryl, benzothiazolyl, benzoxazolyl, chromanyl, furyl, imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, pyrazolidinyl, pyrazolyl, pyrrolyl, quinazolinyl, tetrahydrofuryl, thiazolinyl, purinyl, naphthyridinyl, quinoxalinyl, 1,3-dioxolanyl, oxadiazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, 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 substituents each independently selected from:
(i) halo,
(ii) hydroxy,
(iii) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(iv) —C 3-6 cycloalkyl,
(v) phenyl,
(vi) —CO 2 R 9 , and
(vii) —NR 10 R 11 ,
(b) halo,
(c) hydroxy,
(d) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(e) —C 3-6 cycloalkyl,
(f) phenyl or heterocycle, wherein heterocycle is selected from: pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) —C 1-6 alkyl,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(g) —CO 2 R 9 ,
(h) —(CO)R 9 ,
(i) —NR 10 R 11 ,
(j) —CONR 10a R 11a ,
(k) oxo
(l) —SR 12 ,
(m) —S(O)R 12 ,
(n) —SO 2 R 12 ,
(o) —SO 2 NR 10a R 11a , and
(p) —CN,
(4) halo,
(5) oxo,
(6) hydroxy,
(7) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —C 3-6 cycloalkyl,
(d) phenyl,
(e) —CO 2 R 9 , and
(f) —NR 10 R 11 ,
(8) —CN,
(9) —CO 2 R 9 ,
(10) —NR 10 R 11 ,
(11) —SR 12 ,
(12) —S(O)R 12 ,
(13) —SO 2 R 12 ,
(14) —SO 2 NR 10a R 11a ,
(15) —CONR 10a R 11a ,
(16) —OCO 2 R 9 ,
(17) —(NR 10a )CO 2 R 9 ,
(18) —O(CO)NR 10a R 11a ,
(19) —(NR 9 )(CO)NR 10a R 11a ,
(20) —(CO)—(CO)NR 10a R 11a , and
(21) —(CO)—(CO)OR 9 ;
or where R 3a and R 3b and the atom(s) to which they are attached join to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, dihydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, dihydrothiopyranyl, tetrahydrothiopyranyl, imidazolyl, imidazolinyl, and piperazinyl, 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, which is unsubstituted or substituted with 1-3 halo,
(iv) —C 3-6 cycloalkyl,
(v) 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:
(I) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(III) halo,
(IV) hydroxy,
(V) trifluoromethyl, and
(VI) —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: pyridinyl, 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:
(i) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(ii) halo,
(iii) hydroxy,
(iv) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro, and
(v) —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) —NR 10 R 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 , and
(n) —(NR 9 )(CO)NR 10a R 11a ;
A 1 , A 2 and A 3 are each independently selected from:
(1) a bond,
(2) —CR 13 R 14 —, wherein R 13 and R 14 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) —C 3-6 cycloalkyl,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) phenyl,
(c) hydroxy, and
(d) halo,
(3) —NR 10 —,
(4) —CR 13 R 14 —NR 10 —,
(5) —CR 13 R 14 —CH 2 —,
(6) —CH 2 —CR 13 R 14 —,
(7) —O—C R 13 R 14 —,
(8) —C R 13 R 14 —O—,
(9) —C≡C—,
(10) —C(R 13 )═C(R 14 )—, and
(II) —C(═O)—,
or wherein one or two of A 1 , A 2 and A 3 are absent;
A 5 and A 6
—CR 13 R 14 —;
A 4 and A 7 are absent;
E 1 is —N(R 4 )—, E 2 is
E 3 and E 4 are absent, and E 5 is ═N—to form:
E 1 is ═N—, E 2 is
E 3 and E 5 are ═C(R 4 )—and E 4 is absent, form:
E 5 is ═N—, E 2 is
E 1 and E 3 are ═C(R 4 )—and E 4 is absent, form:
E 1 and E 5 are ═N—, E 2 is
E 3 is ═C(H)—and E 4 is absent, form:
E 1 is —N(R 4 )—, E 2 is
E 3 is ═N—and E 4 and E 5 are —CR 4 R 5 —to form:
G 1 G 2 are
═C(R 4 )—
J is
═C(R 6a )—
K is
═C(R 6b )—;
R 4 and R 5 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) hydroxy,
(c) —O—C 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) —O—C 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 and the atom(s) to which they are attached join to form pyridinyl, fused between atoms 2 and 3 as follows:
said pyridinyl 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: 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:
(I) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(III) halo,
(IV) hydroxy,
(V) trifluoromethyl, and
(VI) —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: pyridinyl, 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:
(i) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(ii) halo,
(iii) hydroxy,
(iv) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro, and
(v) —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) —NR 10 R 11 ,
(i) —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;
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
2. The compound of claim 1 having the formula Ib:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
3. The compound of claim 1 , wherein B is selected from the group consisting of: C 3-10 cycloalkyl, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indanyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, morpholinyl, naphthyridinyl, piperidinyl, piperazinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroquinolinyl, phthalazinyl, pyrazolyl, isoxazolinyl, indazolyl, benzoxazolyl, benzoxazolinyl, benzimidazolyl, benzimidazolinyl, thiazolyl, and thienyl, which is unsubstituted or substituted with 1-5 substituents selected from R 1 , R 2 , R 3a and R 3b .
4. The compound of claim 3 , wherein R 1 , R 2 , R 3a and R 3b 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) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl,
(e) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl,
(f) —(NR 10a )CO 2 R 9 , and
(l) NR 10 R 11 ,
(2) C 3-6 cycloalkyl,
(3) —OR 9 ,
(4) —OCF 3 ,
(5) trifluoromethyl,
(6) halo,
(7) oxo,
(8) hydroxy,
(9) —CN,
(10) —COR 12 ,
(11) —CO 2 R 12 ,
(12) —CONR 10a R 11a ,
(13) —NR 10 R 11 ,
(14) phenyl, which is unsubstituted or substituted with 1-5 substituents selected from:
(a) C 1-6 alkyl,
(b) —O—C 1-6 alkyl,
(c) halo,
(d) —OH, and
(e) —CF 3 , and
(15) heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, piperazinyl, piperidinyl, tetrazolyl, or morpholinyl, and which is unsubstituted or substituted with 1-5 substituents selected from:
(a) C 1-6 alkyl,
(b) —O—C 1-6 alkyl,
(c) halo,
(d) —OH, and
(e) —CF 3 .
5. The compound of claim 1 , wherein R 3a and R 3b and the carbon atom(s) to which they are attached join to form a ring selected from piperidinyl, cyclohexyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, and tetrahydrothiopyranyl, which ring is unsubstituted or substituted with 1-3 substituents independently selected from:
(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo, and
(ii) phenyl,
(b) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl and pyrazinyl,
(c) —CO 2 R 9 ,
(d) hydroxy, and
(e) oxo.
6. The compound of claim 1 , wherein R 3a and R 3b and the carbon atom(s) to which they are attached are joined together to form a ring selected from piperidinyl, cyclohexyl, tetrahydropyranyl, and tetrahydrothiopyranyl, which ring is unsubstituted or substituted with 1-3 substituents independently selected from:
(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 substituents independently selected from:
(i) fluoro, and
(ii) phenyl,
(b) —CO 2 —C 1-4 alkyl,
(c) hydroxyl, and
(d) oxo.
7. The compound of claim 1 , wherein A 1 is selected from a bond, —CR 13 R 14 —, —OCH 2 —, —C≡C—, —CH 2 —CH 2 —, —C(H)═C(H)—, —NH— and —C(═O)—; A 2 is selected from a bond, CH 2 , —CH 2 —NH—, —C(═O)—, —C≡C—, —NH— and —CH 2 —CH 2 —; and A 3 is selected from a bond, —CH 2 —, —C(═O)— and —CH 2 O—.
8. The compound of claim 1 , wherein G 1 is ═C(H)— and G 2 is ═C(H)—.
9. A compound selected from:
or a pharmaceutically acceptable salt and individual stereoisomers thereof.
10. 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.
11. A method for treating 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 and individual enantiomers and diastereomers thereof.
12. The compound according to claim 1 wherein A 1 is —CR 13 R 14 —, A 2 , A 3 , A 4 and A 7 are absent, A 5 and A 6 are —CH 2 —, G 1 and G 2 are ═C(R 4 )—, E 1 is ═N—, E 2 is
E 3 and E 5 are ═C(H)—, E 4 is absent, J is ═C(R 6a )—, and K is ═C(R 6b )—, where R 6a and R 6b and the atoms to which they are attached are joined to form a pyridinyl ring, forming the following structure:
13. The compound according to claim 1 wherein A 1 is —CR 13 R 14 —, A 2 , A 3 , A 4 and A 7 are absent, A 5 and A 6 are —CH 2 —, G 1 and G 2 are ═C(R 4 )—, E 5 is ═N—, E 2 is
E 1 and E 3 are ═C(H)—, E 4 is absent, J is ═C(R 6a )—, and K is ═C(R 6b )—, where R 6a and R 6b and the atoms to which they are attached are joined to form a pyridinyl ring, forming the following structure:
14. The compound according to claim 1 wherein A 1 is C(═O)—, A 2 , A 3 , A 4 and A 7 are absent, A 5 and A 6 are —CH 2 —, G 1 and G 2 are ═C(R 4 )—, E 1 is ═N—, E 2 is
E 3 and E 5 are ═C(H)—, E 4 is absent, J is ═C(R 6a )—, and K is ═C(R 6b )—, where R 6a and R 6b and the atoms to which they are attached are joined to form a pyridinyl ring, forming the following structure:
15. The compound according to claim 1 wherein A 1 is —CR 13 R 14 —, A 2 , A 3 , A 4 and A 7 are absent, A 5 and A 6 are —CH 2 —, G 1 and G 2 are ═C(R 4 )—, E 1 and e 5 are ═N—, E 2 is
E 3 is ═C(H)—and E 4 is absent, J is ═C(R 6a )—, and K is ═C(R 6b )—, where R 6a and R 6b and the atoms to which they are attached are joined to form a pyridinyl ring, forming the following structure:
16. The compound according to claim 1 wherein A 1 is —CR 13 R 14 —, A 2 , A 3 , A 4 and A 7 are absent, A 5 and A 6 are —CH 2 —, G 1 and G 2 are ═C(R 4 )—, E 1 is —N(R 4 )—, E 2 is
E 3 and E 4 are absent, E 5 is ═N—, J is ═C(R 6a )—, and K is ═C(R 6b )—, where R 6a and R 6b and the atoms to which they are attached are joined to form a pyridinyl ring, forming the following structure:
17. The compound according to claim 1 wherein A 1 is —CR 13 R 14 —, A 2 , A 3 , A 4 and A 7 are absent, A 5 and A 6 are —CH 2 —, G 1 and G 2 are ═C(R 4 )—, E 1 is —N(H)—, E 2 is
E 3 is ═N—, E 4 and E 5 are —CR 4 R 5 —, J is ═C(R 6a )—, and K is ═C(R 6b )—, where R 6a and R 6b and the atoms to which they are attached are joined to form a pyridinyl ring, forming the following structure: