Carboxamide spirolactam CGRP receptor antagonists
View Patent ↗The present invention is directed to compounds of Formula I: 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 formula I:
wherein:
B is a selected from the group consisting of: C 3-10 cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, 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, oxazepanyl, oxadiazolyl, 2-oxoazepinyl, 4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxopyridinyl, 2-oxoquinolinyl, 2-oxobenzimidazolinyl, piperidinyl, piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridinyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazepinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, and triazolyl,
where B is unsubstituted or substituted with 1-5 substituents each independently selected from R 1 , R 2 , R 3a and R 3b ,
R 1 , R 2 , R 3a and R 3b are 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: 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: —C 1-6 alkyl, —O—C 1-6 alkyl, halo, hydroxy, trifluoromethyl and —OCF 3 ,
(f) —CO 2 R 9 , wherein R 9 is selected from: hydrogen, —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, —C 5-6 cycloalkyl, benzyl and phenyl,
(g) —NR 10 R 11 , wherein R 10 and R 11 are each independently selected from: hydrogen, —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, —C 5-6 cycloalkyl, benzyl, phenyl, —COR 9 and —SO 2 R 12 ,
(h) —SO 2 R 12 , wherein R 12 is selected from: —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, —C 5-6 cycloalkyl, benzyl and phenyl,
(i) CONR 10a R 11a , wherein R 10a and R 11a are each independently selected from:
hydrogen, —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, —C 5-6 cycloalkyl, benzyl and phenyl,
or R 10a and R 11a are joined to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which ring is unsubstituted or substituted with 1-5 substituents each independently selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halo, hydroxyl, phenyl and benzyl,
(j) trifluoromethyl,
(k) —OCO 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 ,
(2) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from: halo, hydroxy, —O—C 1-6 alkyl, trifluoromethyl and phenyl, which phenyl is unsubstituted or substituted with 1-5 substituents each independently selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halo, hydroxy and trifluoromethyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepanyl, benzimidazolyl, benzopyranyl, benzofuryl, benzothiazolyl, benzoxazolyl, chromanyl, furyl, imidazolidinyl, imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, pyrazolidinyl, pyrazolyl, pyrrolyl, quinazolinyl, tetrahydrofuryl, thiazolinyl, purinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, 1,3-dioxolanyl, oxadiazolyl, 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) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(e) —C 3-6 cycloalkyl,
(f) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, thienyl and 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 and trifluoromethyl,
(g) —CO 2 R 9 ,
(h) —NR 10 R 11 ,
(i) —CONR 10 R 11 ,
(j) —SO 2 R 12 , and
(k) oxo,
(4) halo,
(5) oxo,
(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 ,
(14) —(NR 10a )CO 2 R 9 ,
(15) —O(CO)NR 10a R 11a ,
(16) —(NR 9 )(CO)NR 10a R 11a ,
(17) —SO 2 NR 10a R 11a ,
(18) —SR 12 ,
(19) —S(O)R 12 ,
(20) —(NR 9 )(CO)NR 10a R 11a
(21) —(CO)—(CO)NR 10a R 11a , and
(22) —(CO)—(CO)OR 9 ;
or R 3a and R 3b and the atom(s) to which they are attached are joined to form a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, pyrrolinyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, furanyl, dihydrofuranyl, dihydropyranyl 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 1-5 substituents each independently selected from: —O—C 1-6 alkyl, halo, and hydroxy, (iv)
—C 3-6 cycloalkyl, which 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 , (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: —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) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from: halo, hydroxy, —O—C 1-6 alkyl, trifluoromethyl and phenyl,
(c) 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: halo, hydroxy, —C 3-6 cycloalkyl, —O—C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, and —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro,
(d) halo,
(e) —SO 2 R 12 ,
(f) hydroxy,
(g) —O—C 1-6 alkyl which is unsubstituted or substituted with 1-5 halo,
(h) —CN,
(i) —COR 12 ,
(j) —NR 10 R 11 ,
(k) —CONR 10a R 11a ,
(l) —CO 2 R 9 ,
(m) —(NR 10a )CO 2 R 9 ,
(n) —O(CO)NR 10a R 11a ,
(o) —(NR 9 )(CO)NR 10a R 11a , and
(p) oxo;
A 1 and A 2 are each independently selected from:
(1) a bond,
(2) —CR 13 R 14 —, wherein R 13 and R 14 are independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from: halo, hydroxy, —NR 10 R 11 , —CONR 10a R 11a and —CO 2 R 9 ,
(c) phenyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from: C 1-4 alkyl, hydroxyl and halo,
(d) —CONR 10 —(C 1-6 alkyl)-NR 15 R 16 , wherein R 15 and R 16 are each independently selected from: hydrogen, —C 1-6 alkyl, —COR 9 and —CO 2 R 9 ,
(e) —CO 2 R 9 ,
(f) —CONR 10a R 11a , and
(g) hydroxy, and
(3) —CH 2 CR 13 R 14 —,
wherein one of A 1 and A 2 is optionally absent;
J is selected from: ═C(R 6a )—, —CR 13 R 14 — and —C(═O)—;
K is selected from: ═C(R 6b )—, —CR 13 R 14 —, —C(═O)—, —SO 2 —, ═N— and —N(R 6b )—;
R 4 is selected from: hydrogen, C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, C 5-6 cycloalkyl, benzyl and phenyl,
or R 4 is joined to B to form a ring selected from piperidinyl, pyrrolidinyl, piperazinyl, azetidinyl, azepinyl and morpholinyl, which ring is unsubstituted or substituted with 1-5 substituents each independently selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halo, hydroxy, phenyl and benzyl;
R 5a , R 5b and R 5c are each independently selected from: hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, —OCF 3 , trifluoromethyl, halo, hydroxy and —CN;
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,
(d) phenyl or heterocycle, wherein heterocycle is selected from: imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, or 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 ,
(4) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, 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: —C 1-4 alkyl which is unsubstituted or substituted with 1-5 fluoro, halo, hydroxy, —O—C 1-4 alkyl which is unsubstituted or substituted with 1-5 fluoro, —C 3-6 cycloalkyl and phenyl,
(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 , and
(11) —CONR 10a R 11a ,
or 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, pyridinyl, 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: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, or morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are 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: 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: —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro, —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro, halo, hydroxy, 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) —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 ,
(n) —(NR 9 )(CO)NR 10a R 11a , and
(o) oxo;
m is 1 or 2;
n is 1 or 2;
a pharmaceutically acceptable salt or individual diastereoisomer thereof.
2. The compound of claim 1 having the formula Ia:
a pharmaceutically acceptable salt or individual diastereoisomer thereof.
3. The compound of claim 1 having the formula Ib:
a pharmaceutically acceptable salt or individual diastereoisomer thereof.
4. The compound of claim 1 having the formula Ic:
a pharmaceutically acceptable salt or individual diastereoisomer thereof.
5. The compound of claim 1 having the formula Id:
a pharmaceutically acceptable salt or individual diastereoisomer thereof.
6. The compound of claim 1 having the formula Ie:
a pharmaceutically acceptable salt or individual diastereoisomer thereof.
7. The compound of claim 1 having the formula If:
a pharmaceutically acceptable salt or individual diastereoisomer thereof.
8. The compound of claim 1 having the formula Ig:
a pharmaceutically acceptable salt or individual diastereoisomer thereof.
9. The compound of claim 1 , wherein B is selected from the group consisting of: C 3-10 cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, azepanyl, benzimidazolyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, morpholinyl, naphthyridinyl, oxazepanyl, 2-oxoazepanyl, 2-oxooxazepanyl, 2-oxopyrrolidinyl, 2-oxopyridinyl, piperazinyl, piperidinyl, pyrazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, and thiazolinyl,
where B is unsubstituted or substituted with 1-5 substituents each independently selected from R 1 , R 2 , R 3a and R 3b .
10. The compound of claim 1 , wherein R 1 , R 2 , R 3a and R 3b are 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,
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 ,
(f) —NR 10 R 11 ,
(g) —CONR 10a R 11a ,
(2) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from: halo, hydroxy, —O—C 1-6 alkyl, trifluoromethyl and phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, imidazolidinyl, imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, tetrahydrofuryl, 1,3-dioxolanyl, oxadiazolyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro,
(b) halo,
(c) hydroxy,
(d) —O—C 1-16 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(e) —C 3-6 cycloalkyl,
(f) phenyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halo, hydroxy and trifluoromethyl,
(g) —NR 10 R 11 , and
(h) oxo,
(4) halo,
(5) oxo,
(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 , and
(13) —SO 2 NR 10a R 11a .
11. The compound of claim 1 , wherein R 1 , R 2 , R 3a and R 3b are independently selected from:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from: halo, hydroxy, —C 3-6 cycloalkyl and phenyl, which phenyl is unsubstituted or substituted with 1-3 substituents each independently selected from: —C 1-6 alkyl, halo and trifluoromethyl,
(2) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolinyl, imidazolidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, halo and oxo,
(3) halo,
(4) oxo,
(5) hydroxy,
(6) —O—C 1-16 alkyl, which is unsubstituted or substituted with 1-5 halo,
(7) —CN,
(8) —SO 2 R 12 , and
(9) —SO 2 NR 10a R 11a ,
or R 3a and R 3b and the atom(s) to which they are attached are joined to form a ring selected from phenyl, thiazolinyl, triazoyl, imidazolyl, imidazolinyl, pyridinyl, moipholinyl, pyrrolidinyl, piperidinyl, and tetrahydrofuranyl, 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,
(v) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from: —O—C 1-6 alkyl, halo, and hydroxy,
(vi) —C 3-6 cycloalkyl, and
(b) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, hydroxy, —O—C 1-6 alkyl, trifluoromethyl and phenyl,
(c) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrrolidinyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, hydroxy, —C 3-6 cycloalkyl, —O—C 1-6 alkyl, and —C 1-6 alkyl,
(d) halo,
(f) hydroxy,
(g) —O—C 1-6 alkyl which is unsubstituted or substituted with 1-5 halo,
(i) —COR 12 ,
(j) —NR 10 R 11 ,
(k) —CONR 10a R 11a , and
(p) oxo.
12. The compound of claim 1 , wherein A 1 is —CH 2 — or a bond, and A 2 is —CHR 13 — or a bond.
13. The compound of claim 1 , wherein J is ═C(R 6a )— or —CH 2 —.
14. The compound of claim 1 , wherein K is selected from:
═C(R 6b )—, —CH 2 — and —C(═O)—.
15. The compound of claim 1 , wherein R 4 is hydrogen or —C 1-6 alkyl which is unsubstituted or substituted with fluoro, or R 4 is joined to B to form a piperidinyl ring.
16. The compound of claim 1 , wherein R 5a , R 5b and R 5c are each independently selected from hydrogen, C 1-6 alkyl and halo.
17. The compound of claim 1 , wherein R 6a and R 6b are each independently selected from:
(1) hydrogen;
(2) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from: halo, —O—C 1-16 alkyl, —C 3-6 cycloalkyl, and phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, tetrahydrofuryl, piperidinyl, and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, hydroxy, —C 1-4 alkyl which is unsubstituted or substituted with 1-3 fluoro, and —O—C 1-4 alkyl which is unsubstituted or substituted with 1-3 fluoro,
(4) halo,
(5) —NR 10 R 11 ,
(6) hydroxy,
(7) —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo.
18. The compound of claim 1 , wherein R 6a and R 6b and the atom(s) to which they are attached join to form a ring selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl, thienyl, which ring 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 substituents each independently selected from: halo, —O—C 1-6 alkyl, —CO 2 R 9 , —NR 10 R 11 , —CONR 10a R 11a ,
(b) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, hydroxyl, —C 1-4 alkyl which is unsubstituted or substituted with 1-5 fluoro, and —O—C 1-4 alkyl which is unsubstituted or substituted with 1-3 fluoro,
(c) halo,
(d) hydroxy,
(e) —O—C 1-6 alkyl which is unsubstituted or substituted with 1-5 halo,
(f) —CN,
(g) —NR 10 R 11 ,
(h) —CONR 10a R 11a , and
(i) oxo.
19. The compound of claim 1 , wherein R 13 and R 14 are independently selected from:
(a) hydrogen,
(b) phenyl,
(c) —CONR 10 —(C 1-6 alkyl)—NR 15 R 16 , wherein R 15 and R 16 are independently selected from: hydrogen, —C 1-6 alkyl and —CO 2 R 9 , and
(d) —CO 2 R 9 .
20. A compound selected from:
and pharmaceutically acceptable salts and individual diastereomers thereof.
21. A Compound selected from:
a pharmaceutically acceptable salt or individual diastereoisomer thereof.
22. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .
23. 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 .