Spirolactam tricyclic 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 , B 1 , B 2 , B 3 , B 4 , D 1 , D 2 , E 1 , E 2 , E 3 , E 4 , E 5 , G 1 , G 2 , J, K, T, U, V, W, X, Y and Z 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 , 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—CR 13 R 14 —,
(8) —CR 13 R 14 —O—,
(9) —C≡C—,
(10) —C(R 13 )═C(R 14 )—, and
(11) —C(═O)—,
where one or two of A 1 , A 2 and A 3 are optionally absent;
A 5 and A 6 are
—CR 13 R 14 ,
both of A 4 and A 7 are absent;
B 1 and B 4 are each independently selected from:
B 2 and B 3 are each independently selected from:
(1) a bond
(2) ═C(R 1 )—,
(3) —CR 1 R 2 —,
(4) —C(═O)—,
(5) —C(═S)—,
(6) —C(═NR 1 )—,
(7) ═N—,
(8) —N(R 1 )—,
(9) —O—,
(10) —S—, and
(11) —SO 2 —,
where one of B 2 and B 3 is optionally absent;
D 1 and D 2 are each independently selected from:
(1) ═C(R 1 )—,
(2) —CR 1 R 2 —,
(3) —C(═O)—,
(4) —C(═S)—,
(5) ═N—,
(6) —N(R 1 )—,
(7) —O—,
(8) —S—,
(9) —SO 2 —, and
(10) —C(═NR 1 )—;
E 1 and E 5 are each independently selected from:
(1) ═C(R 4 )—,
(2) —CR 4 R 5 —,
(3) —C(═O)—,
(4) —C(═S)—,
(5) ═N—,
(6) ═N + (O − )—,
(7) —N(R 4 )—,
(8) —O—,
(9) —S—, and
(10) —SO 2 —;
E 3 and E 4 are each independently selected from:
(1) a bond,
(2) ═C(R 4 )—,
(3) —CR 4 R 5 —,
(4) —C(═O)—,
(5) ═N—,
(6) ═N + (O − )—,
(7) —N(R 4 )—, and
(8) —O—,
where one or both of E 3 and E 4 are optionally absent;
E 2 is selected from:
G 1 and G 2 are
═C(R 4 )—;
J is:
═C(R 6a )—;
K is:
═C(R 6b )—;
T, U and V are each independently selected from:
(1) ═C(R 1 )—,
(2) ═N—, and
(3) ═N + (O − )—;
wherein at least one of T, U, and V is ═C(R 1 )—;
W, X, Y, and Z are each independently selected from:
(1) a bond
(2) ═C(R 1 )—,
(3) —CR 1 R 2 —,
(4) —C(═O)—,
(5) —C(═S)—,
(6) ═N—,
(7) —N(R 1 )—,
(8) —O—,
(9) —S—,
(10) —S(O)—,
(11) —SO 2 —, and
(12) —C(═NR 1 )—;
where 1-4 of W, X, Y and Z are optionally absent;
R 1 and R 2 are each 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) 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, azepanyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azepinyl, piperazinyl, pyrazolyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, tetrazolyl, tetrahydrofuryl, or 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) oxo,
(vi) amino,
(vii) phenyl, and
(viii) 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 1-5 halo, 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,
(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 where the substituents are independently selected from:
(I) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(III) halo,
(IV) hydroxy,
(V) trifluoromethyl,
(VI) —OCF 3 , and
(VII) CN, and
(v) benzyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(I) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(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, or morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents independently selected from:
(I) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(III) halo,
(IV) hydroxy,
(V) trifluoromethyl,
(VI) —OCF 3 , and
(VII) CN, and
(iv) benzyl, which is unsubstituted or substituted with 1-5 substituents independently selected from:
(I) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(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,
(II) halo,
(III) hydroxy,
(IV) —OCF 3 ,
(V) —C 3-6 cycloalkyl, and
(VI) phenyl,
(iii) —C 5-6 cycloalkyl,
(iv) phenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are 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 where the substituents are 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, or 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,
(VI) benzyl,
(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)—O—C 3-6 cycloalkyl,
(p) —SO 2 NR 10a R 11a , and
(q) —CN,
(3) —C 3-6 cycloalkyl, 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 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,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(4) 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 where the substituents are 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 fluoro,
(e) —C 3-6 cycloalkyl,
(f) phenyl or heterocycle, wherein heterocycle is selected from: pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, thienyl, or 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, 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)—CN and
(p) —SO 2 NR 10a R 11a ,
(5) halo,
(6) oxo,
(7) hydroxy,
(8) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are 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 ,
(9) —CN,
(10) —CO 2 R 9 ,
(11) —NR 10 R 11 ,
(12) —SR 12 ,
(13) —S(O)R 12 ,
(14) —SO 2 R 12 ,
(15) —SO 2 NR 10a R 11a ,
(16) —CONR 10a R 11a ,
(17) —OCO 2 R 9 ,
(18) —(NR 10a )CO 2 R 9 ,
(19) —O(CO)NR 10a R 11a ,
(20) —(NR 9 )(CO)NR 10a R 11a ,
(21) —(CO)—(CO)NR 10a R 11a , and
(22) —(CO)—(CO)OR 9 ;
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, which is unsubstituted or substituted with 1-5 halo,
(d) —C 3-6 cycloalkyl,
(e) phenyl,
(f) —CO 2 R 9 ,
(g) —NR 10 R 11 , and
(h) —CONR 10a R 11a
(3) —C 3-6 cycloalkyl,
(4) phenyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo,
(b) halo,
(c) hydroxy, and
(d) —O—C 1-4 -alkyl, which is unsubstituted or substituted with 1-3 halo,
(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 are joined together to form a pyridinyl ring, 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 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 ,
(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 Ia:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
3. The compound of claim 1 having the formula Ib:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
4. The compound of claim 1 having the formula Ic:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
5. The compound of claim 1 having the formula Id:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
6. The compound of claim 1 having the formula Ie:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
7. The compound of claim 1 wherein A 1 is selected from —C(═O)— and CH 2 ; A 2 is a bond; and A 3 is a bond.
8. The compound of claim 1 wherein B 1 is selected from
B 4 is selected from
B 2 is selected from C(R 1 )—, —CR 1 , R 2 —, and —C(═O)—; and B 3 is selected from ═C(H)—, —CH 2 —, —C(═O)—, and a bond.
9. The compound of claim 1 wherein D 1 is selected from ═C(R 1 )—, —CR 1 R 2 —, —C(═O)—, and —N(R 1 )—; and D 2 is selected from —CR 1 R 2 — and —N(R 1 )—.
10. The compound of claim 1 wherein E 1 is selected from: ═C(R 4 )—, —CR 4 R 5 —, ═N—, and —N(R 4 )—; E 2 is selected f from
E 3 is selected from: a bond, ═C(R 4 )—, —CR 4 R 5 —, ═N—; and —N(R 4 )—; E 4 is selected from a bond and —CH 2 —; and E 5 is selected from ═C(R 4 )—, —CR 4 R 5 —, ═N— and —N(R 4 )—.
11. The compound of claim 1 wherein T is selected from ═C(R 1 )— and ═N—; U is selected from ═C(R 1 )— and ═N—; and V is ═C(H)—.
12. The compound of claim 1 wherein W is selected from a bond, —CR 1 R 2 — and —C(═O)—; X is selected from a bond, —CR 1 R 2 —, and —C(═O)—; Y is selected from a bond, —CR 1 R 2 —, and —C(═O)—; and Z is selected from a bond, —CR 1 R 2 —, and —C(═O)—.
13. The compound of claim 1 wherein R 1 and R 2 are 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) hydroxy,
(c) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(d) —C 3-6 cycloalkyl,
(e) phenyl or heterocycle, wherein heterocycle is selected from: azetidinyl, imidazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, tetrazolyl, tetrahydrofuryl, or morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) —C 1-4 -alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(ii) —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(iii) halo,
(iv) hydroxy,
(v) trifluoromethyl, and
(vi) —OCF 3 ,
(f) —CO 2 R 9 ,
(g) —NR 10 R 11 ,
(h) —CONR 10a R 11a ,
(i) —(NR 10a )CO 2 R 9 ,
(3) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —C 1-6 alkyl, and
(d) —O—C 1-6 alkyl,
(4) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, azetidinyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, benzimidazolyl, benzoxazolyl, imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, quinazolinyl, tetrahydrofuryl, naphthyridinyl, quinoxalinyl, 1,3-dioxolanyl, oxadiazolyl, piperidinyl, tetrahydropyranyl, 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 1-3 fluoro,
(b) halo,
(c) hydroxy,
(d) —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(e) —C 3-6 cycloalkyl,
(g) —CO 2 R 9 ,
(h) —NR 10 R 11 , and
(i) —CONR 10a R 11a ,
(5) halo,
(6) hydroxy,
(7) —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo,
(8) —CN,
(9) —CO 2 R 9 ,
(10) —NR 10 R 11 ,
(11) —CONR 10a R 11a , and
(12) —(NR 10a )CO 2 R 9 .
14. The compound of claim 1 wherein R 1 and R 2 are independently selected from:
(1) hydrogen;
(2) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —O—C 1-4 alkyl,
(c) phenyl or heterocycle, wherein heterocycle is selected from: azetidinyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuryl, or morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) —C 1-4 alkyl,
(ii) —O—C 1-4 alkyl,
(iii) halo, and
(iv) hydroxy,
(d) —CO 2 R 9 ,
(e) —NR 10 R 11 ,
(f) —CONR 10a R 11a ,
(3) —C 3-6 cycloalkyl,
(4) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, azetidinyl, oxazolyl, imidazolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, tetrahydrofuryl, oxadiazolyl, 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 1-3 fluoro,
(b) halo,
(c) hydroxy,
(d) —O—C 1-4 alkyl,
(e) —C 3-6 cycloalkyl,
(f) —NR 10 R 11 , and
(g) —CONR 10 R 11 ,
(5) halo,
(6) hydroxy,
(7) —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo,
(8) —CN,
(9) —CO 2 R 9 ,
(10) —NR 10 R 11 ,
(11) —CONR 10a R 11a , and
(12) —(NR 10a )CO 2 R 9 .
15. The compound of claim 1 wherein R 4 and R 5 are independently selected from:
(1) hydrogen;
(2) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl, and
(e) phenyl,
(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, and
(b) halo,
(5) halo,
(6) hydroxy,
(7) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(8) —CN, and
(9) —NR 10 R 11 .
16. The compound of claim 1 , wherein R 6a and R 6b and the atom(s) to which they are attached join to form pyridinyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from:
(i) halo,
(ii) —O—C 1-6 alkyl,
(iii) —CO 2 R 9 ,
(iv) —NR 10 R 11 , and
(v) —CONR 10a R 11a ,
(b) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from:
(i) —C 1-4 alkyl, which is unsubstituted or substituted with 1-5 fluoro,
(ii) halo,
(iii) hydroxy, and
(iv) —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.
17. The compound of claim 1 wherein R 9 is selected from:
(i) hydrogen,
(ii)-C 1-6 alkyl, which is unsubstituted or substituted with 1-3 substituents, substituents each independently selected from:
(I) halo,
(II) hydroxy,
(III) —O—C 1-4 alkyl,
(IV) —C 3-6 cycloalkyl,
(V) phenyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(1) —C 1-4 alkyl,
(2) —O—C 1-4 alkyl, and
(3) halo,
(iii) —C 3-6 cycloalkyl, and
(iv) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl, piperidinyl, piperazinyl, and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(I) halo,
(II) —C 1-4 alkyl,
(III) —O—C 1-4 alkyl, and
(IV) oxo.
18. A compound selected from:
or a pharmaceutically acceptable salt and individual stereoisomers thereof.
19. 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.
20. 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.