Bicyclic anilide heterocyclic CGRP receptor antagonists

1. A compound of the formula I:

wherein:

B is a bicycloheterocycle selected from the group consisting of:

B is unsubstituted or substituted with 1-5 substituents each 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,

(d) —C 3-6 cycloalkyl,

(e) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, oxazolyl, thiazolyl, 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 3-6 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 join 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 ,

(n) —(NR 9 )(CO)NR 10a R 11a , and

(o) —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) —O—C 1-6 alkyl,

(d) trifluoromethyl, and

(e) phenyl, which 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: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepanyl, 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 1-6 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: pyridyl, 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) —(CO)R 9 ,

(i) —NR 10 R 11 ,

(j) —CONR 10 R 11 ,

(k) oxo,

(l) —SR 12 ,

(m) —S(O)R 12 , and

(n) —SO 2 R 12 ,

(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) —(CO)—(CO)NR 10a R 11a ,

(18) —(CO)—(CO)OR 9 , and

(19) —SO 2 NR 10a R 11a ;

or R 3a and R 3b and the carbon atom(s) to which they are attached join to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, dihydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, dihydrothiopyranyl, tetrahydrothiopyranyl 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,

(iv) —C 3-6 cycloalkyl,

(v) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halo, hydroxy, trifluoromethyl and —OCF 3 ,

(vi) —CO 2 R 9 ,

(vii) —NR 10 R 11 ,

(viii) —SO 2 R 12 ,

(ix) —CONR 10a R 11a , and

(x) —(NR 10a )CO 2 R 9 ,

(b) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, halo, hydroxy, —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro, and —C 3-6 cycloalkyl,

(c) halo,

(d) —SO 2 R 12 ,

(e) hydroxy,

(f) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,

(g) —CN,

(h) —COR 12 ,

(i) —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;

A 1 and A 2 are each independently selected from: a bond and —CR 13 R 14 —,

wherein R 13 and R 14 are each independently selected from: hydrogen, C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, hydroxy and halo,

wherein one of A 1 and A 2 is optionally absent;

G 1 , G 2 and G 3 are each independently selected from:

(1) —C(R 5 )═,

(2) —N═, and

(3) —(N + —O − )═,

wherein no more than two of G 1 , G 2 and G 3 are selected to be —C(R 5 )═;

or wherein G 1 is selected from:

(1) —C(R 5 )═,

(2) —N═, and

(3) —(N + —O − )═,

and -G 2 =G 3 -taken together are selected from:

(1) —S—,

(2) —O—,

(3) —N(R 10 )—;

J is selected from:

(1) ═C(R 6a )—,

(2) —CR 13 R 14 —,

(3) —C(═O)—, and

(4) —N(R 15 )—;

Y is selected from:

(1) ═C(R 6b )—,

(2) —CR 13 R 14 —,

(3) —C(═O)—,

(4) —SO 2 —,

(5)═N—, and

(6) —N(R 6b )—;

R 4 is selected from: hydrogen, C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, C 5-6 cycloalkyl, benzyl and phenyl;

R 5 is independently selected from:

(1) hydrogen,

(2) C 1-6 alkyl,

(3) —O—C 1-6 alkyl,

(4) —OCF 3 ,

(5) trifluoromethyl,

(6) halo,

(7) hydroxy, and

(8) —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, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 each independently selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halo, hydroxy, trifluoromethyl and —OCF 3 ,

(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, azetidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrahydrofuryl, piperidinyl, and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: —C 1-4 alkyl which is unsubstituted or substituted with 1-5 fluoro, —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-5 fluoro, halo, hydroxy, —C 3-6 cycloalkyl and phenyl,

(4) halo,

(5) hydroxy,

(6) —O—C 1-6 alkyl which is unsubstituted or substituted with 1-5 halo,

(7) —CN,

(8) —CO 2 R 9 ,

(9) —NR 10 R 11 , and

(10) —CONR 10a R 11a ;

or R 6a and R 6b 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) hydroxy,

(iii) —O—C 1-6 alkyl,

(iv) —C 3-6 cycloalkyl,

(v) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl 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) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: —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, hydroxyl 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;

R 15 is selected from:

(1) hydrogen,

(2) —C 1-6 alkyl or —C 3-6 cycloalkyl, 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, 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,

(f) —CO 2 R 9 ,

(g) —NR 10 R 11 ,

(h) —CONR 10 R 11 ,

(i) —SO 2 R 12 , and

(j) trifluoromethyl, and

(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:

(a) —C 1-6 alkyl,

(b) —O—C 1-6 alkyl,

(c) halo,

(d) hydroxy, and

(e) trifluoromethyl;

m is 1 or 2;

n is 1 or 2;

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 having the formula If:

or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.

8. 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) fluoro,

(b) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl,

(c) —CO 2 R 9 , wherein R 9 is independently selected from: hydrogen, and —C 1-6 alkyl,

(d) —CONR 10a R 11a wherein R 10a and R 11a are each independently selected from: hydrogen and —C 1-6 alkyl,

or R 10a and R 11a are joined to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, and

(e) —O—C 3-6 cycloalkyl,

(2) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, thiazolyl, isothiazolyl, 2-oxopyrrolidinyl, tetrahydrofuryl, piperidinyl, tetrahydrothienyl and tetrahydrothiopyranyl, 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 1-3 fluoro,

(b) halo,

(c) —CO 2 R 9 , wherein R 9 is selected from: hydrogen, —C 1-4 alkyl, and —C 3-6 cycloalkyl,

(d) —(CO)R 9 ,

(e) —CONR 10 R 11 , wherein R 10 and R 11 are independently selected from: hydrogen and —C 1-6 alkyl,

(f) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-3 fluoro,

(g) hydroxy,

(h) oxo,

(i) —S—C 1-4 alkyl,

(j) —S(O)—C 1-4 alkyl, and

(k) —SO 2 —C 1-4 alkyl,

(3) halo,

(4) hydroxy,

(5) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-3 fluoro,

(6) —NR 10 R 11 , wherein R 10 and R 11 are each independently selected from: hydrogen, —C 1-4 alkyl which is unsubstituted or substituted with 1-5 fluoro, —C 5-6 cycloalkyl, and —COR 9 ,

(7) —C 3-6 cycloalkyl,

(8) —(CO)—(CO)NR 10a R 11a , wherein R 10a and R 11a are independently selected from: hydrogen and —C 1-6 alkyl, and

(9) —CN,

or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.

9. The compound of claim 1 , wherein R 1 and R 2 are independently selected from:

(1) —C 1-4 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:

(a) fluoro,

(b) phenyl,

(c) —CO 2 R 9 , wherein R 9 is independently selected from: hydrogen and —C 1-4 alkyl,

(d) —CONR 10a R 11a wherein R 10a and R 11a are each independently selected from: hydrogen and —C 1-4 alkyl,

or R 10a and R 11a are joined to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and

(e) —O—C 3-6 cycloalkyl,

(2) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, thiazolyl, tetrahydrofuryl, piperidinyl and tetrahydrothiopyranyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:

(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 fluoro

(b) halo,

(c) —CO 2 R 9 , wherein R 9 is selected from: hydrogen, —C 1-4 alkyl, and —C 3-6 cycloalkyl,

(d) —(CO)R 9 ,

(e) —CONR 10 R 11 , wherein R 10 and R 11 are independently selected from: hydrogen and —C 1-4 alkyl,

(f) —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-3 fluoro,

(g) hydroxy,

(h) oxo

(i) —S—C 1-4 alkyl,

(j) —S(O)—C 1-4 alkyl, and

(k) —SO 2 —C 1-4 alkyl,

(3) halo,

(4) hydroxy,

(5) —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-3 fluoro,

(6) —CN,

(7) —C 3-6 cycloalkyl,

(8) —(CO)—(CO)NR 10a R 11a , wherein R 10a and R 11a are independently selected from: hydrogen and —C 1-4 alkyl, and

(9) —NR 10 R 11 , wherein R 10 and R 11 are each independently selected from: hydrogen, —C 1-4 alkyl, and —COR 9 ,

or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.

10. The compound of claim 1 , wherein J is selected from:

═C(R 6a )—, —CH 2 — and —N(R 15 )—, or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.

11. The compound of claim 1 , wherein Y is selected from:

=C(R 6b )—, —CH 2 — and —C(═O)—, or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.

12. 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 each independently selected from: halo, —O—C 1-6 alkyl, —C 3-6 cycloalkyl, and phenyl,

(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, 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 1-3 fluoro, —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-3 fluoro, halo and hydroxyl,

(4) halo,

(5) —NR 10 R 11 ,

(6) hydroxy,

(7) —O—C 1-4 alkyl which is unsubstituted or substituted with 1-3 halo,

or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.

13. The compound of claim 1 , wherein G 1 , G 2 and G 3 are each independently selected from: —C(R 5 )═ and —N═; wherein no more than two of G 1 , G 2 and G 3 are selected to be —C(R 5 )═, or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.

14. The compound of claim 1 , wherein G 1 is selected from: —C(R 5 )═ and —N═, and -G 2 =G 3 -taken together are selected from: —S— and —N(R 10 )—, or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.

15. The compound of claim 1 , wherein one of G 1 , G 2 and G 3 is —N═ and the remaining two of G 1 , G 2 and G 3 are —C(H)═, or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.

16. A compound selected from:

or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.

17. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .