Tricyclic anilide heterocyclic CGRP receptor antagonists

1. A compound of formula I:

wherein:

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

B 1 and B 4 are each independently selected from:

B 2 and B 3 are each independently selected from: a bond, ═C(R 1 )—, —CR 1 R 2 —, —C(═O)—, —C(═S)—, —C(═NR 1 )—, ═N—, —N(R 1 )—, —O—, —S—, and —SO 2 —;

D 1 and D 2 are each independently selected from: ═C(R 1 )—, —CR 1 R 2 —, —C(═O)—, —C(═S)—, —C(═NR 1 )—, ═N—, —N(R 1 )—, —O—, —S— and —SO 2 —;

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 —C(R 5 )═;

J is independently selected from:

(1) ═C(R 6a )—,

(2) —CR 13 R 14 —,

(3) —C(═O)—, and

(4) —N(R 15 )—;

Y is independently selected from:

(1) ═C(R 6b )—,

(2) —CR 13 R 14 —,

(3) —C(═O)—,

(4) —SO 2 —,

(5) ═N—, and

(6) —N(R 6b )—;

T, U and V are each independently selected from: ═C(R 1 )— and ═N—, wherein at least one of T, U, and V is ═C(R 1 )—;

W, X, and Z are each independently selected from: a bond, ═C(R 1 )—, —CR 1 R 2 —, —C(═O)—, —C(═S)—, —C(═NR 1 )—, ═N—, —N(R 1 )—, —O—, —S—, —S(O)— and —SO 2 —;

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,

(d) —C 3-6 cycloalkyl,

(e) phenyl or heterocycle, wherein the heterocycle is selected from azetidinyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azepanyl, 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: —C 1-6 alkyl, —O—C 1-6 alkyl, halo, hydroxy, trifluoromethyl, —OCF 3 and oxo,

(f) —CO 2 R 9 ,

(g) —NR 10 R 11 ,

(h) —SO 2 R 12 ,

(i) —CONR 10a R 11a ,

(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,

(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,

(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,

(4) —C 2-6 alkynyl, 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,

(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,

(5) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azepanyl, azetidinyl, 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 1-6 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 the 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 ,

(n) —SO 2 R 12 , and

(o) —CN

(6) halo,

(7) oxo,

(8) hydroxy,

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

(10) —CN,

(11) —CO 2 R 9 ,

(12) —NR 10 R 11 ,

(13) —SO 2 R 12 ,

(14) —CONR 10a R 11a ,

(15) —OCO 2 R 9 ,

(16) —(NR 10a )CO 2 R 9 ,

(17) —O(CO)NR 10a R 11a ,

(18) —(NR 9 )(CO)NR 10a R 11a ,

(19) —(CO)—(CO)NR 10a R 11a ,

(20) —(CO)—(CO)OR 9 , and

(21) —(NR 10 )(CO)R 9 ;

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 where the substituents are each independently selected from:

(a) halo,

(b) —O—C 1-6 alkyl,

(c) —C 3-6 cycloalkyl,

(d) phenyl or heterocycle, wherein the heterocycle is selected from imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, or morpholinyl, wherein said heterocycle is unsubstituted or substituted with 1-3 substituents where the substituents are 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 ,

(3) phenyl or heterocycle, wherein the heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, azetidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrahydrofuryl, piperidinyl, and morpholinyl, wherein said heterocycle 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 1-5 fluoro,

(b) halo,

(c) hydroxy,

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

(e) —C 3-6 cycloalkyl, and

(f) 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 where R 6a and R 6b and the atom(s) to which they are attached may be joined together to form a ring selected from cyclopentenyl, cyclohexenyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, dihydrofuranyl, dihydropyranyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thienyl, dihydrothienyl, or dihydrothiopyranyl, wherein said ring is unsubstituted or substituted with 1-5 substituents where the substituents are each independently selected from:

(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from:

(i) halo,

(ii) hydroxy,

(iii) —O—C 1-6 alkyl,

(iv) —C 3-6 cycloalkyl,

(v) phenyl or heterocycle, wherein the heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, or morpholinyl, wherein said heterocycle is unsubstituted or substituted with 1-5 substituents where the substituents are 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 the heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, wherein said heterocycle is unsubstituted or substituted with 1-3 substituents where the substituents are 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) —C(O)R 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 9 is independently selected from:

(1) hydrogen,

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

(3) —C 3-6 cycloalkyl,

(4) benzyl, and

(5) phenyl;

R 10 and R 11 are each independently selected from:

(1) hydrogen,

(2) C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,

(3) —C 5-6 cycloalkyl,

(4) benzyl,

(5) phenyl,

(6) —COR 9 , and

(7) —SO 2 R 12 ;

R 10a and R 11a are each independently selected from:

(1) hydrogen,

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

(3) —C 5-6 cycloalkyl,

(4) benzyl, and

(5) 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;

R 12 is independently selected from:

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

(2) —C 5-6 cycloalkyl,

(3) benzyl, and

(4) phenyl;

R 13 and R 14 are each independently selected from:

(1) hydrogen,

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

(3) hydroxy, and

(4) halo;

R 15 is selected from:

(1) hydrogen,

(2) —C 1-6 alkyl or —C 3-6 cycloalkyl which are unsubstituted or substituted with 1-7 substituents where the substituents are 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 where the substituents are 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, or morpholinyl, wherein said heterocycle is unsubstituted or substituted with 1-5 substituents where the substituents are 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. A compound of claim 1 in which the compound of formula (I) is a compound of formula (Ia):

wherein B 1 , B 2 , B 3 , B 4 , D 1 , D 2 , G 1 , G 2 , G 3 , J, Y, T, U, V, W, X, Z and n are as defined in claim 1 , or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.

3. A compound of claim 1 in which the compound of formula (I) is a compound of formula (Ib):

wherein B 1 , B 2 , B 4 , D 1 , D 2 , G 1 , G 2 , G 3 , J, Y, T, U, V, W, X, and Z are defined in claim 1 , or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.

4. A compound of claim 1 in which the compound of formula (I) is a compound of formula (Ic):

wherein B 1 , B 2 , B 4 , D 1 , D 2 , J, Y, T, U, V, W, X, and Z are defined in claim 1 , and R 5a and R 5b are each selected from the same group as R 5 as defined in claim 1 ;

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

5. A compound of claim 1 in which the compound of formula (I) is a compound of formula (Id):

wherein B 1 , B 2 , B 4 , D 1 , D 2 , J, Y, T, U, V, W, X, and Z are defined in claim 1 , and R 5a and R 5b are each selected from the same group as R 5 as defined in claim 1 ;

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

6. A compound of claim 1 in which the compound of formula (I) is a compound of formula (Ie):

wherein B 1 , B 2 , B 4 , D 1 , D 2 , J, Y, T, U, V, W, X, and Z are defined in claim 1 , and R 5a and R 5b are each selected from the same group as R 5 as defined in claim 1 ;

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

7. A compound of claim 1 in which the compound of formula (I) is a compound of formula (If):

wherein B 1 , B 2 , B 4 , D 1 , D 2 , G 1 , G 2 , G 3 , T, U, V, W, X, and Z are defined in claim 1 , or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.

8. A compound of claim 1 in which the compound of formula (I) is a compound of formula (Ig):

wherein B 1 , B 2 , B 4 , D 1 , D 2 , G 1 , G 2 , G 3 , R 15 , T, U, V, W, X, and Z are defined in claim 1 ,

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

9. A compound of claim 1 , wherein A 1 is CH 2 and A 2 is a bond, or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.

10. A compound of claim 1 , wherein B 1 is selected from:

B 4 is selected from:

and B 2 is selected from:

═C(R 1 )—; —CR 1 R 2 —; and —C(═O)—; or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.

11. A compound of claim 1 wherein D 1 is —CR 1 R 2 —, and D 2 is selected from —CR 1 R 2 — and —N(R 1 )—; or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.

12. A compound of claim 1 wherein V, T and U are each ═C(R 1 )—; or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.

13. A compound of claim 1 , wherein W is selected from a bond, —CR 1 R 2 — and —C(═O)—; or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.

14. A compound of claim 1 , wherein X is selected from a bond, —CR 1 R 2 — and —C(═O)—; or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.

15. A compound of claim 1 , wherein Z is selected from a bond, —CR 1 R 2 — and —C(═O)—; or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.

16. A compound of claim 1 , wherein J is ═C(R 6a )— and Y is ═C(R 6b )—, and R 6a and R 6b are linked together to form a pyridyl group; or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.

17. A 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.

18. A compound of claim 1 which is selected from the group consisting of

(±)-2-(4-Oxo-4,5-dihydropyrrolo[4,3,2-de]quinolin-1(3H)-yl)-N-(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl)acetamide;

2-(2a-Methyl-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)-N-(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl)acetamide;

2-(8-Methyl-2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)-N-(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl)acetamide;

2-(2,5-Dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)-N-(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl)acetamide; and

2-(2a-Methyl-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)-N-(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl)acetamide;

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

20. A method for treating headache, migraine or cluster headache in a mammalian patient in need thereof, which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.