Bicyclic anilide spirohydantoin CGRP receptor antagonists

1. A compound of the formula I:

wherein:

B is a bicycloheterocycle selected from the group consisting of:

where T, U, V, W, X and Y are each independently a carbon atom or a nitrogen atom wherein no more than two of T, U, V and W, and no more than three of T, U, V, W, X and Y, are a nitrogen atom,

where B is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from R 1 , R 2 , R 3a and R 3b , 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 1–7 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 or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, or morpholinyl,

 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, and

(vi) —OCF 3 ,

(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 fluoro,

(iii) —C 3-6 cycloalkyl,

(iv) benzyl, and

(v) phenyl,

(g) —NR 10 R 11 , wherein R 10 and R 11 are independently selected from:

(i) hydrogen,

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

(iii) —C 5-6 cycloalkyl,

(iv) benzyl,

(v) phenyl,

(vi) —COR 9 , and

(vii) —SO 2 R 12 ,

(h) —SO 2 R 12 , wherein R 12 is independently selected from:

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

(ii) —C 5-6 cycloalkyl,

(iii) benzyl, and

(iv) phenyl,

(i) —CONR 10a R 11a , wherein R 10a and R 11a are independently selected from:

(i) hydrogen,

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

(iii) —C 5-6 cycloalkyl,

(iv) benzyl,

(v) phenyl,

or where R 10a and R 11a may be joined together to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, 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) phenyl, and

(VI) 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 where the substituents are independently selected from:

(a) halo,

(b) hydroxy,

(c) —O—C 1-6 alkyl,

(d) trifluoromethyl,

(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,

(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, 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 is unsubstituted or substituted with 1–5 substituents where the substituents are 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, or morpholinyl, 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,

(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 , and

(18) —(CO)—(CO)OR 9 ;

or where R 3a and R 3b and the carbon atom(s) to which they are attached may be joined together to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, dihydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, dihydrothiopyranyl, tetrahydrothiopyranyl or piperazinyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:

(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1–3 substituents where the substituents are 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, or morpholinyl, 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, 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: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which is unsubstituted or substituted with 1–3 substituents where the substituents are 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;

A 1 and A 2 are 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 1–6 fluoro, and

(c) hydroxy,

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

R 4 is 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;

R 5a , R 5b and R 5c are 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 6 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

(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, or morpholinyl, which 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;

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

2. The compound of claim 1 of the formula:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

3. The compound of claim 1 of the formula:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

4. The compound of claim 1 of the formula:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

5. The compound of claim 1 of the formula:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

6. The compound of claim 1 of the formula:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

7. The compound of claim 1 , wherein B is selected from:

where B is unsubstituted or substituted with 1–5 substituents selected from R 1 , R 2 , R 3a and R 3b ,

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

8. The compound of claim 1 , wherein B is selected from benzimidazolyl, 2-oxobenzoxazolinyl, 2-oxobenzimidazolinyl, indolyl, 2-oxoindolinyl, 2-oxobenzothiazolinyl, 1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-one, naphtho[2,1-d][1,3]oxazolin-2(3H)-one and naphtho[1,2-d][1,3]oxazolin-2(1H)-one.

9. 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 where the substituents are independently selected from:

(a) fluoro,

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

(c) —CO 2 R 9 , wherein R 9 is independently selected from:

(i) hydrogen, and

(ii) —C 1-6 alkyl,

(d) —CONR 10a R 11a , wherein R 10a and R 11a are independently selected from:

(i) hydrogen, and

(ii) —C 1-6 alkyl,

or where R 10a and R 11a may be joined together 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, or tetrahydrothiopyranyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are 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:

(i) hydrogen,

(ii) —C 1-4 alkyl, and

(iii) —C 3-6 cycloalkyl,

(d) —(CO)R 9 ,

(e) —CONR 10a R 11a , wherein R 10a and R 11a are independently selected from:

(i) hydrogen, and

(ii) —C 1-6 alkyl,

or where R 10a and R 11a may be joined together to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl,

(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) —NH 2 ,

(7) —C 3-6 cycloalkyl,

(8) —(CO)—(CO)NR 10a R 11a , wherein R 10a and R 11a are independently selected from:

(a) hydrogen, and

(b) —C 1-6 alkyl, and

(9) —CN.

10. 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 where the substituents are independently selected from:

(a) fluoro,

(b) phenyl,

(c) —CO 2 R 9 , wherein R 9 is independently selected from:

(i) hydrogen, and

(ii) —C 1-4 alkyl,

(d) —CONR 10a R 11a , wherein R 10a and R 11a are independently selected from:

(i) hydrogen, and

(ii) —C 1-4 alkyl,

or where R 10a and R 11a may be joined together 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, tetrahydrofuryl, piperidinyl, or tetrahydrothienyl, which is unsubstituted or substituted with 1–5 substituents where the substituents are 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:

(i) hydrogen,

(ii) —C 1-4 alkyl, and

(iii) —C 3-6 cycloalkyl,

(d) —(CO)R 9 ,

(e) —CONR 10a R 11a , wherein R 10a and R 11a are independently selected from:

(i) hydrogen, and

(ii) —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) —NH 2 ,

(7) —C 3-6 cycloalkyl,

(8) —(CO)—(CO)NR 10a R 11a , wherein R 10a and R 11a are independently selected from:

(a) hydrogen, and

(b) —C 1-4 alkyl, and

(9) —CN.

11. 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, cyclohexenyl, cyclohexyl and pyrrolidinyl, which 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) halo, and

(ii) phenyl,

(b) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl and pyrazinyl,

(c) —CO 2 R 9 , wherein R 9 is selected from:

(i) hydrogen, and

(ii) —C 1-4 alkyl.

12. 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 piperidine ring, which is unsubstituted or substituted with 1–3 substituents where the substituents are independently selected from:

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

(i) fluoro, and

(ii) phenyl,

(b) —CO 2 —C 1-4 alkyl.

13. The compound of claim 1 , wherein R 4 is selected from: hydrogen and —C 1-6 alkyl, which is unsubstituted or substituted with fluoro.

14. The compound of claim 1 , wherein R 5a , R 5b and R 5c are independently selected from hydrogen, C 1-6 alkyl and halo.

15. The compound of claim 1 , wherein R 6 is selected from:

(1) hydrogen,

(2) —C 1-4 alkyl which is unsubstituted or substituted with 1–5 substituents where the substituents are independently selected from:

(a) halo,

(b) hydroxy,

(c) —C 3-6 cycloalkyl, and

(d) phenyl, and

(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, or pyrazinyl.

16. A compound selected from:

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

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

18. A method of treating migraine headaches or cluster headaches, said method comprising the administration, to a person in need of such treatment, of a therapeutically effective amount of the compound of claim 1 .