Constrained spirocyclic compounds as CGRP receptor antagonists

1. A compound of the formula I:

wherein:

R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, C 1-6 (C 3-7 cycloalkyl)alkyl, C 1-6 haloalkyl, C 1-6 (C 1-6 alkoxy)alkyl, C 1-6 (Ar 1 )alkyl, C 1-6 (NR 7 R 8 )alkyl, N—(R 16 )-pyrrolidinyl and N—(R 16 )-piperidinyl;

R 2 and R 3 are on adjacent carbon atoms and together form —C(H)═N—N(R 9 )—, thereby forming a fused ring;

R 4 is hydrogen, halo, C 1-6 alkyl, or C 2-6 alkenyl;

R 7 is hydrogen or C 1-6 alkyl;

R 8 is hydrogen or C 1-6 alkyl;

or NR 7 R 8 join to form a ring selected from the group consisting of pyrrolidinyl, piperidinyl, N—(R 16 )-piperazinyl, morpholinyl, and thiomorpholinyl;

R 16 is hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, or C 1-6 alkoxycarbonyl;

Ar 1 is phenyl, naphthyl, pyridinyl, or imidazolyl, where Ari is substituted with 0-2 substituents selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl,

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

(1) a bond,

(2) —CR 13 R 14 —,

(3) —C(═O)—,

(4) —O—,

(5) —N(R 9 )—, or

(6) —C(═N—CN)—,

wherein one or two of A 1 , A 2 and A 3 are optionally absent;

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

(1) —C(R 5 )═,

(2) —N═, and

(3) —(N + —O − )═;

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 )—;

R 5 is independently selected from:

(1) hydrogen,

(2) C 1-— 6alkyl,

(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 3-6 alkyl,

(c) —C 3-6 cycloalkyl,

(d) phenyl or heterocycle, wherein said 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 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 ,

(3) phenyl or heterocycle, wherein said 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 where 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 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 said 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:

(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 said 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:

(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 OR 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 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;

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) —C 1-6 alkyl and —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) —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 OR 11 ,

(i) —SO 2 R 12 , and

(j) trifluoromethyl, and

(2) phenyl or heterocycle, wherein said 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 0 or 1;

n is 1 or 2;

p 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. A compound selected from:

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

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

10. A method for treating headache in a mammalian patient in need thereof, said method comprising the step of administering to said patient a therapeutically effective amount of the compound of claim 1 .

11. A method for treating migraine headache or cluster headache in a mammalian patient in need thereof, said method comprising the step of administering to said patient a therapeutically effective amount of the compound of claim 1 .

12. A method of treating migraine headaches or cluster headaches in a mammalian patient in need thereof, said method comprising the step of co-administration to said patient a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a second agent selected from serotonin agonists, analgesics, anti-inflamatory agents, anti-hypertensives and anticonvulsants.