Tricyclic anilide spirohydantion CGRP receptor antagonists
View Patent ↗The present invention is directed to compounds of Formula I: I (where A 1 , A 2 , B 1 , B 2 , B 3 , B 4 , D 1 , D 2 , T, U, V, W, X, Y, Z, R 4 , R 5a ?, R 5b , R 5c , R 6 , m and n are defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which the CGRP is involved, such as headache, migraine and cluster headache. 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 formula I:
wherein:
A 1 and A 2 are each independently selected from:
(1) a bond,
(2) —CR 13 R 14 —, wherein R 13 and R 14 are each independently selected from:
hydrogen, hydroxy, halo, and C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro,
where one of A 1 and A 2 is optionally absent;
B 1 and B 4 are each independently selected from: ═C—, —C(R 1 )—, and —N—;
B 2 and B 3 are each independently selected from: a bond, ═C(R 1 )—, —CR 1 R 2 —, —C(═O)—, —C(═S)—, ═N—, —N(R 1 )—, —O—, —S—, and —SO 2 —, where one of B 2 and B 3 is optionally absent;
D 1 and D 2 are each independently selected from: ═C(R 1 )—, —C R 1 R 2 —, —C(═O)—, —C(═S)—, ═N—, —N(R 1 )—, —O—, —S—, and —SO 2 —;
T, U and V are each independently selected from: ═C(R 1 )—, and ═N—, where at least one of T, U, and V is ═C(R 1 )—;
W, X, Y, and Z are each independently selected from: a bond, ═C(R 1 )—, —CR 1 R 2 —, —C(═O)—, —C(═S)—, ═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 heterocycle is selected from: azetidinyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azepinyl, 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 , wherein R 9 is independently selected from: hydrogen, —C 3-6 cycloalkyl, benzyl, phenyl, and —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro,
(g) —NR 10 R 11 , wherein R 10 and R 11 are each independently selected from: hydrogen, —C 5-6 cycloalkyl, benzyl, phenyl, —COR 9 , —SO 2 R 12 , and —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro,
(h) —SO 2 R 12 , wherein R 12 is independently selected from: —C 5-6 cycloalkyl, benzyl, phenyl, and —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro,
(i) —CONR 10a R 11a , wherein R 10a and R 11a are each independently selected from: hydrogen, —C 5-6 cycloalkyl, benzyl, phenyl, and —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro,
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,
(j) trifluoromethyl,
(k) —OCO 2 R 9 ,
(l) (NR 10a )CO 2 R 9 ,
(m)-0(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,
(e) phenyl which is unsubstituted or substituted with 1-5 substituents independently selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halo, hydroxy, and trifluoromethyl,
(4) 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 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 ,
(n) —SO 2 R 12 , and
(o) —CN,
(5) halo,
(6) oxo,
(7) hydroxy,
(8) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(9) —CN,
(10) —CO 2 R 9 ,
(11) —NR 10 R 11 ,
(12) —SO 2 R 12 ,
(13) —CONR 10a R 11a ,
(14) —OCO 2 R 9 ,
(15) (NR 10a )CO 2 R 9 ,
(16) —O(CO)NR 10a R 11a ,
(17) —(NR 9 )(CO)NR 10a R 11a ,
(18) —(CO)—(CO)NR 10a R 11a , and
(19) —(CO)—(CO)OR 9 ;
R 4 is selected from: hydrogen, C 5-6 cycloalkyl, benzyl, phenyl and C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro,
R 5a , R 5b and R 5c are each independently selected from: hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, —OCF 3 , trifluoromethyl, halo, hydroxy and —CN;
R 6 is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl or —C 3-6 cycloalkyl, unsubstituted or substituted with 1-7 substituents 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: —C 1-6 alkyl, —O—C 1-6 alkyl, halo, hydroxy, and 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 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;
m is 1 or 2;
n is 1 or 2;
or a pharmaceutically acceptable salt or enantiomer or diastereomer thereof.
2. The compound of claim 1 , having the formula Ia:
or a pharmaceutically acceptable salt or enantiomer or diastereomer thereof.
3. The compound of claim 1 , having the formula Ib:
or a pharmaceutically acceptable salt or enantiomer or diastereomer thereof.
4. The compound of claim 1 , having the formula Ic:
or a pharmaceutically acceptable salt or enantiomer or diastereomer thereof.
5. The compound of claim 1 , having the formula Id:
or a pharmaceutically acceptable salt or enantiomer or diastereomer thereof.
6. The compound of claim 1 , having the formula Ie:
or a pharmaceutically acceptable salt or enantiomer or diastereomer thereof.
7. The compound of claim 1 , wherein B 1 is selected from:
═C—, —C(R 1 )—, and —N—.
8. The compound of claim 1 , wherein B 4 is selected from:
═C—, —C(H)—, and —N—.
9. The compound of claim 1 , wherein B 2 is selected from:
═C(R 1 )—, —CR 1 R 2 —, and —C(═O)—, where R 1 and R 2 are defined herein.
10. The compound of claim 1 , wherein B 3 is a bond.
11. The compound of claim 1 , wherein D 1 is selected from:
—CR 1 R 2 —, and —N(R 1 )—.
12. The compound of claim 1 , wherein D 2 is selected from:
—CR 1 R 2 — and —N(R 1 )—.
13. 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)—.
14. 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)—.
15. The compound of claim 1 , wherein R 1 and R 2 are each 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,
(d) —C 3-6 cycloalkyl,
(e) phenyl or heterocycle, wherein heterocycle is selected from: azetidinyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, tetrazolyl, tetrahydrofuryl and morpholinyl,
which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: —C 1-4 alkyl, —O—C 1-4 -alkyl, halo, hydroxy, trifluoromethyl and —OCF 3 ,
(f) —CO 2 R 9 , wherein R 9 is selected from: hydrogen and —C 1-4 alkyl,
(g) —NR 10 R 11 , wherein R 10 and R 11 are each independently selected from: hydrogen, —COR 9 , —SO 2 R 12 and —C 1-4 alkyl which is unsubstituted or substituted with 1-3 fluoro,
(h) —CONR 10a R 11a , wherein R 10a and R 11a are each independently selected from: hydrogen, —C 5-6 cycloalkyl, and —C 1-4 alkyl which is unsubstituted or substituted with 1-3 fluoro,
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 1-3 substituents each independently selected from: —C 1-4 alkyl, —O—C 1-4 alkyl, halo and hydroxyl, and
(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: halo, hydroxy and —O—C 1-6 alkyl,
(4) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, 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: halo, hydroxy, —C 3-6 cycloalkyl, —CO 2 R 9 , —NR 10 R 11 , —CONR 10 R 11 , —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 fluoro, and —O—C 1-4 -alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(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 ,
or a pharmaceutically acceptable salt or enantiomer or diastereomer thereof.
16. The compound of claim 1 , wherein R 4 is selected from:
hydrogen and —C 1-6 alkyl, which is unsubstituted or substituted with fluoro, and R 5a , R 5b and R 5c are each independently selected from hydrogen, C 1-6 alkyl and halo.
17. The compound of claim 1 , wherein R 6 is selected from:
hydrogen, —C 1-4 alkyl which is unsubstituted or substituted with 1-5 substituents each independently selected from: halo, hydroxy, —C 3-6 cycloalkyl and phenyl, and phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl and pyrazinyl.
18. A compound selected from:
or a pharmaceutically acceptable salt and individual diastereomer thereof.
19. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .
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 .