IP Library › Granted Patent US 7,696,192

Granted Patent B2

US 7,696,192 · App. 11/662,246 · Granted Apr 13, 2010

Tricyclic anilide spirolactam CGRP receptor antagonists

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Quick Facts

Patent No.: US 7,696,192
App. No.: 11/662,246
Granted: Apr 13, 2010
Kind: B2

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Abstract

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 , J, K, T, U, V, W, X, Y, Z, R 4 , R 5a , R 5b , R 5c , 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.

Claims (194)

1. A compound of formula I:

wherein:

one of A 1 and A 2 is —C(R 13 R 14 )— and the other is a bond;

B 1 and B 4 are each independently selected from: ═C 1 —, —C 1 (R 1 )—, —N 1 —;

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

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

J is selected from: ═C(R 6a )—, —C(R 13 R 14 )— and —C(═O)—;

K is selected from: ═C(R 6b )—, —C(R 13 R 14 )—, —C(═O)—;

T, U and V are each ═C(R 1 )—;

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

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,

(d) —C 3-6 cycloalkyl,

(e) phenyl or heterocycle, wherein 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 , 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, beuzyl, 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 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, phenyl,

or R 10a and R 1la 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) —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,

(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,

(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,

(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

(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 l0 )(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 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 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,

(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 substituents 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:

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

(b) halo,

(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 R 6a and R 6b and the atom(s) to which they are attached are joined 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: halo, hydroxy, —C 3-6 cycloalkyl, —C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, and —O—C 1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro,

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

m is 1;

n is 1;