US 8,133,891 B2 · Tricyclic anilide spirolactam CGRP receptor antagonists

Abstract

The present invention is directed to compounds of Formula I: I (where A1, A2, B1, B2, B3, B4, D1, D2, J, K, T, U, V, W, X, Y, Z, R4, R5a, R5b, R5c, 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.

A compound of formula I:

wherein:
one of A1 and A2 is —CR13R14— and the other is a bond;
B1 and B4 are each independently selected from:
B2 and B3 are each independently selected from:
a bond, ═C(R1)—, —C(R1R2)—, —C(═O)—, —C(═S)— and —C(═NR1)—;
D1 and D2 are each independently selected from:
═C(R1)—, —C(R1R2)—, —C(═O)—, —C(═S)—, —C(═NR1)—, ═N— and —N(R1)—;
J is selected from:
═C(R6a)—, —C(R13R14)— and —C(═O)—;
K is selected from:
═C(R6b)—, —C(R13R14)— and —C(═O)—;
T, U and V are each independently selected from:
═C(R1)— and ═N—, wherein at least one but no more than two of T, U, and V is ═N—;
W, X, Y, and Z are each independently selected from:
a bond, ═C(R1)—, —C(R1R2)—, —C(═O)—, —C(═S)— and —C(═NR1)—;
R1 and R2 are each independently selected from:
(1) hydrogen;
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) —C3-6cycloalkyl,
(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:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxy, trifluoromethyl, —OCF3 and oxo,
(f) —CO2R9, wherein R9 is independently selected from:
hydrogen, —C3-6cycloalkyl, benzyl, phenyl and —C1-6alkyl which is unsubstituted or substituted with 1-6 fluoro,
(g) —NR10R11 wherein R10 and R11 are each independently selected from:
hydrogen, —C5-6 cycloalkyl, benzyl, phenyl, —COR9, —SO2R12, and —C1-6alkyl which is unsubstituted or substituted with 1-6 fluoro,
(h) —SO2R12 wherein R12 is selected from:
—C1-6alkyl which is unsubstituted or substituted with 1-6 fluoro, —C5-6cycloalkyl, benzyl and phenyl,
(i) —CONR10aR11a, wherein R10a and R11a are each independently selected from:
hydrogen, —C1-6alkyl which is unsubstituted or substituted with 1-6 fluoro, —C5-6cycloalkyl, benzyl and phenyl,
or R10a and R11a 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:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxyl, phenyl and benzyl,
(j) trifluoromethyl,
(k) —OCO2R9,
(l) —(NR10a)CO2R9,
(m) —O(CO)NR10aR11a,
(n) —(NR9)(CO)NR10aR11a, and
(o) —O—C3-6cycloalkyl,
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6 alkyl,
(d) trifluoromethyl, and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxy and trifluoromethyl,
(4) —C2-6alkynyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6 alkyl,
(d) —C3-6cycloalkyl,
(d) trifluoromethyl, and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
—C1-6alkyl, —O—C1-6alkyl, 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) —C1-6alkyl which is unsubstituted or substituted with 1-6 fluoro,
(b) halo,
(c) hydroxy,
(d) —O—C1-6alkyl which is unsubstituted or substituted with 1-6 fluoro,
(e) —C3-6cycloalkyl,
(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:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxy and trifluoromethyl,
(g) —CO2R9,
(h) —(CO)R9,
(i) —NR10R11,
(j) —CONR10R11,
(k) oxo
(l) —SR12,
(m) —S(O)R12,
(n) —SO2R12, and
(o)—CN
(6) halo,
(7) oxo,
(8) hydroxy,
(9) —O—C1-6alkyl which is unsubstituted or substituted with 1-5 halo,
(10) —CN,
(11) —CO2R9,
(12) —NR10R11,
(13) —SO2R12,
(14) —CONR10aR11a,
(15) —OCO2R9,
(16) —(NR10a)CO2R9,
(17) —O(CO)NR10aR11a,
(18) —(NR9)(CO)NR10aR11a,
(19) —(CO)—(CO)NR10aR11a,
(20) —(CO)—(CO)OR9, and
(21) —(NR10)(CO)R9;
R4 is selected from:
hydrogen, C1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, C5-6 cycloalkyl, benzyl and phenyl;
R5a, R5b and R5c are each independently selected from:
hydrogen, C1-6 alkyl, —O—C1-6alkyl, —OCF3, trifluoromethyl, halo, hydroxy and —CN;
R6a and R6b are each independently selected from:
(1) hydrogen;
(2) —C1-4alkyl which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —O—C1-6alkyl,
(c) —C3-6cycloalkyl,
(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:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxy, trifluoromethyl and —OCF3,
(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) —C1-44alkyl which is unsubstituted or substituted with 1-5 fluoro,
(b) halo,
(c) hydroxy,
(d) —O—C1-4alkyl which is unsubstituted or substituted with 1-5 fluoro,
(e) —C3-6cycloalkyl, and
(f) phenyl,
(4) halo,
(5) hydroxy,
(6) —O—C1-6alkyl which is unsubstituted or substituted with 1-5 halo,
(7) —CN,
(8) —CO2R9,
(9) —NR10R11, and
(10) —CONR10aR11a;
or R6a and R6b 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) —C1-6alkyl which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) hydroxy,
(iii) —O—C1-6alkyl,
(iv) —C3-6cycloalkyl,
(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:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxy, trifluoromethyl and —OCF3,
(vi) —CO2R9,
(vii) —NR10R11,
(viii) —SO2R12,
(ix) —CONR10aR11a, and
(x) —(NR10a)CO2R9,
(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, —C3-6cycloalkyl, —C1-6alkyl which is unsubstituted or substituted with 1-6 fluoro, and —O—C1-6alkyl which is unsubstituted or substituted with 1-6 fluoro,
(c) halo,
(d) —SO2R12,
(e) hydroxy,
(f) —O—C1-6alkyl which is unsubstituted or substituted with 1-5 halo,
(g) —CN,
(h) —COR12,
(i) —NR10R11,
(j) —CONR10aR11a,
(k) —CO2R9,
(l) —(NR10a)CO2R9,
(m) —O(CO)NR10aR11a,
(n) —(NR9)(CO)NR10aR11a, and
(o) oxo;
R13 and R14 are each independently selected from:
hydrogen, hydroxyl, halo and C1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro;
m is 1;
n is 1;
or a pharmaceutically acceptable salt, individual enantiomer or individual diastereomer thereof.

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Tricyclic anilide spirolactam CGRP receptor antagonists

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Tricyclic anilide spirolactam CGRP receptor antagonists

Life of this patent

Abstract

Claims19