Monocyclic amide CGRP receptor antagonists
View Patent ↗Compounds of formula (I): wherein variables B, m, n, J, R 4 , E a , E b , E c , R e , R f , R PG and Y are as described herein, which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. 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:
B is a heterocycle selected from the group consisting of:
wherein B is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 3-6 cycloalkyl,
(d) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, oxazolyl, thiazolyl, indolyl, indazolyl, benzimidazolyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(iii) —OR a ,
(iv) —NR b R c ,
(v) —CN, and
(vi) oxo,
(e) —CO 2 R a ,
(f) —NR b R c ,
(g) —S(O) v R d ,
(h) —C(═O)NR b R c ,
(i) —CN,
(j) —CF 3 ,
(k) —OCO 2 R d ,
(l) —N(R b )CO 2 R a ,
(m) —N(R b )C(═O)R a ,
(n) —N(R b )C(═O)NR b R c ,
(O) —N(R b )SO 2 R d ,
(p) —OC(═O)NR b R c , and
(q) —C(═O)R a ,
(2) —C 3-8 cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —CN,
(d) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 halo, and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 halo,
(iii) —OR a , and
(iv) —CN,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, isoindolyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepanyl, 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 halo,
(b) halo,
(c) —OR a ,
(d) —CN,
(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) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 halo,
(iii) —OR a , and
(iv) —CN,
(g) —CO 2 R a ,
(h) —C(═O)R a ,
(i) —NR b R c ,
(j) —C(═O)NR b R c ,
(k) oxo,
(l) —S(O) v R d ,
(m) —OCO 2 R d ,
(n) —N(R b )CO 2 R a ,
(o) —N(R b )C(═O)R a ,
(p) —N(R b )C(═O)NR b R c ,
(q) —N(R b )SO 2 R d ,
(r) —OC(═O)NR b R c , and
(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 a ,
(10) —NR b R c ,
(11) —S(O) v R d ,
(12) —C(═O)NR b R c ,
(13) —OC(═O)R a ,
(14) —N(R b )C(═O)R a ,
(15) —N(R b )C(═O)OR a ,
(16) —OC(═O)NR b R c ,
(17) —N(R b )C(═O)NR b R c ,
(18) —C(═O)—C(═O)NR b R c ,
(19) —C(═O)—C(═O)OR a , and
(20) —SO 2 NR b R c ;
or B is a heterocycle selected from the group consisting of:
wherein B is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 3-6 cycloalkyl,
(d) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, oxazolyl, thiazolyl, indolyl, indazolyl, benzimidazolyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(iii) —OR a ,
(iv) —NR b R c ,
(v) —CN, and
(vi) oxo,
(e) —CO 2 R a ,
(f) —NR b R c ,
(g) —S(O) v R d ,
(h) —C(═O)NR b R c ,
(i) —CN,
(j) —CF 3 ,
(k) —OCO 2 R d ,
(l) —N(R b )CO 2 R a ,
(m) —N(R b )C(═O)R a ,
(n) —N(R b )C(═O)NR b R c ,
(o) —N(R b )SO 2 R d ,
(p) —OC(═O)NR b R c , and
(q) —C(═O)R a ,
(2) —C 3-8 cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —CN,
(d) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 halo, and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 halo,
(iii) —OR a , and
(iv) —CN,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, isoindolyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepanyl, 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 halo,
(b) halo,
(c) —OR a ,
(d) —CN,
(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) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 halo,
(iii) —OR a , and
(iv) —CN,
(g) —CO 2 R a ,
(h) —C(═O)R a ,
(i) —NR b R c ,
(j) —C(═O)NR b R c ,
(k) oxo
(l) —S(O) v R d ,
(m) —OCO 2 R d ,
(n) —N(R b )CO 2 R a ,
(o) —N(R b )C(═O)R a ,
(p) —N(R b )C(═O)NR b R c ,
(q) —N(R b )SO 2 R d ,
(r) —OC(═O)NR b R c , and
(4) halo,
(5) —O—C 1-6 alkyl which is unsubstituted or substituted with 1-5 halo,
(6) —CN,
(7) —CO 2 R a ,
(8) —NR b R c ,
(9) —S(O) v R d ,
(10) —C(═O)NR b R c ,
(11) —OC(═O)R a ,
(12) —N(R b )C(═O)R a ,
(13) —N(R b )C(═O)OR a ,
(14) —OC(═O)NR b R c ,
(15) —N(R b )C(═O)NR b R c ,
(16) —C(═O)—C(═O)NR b R c ,
(17) —C(═O)—C(═O)OR a , and
(18) —SO 2 NR b R c ;
R 4 is 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) —C 3-6 cycloalkyl,
(c) —CF 3 , and
(d) —O—R a ,
(3) —C 3-6 cycloalkyl,
(4) benzyl, and
(5) phenyl;
E a is selected from:
(1) —C(R 5a )═,
(2) —N═, and
(3) —(N + —O − )═;
E b is selected from:
(1) —C(R 5b )═,
(2) —N═, and
(3) —(N + —O − )═;
E c is selected from:
(1) —C(R 5c )═,
(2) —N═, and
(3) —(N + —O − )═;
R 5a , R 5 and R 5c are each independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(3) halo,
(4) —OR a , and
(5) —CN;
R PG is independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl which is unsubstituted or substituted with 1-5 halo,
(3) —CH 2 OR a ,
(4) —CH 2 —O—CH 2 CH 2 Si(CH 3 ) 3 ,
(5) —CH 2 OP(═O)(OR c ) 2 ,
(6) —(CH 2 ) k -phenyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —CN, and
(d) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo;
J is independently selected from:
(1) ═C(R 16a )—,
(2) —CR 17 R 18 —,
(3) —C(═O)—, and
(4) —N(R b )—;
Y is independently selected from:
(1) ═C(R 16b )—,
(2) —CR 17 R 18 —,
(3) —C(═O)—,
(4) ═N—, and
(5) —N(R 16b )—;
R 17 and R 18 are each independently selected from:
(1) hydrogen,
(2) halo,
(3) —OR a ,
(4) —C 1-6 alkyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —CN,
(d) phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) —OR a ,
(ii) halo,
(iii) —CN,
(iv) —C 1-6 alkyl which is unsubstituted or substituted with 1-6 halo,
(5) phenyl or heterocycle wherein heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —CN,
(c) —OR a ,
(d) nitro,
(e) —C 1-6 alkyl which is unsubstituted or substituted with 1-6 halo;
or R 17 and R 18 and the atom to which they are attached join to form a 4-, 5-, or 6-membered ring optionally containing a heteroatom selected from N, O, and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(d) phenyl;
R 16a and R 16b 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) —OR a ,
(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, isoxazolyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —OR a ,
(iii) —CN, and
(iv) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(3) phenyl or heterocycle, wherein heterocycle is selected from: imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrahydrofuryl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, thiazolyl, thienyl, triazolyl, isoxazolyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 3-6 cycloalkyl,
(d) —C 1-4 alkyl which is unsubstituted or substituted with 1-6 halo, and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iii) —OR a ,
(4) halo,
(5) —OR a ,
(6) —CN,
(7) —CO 2 R a ,
(8) —NR b R c , and
(9) —C(═O)NR b R c ;
or R 16a and R 16b and the atom(s) to which they are attached 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) —OR a ,
(iii) —C 3-6 cycloalkyl,
(iv) 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:
(I) —OR a ,
(II) halo,
(III) —CN, and
(IV) —C 1-6 alkyl which is unsubstituted or substituted with 1-6 halo,
(v) —CO 2 R a ,
(vi) —NR b R c ,
(vii) —S(O) v R d ,
(viii) —C(═O)NR b R c ,
(ix) —N(R b )CO 2 R a , and
(x) —N(R b )SO 2 R d ,
(b) phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —OR a ,
(iii) —CN, and
(iv) —C 1-6 alkyl which is unsubstituted or substituted with 1-6 halo,
(c) halo,
(d) —S(O) v R d ,
(e) —OR a ,
(f) —CN,
(g) —C(═O)R a ,
(h) —NR b R c ,
(i) —C(═O)NR b R c ,
(j) —CO 2 R a ,
(k) —(NR b )CO 2 R a ,
(l) —O—(C═O)—NR b R c ,
(m) —(NR b )—(C═O)—NR b R c ,
(n) oxido,
(o) oxo, and
(p) —(NR b )SO 2 R d ;
R a is 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) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(c) hydroxyl,
(d) —CN, and
(e) phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(iii) —CN,
(iv) nitro,
(v) hydroxyl, and
(vi) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(3) phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —CN,
(c) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(d) nitro,
(e) hydroxyl, and
(f) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(4) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo;
R b and R c are 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) —OR a ,
(c) —CN,
(d) —CO 2 R a ,
(e) phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —OR a ,
(iii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iv) nitro,
(3) phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(d) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(e) —CN, and
(f) —CO 2 R a ,
(4) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo; or R b and R c and the nitrogen to which they are attached join to form a 4-, 5-, or 6-membered ring optionally containing an additional heteroatom selected from N, O, and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) —OR a , and
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(d) phenyl;
R d is independently selected from:
(1) C 1-6 alkyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —CO 2 R a ,
(d) —CN, and
(e) phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —OR a ,
(iii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iv) nitro,
(2) phenyl or heterocycle, wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(d) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo
(e) —CN, and
(f) —CO 2 R a , and
(3) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo;
R e and R f are independently selected from:
(1) hydrogen,
(2) —C 1-4 alkyl, which is unsubstituted or substituted with 1-6 halo,
(3) phenyl, and
(4) benzyl;
or where R e and R f and the atom to which they are attached join to form a 3-, 4-, 5-, or 6-membered ring optionally containing a heteroatom selected from N, O, and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(d) phenyl;
m is 1, 2, or 3;
n is 1, 2, or 3;
v is 0, 1, or 2;
k is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is selected from the group (A) heterocyclic radicals.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein B is one of the following group (A) radicals:
wherein B is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 3-6 cycloalkyl,
(d) phenyl, which phenyl is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo, or
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo;
(2) —C 3-8 cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo, or
(b) —OR a ,
(3) phenyl or heterocycle, wherein the heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, isoindolyl, 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 halo,
(b) halo, or
(c) —OR a ,
(4) halo,
(5) oxo,
(6) hydroxy,
(7) —NR b R c ,
(8) —N(R b )C(═O)OR a .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is selected from the group (B) heterocyclic radicals.
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein B is one of the following group (B) radicals:
wherein B is unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 3-6 cycloalkyl,
(d) phenyl, which phenyl is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo, or
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo;
(2) —C 3-8 cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo, or
(b) —OR a ,
(3) phenyl or heterocycle, wherein the heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, isoindolyl, 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 halo,
(b) halo, or
(c) —OR a ,
(4) halo,
(5) —NR b R c ,
(6) —N(R b )C(═O)OR a .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E a , E b and E c are each independently selected from:
(1) —CH═, or
(2) —N═.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:
(1) hydrogen, or
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —C 3-6 cycloalkyl,
(c) —CF 3 , and
(d) —O—R a .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R PG is selected from:
(1) hydrogen, or
(2) —C 1-6 alkyl which is unsubstituted or substituted with 1-5 halo.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein J is selected from:
(1) ═C(R 16a )—,
(2) —CR 17 R 18 —, or
(3) —N(R b ).
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is selected from:
(1) ═C(R 16b )—,
(2) —CR 17 R 18 —, or
(3) —C(═O)—.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein J is ═C(R 16a )—, and Y is ═C(R 16b )—, and R 16a and R 16b and the atom(s) to which they are attached 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.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R e and R f are independently selected from:
(1) hydrogen,
(2) —C 1-4 alkyl, which is unsubstituted or substituted with 1-6 halo, or R e and R f and the atom to which they are attached join to form a 3-, 4-, 5-, or 6-membered ring optionally containing a heteroatom selected from N, O, and S, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, which ring is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(d) phenyl.
13. The compound of claim 1 of the formula (II):
wherein B, R 4 , E a , E b , E c , R e and R f are as claimed in claim 1 , or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
14. The compound of claim 1 of the formula (III):
wherein B, J, R 4 , E c , R e , R f , R PG and Y are as claimed in claim 1 , or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
15. The compound of claim 1 which is selected from the group consisting of
Benzyl (2-(3,5-difluorophenyl)-6-oxo-1-{2-oxo-2-[(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)amino]ethyl}-1,6-dihydropyrimidin-5-yl)carbamate;
2-[6-tert-Butyl-2-oxo-3-(1H-tetrazol-5-ylamino)pyrazin-1(2H)-yl]-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)butanamide;
2-[5-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxo-1,3-thiazepan-3-yl]-N-(3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl)acetamide;
2-[5-Chloro-3-(isopropylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl]-N-(2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl)acetamide; or
2-(5-Chloro-2-oxo-6-phenyl-3-pyrrolidin-1-ylpyrazin-1(2H)-yl)-N-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl)acetamide;
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
17. A method for treating headache, migraine or cluster headache in a mammalian patient in need thereof, which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.