Non-amidic linkers with branched termini as CGRP receptor antagonists
View Patent ↗The present invention is directed to novel non-amidic linkers with branched termini derivatives which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which 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 the formula I:
wherein:
E1 is CH,
E2 is CH,
E3 is ═N—,
Q 1 is selected from:
(1) —CR 1 R 2 —,
(2) —CR 1 R 2 CR 1 R 2 —, and
(3) a bond between W and the aryl ring;
Q 2 is selected from:
(1) —CR 1 R 2 —,
(2) —CR 1 R 2 CR 1 R 2 —, and
(3) a bond between W and Z;
Q 3 is selected from:
(1) —CR 1 R 2 —,
(2) —CR 1 R 2 CR 1 R 2 —, and
(3) a bond between Z and G 4 ;
Z is selected from:
(1) N, and
(2) C(R a );
W is selected from:
(1) —CR 1 R 2 —,
(2) —CR 1 R 2 CR 1 R 2 —,
(3) —(CR 1 )═(CR 2 )—,
(4) —C≡C—,
(5) —CR 1 R 2 —O—,
(6) —CR 1 R 2 —S(O) v —, and
(7) phenyl or heterocycle, wherein heterocycle is selected from: imidazolinyl, imidazolyl, indolinyl, indolyl, isoquinolinyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrazolyl, thiazolyl, thienyl, and triazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(c) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —C 3-6 cycloalkyl,
(e) oxo,
(f) —CN,
(g) hydroxyl, and
(h) phenyl;
Q 2 is independently selected from:
(1) —C(═O)R 29 ,
(2) —S(═O)R d ,
(3) —SO 2 R d ,
(4) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 substituents, substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —C 3-6 cycloalkyl,
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) —C 1-4 alkyl,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) trifluoromethyl, and
(v) —OCF 3 ,
(5) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 substituents, substituents each independently selected from:
(a) halo,
(b) hydroxyl,
(c) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo, and
(e) phenyl,
(6) phenyl or heterocycle, wherein heterocycle is selected from: benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isoindolinyl, isoquinolinyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(c) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —C 3-6 cycloalkyl,
(e) oxo,
(f) —CN,
(g) hydroxyl and
(h) phenyl;
R 29 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) —OR a ,
(c) —CN,
(d) —CO 2 R a ,
(e) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(f) —C(═O)NR b R c ,
(g) —S(O) v R d ,
(h) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(i) —NR b R c ,
(j) —O—CO 2 R d ,
(k) —C≡C—R a ,
(l) —N(R b )—CO 2 R d ,
(m) —N(R b )—SO 2 R d ,
(n) —C(═O)R a ,
(o) —O—C(═O)R a ,
(p) oxo,
(q) —N(R b )—C(═O)R a , and
(r) phenyl or heterocycle, wherein heterocycle is selected from: furanyl, isoxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, and thienyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —OR a ,
(iii) —CN,
(iv) —CO 2 R a ,
(v) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(vi) —C(═O)NR b R c ,
(vii) —S(O) v R d ,
(viii) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(ix) —NR b R c ,
(x) —O—CO 2 R d ,
(xi) —C≡C—R a ,
(xii) —N(R b )—CO 2 R d ,
(xiii) —N(R b )—SO 2 R d ,
(xiv) —C(═O)R a ,
(xv) —O—C(═O)R a ,
(xvi) oxo, and
(xvii) —N(R b )—C(═O)R a ,
(3) a group independently selected from: C 3-10 cycloalkyl, anthryl, azepanyl, azepinyl, azetidinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzofuryl, benzopyranyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzothiopyranyl, benzotriazolyl, benzoxazolyl, biphenyl, chromanyl, cinnolinyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydroindenyl, furanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indanyl, indenyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxadiazolyl, oxetanyl, 2-oxoazepinyl, 4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyridyl, 2-oxopyrrolidinyl, oxoquinolinyl, phenyl, phenanthryl, piperazinyl, piperidinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl, tetrahydronaphthyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydrothiapyranyl, tetrahydrothienyl, tetrazolyl, thiamorpholinyl, thiamorpholinyl sulfone, thiamorpholinyl sulfoxide, thiazolinyl, thiazolyl, thienofuryl, thienothienyl, thienyl, thietanyl, and triazolyl, which group is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —CN,
(d) —CO 2 R a ,
(e) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(f) —C(═O)NR b R c ,
(g) —S(O) v R d ,
(h) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(i) —NR b R c ,
(j) —O—CO 2 R d ,
(k) —C≡C—R a ,
(l) —N(R b )—CO 2 R d ,
(m) —N(R b )—SO 2 R d ,
(n) —C(═O)R a ,
(o) —O—C(═O)R a ,
(p) oxo,
(q) —N(R b )—C(═O)R a , and
(r) phenyl or heterocycle, wherein heterocycle is selected from; furanyl, isoxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, and thienyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —OR a ,
(iii) —CN,
(iv) —CO 2 R a ,
(v) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(vi) —C(═O)NR b R c ,
(vii) —S(O) v R d ,
(viii) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(ix) —NR b R c ,
(x) —O—CO 2 R d ,
(xi) —C≡C—R a ,
(xii) —N(R b )—CO 2 R d ,
(xiii) —N(R b )—SO 2 R d ,
(xiv) —C(═O)R a ,
(xv) —O—C(═O)R a ,
(xvi) oxo, and
(xvii) —N(R b )—C(═O)R a ,
(4) —CO 2 R a ,
(5) —NR b R c ,
(6) —OR d , and
(7) —C 5-11 bi- or tricycle, where one or two non-bridge head carbon(s) may be optionally replaced with oxygen(s), and one or two carbon(s) may be optionally replaced with nitrogen(s), which polycycles are 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) —C 1-6 alkyl, which is optionally substituted with 1-6 halo;
G 4 is selected from:
C 1-8 alkyl, C 3-10 cycloalkyl, anthryl, azepanyl, azepinyl, azetidinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzofuryl, benzopyranyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzothiopyranyl, benzotriazolyl, benzoxazolyl, biphenyl, chromanyl, cinnolinyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydroindenyl, furanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indanyl, indazolyl, indenyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxadiazolyl, oxatanyl, oxazolidinyl, oxazolinyl, oxazolyl, 2-oxoazepinyl, 4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyridyl, 2-oxopyrrolidinyl, 2-oxoquinolinyl, phenanthryl, phenyl, phthalazinyl, piperazinyl, piperidyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl, tetrahydronaphthyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydrothiapyranyl, tetrahydrothienyl, tetrazolyl, thiamorpholinyl, thiamorpholinyl sulfone, thiamorpholinyl sulfoxide, thiazolinyl, thiazolyl, thienofuryl, thienothienyl, thienyl, triazolinyl, and triazolyl, which is unsubstituted or substituted with 1-5 substituents independently selected from R 3 , R 4 , R 6 , R 7 and R 8 ;
each R 1 and R 2 are independently selected from:
(1) hydrogen,
(2) C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-5 halo,
(b) —OR a ,
(c) —CO 2 R a ,
(d) halo and,
(e) phenyl, which is unsubstituted or substituted with 1-5 halo,
(3) halo, and
(4) phenyl or pyridinyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —CN, and
(d) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo;
and R 1 and R 2 and the atom(s) to which they are attached may 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) —CO 2 R a ,
(d) oxo,
(e) —CN,
(f) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(g) phenyl;
R 3 , R 4 , R 6 , R 7 and R 8 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) —OR a ,
(c) —C 3-6 cycloalkyl,
(d) phenyl or heterocycle, wherein said heterocycle is selected from: benzodioxolyl, imidazolyl, indolyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, thiazolyl, and thienyl, and 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, and
(iii) —OR a ,
(e) —CO 2 R a ,
(f) —C(═O)NR b R c ,
(g) —S(O) v R d ,
(h) —CN,
(i) —NR b R c ,
(j) —N(R b )C(═O)R a ,
(k) —N(R b )SO 2 R d ,
(l) —CF 3 ,
(m) —O—CO 2 R d ,
(n) —O—(C═O)—NR b R c ,
(o) —NR b —(C═O)—NR b R c , and
(p) —C(═O)R a ,
(3) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(q) halo,
(r) —CN,
(s) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(t) —OR a , and
(u) phenyl, which 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 1-5 halo,
(4) phenyl or heterocycle, wherein said heterocycle is selected from: benzimidazolyl, benzoxazolyl, indanyl, indolyl, morpholinyl, oxadiazolyl, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrazolyl, thiazolyl, and thienyl, which phenyl or heterocycle 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 pyridyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(v) halo,
(vi) C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(vii) —OR a ,
(e) —CO 2 R a ,
(f) —C(═O)NR b R c ,
(g) —S(O) v R d ,
(h) —CN,
(i) —NR b R c ,
(j) —N(R b )C(═O)R a ,
(k) —N(R b )SO 2 R d ,
(l) —O—CO 2 R d ,
(m) —O—(C═O)—NR b R c ,
(n) —NR b —(C═O)—NR b R c ,
(o) —C(═O)R a , and
(p) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(5) halo,
(6) oxo,
(7) —OR a ,
(8) —CN,
(9) —CO 2 R a ,
(10) —C(═O)R a ,
(11) —NR b R c ,
(12) —S(O) v R d ,
(13) —C(═O)NR b R c ,
(14) —O—(C═O)R a ,
(15) —O—CO 2 R d ,
(16) —N(R b )CO 2 R d ,
(17) —O—(C═O)—NR b R c ,
(18) —NR b —(C═O)—NR b R c ,
(19) —SO 2 NR b R c , and
(20) —N(R b )SO 2 R d ;
and R 7 and R 8 and the atom(s) to which they are attached may join to form a ring selected from azetidinyl, aziridinyl, cyclobutyl, cycloheptyl, cyclohexyl, cyclooctyl, cyclopentyl, cyclopropyl, dihydrobenzofuranyl, dihydrobenzopyranyl, dioxanyl, dioxoalanyl, indanyl, indenyl, indolinyl, isoindolinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrahydrothiapyranyl, tetrahydrothienyl, thiamorpholinyl, and thietanyl, wherein the sulfur is optionally oxidized to the sulfone or sulfoxide, 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) —CO 2 R a ,
(v) —NR b R c ,
(vi) —S(O) v R d ,
(vii) —C(═O)NR b R c , and
(viii) phenyl, which is unsubstituted or substituted with 1-5 halo,
(b) phenyl or heterocycle, wherein heterocycle is selected from: morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, thiazolyl, and thienyl, wherein the phenyl or heterocycle is optionally fused to the ring, and 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, and
(iii) —OR a ,
(c) —OR a ,
(d) halo,
(e) —CO 2 R a ,
(f) —C(═O)NR b R c ,
(g) —S(O) v R d ,
(h) —CN,
(i) —NR b R c ,
(j) —N(R b )C(═O)R a ,
(k) —N(R b )SO 2 R d ,
(l) —O—(C═O)R a ,
(m) —O—CO 2 R d ,
(n) —O—(C═O)—NR b R c ,
(o) —NR b —(C═O)—NR b R c ,
(p) —C(═O)R a , and
(q) oxo;
R PG is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl which is unsubstituted or substituted with 1-5 halo,
(3) —CH 2 OR a ,
(4) —C(═O)OR a ,
(5) —CH 2 OP(═O)(OR c ) 2 ,
(6) —CH 2 —O—CH 2 CH 2 Si(CH 3 ) 3 , and
(7) —(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 selected from:
(1) ═C(R 16a )—,
(2) —CR 17 R 18 —,
(3) —C(═O)—, and
(4) —N(R b )—;
Y is selected from:
(1) ═C(R 16b )—,
(2) —CR 17 R 18 —,
(3) —C(═O)—,
(4) ═N—, and
(5) —N(R b )—;
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: azetidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thienyl, 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: azetidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thienyl, 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;
and R 17 and R 18 and the atom to which they are attached may 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, which is unsubstituted or substituted with 1-6 halo;
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, isoxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, thiazolyl, thienyl, and triazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(i) —OR a ,
(ii) —CN, and
(iii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(3) phenyl or heterocycle, wherein heterocycle is selected from: azetidinyl, imidazolyl, isoxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydropyranyl, thiazolyl, thienyl and triazolyl, 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: cyclohexenyl, cyclopentenyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dihydrothiopyranyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, phenyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, and triazolyl, 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: morpholinyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, and thienyl, 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 heterocycle is selected from: azetidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, and thienyl, 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) oxo, and
(o) —(NR b )SO 2 R d ;
each 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) —C(═O)—O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(e) —CN, and
(f) phenyl or heterocycle wherein heterocycle is selected from: azetidinyl, furanyl, morpholinyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thienyl, 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 heterocycle is selected from: azetidinyl, furanyl, indolyl, morpholinyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thienyl, 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) —C(═O)—O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(f) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(g) hydroxyl, and
(h) —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;
each 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 heterocycle is selected from: azetidinyl, furanyl, morpholinyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thienyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —OR a ,
(iii) —CN,
(iv) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(v) nitro,
(3) phenyl or heterocycle, wherein heterocycle is selected from: azetidinyl, furanyl, morpholinyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thienyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —OR a ,
(c) nitro,
(d) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(e) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(f) —CN, and
(g) —CO 2 R a ,
(4) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo; and R b and R c and the nitrogen to which they are attached may 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 ,
(c) —CO 2 R a ,
(d) —CN,
(e) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(f) phenyl;
each R d is 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) —CO 2 R a
(d) —CN, and
(e) phenyl or heterocycle wherein heterocycle is selected from: azetidinyl, furanyl, morpholinyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thienyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —OR a ,
(iii) —CN,
(iv) nitro, and
(v) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(2) phenyl or heterocycle wherein heterocycle is selected from: azetidinyl, furanyl, morpholinyl, piperazinyl, piperidinyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and thienyl, 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) nitro,
(f) —CN, and
(g) —CO 2 R a ,
(3) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halo;
m is 1,
n is 1,
v is 0, 1, or 2;
k is 0, 1, or 2;
and pharmaceutically acceptable salts thereof.
2. The compound according to claim 1 wherein G 2 is —C(═O)R 29 and pharmaceutically acceptable salts thereof.
3. The compound according to claim 1 wherein:
Q 1 is a bond between W and the aryl ring;
Q 2 is —CR 1 R 2 —;
W is selected from:
(1) —CR 1 R 2 —,
(2) —(CR 1 )═(CR 2 )— and
(3) —C≡C—;
and pharmaceutically acceptable salts thereof.
4. The compound according to claim 1 of formula Ia
and pharmaceutically acceptable salts thereof.
5. The compound according to claim 1 of formula Ib
and pharmaceutically acceptable salts thereof.
6. The compound according to claim 1 of formula Ic
and pharmaceutically acceptable salts thereof.
7. The compound according to claim 6 of formula Id
wherein is a single, double or triple bond;
and pharmaceutically acceptable salts thereof.
8. The compound according to claim 7 wherein:
Q 3 is —CR 1 R 2 —; and
G 4 is phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from R 3 , R 4 , R 6 , R 7 and R 8 ;
and pharmaceutically acceptable salts thereof.
9. The compound according to claim 7 wherein:
Q 3 is a bond between Z and G 4 ; and
G 4 is dihydroindenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from R 3 , R 4 , R 6 , R 7 and R 8 ;
and pharmaceutically acceptable salts thereof.
10. The compound according to claim 1 selected from the following:
or a pharmaceutically acceptable salt of any of the foregoing compounds;
or a stereoisomer of any of the foregoing compounds;
or a pharmaceutically acceptable salt of the stereoisomer thereof.
11. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .