Bicyclic spirohydantoin CGRP receptor antagonists
View Patent ↗Compounds of formula I: (wherein variables A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , B, E 1 , E 2 , E 3 , E 4 , E 5 , G 1 , G 2 and R 6 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 the formula I:
wherein:
B is a bicycloheterocycle selected from the group consisting of:
where T, U, V, W, X and Y are each independently a carbon atom or a nitrogen atom, wherein no more than two of T, U, V and W, or no more than three of T, U, V, W, X and Y, are a nitrogen atom,
where B is unsubstituted or substituted with 1-5 substituents independently selected from R 1 , R 2 , R 3a and R 3b , where R 1 , R 2 , R 3a and R 3b 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) 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, azepanyl, 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:
(i) —C 1-6 alkyl,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) hydroxy,
(v) trifluoromethyl,
(vi) —OCF 3 ,
(vii) oxo,
(viii) amino,
(ix) phenyl, and
(x) benzyl,
(f) —CO 2 R 9 , wherein R 9 is independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 substituents, substituents each independently selected from:
(I) halo,
(II) hydroxy,
(III) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(IV) —C 3-6 cycloalkyl,
(V) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(1) —C 1-4 alkyl,
(2) —O—C 1-6 alkyl,
(3) halo,
(4) trifluoromethyl, and
(5) —OCF 3 ,
(iii) —C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-5 halo, and
(iv) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, imidazolinyl, indolinyl, indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydrofuryl, quinoxalinyl, piperidinyl, piperazinyl, 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) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo
(IV) —C 3-6 cycloalkyl,
(V) oxo,
(VI) —CN,
(VII) hydroxy, and
(VIII) phenyl,
(g) —NR 10 R 11 , wherein R 10 and R 11 are each independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 substituents each independently selected from:
(I) —O—C 1-6 alkyl,
(II) halo,
(III) hydroxy,
(IV) —OCF 3 ,
(V) —C 3-6 cycloalkyl, and
(VI) phenyl,
(iii) —C 4-6 cycloalkyl,
(iv) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(I) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(III) halo,
(IV) hydroxy,
(V) trifluoromethyl,
(VI) —OCF 3 , and
(VII) CN, and
(v) benzyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(I) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(III) halo, and
(IV) trifluoromethyl,
(vi) —COR 9 , and
(vii) —SO 2 R 12 ,
(h) —SO 2 R 12 , wherein R 12 is selected from:
(i) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(ii) —C 3-6 cycloalkyl,
(iii) 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) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(III) halo,
(IV) hydroxy,
(V) trifluoromethyl,
(VI) —OCF 3 , and
(VII) CN, and
(iv) benzyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(I) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(III) halo, and
(IV) trifluoromethyl,
(i) —CONR 10a R 11a , wherein R 10a and R 11a are each independently selected from:
(i) hydrogen,
(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 substituents each independently selected from:
(I) —O—C 1-6 alkyl,
(II) halo,
(III) hydroxy,
(IV) —OCF 3 ,
(V) —C 3-6 cycloalkyl, and
(VI) phenyl,
(iii) —C 5-6 cycloalkyl,
(iv) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(I) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(III) halo,
(IV) hydroxy,
(V) trifluoromethyl,
(VI) —OCF 3 , and
(VII) CN, and
(v) benzyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(I) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(III) halo, and
(IV) trifluoromethyl,
or where R 10a and R 11a join to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, and morpholinyl, which ring is unsubstituted or substituted with 1-5 substituents each independently selected from:
(I) —C 1-6 alkyl
(II) —O—C 1-6 alkyl
(III) halo
(IV) hydroxy
(V) phenyl,
(VI) benzyl,
(VII) —COR 9 , and
(VIII) —SO 2 R 12 ,
(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 ,
(o)—SO 2 NR 10a R 11a , and
(p) —O—C 3-6 cycloalkyl,
(2) —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 each independently selected from:
(i) —C 1-6 alkyl,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(3) 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 1-5 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl,
(e) phenyl,
(f) —CO 2 R 9 , and
(g) —NR 10 R 11 ,
(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: pyrrolidinyl, piperidinyl, piperazinyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) —C 1-6 alkyl,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(g) —CO 2 R 9 ,
(h) —(CO)R 9 ,
(i) —NR 10 R 11 ,
(i) —CONR 10a R 11a ,
(k) oxo
(l) —SR 12 ,
(m) —S(O)R 12 ,
(n) —SO 2 R 12 ,
(o) —SO 2 NR 10a R 11a , and
(p) —CN,
(4) halo,
(5) oxo,
(6) hydroxy,
(7) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are each independently selected from:
(a) halo,
(b) hydroxy,
(c) —C 3-6 cycloalkyl,
(d) phenyl,
(e) —CO 2 R 9 , and
(f) —NR 10 R 11 ,
(8) —CN,
(9) —CO 2 R 9 ,
(10) —NR 10 R 11 ,
(11) —SR 12 ,
(12) —S(O)R 12 ,
(13) —SO 2 R 12 ,
(14) —SO 2 NR 10a R 11a ,
(15) —CONR 10a R 11a ,
(16) —OCO 2 R 9 ,
(17) —(NR 10a )CO 2 R 9 ,
(18) —O(CO)NR 10a R 11a ,
(19) —(NR 9 )(CO)NR 10a R 11a ,
(20) —(CO)—(CO)NR 10a R 11a , and
(21) —(CO)—(CO)OR 9 ;
or where R 3a and R 3b and the carbon atom(s) to which they are attached join to form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, dihydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, dihydrothiopyranyl, tetrahydrothiopyranyl, imidazolyl, imidazolinyl, and piperazinyl, which ring is unsubstituted or substituted with 1-5 substituents independently selected from:
(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 substituents 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:
(I) —C 1-6 alkyl,
(II) —O—C 1-6 alkyl,
(III) halo,
(IV) hydroxy,
(V) trifluoromethyl, and
(VI) —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:
(i) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(ii) halo,
(iii) hydroxy,
(iv) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro, and
(v) —C 3-6 cycloalkyl,
(c) halo,
(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;
A 1 , A 2 and A 3 are each independently selected from:
(1) a bond,
(2) —CR 13 R 14 —, wherein R 13 and R 14 are each independently selected from:
(a) hydrogen,
(b) C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) —C 3-6 cycloalkyl,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) phenyl,
(c) hydroxy, and
(d) halo,
(3) —NR 10 —,
(4) —CR 13 R 14 —NR 10 —,
(5) —CR 13 R 14 —CH 2 —,
(6) —CH 2 —CR 13 R 14 —,
(7) —O—CR 13 R 14 —,
(8) —CR 13 R 14 —O—,
(9) —C≡C—,
(10) —C(R 13 )═C(R 14 )—, and
(11) —C(═O)—,
or where one or two of A 1 , A 2 and A 3 are optionally absent;
0-1 of A 4 , A 5 , A 6 and A 7 is selected from:
(1) —O—,
(2) —C(═O)—
(3) —N(R 15 )—, wherein R 15 is selected from:
(i) hydrogen,
(ii) C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are each independently selected from:
(a) hydroxy,
(b) —O—C 1-6 alkyl,
(c) halo,
(d) —C 3-6 cycloalkyl,
(e) trifluoromethyl, and
(f) phenyl,
where the remainder of A 4 , A 5 , A 6 and A 7 are each independently selected from:
(1) a bond, and
(2) —CR 13 R 14 —,
where one or both of A 4 and A 7 are optionally absent;
E 1 and E 5 are each independently selected from:
(1) ═C(R 4 )—,
(2) —CR 4 R 5 —,
(3) —C(═O)—,
(4) —C(═S)—,
(5) ═N—,
(6) ═N + (O − )—,
(7) —N(R 4 )—,
(8) —O—,
(9) —S—, and
(10) —SO 2 —;
E 3 and E 4 are each independently selected from:
(1) a bond,
(2) ═C(R 4 )—,
(3) —CR 4 R 5 —,
(4) —C(═O)—,
(5) ═N—,
(6) ═N + (O − )—,
(7) —N(R 4 )—, and
(8) —O—,
where one or both of E 3 and E 4 are optionally absent;
E 2 is selected from:
G 1 and G 2 are each independently selected from:
(1) ═C(R 4 )—,
(2) ═N—, and
(3)=N + (O − )—;
R 4 and R 5 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) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl,
(e) phenyl,
(f) —CONR 10a R 11a ,
(g) —CO 2 R 9 , and
(h) —NR 10 R 11 ,
(3) —C 3-6 cycloalkyl,
(4) phenyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(b) halo,
(c) hydroxy, and
(d) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(5) halo,
(6) hydroxy,
(7) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(8) —CN,
(9) —CO 2 R 9 ,
(10) —NR 10 R 11 ,
(11) —SO 2 R 12 ,
(12) —CONR 10a R 11a ,
(13) —OCO 2 R 9 , and
(14) —(NR 10a )CO 2 R 9 ;
R 6 is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl or —C 3-6 cycloalkyl which are 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, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) —C 1-6 alkyl,
(ii) —O—C 1-6 alkyl,
(iii) halo,
(iv) hydroxy, and
(v) 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 is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-6 alkyl,
(b) —O—C 1-6 alkyl,
(c) halo,
(d) hydroxy, and
(e) trifluoromethyl;
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
2. The compound of claim 1 having the formula Ia:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
3. The compound of claim 1 having the formula Ib:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
4. The compound of claim 1 having formula Ic:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
5. The compound of claim 1 having the formula Id:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
6. The compound of claim 1 wherein B is selected from
where B is unsubstituted or substituted with 1-5 substituents each independently selected from R 1 , R 2 , R 3a and R 3b .
7. The compound of claim 1 , wherein B is selected from 2-oxobenzimidazolinyl, indolyl, indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 2-oxoindolinyl, 2-oxobenzoxazolinyl, azaindolinyl, 2-oxoazabenzimidazolinyl, phthalimidyl, 2-oxotetrahydroquinolinyl, benzimidazolyl.
8. The compound of claim 1 , wherein R 1 , R 2 , R 3a and R 3b are each independently selected from:
(1) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) fluoro,
(b) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl,
(c) —CO 2 R 9 ,
(d) —CONR 10a R 11a ,
(e) —O—C 1-6 alkyl,
(f) —O—C 3-6 cycloalkyl, and
(g) hydroxy,
(2) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, thiazolyl, isothiazolyl, 2-oxopyrrolidinyl, tetrahydrofuryl, piperidinyl, tetrahydrothienyl, and tetrahydrothiopyranyl, 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 1-3 fluoro
(b) halo,
(c) —CO 2 R 9 ,
(d) —(CO)R 9 ,
(e) —CONR 10a R 11a ,
(f) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(g) hydroxy,
(h) oxo,
(i) —S—C 1-4 alkyl,
(j) —S(O)—C 1-4 alkyl, and
(k) —SO 2 —C 1-4 alkyl,
(3) halo,
(4) hydroxy,
(5) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(6) —NH 2 ,
(7) —C 3-6 cycloalkyl,
(8) —(CO)—(CO)NR 10a R 11a ,
(9) —CN, and
(10) —SO 2 NR 10a R 11a .
9. The compound of claim 1 , wherein R 1 and R 2 are each independently selected from:
(1) —C 1-4 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) fluoro,
(b) phenyl,
(c) —CO 2 R 9 ,
(d) —CONR 10a R 11a ,
(e) —O—C 3-6 cycloalkyl,
(2) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, thiazolyl, tetrahydrofuryl, piperidinyl, and tetrahydrothiopyranyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 fluoro
(b) halo,
(c) —CO 2 R 9 ,
(d) —(CO)R 9 ,
(e) —CONR 10a R 11a ,
(f) —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(g) hydroxy,
(h) oxo
(i) —S—C 1-4 alkyl,
(j) —S(O)—C 1-4 alkyl, and
(k) —SO 2 —C 1-4 alkyl,
(3) halo,
(4) hydroxy,
(5) —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(6) —CN,
(7) —C 3-6 cycloalkyl,
(8) —(CO)—(CO)NR 10a R 11a , and
(9) —SO 2 NR 10a R 11a .
10. The compound of claim 1 , wherein R 3a and R 3b and the carbon atom(s) to which they are attached join to form a ring selected from piperidinyl, cyclohexyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, and tetrahydrothiopyranyl, which ring is unsubstituted or substituted with 1-3 substituents independently selected from:
(a) —C 1-6 alkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo, and
(ii) phenyl,
(b) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl and pyrazinyl,
(c) —CO 2 R 9 , hydroxy, and
(d) oxo.
11. The compound of claim 1 , wherein A 1 is CH 2 , a bond or —C(═O)—; A 2 is CH 2 or a bond; A 3 is a bond; A 4 is CH 2 or a bond; A 5 is CH 2 ; A 6 is CH 2 ; and A 7 is CH 2 or a bond.
12. The compound of claim 1 , wherein G 1 is ═C(R 4 )— and G 2 is ═C(R 4 )—.
13. The compound of claim 1 , wherein R 4 and R 5 are independently selected from:
(1) hydrogen;
(2) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 3-6 cycloalkyl, and
(e) phenyl,
(3) —C 3-6 cycloalkyl,
(4) phenyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 fluoro, and
(b) halo,
(5) halo,
(6) hydroxy,
(7) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(8) —CN, and
(9) —NR 10 R 11 .
14. The compound of claim 1 , wherein R 6 is 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) hydroxy,
(c) —C 3-6 cycloalkyl, and
(d) phenyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, and pyrazinyl.
15. The compound of claim 1 , wherein R 9 is independently selected from:
(i) hydrogen,
(ii) —C 1-5 alkyl, which is unsubstituted or substituted with 1-5 substituents, substituents each independently selected from:
(I) halo,
(II) hydroxy,
(III) —O—C 1-6 alkyl,
(IV) —C 3-6 cycloalkyl,
(V) phenyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(1) —C 1-4 alkyl,
(2) —O—C 1-4 alkyl, and
(3) halo,
(iii) —C 3-6 cycloalkyl, and
(iv) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, indolinyl, indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydrofuryl, piperidinyl, piperazinyl, and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
(I) halo,
(II) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo,
(III) —O—C 1-4 alkyl, which is unsubstituted or substituted with 1-3 halo,
(IV) —C 3-6 cycloalkyl,
(V) oxo,
(VI) —CN, and
(VII) hydroxy.
16. The compound of claim 1 , wherein R 10 and R 11 are each independently selected from:
(i) hydrogen,
(ii) —C 1-5 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(I) —O—C 1-4 alkyl,
(II) halo,
(III) hydroxy, and
(IV) —OCF 3 ,
(iii) —C 4-6 cycloalkyl,
(iv) phenyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(I) —C 1-4 alkyl,
(II) —O—C 1-4 alkyl,
(III) halo,
(IV) trifluoromethyl, and
(V) —OCF 3 , and
(v) benzyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(I) —C 1-4 alkyl,
(II) —O—C 1-4 alkyl,
(III) halo, and
(IV) trifluoromethyl,
(vi) —COR 9 , and
(vii) —SO 2 R 12 .
17. The compound of claim 1 , wherein R 10a and R 11a are each independently selected from:
(i) hydrogen,
(ii) —C 1-4 alkyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(I) halo, and
(II) hydroxy,
(iii) —C 5-6 cycloalkyl,
(iv) phenyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(I) —C 1-4 alkyl,
(II) —O—C 1-4 alkyl,
(III) halo, and
(V) trifluoromethyl,
(v) benzyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(I) —C 1-4 alkyl,
(II) —O—C 1-4 alkyl,
(III) halo, and
(IV) trifluoromethyl,
or where R 10a and R 11a join 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:
(I) —C 1-4 alkyl
(II) —O—C 1-4 alkyl
(III) halo
(IV) hydroxy,
(V) phenyl,
(VI) benzyl, and
(VII) —COR 9 .
18. The compound of claim 1 , wherein R 12 is selected from:
(i) —C 1-4 alkyl, which is unsubstituted or substituted with 1-3 fluoro,
(ii) —C 3-6 cycloalkyl,
(iii) phenyl which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(I) —C 1-4 alkyl,
(II) —O—C 1-4 alkyl,
(III) halo, and
(IV) trifluoromethyl,
(iv) benzyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(I) —C 1-4 alkyl,
(II) —O—C 1-4 alkyl,
(III) halo, and
(IV) trifluoromethyl.
19. A compound selected from:
or a pharmaceutically acceptable salt and individual stereoisomers thereof.
20. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 , or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.