Branched 3- and 6-substituted quinolines as CGRP receptors antagonists
The present invention is directed to novel branched 3- and 6-substituted quinoline 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:
E 1 and E 2 are independently selected from:
(1) ═N—,
(2) ═N + (O − )—, and
(3) ═C(R 5 )—
wherein at least one of E 1 and E 2 must be selected to contain nitrogen;
each Q is independently selected from:
(1) ═N—,
(2) ═N + (O − )—, and
(3) ═C(R 5 )—;
A 1 is selected from:
wherein when k=0, this represents a bond between nitrogen and G 1 or G 4 ;
R 1 and R 2 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) —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;
each R 5 is 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;
G 1 is selected from:
(1) oxatanyl, tetrahydropyranyl, tetrahydrothiapyranyl and tetrahydrothienyl, which is unsubstituted or substituted with 1-5 substituents independently selected from R 3 , R 4 , R 6 , R 7 and R 8 , and
(2) pyrrolidinyl, which is substituted with —CO 2 R a , and optionally substituted with 1-3 groups independently selected from:
(a) phenyl,
(b) OR a ,
(c) halo,
(d) —CN, and
(e) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo;
G 2 is selected from:
(1) hydrogen,
(2) —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 ,
(3) —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,
(4) 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:
(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, and
(5) a group selected from G 3 ;
G 3 is selected from:
(1) tetrahydropyranyl, which is unsubstituted or substituted with 1-4 substitutents each independently selected from:
(a) halo,
(b) —OR a ,
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —C 3-6 cycloalkyl,
(e) —CO 2 R a ,
(f) oxo, and
(g) phenyl,
(2) —C 1-6 alkyl which is optionally substituted with 1-5 halo, but which must be further substituted with 1-4 substitutents each independently selected from:
(a) —SR a ,
(b) —S(O) v R d ,
(c) —NR a R c ,
(d) —OBn, which is unsubstituted or substituted with 1-5 halo,
(e) —OC(═O)R a ,
(f) —CO 2 R a ,
(g) —C(═O)NR b R c ,
(h) —C(═O)R a ,
(i) —C 1-6 alkyl-O—C 1-6 alkyl-OR a ,
(j) —N(R a )—C(═O)NR b R c , and
(k) —N(R a )—CO 2 R d ,
(3) piperidinyl or pyrrolidinyl which is substituted with 1-4 substitutents each independently selected from:
(a) —C(═O)R a ,
(b) —OC(═O)R a ,
(c) —C(═O)NR b R c , and
(d) —S(O) v R d ,
G 4 is selected from:
(1) C 3-10 cycloalkyl, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, azepanyl, azepinyl, azetidinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, chromanyl, cinnolinyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, (uranyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, isothiazolidinyl, isothiazolyl, morpholinyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, oxazolidinyl, 2-oxoazepinyl, 4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, phthalazinyl, piperidyl, piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, triazolyl and triazolinyl, which is unsubstituted or substituted with 1-5 substituents independently selected from R 3 , R 4 , R 6 , R 7 and R 8 , and
(2) a group selected from G 1 ;
G 5 is selected from:
(1) —C 1-4 alkyl-phenyl which is optionally substituted with 1-5 halo, but which must be substituted further with 1-4 substituents independently selected from:
(a) —CO 2 R a ,
(b) —C(═O)R a ,
(c) —OC(═O)R a ,
(d) —C(═O)NR b R c ,
(e) —SR a ,
(f) —S(O) v R d , and
(g) —N(R a )SO 2 R d ,
(2) —C 1-4 alkyl-heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, and indazolyl, which is optionally substituted with 1-5 halo, but which must be substituted further with 1-4 substituents independently selected from:
(a) —CO 2 R a ,
(b) —C(═O)R a ,
(c) —OC(═O)R a ,
(d) —C(═O)NR b R c ,
(e) —SR a ,
(O—S(O) v R d , and
(g) —N(R a )SO 2 R d , and
(3) —C 1-4 alkyl which is optionally substituted with 1-5 halo, but which must be substituted further with 1-4 substituents independently selected from:
(a) —CO 2 R a ,
(b) —C(═O)R a ,
(c) —OC(═O)R a ,
(d) —C(═O)NR b R c ,
(e) —SR a ,
(f) —S(O) v R d , and
(g) —N(R a )SO 2 R d ;
G 6 is selected from
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 groups independently selected from:
(a) halo,
(b) OR a ,
(c) —CN, and
(d) phenyl, which is unsubstituted or substituted with 1-5 halo, and
(3) —C 1-6 cycloalkyl, which is unsubstituted or substituted with 1-5 groups independently selected from:
(a) halo,
(b) OR a ,
(c) —CN, and
(d) phenyl, which is unsubstituted or substituted with 1-5 halo;
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, indoolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, 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:
(a) halo,
(b) —CN,
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —OR a , and
(e) 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, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, tetrazolyl and thiazolyl, 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:
(i) halo,
(ii) C 1-6 alkyl, which is unsubstituted or substituted with 1-6 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) —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: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, 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) —CH 2 —O—CH 2 CH 2 Si(CH 3 ) 3 ,
(5) —(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 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;
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, 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 ;
and R 16a and R 16b and the atom(s) to which they are attached may 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) 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 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, indolyl, 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) —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 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) —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;
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 , and
(c) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo, and
(d) 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 said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl, 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) —CN,
(iv) nitro, and
(v) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halo,
(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) 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, 2, or 3;
n is 1, 2, or 3;
v is 0, 1, or 2;
k is 0, 1, or 2;
and pharmaceutically acceptable salts thereof.
2. The compound of claim 1 wherein m is 1 and n is 1.
3. The compound of claim 1 having the formula Ia
and pharmaceutically acceptable salts thereof.
4. The compound of claim 1 having the formula Ib
and pharmaceutically acceptable salts thereof.
5. The compound of claim 1 having the formula Ic
and pharmaceutically acceptable salts thereof.
6. The compound of claim 1 having the formula Id
and pharmaceutically acceptable salts thereof.
7. The compound according to claim 6 wherein A 1 is
8. The compound according to claim 6 wherein A 1 is
9. The compound according to claim 6 wherein A 1 is
10. The compound of claim 1 having the formula Ie
and pharmaceutically acceptable salts thereof.
11. The compound according to claim 10 wherein A 1 is
12. The compound according to claim 10 wherein A 1 is
13. The compound according to claim 10 wherein A 1 is
14. A compound according to claim 1 selected from the following:
R i
R ii
A
B
Tetrahydro-2H-pyran-4-yl
(1R)-1-(3,5-difluorophenyl) ethyl
N
CH
2-ethoxy-2-oxoethyl
Benzyl
N
CH
tetrahydro-2H-pyran-4-yl
(1R)-2,3-dihydro-1H- inden-1-yl
N
CH
tetrahydro-2H-pyran-4-yl
(1R)-1-(3-chlorophenyl) ethyl
N
CH
tert-butyl
tetrahydro-2H-thiopyran- 4-yl
N
CH
tetrahydro-2H-pyran-4-yl
cycloheptyl
N
CH
tetrahydro-2H-pyran-3-yl
(1R)-1-(3,5-difluorophenyl) ethyl
N
CH
tetrahydro-2H-pyran-4-yl
3,5-dichlorobenzyl
N
CH
tetrahydro-2H-pyran-4-yl
3-fluorobenzyl
N
CH
tetrahydro-2H-pyran-2-yl
3-fluorobenzyl
N
CH
1-(acetyloxy)-1-methylethyl
(1R)-2,3-dihydro-1H- inden-1-yl
N
CH
Tert-butyl
tetrahydro-2H-pyran-4-yl
N
CH
(1S)-1-(benzyloxy)-2,2,2- trifluoro-1-methylethyl
(1R)-1-(3,5-difluorophenyl) ethyl
N
CH
(1S)-1-(benzyloxy)-2,2,2- trifluoro-1-methylethyl
(1R)-2,3-dihydro-1H- inden-1-yl
N
CH
(1S)-1-(benzyloxy)-2,2,2- trifluoro-1-methylethyl
3-fluorobenzyl
N
CH
tetrahydro-2H-pyran-4-yl
[1-(tert-butoxycarbonyl)-4- phenylpyrrolidin-3-yl]
N
CH
2-(methylthio)ethyl
3-fluorobenzyl
N
CH
2-thienylmethyl
3-fluorobenzyl
N
CH
3-methoxy-3-oxopropyl
3-fluorobenzyl
N
CH
(2-methoxyethoxy)methyl
3-fluorobenzyl
N
CH
tetrahydro-2H-pyran-4-yl
cis-2-phenylcyclopentyl
N
CH
tetrahydro-2H-pyran-4-yl
trans-2-phenylcyclopentyl
N
CH
tetrahydro-2H-pyran-4-yl
cis-2-(4-chlorophenyl) cyclopentyl
N
CH
2-ethoxy-2-oxoethyl
3-fluorobenzyl
N
CH
1-(acetyloxy)ethyl
(1R)-2,3-dihydro-1H- inden-1-yl
N
CH
1-(acetyloxy)-1-methylethyl
(1R)-2,3-dihydro-1H- inden-1-yl
CH
N
(dimethylamino)methyl
3-fluorobenzyl
N
CH
tetrahydro-2H-pyran-4-yl
(1S,2S)-2-(benzyloxy) cyclopentyl
N
CH
tetrahydro-2H-pyran-4-yl
(1R,2R)-2-(benzyloxy) cyclopentyl
N
CH
tetrahydro-2H-pyran-4-yl
4-phenylpyrrolidin-3-yl
N
CH
1-(acetyloxy)-1-methylethyl
(1R)-2,3-dihydro-1H- inden-1-yl
CH
N
and pharmaceutically acceptable salts of any of the foregoing compounds.
15. A compound according to claim 1 selected from the following:
R iii
R iv
2-tert-butoxy-2-oxoethyl
Bn
(1R)-2-tert-butoxy-2-oxo-1-phenylethyl
H
(1S)-2-tert-butoxy-2-oxo-1-phenylethyl
H
2-methoxy-1-[(7-methyl-1H-indazol-5- yl)methyl]-2-oxoethyl
H
3-tert-butoxy-3-oxo-1-phenylpropyl
H
1-benzyl-2-tert-butoxy-2-oxoethyl
H
and pharmaceutically acceptable salts of any of the foregoing compounds.
16. A pharmaceutical composition which comprises an inert carrier and the compound of claim 1 .
17. A method for antagonism of CGRP receptor activity in a mammal which comprises the administration of an effective amount of the compound of claim 1 .
18. A method for treating, headache, migraine or cluster headache in a mammalian patient in need of such which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 .
19. A method of treating migraine headaches, cluster headaches, and headaches, said method comprising the co-administration, to a person in need of such treatment, of:
a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof; and
a therapeutically effective amount of a second agent selected from serotonin agonists, analgesics, anti-inflamatory agents, anti-hypertensives and anticonvulsants.