US 8,507,477 B2Granted

3- and 6-quinolines with N-attached heterocyclic CGRP receptor antagonists

AssigneeMerck Sharp & Dohme Corp.

InventorsMichael R. Wood, Ian M. Bell, June J. Kim, Harold G. Selnick, Craig A. Stump

Life of this patent

Estimating the term…

Abstract

Compounds of Formula (I): (where variables R1A, R1B, R2, R3, R4, A, and Z are as defined herein) which are useful as antagonists of CGRP receptors, and useful in the treatment or prevention of diseases in which CGRP receptors are involved, such as headache, and in particular migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP receptors are involved.

Claims21

Dependent claims

A compound of Formula I:

wherein:
E1 and E2 are each independently selected from the group consisting of:
(1) ═N—,
(2) ═N+(O−)—, and
(3) ═C(R5)—
wherein at least one of E1 and E2 must contain nitrogen;
each Q is ═C(R5)—;
A1, A2 and A3 are each independently selected from the group consisting of:
(1) a bond,
(2) —CR1R2—,
(3) —NRb—,
(4) —CR1R2—NRb—,
(5) —CR1R2—CH2—,
(6) —O—CR1R2—,
(7) —CR1R2—O—, and
(8) —C(═O)—,
provided that at least one of A1, A2 and A3 is not a bond;
R1 and R2 are each independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(a) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-5 halo,
(b) —ORa,
(c) halo, and
(d) phenyl, which is unsubstituted or substituted with 1-5 halo,
(3) —ORa,
(4) halo, and
(5) phenyl or pyridinyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(a) halo,
(b)—ORa,
(c)—CN, and
(d)—C1-6alkyl, which is unsubstituted or substituted with 1-5 halo;
R5 is selected from the group consisting of:
(1) hydrogen
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(3) halo,
(4) —ORa, and
(5) —CN;
B is a heterocycle selected from the group consisting of:
where B is linked to A1 via a nitrogen atom in B and
where B is unsubstituted or substituted with 1-6 substitutents independently selected from the group consisting of R3, R4, R6, R7, R8 and R9;
R3, R4, R6, R7, R8 and R9 are each independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(a) halo,
(b) —ORa,
(c) —C3-6cycloalkyl,
(d) phenyl or heterocycle, wherein said heterocycle is selected from the group consisting of:
benzodioxolyl, imidazolyl, indolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(i) halo,
(ii) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo, and
(iii) —ORa,
(e) —CO2Ra,
(f) —C(═O)NRbRc,
(g) —S(O)vRd,
(h) —CN,
(i) —NRbRa,
(j) —N(Rb)C(═O)Ra,
(k) —N(Rb)SO2Rd,
(l) —CF3,
(m) —O—CO2Rd,
(n) —O—(C═O)—NRbRc,
(o) —NRb—(C═O)—NRbRc, and
(p) —C(═O)Ra,
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(a) halo,
(b) —CN,
(c) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —ORa,and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(i) —ORa,
(ii) halo,
(iii) —CN, and
(iv) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(4) phenyl or heterocycle, wherein said heterocycle is selected from:
benzimidazolyl, benzoxazinyl, benzoxazolyl, indanyl, indolyl, morpholinyl, oxadiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, piperdinyl, piperazinyl, pyrrolidinyl, thienyl, tetrazolyl, thiazolyl, and triazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(a) halo,
(b) ORa,
(c)—C3-6cycloalkyl,
(d) phenyl or pyridyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(i) halo,
(ii) C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iii) —ORa,
(e) —CO2Ra,
(f) —C(═O)NRbRc,
(g) —S(O)vRd,
(h) —CN,
(i) —NRbRc,
(j) —N(Rb)C(═O)Ra,
(k) —N(Rb)SO2Rd,
(l) —O—CO2Rd,
(m) —O—(C═O)—NRbRc,
(n) —NRb—(C═O)—NRbRc,
(o) oxo,
(p) —C(═O)Ra, and
(q) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(5) halo,
(6) oxo,
(7) —ORa,
(8) —CN,
(9) —CO2Ra,
(10) —C(═O)Ra,
(11) —NRbRc,
(12) —S(O)vRd,
(13) —C(═O)NRbRc,
(14) —O—(C═O)Ra,
(15) —O—CO2Rd,
(16) —N(Rb)CO2Rd,
(17) —O—(C═O)—NRbRc,
(18) —NRb—(C═O)—NRbRc,
(19) —SO2 NRbRc, and
(20) —N(Rb)SO2Rd,
or R7 and R8 and the atom(s) to which they are attached join to form a ring selected from the group consisting of 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 the group consisting of:
(a) —C1-6alkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of:
(i) halo,
(ii) —ORa,
(iii) —C3-6cycloalkyl,
(iv) —CO2Ra,
(v) —NRbRc,
(vi) —S(O)vRd,
(vii) —C(═O)NRbRc, and
(viii) phenyl, which is unsubstituted or substituted with 1-5 halo,
(b) phenyl or heterocycle, wherein heterocycle is selected from the group consisting of:
pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl, 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) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo, and
(iii) —ORa,
(c)—ORa,
(d)halo,
(e)—CO2Ra,
(f)—C(═O)NRbRc,
(g)—S(O)vRd,
(h)—CN,
(i)—NRbRc,
(j)—N(Rb)C(═O)Ra,
(k)—N(Rb)SO2Rd,
(l) —O—(C═O)Ra,
(m)—O—CO2Rd,
(n)—O—(C═O)—NRbRc,
(o)—NRb—(C═O)—NRbRc,
(p)—C(═O)Ra, and
(q) oxo;
RPG is independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-6alkyl which is unsubstituted or substituted with 1-5 halo,
(3) —CH2ORa,
(4) —CH2—O—CH2CH2Si(CH3)3,
(5) —(CH2)k-phenyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of:
(a) halo,
(b) —ORa,
(c) —CN, and
(d) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo;
J is
Y is
R16a and R16b and the atom(s) to which they are attached join to form a pyridyl ring which ring is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(a)—C1-6allcyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of:
(i) halo,
(ii) —ORa,
(iii) —C3-6cycloalkyl,
(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 the group consisting of:
(I) —ORa,
(II) halo,
(III) —CN, and
(IV) —C1-6alkyl which is unsubstituted or substituted with 1-6 halo,
(v) —CO2Ra,
(vi) —NRbRc,
(vii) —S(O)vRd,
(viii) —C(═O)NRbRc,
(ix) —N(Rb)CO2Ra, and
(x) —N(Rb)SO2Rd,
(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 the group consisting of:
(i) halo,
(ii) —ORa,
(iii) —CN, and
(iv) —C1-6alkyl which is unsubstituted or substituted with 1-6 halo,
(c) halo,
(d) —S(O)vRd,
(e) —ORa,
(f) —CN,
(g) —C(═O)Ra,
(h) —NRbRc,
(i) —C(═O)NRbRc,
(j) —CO2Ra,
(k) —(NRb)CO2Ra,
(l) —O—(C═O)—NRbRc,
(m) —(NRb)—(C═O)—NRbRc,
(n) oxo, and
(o) —(NRb)SO2Rd;
Rais selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from the group consisting of:
(a) halo,
(b) —O—C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(c) hydroxyl,
(d) —C(═O)—O—C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(e) —CN, and
(f) phenyl or heterocycle wherein said heterocycle is selected from the group consisting of 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 the group consisting of:
(i) halo,
(ii) —O—C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(iii) —CN,
(iv) nitro,
(v) hydroxyl, and
(vi) —C1-6allcyl, 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 the group consisting of:
(a) halo,
(b) —CN,
(c) —O—C1-6allcyl, which is unsubstituted or substituted with 1-6 halo,
(d) nitro,
(e) hydroxyl, and
(f) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and
(4) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo;
Rb and Rcare each independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from the group consisting of:
(a) halo,
(b) —ORa,
(c) —CN,
(d) —CO2Ra,
(e) phenyl or heterocycle, wherein said heterocycle is selected from the group consisting of 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 the group consisting of:
(i) halo,
(ii) —ORa,
(iii) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iv) nitro,
(3) phenyl or heterocycle, wherein said heterocycle is selected from the group consisting of 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 the group consisting of:
(a) halo,
(b) —ORa,
(c) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(d) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(e) —CN, and
(f) —CO2Ra,
(4) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo;
or Rb and Rcand 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 the group consisting of:
(a) halo,
(b) —ORa, and
(c) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and
(d) phenyl;
Rd is selected from the group consisting of:
(1) C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from the group consisting of:
(a) halo,
(b) —ORa,
(c) —CO2Ra
(d) —CN, and
(e) phenyl or heterocycle wherein said heterocycle is selected from the group consisting of 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 the group consisting of:
(i) halo,
(ii) —ORa,
(iii) —CN,
(iv) nitro, and
(v) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(2) phenyl or heterocycle wherein said heterocycle is selected from the group consisting of 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 the group consisting of:
(a) halo,
(b) —ORa,
(c) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(d) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo
(e) nitro,
(f) —CN, and
(g) —CO2Ra,
(3)—C3-6cycloalkyl, 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;
or a pharmaceutically acceptable salt thereof and tautomers thereof and individual enantiomers and diastereomers thereof.

258 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/059,164Filed 14 Aug 2009 · us provisional application
Priority: 18 Aug 2008
Published: US 2011/0306604 A115 Dec 2011
Granted: 13 Aug 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 471/20
In which the condensed system contains three hetero rings: spiro-condensed systems
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/00
Drugs for disorders of the cardiovascular system

Family

Application61/189,298Us provisional application · filed 18 Aug 2008
US 2011/0306604 A1Pre-grant publication · published 15 Dec 2011
US 8,507,477 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A compound of Formula I:

wherein:
E1 and E2 are each independently selected from the group consisting of:
(1) ═N—,
(2) ═N+(O−)—, and
(3) ═C(R5)—
wherein at least one of E1 and E2 must contain nitrogen;
each Q is ═C(R5)—;
A1, A2 and A3 are each independently selected from the group consisting of:
(1) a bond,
(2) —CR1R2—,
(3) —NRb—,
(4) —CR1R2—NRb—,
(5) —CR1R2—CH2—,
(6) —O—CR1R2—,
(7) —CR1R2—O—, and
(8) —C(═O)—,
provided that at least one of A1, A2 and A3 is not a bond;
R1 and R2 are each independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(a) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-5 halo,
(b) —ORa,
(c) halo, and
(d) phenyl, which is unsubstituted or substituted with 1-5 halo,
(3) —ORa,
(4) halo, and
(5) phenyl or pyridinyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(a) halo,
(b)—ORa,
(c)—CN, and
(d)—C1-6alkyl, which is unsubstituted or substituted with 1-5 halo;
R5 is selected from the group consisting of:
(1) hydrogen
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(3) halo,
(4) —ORa, and
(5) —CN;
B is a heterocycle selected from the group consisting of:
where B is linked to A1 via a nitrogen atom in B and
where B is unsubstituted or substituted with 1-6 substitutents independently selected from the group consisting of R3, R4, R6, R7, R8 and R9;
R3, R4, R6, R7, R8 and R9 are each independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(a) halo,
(b) —ORa,
(c) —C3-6cycloalkyl,
(d) phenyl or heterocycle, wherein said heterocycle is selected from the group consisting of:
benzodioxolyl, imidazolyl, indolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(i) halo,
(ii) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo, and
(iii) —ORa,
(e) —CO2Ra,
(f) —C(═O)NRbRc,
(g) —S(O)vRd,
(h) —CN,
(i) —NRbRa,
(j) —N(Rb)C(═O)Ra,
(k) —N(Rb)SO2Rd,
(l) —CF3,
(m) —O—CO2Rd,
(n) —O—(C═O)—NRbRc,
(o) —NRb—(C═O)—NRbRc, and
(p) —C(═O)Ra,
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(a) halo,
(b) —CN,
(c) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —ORa,and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(i) —ORa,
(ii) halo,
(iii) —CN, and
(iv) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(4) phenyl or heterocycle, wherein said heterocycle is selected from:
benzimidazolyl, benzoxazinyl, benzoxazolyl, indanyl, indolyl, morpholinyl, oxadiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, piperdinyl, piperazinyl, pyrrolidinyl, thienyl, tetrazolyl, thiazolyl, and triazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(a) halo,
(b) ORa,
(c)—C3-6cycloalkyl,
(d) phenyl or pyridyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(i) halo,
(ii) C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iii) —ORa,
(e) —CO2Ra,
(f) —C(═O)NRbRc,
(g) —S(O)vRd,
(h) —CN,
(i) —NRbRc,
(j) —N(Rb)C(═O)Ra,
(k) —N(Rb)SO2Rd,
(l) —O—CO2Rd,
(m) —O—(C═O)—NRbRc,
(n) —NRb—(C═O)—NRbRc,
(o) oxo,
(p) —C(═O)Ra, and
(q) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(5) halo,
(6) oxo,
(7) —ORa,
(8) —CN,
(9) —CO2Ra,
(10) —C(═O)Ra,
(11) —NRbRc,
(12) —S(O)vRd,
(13) —C(═O)NRbRc,
(14) —O—(C═O)Ra,
(15) —O—CO2Rd,
(16) —N(Rb)CO2Rd,
(17) —O—(C═O)—NRbRc,
(18) —NRb—(C═O)—NRbRc,
(19) —SO2 NRbRc, and
(20) —N(Rb)SO2Rd,
or R7 and R8 and the atom(s) to which they are attached join to form a ring selected from the group consisting of 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 the group consisting of:
(a) —C1-6alkyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of:
(i) halo,
(ii) —ORa,
(iii) —C3-6cycloalkyl,
(iv) —CO2Ra,
(v) —NRbRc,
(vi) —S(O)vRd,
(vii) —C(═O)NRbRc, and
(viii) phenyl, which is unsubstituted or substituted with 1-5 halo,
(b) phenyl or heterocycle, wherein heterocycle is selected from the group consisting of:
pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl, 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) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo, and
(iii) —ORa,
(c)—ORa,
(d)halo,
(e)—CO2Ra,
(f)—C(═O)NRbRc,
(g)—S(O)vRd,
(h)—CN,
(i)—NRbRc,
(j)—N(Rb)C(═O)Ra,
(k)—N(Rb)SO2Rd,
(l) —O—(C═O)Ra,
(m)—O—CO2Rd,
(n)—O—(C═O)—NRbRc,
(o)—NRb—(C═O)—NRbRc,
(p)—C(═O)Ra, and
(q) oxo;
RPG is independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-6alkyl which is unsubstituted or substituted with 1-5 halo,
(3) —CH2ORa,
(4) —CH2—O—CH2CH2Si(CH3)3,
(5) —(CH2)k-phenyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of:
(a) halo,
(b) —ORa,
(c) —CN, and
(d) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo;
J is
Y is
R16a and R16b and the atom(s) to which they are attached join to form a pyridyl ring which ring is unsubstituted or substituted with 1-5 substituents each independently selected from the group consisting of:
(a)—C1-6allcyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from the group consisting of:
(i) halo,
(ii) —ORa,
(iii) —C3-6cycloalkyl,
(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 the group consisting of:
(I) —ORa,
(II) halo,
(III) —CN, and
(IV) —C1-6alkyl which is unsubstituted or substituted with 1-6 halo,
(v) —CO2Ra,
(vi) —NRbRc,
(vii) —S(O)vRd,
(viii) —C(═O)NRbRc,
(ix) —N(Rb)CO2Ra, and
(x) —N(Rb)SO2Rd,
(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 the group consisting of:
(i) halo,
(ii) —ORa,
(iii) —CN, and
(iv) —C1-6alkyl which is unsubstituted or substituted with 1-6 halo,
(c) halo,
(d) —S(O)vRd,
(e) —ORa,
(f) —CN,
(g) —C(═O)Ra,
(h) —NRbRc,
(i) —C(═O)NRbRc,
(j) —CO2Ra,
(k) —(NRb)CO2Ra,
(l) —O—(C═O)—NRbRc,
(m) —(NRb)—(C═O)—NRbRc,
(n) oxo, and
(o) —(NRb)SO2Rd;
Rais selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from the group consisting of:
(a) halo,
(b) —O—C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(c) hydroxyl,
(d) —C(═O)—O—C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(e) —CN, and
(f) phenyl or heterocycle wherein said heterocycle is selected from the group consisting of 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 the group consisting of:
(i) halo,
(ii) —O—C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(iii) —CN,
(iv) nitro,
(v) hydroxyl, and
(vi) —C1-6allcyl, 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 the group consisting of:
(a) halo,
(b) —CN,
(c) —O—C1-6allcyl, which is unsubstituted or substituted with 1-6 halo,
(d) nitro,
(e) hydroxyl, and
(f) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and
(4) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo;
Rb and Rcare each independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from the group consisting of:
(a) halo,
(b) —ORa,
(c) —CN,
(d) —CO2Ra,
(e) phenyl or heterocycle, wherein said heterocycle is selected from the group consisting of 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 the group consisting of:
(i) halo,
(ii) —ORa,
(iii) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iv) nitro,
(3) phenyl or heterocycle, wherein said heterocycle is selected from the group consisting of 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 the group consisting of:
(a) halo,
(b) —ORa,
(c) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(d) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(e) —CN, and
(f) —CO2Ra,
(4) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo;
or Rb and Rcand 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 the group consisting of:
(a) halo,
(b) —ORa, and
(c) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and
(d) phenyl;
Rd is selected from the group consisting of:
(1) C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from the group consisting of:
(a) halo,
(b) —ORa,
(c) —CO2Ra
(d) —CN, and
(e) phenyl or heterocycle wherein said heterocycle is selected from the group consisting of 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 the group consisting of:
(i) halo,
(ii) —ORa,
(iii) —CN,
(iv) nitro, and
(v) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(2) phenyl or heterocycle wherein said heterocycle is selected from the group consisting of 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 the group consisting of:
(a) halo,
(b) —ORa,
(c) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(d) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo
(e) nitro,
(f) —CN, and
(g) —CO2Ra,
(3)—C3-6cycloalkyl, 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;
or a pharmaceutically acceptable salt thereof and tautomers thereof and individual enantiomers and diastereomers thereof.

258 more elements

Facts

Application

13/059,164Filed 14 Aug 2009 · us provisional application

Priority

18 Aug 2008

Published

US 2011/0306604 A115 Dec 2011

Granted

13 Aug 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification22 codes

C07D 471/20
In which the condensed system contains three hetero rings: spiro-condensed systems
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/00
Drugs for disorders of the cardiovascular system