US 2010/0137328 A1Published application

Tricyclic anilide heterocyclic cgrp receptor antagonists

AssigneeMerck Sharp & Dohme Corp.

InventorsIan Bell, Craig A. Stump

Life of this patent

Estimating the term…

Abstract

Compounds of formula I: wherein variables A1, A2, B, m, n, J, R4, G1, G2, G3 and Y are as described herein, which are antagonists of CGRP receptors and which are useful in the treatment or prevention of diseases in which the CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

Claims23

Dependent claims

A compound of formula I:

wherein:
A1 and A2 are each independently selected from:
a bond and —CR13R14—;
B1 and B4 are each independently selected from:
B2 and B3 are each independently selected from:
a bond, ═C(R1)—, —CR1R2—, —C(═O)—, —C(═S)—, —C(═NR1)—, —N(R1)—, —O—, —S—, and —SO2—;
D1 and D2 are each independently selected from:
═C(R1)—, —CR1R2—, —C(═O)—, —C(═S)—, —C(═NR1)—, ═N—, —N(R1)—, —O—, —S— and —SO2—;
G1, G2 and G3 are each independently selected from:
(1) —C(R5)═,
(2) —N═, and
(3)
wherein no more than two of G1, G2 and G3 are —C(RS)═;
or wherein G1 is selected from:
(1) —C(R5)═,
(2) —N═, and
(3) —(N+—O−)═,
and -G2=G3- taken together are selected from:
(1) —S—,
(2) —O—, and
(3) —N(R10)—;
J is independently selected from:
(1)=C(R6a)—,
(2) —CR13R14—,
(3) —C(═O)—, and
(4) —N(R15)—;
Y is independently selected from:
(1) ═C(R6b)—,
(2) —CR13R14—,
(3) —C(═O)—,
(4) —SO2—,
(5) ═N—, and
(6) —N(R6b)—;
T, U and V are each independently selected from:
═C(R1)— and ═N—, wherein at least one of T, U, and V is ═C(R1)—;
W, X, and Z are each independently selected from:
a bond, ═C(R1)—, —CR1R2—, —C(═O)—, —C(═S)—, —C(═NR1)—, ═N—, —N(R1)—, —O—, —S—, —S(O)— and —SO2—;
R1 and R2 are each independently selected from:
(1) hydrogen,
(2)-C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) —C3-6cycloalkyl,
(e) phenyl or heterocycle, wherein the heterocycle is selected from azetidinyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azepanyl, 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:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxy, trifluoromethyl, —OCF3 and oxo,
(f) —CO2R9,
(g) —NR10R11,
(h) —SO2R12,
(i) —CONR10aR11a,
(j) trifluoromethyl,
(k) —OCO2R9,
(l) —(NR10a)CO2R9,
(m) —O(CO)NR10aR11a,
(n) —(NR9)(CO)NR10aR11a, and
(o) —O—C3-6cycloalkyl,
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) trifluoromethyl, and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxy and trifluoromethyl,
(4) —C2-6alkynyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) —C3-6cycloalkyl,
(d) trifluoromethyl, and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxy and trifluoromethyl,
(5) phenyl or heterocycle, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azepanyl, 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) —C1-6alkyl which is unsubstituted or substituted with 1-6 fluoro,
(b) halo,
(c) hydroxy,
(d) —O—C1-6alkyl which is unsubstituted or substituted with 1-6 fluoro,
(e) —C3-6cycloalkyl,
(f) phenyl or heterocycle, wherein the heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxy and trifluoromethyl,
(g) —CO2R9,
(h) —(CO)R9,
(i) —NR10R11,
(j) —CONR10R11,
(k) oxo
(l) —SR12,
(m) —S(O)R12,
(n) —SO2R12, and
(o) —CN
(6) halo,
(7) oxo,
(8) hydroxy,
(9) —O—C1-6alkyl which is unsubstituted or substituted with 1-5 halo,
(10) —CN,
(11) —CO2R9,
(12) —NR10R11,
(13) —SO2R12,
(14) —CONR10aR11a,
(15) —OCO2R9,
(16) —(NR10a)CO2R9,
(17) —O(CO)NR10aR11a,
(18) —(NR9)(CO)NR10aR11a,
(19) —(CO)—(CO)NR10aR11a,
(20) —(CO)—(CO)OR9, and
(21) —(NR10)(CO)R9;
R4 is selected from:
hydrogen, C1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, C5-6 cycloalkyl, benzyl and phenyl;
R5 is independently selected from:
(1) hydrogen,
(2) C1-6alkyl,
(3) —O—C1-6alkyl,
(4) —OCF3,
(5) trifluoromethyl,
(6) halo,
(7) hydroxy, and
(8) —CN;
R6a and R6b are each independently selected from:
(1) hydrogen;
(2) —C1-4alkyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are each independently selected from:
(a) halo,
(b) —O—C1-6alkyl,
(c) —C3-6cycloalkyl,
(d) phenyl or heterocycle, wherein the heterocycle is selected from imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, or morpholinyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from:
(i) —C1-6alkyl,
(ii) —O—C1-6alkyl,
(iii) halo,
(iv) hydroxy,
(v) trifluoromethyl, and
(vi)-OCF3,
(3) phenyl or heterocycle, wherein the heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, azetidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrahydrofuryl, piperidinyl, and morpholinyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from:
(a) —C1-4alkyl, which is unsubstituted or substituted with 1-5 fluoro,
(b) halo,
(c) hydroxy,
(d) —O—C1-4alkyl, which is unsubstituted or substituted with 1-5 fluoro,
(e) —C3-6cycloalkyl, and
(f) phenyl,
(4) halo,
(5) hydroxy,
(6) —O—C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(7) —CN,
(8) —CO2R9,
(9) —NR10R11, and
(10) —CONR10aR11a;
or where R6a and R6b and the atom(s) to which they are attached may be joined together to form a ring selected from cyclopentenyl, cyclohexenyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, (uranyl, dihydrofuranyl, dihydropyranyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thienyl, dihydrothienyl, or dihydrothiopyranyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are each independently selected from:
(a) —C1-6alkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from:
(i) halo,
(ii) hydroxy,
(iii)-O—C1-6alkyl,
(iv)-C3-6cycloalkyl,
(v) phenyl or heterocycle, wherein the heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, or morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are each independently selected from:
(I) —C1-6alkyl,
(II) —O—C1-6alkyl,
(III) halo,
(IV) hydroxy,
(V) trifluoromethyl, and
(VI) —OCF3,
(vi) —CO2R9,
(vii) —NR10R11,
(viii) —SO2R12,
(ix) —CONR10aR11a, and
(x) —(NR10a)CO2R9,
(b) phenyl or heterocycle, wherein the heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from:
(i) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(ii) halo,
(iii) hydroxy,
(iv)-O—C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro, and
(v) —C3-6cycloalkyl,
(c) halo,
(d) —SO2R12,
(e) hydroxy,
(f) —O—C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(g) —CN,
(h) —C(O)R12,
(i) —NR10R11,
(j) —CONR10aR11a,
(k) —CO2R9,
(l) —(NR10a)CO2R9,
(m) —O(CO)NR10aR11a,
(n) —(NR9)(CO)NR10aR11a, and
(o) oxo;
R9 is independently selected from:
(1) hydrogen,
(2)-C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(3) —C3-6cycloalkyl,
(4) benzyl, and
(5) phenyl;
R10 and R11 are each independently selected from:
(1) hydrogen,
(2) C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(3) —C1-6cycloalkyl,
(4) benzyl,
(5) phenyl,
(6) —COR9, and
(7) —SO2R12;
R10a and R11a are each independently selected from:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(3) —C5-6cycloalkyl,
(4) benzyl, and
(5) phenyl;
or R10a and R11a are joined to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which ring is unsubstituted or substituted with 1-5 substituents each independently selected from:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxyl, phenyl and benzyl;
R12 is independently selected from:
(1) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(2) —C5-6cycloalkyl,
(3) benzyl, and
(4) phenyl;
R13 and R14 are each independently selected from:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(3) hydroxy, and
(4) halo;
R15 is selected from:
(1) hydrogen,
(2) —C1-6alkyl or —C3-6cycloalkyl which are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) —C3-6cycloalkyl,
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C1-6alkyl,
(ii) —O—C1-6alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —CO2R9,
(g) —NR10R11,
(h) —CONR10R11,
(i) —SO2R12, and
(j) trifluoromethyl, and
(3) phenyl or heterocycle, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, thienyl, or morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C1-6alkyl,
(b) —O—C1-6alkyl,
(c) halo,
(d) hydroxy, and
(e) trifluoromethyl;
m is 1 or 2;
n is 1 or 2;
and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.

237 more elements

Dependencies are inferred from the claim text.

patentgrep

Loading patent…

Abstract

A compound of formula I:

wherein:
A1 and A2 are each independently selected from:
a bond and —CR13R14—;
B1 and B4 are each independently selected from:
B2 and B3 are each independently selected from:
a bond, ═C(R1)—, —CR1R2—, —C(═O)—, —C(═S)—, —C(═NR1)—, —N(R1)—, —O—, —S—, and —SO2—;
D1 and D2 are each independently selected from:
═C(R1)—, —CR1R2—, —C(═O)—, —C(═S)—, —C(═NR1)—, ═N—, —N(R1)—, —O—, —S— and —SO2—;
G1, G2 and G3 are each independently selected from:
(1) —C(R5)═,
(2) —N═, and
(3)
wherein no more than two of G1, G2 and G3 are —C(RS)═;
or wherein G1 is selected from:
(1) —C(R5)═,
(2) —N═, and
(3) —(N+—O−)═,
and -G2=G3- taken together are selected from:
(1) —S—,
(2) —O—, and
(3) —N(R10)—;
J is independently selected from:
(1)=C(R6a)—,
(2) —CR13R14—,
(3) —C(═O)—, and
(4) —N(R15)—;
Y is independently selected from:
(1) ═C(R6b)—,
(2) —CR13R14—,
(3) —C(═O)—,
(4) —SO2—,
(5) ═N—, and
(6) —N(R6b)—;
T, U and V are each independently selected from:
═C(R1)— and ═N—, wherein at least one of T, U, and V is ═C(R1)—;
W, X, and Z are each independently selected from:
a bond, ═C(R1)—, —CR1R2—, —C(═O)—, —C(═S)—, —C(═NR1)—, ═N—, —N(R1)—, —O—, —S—, —S(O)— and —SO2—;
R1 and R2 are each independently selected from:
(1) hydrogen,
(2)-C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) —C3-6cycloalkyl,
(e) phenyl or heterocycle, wherein the heterocycle is selected from azetidinyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azepanyl, 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:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxy, trifluoromethyl, —OCF3 and oxo,
(f) —CO2R9,
(g) —NR10R11,
(h) —SO2R12,
(i) —CONR10aR11a,
(j) trifluoromethyl,
(k) —OCO2R9,
(l) —(NR10a)CO2R9,
(m) —O(CO)NR10aR11a,
(n) —(NR9)(CO)NR10aR11a, and
(o) —O—C3-6cycloalkyl,
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) trifluoromethyl, and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxy and trifluoromethyl,
(4) —C2-6alkynyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) —C3-6cycloalkyl,
(d) trifluoromethyl, and
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxy and trifluoromethyl,
(5) phenyl or heterocycle, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azepanyl, 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) —C1-6alkyl which is unsubstituted or substituted with 1-6 fluoro,
(b) halo,
(c) hydroxy,
(d) —O—C1-6alkyl which is unsubstituted or substituted with 1-6 fluoro,
(e) —C3-6cycloalkyl,
(f) phenyl or heterocycle, wherein the heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxy and trifluoromethyl,
(g) —CO2R9,
(h) —(CO)R9,
(i) —NR10R11,
(j) —CONR10R11,
(k) oxo
(l) —SR12,
(m) —S(O)R12,
(n) —SO2R12, and
(o) —CN
(6) halo,
(7) oxo,
(8) hydroxy,
(9) —O—C1-6alkyl which is unsubstituted or substituted with 1-5 halo,
(10) —CN,
(11) —CO2R9,
(12) —NR10R11,
(13) —SO2R12,
(14) —CONR10aR11a,
(15) —OCO2R9,
(16) —(NR10a)CO2R9,
(17) —O(CO)NR10aR11a,
(18) —(NR9)(CO)NR10aR11a,
(19) —(CO)—(CO)NR10aR11a,
(20) —(CO)—(CO)OR9, and
(21) —(NR10)(CO)R9;
R4 is selected from:
hydrogen, C1-6 alkyl which is unsubstituted or substituted with 1-6 fluoro, C5-6 cycloalkyl, benzyl and phenyl;
R5 is independently selected from:
(1) hydrogen,
(2) C1-6alkyl,
(3) —O—C1-6alkyl,
(4) —OCF3,
(5) trifluoromethyl,
(6) halo,
(7) hydroxy, and
(8) —CN;
R6a and R6b are each independently selected from:
(1) hydrogen;
(2) —C1-4alkyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are each independently selected from:
(a) halo,
(b) —O—C1-6alkyl,
(c) —C3-6cycloalkyl,
(d) phenyl or heterocycle, wherein the heterocycle is selected from imidazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolyl, thienyl, triazolyl, or morpholinyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from:
(i) —C1-6alkyl,
(ii) —O—C1-6alkyl,
(iii) halo,
(iv) hydroxy,
(v) trifluoromethyl, and
(vi)-OCF3,
(3) phenyl or heterocycle, wherein the heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyrrolidinyl, azetidinyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, tetrahydrofuryl, piperidinyl, and morpholinyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from:
(a) —C1-4alkyl, which is unsubstituted or substituted with 1-5 fluoro,
(b) halo,
(c) hydroxy,
(d) —O—C1-4alkyl, which is unsubstituted or substituted with 1-5 fluoro,
(e) —C3-6cycloalkyl, and
(f) phenyl,
(4) halo,
(5) hydroxy,
(6) —O—C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(7) —CN,
(8) —CO2R9,
(9) —NR10R11, and
(10) —CONR10aR11a;
or where R6a and R6b and the atom(s) to which they are attached may be joined together to form a ring selected from cyclopentenyl, cyclohexenyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, (uranyl, dihydrofuranyl, dihydropyranyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, thienyl, dihydrothienyl, or dihydrothiopyranyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are each independently selected from:
(a) —C1-6alkyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from:
(i) halo,
(ii) hydroxy,
(iii)-O—C1-6alkyl,
(iv)-C3-6cycloalkyl,
(v) phenyl or heterocycle, wherein the heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, or morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are each independently selected from:
(I) —C1-6alkyl,
(II) —O—C1-6alkyl,
(III) halo,
(IV) hydroxy,
(V) trifluoromethyl, and
(VI) —OCF3,
(vi) —CO2R9,
(vii) —NR10R11,
(viii) —SO2R12,
(ix) —CONR10aR11a, and
(x) —(NR10a)CO2R9,
(b) phenyl or heterocycle, wherein the heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, piperidinyl and morpholinyl, which is unsubstituted or substituted with 1-3 substituents where the substituents are each independently selected from:
(i) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(ii) halo,
(iii) hydroxy,
(iv)-O—C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro, and
(v) —C3-6cycloalkyl,
(c) halo,
(d) —SO2R12,
(e) hydroxy,
(f) —O—C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(g) —CN,
(h) —C(O)R12,
(i) —NR10R11,
(j) —CONR10aR11a,
(k) —CO2R9,
(l) —(NR10a)CO2R9,
(m) —O(CO)NR10aR11a,
(n) —(NR9)(CO)NR10aR11a, and
(o) oxo;
R9 is independently selected from:
(1) hydrogen,
(2)-C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(3) —C3-6cycloalkyl,
(4) benzyl, and
(5) phenyl;
R10 and R11 are each independently selected from:
(1) hydrogen,
(2) C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(3) —C1-6cycloalkyl,
(4) benzyl,
(5) phenyl,
(6) —COR9, and
(7) —SO2R12;
R10a and R11a are each independently selected from:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(3) —C5-6cycloalkyl,
(4) benzyl, and
(5) phenyl;
or R10a and R11a are joined to form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which ring is unsubstituted or substituted with 1-5 substituents each independently selected from:
—C1-6alkyl, —O—C1-6alkyl, halo, hydroxyl, phenyl and benzyl;
R12 is independently selected from:
(1) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(2) —C5-6cycloalkyl,
(3) benzyl, and
(4) phenyl;
R13 and R14 are each independently selected from:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(3) hydroxy, and
(4) halo;
R15 is selected from:
(1) hydrogen,
(2) —C1-6alkyl or —C3-6cycloalkyl which are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl,
(d) —C3-6cycloalkyl,
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(i) —C1-6alkyl,
(ii) —O—C1-6alkyl,
(iii) halo,
(iv) hydroxy, and
(v) trifluoromethyl,
(f) —CO2R9,
(g) —NR10R11,
(h) —CONR10R11,
(i) —SO2R12, and
(j) trifluoromethyl, and
(3) phenyl or heterocycle, wherein heterocycle is selected from:
pyridyl, pyrimidinyl, pyrazinyl, thienyl, or morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from:
(a) —C1-6alkyl,
(b) —O—C1-6alkyl,
(c) halo,
(d) hydroxy, and
(e) trifluoromethyl;
m is 1 or 2;
n is 1 or 2;
and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.

237 more elements