# US 8,569,291 B2 · Bicyclic dihydroimidazolone CGRP receptor antagonists

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- Number: US 8,569,291 B2
- Document ID: US8569291B2
- Status: Granted
- Kind: B2
- Application number: 13/119,534
- Filed: 2009-09-10
- Published: 2011-09-15
- Granted: 2013-10-29
- Earliest claimed: 2008-09-18
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Craig A. Stump
- Inventors: Craig A. Stump
- Web page: https://patentgrep.com/patent/US8569291B2

## CPC

- C07D 417/14: containing three or more hetero rings
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of formula (I): wherein variables B, G1, G2, G3, G4, Ea, Eb, Ec, A1, A2, A3, A4, R6 and RPG 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.

## Claims

### Claim 1

A compound of formula ID:
wherein:
B is a heterocycle selected from the group consisting of:
wherein T, U, V, and W are each independently a carbon atom or a nitrogen atom, wherein no more than two of T, U, V and W are nitrogen atoms;
wherein X is selected from:
(1) —O—,
(2) —S(O)q—,
(3) —Si(ORa)—C1-4alkyl-, where alkyl is unsubstituted or substituted with 1-5 halo,
(4) —Si(C1-4alkyl)2, where each alkyl is independently unsubstituted or substituted with 1-5 halo-,
(5) —N(R8)—,
(6) —(C═O)—,
(7) —C(R8)(Ra)—,
(8) —C(N(Rb)—SO2Rd)(Ra)—,
(9) —C(N(Rb)(C═O)Ra)(Ra)—,
(10) —C(N(Rb)(C═O)ORa)(Ra)—,
(11) —CR10R11—,
(12) —N(R11)—, and
(13) —CR3R4—;
B is unsubstituted or substituted with 1-7 substituents each independently selected from R1, R2, R3, R4, R10, and R11, wherein R1, R2, and R3 are independently selected from:
(1) —C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6 alkyl,
(d) —C3-6 cycloalkyl,
(e) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, oxazolyl, thiazolyl, 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, trifluoromethyl and —OCF3,
(f) —CO2R19
(g) —NR20R21,
(h) —SO2R22,
(i) —CONR20aR21a,
(j) trifluoromethyl,
(k) —OCO2R19,
(l) —(NR20a)CO2R19,
(m) —O(CO)NR20aR21a,
(n) —(NR19)(CO)NR20aR21a, and
(o) —O—C3-6cycloalkyl,
(2) —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,
(e) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from: —C1-6alkyl, —O—C1-6alkyl, halo, hydroxy and trifluoromethyl,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepanyl, 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 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: —C1-6alkyl, —O—C1-6alkyl, halo, hydroxy and trifluoromethyl,
(g) —CO2R19,
(h) —(CO)R19,
(i) —NR20R21,
(j) —CONR20R21,
(k) oxo, and
(l) —S(O)qR22,
(4) halo,
(5) oxo,
(6) hydroxy,
(7) —O—C1-6alkyl which is unsubstituted or substituted with 1-5 halo,
(8) —CN,
(9) —CO2R19,
(10) —NR20R21,
(11) —SO2R22,
(12) —CONR20aR21a,
(13) —OCO2R19,
(14) —(NR20a)CO2R19,
(15) —O(CO)NR20aR21a,
(16) —(NR19)(CO)NR20aR21a,
(17) —(CO)—(CO)NR20aR21a,
(18) —(CO)—(CO)OR19,
(19) —SO2NR20aR21a, and
(20) hydrogen;
or R3 and R4 and the carbon atom to which they are attached join to form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, dioxolanyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiapyranyl, oxetanyl, thietanyl and tetrahydrothienyl, 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) —C1-6allcyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —ORa,
(iii) —C3-6cycloalkyl,
(iv) —CO2Ra,
(v) —NRbRc,
(vi) —S(O)qRd,
(vii) —C(═O)NRbRc, and
(viii) phenyl,
(b) phenyl or heterocycle, wherein heterocycle is selected from: 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,
(iii) —ORa,
(iv) —CO2Ra,
(v) —O(C═O)Ra,
(vi) —CN,
(vii) —NRbRc,
(viii) oxo,
(ix) —C(═O)NRbRc,
(x) —N(Rb)C(═O)Ra,
(xi) —N(Rb)CO2Ra,
(xii) —O(C═O)NRbRc, and
(xiii) —S(O)qRd,
(c) —ORa,
(d) halo,
(a) —CO2Ra,
(b) —C(═O)NRbRc,
(c) —S(O)qRd,
(d) —CN,
(e) —NRbRc,
(f) —N(Rb)C(═O)Ra,
(g) —N(Rb)SO2Rd,
(h) —O—CO2Rd,
(i) —O—(C═O)—NRbRc,
(j) —NRb—(C═O)—NRbRc,
(k) —C(═O)Ra, and
(l) oxo;
R4 is independently selected from:
(1) hydrogen,
(2) —C(═O)Ra,
(3) —CO2Ra,
(4) —S(═O)Rd,
(5) —SO2Rd,
(6) —C(═O)NRbRc,
(7) —C1-6alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —ORa,
(c) —C3-6cycloalkyl,
(d) phenyl or heterocycle, wherein said heterocycle is selected from: 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) —C1-6 alkyl, which is unsubstituted or substituted with 1-5 halo,
(iii) —ORa,
(iv) —NRbRc,
(v) —C(═O)Ra,
(vi) —CO2Ra, and
(vii) oxo;
(e) —CO2Ra,
(f) —C(═O)NRbRc,
(g) —S(O)qRd,
(h) —CN,
(i) —NRbRc,
(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;
(8) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 substituents each independently selected from:
(a) halo,
(b) —CN,
(c) —ORa, and
(d) C1-6alkyl, which is unsubstituted or substituted with 1-6 halo;
R6 is selected from:
(1) hydrogen;
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-6 substituents each independently selected from:
(a) halo,
(b) —O—C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(c) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 fluoro, and
(d) phenyl or heterocycle, wherein heterocycle is selected from: azepinyl, azepanyl, azetidinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, morpholinyl, naphthyridinyl, oxazolyl, oxadiazolyl, 2-oxoazepinyl, 4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl, piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, isoxazolyl, tetrahydrothienyl, tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, thietanyl, and triazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from: —C1-6alkyl, —O—C1-6alkyl, halo, hydroxy, trifluoromethyl, —CN, and —OCF3,
(3) phenyl or heterocycle, wherein heterocycle is selected from: azepinyl, azepanyl, azetidinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, morpholinyl, naphthyridinyl, oxazolyl, oxadiazolyl, 2-oxoazepinyl, 4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl, piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, isoxazolyl, tetrahydrothienyl, tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, thietanyl, and triazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-3 substituents each independently selected from:
(a) halo,
(b) —ORa,
(c) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 fluoro,
(d) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) halo,
(ii) —CN,
(iii) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo, and
(iv) —ORa,
(a) —CO2Ra,
(f) —C(═O)NRbRc,
(a) —S(O)qRd,
(b) —CN,
(c) —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) —C(═O)Ra, and
(p) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(4) —O—C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(5) —CN,
(6) —CO2R19,
(7) —NR20R21, and
(8) —CONR20aR21a
(9) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(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 where the substituents are each independently selected from:
(i) —ORa,
(ii) halo,
(iii) —CN, and
(iv) —C1-6allcyl, which is unsubstituted or substituted with 1-5 halo,
R8 is selected from:
(1) hydrogen,
(2) —C(═O)Ra,
(3) —CO2Ra,
(4) —S(═O)Rd,
(5) —SO2Rd,
(6) —C(═O)NRbRc,
(7) —C1-6alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —ORa,
(c) —C3-6cycloalkyl,
(d) phenyl or heterocycle, wherein said heterocycle is selected from: 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) —C1-6allcyl, which is unsubstituted or substituted with 1-5 halo,
(iii) —ORa,
(iv) —NRbRc,
(v) —C(═O)Ra,
(vi) —CO2Ra,
(vii) oxo, and
(viii) —CN,
(e) —CO2Ra,
(f) —C(═O)NRbRc,
(g) —S(O)qRd,
(h) —CN,
(i) —NRbRc,
(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,
(8) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 substituents each independently selected from:
(a) halo,
(b) —CN,
(c) —ORa, and
(d) C1-6alkyl, which is unsubstituted or substituted with 1-6 halo;
or R4 and R8 and the atoms to which they are attached join to form a 4-, 5-, 6- or 7-membered alkyl- or heteroalkyl-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) phenyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from: halo, ORa, CN, and —C(═O)ORa,
(c) —ORa, and
(d) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo;
R10 is selected from:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —ORa,
(c) —CN,
(d) phenyl, and
(e) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo;
R11 is selected from the group consisting of:
phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, azepinyl, azepanyl, azetidinyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, chromanyl, cinnolinyl, dibenzofuranyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, morpholinyl, naphthyridinyl, oxazolyl, oxadiazolyl, 2-oxoazepinyl, 4-oxonaphthyridinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxopyridyl, 2-oxoquinolinyl, piperidyl, piperazinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroimidazopyridinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, triazolyl, isoxazolyl, tetrahydrothienyl, tetrahydropyranyl, oxetanyl, tetrahydrothiapyranyl, and thietanyl, where R11 is unsubstituted or substituted with 1-5 substituents each independently selected from R12, R13, R14, R15a and R15b;
R12, R13, R14, R15a and R15b are each independently selected from:
(1) —C1-6allcyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) halo,
(b) —ORa,
(c) —C3-6cycloalkyl,
(d) phenyl or heterocycle, wherein said heterocycle is selected from: 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:
(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)qRd,
(h) —CN,
(i) —NRbRc,
(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,
(2) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(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 where the substituents are each independently selected from:
(i) —ORa,
(ii) halo,
(iii) —CN, and
(iv) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(3) phenyl or heterocycle, wherein said heterocycle is selected from: 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:
(a) halo,
(b) —ORa,
(c) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(d) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(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)qRd,
(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) —C(═O)Ra, and
(p) —C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(4) halo,
(5) oxo,
(6) —ORa,
(7) —CN,
(8) —CO2Ra,
(9) —C(═O)Ra,
(10) —NRbRc,
(11) —S(O),:iRd,
(12) —C(═O)NRbRc,
(13) —O—CO2Rd,
(14) —N(Rb)CO2Rd,
(15) —O—(C═O)—NRbRc,
(16) —NRb—(C═O)—NRbRc,
(17) —SO2NRbRc,
(18) —N(Rb)SO2Rd,
or R15a and R15b and the atom(s) to which they are attached join to form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thietanyl and tetrahydrothienyl, 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) —C1-6allcyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —ORa,
(iii) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(iv) —CO2Ra,
(v) —NRbRc,
(vi) —S(O)qRd,
(vii) —C(═O)NRbRc, and
(viii) phenyl,
(b) phenyl or heterocycle, wherein said heterocycle is selected from: 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) —C1-6allcyl, 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)qRd,
(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, and
(o) —C(═O)Ra;
R19 is selected from:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-6 substituents, each independently selected from:
(a) halo,
(b) hydroxy,
(c) —OC1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —C3-6cycloalkyl, 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) —C1-4alkyl,
(ii) —OC1-6alkyl,
(iii) halo,
(iv) trifluoromethyl, and
(v) —OCF3,
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 substituents, substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —O—C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(d) —C1-6alkyl, 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) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo
(c) —OC1-6alkyl, which is unsubstituted or substituted with 1-5 halo
(d) —C3-6cycloalkyl,
(e) oxo,
(f) —CN,
(g) hydroxy, and
(h) phenyl;
R20 and R21 are each independently selected from:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-6 substituents each independently selected from:
(a) halo,
(b) hydroxy,
(c) —OCF3,
(d) —C3-6cycloalkyl, 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) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(ii) —OC1- 6alkyl, which is unsubstituted or substituted with 1-5 halo,
(iii) —CN,
(iv) halo, and
(v) trifluoromethyl,
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo,
(4) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(b) —OC1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(c) halo,
(d) hydroxy,
(e) trifluoromethyl,
(f) —OCF3, and
(g) —CN,
(5) —COR19, and
(6) —SO2R22;
R20a and R21a are each independently selected from:
(1) hydrogen,
(2) —C1-6alkyl, which is unsubstituted or substituted with 1-6 substituents each independently selected from:
(a) —O—C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(b) halo,
(c) hydroxy,
(d) —OCF3,
(e) —C3-6cycloalkyl, and
(f) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(ii) —OC1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(iii) —CN
(iv) halo, and
(v) trifluoromethyl,
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-5 halo,
(4) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(b) —OC1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(c) halo,
(d) hydroxy,
(e) trifluoromethyl,
(f) —OCF3, and
(g) —CN,
or where R20a and R21a 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:
(1) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(2) —O—C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(3) halo,
(4) hydroxy,
(5) phenyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C1-4alkyl, which is unsubstituted or substituted with 1-3 halo,
(b) —O—C1-4alkyl, which is unsubstituted or substituted with 1-3 halo, and
(c) halo,
(6) benzyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(a) —C1-4alkyl, which is unsubstituted or substituted with 1-3 halo,
(b) —OC1-4alkyl, which is unsubstituted or substituted with 1-3 halo, and
(c) halo,
(7) —COR19, and
(8) —SO2R22;
R22 is selected from:
(1) —C1-6alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(2) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-5 halo,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridinyl, 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:
(a) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(b) —O—C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(c) halo,
(d) hydroxy,
(e) trifluoromethyl,
(f) —OCF3,
(g) —CN, and
(h) benzyl, which is unsubstituted or substituted with 1-5 substituents each independently selected from:
(i) —C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(ii) —O—C1-6alkyl, which is unsubstituted or substituted with 1-5 halo,
(iii) halo, and
(iv) trifluoromethyl;
Ra is independently selected from:
(1) hydrogen,
(2) C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) —O—C1-6alkyl, which is unsubstituted or substituted with 1-6 halo,
(c) hydroxyl,
(d) —C3-6cycloalkyl, 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—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, 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—C1-6alkyl, 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 Rc are independently selected from:
(1) hydrogen,
(2) C1-6allcyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) halo,
(b) —ORa,
(c) —CN,
(d) —CO2Ra,
(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) —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 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)—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 Rc and 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:
(i) halo,
(ii) —ORa, and
(iii) —C1-6allcyl, which is unsubstituted or substituted with 1-6 halo, and
(iv) phenyl;
Rd is independently selected from:
(1) C1-6allcyl, which is unsubstituted or substituted with 1-4 substituents each independently selected from:
(a) halo,
(b) —ORa,
(c) —CO2Ra,
(d) —CN, and
(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) —ORa,
(iii) —C1-6allcyl, which is unsubstituted or substituted with 1-6 halo, and
(iv) nitro,
(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)—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, and
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-6 halo;
q is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.

### Claim 2 (depends on 1)

A compound of claim 1 wherein B is selected from the group consisting of:
which is unsubstituted or substituted with 1-7 substituents each independently selected from R1, R2, R3, R4, R10, and R11, wherein T, U, V, W, X, R1, R2, R3, R4, R10, and R11 are defined herein;
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

### Claim 3 (depends on 2)

A compound of claim 2, wherein B is selected from the group consisting of:
which is unsubstituted or substituted with 1-7 substituents each independently selected from R1, R2, R3, R4, R10, and R11, wherein R1, R2, R3, R4, R10, and R11 are defined herein;
and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

### Claim 4 (depends on 1)

A compound of any of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3 are each independently selected from:
(1) —C1-6alkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) fluoro,
(b) hydroxy,
(c) —O—C1-6 alkyl,
(d) —C3-6 cycloalkyl,
(e) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, oxazolyl, thiazolyl, 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, trifluoromethyl and —OCF3,
(f) —CO2R19
(g) —NR20R21,
(h) —SO2R22,
(i) —CONR20aR21a,
(j) trifluoromethyl,
(k) —(NR20a)CO2R19,
(l) —(NR19)(CO)NR20aR21a, and
(m) —O—C3-6cycloalkyl,
(2) —C3-6cycloalkyl, which is unsubstituted or substituted with 1-7 substituents each independently selected from:
(a) fluoro,
(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,
(3) phenyl or heterocycle, wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, thienyl, pyridazinyl, pyrrolidinyl, azetidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, azepanyl, 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) —CF3,
(b) halo,
(c) hydroxy,
(d) —O—CF3,
(e) —C3-6cycloalkyl,
(f) —CO2R19,
(g) —(CO)R19,
(h) —CONR20R21,
(i) oxo, and
(j) —S(O)qR22,
(4) halo,
(5) oxo,
(6) hydroxy,
(7) —O—C1-6alkyl which is unsubstituted or substituted with 1-5 halo,
(8) —CN,
(9) —CO2R19,
(10) —NR20R21,
(11) —SO2R22,
(12) —CONR20aR21a,
(13) —SO2NR20aR21a, and
(14) hydrogen.

### Claim 5 (depends on 1)

A compound of any of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 and the carbon atom to which they are attached join to form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, dioxolanyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiapyranyl, oxetanyl, thietanyl and tetrahydrothienyl, 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) —C1-6allcyl, which is unsubstituted or substituted with 1-3 substituents each independently selected from:
(i) halo,
(ii) —ORa,
(iii) —C3-6cycloalkyl,
(iv) —CO2Ra,
(v) —NRbRc,
(vi) —S(O)qRd,
(vii) —C(═O)NRbRc, and
(viii) phenyl,
(b) phenyl or heterocycle, wherein heterocycle is selected from: 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) —CF3
(iii) —ORa,
(iv) —CO2Ra,
(v) —O(C═O)Ra,
(vi) —CN,
(vii) oxo, and
(viii) —C(═O)NRbRc,
(c) halo,
(d) —CO2Ra,
(e) —C(═O)NRbRc,
(f) —CN,
(g) —C(═O)Ra, and
(h) oxo.

### Claim 6 (depends on 1)

A compound of any of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is selected from:
(1) —O—,
(2) —S(O)q—,
(3) —N(R8)—,
(4) —(C═O)—,
(5) —C(R8)(Ra)—,
(6) —C(N(Rb)—SO2Rd)(Ra)—,
(7) —C(N(Rb)(C═O)Ra)(Ra)—,
(8) —C(N(Rb)(C═O)ORa)(Ra)—,
(9) —CR10R11—,
(10) —N(R11)—, and
(11) —CR3R4—.

### Claim 7 (depends on 1)

A compound of any of claim 1, or a pharmaceutically acceptable salt thereof, wherein R6 is phenyl or pyridyl.

### Claim 8 (depends on 1)

A compound of claim 1, which is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of claim 1, or a pharmaceutically acceptable salt thereof.