IP Library › Granted Patent US 9,650,375

Granted Patent B2

US 9,650,375 · App. 14/769,159 · Granted May 16, 2017

Indole derivatives useful as anti-diabetic agents

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Quick Facts

Patent No.: US 9,650,375
App. No.: 14/769,159
Granted: May 16, 2017
Kind: B2

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Abstract

Novel compounds of the structural formula (I) are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

Claims (582)

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:

T is selected from the group consisting of: CR 3 , N and N-oxide;

U is selected from the group consisting of: CR 1 , N and N-oxide;

V is selected from the group consisting of: CR 2 , N and N-oxide;

W is selected from the group consisting of: CR 4 , N and N-oxide;

X is selected from:

(1) —CH 2 —,

(2) —CHF—,

(3) —CF 2 —,

(4) —S—,

(5) —S(O)—,

(6) —S(O) 2 —,

(7) —O—,

(8) —O—CH 2 —,

(9) —CH 2 —O—,

(10) —CH 2 —S—,

(11) —NH—,

(12) —C(O)—,

(13) —NHC(O)—,

(14) —C(O)NH—,

(15) —NHSO 2 —,

(16) —SO 2 NH—, and

(17) —CO 2 —,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: hydroxy, halogen, NH 2 , C 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, COC 1-6 alkyl, phenyl and —CH 2 phenyl, and wherein each NH is unsubstituted or substituted with 1 substituent selected from: C 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, COC 1-6 alkyl, phenyl and —CH 2 phenyl;

Y is selected from:

(1) —C 1-6 alkyl,

(2) —C 2-6 alkynyl,

(3) C 3-10 cycloalkyl,

(4) C 2-10 cycloheteroalkyl,

(5) aryl,

(6) heteroaryl, and

wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ;

Z is selected from:

(1) hydrogen,

(2) oxo,

(3) —(CH 2 ) n CO 2 H,

(4) —(CH 2 ) n CO 2 R i ,

(5) —(CH 2 ) n OCOR i ,

(6) —(CH 2 ) n OH, and

(7) —(CH 2 ) n P(O)(OR j ) 2 ,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, —OH and —NH 2 ;

each R 1 and R 2 is independently selected from:

(2) halogen,

(3) aryl,

(4) -aryl-C 3-7 cycloalkyl,

(5) -aryl-C 3-7 cycloalkenyl,

(6) -aryl-C 2-10 cycloheteroalkyl,

(7) aryl-aryl,

(8) -aryl-heteroaryl,

(9) heteroaryl, and

(10) —C 2-6 alkynyl-aryl,

wherein each alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a , provided that at least one of and only one of R 1 and R 2 is selected from the group consisting of: halogen;

R 3 is hydrogen or absent;

R 4 is hydrogen or absent;

R 5 is hydrogen;

R 6 is selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —(CH 2 ) m OC 1-6 alkyl,

(4) halogen,

(5) —(CH 2 ) m CN,

(6) —(CH 2 ) m CF 3 ,

(7) —(CH 2 ) m OCF 3 ,

(8) —(CH 2 ) m CHF 2 ,

(9) —(CH 2 ) m CH 2 F,

(10) —(CH 2 ) m SO 2 C 1-6 alkyl,

(11) —(CH 2 ) m CO 2 H,

(12) —(CH 2 ) m CO 2 C 1-6 alkyl,

(13) —(CH 2 ) m C(O)H,

(14) —(CH 2 ) m C(O)NH 2 ,

(15) —(CH 2 ) m C 3-6 cycloalkyl,

(16) —(CH 2 ) m C 2-7 cycloheteroalkyl,

(17) —(CH 2 ) m aryl, and

(18) —(CH 2 ) m heteroaryl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —(CH 2 ) 0-5 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —SO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl;

each R a is independently selected from the group consisting of:

(1) —(CH 2 ) m -halogen,

(2) oxo,

(3) —(CH 2 ) m OH,

(4) —(CH 2 ) m N(R j ) 2 ,

(5) —(CH 2 ) m NO 2 ,

(6) —(CH 2 ) m CN,

(7) —C 1-6 alkyl,

(8) —(CH 2 ) m CF 3 ,

(9) —(CH 2 ) m OCF 3 ,

(10) —O—(CH 2 ) m —OC 1-6 alkyl,

(11) —(CH 2 ) m C(O)N(R j ) 2 ,

(12) —(CH 2 ) m C(═N—OH)N(R j ) 2 ,

(13) —(CH 2 ) m OC 1-6 alkyl,

(14) —(CH 2 ) m O—(CH 2 ) m —C 3-7 cycloalkyl,

(15) —(CH 2 ) m O—(CH 2 ) m —C 2-7 cycloheteroalkyl,

(16) —(CH 2 ) m O—(CH 2 ) m -aryl,

(17) —(CH 2 ) m O—(CH 2 ) m -heteroaryl,

(18) —(CH 2 ) m SC 1-6 alkyl,

(19) —(CH 2 ) m S(O)C 1-6 alkyl,

(20) —(CH 2 ) m SO 2 C 1-6 alkyl,

(21) —(CH 2 ) m SO 2 C 3-7 cycloalkyl,

(22) —(CH 2 ) m SO 2 C 2-7 cycloheteroalkyl,

(23) —(CH 2 ) m SO 2 -aryl,

(24) —(CH 2 ) m SO 2 -heteroaryl,

(25) —(CH 2 ) m SO 2 NHC 1-6 alkyl,

(26) —(CH 2 ) m SO 2 N(C 1-6 alkyl) 2 ,

(27) —(CH 2 ) m SO 2 NHC 3-7 cycloalkyl,

(28) —(CH 2 ) m SO 2 NHC 2-7 cycloheteroalkyl,

(29) —(CH 2 ) m SO 2 NH-aryl,

(30) —(CH 2 ) m SO 2 NH-heteroaryl,

(31) —(CH 2 ) m NHSO 2 —C 1-6 alkyl,

(32) —(CH 2 ) m NHSO 2 —C 3-7 cycloalkyl,

(33) —(CH 2 ) m NHSO 2 —C 2-7 cycloheteroalkyl,

(34) —(CH 2 ) m NHSO 2 -aryl,

(35) —(CH 2 ) m NHSO 2 NH-heteroaryl,

(36) —(CH 2 ) m N(R j )—C 1-6 alkyl,

(37) —(CH 2 ) m N(R j )—C 3-7 cycloalkyl,

(38) —(CH 2 ) m N(R j )—C 2-7 cycloheteroalkyl,

(39) —(CH 2 ) m N(R j )—C 2-7 cycloheteroalkenyl,

(40) —(CH 2 ) m N(R j )-aryl,

(41) —(CH 2 ) m N(R j )-heteroaryl,

(42) —(CH 2 ) m C(O)R f ,

(43) —(CH 2 ) m C(O)N(R j ) 2 ,

(44) —(CH 2 ) m N(R j )C(O)N(R j ) 2 ,

(45) —(CH 2 ) m CO 2 H,

(46) —(CH 2 ) m OCOH,

(47) —(CH 2 ) m CO 2 R f ,

(48) —(CH 2 ) m OCOR f ,

(49) —(CH 2 ) m C 3-7 cycloalkyl,

(50) —(CH 2 ) m C 3-7 cycloalkenyl,

(51) —(CH 2 ) m C 2-6 cycloheteroalkyl,

(52) —(CH 2 ) m C 2-6 cycloheteroalkenyl,

(53) —(CH 2 ) m aryl, and

(54) —(CH 2 ) m heteroaryl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —(CH 2 ) 0-5 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —SO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl;

each R b is independently selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 3-6 cycloalkyl,

(4) —C 3-6 cycloalkenyl,

(5) —C 2-6 cycloheteroalkyl,

(6) —C 2-6 cycloheteroalkenyl,

(7) aryl,

(8) heteroaryl,

(9) —(CH 2 )t-halogen,

(10) —(CH 2 )s-OH,

(11) —(CH 2 )sNO 2 ,

(12) —(CH 2 )sNH 2 ,

(13) —(CH 2 )sNH(C 1-6 alkyl),

(14) —(CH 2 )sN(C 1-6 alkyl) 2 ,

(15) —(CH 2 )sOC 1-6 alkyl,

(16) —(CH 2 )qCO 2 H,

(17) —(CH 2 )qCO 2 C 1-6 alkyl,

(18) —(CH 2 )sCF 3 ,

(19) —(CH 2 )sOCF 3 ,

(20) —(CH 2 )sCHF 2 ,

(21) —(CH 2 )sCH 2 F,

(22) —(CH 2 )sCN,

(23) —(CH 2 )sSO 2 C 1-6 alkyl, and

(24) —(CH 2 )sCON(R e ) 2 ,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 halogens, and wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2 or 3 halogens, and wherein two R b substituents together with the atom to which they are attached may form a C 3-6 cycloalkyl ring or a C 2-6 cycloheteroalkyl ring;

each R c is independently selected from:

(1) halogen,

(2) oxo,

(3) —(CH 2 ) r OH,

(4) —(CH 2 ) r N(R e ) 2 ,

(5) —(CH 2 ) r CN,

(6) —C 1-6 alkyl,

(7) —CF 3 ,

(8) —C 1-6 alkyl-OH,

(9) —OCH 2 OC 1-6 alkyl,

(10) —(CH 2 ) r OC 1-6 alkyl,

(11) —OCH 2 aryl,

(12) —(CH 2 ) r SC 1-6 alkyl,

(13) —(CH 2 ) r C(O)R f ,

(14) —(CH 2 ) r C(O)N(R e ) 2 ,

(15) —(CH 2 ) r CO 2 H,

(16) —(CH 2 ) r CO 2 R f ,

(17) —(CH 2 ) r C 3-7 cycloalkyl,

(18) —(CH 2 ) r C 2-6 cycloheteroalkyl,

(19) —(CH 2 ) r aryl, and

(20) —(CH 2 ) r heteroaryl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —CN, —N(R h ) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl and heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —N(R h ) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl and heteroaryl;

each R e , R g and R h is independently selected from:

(1) hydrogen,

(2) —C 1-6 alkyl, and

(3) —O—C 1-6 alkyl,

wherein each alkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C 1-6 alkyl, —OC 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ;

each R j is independently selected from:

(1) hydrogen,

(2) C 1-6 alkyl,

(3) C 3-6 cycloalkyl,

(4) —C(O)R i , and

(5) —SO 2 R i ,

wherein each alkyl and cycloalkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C 1-6 alkyl, —OC 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ;

each R f and R i is independently selected from:

(1) C 1-6 alkyl,

(2) C 4-7 cycloalkyl,

(3) C 4-7 cycloalkenyl,

(4) C 3-7 cycloheteroalkyl,

(5) C 3-7 cycloheteroalkenyl,

(6) aryl, and

(7) heteroaryl,

wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloakyl, and heteroaryl;

each a independently selected from 0, 1 or 2;

each b independently selected from 0, 1 or 2;

each n independently selected from 0, 1, 2, 3 or 4;

each m independently selected from 0, 1, 2, 3 or 4;

each p independently selected from 0, 1, 2, or 3;

each q independently selected from 0, 1, 2, 3 or 4;

each r independently selected from 0, 1 or 2;

each s independently selected from 0, 1, 2, 3 or 4; and

each t independently selected from 0, 1, 2, 3 or 4.

2. The compound of structural formula I according to claim 1

or a pharmaceutically acceptable salt thereof, wherein:

T is selected from the group consisting of: CR 3 , N and N-oxide;

U is selected from the group consisting of: CR 1 , N and N-oxide;

V is selected from the group consisting of: CR 2 , N and N-oxide;

W is selected from the group consisting of: CR 4 , N and N-oxide;

X is selected from:

(1) —CH 2 —,

(2) —CHF—,

(3) —CF 2 —,

(4) —S—,

(5) —O—,

(6) —O—CH 2 —,

(7) —CH 2 —O—,

(8) —NH—,

(9) —C(O)—,

(10) —NHC(O)—,

(11) —C(O)NH—,

(12) —NHSO 2 —,

(13) —SO 2 NH—, and

(14) —CO 2 —,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: hydroxy, halogen, NH 2 , C 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, and COC 1-6 alkyl, and wherein each NH is unsubstituted or substituted with 1 substituent selected from: C 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, and COC 1-6 alkyl;

Y is selected from:

(1) —C 1-6 alkyl,

(2) —C 1-6 alkynyl,

(3) C 3-10 cycloalkyl,

(4) C 2-10 cycloheteroalkyl,

(5) aryl,

(6) heteroaryl, and

wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ;

Z is selected from:

(1) hydrogen,

(2) oxo,

(3) —(CH 2 ) n CO 2 H,

(4) —(CH 2 ) n CO 2 R i ,

(5) —(CH 2 ) n OCOR i ,

(6) —(CH 2 ) n OH, and

(7) —(CH 2 ) n P(O)(OR j ) 2 ,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, —OH and —NH 2 ;

each R 1 and R 2 is independently selected from:

(2) halogen,

(3) aryl,

(4) -aryl-C 3-7 cycloalkyl,

(5) -aryl-C 3-7 cycloalkenyl,

(6) -aryl-C 2-10 cycloheteroalkyl,

(7) aryl-aryl,

(8) -aryl-heteroaryl,

(9) heteroaryl, and

(10) —C 2-6 alkynyl-aryl,

R 3 is hydrogen or absent;

R 4 is hydrogen or absent;

R 5 is hydrogen;

R 6 is selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —(CH 2 ) m OC 1-6 alkyl,

(4) halogen,

(5) —(CH 2 ) m CN,

(6) —(CH 2 ) m CF 3 ,

(7) —(CH 2 ) m OCF 3 ,

(8) —(CH 2 ) m CHF 2 ,

(9) —(CH 2 ) m CH 2 F,

(10) —(CH 2 ) m SO 2 C 1-6 alkyl,

(11) —(CH 2 ) m C 3-6 cycloalkyl,

(12) —(CH 2 ) m C 2-7 cycloheteroalkyl,

(13) —(CH 2 ) m aryl, and

(14) —(CH 2 ) m heteroaryl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —(CH 2 ) 0-5 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —SO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl;

each R a is independently selected from the group consisting of:

(1) —(CH 2 ) m -halogen,

(2) oxo,

(3) —(CH 2 ) m OH,

(4) —(CH 2 ) m N(R j ) 2 ,

(5) —(CH 2 ) m NO 2 ,

(6) —(CH 2 ) m CN,

(7) —C 1-6 alkyl,

(8) —(CH 2 ) m CF 3 ,

(9) —(CH 2 ) m OCF 3 ,

(10) —O—(CH 2 ) m —OC 1-6 alkyl,

(11) —(CH 2 ) m C(O)N(R j ) 2 ,

(12) —(CH 2 ) m C(═N—OH)N(R j ) 2 ,

(13) —(CH 2 ) m OC 1-6 alkyl,

(14) —(CH 2 ) m O—(CH 2 ) m —C 3-7 cycloalkyl,

(15) —(CH 2 ) m O—(CH 2 ) m —C 2-7 cycloheteroalkyl,

(16) —(CH 2 ) m O—(CH 2 ) m -aryl,

(17) —(CH 2 ) m O—(CH 2 ) m -heteroaryl,

(18) —(CH 2 ) m SC 1-6 alkyl,

(19) —(CH 2 ) m S(O)C 1-6 alkyl,

(20) —(CH 2 ) m SO 2 C 1-6 alkyl,

(21) —(CH 2 ) m SO 2 C 3-7 cycloalkyl,

(22) —(CH 2 ) m SO 2 C 2-7 cycloheteroalkyl,

(23) —(CH 2 ) m SO 2 -aryl,

(24) —(CH 2 ) m SO 2 -heteroaryl,

(25) —(CH 2 ) m SO 2 NHC 1-6 alkyl,

(26) —(CH 2 ) m SO 2 N(C 1-6 alkyl) 2 ,

(27) —(CH 2 ) m SO 2 NHC 3-7 cycloalkyl,

(28) —(CH 2 ) m SO 2 NHC 2-7 cycloheteroalkyl,

(29) —(CH 2 ) m SO 2 NH-aryl,

(30) —(CH 2 ) m SO 2 NH-heteroaryl,

(31) —(CH 2 ) m NHSO 2 —C 1-6 alkyl,

(32) —(CH 2 ) m NHSO 2 —C 3-7 cycloalkyl,

(33) —(CH 2 ) m NHSO 2 —C 2-7 cycloheteroalkyl,

(34) —(CH 2 ) m NHSO 2 -aryl,

(35) —(CH 2 ) m NHSO 2 NH-heteroaryl,

(36) —(CH 2 ) m N(R j )—C 1-6 alkyl,

(37) —(CH 2 ) m N(R j )—C 3-7 cycloalkyl,

(38) —(CH 2 ) m N(R j )—C 2-7 cycloheteroalkyl,

(39) —(CH 2 ) m N(R j )—C 2-7 cycloheteroalkenyl,

(40) —(CH 2 ) m N(R j )-aryl,

(41) —(CH 2 ) m N(R j )-heteroaryl,

(42) —(CH 2 ) m C(O)R f ,

(43) —(CH 2 ) m C(O)N(R j ) 2 ,

(44) —(CH 2 ) m N(R j )C(O)N(R j ) 2 ,

(45) —(CH 2 ) m CO 2 H,

(46) —(CH 2 ) m OCOH,

(47) —(CH 2 ) m CO 2 R f ,

(48) —(CH 2 ) m OCOR f ,

(49) —(CH 2 ) m C 3-7 cycloalkyl,

(50) —(CH 2 ) m C 3-7 cycloalkenyl,

(51) —(CH 2 ) m C 2-6 cycloheteroalkyl,

(52) —(CH 2 ) m C 2-6 cycloheteroalkenyl,

(53) —(CH 2 ) m aryl, and

(54) —(CH 2 ) m heteroaryl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl, and wherein alkyl, cycloalkyl cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —(CH 2 ) 0-5 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —SO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl;

each R b is independently selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) —C 3-6 cycloalkyl,

(4) —C 3-6 cycloalkenyl,

(5) —C 2-6 cycloheteroalkyl,

(6) —C 2-6 cycloheteroalkenyl,

(7) aryl,

(8) heteroaryl,

(9) —(CH 2 )t-halogen,

(10) —(CH 2 )s-OH,

(11) —(CH 2 )sNO 2 ,

(12) —(CH 2 )sNH 2 ,

(13) —(CH 2 )sNH(C 1-6 alkyl),

(14) —(CH 2 )sN(C 1-6 alkyl) 2 ,

(15) —(CH 2 )sOC 1-6 alkyl,

(16) —(CH 2 )qCO 2 H,

(17) —(CH 2 )qCO 2 C 1-6 alkyl,

(18) —(CH 2 )sCF 3 ,

(19) —(CH 2 )sOCF 3 ,

(20) —(CH 2 )sCHF 2 ,

(21) —(CH 2 )sCH 2 F,

(22) —(CH 2 )sCN,

(23) —(CH 2 )sSO 2 C 1-6 alkyl, and

(24) —(CH 2 )sCON(R e ) 2 ,

each R c is independently selected from:

(1) halogen,

(2) oxo,

(3) —(CH 2 ) r OH,

(4) —(CH 2 ) r N(R e ) 2 ,

(5) —(CH 2 ) r CN,

(6) —C 1-6 alkyl,

(7) —CF 3 ,

(8) —C 1-6 alkyl-OH,

(9) —OCH 2 OC 1-6 alkyl,

(10) —(CH 2 ) r OC 1-6 alkyl,

(11) —OCH 2 aryl,

(12) —(CH 2 ) r SC 1-6 alkyl,

(13) —(CH 2 ) r C(O)R f ,

(14) —(CH 2 ) r C(O)N(R e ) 2 ,

(15) —(CH 2 ) r CO 2 H,

(16) —(CH 2 ) r CO 2 R f ,

(17) —(CH 2 ) r C 3-7 cycloalkyl,

(18) —(CH 2 ) r C 2-6 cycloheteroalkyl,

(19) —(CH 2 ) r aryl, and

(20) —(CH 2 ) r heteroaryl,

each R e , R g and R h is independently selected from:

(1) hydrogen,

(2) —C 1-6 alkyl, and

(3) —O—C 1-6 alkyl,

each R j is independently selected from:

(1) hydrogen,

(2) C 1-6 alkyl,

(3) C 3-6 cycloalkyl,

(4) —C(O)R i , and

(5) —SO 2 R i ,

each R f and R i is independently selected from:

(1) C 1-6 alkyl,

(2) C 4-7 cycloalkyl,

(3) C 4-7 cycloalkenyl,

(4) C 3-7 cycloheteroalkyl,

(5) C 3-7 cycloheteroalkenyl,

(6) aryl, and

(7) heteroaryl,

a is 0, 1 or 2;

b is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

m is 0, 1, 2, 3 or 4;

p is 0, 1, 2, or 3;

q is 0, 1, 2, 3 or 4;

r is 0, 1 or 2;

s is 0, 1, 2, 3 or 4; and

t is 0, 1, 2, 3 or 4.

3. The compound according to claim 1 , wherein

T is selected from —CR 3 — and N;

U is —CR 1 —;

V is —CR 2 —; and

W is selected from —CR 4 — and N,

provided that one of T and W is N, and further provided that if W is N, then R 1 is selected from hydrogen, halogen, —CN, —CF 3 , —C 1-6 alkyl, —C 2-6 alkenyl and —C 2-6 alkynyl, and if T is N then R 2 is selected from hydrogen, halogen, —CN, —CF 3 , —C 1-6 alkyl, —C 2-6 alkenyl and —C 2-6 alkynyl;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein T is —CR 3 — or N; U is —CR 1 —; V is —CR 2 —; and W is —CR 4 —; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 , wherein X is selected from:

(1) —CH 2 —,

(2) —S—,

(3) —S(O)—,

(4) —S(O) 2 —,

(5) —O—,

(6) —O—CH 2 —,

(7) —CH 2 —O—,

(8) —CH 2 —S—,

(9) —NH—,

(10) —C(O)—, and

(11) —C(O)NH—,

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 4 , wherein X is —CH 2 —; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 , wherein Y is selected from:

(1) C 1-6 alkyl,

(2) C 3-10 cycloalkyl, and

(3) aryl,

wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7 , wherein Z is selected from:

(1) —(CH 2 ) n CO 2 H, and

(2) —(CH 2 ) n OH,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, —OH and —NH 2 ; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 , wherein

each R 1 and R 2 is independently selected from:

(1) halogen,

(2) aryl,

(3) aryl-C 3-7 cycloalkyl,

(4) aryl-C 2-10 cycloheteroalkyl,

(5) aryl-aryl,

(6) aryl-heteroaryl, and

(7) heteroaryl,

wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a , provided that at least one of and only one of R 1 and R 2 is halogen;

or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 , wherein R 1 is independently selected from:

(1) aryl,

(2) -aryl-C 3-7 cycloalkyl,

(3) -aryl-C 2-10 cycloheteroalkyl,

(4) aryl-aryl, and

(5) -aryl-heteroaryl,

wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a , and

R 2 is halogen; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10 , wherein R 1 is independently selected from:

(1) phenyl,

(2) -phenyl-cyclopropyl,

(3) -phenyl-pyrrolidine,

(4) biphenyl, and

(5) -phenyl-pyridine,

wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ; and

R 2 is halogen; or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 wherein R 6 is selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) halogen,

(4) CN,

(5) CF 3 ,

(6) —CO 2 H,

(7) —C(O)H,

(8) —C(O)NH 2 ,

(9) —C 3-6 cycloalkyl, and

(10) aryl,

wherein alkyl, cycloalkyl, and aryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —(CH 2 ) 0-5 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, and —SO 2 C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 , wherein R 3 is hydrogen or absent; R 4 is hydrogen; R 5 is hydrogen, and R 6 is hydrogen; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 wherein:

T is selected from —CR 3 — and N;

U is —CR 1 —;

V is —CR 2 —; and

W is selected from —CR 4 — and N,

X is selected from:

(1) —CH 2 —,

(2) —S—,

(3) —S(O)—,

(4) —S(O) 2 —,

(5) —O—,

(6) —O—CH 2 —,

(7) —CH 2 —O—,

(8) —CH 2 —S—,

(9) —NH—,

(10) —C(O)—, and

(11) —C(O)NH—,

Y is selected from:

(1) —C 1-6 alkyl,

(2) —C 2-6 alkynyl,

(3) C 3-10 cycloalkyl,

(4) C 2-10 cycloheteroalkyl,

(5) aryl,

(6) heteroaryl, and

wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ;

Z is selected from:

(1) hydrogen,

(2) oxo,

(3) —(CH 2 ) n CO 2 H,

(4) —(CH 2 ) n CO 2 R i ,

(5) —(CH 2 ) n OCOR i ,

(6) —(CH 2 ) n OH, and

(7) —(CH 2 ) n P(O)(OR j ) 2 ,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, —OH and —NH 2 ;

R 1 and R 2 are independently selected from:

(2) halogen,

(3) aryl,

(4) -aryl-C 3-7 cycloalkyl,

(5) -aryl-C 3-7 cycloalkenyl,

(6) -aryl-C 2-10 cycloheteroalkyl,

(7) aryl-aryl,

(8) -aryl-heteroaryl,

(9) heteroaryl, and

(10) —C 2-6 alkynyl-aryl,

R 3 is hydrogen or absent;

R 4 is hydrogen or absent;

R 5 is hydrogen, and

R 6 is selected from:

(1) hydrogen,

(2) —C 1-6 alkyl,

(3) halogen,

(4) CN,

(5) CF 3 ,

(6) —CO 2 H,

(7) —C(O)H,

(8) —C(O)NH 2 ,

(9) —C 3-6 cycloalkyl, and

(10) aryl,

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 wherein:

T is —CR 3 — or N;

U is —CR 1 —;

V is —CR 2 —;

W is —CR 4 —;

X is —CH 2 —;

Y is selected from:

(1) C 1-6 alkyl,

(2) C 3-10 cycloalkyl, and

(3) aryl,

wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R b ;

Z is selected from:

(1) —(CH 2 ) n CO 2 H, and

(2) —(CH 2 ) n OH,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from C 1-6 alkyl, —OH and —NH 2 ;

R 1 is independently selected from:

(1) phenyl,

(2) -phenyl-cyclopropyl,

(3) -phenyl-pyrrolidine,

(4) biphenyl, and

(5) -phenyl-pyridine,

wherein each cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ;

R 2 is halogen;

R 3 is hydrogen or absent;

R 4 is hydrogen;

R 5 is hydrogen, and

R 6 is hydrogen;

or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 15 , selected from:

or a pharmaceutically acceptable salt thereof.

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

18. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a compound selected from simvastatin, ezetimibe and sitagliptin; and a pharmaceutically acceptable carrier.

19. A method for the treatment of Type 2 diabetes, hyperglycemia, Metabolic Syndrome, obesity, hypercholesterolemia, and hypertension, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of claim 1 .

Assignments (1)

MERGER Recorded Aug 8, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061102/0145 →