Indole derivatives useful as anti-diabetic agents

Patent metadata

Field	Value
Publication number	US-9650375-B2
Application number	US-201414769159-A
Country	US
Kind code	B2
Filing date	Mar 10, 2014
Priority date	Mar 14, 2013
Publication date	May 16, 2017
Grant date	May 16, 2017

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.

First claim

What is claimed is:

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,
(1

Assignees

• Merck Sharp & Dohme
• Acton Iii John J
• Anand Rajan
• Arasappan Ashok
• Dang Qun
• Sebhat Iyassu
• Pu Zhifa
• Suzuki Takao

Inventors

• Acton Iii John J
• Anand Rajan
• Arasappan Ashok
• Dang Qun
• Sebhat Iyassu
• Pu Zhifa
• Suzuki Takao

Classifications

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/397

  having four-membered rings, e.g. azetidine · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• A61K31/366

  having six-membered rings, e.g. delta-lactones · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title