Antidiabetic heterocyclic compounds

Patent metadata

Field	Value
Publication number	US-11072602-B2
Application number	US-201716461569-A
Country	US
Kind code	B2
Filing date	Dec 1, 2017
Priority date	Dec 6, 2016
Publication date	Jul 27, 2021
Grant date	Jul 27, 2021

Abstract

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

First claim

What is claimed is:

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein
“a” is a single bond;
T is CH;
U is CR 1 ;
V is CR 2 ;
W is CH;
Y is selected from the group consisting of: —CR g R g ;
A is selected from the group consisting of:
(1) —C 1-6 alkyl-N(R n )—,
(2) —C 1-6 alkyl-C 6-14 cycloheteroalkyl, and
(3) —C 6-14 cycloheteroalkyl,

wherein A is unsubstituted or substituted with one to five substituents selected from R a ;
B is selected from the group consisting of:
(1) hydrogen,
(2) aryl,
(3) aryl-O—,
(4) aryl-C 1-10 alkyl-,
(5) aryl-C 1-10 alkyl-O—,
(6) C 3-6 cycloalkyl,
(7) C 3-6 cycloalkyl-C 1-10 alkyl-,
(8) C 3-6 cycloalkyl-C 1-10 alkyl-O—,
(9) C 3-6 cycloalkenyl,
(10) C 3-6 cycloalkenyl-C 1-10 alkyl-,
(11) C 3-6 cycloalkenyl-C 1-10 alkyl-O—,
(12) C 2-5 cycloheteroalkyl,
(13) C 3-6 cycloheteroalkyl-C 1-10 alkyl-,
(14) C 3-6 cycloheteroalkyl-C 1-10 alkyl-O—,
(15) heteroaryl,
(16) heteroaryl-O—,
(17) heteroaryl-C 1-10 alkyl-, and
(18) heteroaryl-C 1-10 alkyl-O—,

wherein B is unsubstituted or substituted with one to five substituents selected from R b ;
R 1 is selected from —C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R L , and wherein R 1 is substituted with a substituent selected from R 7 ;
R 2 is hydrogen;
R 3 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OR e ,
(4) —CN,
(5) —C 1-6 alkyl,
(6) —C 3-6 cycloalkyl, and
(7) —C 3-6 cycloalkyl-C 1-3 alkyl-,

wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R i ;
R 4 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) OR e ,
(4) C 1-6 alkyl,
(5) C 1-6 alkyl-O—,
(6) C 3-6 cycloalkyl,
(7) C 3-6 cycloalkyl-O—,
(8) C 3-6 cycloalkyl-C 1-10 alkyl-,
(9) C 3-6 cycloalkyl-C 1-10 alkyl-O—,
(10) C 2-5 cycloheteroalkyl,
(11) C 2-5 cycloheteroalkyl-O—,
(12) C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(13) C 2-5 cycloheteroalkyl-C 1-10 alkyl-O—,
(14) aryl,
(15) aryl-O—,
(16) aryl-C 1-10 alkyl-,
(17) heteroaryl,
(18) heteroaryl-O—, and
(19) heteroaryl-C 1-10 alkyl-,

wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R j ,
provided that when R 4 is selected from the group consisting of:
(1) OR e ,
(2) C 1-6 alkyl-O—,
(3) C 3-6 cycloalkyl-O—,
(4) C 3-6 cycloalkyl-C 1-10 alkyl-O—,
(5) C 2-5 cycloheteroalkyl-O—,
(6) C 2-5 cycloheteroalkyl-C 1-10 alkyl-O—,
(7) aryl-O—, and
(8) heteroaryl-O—,

then Y is selected from the group consisting of: —CR g R g ;
R 5 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —C 3-6 cycloalkyl,

wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R j ;
R 6 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —C 3-6 cycloalkyl,

wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R j ;
R 7 is selected from the group consisting of:
(1) —CO 2 R 8 ,
(2) —C 1-6 alkyl-CO 2 R 8 ,
(3) —C 1-6 alkyl-CONHSO 2 R m ,
(4) —C 1-6 alkyl-SO 2 NHCOR m ,
(5) —C 1-6 alkyl-tetrazolyl, and
(6) a cycloheteroalkyl selected from the group consisting of:

R 8 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 3-6 cycloalkyl, and
(4) aryl-C 1-6 -alkyl,

wherein each alkyl, cycloalkyl and aryl is unsubstituted or substituted with one to three substituents selected from R j ;
R a is selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) halogen,
(3) —OR e ,
(4) —NR c S(O) n R e ,
(5) —S(O) n R e ,
(6) —S(O) n NR c R d ,
(7) —NR c R d ,
(8) —C(O)R e ,
(9) —OC(O)R e ,
(10) —CO 2 R e ,
(11) —CN,
(12) —C(O)NR c R d ,
(13) —NR c C(O)R e ,
(14) —NR c C(O)OR e ,
(15) —NR c C(O)NR c R d ,
(16) —CF 3 ,
(17) —OCF 3 ,
(18) —OCHF 2 ,
(19) aryl,
(20) heteroaryl,
(21) —C 3-6 cycloalkyl,
(22) —C 3-6 cycloalkenyl, and
(23) —C 2-5 cycloheteroalkyl,

wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with —C 1-6 alkyl, halogen, —O—C 1-6 alkyl and —CF 3 ;
R b is independently selected from the group consisting of:
(1) —C 1-10 alkyl,
(2) —C 2-10 alkenyl,
(3) —CF 3 ,
(4) halogen,
(5) —CN,
(6) —OH,
(7) —OC 1-10 alkyl,
(8) —OC 2-10 alkenyl,
(9) —O(CH 2 ) p OC 1-10 alkyl,
(10) —O(CH 2 ) p C 3-6 cycloalkyl,
(11) —O(CH 2 ) p C 3-6 cycloalkyl-C 1-10 alkyl-,
(12) —O(CH 2 ) p C 2-5 cycloheteroalkyl,
(13) —O(CH 2 ) p C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(14) —O-aryl,
(15) —O-heteroaryl,
(16) —O-aryl-C 1-10 alkyl-,
(17) —O-heteroaryl-C 1-10 alkyl-,
(18) —O(CH 2 ) p NR c S(O) m R e ,
(19) —O(CH 2 ) p S(O) m R e ,
(20) —O(CH 2 ) p S(O) m NR c R d ,
(21) —O(CH 2 ) p NR c R d ,
(22) —C(O)R e ,
(23) —OC(O)R e ,
(24) —CO 2 R e ,
(25) —C(O)NR c R d ,
(26) —NR c C(O)R e ,
(27) —NR c C(O)OR e ,
(28) —NR c C(O)NR c R d ,
(29) —O(CH 2 ) p O—C 3-6 cycloalkyl,
(30) —O(CH 2 ) p O—C 2-5 cycloheteroalkyl,
(31) —OCF 3 ,
(32) —OCHF 2 ,
(33) —(CH 2 ) p C 3-6 cycloalkyl,
(34) —(CH 2 ) p C 2-5 cycloheteroalkyl,
(35) aryl,
(36) heteroaryl,
(37) aryl-C 1-10 alkyl-, and
(38) heteroaryl-C 1-10 alkyl-,

wherein each CH, CH 2 , alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with —C 1-6 alkyl, halogen, —O—C 1-6 alkyl and —CF 3 ;
R c and R d are each independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 2-10 alkenyl,
(4) C 3-6 cycloalkyl,
(5) C 3-6 cycloalkyl-C 1-10 alkyl-,
(6) C 2-5 cycloheteroalkyl,
(7) C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(8) aryl,
(9) heteroaryl,
(10) aryl-C 1-10 alkyl-, and
(11) heteroaryl-C 1-10 alkyl-,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from R f ;
each R e is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) —C 3-6 cycloalkyl,
(5) —C 3-6 cycloalkyl-C 1-10 alkyl-,
(6) —C 2-5 cycloheteroalkyl,
(7) —C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(8) aryl,
(9) aryl-C 1-10 alkyl-,
(10) heteroaryl, and
(11) heteroaryl-C 1-10 alkyl-,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R h ;
each R f is selected from the group consisting of:
(1) halogen,
(2) C 1-10 alkyl,
(3) —OH,
(4) —O—C 1-4 alkyl,
(5) —S(O) m —C 1-4 alkyl,
(6) —CN,
(7) —CF 3 ,
(8) —OCHF 2 , and
(9) —OCF 3 ,

wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C 1-6 alkyl, cyano and S(O) 2 C 1-6 alkyl;
each R g is selected from the group consisting of:
(1) hydrogen,
(2) —C(O)R e , and
(3) —C 1-10 alkyl,

wherein each alkyl is unsubstituted or substituted with one to five halogens;
each R h is selected from the group consisting of:
(1) halogen,
(2) C 1-10 alkyl,
(3) —OH,
(4) —O—C 1-4 alk

Assignees

• Merck Sharp & Dohme
• Miller Michael
• Chobanian Harry R
• He Shuwen
• Hao Jinsong
• Pio Barbara

Inventors

• Miller Michael
• Chobanian Harry R
• He Shuwen
• Hao Jinsong
• Pio Barbara

Classifications

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D451/14

  containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D471/08

  Bridged systems · CPC title