Antidiabetic spirochroman compounds

Patent metadata

Field	Value
Publication number	US-10968232-B2
Application number	US-201716465156-A
Country	US
Kind code	B2
Filing date	Dec 15, 2017
Priority date	Dec 20, 2016
Publication date	Apr 6, 2021
Grant date	Apr 6, 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
T is CH;
U is CR 1 ;
V is CR 2 ;
W is CH;
X is selected from the group consisting of:
(1) oxygen,
(2) —CR b R b ,
(3) —C═O, and
(4) —C(R b )OR b , and
(5) N(R b );

Z is selected from:

Y is selected from the group consisting of:
(1) —C(R g )—,
(2) —C(F)—, and
(3) —N—;

R 1 and R 2 are each independently selected from:
(1) hydrogen, and
(2) —C 1-6 alkyl,

wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R L , and wherein one of R 1 and R 2 is C 1-6 alkyl, wherein —C 1-6 alkyl is substituted with R 7 ;
each R 3 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen, —CN,
(3) —CF 3 , and
(4) —C 1-6 alkyl;

R 4 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —CF 3 , and
(4) —C 1-6 alkyl;

R 5 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —CN,
(4) —CF 3 ,
(5) —C 1-6 alkyl, and
(6) —C 1-5 spirocycloalkyl,

or two R 5 groups, and the carbons they are attached to, form a —C 3-6 cycloalkyl ring or a —C 2-5 cycloheteroalkyl ring;
R 6 is selected from the group consisting of:
(1) aryl,
(2) aryl-SO 2 ,
(3) aryl-C 1-10 alkyl-,
(4) aryl-N(R i )—,
(5) aryl-C 1-10 alkyl-N(R i )—,
(6) heteroaryl,
(7) heteroaryl-C 1-10 alkyl-, and
(8) heteroaryl-N(R i )—,

wherein each CH 2 is unsubstituted or substituted with 1-2 substituents selected from R a , and wherein each aryl, and heteroaryl is unsubstituted or substituted with 1-5 substituents selected from R a :
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) —OC 1-6 alkyl,
(3) halogen,
(4) —S(O) n R e ,
(5) —S(O) n NR c R d ,
(6) —NR c R d ,
(7) —C(O)R e ,
(8) —OC(O)R e ,
(9) —CO 2 R e ,
(10) —CN,
(11) —C(O)NR c R d ,
(12) —CF 3 ,
(13) —OCF 3 ,
(14) —OCHF 2 ,
(15) —OCH 2 CF 3 ,
(16) aryl,
(17) heteroaryl,
(18) C 3-6 cycloalkyl, and
(19) C 2-5 cycloheteroalkyl,

wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-3 substituents selected from: halogen, —C 1-6 alkyl, —O—C 1-6 alkyl, —CF 3 , CO 2 H, and —CO 2 C 1-6 alkyl;
each R b is independently selected from the group consisting of:
(1) hydrogen,
(2) —C(O)R d , and
(3) —C 1-10 alkyl,

wherein each alkyl is unsubstituted or substituted with one to five halogens;
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 R f substituents;
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;
R g is selected from the group consisting of:
(1) hydrogen, and
(2) —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 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;
R i is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl;

R j is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —OR e ,
(3) —NR c S(O) m R e ,
(4) halogen,
(5) —S(O) m R e ,
(6) —S(O) m 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) —C 3-6 cycloalkyl, and
(20) —C 2-5 cycloheteroalkyl;
each R k is independently selected from the group consisting of:
(1) —C 1-10 alkyl,
(2) —C 2-10 alkenyl,
(3) —C 3-6 cycloalkyl,
(4) —C 3-6 cycloalkyl-C 1-10 alkyl-,
(5) —C 2-5 cycloheteroalkyl,
(6) —C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(7) aryl,
(8) heteroaryl,
(9) aryl-C 1-10 alkyl-, and
(10) heteroaryl-C 1-10 alkyl-,

each R L is independently selected from the group consisting of:
(1) —CO 2 C 1-6 alkyl,
(2) —C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) —C 2-10 alkynyl,
(5) —C 3-6 cycloalkyl,
(6) —C 2-6 cycloheteroalkyl,
(7) aryl, and
(8) heteroaryl,

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-4 substituents selected from C 1-6 alkyl, halogen, and —OC 1-6 alkyl;
each n is independently selected from: 0, 1 or 2;
each m is independently selected from: 0, 1 or 2;
each p is independently selected from: 0, 1, or 2;
each q is independently selected from: 0, 1 or 2;
each t is independently selected from: 0, 1 or 2; and
each u is independently selected from: 0, 1, 2, or 3.

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

3. The compound according to claim 1 wherein X is selected from the group consisting of:
(1) —C(R b )(R b ),
(2) —C═O, and
(3) —C(R b )OR b ;

or a pharmaceutically

Assignees

• Merck Sharp & Dohme

Inventors

• Miller Michael
• Chobanian Harry R
• He Shuwen
• Hao Jinsong
• Pio Barbara
• Guo Yan
• Xiao Dong

Classifications

• C07D491/107 Primary

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D311/96

  spiro-condensed with carbocyclic rings or ring systems · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/438

  The ring being spiro-condensed with carbocyclic or heterocyclic ring systems · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title