US 10,059,667 B2 · Antidiabetic compounds

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.

A compound of structural formula I:

or a pharmaceutically acceptable salt thereof;
wherein
A is selected from the group consisting of:
(1) —C3-9cycloalkyl,
(2) —C3-9cycloalkenyl, and
(3) —C2-10cycloheteroalkyl,
wherein each cycloalkyl, cycloalkenyl and cycloheteroalkyl is unsubstituted or substituted with one, two or three substituents selected from Ra;
B is selected from the group consisting of:
(1) —(CH2)u-aryl,
(2) —(CH2)u-heteroaryl,
(3) —(CH2)u—N(Rg)—(CH2)u-aryl, and
(4) —(CH2)u—O—(CH2)u-aryl,
wherein each CH2, aryl and heteroaryl is unsubstituted or substituted with one, two, three, four or five substituents selected from Rb;
T, U, V and W are CH;
Y is selected from:
—O—, —(CH2)xO— and —O—(CH2)x, wherein CH2 is unsubstituted or substituted with one or two substituents selected from Ri;
Z is —CO2H;
R1 is selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6alkyl,
wherein alkyl is unsubstituted or substituted with one, two or three halogens;
R2 is —C3-6cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one, two or three substituents selected from halogen, OH, —C1-6alkyl and —OC1-6alkyl;
each R3 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —(CH2)s—OC1-6alkyl,
(4) —(CH2)s—OH,
(5) —CN, and
(6) —C1-6alkyl,
wherein CH2 and alkyl are unsubstituted or substituted with one, two or three substituents selected from halogen, OH, and OC1-6alkyl;
each Ra is independently selected from the group consisting of:
(1) —C1-6alkyl,
(2) halogen,
(3) —(CH2)u—OC1-6alkyl,
(4) —ORe,
(5) —S(O)uRe,
(6) —S(O)uNRcRd,
(7) —N(Rc)S(O)pRe,
(8) —NRcRd,
(9) —C(O)Re,
(10) —OC(O)Re,
(11) —CO2Re,
(12) —N(Rc)C(O)Re,
(13) —N(Rc)C(O)ORe,
(14) —N(Rc)C(O)NRcRd,
(15) —C(O)NRcRd,
(16) —CN,
(17) —CF3,
(18) —OCF3,
(19) —OCHF2,
(20) —(CH2)raryl,
(21) —(CH2)rheteroaryl,
(22) —(CH2)rC3-6cycloalkyl,
(23) —(CH2)r—C3-6cycloalkenyl,
(24) —(CH2)r—C2-5cycloheteroalkyl, and
(25) —(CH2)r—O—(CH2)r—C3-6cycloalkyl,
wherein each CH2, alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to four substituents selected from:
halogen, —C1-6alkyl, —(CH2)w—OH, —O—C1-6alkyl, —CF3, —CN, —(CH2)v—C3-6cycloalkyl, SH, and —SO2—C1-6alkyl;
each Rb is selected from the group consisting of:
1) —C1-10alkyl,
2) —C2-10alkenyl,
3) —(CH2)v—CF3,
4) —O(CH2)vCF3,
5) —OCHF2,
6) halogen,
7) —(CH2)vCN,
8) —(CH2)vOH,
9) —(CH2)vOC1-10alkyl,
10) —CO2Re,
11) —NRcRd,
12) —(CH2)vC3-6cycloalkyl,
13) —(CH2)vC2-10cycloheteroalkyl,
14) —(CH2)v-aryl, and
15) —(CH2)v-heteroaryl,
wherein each CH, CH2, alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one, two or three substituents selected from:
halogen, —C1-6alkyl, —(CH2)w—OH, —O—C1-6alkyl, —CF3, —CN, —(CH2)v—C3-6cycloalkyl, SH, and —SO2—C1-6alkyl;
each Rc is independently selected from the group consisting of:
(1) hydrogen,
(2) C1-10alkyl,
(3) C3-6cycloalkyl,
(4) C2-5cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,
wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from C1-6alkyl;
each Rd is independently selected from the group consisting of:
(1) hydrogen,
(2) C1-10alkyl,
(3) C3-6cycloalkyl,
(4) C2-5cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,
wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from C1-6alkyl;
each Re is independently selected from the group consisting of:
(1) hydrogen,
(2) C1-10alkyl,
(3) C3-6cycloalkyl,
(4) C2-5cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,
wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from C1-6alkyl;
each Rg is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C1-6alkyl, and
(4) C3-6cycloalkyl;
each Ri is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C1-6alkyl,
(4) —(CH2)s—O—C1-6alkyl,
(5) —(CH2)sOH,
(6) —N(Rc)S(O)2Re,
(7) —S(C1-6alkyl),
(8) —(CH2)sSO2C1-6alkyl,
(9) —(CH2)sSO2—(CH2)t—C3-6cycloalkyl,
(10) —S(O)2NRcRd,
(11) —NRcRd,
(12) —C(O)Re,
(13) —OC(O)Re,
(14) —CO2Re,
(15) —(CH2)sCN,
(16) —C(O)NRcRd,
(17) —N(Rc)C(O)Re,
(18) —N(Rc)C(O)ORe,
(19) —N(Rc)C(O)NRcRd,
(20) —CF3,
(21) —OCF3,
(22) —OCHF2,
(23) —C3-6cycloalkyl, and
(24) —C2-5cycloheteroalkyl,
wherein each CH2, alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one, two, three or four substituents selected from:
—C1-6alkyl and halogen;
n is 1;
m is 1;
each p is independently selected from:
0, 1 and 2;
each q is independently selected from:
0, 1 and 2;
each r is independently selected from:
1, 2, 3 and 4;
each s is independently selected from:
0, 1, 2 and 3;
each t is independently selected from:
0, 1, 2, 3 and 4;
each u is independently selected from:
0, 1, 2 and 3;
each v is independently selected from:
0, 1, 2, 3 and 4;
each w is independently selected from:
0, 1, 2 and 3;
and
each x is independently selected from:
0, 1 and 2.

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Antidiabetic compounds

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Antidiabetic compounds

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Abstract

Claims11