Inhibitors of diacylglycerol acyltransferase
AssigneeMadrigal Pharmaceuticals, Inc.
InventorsDavid Robert Bolin, Stuart Hayden, Yimin Qian, Weiya Yun
Life of this patent
Estimating the term…
Abstract
Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.
Claims52
A compound of formula (I):
- wherein:
- X is oxygen, sulfur or nitrogen;
- Y is carbon or nitrogen;
- Z is carbon or nitrogen;
- R1 is lower alkyl, halo lower alkyl, alkoxy, lower alkyl alkoxy or absent;
- R2, R2′, independently of each other, is halogen, alkoxy, lower alkyl, haloloweralkyl, haloalkoxy, benzyloxy or absent;
- R3 is hydrogen or lower alkyl, wherein if X is oxygen or sulfur, then R3 is absent;
- and
- Q is piperazine-1-carboxylic acid lower alkyl ester, piperazine-1-carboxylic acid lower alkyl ester, piperazin-1-yl-2,2-dimethyl-4-oxo-lower akanoic acid, piperidin-1-yl-2,2-dimethyl-4-oxo-lower alkanoic acid, piperazine-1-carbonyl-4-cyclohexanecarboxylic acid benzyl ester, piperazine-1-carbonyl-4-cyclohexanecarboxylic acid, piperidine-1-carbonyl-4-cyclohexanecarboxylic acid, piperazine-1-carbonyl-2-cyclopentanecarboxylic acid, N-lower alkoxy lower alkyl-N-lower alkyl-amino, N-cyclolower alkyl-N-lower alkyl-amino, N-pyrrolidine-1-carboxylic acid lower alkyl ester, O-pyrrolidine-1-carboxylic acid lower alkyl ester, O-pyrrolidine-1-carboxylic acid lower alkyl ester, pyrrolidine-3-ylamino-1-carboxylic acid lower alkyl ester, pyrrolidin-3-ylamino-1-carboxylic acid lower alkyl amide, piperidin-1-yl-4-oxo-2-phenyl-lower alkanoic acid, piperidine-1-carbonyl-2-cyclopentanecarboxylic acid, piperidin-1-yl-2-oxo-lower alkyl-cyclopentanecarboxylic acid, piperazin-1-yl-4-oxo-lower alkyl acid, piperidin-1-yl-4-oxo-lower alkanoic acid, piperazin-1-yl-2-oxo-ethyl-3-methyl-lower alkanoic acid, piperazin-1-yl-4-oxo-2-cyclohexyl-butyric acid, pyrrolidine-3-oxy-1-carboxylic acid lower alkyl ester, pyrrolidine-3-oxy-1-carboxylic acid lower alkyl ester, pyrrolidin-3-oxy-1-yl-2,2-dimethyl-4-oxo-lower alkanoic acid, pyrrolidin-3-oxy-1-yl-4-benzoic acid, 2,4-dioxo-thiazolidin-5-yl-acetyl-piperazin-1-yl or piperazin-1-yl-4-benzoic acid,
- or pharmaceutically acceptable salt thereof.
The compound according to claim, 1, wherein Z is nitrogen.
A compound, selected from the group consisting of:
- 4-(4-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid,
- 4-(4-{5-[(5-bromo-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid,
- 4-(4-{5-[(4,5-dichloro-1-ethyl-1H-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid,
- trans-4-(4-{5-[(1-ethyl-4-methoxy-1H-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carbonyl)-cyclohexane carboxylic acid,
- (1R,2R)-2-(4-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid,
- (S)-3-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester,
- 1-ethyl-4-methyl-1H-indole-2-carboxylic acid [6-((S)-1-tert-butylcarbamoyl-pyrrolidin-3-ylamino)-pyridin-3-yl]-amide,
- 4-(4-{4-[(4,5-dichloro-1-ethyl-1,1-indole-2-carbonyl)-amino]-phenyl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid,
- 4-((S)-3-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-2,2-dimethyl-4-oxo butyric acid,
- 4-((S)-3-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-benzoic acid,
- 4-ethoxy-1-ethyl-1H-indole-2-carboxylic acid (4-{4-[2-(2,4-dioxo-thiazolidin-5-yl)-acetyl]-piperazin-1-yl}-phenyl)-amide,
- 3-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid ethyl Ester,
- 4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazin-1-yl)-2-dimethyl-4-oxo-butyric acid,
- trans-4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid and
- trans-4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid of a pharmaceutical acceptable salt.
The compound of claim 35 wherein Q is piperazine-1-carboxylic acid lower alkyl ester, piperazine-1-carboxylic acid lower alkyl ester, piperazin-1-yl-2,2-dimethyl-4-oxo-lower alkanoic acid, piperazine-1-carbonyl-4-cyclohexanecarboxylic acid benzyl ester, piperazine-1-carbonyl-4-cyclohexanecarboxylic acid, piperazine-1-carbonyl-2-cyclopentanecarboxylic acid, piperazin-1-yl-4-oxo-lower alkanoic acid, piperidin-1-yl-4-oxo-lower alkanoic acid, piperazin-1-yl-2-oxo-ethyl-3-methyl-lower alkanoic acid, piperazin-1-yl-4-oxo-2-cyclohexyl-lower alkanoic acid, 2,4-dioxo-thiazolidin-5-yl-acetyl-piperazin-1-yl or piperazin-1-yl-4-lower alkanoic acid.
The compound of claim wherein said compound is 4-(4-{4-[(7-methoxy-3-methyl-1h-indole-2-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid or pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.