Glucokinase activators

• US 8,173,645 B2
• Filed: 03/20/2008
• Issued: 05/08/2012
• Est. Priority Date: 03/21/2007
• Status: Expired due to Fees

• Current Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Cheruvallath, Zacharia, Feng, Jun, Guntupalli, Prasuna, Gwaltney, Stephen L., Miura, Joanne, Sabat, Mark, Tang, Mingnam
• Primary Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US12/052,646
• Publication Number:
  US 20090099163A1
• Time in Patent Office: 1,510 Days
• Field of Search: None
• US Class Current: 514/230.5
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Compounds are provided for use with glucokinase that comprise the formula:

wherein the variables are as defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.

Claims

1. A compound having the formula:

2. The compound, polymorph, tautomer, enantiomer or pharmaceutically acceptable salt according to claim 1 wherein:

R₁₂ and R₁₃ are each hydrogen.

3. The compound, polymorph, tautomer, enantiomer or pharmaceutically acceptable salt according to claim 1, wherein R₁ is selected from the group consisting of alkylsulfonyl and cycloalkylsulfonyl, each substituted or unsubstituted.

4. The compound, polymorph, tautomer, enantiomer or pharmaceutically acceptable salt according to claim 1, wherein R₂ is selected from the group consisting of (C_1-10)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, tetrahydro-2H-pyranyl-(C_1-5)alkyl, and benzyl, each unsubstituted or substituted.

5. The compound, polymorph, tautomer, enantiomer or pharmaceutically acceptable salt according to claim 1, wherein R₂ is selected from the group consisting of (C_3-12)cycloalkyl(C_1-5)alkyl and tetrahydro-2H-pyranyl-(C_1-5)alkyl, each unsubstituted or substituted.

6. The compound, polymorph, tautomer, enantiomer or pharmaceutically acceptable salt according to claim 1, wherein R₁₂ is selected from the group consisting of halo and (C_1-5)alkyl.

7. The compound, polymorph, tautomer, enantiomer or pharmaceutically acceptable salt according to claim 1, wherein R₁₈ is selected from the group consisting of (C_1-10)alkyl, (C_3-12)cycloalkyl, (C_4-12)aryl and hetero(C_1-10)aryl, each unsubstituted or substituted.

9. The compound, polymorph, tautomer, enantiomer or pharmaceutically acceptable salt according to claim 1, wherein the compound is present in a mixture of stereoisomers.

10. The compound, polymorph, tautomer, enantiomer or pharmaceutically acceptable salt according to claim 1, wherein the compound comprises a single stereoisomer.

11. A pharmaceutical composition comprising a compound, polymorph, tautomer, enantiomer or pharmaceutically acceptable salt as defined in claim 1, and one or more pharmaceutical excipients.

8. A compound selected from the group consisting of:

(S)-3-cyclohexyl-2-(4-(methylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-3-(3,5-difluorophenyl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-3-(3-methoxyphenyl)-N-(thiazol-2-yl)propanamide;

(2S)-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-3-(3-methoxycyclohexyl)-N-(thiazol-2-yl)propanamide;

2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-N-(5-fluoropyridin-2-yl)-3-(tetrahydrofuran-2-yl)propanamide;

2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-3-(furan-2-yl)-N-(thiazol-2-yl)propanamide;

2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-3-(2,6-difluorophenyl)-N-(thiazol-2-yl)propanamide;

2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-N-(5-fluoropyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-4-methylpentanamide;

(S)-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-N-(5-fluorothiazol-2-yl)-4-methylpentanamide;

(S)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxo-N-phenylpiperazine-1-carboxamide;

(2R)-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-3-yl)-N-(thiazol-2-yl)propanamide;

2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-2-yl)-N-(thiazol-2-yl)propanamide;

N-(5-chlorothiazol-2-yl)-3-cyclopentyl-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)propanamide;

(S)-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-3-(4-methoxyphenyl)-N-(thiazol-2-yl)propanamide;

2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-3-(pyrrolidin-3-yl)-N-(thiazol-2-yl)propanamide;

2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-3-(1-(methylsulfonyl)pyrrolidin-3-yl)-N-(thiazol-2-yl)propanamide;

3-(1-acetylpyrrolidin-3-yl)-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-(2H-pyran-4-yl)propanamide;

(R)-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-(2H-pyran-4-yl)propanamide;

N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-(2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-(2H-pyran-4-yl)propanamide;

(R)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-(2H-pyran-4-yl)propanamide;

2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopentylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(4-(cyclopentylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

2-(4-(cyclopentylsulfonyl)-2-oxopiperazin-1-yl)-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

N-(5-chlorothiazol-2-yl)-2-(4-(4-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(4-(4-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-N-(5-chlorothiazol-2-yl)-2-(4-(4-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

N-(5-chlorothiazol-2-yl)-2-(2-oxo-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(2-oxo-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-N-(5-chlorothiazol-2-yl)-2-(2-oxo-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(naphthalen-2-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(quinolin-8-ylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(benzylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(3-(trifluoromethyl)phenylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(4-chlorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(4-acetamidophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-methoxyphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(5-chloro-1,3-dimethyl-1H-pyrazol-4-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(1,2-dimethyl-1H-imidazol-4-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-(4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxopiperazin-1-ylsulfonyl)benzoic acid;

(S)-2-(4-(benzo[b]thiophen-3-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-chloro-2-methylphenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(2-chloro-4-cyanophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,4-dimethylthiazol-5-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(4-(trifluoromethyl)phenylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,5-dichlorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3,5-dichlorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,4-difluorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(isopropylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(5-methylisoxazol-4-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-cyanophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-chlorobenzylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide

(S)-3-cyclohexyl-2-(2-oxo-4-(4-ureidophenylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(naphthalen-1-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(4-cyanophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-chlorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-fluorobenzylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(4-chlorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-(difluoromethoxy)phenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(2-(trifluoromethyl)phenylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,4-dimethylthiazol-5-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(4-(trifluoromethyl)phenylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,5-dichlorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3,5-dichlorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-N-(naphthalen-1-yl)-3-oxopiperazine-1-carboxamide;

(S)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-N-(4-methoxyphenyl)-3-oxopiperazine-1-carboxamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(phenylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(naphthalen-1-ylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-chlorophenylcarbamothioyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(benzylcarbamothioyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-fluorophenylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(3-(trifluoromethyl)phenylcarbamothioyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(4-(trifluoromethyl)phenylcarbamothioyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-methoxyphenylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3,4-dichlorophenylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3,4-dimethoxyphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3,4-dichlorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-4-(4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxopiperazin-1-ylsulfonyl)benzoic acid;

(S)-3-cyclohexyl-2-(4-(3-methoxyphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(2,2,2-trifluoroethylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-chloro-4-methylphenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2-methoxy-5-methylphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(cyclopropylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(benzo[d]thiazol-6-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(4-chlorophenethylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3-fluoro-4-methoxyphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(3,3,3-trifluoropropylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-isopropoxyphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,3-dihydrobenzofuran-5-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3,4-difluorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(benzo[b]thiophen-2-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3,5-difluorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3-(difluoromethoxy)phenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(5-methylbenzo[b]thiophen-2-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(furan-2-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(1,2-dimethyl-1H-imidazol-5-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(1-ethyl-1H-pyrazol-4-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3,5-dimethyl-1H-pyrazol-4-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(1-methyl-1H-pyrazol-3-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(cyclopentylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(cyclohexylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(furan-2-ylmethylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-cyanophenylcarbamothioyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2-morpholinoethylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3-morpholinopropylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3-fluorobenzylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-fluorobenzylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(2-(piperidin-1-yl)ethylcarbamothioyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-methoxybenzylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(thiophen-2-ylmethylcarbamothioyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-N-(3,4-difluorophenyl)-3-oxopiperazine-1-carboxamide;

(S)-2-(4-(4-chlorophenylcarbamothioyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(4-cyanophenylcarbamothioyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(4-phenoxyphenylcarbamothioyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(cyclopentylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(cyclopropylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxo-N-(4-phenoxyphenyl)piperazine-1-carboxamide;

(S)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-N-(3,4-dichlorophenyl)-3-oxopiperazine-1-carboxamide;

(S)-N-(4-cyanophenyl)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxopiperazine-1-carboxamide;

(S)-3-cyclohexyl-2-(4-(3-(diethylamino)propylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(4-sulfamoylphenylcarbamothioyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-(difluoromethoxy)phenylcarbamothioyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(2-(trifluoromethoxy)phenylcarbamothioyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-N-(4-chlorophenyl)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxopiperazine-1-carboxamide;

(S)-N-(4-chlorobenzyl)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxopiperazine-1-carboxamide;

(S)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-N-(naphthalen-2-yl)-3-oxopiperazine-1-carboxamide;

(S)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-N-cyclopentyl-3-oxopiperazine-1-carboxamide;

(S)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxo-N-(3-(trifluoromethyl)phenyl)piperazine-1-carboxamide;

(S)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxo-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide;

(S)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-N-(3,4-dimethoxyphenethyl)-3-oxopiperazine-1-carboxamide;

(S)-N-(benzo[b]thiophen-5-yl)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxopiperazine-1-carboxamide;

(S)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopiperazine-1-carboxamide;

(S)-N-(4-(benzyloxy)phenyl)-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxopiperazine-1-carboxamide;

N-(5-chlorothiazol-2-yl)-2-(4-(3-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

2-(4-(3-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-N-(5-chlorothiazol-2-yl)-2-(4-(3-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(4-(3-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-2-(4-(3-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-2-(4-(3-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

N-(5-chlorothiazol-2-yl)-2-(4-(1-methylpiperidin-4-ylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-N-(5-chlorothiazol-2-yl)-2-(4-(1-methylpiperidin-4-ylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(R)-N-(5-chlorothiazol-2-yl)-2-(4-(1-methylpiperidin-4-ylsulfonyl)-2-oxopiperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3-nitrophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-methyl 5-(4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxopiperazin-1-ylsulfonyl)-4-methylthiophene-2-carboxylate;

(S)-methyl 5-(4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxopiperazin-1-ylsulfonyl)furan-2-carboxylate;

(S)-methyl 5-(4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxopiperazin-1-ylsulfonyl)-2-methylfuran-3-carboxylate;

(S)-3-cyclohexyl-2-(4-(5-methyl-2-(trifluoromethyl)furan-3-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(5-(oxazol-5-yl)thiophen-2-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-methyl 4-(4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxopiperazin-1-ylsulfonyl)-2,5-dimethylfuran-3-carboxylate;

(S)-3-cyclohexyl-2-(4-(5-methyl-1-phenyl-1H-pyrazol-4-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(6-chloroimidazo[2,1-b]thiazol-5-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(5-(5-chloro-1,2,4-thiadiazol-3-yl)thiophen-2-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(5-(5-(trifluoromethyl)isoxazol-3-yl)thiophen-2-ylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-ethyl 3-(5-(4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxopiperazin-1-ylsulfonyl)thiophen-2-yl)-1,2,4-oxadiazole-5-carboxylate;

(S)-3-cyclohexyl-2-(4-(5-(dimethylamino)naphthalen-1-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3-(2-methylpyrimidin-4-yl)phenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4,5-dichlorothiophen-2-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(benzo[c][1,2,5]thiadiazol-4-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(5-chlorothiophen-2-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3,5-dimethylisoxazol-4-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(5-(isoxazol-5-yl)thiophen-2-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)thiophen-2-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(benzo[c][1,2,5]oxadiazol-4-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-chloro-4-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(3-picolinoylphenylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3-isonicotinoylphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,5-dimethylthiophen-3-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,5-dimethylfuran-3-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-methoxy-2,3,6-trimethylphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(2,3,4-trifluorophenylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,5-difluorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(5-chloro-2-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(4-chloro-2,5-dimethylphenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-chloro-5-fluoro-2-methylphenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-chloro-2-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3-fluoro-4-methylphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(4-chloro-2,5-difluorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(5-fluoro-2-methylphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(m-tolylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophen-2-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,5-dimethoxyphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3,5-dimethylphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-acetylphenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(2-acetamido-4-methylthiazol-5-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2-methyl-5-nitrophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,5-dimethylphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(benzo[c][1,2,5]thiadiazol-5-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-tosylpiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(5-bromothiophen-2-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(4-bromophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(4-acetylphenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(4-(pyridin-2-yloxy)phenylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-(4-methoxyphenoxy)phenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(6-phenoxypyridin-3-ylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(4-(trifluoromethyl)benzylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3,4-dichlorobenzylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3,5-dichlorobenzylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(3-(trifluoromethyl)benzylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-chloro-4-(3-methylureido)phenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(4-(1H-pyrazol-1-yl)phenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(1,3,5-trimethyl-1H-pyrazol-4-ylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(5-bromo-6-chloropyridin-3-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(o-tolylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(2,4,5-trichlorophenylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(2,3,4-trichlorophenylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2,4-dichloro-5-methylphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(2-fluoro-4-methylphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-fluoro-2-methylphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(4-tert-butylphenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(4-ethylphenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(benzofuran-2-ylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(cyclohexylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3-(4-methoxyphenoxy)phenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(2-oxo-4-(pyrrolidin-1-ylsulfonyl)piperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-cyano-4-fluorophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-3-cyclohexyl-2-(4-(3,4-dibromophenylsulfonyl)-2-oxopiperazin-1-yl)-N-(thiazol-2-yl)propanamide;

(S)-2-(4-(3-bromophenylsulfonyl)-2-oxopiperazin-1-yl)-3-cyclohexyl-N-(thiazol-2-yl)propanamide;

(S)-N-benzyl-4-(3-cyclohexyl-1-oxo-1-(thiazol-2-ylamino)propan-2-yl)-3-oxopiperazine-1-carboxamide; and

a pharmaceutically acceptable salt of any one of the aforementioned compounds.