GLUCOKINASE ACTIVATORS

• US 20090099163A1
• Filed: 03/20/2008
• Published: 04/16/2009
• Est. Priority Date: 03/21/2007
• Status: Active Grant

• Current Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda San Diego, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Gwaltney, Stephen L., Feng, Jun, Tang, Mingnam, Guntupalli, Prasuna, Cheruvallath, Zacharia, Miura, Joanne, Sabat, Mark
• Granted Patent: US 8,173,645 B2
• Time in Patent Office: Days
• 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 according to claim 1 having the formula:

3. The compound according to claim 1 having the formula:

4. The compound according to claim 1 having the formula:

5. The compound according to claim 1 having the formula:

6. The compound according to claim 1 having the formula:

7. The compound according to claim 1 having the formula:

8. The compound according to claim 1 having the formula:

9. The compound according to claim 1 having the formula:

10. The compound according to claim 1 having the formula:

11. The compound according to claim 1 having the formula:

12. The compound according to claim 1 having the formula:

13. The compound according to claim 1 having the formula:

14. The compound according to claim 1 having the formula:

15. The compound according to claim 1 having the formula:

16. The compound according to claim 1 having the formula:

32. The compound according to claim 1, wherein X₁ is —

CO—

.

33. The compound according to claim 1, wherein X₂ is selected from the group consisting of —

CH₂— and

—

CO—

.

34. The compound according to claim 3, wherein X₃ is —

S—

.

35. The compound according to claim 4, wherein X₄ is —

CH═

.

36. The compound according to claim 4, wherein X₅ is selected from the group consisting of —

CH═ and

—

N═

.

37. The compound according to claim 4, wherein X₆ is selected from the group consisting of —

CH═

, —

CF═

, —

CCl═ and

—

N═

.

38. The compound according to claim 4, wherein X₇ is —

CH═

.

39. The compound according to claim 5, wherein

L₁ is selected from the group consisting of —

(CR₂OR₂₁)_n—

, —

CO—

, —

SO₂—

, and combinations thereof,

n is selected from the group consisting from the group consisting of 1, 2, 3, 4, 5 and 6; and

R₂₀ and R₂₁ are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C_1-10)alkoxy, (C_4-12)aryloxy, hetero(C_1-10)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C_1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, hydroxy(C_1-10)alkyl, carbonyl(C_1-10)alkyl, thiocarbonyl(C_1-10)alkyl, sulfonyl(C_1-10)alkyl, sulfinyl(C_1-10)alkyl, aza(C_1-10)alkyl, (C_1-10)oxaalkyl, (C_1-10)oxoalkyl, imino(C_1-10)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-10)alkyl, aryl(C_1-10)alkyl, hetero(C_1-10)aryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-12)bicycloaryl(C_1-5)alkyl, hetero(C_1-10)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, (C_4-12)aryl, hetero(C_1-10)aryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted.

40. The compound according to claim 5, wherein L₁ is —

SO₂—

.

41. The compound according to claim 5, wherein L₁ is —

C(O)—

NR₂₅— and

R₂₅ is selected from the group consisting of hydrogen, cyano, hydroxy, carbonyloxy, (C_1-10)alkoxy, (C_4-12)aryloxy, hetero(C_1-10)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C_1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, hydroxy(C_1-10)alkyl, carbonyl(C_1-10)alkyl, thiocarbonyl(C_1-10)alkyl, sulfonyl(C_1-10)alkyl, sulfinyl(C_1-10)alkyl, aza(C_1-10)alkyl, (C_1-10)oxaalkyl, (C_1-10)oxoalkyl, imino(C_1-10)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-10)alkyl, aryl(C_1-10)alkyl, hetero(C_1-10)aryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-12)bicycloaryl(C_1-5)alkyl, hetero(C_1-10)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, (C_4-12)aryl, hetero(C_1-10)aryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted.

42. The compound according to claim 5, wherein L₁ is —

C(S)—

NR₂₅— and

R₂₅ is selected from the group consisting of hydrogen, cyano, hydroxy, carbonyloxy, (C_1-10)alkoxy, (C_4-12)aryloxy, hetero(C_1-10)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C_1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, hydroxy(C_1-10)alkyl, carbonyl(C_1-10)alkyl, thiocarbonyl(C_1-10)alkyl, sulfonyl(C_1-10)alkyl, sulfinyl(C_1-10)alkyl, aza(C_1-10)alkyl, (C_1-10)oxaalkyl, (C_1-10)oxoalkyl, imino(C_1-10)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-10)alkyl, aryl(C_1-10)alkyl, hetero(C_1-10)aryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-12)bicycloaryl(C_1-5)alkyl, hetero(C_1-10)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, (C_4-12)aryl, hetero(C_1-10)aryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted.

43. The compound according to claim 41, wherein R₂₅ is selected from the group consisting of hydrogen and a substituted or unsubstituted (C_1-10)alkyl.

44. The compound according to claim 16, wherein

L₂ is selected from the group consisting of —

(CR₂OR₂₁)_n—

;

n is selected from the group consisting from the group consisting of 1, 2, 3, 4, 5 and 6; and

R₂₀ and R₂₁ are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C_1-10)alkoxy, (C_4-12)aryloxy, hetero(C_1-10)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C_1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, hydroxy(C_1-10)alkyl, carbonyl(C_1-10)alkyl, thiocarbonyl(C_1-10)alkyl, sulfonyl(C_1-10)alkyl, sulfinyl(C_1-10)alkyl, aza(C_1-10)alkyl, (C_1-10)oxaalkyl, (C_1-10)oxoalkyl, imino(C_1-10)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-10)alkyl, aryl(C_1-10)alkyl, hetero(C_1-10)aryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-12)bicycloaryl(C_1-5)alkyl, hetero(C_1-10)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, (C_4-12)aryl, hetero(C_1-10)aryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted.

45. The compound according to claim 39, wherein n is 1.

46. The compound according to claim 1, wherein R₁ is selected from the group consisting of alkylsulfonyl, cycloalkylsulfonyl, alkylcarbonyl and cycloalkylcarbonyl, each substituted or unsubstituted.

47. The compound according to claim 1, wherein R₂ is selected from the group consisting of (C_1-10)alkyl, halo(C_1-10)alkyl, carbonyl(C_1-3)alkyl, thiocarbonyl(C_1-3)alkyl, sulfonyl(C_1-3)alkyl, sulfinyl(C_1-3)alkyl, amino(C_1-10)alkyl, imino(C_1-3)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, heteroaryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-12)bicycloaryl(C_1-5)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, aryl, heteroaryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted.

48. The compound 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, hetero(C_3-12)cycloalkyl(C_1-5)alkyl, aryl(C_1-10)alkyl, and heteroaryl(C_1-5)alkyl, each substituted or unsubstituted.

49. The compound according to claim 1, wherein R₂ is selected from the group consisting of butyl;

hexylmethyl;

benzyl;

imidazol-4-ylmethyl and phenyl.

50. The compound according to claim 1, wherein R₂ is selected from the group consisting of alkyl, cycloalkyl-alkyl, dihaloaryl-alkyl, alkoxyaryl-alkyl, alkoxycycloalkyl-alkyl, tetrahydrofuranyl-alkyl, furanyl-alkyl and tetrahydro-2H-pyranyl-alky, each substituted or unsubstituted.

51. The compound according to claim 1, wherein R₃ is hydrogen.

52. The compound according to claim 1, wherein R₄ is a substituted or unsubstituted (C_1-10)alkyl.

53. The compound according to claim 1, wherein R₄ is methyl.

54. The compound according to claim 1, wherein R₄ is hydrogen.

55. The compound according to claim 1, wherein R₅ is hydrogen.

56. The compound according to claim 1, wherein R₄ and R₅ are taken together with the carbon to which they are attached to form —

CO—

.

57. The compound according to claim 1, wherein R₆ is selected from the group consisting of hydrogen and a substituted or unsubstituted (C_1-10)alkyl.

58. The compound according to claim 1, wherein R₆ is methyl.

59. The compound according to claim 1, wherein R₆ is hydrogen.

60. The compound according to claim 1, wherein R₇ is hydrogen.

61. The compound according to claim 1, wherein R₆ and R₇ are taken together with the carbon to which they are attached to form —

CO—

.

62. The compound according to claim 1, wherein R₈ comprises:

63. The compound according to claim 62, wherein X₈ is S.

64. The compound according to claim 1, wherein R₈ is selected from the group consisting of thiazolyl and pyridinyl, each substituted or unsubstituted.

65. The compound according to claim 1, wherein R₉ is selected from the group consisting of hydrogen and a substituted or unsubstituted (C_1-10)alkyl.

66. The compound according to claim 1, wherein R₉ is methyl.

67. The compound according to claim 1, wherein R₉ is hydrogen.

68. The compound according to claim 1, wherein R₁₀ is selected from the group consisting of H and a substituted or unsubstituted (C_1-5)alkyl.

69. The compound according to claim 1, wherein R₁₁ is a substituted or unsubstituted (C_1-5)alkyl.

70. The compound according to claim 1, wherein R₁₁ is —

OR₂₄ and R₂₄ is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C_1-10)alkoxy, (C_4-12)aryloxy, hetero(C_1-10)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C_1-10)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C_1-10)alkyl, halo(C_1-10)alkyl, hydroxy(C_1-10)alkyl, carbonyl(C_1-10)alkyl, thiocarbonyl(C_1-10)alkyl, sulfonyl(C_1-10)alkyl, sulfinyl(C_1-10)alkyl, aza(C_1-10)alkyl, (C_1-10)oxaalkyl, (C_1-10)oxoalkyl, imino(C_1-10)alkyl, (C_3-12)cycloalkyl(C_1-5)alkyl, hetero(C_3-12)cycloalkyl(C_1-10)alkyl, aryl(C_1-10)alkyl, hetero(C_1-10)aryl(C_1-5)alkyl, (C_9-12)bicycloaryl(C_1-5)alkyl, hetero(C_8-12)bicycloaryl(C_1-5)alkyl, hetero(C_1-10)alkyl, (C_3-12)cycloalkyl, hetero(C_3-12)cycloalkyl, (C_9-12)bicycloalkyl, hetero(C_3-12)bicycloalkyl, (C_4-12)aryl, hetero(C_1-10)aryl, (C_9-12)bicycloaryl and hetero(C_4-12)bicycloaryl, each substituted or unsubstituted.

71. The compound according to claim 3, wherein R₁₂ is selected from the group consisting of halo and a substituted or unsubstituted (C_1-5)alkyl.

72. The compound according to claim 3, wherein R₁₃ is selected from the group consisting of H, halo and a substituted or unsubstituted (C_1-5)alkyl.

73. The compound according to claim 3, wherein R₁₆ is selected from the group consisting of a substituted or unsubstituted (C_1-5)alkyl.

74. The compound according to claim 4, wherein R₁₇ is selected from the group consisting of H, halo and a substituted or unsubstituted (C_1-5)alkyl.

75. The compound according to claim 5, wherein R₁₈ is selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl, each substituted or unsubstituted.

76. The compound according to claim 16, wherein R₁₉ is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each substituted or unsubstituted.

77. The compound according to claim 39, wherein R₂₀ is selected from the group consisting of H and a substituted or unsubstituted (C_1-5)alkyl.

78. The compound according to claim 39, wherein R₂₁ is selected from the group consisting of H and a substituted or unsubstituted (C_1-5)alkyl.

79. The compound according to claim 63, wherein R₂₂ is selected from the group consisting of H, halo and a substituted or unsubstituted (C_1-5)alkyl.

80. The compound according to claim 63, wherein R₂₃ is absent or R₂₃ is selected from the group consisting of H and a substituted or unsubstituted (C_1-5)alkyl.

88. The compound according to claim 1, wherein the compound is in the form of a pharmaceutically acceptable salt.

89. The compound according to claim 1, wherein the compound is present in a mixture of stereoisomers.

90. The compound according to claim 1, wherein the compound comprises a single stereoisomer.

91. A pharmaceutical composition comprising as an active ingredient a compound according to claim 1.

92. A kit comprising:

a compound according to claim 1; and

instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the compound is to be administered, storage information for the compound, dosing information and instructions regarding how to administer the compound.

93. An article of manufacture comprising:

a compound according to claim 1; and

packaging materials.

94. A therapeutic method comprising administering a compound according to claim 1 to a subject.

95. A method of activating glucokinase comprising contacting glucokinase with a compound according to claim 1.

96. A method of activating glucokinase comprising causing a compound according to claim 1 to be present in a subject in order to activate glucokinase in vivo.

97. A method of activating glucokinase comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound activates glucokinase in vivo, the second compound being a compound according to claim 1.

98. A method of treating a disease state for which increasing glucokinase activity ameliorates the pathology and/or symptomology of the disease state, the method comprising causing a compound according to claim 1 to be present in a subject in a therapeutically effective amount for the disease state.

99. A method of treating a disease state for which increasing glucokinase activity ameliorates the pathology and/or symptomology of the disease state, the method comprising administering a compound according to claim 1 to a subject, wherein the compound is present in the subject in a therapeutically effective amount for the disease state.

100. A method of treating a disease state for which increasing glucokinase activity ameliorates the pathology and/or symptomology of the disease state, the method comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound activates glucokinase in vivo, the second compound being a compound according to claim 1.

101. The method according to claim 98, wherein the disease state is selected from the group consisting of hyperglycemia, diabetes, dyslipidaemia, obesity, insulin resistance, metabolic syndrome X, impaired glucose tolerance, polycystic ovary syndrome and cardiovascular disease.

17. A process comprising:

reacting a compound having the formula

81. The compound according to claim 17, wherein G₁ is selected from the group consisting of t-butyl, benzyl and fluoroureaylmethyl.

82. The compound according to claim 17, wherein G₂ is selected from the group consisting of (C_1-3)alkyl and benzyl.

83. The compound according to claim 17, wherein G₃ is halo.

84. The compound according to claim 17, wherein G₄ is selected from the group consisting of hydroxyl, halo and sulfonyl.

85. The compound according to claim 17, wherein G₅ is selected from the group consisting of halo, hydroxy and sulfonyl.

18. A process comprising:

reacting a compound having the formula

19. A process comprising:

reacting a compound having the formula

86. The compound according to claim 19, wherein G₆ is selected from the group consisting of t-butyl, benzyl and fluoroureaylmethyl.

20. A process comprising:

reacting a compound having the formula

21. A process comprising:

reacting a compound having the formula

22. A process comprising:

reacting a compound having the formula

23. A process comprising:

reacting a compound having the formula

24. A compound having the formula:

25. A compound having the formula:

26. A compound having the formula:

27. A compound having the formula:

28. A compound having the formula:

29. A compound having the formula:

30. A compound having the formula:

31. A compound having the formula:

87. A compound selected from the group consisting of:

(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;

(S)-3-Cyclohexyl-N-thiazol-2-yl-2-((R)-1,1,4-trioxo-hexahydro-1λ

*6*-thia-5,7a-diaza-inden-5-yl)-propionamide;

(S)-3-Cyclohexyl-N-thiazol-2-yl-2-((S)-1,1,4-trioxo-hexahydro-1λ

*6*-thia-5,7a-diaza-inden-5-yl)-propionamide;

N-(5-Chloro-thiazol-2-yl)-3-cyclohexyl-2-(1,1,4-trioxo-hexahydro-1λ

*6*-thia-5,7a-diaza-inden-5-yl)-propionamideN-(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; and

(S)—

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