COMPOUNDS AND METHODS FOR INHIBITING HISTONE DEMETHYLASES

• US 20160102096A1
• Filed: 08/26/2015
• Published: 04/14/2016
• Est. Priority Date: 08/27/2014
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: EpiTherapeutics ApS (Gilead Sciences Inc.)
• Inventors: Boesen, Thomas, Labelle, Marc, Saraswat, Neerja, Vakiti, Ramkrishna Reddy, Ullah, Farman, Yang, Ying, Dudekula, Dastagiri, Cook, Cyril John, Zhang, Rui
• Granted Patent: US 9,802,941 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5355 Non-condensed oxazines and containing further heterocyclic rings
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/48 : Aldehydo radicals
• CPC Class Codes: C07D 213/56 : Amides
• CPC Class Codes: C07D 213/79 : Acids; Esters
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present application relates to compounds being of Formula (I), (II), (III), (IV), (V), (VI), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), and (IIIg). Compounds of Formula (I) have the structure:

wherein Q, R¹, R¹⁸, R¹⁹, M, A and Y are as defined herein. The compounds of the application can modulate the activity of histone demethylases (HDMEs), and can be useful for the prevention and/or treatment of diseases in which genomic dysregulation is involved in the pathogenesis, e.g., cancer.

Claims

1. A compound being of Formula (I):

2. The compound of claim 1, wherein A is selected from —

Z-heterocyclylene, —

Z-arylene, and —

Z-heteroarylene.

5. The compound of claim 1, wherein Y is —

H or C_1-8 alkyl.

6. The compound of claim 1, wherein R³ is —

Z-aryl.

7. The compound of claim 1, wherein Z is a single bond or C_1-4 alkylene.

8. The compound of claim 1, wherein R¹ is —

H.

9. The compound of claim 1, wherein R¹⁸ is —

H.

11. The compound of claim 1, wherein R¹⁹ is C_1-8 alkyl optionally substituted with one —

Z—

OR⁷.

15. The compound of claim 1, wherein Q is CO₂H.

16. The compound of claim 1 being of Formula (II),

17. The compound of claim 16, wherein D is imidazolyl optionally substituted with one to three R²³.

18. The compound of claim 16, wherein D is pyridinyl optionally substituted with one to three R²³.

19. The compound of claim 16, wherein D is triazolyl optionally substituted with one to three R²³.

27. The compound of claim 16, wherein E is Z-aryl optionally substituted with one to three R²⁴.

30. The compound of claim 16, wherein R¹⁹ is —

CH₂OH.

31. The compound of claim 16, wherein R¹⁹ is methyl.

32. The compound of claim 16, wherein Q is CO₂H.

33. The compound of claim 1 being of Formula (III),

43. The compound of claim 33, wherein Q is CO₂H.

44. The compound of claim 1 being of Formula (IV),

53. The compound of claim 44, wherein Q is CO₂H.

54. The compound of claim 1 being of Formula (V),

60. The compound of claim 54, wherein Q is CO₂H.

68. The compound of claim 1 being of Formula (IIIa),

69. The compound of claim 1 being of Formula (IIIb),

70. The compound of claim 1 being of Formula (IIIc),

71. The compound of claim 1 being of Formula (IIId),

72. The compound of claim 1 being of Formula (IIIe),

73. The compound of claim 1 being of Formula (IIIf),

74. The compound of claim 1 being of Formula (IIIg),

78. The compound of claim 1, selected from any one of the following:

79. The compound of claim 1, selected from any one of the following:

80. A pharmaceutical composition comprising at least one compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and optionally one or more pharmaceutically acceptable excipients, diluents and/or carriers.

81. The pharmaceutical composition according to claim 80, which comprises one or more further active substances.

85. A method of treating a HDME-dependent disease in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of at least one compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

86. A method of inhibiting a HDME, comprising contacting a cell with a compound of claim 1 in an amount effective to produce a concentration sufficient to inhibit the demethylation of a histone in a cell.

87. The method of claim 86, wherein the HDME is a member of the KDM7 family, PHF8 family, KDM6 family, KDM5 family, KDM4 family, or KDM2 family.

88. The method of claim 86 or 87, wherein the HDME is KDM4C, KDM2B, PHF8, KDM6A, or KDM5B.

3-4. -4. (canceled)

10. (canceled)

12-14. -14. (canceled)

20-26. -26. (canceled)

28-29. -29. (canceled)

34-42. -42. (canceled)

45-52. -52. (canceled)

55-59. -59. (canceled)

61. A compound being of Formula (VI):

62. The compound of claim 61, wherein:

M is CH;

A is selected from —

Z-heterocyclylene, —

Z-arylene, and —

Z-heteroarylene;

Y is selected from —

H and C_1-8 alkyl;

R¹ is H;

each R³ is independently selected from —

Z-heterocyclyl, —

Z-aryl, and —

Z-heteroaryl;

R¹⁸ is H;

Z is selected from a single bond and C_1-4 alkylene; and

R¹⁹ is methyl.

63. The compound of claim 61, wherein:

M is CH;

A is selected from —

Z-heterocyclylene, —

Z-arylene, and —

Z-heteroarylene;

Y is selected from —

H and C_1-8 alkyl;

R¹ is H;

each R³ is independently selected from —

Z-heterocyclyl, —

Z-aryl, and —

Z-heteroaryl;

R¹⁸ is H;

Z is selected from a single bond and C_1-4 alkylene; and

R¹⁹ is —

CH₂OH.

64. The compound of claim 61, wherein R²¹ is (R²²)₂N—

.

65. The compound of claim 64, wherein one R²² is —

H, and the other R²² is C_1-8 alkyl or C_3-10 cycloalkyl.

66. The compound of claim 61, wherein R²¹ is R²²O.

67. The compound of claim 66, wherein R²² is C_1-8 alkyl optionally substituted with one or more —

F.

95. A pharmaceutical composition comprising at least one compound of claim 61, or a pharmaceutically acceptable salt or solvate thereof, and optionally one or more pharmaceutically acceptable excipients, diluents and/or carriers.

96. A method of treating a HDME-dependent disease in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of at least one compound according to claim 61, or a pharmaceutically acceptable salt or solvate thereof.

75-77. -77. (canceled)

82-84. -84. (canceled)

89-94. -94. (canceled)