TRICYCLIC INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE

• US 20140221314A1
• Filed: 05/31/2012
• Published: 08/07/2014
• Est. Priority Date: 05/31/2011
• Status: Abandoned Application

• Current Assignee: NewGen Therapeutics, Inc.
• Original Assignee: NewGen Therapeutics, Inc.
• Inventors: Shen, Wang, Maung, Jack, Zhang, Aimin, Zheng, Xiaoling
• Application Number:
  US14/122,983
• Publication Number:
  US 20140221314A1
• Time in Patent Office: Days
• US Class Current: 514/80
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07F 9/6584 having one phosphorus atom as ring hetero atom

Abstract

The invention provides for compositions comprising phosphorous containing tricyclic compounds, including phthalazin-1(2H)-one derivatives. The compounds are potent inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), particularly PARP-1 and potentially PARP-2. The also show good cellular activity in inhibiting poly(ADP-ribose) oligomer formation. The compounds may be useful as mono-therapy or in combination with other therapeutic agents in the treatment conditions where PARP is implicated, such as cancer, inflammatory diseases and ischemic conditions. Thus, also provided are methods for the treatment of a condition where PARP is implicated comprising administering to an effective amount of a compound of the invention to an individual in need thereof.

Claims

1. A compound of the formula (I):

2. The compound of claim 1, wherein each R¹ and R² is hydrogen;

or a pharmaceutically acceptable salt or solvate thereof.

11. The compound of claim 1, wherein R^A and R^B are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted 5, 6 or 7-membered ring containing 0, 1 or 2 heteroatoms selected from S, O and N;

or a pharmaceutically acceptable salt or solvate thereof.

12. The compound of claim 11, wherein R^A and R^B are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted 5, 6 or 7-membered carbocycle;

or a pharmaceutically acceptable salt or solvate thereof.

16. The compound of claim 11, wherein the compound is of the formula (II):

17. The compound of claim 16, wherein R^F is hydrogen;

or a pharmaceutically acceptable salt or solvate thereof.

20. The compound of claim 17, wherein each R¹ and R² is hydrogen;

or a pharmaceutically acceptable salt or solvate thereof.

21. The compound of claim 20, wherein one or both of R¹ and R² is deuterium;

or a pharmaceutically acceptable salt or solvate thereof

22. The compound of claim 17, wherein one of R¹ and R² is hydrogen and the other one of R¹ and R² is hydroxy;

or a pharmaceutically acceptable salt or solvate thereof.

23. The compound of claim 1, wherein Z is a 5 or 6-membered heteroaryl substituted with R^C and R^P;

or a pharmaceutically acceptable salt or solvate thereof.

30. The compound of claim 1, wherein the compound is of the formula (III):

31. The compound of claim 30, wherein R^F is hydrogen or fluoro;

or a pharmaceutically acceptable salt or solvate thereof.

34. The compound of claim 30, wherein each R¹ and R² is hydrogen;

or a pharmaceutically acceptable salt or solvate thereof.

38. The compound of claim 1, wherein R^C is fluoro;

or a pharmaceutically acceptable salt or solvate thereof.

45. The compound of claim 1, wherein the compound is of the formula (IIIa):

47. The compound of claim 45, wherein R^D is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;

or a pharmaceutically acceptable salt or solvate thereof.

48. The compound of claim 47, wherein R^D is substituted or unsubstituted C₁-C₆ alkyl;

or a pharmaceutically acceptable salt or solvate thereof.

50. The compound of claim 47, wherein R^D is a substituted or unsubstituted C₃-C₈ cycloalkyl;

or a pharmaceutically acceptable salt or solvate thereof.

51. The compound of claim 47, wherein R^D is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, isopentyl, trifluoroethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl and cyclopentyl;

or a pharmaceutically acceptable salt or solvate thereof.

52. The compound of claim 45, wherein R^D is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, —

C(O)NR⁵R⁶, —

C(═

N—

CN)NR⁸R⁹, or —

SO₂R³;

or a pharmaceutically acceptable salt or solvate thereof.

53. The compound of claim 52, wherein R^D is substituted or unsubstituted phenyl;

a substituted or unsubstituted heteroaryl selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, quinazolinyl, imidazolyl, oxazolyl, oxadiazolyl, pyrazolyl, thiazolyl, and thiadiazolyl;

—

C(O)NR⁵R⁶ wherein R⁵ and R⁶ is independently hydrogen or an unsubstituted alkyl;

—

C(═

N—

CN)NR⁸R⁹ wherein R⁸ and R⁹ are taken together with the nitrogen to which they are attached to form a heterocyclyl;

or —

SO₂R³ wherein R³ is cyclopropyl;

or a pharmaceutically acceptable salt or solvate thereof.

69. The compound of claim 45, wherein R^D is —

C(O)R⁴;

or a pharmaceutically acceptable salt or solvate thereof.

71. The compound of claim 69, wherein R⁴ is an unsubstituted C₁-C₆ alkyl or unsubstituted C₃-C₈ cycloalkyl;

or a pharmaceutically acceptable salt or solvate thereof.

73. The compound of claim 69, wherein R⁴ is a substituted or unsubstituted heterocyclyl selected from pyrrolidinyl and tetrahydrofuranyl;

or a pharmaceutically acceptable salt or solvate thereof.

77. The compound of claim 1, wherein the compound is of the formula (IIIb):

79. The compound of claim 77, wherein R^E is substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;

or a pharmaceutically acceptable salt or solvate thereof.

81. The compound of claim 77, wherein R^E is substituted or unsubstituted aryl;

or a pharmaceutically acceptable salt or solvate thereof.

82. The compound of claim 77, wherein R^E is —

OR⁷;

or a pharmaceutically acceptable salt or solvate thereof.

83. The compound of claim 82, wherein R⁷ is a substituted or unsubstituted C₁-C₆ alkyl or substituted or unsubstituted C₃-C₈ cycloalkyl;

or a pharmaceutically acceptable salt or solvate thereof.

85. The compound of claim 1, wherein the compound is selected from the group consisting of:

4-(3-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(3-(1-(cyclopentanecarbonyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(3-(1-(cyclopropanecarbonyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(3-(1-(cyclobutanecarbonyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(3-(1-(3,3-dimethylbutanoyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(3-(1-(3,3-difluoropyrrolidine-1-carbonyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(tetrahydrofuran-2-carbonyl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-pivaloyl-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N,N-dimethyl-1,4-azaphosphinane-1-carboxamide 4-oxide;

4-(4-fluoro-3-(4-oxido-1-pivaloyl-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

N-(azetidin-1-yl(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4-oxido-1,4-azaphosphinan-1-yl)methylene)cyanamide;

4-(4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(3-(1-(6-chloropyridazin-3-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

6-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4-oxido-1,4-azaphosphinan-1-yl)nicotinonitrile;

4-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4-oxido-1,4-azaphosphinan-1-yl)benzonitrile;

2-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4-oxido-1,4-azaphosphinan-1-yl)nicotinonitrile;

4-(3-(1-(2-chloropyrimidin-4-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(3-(1-(4-chloropyrimidin-2-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(3-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(quinazolin-4-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(3-(1-(6-chloropyrimidin-4-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(1-(3-fluoropyridin-2-yl)-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(5-(trifluoromethyl)pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(1-(6-fluoropyridin-2-yl)-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(4-(trifluoromethyl)pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(3-(trifluoromethyl)pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(1-(3,5-difluoropyridin-2-yl)-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(1-(5-fluoropyridin-2-yl)-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(quinazolin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(6-(trifluoromethyl)pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(thiazol-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(thiadiazol-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(3-(acetyl)pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

(±

)-4-(4-fluoro-3-(4-oxido-1-(3-(1-hydoxyethyl)pyridin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(5-(fluoro)pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(5-(chloro)pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(5-(n-propyl)pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(3-(1-cyclobutyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(1-methyl-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(3-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(1-isopropyl-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(3-(1-(cyclopropylmethyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(1-isobutyl-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-45propyl-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(1-neopentyl-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(1-neopentyl-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(4-fluoro-3-(1-isopentyl)-4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one;

4-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one;

4-[[4-fluoro-3-(4-methyl-4-oxo-1,4-azaphosphinane-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one;

4-[[4-fluoro-3-(4-ethyl-4-oxo-1,4-azaphosphinane-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one;

4-[[4-fluoro-3-(4-isopropyl-4-oxo-1,4-azaphosphinane-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one;

4-[[4-fluoro-3-(4-ethoxyl-4-oxo-1,4-azaphosphinane-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one;

4-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)-7-fluorophthalazin-1(2H)-one;

4-[(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorophenyl)dideuteromethyl]-7-fluorophthalazin-1(2H)-one;

4-(4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)-7-fluorophthalazin-1(2H)-one;

4-[(4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)phenyl)dideuteromethyl]-7-fluorophthalazin-1(2H)-one;

(±

)-4-[(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluoro-1-phenyl)(hydroxymethl)]phthalazin-1(2H)-one; and

(±

)-4-{[4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)phenyl)](hydroxymethyl)]-7-fluorophthalazin-1(2H)-one;

or a pharmaceutically acceptable salt or solvate thereof.

116. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

118. A method for the treatment or prevention of a condition which can be ameliorated by inhibition of PARP in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

119. The method of claim 118, wherein the condition which can be ameliorated by inhibition of PARP is a condition selected from the group consisting of cancer, inflammatory diseases, and ischemic conditions.

121. The method of claim 118, wherein the condition which can be ameliorated by inhibition of PARP is a breast cancer, an ovarian cancer or a brain cancer.

129. A kit for the treatment or prevention in an individual of a condition mediated by PARP enzymatic activity, comprising:

(a) a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof; and

(b) packaging.

3-10. -10. (canceled)

13-15. -15. (canceled)

18-19. -19. (canceled)

24-29. -29. (canceled)

32-33. -33. (canceled)

35-37. -37. (canceled)

39-44. -44. (canceled)

46. (canceled)

49. (canceled)

54-68. -68. (canceled)

70. (canceled)

72. (canceled)

74-76. -76. (canceled)

78. (canceled)

80. (canceled)

84. (canceled)

86. A compound of the formula (IV):

87. The compound of claim 86, wherein the compound is of the formula (IVa):

88. The compound of claim 87, wherein R^C is fluoro;

or a pharmaceutically acceptable salt or solvate thereof.

100. The compound of claim 87, wherein R^D is selected from the group consisting of:

101. The compound of claim 86, wherein the compound is of the formula (IVb):

89-99. -99. (canceled)

102-105. -105. (canceled)

106. A compound of the formula (V):

109. The compound of claim 106, wherein R^F is fluoro, each R¹ and R² is hydrogen, and R^D is cyclopropyl or 2-pyrimidinyl;

or a pharmaceutically acceptable salt or solvate thereof.

107-108. -108. (canceled)

110-115. -115. (canceled)

117. (canceled)

120. (canceled)

122-128. -128. (canceled)

130-132. -132. (canceled)