PYRIMIDINE TRICYCLIC ENONE DERIVATIVES FOR INHIBITION OF ROR-GAMMA AND OTHER USES

• US 20200131148A1
• Filed: 12/16/2017
• Published: 04/30/2020
• Est. Priority Date: 12/16/2016
• Status: Active Grant

• Current Assignee: Reata Pharmaceuticals, Inc. (Biogen, Inc.)
• Original Assignee: Reata Pharmaceuticals, Inc. (Biogen, Inc.)
• Inventors: JIANG, Xin, BENDER, Christopher F., VISNICK, Melean, HOTEMA, Martha R., SHELDON, Zachary S., LEE, Chitase, CAPRATHE, Bradley William, BOLTON, Gary, KORNBERG, Brian
• Granted Patent: US 11,292,781 B2
• Time in Patent Office: Days
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07D 221/04 Ortho- or peri-condensed ring systems
• CPC Class Codes: C07D 239/70 condensed with carbocyclic rings or ring systems
• 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 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are compounds of the formulas: as well as analogs thereof, wherein the variables are defined herein. Also provided are pharmaceutical compositions thereof. In some aspects, the compounds and compositions provided herein may be used to inhibit RORγ and/or reduce the expression of IL-17. Also provided are methods of administering compounds and composition provided herein to a patient in need thereof, for example, for the treatment or prevention of diseases or disorders associated with inflammation or autoimmune disorders.

Claims

1. A compound of the formula:

2. The compound of claim 1 further defined as:

3. The compound of either claim 1 or claim 2 further defined as:

4. The compound according to any one of claims 1-3 further defined as:

5. The compound according to any one of claims 1-4 further defined as:

6. The compound of claim 5 further defined as:

7. The compound of claim 6 further defined as:

8. The compound of claim 7 further defined as:

9. The compound of claim 8 further defined as:

10. The compound of claim 8 further defined as:

11. The compound of claim 9 further defined as:

13. The compound according to any one of claims 1-6 and 12, wherein the bond between carbon atom 1 and carbon atom 2 is an epoxidized double bond.

14. The compound according to any one of claims 1-6 and 12, wherein the bond between carbon atom 1 and carbon atom 2 is a double bond.

15. The compound according to any one of claims 1-3 and 12-14, wherein the bond between carbon atom 4 and carbon atom 5 is a single bond.

16. The compound according to any one of claims 1-3 and 12-14, wherein the bond between carbon atom 4 and carbon atom 5 is a double bond.

17. The compound according to any one of claims 1, 2, and 12-16, wherein a is 1.

18. The compound according to any one of claims 1, 2, and 12-16, wherein a is 0.

19. The compound according to any one of claims 1, 2, and 12-16, wherein a is 2.

20. The compound according to any one of claims 1-7 and 12-19, wherein R₁ is cyano.

21. The compound according to any one of claims 1-10 and 12-20, wherein R₂ is alkyl_(C≤

12) or substituted alkyl<sub>(C≤

12)</sub>.

22. The compound of claim 21, wherein R₂ is alkyl_(C≤

12).

23. The compound of claim 22, wherein R₂ is methyl, ethyl, or propyl.

24. The compound of claim 23, wherein R₂ is methyl.

25. The compound of claim 21, wherein R₂ is substituted alkyl_(C≤

12).

26. The compound of claim 25, wherein R₂ is 3-hydroxypropyl.

27. The compound according to any one of claims 1-10 and 12-20, wherein R₂ is alkenyl_(C≤

12) or substituted alkenyl<sub>(C≤

12)</sub>.

28. The compound of claim 27, wherein R₂ is alkenyl_(C≤

12).

29. The compound of claim 28, wherein R₂ is 2-propenyl or 2-methyl-prop-2-enyl.

30. The compound according to any one of claims 1-4 and 12-29, wherein R₂′

is hydrogen.

31. The compound according to any one of claims 1-4 and 12-29, wherein R₂′

is alkyl<sub>(C≤

12)</sub> or substituted alkyl<sub>(C≤

12)</sub>.

32. The compound of claim 31, wherein R₂′

is alkyl<sub>(C≤

12)</sub>.

33. The compound of claim 32, wherein R₂′

is methyl.

34. The compound according to any one of claims 1-5 and 12-33, wherein R₃ is alkyl_(C≤

12) or substituted alkyl<sub>(C≤

12)</sub>.

35. The compound of claim 34, wherein R₃ is alkyl_(C≤

12).

36. The compound of claim 35, wherein R₃ is methyl, propyl, or isopentyl.

37. The compound of claim 36, wherein R₃ is methyl.

38. The compound according to any one of claims 1-5 and 12-33, wherein R₃ is aryl_(C≤

12) or substituted aryl<sub>(C≤

12)</sub>.

39. The compound of claim 38, wherein R₃ is aryl_(C≤

12).

40. The compound of claim 39, wherein R₃ is phenyl.

41. The compound according to any one of claims 1-8 and 13-40, wherein R₄ is alkyl_(C≤

18) or substituted alkyl_(C2-18).

42. The compound according to any one of claims 1-40, wherein R₄ is heteroaryl_(C≤

18) or substituted heteroaryl<sub>(C≤

18)</sub>.

43. The compound of claim 42, wherein R₄ is a heteroaryl_(C≤

12) or a substituted heteroaryl<sub>(C≤

12)</sub> group wherein at least one of the heteroatoms in the aromatic ring is a nitrogen atom.

44. The compound of claim 42, wherein R₄ is heteroaryl_(C≤

18).

45. The compound of claim 44, wherein R₄ is 3-pyridinyl, 4-pyridinyl, 4-(2-cycylopropyl)-pyridinyl, 5-(2-cycylopropyl)-pyridinyl, 4-(2-morpholino)-pyridinyl, 4-(2-phenyl)-pyridinyl, 3-(5-methyl)-pyridinyl, 3-(6-methyl)-pyridinyl, 4-(2-methyl)-pyridinyl, 4-(3-methyl)-pyridinyl, 3-pyrazolo[1,5-a]pyridinyl, 3-(N-methyl)-pyrrolo[2,3-b]pyridinyl, 5-isoquinlinyl, 2-isoquinlinyl, 1-isoquinolinyl, 4-(2-phenyl)-pyridinyl, 5-(2-phenyl)-pyridinyl, 3-(5-methyl)-pyridinyl, 4-(3-methyl)-pyridinyl, 4-(3,5-dimethyl)-isoxazolyl, 4-(2-methyl)-pyridinyl, 4-(3-methyl)-pyridinyl, 3-(4-methyl)-pyridinyl, 4-(6-methyl)-pyrimidinyl, 6-(4-methyl)-pyrimidinyl, 4-pyridazinyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 8-quinolinyl, 4-isoquinolinyl, 3-(8-methyl)-quinolinyl, 3-(1-methyl)-quinolinyl, 4-(2-methyl)-quinolinyl, 4-(2-isopropyl)-quinolinyl, 4-(6-methyl)-quinolinyl, 4-(7-methyl)-quinolinyl, 4-(8-methyl)-quinolinyl, 2-(N-methyl)-indolyl, 5-(2,4-dimethyl)-thiazolyl, or 5-(3-methyl)-oxadizolyl.

46. The compound of claim 42, wherein R₄ is substituted heteroaryl_(C≤

18).

47. The compound of claim 46, wherein R₄ is 4-(2-trifluoromethyl)-pyridinyl, 4-(3-fluoro)-pyridinyl, 4-(2-methoxy)-pyridinyl, 4-(2-hydroxymethyl)-pyridinyl, 4-(2-acetylamino)-pyridinyl, 4-(2-fluoromethyl)-pyridinyl, 4-(2-acetamidylethyl)-pyridinyl, 4-(2-fluoromethyl)-quinolinyl, 4-(2-acetoxymethyl)-quinolinyl, 4-(2-formyl)-quinolinyl, 4-(6-fluoro)-quinolinyl, 4-(7-fluoro)-quinolinyl, 4-(8-fluoro)-quinolinyl, 4-(6,8-difluoro)-quinolinyl, 4-(6-fluoro-2-methyl)-quinolinyl, or 4-(8-fluoro-2-methyl)-quinolinyl.

48. The compound according to any one of claims 1-8 and 13-40, wherein R₄ is aryl_(C≤

12) or substituted aryl<sub>(C≤

12)</sub>.

49. The compound of claim 48, wherein R₄ is aryl_(C≤

12).

50. The compound of claim 49, wherein R₄ is phenyl.

51. The compound of claim 48, wherein R₄ is substituted aryl_(C≤

12).

52. The compound of claim 51, wherein R₄ is 2-fluorophenyl or 4-trifluoromethylphenyl.

53. The compound according to any one of claims 1-8 and 12-40, wherein R₄ is cycloalkyl_(C≤

12) or substituted cycloalkyl<sub>(C≤

12)</sub>.

54. The compound of claim 53, wherein R₄ is cycloalkyl_(C≤

12).

55. The compound of claim 54, wherein R₄ is cyclohexyl.

56. The compound according to any one of claims 1-8 and 12-40, wherein R₄ is:

57. The compound of claim 56, wherein R₄ is:

58. The compound of claim 56, wherein R₄ is:

59. The compound according to any one of claims 1-8 and 12-40, wherein R₄ is heterocycloalkyl_(C≤

18) or substituted heterocycloalkyl<sub>(C≤

18)</sub>.

60. The compound of claim 59, wherein R₄ is heterocycloalkyl_(C≤

12).

61. The compound of claim 60, wherein R₄ is morpholinyl, 4-piperidinyl, 3-(5-methyl-)1,2,3,6-tetrahydropyridinyl, or 4-N-methylpiperazinyl.

62. The compound of claim 59, wherein R₄ is substituted heterocycloalkyl_(C≤

12).

63. The compound of claim 62, wherein R₄ is N-t-butyloxycarbonyl-4-piperidinyl, N-acetyl-4-piperidinyl, N-t-butyloxycarbonyl-5-methyl-1,2,3,6-tetrahydropyridinyl, N-acetyl-5-methyl-1,2,3,6-tetrahydropyridinyl, or 4-N-acetylpiperazinyl.

64. The compound according to any one of claims 1-8 and 13-40, wherein R₄ is hydrogen.

65. The compound according to any one of claims 1-8 and 12-40, wherein R₄ is —

X₁—

(CH₂)_m—

R₄′

;

wherein;

X₁ is NR_b, O, or S;

wherein;

R_b is hydrogen, alkyl<sub>(C≤

6)</sub>, or substituted alkyl<sub>(C≤

6)</sub>;

m is 0, 1, 2, 3, or 4; and

R₄′

is alkyl<sub>(C≤

12)</sub>, cycloalkyl<sub>(C≤

18)</sub>, aryl<sub>(C≤

18)</sub>, aralkyl<sub>(C≤

18)</sub>, heteroaryl<sub>(C≤

18)</sub>, heteroaralkyl<sub>(C≤

18)</sub>, heterocycloalkyl<sub>(C≤

18)</sub>, or a substituted version of any of these groups, provided that when X₁ is O, then R₄′

is not methyl.

66. The compound of claim 65, wherein X₁ is NR_b, wherein:

R_b is hydrogen, alkyl<sub>(C≤

6)</sub>, or substituted alkyl<sub>(C≤

6)</sub>.

67. The compound of either claim 65 or claim 66, wherein R_b is hydrogen.

68. The compound according to any one of claims 65-67, wherein m is 0 or 1.

69. The compound of claim 68, wherein m is 0.

70. The compound according to any one of claims 65-69, wherein R₄′

is cycloalkyl<sub>(C≤

18)</sub>, aryl<sub>(C≤

18)</sub>, aralkyl<sub>(C≤

18)</sub>, heteroaryl<sub>(C≤

18)</sub>, heteroaralkyl<sub>(C≤

18)</sub>, heterocycloalkyl<sub>(C≤

18)</sub>, or a substituted version of any of these groups.

71. The compound according to any one of claims 65-70, wherein R₄′

is heteroaryl<sub>(C≤

12)</sub> or substituted heteroaryl<sub>(C≤

12)</sub>.

72. The compound of claim 71, wherein R₄′

is heteroaryl<sub>(C≤

12)</sub>.

73. The compound of claim 72, wherein R₄′

is 4-pyridinyl.

74. The compound according to any one of claims 1-8 and 13-40, wherein R₄ is amino.

75. The compound according to any one of claims 1-8 and 13-40, wherein R₄ is amido_(C≤

12) or substituted amido<sub>(C≤

12)</sub>.

76. The compound of claim 75, wherein R₄ is amido_(C≤

12).

77. The compound of claim 76, wherein R₄ is:

78. The compound according to any one of claims 1-8 and 12-40, wherein R₄ is —

X₂—

(CH₂)p-R₄″

;

wherein;

X₂ is arenediyl<sub>(C≤

12)</sub>, substituted arenediyl<sub>(C≤

12)</sub>, heterocycloalkanediyl<sub>(C≤

12)</sub>, substituted heterocycloalkanediyl<sub>(C≤

12)</sub>, heteroarenediyl<sub>(C≤

12)</sub>, or substituted heteroarenediyl<sub>(C≤

12)</sub>;

p is 0, 1, 2, 3, or 4; and

R₄″

is alkyl<sub>(C≤

8)</sub>, cycloalkyl<sub>(C≤

8)</sub>, aryl<sub>(C≤

8)</sub>, heteroaryl<sub>(C≤

8)</sub>, heterocycloalkyl<sub>(C≤

8)</sub>, acyl<sub>(C≤

8)</sub>, amido<sub>(C≤

8)</sub>, alkoxy<sub>(C≤

8)</sub>, acyloxy<sub>(C≤

8)</sub>, —

C(O)-alkoxy<sub>(C≤

8)</sub>, —

C(O)-alkylamino<sub>(C≤

8)</sub>, —

C(O)-dialkylamino<sub>(C≤

8)</sub>, alkylsulfonyl<sub>(C≤

8)</sub>, arylsulfonyl<sub>(C≤

8)</sub>, alkoxysulfonyl<sub>(C≤

8)</sub>, or a substituted version of any of these groups.

79. The compound of claim 78, wherein X₂ is heteroarenediyl_(C≤

12) or substituted heteroarenediyl<sub>(C≤

12)</sub>.

80. The compound of claim 79, wherein X₂ is heteroarenediyl_(C≤

12).

81. The compound of claim 80, wherein X₂ is pyridin-2,4-diyl or pyridine-2,5-diyl.

82. The compound of claim 78, wherein X₂ is heterocycloalkanediyl_(C≤

12) or substituted heterocycloalkanediyl<sub>(C≤

12)</sub>.

83. The compound of claim 82, wherein X₂ is heterocycloalkanediyl_(C≤

12).

84. The compound of claim 83, wherein X₂ is piperidin-1,4-diyl, piperazin-1,4-diyl, or 1,2,3,6-tetrahydropiperidin-1,5-diyl.

85. The compound according to any one of claims 78-84, wherein p is 0, 1, or 2.

86. The compound of claim 85, wherein p is 0.

87. The compound of claim 85, wherein p is 1.

88. The compound of claim 85, wherein p is 2.

89. The compound according to any one of claims 78-88, wherein R₄″

is acyl<sub>(C≤

8)</sub> or substituted acyl<sub>(C≤

8)</sub>.

90. The compound of claim 89, wherein R₄″

is acyl<sub>(C≤

8)</sub>.

91. The compound of claim 90, wherein R₄″

is acetyl.

92. The compound of claim 89, wherein R₄″

is substituted acyl<sub>(C≤

8)</sub>.

93. The compound of claim 92, wherein R₄″

is carboxy.

94. The compound according to any one of claims 78-88, wherein R₄″

is amido<sub>(C≤

8)</sub> or substituted amido<sub>(C≤

8)</sub>.

95. The compound of claim 94, wherein R₄″

is amido<sub>(C≤

8)</sub>.

96. The compound of claim 95, wherein R₄″

is acetamidyl.

97. The compound according to any one of claims 78-88, wherein R₄″

is cycloalkyl<sub>(C≤

8)</sub> or substituted cycloalkyl<sub>(C≤

8)</sub>.

98. The compound of claim 97, wherein R₄″

is cycloalkyl<sub>(C≤

8)</sub>.

99. The compound of claim 98, wherein R₄″

is cyclopropyl.

100. The compound according to any one of claims 78-88, wherein R₄″

is alkylsulfonyl<sub>(C≤

8)</sub> or substituted alkylsulfonyl<sub>(C≤

8)</sub>.

101. The compound of claim 100, wherein R₄″

is alkylsulfonyl<sub>(C≤

8)</sub>.

102. The compound of claim 101, wherein R₄″

is —

S(O)₂CH₃ or —

S(O)₂CH₂CH₃.

103. The compound according to any one of claims 78-88, wherein R₄″

is —

C(O)-alkoxy<sub>(C≤

8)</sub>.

104. The compound of claim 103, wherein R₄″

is —

C(O)OEt.

105. The compound according to any one of claims 78-88, wherein R₄″

is —

C(O)-dialkylamino<sub>(C≤

8)</sub>.

106. The compound of claim 105, wherein R₄″

is —

C(O)NMe₂.

107. The compound according to any one of claims 1-77, wherein R₅ is aryl_(C≤

12) or substituted aryl<sub>(C≤

12)</sub>.

108. The compound of claim 107, wherein R₅ is aryl_(C≤

12).

109. The compound of claim 108, wherein R₅ is phenyl, 4-methylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 1,3-biphenyl, or 1,4-biphenyl.

110. The compound of claim 107, wherein R₅ further comprises one or more fluorine atoms.

111. The compound of either claim 107 or claim 110, wherein R₅ is substituted aryl_(C≤

12).

112. The compound of claim 111, wherein R₅ is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-hydroxymethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-chlorophenyl, or 3,4-dichlorophenyl.

113. The compound according to any one of claims 1-8 and 13-77, wherein R₅ is cycloalkyl_(C≤

12) or substituted cycloalkyl<sub>(C≤

12)</sub>.

114. The compound of claim 113, wherein R₅ is cyclopropyl.

115. The compound according to any one of claims 1-8 and 12-77, wherein R₅ is cycloalkoxy_(C≤

12)z or substituted cycloalkoxy<sub>(C≤

12)</sub>.

116. The compound of claim 113, wherein R₅ is cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.

117. The compound according to any one of claims 1-8 and 13-77, wherein R₅ is alkylamino_(C≤

12) dialkylamino<sub>(C≤

12)</sub>, or a substituted version of either of these groups.

118. The compound of claim 117, wherein R₅ is dialkylamino_(C≤

12) or substituted dialkylamino<sub>(C≤

12)</sub>.

119. The compound of claim 118, wherein R₅ is dialkylamino_(C≤

8) or substituted dialkylamino<sub>(C≤

8)</sub>.

120. The compound of claim 119, wherein R₅ is dimethylamino.

121. The compound according to any one of claims 1-8 and 13-77, wherein R₅ is alkylsulfonylamino_(C≤

12) or substituted alkylsulfonylamino<sub>(C≤

12)</sub>.

122. The compound of claim 121, wherein R₆ is methylsulfonylamino.

123. The compound according to any one of claims 1-8 and 12-77, wherein R₅ is —

OY₁-A;

wherein;

Y₁ is alkanediyl<sub>(C≤

8)</sub> or substituted alkanediyl<sub>(C≤

8)</sub>; and

A₁ is cycloalkyl<sub>(C≤

8)</sub> or substituted cycloalkyl<sub>(C≤

8)</sub>.

124. The compound of claim 123, wherein Y₁ is methylene.

125. The compound of either claim 123 or claim 124, wherein A₁ is cyclobutyl.

126. The compound of claim 123, wherein R₅ is:

127. The compound according to any one of claims 1-8 and 13-77, wherein R₅ is —

Y₂—

C(O)NR_e-A₂;

wherein;

Y₂ is arenediyl<sub>(C≤

8)</sub> or substituted arenediyl<sub>(C≤

8)</sub>;

R_e is hydrogen, alkyl<sub>(C≤

6)</sub>, or substituted alkyl<sub>(C≤

6)</sub>; and

A₂ is aralkyl<sub>(C≤

12)</sub> or substituted aralkyl<sub>(C≤

12)</sub>.

128. The compound of claim 127, wherein Y₂ is arenediyl_(C≤

8).

129. The compound of claim 128, wherein Y₂ is benzenediyl.

130. The compound according to any one of claims 127-129, wherein R_c is alkyl_(C≤

6).

131. The compound of claim 130, wherein R is methyl.

132. The compound according to any one of claims 127-131, wherein A₂ is aralkyl_(C≤

12).

133. The compound of claim 132, wherein A₂ is benzyl.

134. The compound according to any one of claims 1-8 and 12-77, wherein R₅ is heteroaryl_(C≤

12) or substituted heteroaryl<sub>(C≤

12)</sub>.

135. The compound of claim 134, wherein R₅ is heteroaryl_(C≤

12).

136. The compound of claim 135, wherein R₅ is 5-(3-methyl)-oxadiazolyl, 4-(3,5-dimethyl)-isoxazolyl, furanyl, benzofuranyl, 2-thiazolyl, 5-(2-methyl)-furanyl, 3-pyridinyl, or 4-pyridinyl.

137. The compound according to any one of claims 1-8 and 13-77, wherein R₅ is hydroxy.

138. The compound according to any one of claims 1-8 and 13-77, wherein R₅ is —

OS(O)₂C₆H₄CH₃.

139. The compound according to any one of claims 1-8 and 13-77, wherein R₅ is heterocycloalkyl_(C≤

12) or substituted heterocycloalkyl<sub>(C≤

12)</sub>.

140. The compound of claim 139, wherein R₅ is heterocycloalkyl_(C≤

12).

141. The compound of claim 140, wherein R₅ is pyrrolidinyl.

142. The compound according to any one of claims 1-8 and 13-77, wherein R₅ is alkoxy_(C≤

12) or substituted alkoxy<sub>(C≤

12)</sub>.

143. The compound of claim 142, wherein R₅ is alkoxy_(C≤

12).

144. The compound of claim 143, wherein R₅ is methoxy or isopropoxy.

145. The compound according to any one of claims 1-8 and 13-77, wherein R₅ is aralkyl_(C≤

12) or substituted aralkyl<sub>(C≤

12)</sub>.

146. The compound of claim 145, wherein R₅ is aralkyl_(C≤

12).

147. The compound of claim 146, wherein R₅ is benzyl.

148. The compound according to any one of claims 1-12, wherein the compound is further defined as:

152. A pharmaceutical composition comprising:

(A) a compound according to any one of claims 1-151; and

(B) an excipient.

153. The pharmaceutical composition of claim 152, wherein the pharmaceutical composition is formulated for administration:

orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in cremes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion.

154. The pharmaceutical composition of claim 153, wherein the pharmaceutical composition is formulated for oral administration.

155. The pharmaceutical composition of claim 153, wherein the pharmaceutical composition is formulated for administration via injection.

156. The pharmaceutical composition of claim 155, wherein the pharmaceutical composition is formulated for intraarterial administration, intramuscular administration, intraperitoneal administration, or intravenous administration.

157. The pharmaceutical composition of claim 153, wherein the pharmaceutical composition is formulated for administration topically.

158. The pharmaceutical composition of claim 157, wherein the pharmaceutical composition is formulated for topical administration to the skin or to the eye.

159. The pharmaceutical composition according to any one of claims 152-158, wherein the pharmaceutical composition is formulated as a unit dose.

160. A method of treating or preventing a disease or disorder in a patient in need thereof comprising administering to the patient a pharmaceutically effective amount of a compound or composition according to any one of claims 1-159.

161. The method of claim 160, wherein the patient is a mammal.

162. The method of claim 161, wherein the patient is a human.

163. The method according to any one of claims 160-162, wherein the disease or disorder is associated with increased production of cytokine IL-17.

164. The method according to any one of claims 160-163, wherein the disease or disorder is associated with dysregulated angiogenesis.

165. The method according to any one of claims 160-164, wherein the disease or disorder is an autoimmune disease, organ rejection, asthma, cancer, a neurological disorder, a psychiatric disorder, a neuropsychiatric disorder, chronic pain syndrome, an inflammatory condition, a retinal disorder, or a cardiovascular disease.

166. The method of claim 165, wherein the disease or disorder is cancer.

167. The method of claim 165, wherein the autoimmune disease is psoriasis, multiple sclerosis, scleroderma, rheumatoid arthritis, lupus, psoriatic arthritis, ankylosing spondylitis, Sjö

gren syndrome, vitiligo, uveitis, dry eye syndrome, systemic sclerosis, type 1 diabetes, myasthenia gravis, and inflammatory bowel disease.

168. The method of claim 165, wherein the cardiovascular disease is vasculitis, atherosclerosis, myocardial infarction, myocarditis, heart failure, pulmonary hypertension, or stroke.

169. The method of claim 165, wherein the neurological disorder is epilepsy, multiple sclerosis, spinal cord injury, Guillain-Barre syndrome, or another neurological disorder involving dysregulated inflammatory signaling or oxidative stress.

170. The method of claim 169, wherein the neurodegenerative disorder is Alzheimer'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, or Huntington'"'"'s disease.

171. The method of claim 165, wherein the inflammatory condition is pancreatitis, hepatitis, pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, asthma, dermatitis, gastritis, esophagitis, irritable bowel syndrome, inflammatory bowel disease, nephritis, muscle wasting, or osteoarthritis.

172. The method of claim 165, wherein the chronic pain syndrome is fibromyalgia or neuropathic pain.

173. The method of claim 165, wherein the disease or disorder is a severe inflammatory response to a pathogen.

174. The method of claim 173, wherein the severe inflammatory response to a pathogen is from encephalitis, meningitis, H. pylori, Toxoplasma gondii, or Leishmania spp.

175. The method of claim 165, wherein the disease or disorder is obesity or a condition associated with obesity.

176. The method of claim 175, wherein the condition associated with obesity is insulin resistance or fatty liver disease.

177. The method of claim 165, wherein the retinal disorder is macular degeneration or another disorder of the retina.

178. The method of claim 160, wherein the disease or disorder is associated with inflammation.

179. The method of claim 178, wherein the disease or disorder associated with inflammation is obesity, Type 2 diabetes, or a complication of Type 1 or Type 2 diabetes.

180. The method of claim 179, wherein the complication of Type 1 or Type 2 diabetes is neuropathy, reduced kidney function or chronic kidney disease, retinopathy, diabetic ulcers, or cardiovascular disease.

181. The method of claim 178, wherein the disease or disorder associated with inflammation is chronic kidney disease.

182. The method of claim 181, wherein the chronic kidney disease is hereditary.

183. The method of claim 181, wherein the chronic kidney disease is due to a non-hereditary cause.

184. The method according to any one of claims 160-174, wherein the method comprises administering the compound once.

185. The method according to any one of claims 160-174, wherein the method comprises administering the compound two or more times.

12. A compound of the formula:

149. A compound of the formula:

150. A compound of the formula:

151. A compound further defined as:

(6aR,7R,10aS)-9-cyano-2,4-dimethoxy-7,10a-dimethyl-5,6a,7,10a-tetrahydrobenzo[h]quinazolin-8(6H)-one;

(6aR,7R,10aS)-9-cyano-4-methoxy-2-(2-methoxypyridin-4-yl)-7,10a-dimethyl-5,6a,7,10a-tetrahydrobenzo[h]quinazolin-8(6H)-one;

(6aR,7R,10aS)-9-cyano-4-methoxy-7,10a-dimethyl-2-(2-methylpyridin-4-yl)-5,6a,7,10a-tetrahydrobenzo[h]quinazolin-8(6H)-one;

(6aR,7R,10aS)-9-cyano-4-methoxy-7,10a-dimethyl-2-(3-methylpyridin-4-yl)-5,6a,7,10a-tetrahydrobenzo[h]quinazolin-8(6H)-one;

(6aR,7R,10aS)-9-cyano-4-methoxy-7,10a-dimethyl-2-(pyridin-4-yl)-5,6a,7,10a-tetrahydrobenzo[h]quinazolin-8(6H)-one;

(6aR,7R,10aS)-2-(2-fluoropyridin-4-yl)-9-cyano-4-methoxy-7,10a-dimethyl-5,6a,7,10a-tetrahydrobenzo[h]quinazolin-8(6H)-one;

(6aR,7R,10aS)-9-cyano-4-methoxy-7,10a-dimethyl-2-(pyridin-3-yl)-5,6a,7,10a-tetrahydrobenzo[h]quinazolin-8(6H)-one;

(6aR,7R,10aS)-9-cyano-4-methoxy-7,10a-dimethyl-2-(pyridin-4-ylamino)-5,6a,7,10a-tetrahydrobenzo[h]quinazolin-8(6H)-one;

(6aR,7R,10aS)-9-cyano-4-methoxy-7,10a-dimethyl-2-(quinolin-4-yl)-5,6a,7,10a-tetrahydrobenzo[h]quinazolin-8(6H)-one;

tert-butyl (2-((6aR,7R,10aS)-9-cyano-4-methoxy-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)ethyl)carbamate;

N-(2-((6aR,7R,10aS)-9-cyano-4-methoxy-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)ethyl)formamide;

(6aR,7R,10aS)-2-(2-aminoethyl)-9-cyano-4-methoxy-7,10a-dimethyl-5,6a,7,10a-tetrahydrobenzo[h]quinazolin-8(6H)-one;

(6aR,7R,10aR)-8-hydroxy-7,10a-dimethyl-4-phenyl-2-(pyridin-4-yl)-5,6,6a,7,10,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-8-oxo-4-phenyl-2-(pyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,8aS,9aS,9bR)-7,9b-dimethyl-8-oxo-4-phenyl-2-(pyridin-4-yl)-6,6a,7,8,9a,9b-hexahydrooxireno[2′

,3′

;

3,4]benzo[1,2-h]quinazoline-8a(5H)-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-8-oxo-4-phenyl-2-(pyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carboxamide;

(6aR,7R,10aS)-4-hydroxy-7,10a-dimethyl-8-oxo-2-(pyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-9-cyano-7,10a-dimethyl-8-oxo-2-(pyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-4-yl 4-methylbenzenesulfonate;

(6aR,7R,10aS)-7,10a-dimethyl-8-oxo-2,4-diphenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-8-oxo-4-phenyl-2-(4-(trifluoromethyl)phenyl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(4-(hydroxymethyl)phenyl)-7,10a-dimethyl-8-oxo-2-(pyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-8-oxo-4-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-cyclohexyl-7,10a-dimethyl-8-oxo-4-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-8-oxo-2-(pyridin-4-yl)-4-(4-(trifluoromethyl)phenyl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-8-oxo-4-(pyridin-3-yl)-2-(pyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-8-oxo-2-(pyridin-4-yl)-4-(3-(trifluoromethyl)phenyl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-8-oxo-2-(pyridin-4-yl)-4-(p-tolyl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(4-chlorophenyl)-7,10a-dimethyl-8-oxo-2-(pyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS))-7,10a-dimethyl-8-oxo-2,4-di(pyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(4-methoxyphenyl)-7,10a-dimethyl-8-oxo-2-(pyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(3,4-dichlorophenyl)-7,10a-dimethyl-8-oxo-2-(pyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-8-oxo-4-phenyl-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(2-methoxypyridin-4-yl)-7,10a-dimethyl-8-oxo-4-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-amino-7,10a-dimethyl-8-oxo-4-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

N-((6aR,7R,10aS)-9-cyano-7,10a-dimethyl-8-oxo-4-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)cyclohexanecarboxamide;

(6aR,7R,10aS)-4-benzyl-7,10a-dimethyl-8-oxo-2-(pyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(R)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,8,10a-tetrahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(3-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(4-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-9-cyano-4-isopropoxy-7,10a-dimethyl-2-(quinolin-4-yl)-5,6a,7,10a-tetrahydrobenzo[h]quinazolin-8(6H-one;

(6aR,7R,10aS)-9-cyano-4-isopropyl-7,10a-dimethyl-2-(quinolin-4-yl)-5,6a,7,10a-tetrahydrobenzo[h]quinazolin-8(6H)-one;

(6aR,7R,10aS)-7,10a-dimethyl-2-(2-methylpyridin-4-yl)-8-oxo-4-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

tert-butyl 4-((6aR,7R,10aS)-9-cyano-7,10a-dimethyl-8-oxo-4-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)piperidine-1-carboxylate;

4-((6aR,7R,10aS)-9-cyano-7,10a-dimethyl-8-oxo-4-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)piperidin-1-ium chloride;

(6aR,7R,10aS)-2-(1-acetylpiperidin-4-yl)-7,10a-dimethyl-8-oxo-4-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

tert-butyl 5-((6aR,7R,10aS)-9-cyano-7,10a-dimethyl-8-oxo-4-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate;

5-((6aR,7R,10aS)-9-cyano-7,10a-dimethyl-8-oxo-4-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)-1,2,3,6-tetrahydropyridin-1-ium chloride;

(6aR,7R,10aS)-2-(1-acetyl-1,2,5,6-tetrahydropyridin-3-yl)-7,10a-dimethyl-8-oxo-4-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(4-fluorophenyl)-7,10a-dimethyl-2-(2-methylpyridin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(2-methylpyridin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2,4-difluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(2-cyclopropylpyridin-4-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(2-(trifluoromethyl)pyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aR)-4-(2-fluorophenyl)-8-hydroxy-7,10a-dimethyl-2-(3-methylpyridin-4-yl)-5,6,6a,7,10,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(3-methylpyridin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-2-(3-fluoropyridin-4-yl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(5-methylpyridin-3-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-3-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-6-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

N-(4-((6aR,7R,10aS)-9-cyano-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)pyridin-2-yl)acetamide;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-8-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(8-fluoro-2-methylquinolin-4-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(2-morpholinopyridin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(2-phenylpyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-2-(isoquinolin-4-yl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(pyrazolo[1,5-a]pyridin-3-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(8-methylquinolin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(2-methylquinolin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(2,4-dimethylthiazol-5-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(6-methylquinolin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinazolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-2-(isoquinolin-1-yl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-2-(7-fluoroquinolin-4-yl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-2-(8-fluoroquinolin-4-yl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(6-methylpyrimidin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(pyridazin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(6,7-dihydro-SH-cyclopenta[b]pyridin-4-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2,4-bis(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-2-(2-(hydroxymethyl)pyridin-4-yl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(2-(fluoromethyl)pyridin-4-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-5-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(6-fluoro-2-methylquinolin-4-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-2-(isoquinolin-5-yl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(3,5-dimethylisoxazol-4-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(6-methylpyridin-3-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-2-(6-fluoroquinolin-4-yl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(6,8-difluoroquinolin-4-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(4-methylpiperazin-1-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-morpholino-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-cyclopropyl-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-cyclobutoxy-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(cyclobutylmethoxy)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(cyclohexyloxy)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(cyclopentyloxy)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

N-((6aR,7R,10aS)-9-cyano-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-4-yl)methanesulfonamide;

(6aR,7R,10aS)-4-(dimethylamino)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(3,5-dimethylisoxazol-4-yl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

N-benzyl-4-((6aR,7R,10aS)-9-cyano-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-4-yl)-N-methylbenzamide;

(6aR,7R,10aS)-4-(furan-2-yl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(benzofuran-2-yl)-7,10a-di methyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-4-(5-methylfuran-2-yl)-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-4-(thiazol-2-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(3-fluorophenyl)-7,10a-dimethyl-2-(2-methylquinolin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(4-fluorophenyl)-7,10a-dimethyl-2-(2-methylquinolin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-cyclobutoxy-7,10a-dimethyl-2-(2-methylquinolin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(cyclopentyloxy)-7,10a-dimethyl-2-(2-methylquinolin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-cyclobutoxy-7,10a-dimethyl-8-oxo-2-(quinazolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(3-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinazolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(4-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinazolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(2-(fluoromethyl)quinolin-4-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-2-(2-formylquinolin-4-yl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(4-((6aR,7R,10aS)-9-cyano-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)quinolin-2-yl)methyl acetate;

(6aS,10aR)-4-(2-fluorophenyl)-7,7,10a-trimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aS,10aR)-4-(2-fluorophenyl)-7,7,10a-trimethyl-2-(2-methylquinolin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(cyclopentyloxy)-2-(2-(fluoromethyl)quinolin-4-yl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(cyclopentyloxy)-2-(8-fluoroquinolin-4-yl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aS,10aR)-2-(2-(fluoromethyl)quinolin-4-yl)-4-(2-fluorophenyl)-7,7,10a-trimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-2-(2-isopropylquinolin-4-yl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aS,7R,10aR)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-7-propyl-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aS,10aR)-2-(2-cyclopropylpyridin-4-yl)-4-(2-fluorophenyl)-7,7,10a-trimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aS,7R,10aR)-7-ethyl-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aS,10aR)-4-(2-fluorophenyl)-2-(8-fluoroquinolin-4-yl)-7,7,10a-trimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(R)-4-(2-fluorophenyl)-2-(8-fluoroquinolin-4-yl)-7,10a-dimethyl-8-oxo-5,6,8,10a-tetrahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,8aS,9aS,9bR)-4-(2-fluorophenyl)-2-(7-fluoroquinolin-4-yl)-7,9b-dimethyl-8-oxo-6,6a,7,8,9a,9b-hexahydrooxireno[2′

,3′

;

3,4]benzo[1,2-h]quinazoline-8a(5H)-carbonitrile;

(6aR,7R,8aS,9aS,9bR)-2-(2-cyclopropylpyridin-4-yl)-4-(2-fluorophenyl)-7,9b-dimethyl-8-oxo-6,6a,7,8,9a,9b-hexahydrooxireno[2′

,3′

;

3,4]benzo[1,2-h]quinazoline-8a(5H)-carbonitrile;

(6aR,7R,8aS,9aS,9bR)-4-(2-fluorophenyl)-2-(isoquinolin-4-yl)-7,9b-dimethyl-8-oxo-6,6a,7,8,9a,9b-hexahydrooxireno[2′

,3′

;

3,4]benzo[1,2-h]quinazoline-8a(5H)-carbonitrile;

(6aR,7R,8aS,9aS,9bR)-4-(2-fluorophenyl)-7,9b-dimethyl-8-oxo-2-(quinolin-4-yl)-6,6a,7,8,9a,9b-hexahydrooxireno[2′

,3′

;

3,4]benzo[1,2-h]quinazoline-8a(5N)-carbonitrile;

(6aS,8aS,9aS,9bR)-4-(2-fluorophenyl)-7,7,9b-trimethyl-8-oxo-2-(quinolin-4-yl)-6,6a,7,8,9a,9b-hexahydrooxireno[2′

,3′

;

3,4]benzo[1,2-h]quinazoline-8a(5N)-carbonitrile;

(6aR,7R,10aR)-4-methoxy-7,10a-dimethyl-2-(pyridin-4-yl)-5,6a,7,10a-tetrahydrobenzo[h]quinazolin-8(6H)-one;

methyl (6aS,7R,10aR)-4-methoxy-7,10a-dimethyl-8-oxo-2-(pyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-7-carboxylate;

(6aS,7R,10aR)-2-(2-cyclopropylpyridin-4-yl)-4-(2-fluorophenyl)-7-(3-hydroxypropyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aS,7R,10aR)-2-(2-cyclopropylpyridin-4-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-7-propyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7,10a-dimethyl-8-oxo-4-(pyrrolidin-1-yl)-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(4-acetylpiperazin-1-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(6-cyclopropylpyridin-3-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(6-phenylpyridin-3-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(2-((methylsulfonyl)methyl)pyridin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-2-(2-(2-(methylsulfonyl)ethyl)pyridin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-7-allyl-2-(2-cyclopropylpyridin-4-yl)-4-(2-fluorophenyl)-1a-methyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(2-cyclopropylpyridin-4-yl)-4-(2-fluorophenyl)-10a-methyl-8-oxo-7-propyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(2-cyclopropylpyridin-4-yl)-4-(2-fluorophenyl)-7-methyl-8-oxo-10a-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7-methyl-8-oxo-10a-phenyl-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aS,10aR)-4-(2-fluorophenyl)-7,7,10a-trimethyl-8-oxo-2-(quinolin-5-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

3-(4-((6aR,7R,10aS)-9-cyano-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)pyridin-2-yl)propanoic acid;

ethyl 3-(4-((6aR,7R,10aS)-9-cyano-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)pyridin-2-yl)propanoate;

3-(4-((6aR,7R,10aS)-9-cyano-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)pyridin-2-yl)-N,N-dimethylpropanamide;

(6aR,7R,10aS)-2-(2-(2-(ethylsulfonyl)ethyl)pyridin-4-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(2-((ethylsulfonyl)methyl)pyridin-4-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,10aS)-2-(2-(fluoromethyl)pyridin-4-yl)-4-(2-fluorophenyl)-8-oxo-10a-propyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,10aS)-4-(2-fluorophenyl)-8-oxo-10a-propyl-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aS,10aR)-7-(cyclopropylmethyl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-1a-methyl-8-oxo-7-propyl-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(2-fluorophenyl)-10a-methyl-8-oxo-7-propyl-2-(quinolin-5-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(3-isopropylphenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-(4-isopropylphenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-([1,1′

-biphenyl]-3-yl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-4-([1,1′

-biphenyl]-4-yl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,10aS)-4-(2-fluorophenyl)-10a-isopentyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,10aS)-2-(2-(fluoromethyl)pyridin-4-yl)-4-(2-fluorophenyl)-10a-isopentyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aS,7R,10aR)-4-(2-fluorophenyl)-7,10a-dimethyl-7-(2-methylallyl)-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,10aS)-2-(2-cyclopropylpyridin-4-yl)-4-(2-fluorophenyl)-8-oxo-10a-propyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(2-cyclopropylpyridin-4-yl)-4-(2-fluorophenyl)-8-oxo-7,10a-dipropyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(2-cyclopropylpyridin-4-yl)-4-(2-fluorophenyl)-7-methyl-8-oxo-10a-propyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(5aR,6R,9aS)-4-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-2-(quinolin-4-yl)-5a,6,7,9a-tetrahydro-5H-indeno[1,2-d]pyrimidine-8-carbonitrile;

(5 aR,6R,9aS)-2-(2-(fluoromethyl)pyridin-4-yl)-4-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-5a,6,7,9a-tetrahydro-5H-indeno[1,2-d]pyrimidine-8-carbonitrile;

(5aR,6R,9aS)-2-(8-fluoro-2-methylquinolin-4-yl)-4-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-5a,6,7,9a-tetrahydro-5H-indeno[1,2-d]pyrimidine-8-carbonitrile;

(5aR,6R,9aS)-4-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-2-(quinolin-5-yl)-5a,6,7,9a-tetrahydro-5H-indeno[1,2-d]pyrimidine-8-carbonitrile;

(5aR,6R,9aS)-2-(2-cyclopropylpyridin-4-yl)-4-(2-fluorophenyl)-6,9a-dimethyl-7-oxo-5a,6,7,9a-tetrahydro-5H-indeno[1,2-d]pyrimidine-8-carbonitrile;

(6aS,7S,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aS,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(quinolin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

3-(4-((6aR,7R,10aS)-9-cyano-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)pyridin-2-yl)propanamide;

N-(2-(4-((6aR,7R,10aS)-9-cyano-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazolin-2-yl)pyridin-2-yl)ethyl)acetamide;

(6aR,7R,10aS)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-2-(3-phenylpyridin-4-yl)-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aR,7R,10aS)-2-(3-cyclopropylpyridin-4-yl)-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(6aS,7R,10aR)-2-(2-cyclopropylpyridin-4-yl)-7-ethyl-4-(2-fluorophenyl)-7,10a-dimethyl-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile;

(7aR,8R,11aS)-8,11a-dimethyl-2-(2-methylpyridin-4-yl)-9-oxo-4-phenyl-6,7,7a,8,9,11a-hexahydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-10-carbonitrile;

(7aR,8R,11aS)-8,11a-dimethyl-9-oxo-4-phenyl-2-(quinolin-5-yl)-6,7,7a,8,9,11a-hexahydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-10-carbonitrile;

(6aR,7R,10aS)-4-(4-fluorophenyl)-7,10a-dimethyl-2-(2-methylpyridin-4-yl)-8-oxo-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carboxamide;

(6aR,7R,10aR)-4-(4-fluorophenyl)-7,10a-dimethyl-2-(2-methylpyridin-4-yl)-8-oxo-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazoline-9-carboxamide; and

(6aR,7R,10aR)-4-(4-fluorophenyl)-7,10a-dimethyl-2-(2-methylpyridin-4-yl)-8-oxo-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazoline-9-carbonitrile;

or a pharmaceutically acceptable salt thereof.