Tetrahydroquinoline sulfonamide and related compounds for use as agonists of RORγ and the treatment of disease
The invention provides tetrahydroquinoline sulfonamide compounds, tetrahydronaphthalene sulfonyl compounds, and related compounds, pharmaceutical compositions, methods of promoting RORγ activity, methods of increasing the amount of IL-17 in a subject, and methods of treating cancer and other medical disorders using such compounds.
1. A compound represented by Formula I:
or a pharmaceutically acceptable salt thereof; wherein:
A is phenylene, 5-6 membered heteroarylene, or C 3-6 heterocycloalkylene;
R 1 represents independently for each occurrence halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;
R 2A is one of the following:
(i) C 1-6 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 1-6 alkylene)-CO 2 R 4 , —O—(C 1-6 alkylene)-C(O)—(C 1-6 alkyl), —N(R 4 )—(C 1-6 alkylene)-CO 2 R 4 , or —N(R 4 )—(C 1-6 alkylene)-C(O)—(C 1-6 alkyl), wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 alkylene are optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —C(O)N(R 4 )(R 5 ), —C(O)—N(R 4 )—(C 1-4 alkylene)-CO 2 R 4 , —N(R 4 )C(O)R 8 , —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, —N(R 4 )(R 5 ), —N(R 4 )C(O)N(R 4 )(R 5 ), —N(R 4 )CO 2 R 9 , —N(R 4 )S(O) 2 R 9 , and —N(R 4 )S(O) 2 N(R 4 )(R 5 ); or
(ii) —CO 2 R 4 , —N(R 4 )C(O)R 9 , —N(R 4 )CO 2 R 9 , —N(R 4 )C(O)N(R 4 )(R 5 ), —N(R 4 )C(O)N(R 4 )(heteroaryl), —N(R 4 )S(O) 2 R 9 , —N(R 4 )(R 5 ), or —OH;
R 2B is C 1-6 alkyl, C 1-3 haloalkyl, or fluoro;
R 3 represents independently for each occurrence hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —N(R 4 )(R 8 ), —O—(C 1-6 hydroxyalkyl), or —O—(C 1-6 alkylene)-CO 2 R 4 ; or two vicinal occurrences of R 3 are taken together with intervening atoms to form a 4-6 membered ring;
R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclic ring;
R 6 and R 7 each represent independently for each occurrence hydrogen, fluoro, or C 1-6 alkyl, or R 6 and R 7 are taken together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring; or R 6 and a vicinal occurrence of R 2B are taken together to form a bond;
R 8 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), or aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, or —CO 2 R 4 ; or R 8 is —CO 2 R 4 ;
R 9 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), C 1-6 haloalkyl, or C 1-6 hydroxyalkyl;
X is one of the following:
(i) —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;
(ii) —S-aralkyl, —S-heteroaralkyl, —S-phenyl, —S-heteroaryl, —S-(partially unsaturated bicyclic carbocyclyl), —S—(C 1-6 alkylene)-(C 3-6 cycloalkyl), or —S—(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;
(iii) —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 2-6 alkenylene)-(partially unsaturated 8-10 membered bicyclic ring containing 0-3 heteroatoms), —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), —(C 1-6 alkylene)-(C 3 -C 6 cycloalkyl), -(5-6 membered heterocycloalkylene)-phenyl, or —(C 3-6 cycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;
(iv) —(C 2-6 alkenylene)-(C 1-6 alkyl), —(C 2-6 alkenylene)-(C 3-6 cycloalkyl), or
each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 , wherein A* is a 5-8 membered, partially saturated carbocyclic or heterocyclic ring; or
(v) —(C 1-6 alkylene)-Z 1 or —(C 2-6 alkenylene)-Z 1 , wherein Z 1 is —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), or —N(R 4 )—(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;
Y is —O—;
m and p each represent independently for each occurrence 0, 1, or 2; and
n is 1, 2, or 3.
2. The compound of claim 1 , wherein the compound is represented by Formula I-A:
or a pharmaceutically acceptable salt thereof; wherein:
A is phenylene or a 5-6 membered heteroarylene;
R 1 represents independently for each occurrence halogen, C 1-6 alkyl, or C 3-6 cycloalkyl;
R 2A is C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —N(R 4 )C(O)(C 1-6 alkyl), —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, and —N(R 4 )(R 5 ); or R 2A is —CO 2 R 4 or —N(R 4 )C(O)(C 1-6 alkyl);
R 2B is C 1-6 alkyl or C 1-3 haloalkyl;
R 3 represents independently for each occurrence hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or —O—(C 1-6 alkylene)-OH; or two vicinal occurrences of R 3 are taken together with intervening atoms to form a 4-6 membered ring;
R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring;
R 6 and R 7 each represent independently for each occurrence hydrogen or C 1-6 alkyl, or R 6 and R 7 are taken together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring; or R 6 and R 2A are taken together to form a bond;
X is one of the following:
(i) —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;
(ii) alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy; or
(iii) —(C 1-6 alkylene)-Z 1 or —(C 2-6 alkenylene)-Z 1 , wherein Z 1 is —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;
Y is —O—;
m and p are independently 0, 1, or 2; and
n is 1, 2, or 3.
3. The compound of claim 2 , wherein R 2A is C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —N(R 4 )C(O)(C 1-6 alkyl), —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and —N(R 4 )(R 5 ).
4. The compound of claim 2 , wherein R 2A is C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —N(R 4 )C(O)(C 1-6 alkyl), —CN, hydroxyl, and C 1-6 alkoxy.
5. The compound of claim 2 , wherein A is phenylene.
6. The compound of claim 5 , wherein n is 1.
7. The compound of claim 5 , wherein R 3 represents independently for each occurrence C 1-6 haloalkyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, or —O—(C 1-6 alkylene)-OH.
8. The compound of claim 6 , wherein R 3 is trifluoromethyl.
9. The compound of claim 5 , wherein X is —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 1-6 alkylene)-phenyl, —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), or -(5-6 membered heterocycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.
10. The compound of claim 7 , wherein X is —(C 2-6 alkenylene)-phenyl, —(C 1-6 alkylene)-phenyl, or —(C 1-6 alkylene)-heteroaryl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy.
11. The compound of claim 2 , wherein X is attached at the 6-position of the 3,4-dihydro-2H-benzo[b][1,4]oxazinyl ring.
12. The compound of claim 8 , wherein p is 0, and m is 0.
13. A compound of claim 1 , wherein the compound is represented by Formula I-C:
or a pharmaceutically acceptable salt thereof; wherein:
A is phenylene or pyridinylene;
R 1 represents independently for each occurrence halogen, methyl, ethyl, or cyclopropyl;
R 2A is C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —C(O)N(R 4 )(R 5 ), —N(R 4 )C(O)R 8 , halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and —N(R 4 )(R 5 );
R 2B is methyl or ethyl;
R 3 represents independently for each occurrence C 1-3 haloalkyl, halogen, C 1-3 alkyl, or —O—(C 1-6 hydroxyalkyl);
R 4 and R 5 each represent independently for each occurrence hydrogen or methyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring;
R 8 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, or —(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, and —CO 2 R 4 ;
X is —(C 2-6 alkenylene)-phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and C 1-6 haloalkoxy;
m and p are independently 0 or 1; and
n is 1 or 2.
14. The compound of claim 13 , wherein A is phenylene.
15. The compound of claim 14 , wherein R 2A is C 1-6 alkyl substituted with —CO 2 R 4 .
16. The compound of claim 14 , wherein R 2A is C 1-6 alkyl substituted with —C(O)N(R 4 )(R 5 ), wherein R 4 and R 5 are taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclic ring substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-6 haloalkyl, C 1-6 alkyl, and —CO 2 R 10 , where R 10 is hydrogen or C 1-6 alkyl.
17. The compound of claim 15 , wherein R 3 represents independently for each occurrence trifluoromethyl, halogen, or —O—(C 1-6 hydroxyalkyl).
18. The compound of claim 15 , wherein X is —(C 2-4 alkenylene)-phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and C 1-6 haloalkyl.
19. The compound of claim 15 , wherein X is —(C 2-4 alkenylene)-phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
20. The compound of claim 15 , wherein X is —(C 2-4 alkenylene)-phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl, and said substituents are located at the ortho positions of the phenyl group.
21. The compound of claim 19 , wherein m and p are independently 0.
22. The compound of claim 21 , wherein n is 1.
23. A compound in Table 1-1, 1-A-1, 24-1, or 25-1 below, or a pharmaceutically acceptable salt thereof:
TABLE 1-1
No.
X
Z
I-1
I-2
I-3
I-4
I-5
I-6
I-7
I-8
I-9
I-10
I-11
I-12
I-13
I-14
I-15
I-16
I-17
I-18
I-19
I-20
I-21
I-22
I-23
I-24
I-25
I-26
I-27
I-28
I-29
I-30
I-31
I-32
I-33
I-34
I-35
I-36
I-37
I-38
I-39
I-40
I-41
I-42
I-43
I-44
I-45
I-46
I-47
I-48
I-49
I-50
I-51
I-52
I-53
I-54
I-55
I-56
I-57
I-58
I-59
I-60
I-61
I-62
I-63
I-64
I-65
I-66
I-67
I-68
I-69
I-70
I-71
I-72
I-73
I-74
I-75
I-76
I-77
I-78
I-79
I-80
I-81
I-82
I-83
I-84
I-85
I-86
TABLE 1-A-1
No.
X
Z
I-A1
I-A2
I-A3
I-A4
I-A5
I-A6
I-A7
I-A8
I-A9
I-A10
I-A11
I-A12
I-A13
I-A14
I-A15
I-A16
I-A17
I-A18
I-A19
I-A20
I-A21
I-A22
I-A23
I-A24
I-A25
I-A26
I-A27
I-A28
I-A29
I-A30
I-A31
I-A32
I-A33
I-A34
I-A35
I-A36
I-A37
I-A38
I-A39
I-A40
I-A41
I-A42
I-A43
I-A44
I-A45
I-A46
I-A47
I-A48
I-A49
I-A50
I-A51
I-A52
I-A53
I-A54
I-A55
I-A56
I-A57
I-A58
I-A59
I-A60
I-A61
I-A62
I-A63
I-A64
I-A65
I-A66
I-A67
I-A68
I-A69
I-A70
I-A71
I-A72
I-A73
I-A74
I-A75
I-A76
I-A77
I-A78
I-A79
I-A80
I-A81
I-A82
I-A83
I-A84
I-A85
I-A86
I-A87
I-A88
I-A89
I-A90
I-A91
I-A92
I-A93
I-A94
I-A95
I-A96
I-A97
I-A98
I-A99
I-A100
I-A101
I-A102
I-A103
I-A104
I-A105
I-A106
TABLE 24-1
Compound Structure
TABLE 25-1
Title Compound
from Example No.
Compound Structure
28E
28G
29
30
31
32
33
34
35
36A
36B
36C
37
38A
38B
38C
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86A
86AA
86AB
86AC
86AD
86AE
86AF
86AG
86AH
86AI
86AJ
86AK
86AL
86AM
86AN
86AO
86AP
86AQ
86AR
86AS
86AT
86AU
86AW
86AX
86AY
86AZ
86B
86C
86D
86E
86F
86G
86H
86I
86J
86K
86L
86M
86N
86O
86P
86Q
86R
86S
86T
86U
86V
86W
86X
86Y
86Z
87
88
89A
89AA
89AB
89AC
89AE
89AF
89AG
89AH
89AI
89AJ
89AK
89AL
89AM
89AN
89AO
89AP
89AQ
89AR
89AS
89AT
89AU
89AV
89AW
89AX
89AY
89AZ
89B
89BA
89BB
89BC
89BD
89BE
89BF
89BG
89BH
89BI
89BJ
89BK
89BL
89BM
89BN
89BO
89BP
89BQ
89BR
89BS
89BT
89BU
89BV
89BW
89BX
89BY
89BZ
89C
89CA
89CB
89CC
89CD
89CE
89CF
89CG
89CH
89CI
89CJ
89CK
89CL
89CM
89CN
89CO
89CP
89CQ
89CR
89CS
89CT
89CU
89CV
89CW
89CX
89CY
89CZ
89D
89DA
89DB
89DC
89DE
89DF
89DG
89DH
89DI
89DJ
89DK
89DL
89DM
89DN
89DO
89DP
89DQ
89DS
89DT
89DU
89DV
89DW
89DX
89DY
89DZ
89E
89EA
89EB
89EC
89ED
89EE
89EF
89EG
89EH
89EI
89EJ
89EK
89EL
89EM
89EN
89EP
89EQ
89ER
89ES
89ET
89EU
89EV
89EW
89EX
89EY
89EZ
89FA
89FB
89FC
89FD
89FE
89FF
89FG
89FH
89FI
89FJ
89FK
89FL
89FM
89FN
89G
89H
89I
89J
89K
89L
89M
89N
89O
89P
89Q
89R
89S
89T
89W
89X
90
91
92
93
94
95A
95AA
95AB
95AC
95AD
95B
95C
95D
95E
95F
95G
95H
95I
95J
95K
95L
95M
95N
95O
95P
95Q
95R
95S
95T
95U
95V
95W
95X
95Y
95Z
96
97
98
99
100
101
102
103
104
105
106
107
108
109A
109B
109C
109D
109E
109F
110
111
112
113
114
115
116A
116B
116C
116D
116E
116K
117
118
119A
119B
119C
119D
119E
119F
119G
119H
120
121A
121B
121C
122
123
124
125
126
127A
127B
127C
127D
127E
127F
127G
127H
127I
127J
127K
127L
127M
127N
128
129A
129B
129C
129D
129E
129F
129G
129H
129I
129J
129K
129L
129M
129N
129O
129P
130
131
132
133
134
135A
135B
135C
136
137
190
191A
191B
191C
191D
24. A compound in Table 26-1 below, or a pharmaceutically acceptable salt thereof:
TABLE 26-1
Title Compound
from Example No.
Compound Structure
86BC
89FO
89FP
116N
116O
116P
129Q
191E
191F
191G
191H
192
193
194
195B
195C
195D
195E
195F
195G
195H
25. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
26. A method of treating a disorder selected from the group consisting of cancer, bacterial infection, and fungal infection, comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof to ameliorate a symptom of the disorder, wherein the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, esophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma.
27. The method of claim 26 , wherein the disorder is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, esophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma.
28. A method of increasing the amount of IL-17 in a subject, comprising administering to a subject an effective amount of a compound of claim 1 to increase the amount of IL-17 in the subject.
29. The method of claim 26 , wherein the subject is a human.
30. A method of promoting the activity of RORγ, comprising exposing a RORγ to an effective amount of a compound of claim 1 to promote the activity of said RORγ.
31. A compound represented by Formulae III or IV:
or a pharmaceutically acceptable salt thereof; wherein:
A is phenylene, 5-6 membered heteroarylene, or C 3-6 heterocycloalkylene;
R 1 represents independently for each occurrence halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;
R 2A is —(C 1-2 alkylene)-(2-8 membered heteroalkylene)-CO 2 R 4 , —(C 1-6 alkylene)-C(O)N(R 4 )(C 1-6 hydroxyalkylene)-CO 2 R 4 , or —(C 1-6 alkylene)-N(R 4 )C(O)N(R 4 )—(C 1-6 alkylene)-CO 2 R 4 ; wherein the C 1-6 alkylene is optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —C(O)N(R 4 )(R 5 ), —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, and —N(R 4 )(R 5 );
R 2B is C 1-6 alkyl, C 1-3 haloalkyl, or fluoro;
R 3 represents independently for each occurrence hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —N(R 4 )(R 8 ), —O—(C 1-6 hydroxyalkyl), or —O—(C 1-6 alkylene)-CO 2 R 4 ; or two vicinal occurrences of R 3 are taken together with intervening atoms to form a 4-6 membered ring;
R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclic ring;
R 6 and R 7 each represent independently for each occurrence hydrogen, fluoro, or C 1-6 alkyl, or R 6 and R 7 are taken together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring; or R 6 and a vicinal occurrence of R 2B are taken together to form a bond;
R 8 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), or aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, or —CO 2 R 4 ; or R 8 is —CO 2 R 4 ;
R 9 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), C 1-6 haloalkyl, or C 1-6 hydroxyalkyl;
X is one of the following:
(i) —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), or —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;
(ii) —S-aralkyl, —S-heteroaralkyl, —S-phenyl, —S-heteroaryl, —S-(partially unsaturated bicyclic carbocyclyl), —S—(C 1-6 alkylene)-(C 3-6 cycloalkyl), or —S—(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;
(iii) —(C 2-6 alkenylene)-phenyl, —(C 2-6 alkenylene)-heteroaryl, —(C 1-6 alkenylene)-(partially unsaturated 8-10 membered bicyclic ring containing 0-3 heteroatoms), —(C 1-6 alkylene)-phenyl; —(C 1-6 alkylene)-heteroaryl, —(C 1-6 alkylene)-(partially unsaturated bicyclic heterocyclyl), —(C 1-6 alkylene)-(partially unsaturated bicyclic oxo-heterocyclyl), —(C 1-6 alkylene)-(C 3 -C 6 cycloalkyl), -(5-6 membered heterocycloalkylene)-phenyl, or —(C 3-6 cycloalkylene)-phenyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;
(iv) —(C 2-6 alkenylene)-(C 1-6 alkyl), —(C 2-6 alkenylene)-(C 3-6 cycloalkyl), or
each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 , wherein A* is a 5-8 membered, partially saturated carbocyclic or heterocyclic ring; or
(v) —(C 1-6 alkylene)-Z 1 or —(C 2-6 alkenylene)-Z 1 , wherein Z 1 is —O-aralkyl, —O-heteroaralkyl, —O-phenyl, —O-heteroaryl, —O-(partially unsaturated bicyclic carbocyclyl), —O—(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 3-6 cycloalkyl), —N(R 4 )-aralkyl, —N(R 4 )-phenyl, —N(R 4 )-(partially unsaturated bicyclic carbocyclyl), —N(R 4 )—(C 1-6 alkylene)-(C 3-6 cycloalkyl), or —N(R 4 )—(C 3-6 cycloalkyl), each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;
Y is —O—;
m and p each represent independently for each occurrence 0, 1, or 2; and
n is 1, 2, or 3; and
Formula IV is represented by:
or a pharmaceutically acceptable salt thereof; wherein:
A is phenylene, 5-6 membered heteroarylene, or C 3-6 heterocycloalkylene;
R 1 represents independently for each occurrence halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;
R 2A is one of the following:
(i) hydrogen, C 1-6 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), —O—(C 1-6 alkylene)-CO 2 R 4 , —O—(C 1-6 alkylene)-C(O)—(C 1-6 alkyl), —N(R 4 )—(C 1-6 alkylene)-CO 2 R 4 , or —N(R 4 )—(C 1-6 alkylene)-C(O)—(C 1-6 alkyl), wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and C 1-6 alkylene are optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CO 2 R 4 , —C(O)N(R 4 )(R 5 ), —C(O)—N(R 4 )—(C 1-4 alkylene)-CO 2 R 4 , —N(R 4 )C(O)R 8 , —CN, halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 haloalkyl, —N(R 4 )(R 5 ), —N(R 4 )C(O)N(R 4 )(R 5 ), —N(R 4 )CO 2 R 9 , —N(R 4 )S(O) 2 R 9 , and —N(R 4 )S(O) 2 N(R 4 )(R 5 ); or
(ii) —CO 2 R 4 , —N(R 4 )C(O)R 9 , —N(R 4 )CO 2 R 9 , —N(R 4 )C(O)N(R 4 )(R 5 ), —N(R 4 )C(O)N(R 4 )(heteroaryl), —N(R 4 )S(O) 2 R 9 , —N(R 4 )(R 5 ), —OH, or —(C 1-2 alkylene)-(2-8 membered heteroalkylene)-CO 2 R 4 ;
R 2B is C 1-6 alkyl, C 1-3 haloalkyl, or fluoro;
R 3 represents independently for each occurrence hydrogen; C 1-6 haloalkyl, halogen, hydroxyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —N(R 4 )(R 8 ), —O—(C 1-6 hydroxyalkyl), or —O—(C 1-6 alkylene)-CO 2 R 4 ; or two vicinal occurrences of R 3 are taken together with intervening atoms to form a 4-6 membered ring;
R 4 and R 5 each represent independently for each occurrence hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; or an occurrence of R 4 and R 5 attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a 3-8 membered heterocyclic ring;
R 6 and R 7 each represent independently for each occurrence hydrogen, fluoro, or C 1-6 alkyl, or R 6 and R 7 are taken together with the carbon atom to which they are attached to form a 3-6 membered carbocyclic ring; or R 6 and a vicinal occurrence of R 2B are taken together to form a bond;
R 8 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), or aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, or —CO 2 R 4 ; or R 8 is —CO 2 R 4 ;
R 9 represents independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, —(C 1-6 alkylene)-(C 3-6 cycloalkyl), C 1-6 haloalkyl, or C 1-6 hydroxyalkyl;
X is C 4-7 cycloalkenyl, C 3-7 cycloalkyl, or an 8-10 membered, bicyclic partially saturated carbocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), hydroxyl, cyano, —C(O)R 9 , and —SO 2 R 9 ;
Y is —O—;
m and p each represent independently for each occurrence 0, 1, or 2; and
n is 1, 2, or 3.
32. A pharmaceutical composition comprising a compound of claim 31 and a pharmaceutically acceptable carrier.
33. A method of treating a disorder selected from the group consisting of cancer, bacterial infection, and fungal infection, comprising administering a therapeutically effective amount of a compound of claim 31 to a subject in need thereof to ameliorate a symptom of the disorder, wherein the cancer is colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma lung cancer, leukemia, bladder cancer stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterus cancer, esophagus cancer, liver cancer, an acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma or retinoblastoma.
34. A pharmaceutical composition comprising a compound of claim 9 and a pharmaceutically acceptable carrier.
35. A pharmaceutical composition comprising a compound of claim 13 and a pharmaceutically acceptable carrier.
36. A pharmaceutical composition comprising a compound of claim 18 and a pharmaceutically acceptable carrier.
37. A compound selected from one of the following or a pharmaceutically acceptable salt thereof:
38. The compound of claim 37 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
39. The compound of claim 37 , wherein the compound is
40. The compound of claim 37 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
41. The compound of claim 37 , wherein the compound is
42. The compound of claim 37 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
43. The compound of claim 37 , wherein the compound is
44. The compound of claim 37 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
45. The compound of claim 37 , wherein the compound is
46. The compound of claim 37 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
47. The compound of claim 37 , wherein the compound is
48. A pharmaceutical composition comprising a compound of claim 37 and a pharmaceutically acceptable carrier.
49. A pharmaceutical composition comprising a compound of claim 38 and a pharmaceutically acceptable carrier.
50. A pharmaceutical composition comprising a compound of claim 39 and a pharmaceutically acceptable carrier.
51. A pharmaceutical composition comprising a compound of claim 40 and a pharmaceutically acceptable carrier.
52. A pharmaceutical composition comprising a compound of claim 41 and a pharmaceutically acceptable carrier.
53. A pharmaceutical composition comprising a compound of claim 42 and a pharmaceutically acceptable carrier.
54. A pharmaceutical composition comprising a compound of claim 43 and a pharmaceutically acceptable carrier.
55. A pharmaceutical composition comprising a compound of claim 44 and a pharmaceutically acceptable carrier.
56. A pharmaceutical composition comprising a compound of claim 45 and a pharmaceutically acceptable carrier.
57. A pharmaceutical composition comprising a compound of claim 46 and a pharmaceutically acceptable carrier.
58. A pharmaceutical composition comprising a compound of claim 47 and a pharmaceutically acceptable carrier.