Cycloalkyl guanidine F
View Patent ↗The invention provides cycloalkyl guanidine compounds that inhibit F 1 F 0 -ATPase, and methods of using cyclalkyl guanidine compounds as therapeutic agents in therapy, such as treating an immune disorder, inflammatory condition, or cancer.
1. A compound represented by Formula I:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
A is cycloalkylene;
R 1 represents independently for each occurrence halogen, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, C 1 -C 6 alkoxy, cyano, —CO 2 R 9 , —C(O)R 10 , —S(O)R 10 , —SO 2 R 10 , —SO 2 N(R 11 )(R 12 ), —C(O)N(R 11 )(R 12 ), —N(R 11 )(R 12 ), or —N(R 9 )C(O)(R 10 );
R 2 represents independently for each occurrence hydrogen or alkyl;
R 3 is —N(R 5 )CO 2 R 6 , —N(R 5 )C(O)R 6 , —N(R 5 )C(O)N(R 7 )(R 8 ), —N(R 5 )SO 2 R 6 , —N(R 7 )(R 8 ), —OC(O)N(R 7 )(R 8 ), —OC(O)R 6 , —OR 5 , —C(O)N(R 7 )(R 8 ), —CO 2 R 5 , —C(O)R 5 , oxo, or heterocyclyl;
R 4 is aryl, aralkyl, cycloalkyl, -alkylene-cycloalkyl, alkyl, or haloalkyl, wherein said aryl, aralkyl, and cycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, C 1 -C 6 alkoxy, —N(R 5 )CO 2 R 6 , and —N(R 5 )C(O)R 6 ;
R 5 represents independently for each occurrence hydrogen, alkyl, cycloalkyl, haloalkyl, or heterocycloalkyl;
R 6 represents independently for each occurrence alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, or -alkylene-heterocyclyl;
R 7 and R 8 each represent independently for each occurrence hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkenylene, aryl, or heterocyclyl; or R 7 and R 8 are taken together with the nitrogen to which they are attached to form a 3-7 membered heterocyclic ring;
R 9 represents independently for each occurrence hydrogen, alkyl, or cycloalkyl;
R 10 represents independently for each occurrence alkyl or cycloalkyl;
R 11 and R 12 each represent independently for each occurrence hydrogen, alkyl, or cycloalkyl; or R 11 and R 12 are taken together with the nitrogen atom to which they are attached to form a 3 to 7 membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, and C 1 -C 6 alkoxy; and
n is 0, 1, 2, or 3.
2. The compound of claim 1 , wherein A is cycloalkylene, that in addition to R 3 , is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, cycloalkyl, —N(R 5 )CO 2 R 6 , —N(R 5 )C(O)R 6 , —N(R 7 )(R 8 ), —OR 5 , and —C(O)R 5 .
3. The compound of claim 1 , wherein A is cyclobutylene, cyclopentylene, or cyclohexylene, each of which is, in addition to R 3 , optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, hydroxyl, and —N(R 7 )(R 8 ).
4. The compound of claim 1 , wherein A is cyclohexylene.
5. The compound of claim 1 , wherein R 1 represents independently for each occurrence halogen, haloalkyl, alkyl, or C 1 -C 6 alkoxy.
6. The compound of claim 1 , wherein R 1 represents independently for each occurrence chloro, fluoro, or trifluoromethyl.
7. The compound of claim 1 , wherein R 2 is hydrogen.
8. The compound of claim 1 , wherein R 3 is —N(R 5 )CO 2 R 6 , —N(R 5 )C(O)R 6 , —N(R 5 )C(O)N(R 7 )(R 8 ), —N(R 5 )SO 2 R 6 , or —N(R 7 )(R 8 ).
9. The compound of claim 1 , wherein R 3 is —N(R 5 )CO 2 R 6 .
10. The compound of claim 1 , wherein R 3 is —N(R 5 )C(O)R 6 .
11. The compound of claim 1 , wherein R 4 is aryl or aralkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, and C 1 -C 6 alkoxy.
12. The compound of claim 1 , wherein R 4 is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, and C 1 -C 6 alkoxy.
13. The compound of claim 1 , wherein R 4 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
14. The compound of claim 1 , wherein R 4 is benzyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of chloro, fluoro, trifluoromethyl, cyclopropyl, and (C 1 -C 4 )alkyl.
15. The compound of claim 1 , wherein R 5 represents independently for each occurrence hydrogen or (C 1 -C 4 )alkyl.
16. The compound of claim 1 , wherein R 6 represents independently for each occurrence (C 1 -C 4 )alkyl, (C 3 -C 7 )cycloalkyl, or haloalkyl.
17. The compound of claim 1 , wherein n is 1 or 2.
18. The compound of claim 1 , wherein said compound is represented by Formula 1-A1:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
R 1 and R 2 each represent independently hydrogen, chloro, fluoro, —CF 3 , methyl, or methoxyl;
R 3 is —N(R 5 )CO 2 R 6 , —N(R 5 )C(O)R 6 , —N(R 5 )C(O)N(R 7 )(R 8 ), —N(R 5 )SO 2 R 6 , —N(R 7 )(R 8 ), —OC(O)N(R 7 )(R 8 ), —OC(O)R 6 , —OH, —C(O)N(R 7 )(R 8 ), —CO 2 R 5 , haloalkyl, or heterocyclyl;
R 4 is aryl, aralkyl, cycloalkyl, -alkylene-cycloalkyl, alkyl, or haloalkyl, wherein said aryl, aralkyl, and cycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, and C 1 -C 6 alkoxy;
R 5 represents independently for each occurrence hydrogen, alkyl, cycloalkyl, haloalkyl, or heterocycloalkyl;
R 6 represents independently for each occurrence alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, or -alkylene-heterocyclyl; and
R 7 and R 8 each represent independently for each occurrence hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkenylene, aryl, or heterocyclyl; or R 7 and R 8 are taken together with the nitrogen to which they are attached to form a 3-7 membered heterocyclic ring.
19. The compound of claim 18 , wherein R 1 and R 2 are chloro or fluoro.
20. The compound of claim 18 , wherein R 3 is —N(R 5 )CO 2 R 6 ; R 5 is hydrogen or methyl; and R 6 is methyl, ethyl, propyl or butyl.
21. The compound of claim 20 , wherein R 4 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
22. A compound listed in one of the following Tables, or a pharmaceutically acceptable salt or hydrate of said compound:
TABLE 1
No.
A
X
Y
Z
I-1
4-chlorophenyl
4-N(H)CO 2 CH 3
2-H
3-chlorophenyl
I-2
3-chlorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
4-chlorophenyl
I-3
4-fluorophenyl
4-N(H)CO 2 CH 3
2-H
3 -chlorophenyl
I-4
3-fluorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
4-chlorophenyl
I-5
3,4-dichlorophenyl
4-N(H)CO 2 CH 3
2-H
3-chlorophenyl
I-6
3,4-difluorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
4-chlorophenyl
I-7
4-trifluoromethylphenyl
4-N(H)CO 2 CH2CH 3
2-H
3-cyclopropylphenyl
I-8
4-chlorophenyl
4-N(H)C(O)CH 3
2-H
3,5-dichlorophenyl
I-9
3-chlorophenyl
4-N(H)C(O)CH 3
2-H
3,5-dichlorophenyl
I-10
4-fluorophenyl
4-N(H)C(O)CH 3
2-H
3,5-dichlorophenyl
I-11
3-fluorophenyl
4-N(H)C(O)CF 3
2-H
3-chloro-5-fluorophenyl
I-12
3,4-dichlorophenyl
4-N(H)C(O)-cyclopropyl
2-H
3-chloro-5-fluorophenyl
I-13
3,4-difluorophenyl
4-N(H)C(O)-phenyl
2-H
3-chloro-5-fluorophenyl
I-14
4-trifluoromethylphenyl
4-N(H)C(O)-benzyl
2-H
3-chloro-5-fluorophenyl
I-15
4-chlorophenyl
2-H
3-chlorophenyl
I-16
3-chlorophenyl
2-H
4-chlorophenyl
I-17
4-fluorophenyl
2-H
3-chlorophenyl
I-18
3-fluorophenyl
2-CH 3
4-chlorophenyl
I-19
3,4-dichlorophenyl
2-CH 3
3-chlorophenyl
I-20
3 ,4-difluorophenyl
2-H
4-chlorophenyl
I-21
4-trifluoromethylphenyl
2-H
3-chlorophenyl
I-22
4-chlorophenyl
2-H
4-chlorophenyl
I-23
3-chlorophenyl
2-H
3-chlorophenyl
I-24
4 -fluorophenyl
2-H
4-chlorophenyl
I-25
3-fluorophenyl
2-H
3-chlorophenyl
I-26
3,4-dichlorophenyl
2-H
4-chlorophenyl
I-27
3,4-difluorophenyl
4-NH 2
2-H
3-chlorophenyl
I-28
4-trifluoromethylphenyl
4-N(H)CH 3
2-H
4-chlorophenyl
I-29
4-chlorophenyl
4-N(H)CO 2 CH 3
2-H
2-trifluoromethylphenyl
I-30
3-chlorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
2-trifluoromethylphenyl
I-31
4-fluorophenyl
4-N(H)CO 2 CH 3
2-H
2-trifluoromethylphenyl
I-32
3-fluorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
2-tert-butylphenyl
I-33
3,4-dichlorophenyl
4-N(H)CO 2 CH 3
2-H
2-tert-butylphenyl
I-34
3,4-difluorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
2-trifluoromethylphenyl
I-35
4-chlorophenyl
4-
2-H
3 -chlorophenyl
N(H)C(O)N(H)CH 2 CH 3
I-36
3-chlorophenyl
4-N(H)C(O)N(H)-benzyl
2-H
4-chlorophenyl
I-37
4-fluorophenyl
4-N(H)SO 2 CH 2 CH 3
2-H
3-cyclopropylphenyl
I-38
3 -fluorophenyl
4-N(H)SO 2 -benzyl
2-H
3,5-dichlorophenyl
I-39
3,4-dichlorophenyl
4-OC(O)N(H)CH 3
2-H
3,5-fluorophenyl
I-40
3,4-difluorophenyl
4-OC(O)N(H)-benzyl
2-H
3-cyclopropyl-5-
fluorophenyl
I-41
4-chlorophenyl
4-OC(O)CH 2 CH 3
2-H
3-chlorophenyl
I-42
3-chlorophenyl
4-OH
2-H
4-chlorophenyl
I-43
4-fluorophenyl
4-OH
2-H
3-cyclopropylphenyl
I-44
3-fluorophenyl
3-OH
2-H
3,5-dichlorophenyl
I-45
3,4-dichlorophenyl
3-OH
2-H
3,5-fluorophenyl
I-46
3,4-difluorophenyl
4-C(O)N(H)CH 2 CH 3
2-H
3-cyclopropyl-5-
fluorophenyl
I-47
4-chlorophenyl
4-C(O)N(H)-cyclopropyl
2-H
3-chlorophenyl
I-48
3-chlorophenyl
4-C(O)N(H)CF 3
2-H
4-chlorophenyl
I-49
4-fluorophenyl
4-CO 2 H
2-H
3-cyclopropylphenyl
I-50
3-fluorophenyl
4-CO 2 CH 3
2-H
3,5-dichlorophenyl
I-51
3,4-dichlorophenyl
4-C(O)CH 3
2-H
3,5-fluorophenyl
I-52
4-chlorophenyl
3-CH 3
3-cyclopropyl-5- fluorophenyl
I-53
3-chlorophenyl
3-CH 3
3-fluorophenyl
I-54
4-fluorophenyl
3-CH 3
4-fluorophenyl
I-55
3,4-dichlorophenyl
3-CF 3
5-CF 3
3-fluorophenyl
I-56
4-chlorophenyl
3-N(H)CO 2 CH 3
5-N(CH 3 ) 2
3-chlorophenyl
I-57
3 -chlorophenyl
3-N(H)CO 2 CH 2 CH 3
5-N(CH 3 ) 2
4-chlorophenyl
I-58
4-chlorophenyl
4-N(H)CO 2 CH 3
2-H
3-chlorobenzyl
I-59
3-chlorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
4-chlorobenzyl
I-60
4-fluorophenyl
4-N(H)CO 2 CH 3
2-H
3-fluorobenzyl
I-61
3-fluorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
4-fluorobenzyl
I-62
3,4-dichlorophenyl
4-N(H)CO 2 CH 3
2-H
3-chloro-5-fluorobenzyl
I-63
3,4-difluorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
3,5-dichlorobenzyl
I-64
4-trifluoromethylphenyl
4-N(H)CO 2 CH 2 CH 3
2-H
3,5-difluorobenzyl
I-65
4-chlorophenyl
4-N(H)CO 2 CH 3
2-H
3-cyclopropylbenzyl
I-66
3 -chlorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
3-trifluoromethylbenzyl
I-67
4-fluorophenyl
4-N(H)CO 2 CH 3
2-H
4-trifluoromethylbenzyl
I-68
3-fluorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
cyclopropyl
I-69
3,4-dichlorophenyl
4-N(H)CO 2 CH 3
2-H
cyclopentyl
I-70
3,4-difluorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
cyclohexyl
I-71
4-trifluoromethylphenyl
4-N(H)CO 2 CH 2 CH 3
2-H
4-methylcyclohexyl
I-72
4-chlorophenyl
4-N(H)CO 2 CH 3
2-H
ethyl
I-73
3-chlorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
tert-butyl
I-74
4-fluorophenyl
4-N(H)CO 2 CH 3
2-H
2,2,2-trifluoroethyl
I-75
3-fluorophenyl
4-N(H)CO 2 CH 2 CH 3
2-H
1-methylcyclobutyl
TABLE 2
No.
A
X
n
Z
II-1
4-chlorophenyl
2-N(H)CO 2 CH 3
1
4-fluorophenyl
II-2
3-chlorophenyl
2 -N(H)CO 2 CH 2 CH 3
1
3-fluorophenyl
II-3
4-fluorophenyl
2-N(H)CO 2 CH 3
1
3,4-dichlorophenyl
II-4
3-fluorophenyl
2 -N(H)CO 2 CH 2 CH 3
1
3,4-difluorophenyl
II-5
3,4-dichlorophenyl
1
4-trifluoromethylphenyl
II-6
3,4-difluorophenyl
1
4-fluorobenzyl
II-7
trifluoromethylphenyl
2-NH 2
1
3 -fluorobenzyl
II-8
4-chlorophenyl
2-N(H)C(O)CH 3
1
3,4-dichlorobenzyl
II-9
3-chlorophenyl
2-N(H)C(O)-phenyl
1
3,4-difluorobenzyl
II-10
4-fluorophenyl
2-CF 3
1
4-trifluoromethylbenzyl
II-11
4-chlorophenyl
3-N(H)CO 2 CH 3
2
4-fluorophenyl
II-12
3 -chlorophenyl
3-N(H)CO 2 CH 2 CH 3
2
3-fluorophenyl
II-13
4-fluorophenyl
3-N(H)CO 2 CH 3
2
3,4-dichlorophenyl
II-14
3-fluorophenyl
3-N(H)CO 2 CH 2 CH 3
2
3,4-difluorophenyl
II-15
3,4-dichlorophenyl
2
4-trifluoromethylphenyl
II-16
3,4-difluorophenyl
2
4-fluorobenzyl
II-17
4-trifluoromethylphenyl
3-NH 2
2
3-fluorobenzyl
II-18
4-chlorophenyl
3-N(H)C(O)CH 3
2
3,4-dichlorobenzyl
II-19
3-chlorophenyl
3-N(H)C(O)-phenyl
2
3,4-difluorobenzyl
II-20
4-fluorophenyl
3-CF 3
2
4-trifluoromethylbenzyl
II-21
4-chlorophenyl
4-N(H)CO 2 CH 3
3
4-fluorophenyl
II-22
3-chlorophenyl
4-N(H)CO 2 CH 2 CH 3
3
3-fluorophenyl
II-23
4-fluorophenyl
4-N(H)CO 2 CH 3
3
3,4-dichlorophenyl
II-24
3 -fluorophenyl
4-N(H)CO 2 CH 2 CH 3
3
3,4-difluorophenyl
II-25
3,4-dichlorophenyl
3
4-trifluoromethylphenyl
II-26
3,4-difluorophenyl
3
4-fluorobenzyl
II-27
4-trifluoromethylphenyl
4-NH 2
3
3 -fluorobenzyl
II-28
4-chlorophenyl
4-N(H)C(O)CH 3
3
3 ,4-dichlorobenzyl
II-29
3-chlorophenyl
4-N(H)C(O)-phenyl
3
3 ,4-difluorobenzyl
II-30
4-fluorophenyl
4-CF 3
3
4-trifluoromethylbenzyl
TABLE 3
Compound
No.
Chemical Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
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
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
23. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
24. A method of treating a disorder selected from the group consisting of psoriasis, lupus, B cell lymphoma and leukemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 in order to ameliorate a symptom of the disorder.
25. A method of inhibiting a F 1 F 0 -ATPase, comprising exposing a F 1 F 0 -ATPase to a compound of claim 1 .