Indazole guanidine F
View Patent ↗The invention provides indazole guanidine compounds that inhibit F 1 F 0 -ATPase, and methods of using indazole guanidine compounds as therapeutic agents to treat medical disorders, such as 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 1 is one of the following:
(i) phenyl or a six-membered heteroaryl, each of which is optionally substituted with 1,2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, C 1 -C 6 alkoxy, cyano, —CO 2 R 4 , —C(O)R 5 , —S(O)R 5 , —SO 2 R 5 , —SO 2 N(R 6 )(R 7 ), —C(O)N(R 6 )(R 7 ), —N(R 6 )(R 7 ), and —N(R 4 )C(O)(R 5 ); or
that is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, and C 1 -C 6 alkoxy; wherein B 1 is a 5-membered or 6-membered heterocycle;
A 2 is
wherein B 2 is a 6-membered heteroaromatic group;
R 1 and R 2 each represent independently hydrogen or alkyl;
R 3 is one of the following:
(i) alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl, alkoxyl, —O—(C(R 4 ) 2 ) m -alkoxyl, —O—(C(R 4 ) 2 ) m —OH, —N(R 6 )(R 7 ), cycloalkyl, heterocycloalkyl, —N(R 6 )C(O)R 8 , —C(O)N(R 6 )(R 7 ), —N(R 6 )C(O)N(R 6 )(R 7 ), halogen, haloalkyl, and cyano;
(ii) cycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, cycloalkyl, hydroxyalkyl, alkoxy, —O—(C(R 4 ) 2 ) m -alkoxyl, —O—(C(R 4 ) 2 ) m —OH, and cyano; or
(iii) heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, alkoxy, —O—(C(R 4 ) 2 ) m -alkoxyl, —O—(C(R 4 ) 2 ) m —OH, and cyano;
R 4 represents independently for each occurrence hydrogen, alkyl, or cycloalkyl; or two occurrences of R 4 attached to the same carbon atom are taken together with said carbon atom to form a saturated carbocylic ring;
R 5 represents independently for each occurrence alkyl or cycloalkyl;
R 6 and R 7 each represent independently for each occurrence hydrogen, alkyl, or cycloalkyl; or R 6 and R 7 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;
R 8 is hydrogen, or R 8 is alkyl substituted by hydroxyl, —N(H)(R 6 ), heterocycloalkyl, —N(H)C(O)R 10 , —C(O)N(H)(R 6 ), or —N(H)C(O)N(R 6 )(R 7 );
R 9 represents independently for each occurrence halogen, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, C 1 -C 6 alkoxy, or cyano;
R 10 is alkyl, cycloalkyl, aryl, or aralkyl; and
n is 0, 1, 2, 3, or 4; and
m is 1, 2, 3, 4, or 5.
2. The compound of claim 1 , wherein A 1 is phenyl or a six-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, and C 1 -C 6 alkoxy.
3. The compound of claim 1 , wherein A 1 is phenyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, and hydroxyl.
4. The compound of claim 1 , wherein A 1 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro and fluoro.
5. The compound of claim 1 , wherein A 1 is one of the following:
6. The compound of claim 2 , wherein A 2 is
7. The compound of claim 2 , wherein R 8 is hydrogen.
8. The compound of claim 2 , wherein R 9 represents independently for each occurrence halogen or haloalkyl.
9. The compound of claim 6 , wherein R 9 represents independently for each occurrence chloro, fluoro, or trifluoromethyl.
10. The compound of claim 2 , wherein n is 1 or 2.
11. The compound of claim 2 , wherein A 2 is one of the following:
12. The compound of claim 2 , wherein R 3 is alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl, alkoxyl, —O—(C(R 4 ) 2 ) m -alkoxyl, —O—(C(R 4 ) 2 ) m —OH, —N(R 6 )(R 7 ), and cycloalkyl.
13. The compound of claim 2 , wherein R 3 is alkyl or cycloalkyl.
14. The compound of claim 2 , wherein R 3 is C 1-6 alkyl substituted by C 1-6 alkoxyl.
15. The compound of claim 1 , wherein said compound is represented by Formula I-A1:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
X 1 and X 2 each represent independently hydrogen, chloro, fluoro, or —CF 3 ;
Y 1 , Y 2 , Y 3 , and Y 4 each represent independently hydrogen, chloro, fluoro, hydroxyl, or —CF 3 ; and
R* is one of the following:
(i) alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl, alkoxyl, and cycloalkyl; or
(ii) cycloalkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl, hydroxyalkyl, and alkoxyl.
16. The compound of claim 15 , wherein X 1 and X 2 are each independently chloro or fluoro.
17. The compound of claim 16 , wherein Y 1 , Y 2 , and Y 4 are hydrogen; and Y 3 is fluoro or —CF 3 .
18. The compound of claim 16 , wherein Y 1 and Y 4 are hydrogen; and Y 2 and Y 3 are each independently fluoro or —CF 3 .
19. The compound of claim 16 , wherein R* is alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl, alkoxyl, and cycloalkyl.
20. The compound of claim 16 , wherein R* is alkyl or cycloalkyl.
21. The compound of claim 16 , wherein R* is C 1-6 alkyl substituted by C 1-6 alkoxyl.
22. A compound represented by Formula III:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
A 1 is one of the following:
(i) phenyl or a six-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, C 1 -C 6 alkoxy, cyano, —CO 2 R 4 , —C(O)R 5 , —S(O)R 5 , —SO 2 R 5 , —SO 2 N(R 6 )(R 7 ), —C(O)N(R 6 )(R 7 ), —N(R 6 )(R 7 ), and —N(R 4 )C(O)(R 5 ); or
that is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, and C 1 -C 6 alkoxy; wherein B 1 is a 5-membered or 6-membered heterocycle;
A 2 is
wherein B 2 is a 6-membered heteroaromatic group;
R 1 and R 2 each represent independently hydrogen or alkyl;
R 3 is one of the following:
(i) alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl, alkoxyl, —O—(C(R 4 ) 2 ) m -alkoxyl, —O—(C(R 4 ) 2 ) m —OH, —N(R 6 )(R 7 ), cycloalkyl, heterocycloalkyl, —N(R 6 )C(O)R 8 , —C(O)N(R 6 )(R 7 ), —N(R 6 )C(O)N(R 6 )(R 7 ), halogen, haloalkyl, and cyano; or
(ii) cycloalkyl or heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, alkoxy, —O—(C(R 4 ) 2 ) m -alkoxyl, —O—(C(R 4 ) 2 ) m —OH, and cyano;
R 4 represents independently for each occurrence hydrogen, alkyl, or cycloalkyl; or two occurrences of R 4 attached to the same carbon atom are taken together with said carbon atom to form a saturated carbocylic ring;
R 5 represents independently for each occurrence alkyl or cycloalkyl;
R 6 and R 7 each represent independently for each occurrence hydrogen, alkyl, or cycloalkyl; or R 6 and R 7 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;
R 8 is alkyl, —CH 2 —S-alkyl, —CO 2 -alkylene-Z, —CO 2 -alkyl, or —C(O)-alkyl optionally substituted by one or more of hydroxyl, halogen, and —N(R 6 )(R 7 );
R 9 represents independently for each occurrence halogen, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, C 1 -C 6 alkoxy, or cyano;
Z is —O—P(O)(OH) 2 , —OC(O)-arylene-alkylene-O—P(O)(OH) 2 , —OC(O)-arylene-O—P(O)(OH) 2 , or —OC(O)-alkylene-O—P(O)(OH) 2 ;
n is 0, 1, 2, 3, or 4; and
m is 1, 2, 3, 4, or 5.
23. A compound listed in Table 1A, 2A, or 4A below, or a pharmaceutically acceptable salt thereof:
TABLE 1A
No.
A
X
Y
I-1
3-chlorophenyl
isobutyl
I-2
4-chlorophenyl
sec-butyl
I-3
3-fluorophenyl
tert-butyl
I-4
4-fluorophenyl
ethyl
I-5
3,4-dichlorophenyl
propyl
I-6
3,4-difluorophenyl
isopropyl
I-7
4-trifluoromethylphenyl
—C(H)(Me)CH 2 OMe
I-8
3-chlorophenyl
—CH 2 CH 2 OMe
I-9
4-chlorophenyl
—CH 2 CH 2 OEt
I-10
3-fluorophenyl
cyclopropyl
I-11
4-fluorophenyl
cyclopentyl
I-12
3,4-dichlorophenyl
cyclohexyl
I-13
3,4-difluorophenyl
1-methylcyclobutyl
I-14
4-trifluoromethylphenyl
1-methylcyclopentyl
I-15
3-chlorophenyl
4-methylcyclohexyl
I-16
4-chlorophenyl
isobutyl
I-17
3-fluorophenyl
sec-butyl
I-18
4-fluorophenyl
tert-butyl
I-19
3,4-dichlorophenyl
ethyl
I-20
3,4-difluorophenyl
propyl
I-21
4-trifluoromethylphenyl
isopropyl
I-22
3-chlorophenyl
—C(H)(Me)CH 2 OMe
I-23
4-chlorophenyl
—CH 2 CH 2 OMe
I-24
3-fluorophenyl
—CH 2 CH 2 OEt
I-25
4-fluorophenyl
cyclopropyl
I-26
3,4-dichlorophenyl
cyclopentyl
I-27
3,4-difluorophenyl
cyclohexyl
I-28
4-trifluoromethylphenyl
1-methylcyclobutyl
I-29
3-chlorophenyl
1-methylcyclopentyl
I-30
4-chlorophenyl
4-methylcyclohexyl
I-31
4-hydroxyphenyl
isobutyl
I-32
4-hydroxyphenyl
sec-butyl
I-33
4-hydroxyphenyl
isopropyl
I-34
4-hydroxyphenyl
—C(H)(Me)CH 2 OMe
I-35
4-hydroxyphenyl
—C(H)(Me)CH 2 OMe
I-36
3-chlorophenyl
isobutyl
I-37
4-chlorophenyl
sec-butyl
I-38
3-fluorophenyl
tert-butyl
I-39
4-fluorophenyl
isopropyl
I-40
3-chlorophenyl
—C(H)(Me)CH 2 OMe
I-41
3-fluorophenyl
I-42
4-fluorophenyl
I-43
3,4-dichlorophenyl
I-44
3,4-difluorophenyl
I-45
3,4-difluorophenyl
I-46
3-fluorophenyl
isobutyl
I-47
4-fluorophenyl
sec-butyl
I-48
3,4-dichlorophenyl
isopropyl
I-49
3,4-difluorophenyl
—C(H)(Me)CH 2 OMe
I-50
4-trifluoromethylphenyl
—C(H)(Me)CH 2 OMe
I-51
3-chlorophenyl
isobutyl
I-52
4-chlorophenyl
1-methylcyclopentyl
I-53
3-fluorophenyl
cyclohexyl
I-54
4-hydroxyphenyl
TABLE 2A
Com-
pound
No.
Chemical Structure
A-2
A-3
A-4
A-5
A-6
A-7
A-8
A-9
A-10
A-11
A-12
A-13
A-14
A-15
A-16
A-17
A-18
A-19
A-20
A-21
A-22
A-23
A-24
A-25
A-26
A-27
A-28
A-29
A-30
A-31
A-32
A-33
A-34
A-35
A-36
A-37
A-38
A-39
A-40
A-41
A-42
A-43
A-44
A-45
A-46
A-47
A-48
A-49
A-50
A-51
A-52
A-53
A-54
A-55
A-56
A-57
A-58
A-59
A-60
A-61
A-62
A-63
A-64
A-65
A-66
A-67
A-68
A-69
A-70
A-71
A-72
A-73
A-74
A-75
A-76
A-77
A-78
A-79
A-80
A-81
A-82
A-83
A-84
A-85
A-86
A-87
A-88
A-89
A-90
A-91
A-92
A-93
A-94
A-95
A-96
A-97
A-98
A-99
A-100
A-101
A-102
A-103
A-104
A-105
A-106
A-107
A-108
A-109
A-110
A-111
A-112
A-113
A-114
A-115
A-116
TABLE 4A
Compound
No.
Chemical Structure
1
2
3
4
6
24. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
25. A method of treating a disorder selected from the group consisting of rheumatoid arthritis, psoriasis, chronic graft-versus-host disease, acute graft-versus-host disease, Crohn's disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren's syndrome, scleroderma, ulcerative colitis, asthma, uveitis, and epidermal hyperplasia, 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.
26. The method of claim 25 , wherein the patient is a human.
27. A method of inhibiting a F 1 F 0 -ATPase, comprising exposing a F 1 F 0 -ATPase to a compound of claim 1 to inhibit said F 1 F 0 -ATPase.