Saturated acyl guanidine for inhibition of F
View Patent ↗The invention provides saturated acyl guanidine compounds that inhibit F 1 F 0 -ATPase, and methods of using saturated acyl 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 pyrazolyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of phenyl, alkyl, haloalkyl, cycloalkyl, halogen, hydroxyl, hydroxyalkyl, and C 1-6 alkoxy, wherein the phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, C 1-6 alkoxy, and cyano;
R 1 is alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, alkylene-O-alkyl, alkylene-cycloalkyl, alkylene-heterocycloalkyl, aralkyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, or 1,2,3,4-tetrahydronaphthalen-2-yl, wherein the cycloalkyl, heterocycloalkyl, aralkyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, and 1,2,3,4-tetrahydronaphthalen-2-yl are optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, hydroxyl, alkoxyl, and cyano;
R 2 and R 4 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 5 ) 2 ) m -alkoxyl, —N(R 6 )(R 7 ), heterocycloalkyl, —N(R 6 )C(O)-alkyl, —C(O)N(R 6 )(R 7 ), —N(R 6 )C(O)N(R 6 )(R 7 ), halogen, haloalkyl, and cyano; or
(ii) cycloalkyl, —(C(R 5 ) 2 ) m -cycloalkyl, aryl, or aralkyl, each of which are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, alkoxy, —S-alkyl, and cyano;
R 5 represents independently for each occurrence hydrogen, alkyl, or cycloalkyl; or two occurrences of R 5 attached to the same carbon atom are taken together with said carbon atom to form a saturated carbocylic ring;
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 1-6 alkoxy; and
m is 1, 2, 3, 4, or 5.
2. The compound of claim 1 , wherein A 1 is pyrazolyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl, halogen, and hydroxyl.
3. The compound of claim 1 , wherein A 1 is pyrazolyl substituted with haloalkyl, or A 1 is pyrazolyl substituted with phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen and haloalkyl.
4. The compound of claim 1 , wherein A 1 is pyrazolyl substituted with 1 or 2 substituents independently selected from the group consisting of alkyl and haloalkyl.
5. The compound of claim 1 , wherein A 1 is represented by:
wherein R* is haloalkyl.
6. The compound of claim 1 , wherein A 1 is one of the following:
7. A compound represented by Formula II:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
A 1 is
wherein B 2 is a 6-membered heteroaromatic group;
R 1 is alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, alkylene-O-alkyl, alkylene-cycloalkyl, alkylene-heterocycloalkyl, aralkyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, or 1,2,3,4-tetrahydronaphthalen-2-yl; wherein the cycloalkyl, heterocycloalkyl, aralkyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, and 1,2,3,4-tetrahydronaphthalen-2-yl are optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, hydroxyl, alkoxyl, and cyano;
R 2 and R 4 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 5 ) 2 ) m -alkoxyl, —N(R 6 )(R 7 ), heterocycloalkyl, —N(R 6 )C(O)-alkyl, —C(O)N(R 6 )(R 7 ), —N(R 6 )C(O)N(R 6 )(R 7 ), halogen, haloalkyl, and cyano; or
(ii) cycloalkyl, —(C(R 5 ) 2 ) m -cycloalkyl, aryl, or aralkyl, each of which are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, alkoxy, —S-alkyl, and cyano;
R 5 represents independently for each occurrence hydrogen, alkyl, or cycloalkyl; or two occurrences of R 5 attached to the same carbon atom are taken together with said carbon atom to form a saturated carbocylic ring;
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 1-6 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 1-6 alkoxy, or cyano;
R 10 is alkyl, cycloalkyl, aryl, or aralkyl;
m is 1, 2, 3, 4, or 5; and
n is 0, 1, 2, 3, or 4.
8. The compound of claim 1 , wherein R 1 is alkyl.
9. The compound of claim 1 , wherein R 1 is cycloalkyl or alkylene-cycloalkyl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, hydroxyl, and alkoxyl.
10. The compound of claim 1 , wherein R 1 is aralkyl optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, cycloalkyl, hydroxyl, alkoxyl, and cyano.
11. The compound of claim 1 , wherein R 1 is benzyl optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, and alkoxyl.
12. The compound of claim 1 , wherein R 2 and R 4 are hydrogen.
13. The compound of claim 1 , wherein R 3 is alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl, alkoxyl, —O—(C(R 5 ) 2 ) m -alkoxyl, —N(R 6 )(R 7 ), heterocycloalkyl, —N(R 6 )C(O)-alkyl, —C(O)N(R 6 )(R 7 ), —N(R 6 )C(O)N(R 6 )(R 7 ), halogen, haloalkyl, and cyano.
14. The compound of claim 1 , wherein R 3 is alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl and alkoxyl.
15. The compound of claim 1 , wherein R 3 is alkyl or cycloalkyl.
16. The compound of claim 1 , wherein R 3 is phenyl, benzyl, or —(C(R 5 ) 2 ) m -cycloalkyl, each of which are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, alkoxy, —S-alkyl, and cyano.
17. The compound of claim 1 , wherein R 3 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
18. The compound of claim 1 , wherein R 5 is hydrogen, and R 6 and R 7 are hydrogen.
19. 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:
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkylene-O—C 1-6 alkyl, C 1-6 alkylene- C 3-6 cycloalkyl, or C 1-6 alkylene-heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted by 1 or 2 substituents independently selected from the group consisting of halogen, haloalkyl, and alkyl;
R 3 is one of the following:
(i) C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl and alkoxyl; or
(ii) C 3-6 cycloalkyl or —(CH 2 ) m -cycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl, alkyl, hydroxyalkyl, and alkoxy;
R* is phenyl, alkyl, haloalkyl, or cycloalkyl; wherein the phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, and C 1-6 alkoxy; and
m is 1, 2, or 3.
20. The compound of claim 19 , wherein R 1 is C 1-6 alkyl.
21. The compound of claim 19 , wherein R 1 is C 3-6 cycloalkyl or C 1-6 alkylene-C 3-6 cycloalkyl, wherein the cycloalkyl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of halogen, haloalkyl, and alkyl.
22. The compound of claim 19 , wherein R 3 is C 1-6 alkyl optionally substituted by alkoxyl.
23. The compound of claim 19 , wherein R* is haloalkyl.
24. The compound of claim 19 , wherein R* is trifluoromethyl.
25. A compound listed in any one of Tables 1-4 or a pharmaceutically acceptable salt thereof:
TABLE 1
No.
Compound
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
TABLE 2
No.
A
X
Y
II-1
isobutyl
II-2
sec-butyl
II-3
tert-butyl
II-4
ethyl
II-5
propyl
II-6
isopropyl
II-7
—C(H)(Me)CH 2 OMe
II-8
—CH 2 CH 2 OMe
II-9
—CH 2 CH 2 OEt
II-10
cyclopropyl
II-11
cyclopentyl
II-12
cyclohexyl
II-13
1-methylcyclobutyl
II-14
1-methylcyclopentyl
II-15
1-methylcyclohexyl
II-16
—CF 3
isobutyl
II-17
—CF 3
sec-butyl
II-18
—CF 3
tert-butyl
II-19
—CF 3
ethyl
II-20
—CF 3
propyl
II-21
—CF 3
isopropyl
II-22
—CF 3
—C(H)(Me)CH 2 OMe
II-23
—CF 3
—CH 2 CH 2 OMe
II-24
—CH 2 CH 2 OEt
II-25
cyclopropyl
II-26
cyclopentyl
II-27
cyclohexyl
II-28
1-methylcyclobutyl
II-29
1-methylcyclopentyl
II-30
1-methylcyclohexyl
II-31
isobutyl
II-32
sec-butyl
II-33
isopropyl
II-34
—C(H)(Me)CH 2 OMe
II-35
—C(H)(Me)CH 2 OMe
II-36
isobutyl
II-37
sec-butyl
II-38
tert-butyl
II-39
isopropyl
II-40
—C(H)(Me)CH 2 OMe
II-41
II-42
II-43
—CF 3
II-44
II-45
TABLE 3
No.
Compound
III-1
III-2
III-3
III-4
III-5
III-6
III-7
III-8
III-9
III-10
III-11
III-12
III-13
III-14
III-15
III-16
III-17
III-18
III-19
III-20
III-21
III-22
III-23
III-24
III-25
III-26
III-27
III-28
III-29
III-30
III-31
III-32
III-33
III-34
III-35
III-36
TABLE 4
No.
A
X
Y
IV-1
isobutyl
IV-2
sec-butyl
IV-3
tert-butyl
IV-4
ethyl
IV-5
propyl
IV-6
isopropyl
IV-7
—C(H)(Me)CH 2 OMe
IV-8
—CH 2 CH 2 OMe
IV-9
—CH 2 CH 2 OEt
IV-10
cyclopropyl
IV-11
cyclopentyl
IV-12
cyclohexyl
IV-13
1-methylcyclobutyl
IV-14
1-methylcyclopentyl
IV-15
4-methylcyclohexyl
IV-16
isobutyl
IV-17
sec-butyl
IV-18
tert-butyl
IV-19
ethyl
IV-20
propyl
IV-21
isopropyl
IV-22
—CF 3
—C(H)(Me)CH 2 OMe
IV-23
—CF 3
—CH 2 CH 2 OMe
IV-24
—CF 3
—CH 2 CH 2 OEt
IV-25
—CF 3
cyclopropyl
IV-26
—CF 3
cyclopentyl
IV-27
—CF 3
cyclohexyl
IV-28
—CF 3
1-methylcyclobutyl
IV-29
1-methylcyclopentyl
IV-30
4-methylcyclohexyl
IV-31
isobutyl
IV-32
sec-butyl
IV-33
isopropyl
IV-34
—C(H)(Me)CH 2 OMe
IV-35
—C(H)(Me)CH 2 OMe
IV-36
isobutyl
IV-37
sec-butyl
IV-38
tert-butyl
IV-39
isopropyl
IV-40
—C(H)(Me)CH 2 OMe
IV-41
IV-42
IV-43
IV-44
IV-45
IV-46
isobutyl
IV-47
sec-butyl
IV-48
isopropyl
IV-49
—C(H)(Me)CH 2 OMe
IV-50
—C(H)(Me)CH 2 OMe
IV-51
isobutyl
IV-52
1-methylcyclopentyl
IV-53
—CCF 3
cyclohexyl
IV-54
IV-55
26. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
27. A method of treating a disorder associated with dysregulation of cell death selected from the group consisting of an immune disorder, inflammatory disorder, cardiovascular disease, myeloma, lymphoma, cancer, and bacterial infection, 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.
28. The method of claim 27 , wherein the disorder is 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, or epidermal hyperplasia.
29. The method of claim 27 , wherein the patient is a human.
30. 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.