SSAO inhibitors and use thereof
The application relates to a compound of Formula (I′) or (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which modulates the activity of SSAO, a pharmaceutical composition comprising a compound of Formula (I′) or (I), and a method of treating or preventing a disease in which SSAO plays a role.
1. A compound of Formula (I)
or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein:
each X is independently Cl or F;
p is 0, 1, 2, or 3;
L is absent, —O—, (C 1 -C 4 ) alkylene, substituted (C 1 -C 4 ) alkylene, —O—(C 1 -C 4 ) alkylene, substituted —O—(C 1 -C 4 ) alkylene, (C 1 -C 4 ) alkylene-O—, or substituted (C 1 -C 4 ) alkylene-O—, wherein the substituted (C 1 -C 4 ) alkylene, substituted —O—(C 1 -C 4 ) alkylene, or substituted (C 1 -C 4 ) alkylene-O— is substituted with one or more L 1 ;
each L 1 is independently (C 1 -C 4 ) alkyl, F, or CF 3 ; or two L 1 , together with the atom to which they are attached, form a 3- to 5-membered cycloalkyl ring;
each R 1 is independently H, F, methyl, ethyl, or CF 3 ;
R 2 is (C 1 -C 4 ) alkyl substituted with one or more (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkoxy, NR 3 C(O)R 4 , or C(O)NR 3 R 4 ; or
R 2 is
wherein R 2 is optionally substituted with one or more R 5 ;
R 3 is H, methyl, or ethyl;
R 4 is (C 1 -C 4 ) alkyl or (C 3 -C 10 ) cycloalkyl optionally substituted with one or more R 8 ; or
R 3 and R 4 , together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R 5 ;
each R 5 is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxy, cyano, oxo, C(O)R 7 , C(O)NR 7 R 7′ , NR 3 C(O)R 7 , NR 3 S(O) 2 R 4 , S(O) 2 R 4 , (C 1 -C 4 ) alkyl substituted with one or more hydroxy or R 6 , (C 3 -C 10 ) cycloalkyl optionally substituted with one or more hydroxy or R 6 , or heterocyclyl comprising one or two 3- to 6-membering rings and 1 to 3 heteroatoms selected from N and O and optionally substituted with one or more hydroxy or R 6 ; or two R 5 , together with the atom or atoms to which they are attached, form a 3- to 5-membered saturated or 5- or 6-membered aromatic ring optionally comprising 1 or 2 heteroatoms selected from N and O;
each R 6 is independently NR 3 C(O)R 7 or C(O)NR 3 R 7 ;
each R 7 is independently
OH, (C 1 -C 4 ) alkoxy, (C 1 -C 6 ) alkyl optionally substituted with one or more (C 1 -C 4 ) alkoxy, CF 3 , F, or (C 3 -C 10 ) cycloalkyl,
(C 3 -C 10 ) cycloalkyl optionally substituted with one or more R 8 , or
phenyl optionally substituted with one or more R 8 ;
each R 7′ is independently H, methyl, or ethyl; or
R 7 and R 7′ , together with the atom to which they are attached, form a 3- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R 8 ; or
R 3 and R 7 , together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R 8 ; and
each R 8 is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, CF 3 , OH, or F.
2. The compound of claim 1 , wherein X is F.
3. The compound of claim 1 , wherein p is 1.
4. The compound of claim 1 , wherein L is absent or (C 1 -C 4 ) alkylene.
5. The compound of claim 1 , wherein each L 1 is independently methyl or two L 1 , together with the atom to which they are attached, form a cyclopropyl ring.
6. The compound of claim 1 , wherein each R 1 is H or methyl.
7. The compound of claim 1 , wherein R 2 is (C 1 -C 4 ) alkyl substituted with one or more (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkoxy, NR 3 C(O)R 4 , or C(O)NR 3 R 4 .
8. The compound of claim 7 , wherein R 3 and R 4 , together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R 5 .
9. The compound of claim 1 , wherein R 2 is
wherein R 2 is optionally substituted with one or more R 5 .
10. The compound of claim 1 , wherein R 2 is
wherein R 2 is optionally substituted with one or more R 5 .
11. The compound of claim 10 , wherein R 2 is
wherein R 2 is optionally substituted with one or more R 5 .
12. The compound of claim 1 , wherein R 2 is
wherein R 2 is optionally substituted with one or more R 5 .
13. The compound of claim 1 , wherein at least one R 5 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxy, cyano, oxo, C(O)R 7 , C(O)NR 7 R 7′ , NR 3 C(O)R 7 , NR 3 S(O) 2 R 4 , S(O) 2 R 4 , or (C 1 -C 4 ) alkyl substituted with one or more hydroxy or R 6 .
14. The compound of claim 1 , wherein at least one R 5 is (C 3 -C 10 ) cycloalkyl optionally substituted with one or more hydroxy or R 6 , or heterocyclyl comprising one or two 3- to 6-membering rings and 1 to 3 heteroatoms selected from N and O and optionally substituted with one or more hydroxy or R 6 ; or two R 5 , together with the atom or atoms to which they are attached, form a 3- to 5-membered saturated or 5- or 6-membered aromatic ring optionally comprising 1 or 2 heteroatoms selected from N and O.
15. The compound of claim 1 , wherein at least one R 7 is (C 1 -C 4 ) alkoxy, (C 1 -C 6 ) alkyl optionally substituted with one or more (C 1 -C 4 ) alkoxy, CF 3 , F, or (C 3 -C 10 ) cycloalkyl.
16. The compound of claim 1 , wherein at least one R 7 is (C 3 -C 10 ) cycloalkyl or phenyl optionally substituted with one or more R 8 .
17. The compound of claim 1 , wherein R 7 and R 7′ , together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R 8 .
18. The compound of claim 1 , wherein R 3 and R 7 , together with atom(s) to which they are attached, form a 3- to 6-membered ring optionally comprising one additional heteroatom selected from N and O and optionally substituted with one or more R 8 .
19. The compound of claim 1 , wherein at least one R 8 is (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy.
20. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient or carrier.
21. A method of modulating SSAO or treating a SSAO-mediated disorder, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein the SSAO-mediated disorder is liver inflammation, liver fibrosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, or stroke.