Tetrahydroisoquinoline derivatives for the treatment of red blood disorders and inflammatory diseases
Provided herein are compounds and compositions thereof for activating nuclear factor erythroid 2-related factor 2 (Nrf2) for treating red blood cell diseases and inflammatory diseases.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R is H or C 1-6 alkyl optionally substituted with one substituent selected from —OH, C 1-6 alkyloxy, or C 6-12 aryl;
R 1 is H or C 1-6 alkyl;
R 2 is H or C 1-6 alkyl;
R 3 is H or C 1-6 alkyl;
Ring B is C 6-12 arylene or C 3-12 heteroarylene containing 1 to 4 heteroatoms independently selected from N and O provided that Ring B is not
wherein the * designates a bond to L;
n is 0, 1, 2, or 3;
each R 5 is independently halo, C 1-6 alkyl, or C 1-6 alkyloxy;
Ring A is C 6-12 arylene or C 3-12 heteroarylene containing 1-2 heteroatoms independently selected from N and O;
m is 1, 2, 3, or 4;
each R 4 is independently H, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted with 1-3 groups independently selected from halo, C 1-6 alkyloxy, amido, and N,N-dimethylamido groups; and
L is C 4-8 alkylene, C 4-8 alkenylene, C 4-8 heteroalkylene, or C 4-8 heteroalkenylene, each of which is optionally substituted with 1 or 4 groups independently selected from halo and C 1-6 alkyl, and wherein the heteroalkylene and heteroalkenylene comprise 1 to 4 oxygen atoms.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (IA):
wherein:
L′ is C 4-6 alkylene, C 4-6 alkenylene, C 4-6 heteroalkylene, or C 4-6 heteroalkenylene, each of which is optionally substituted with 1 or 2 groups independently selected from halo and C 1-6 alkyl, and wherein the heteroalkylene and heteroalkenylene comprise 1 or 2 oxygen atoms;
X 3 is CH 2 or O;
n is 0, 1, or 2; and
X 1 and X 2 are independently CH or N.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently methyl or methoxy.
4 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein the C 4-6 alkenylene or C 4-6 heteroalkenylene comprise one unsaturated bond.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (IB):
wherein:
L″ is C 4-6 alkylene, C 4-6 alkenylene, C 4-6 heteroalkylene, or C 4-6 heteroalkenylene, each of which is optionally substituted with 1 or 2 groups independently selected from halo and C 1-6 alkyl, and wherein the heteroalkylene and heteroalkenylene comprise 1 to 2 oxygen atoms;
Ring B″ is selected from
wherein the * designates a bond to L″; X 4 is CR 5 , CH or N; Ring B″ is substituted with —(R 5 ) n where n is 0, 1, 2, or 3; and each R 5 is independently halo, C 1-4 alkyl, or C 1-4 alkyloxy; provided that the ring is not
6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently methyl or methoxy.
7 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein L″ is C 4-6 alkenylene or C 4-6 heteroalkenylene, wherein the heteroalkenylene comprises 1 oxygen atom, and wherein the C 4-6 alkenylene and C 4-6 heteroalkylene comprise one unsaturated bond.
8 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently F, Cl, or methyl.
9 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein Ring A is phenylene, indolylene, pyrrolopyridinylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, naphthalenylene, quinolinylene, benzoimidazolylene, or benzofuranylene.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is
wherein the * designates a bond to L,
Ring A is substituted with —(R 4 ) m where m is 1, 2, 3, or 4; and each R 4 is independently H, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl and C 1-6 alkoxy groups are optionally substituted with 1-3 groups independently selected from halo, C 1-6 alkyloxy, amido, and N,N-dimethylamido groups.
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from H, methyl, isobutyl, F, Cl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, N,N-dimethylamido, 3,3,3-trifluoropropyl, 2,2-difluoroethyl, 3-fluoropropyl, and methoxyethyl.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is H, methyl, ethyl, 2-hydroxy-ethyl, or benzyl.
13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H or methyl.
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H or methyl.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H or methyl.
16 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
17 . A method of treating sickle cell disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
Comp'd
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19 . A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from anemia, hemoglobinopathies, asthma, rheumatoid arthritis, ulcerative colitis and Crohn's disease.
20 . A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from anemia, sickle cell disease, thalassemia, asthma, rheumatoid arthritis, ulcerative colitis and Crohn's disease.