Uses of Bicyclic Compounds for the Treatment of Diseases
Provided herein are compounds and compositions thereof for modulating hepatocyte growth factors. In some embodiments, the compounds and compositions are provided for treatment of diseases, including neurological disorders.
1 . A method of treating mild cognitive impairment in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
L is a direct bond, —C(═O)—, —(CR a R b ) m —C(═O)—, —C(═O)—(CR a R b ) m —, or —(CR a R b ) m —;
each R a and R b is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 1a and R 1b are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halo, or C 6 -C 10 arylalkyl;
R 2 is H, oxo, or thioxo;
R 3 is C 2 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 6 cycloalkylalkyl, C 6 -C 10 arylalkyl, 5- to 10-membered heteroarylalkyl, or 5- to 10-membered heterocyclylalkyl,
wherein the 5- to 10-membered heteroarylalkyl or 5- to 10-membered heterocyclylalkyl contains 1-3 heteroatoms selected from nitrogen and oxygen;
R 4 is C 6 -C 10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl,
wherein the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl contains 1-3 heteroatoms selected from nitrogen and oxygen;
each R 5 is independently C 1 -C 6 alkyl, oxo, or halo;
R 6 is H, C 1 -C 6 alkyl, or oxo;
R 7 is H or oxo;
m is 1 or 2; and
n is an integer from 0 to 3;
wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkylalkyl, C 6 -C 10 aryl, C 6 -C 10 arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heterocyclylalkyl is optionally substituted with one to five substituents selected from hydroxyl, halo, amino, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyano, —(C═O)NH 2 , nitro, —SO 2 (C 1 -C 6 alkyl), and —CO 2 H.
2 . The method of claim 1 , wherein L is —C(═O)— or —(CR a R b ) m —.
3 . The method of claim 1 or 2 , wherein L is a —C(═O)—.
4 . The method of claim 1 or 2 , wherein L is —(CR a R b ) m —.
5 . The method of claim 4 , wherein R a and R b are each H, and m is 1.
6 . The method of any one of claims 1-5 , wherein R 1a and R 1b are each independently H; C 1 -C 6 alkyl optionally substituted with 1-3 substituents selected from halo, —CO 2 H, and —C(═O)NH 2 ; C 1 -C 6 alkoxy; halo; or C 6 -C 10 arylalkyl optionally substituted by 1-3 substituents selected from halo and amino.
7 . The method of claim 6 , wherein R 1a and R 1b are each independently H, methyl, fluoro, 2-methylbutyl, —CH 2 F, methoxy, —CH 2 CO 2 H, —CH 2 C(═O)NH 2 , benzyl, or 4-aminobenzyl.
8 . The method of claim 6 , wherein R 1a and R 1b are each independently H or C 1 -C 3 alkyl.
9 . The method of claim 8 , wherein R 1a is methyl and R 1b is H.
10 . The method of claim 8 , wherein R 1a and R 1b are each H.
11 . The method of any one of claims 1-10 , wherein R 2 is H.
12 . The method of any one of claims 1-10 , wherein R 2 is thioxo.
13 . The method of any one of claims 1-10 , wherein R 2 is oxo.
14 . The method of any one of claims 1-13 , wherein R 3 is C 3 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 6 cycloalkylalkyl, C 6 -C 10 arylalkyl, 5- to 10-membered heteroarylalkyl, or 5- to 10-membered heterocyclylalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or heterocyclylalkyl is optionally substituted with one to five substituents selected from hydroxyl, halo, amino, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cyano, —(C═O)NH 2 , nitro, —SO 2 (C 1 -C 6 alkyl), and —CO 2 H.
15 . The method of any one of claims 1-13 , wherein R 3 is C 2 -C 6 alkyl optionally substituted by 1-3 substituents selected from halo, C 1 -C 3 alkoxy, hydroxy, —NH 2 , —SO 2 (C 1 -C 3 alkyl), and —C(═O)NH 2 ; C 2 -C 6 alkenyl; C 3 -C 6 cycloalkylalkyl; 5- to 6-membered heteroarylalkyl; 5- to 6-membered heterocyclylalkyl; or C 6 arylalkyl.
16 . The method of claim 15 , wherein R 3 is C 2 alkyl substituted by 1-3 substituents selected from C 1 -C 3 alkoxy, hydroxy, —NH 2 , and —SO 2 (C 1 -C 3 alkyl).
17 . The method of any one of claims 14-16 , wherein R 3 is:
18 . The method of claim 17 , wherein R 3 is:
19 . The method of any one of claims 1-18 , wherein R 4 is C 6 -C 10 aryl optionally substituted with 1-3 substituents selected from halo, hydroxyl, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
20 . The method of claim 19 , wherein R 4 is phenyl substituted with 1-3 substituents selected from —CF 3 , —OCHF 2 , —OH, fluoro, and chloro.
21 . The method of claim 20 , wherein R 4 is:
22 . The method of claim 21 , wherein R 4 is:
23 . The method of any one of claims 1-18 , wherein R 4 is 5- to 10-membered heteroaryl optionally substituted with 1-3 substituents selected from halo, hydroxyl, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
24 . The method of claim 23 , wherein
R 4 is pyridyl or indolyl optionally substituted with 1-3 substituents selected from halo, hydroxyl, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
25 . The method of claim 24 , wherein
R 4 is
26 . The method of claim 25 , wherein
R 4 is
27 . The method of any one of claims 1-18 , wherein R 4 is 5- to 10-membered heterocyclyl optionally substituted with 1-3 substituents selected from halo, hydroxyl, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
28 . The method of claim 27 , wherein R 4 is indolinyl.
29 . The method of claim 28 , wherein R 4 is
30 . The method of any one of claims 1-26 , wherein -L-R 4 is:
31 . The method of any one of claims 1-30 , wherein n is 0.
32 . The method of any one of claims 1-30 , wherein n is 1.
33 . The method of claim 32 , wherein R 5 is oxo or halo.
34 . The method of claim 33 , wherein R 5 is oxo or fluoro.
35 . The method of any one of claims 1-34 , wherein R 6 is H.
36 . The method of any one of claims 1-35 , wherein R 7 is oxo.
37 . The method of any one of claims 1-10, 13-31, 35, and 36 , wherein the compound is of Formula (V):
or a pharmaceutically acceptable salt thereof.
38 . The method of claim 37 , wherein:
L is —C(═O)— or —CH 2 —;
R 1a and R 1b are independently H or C 1 -C 3 alkyl optionally substituted with —CO 2 H;
R 3 is C 4 -C 5 alkyl, C 4 -C 5 alkenyl, or C 1 -C 3 alkyl substituted with C 3 -C 5 cycloalkyl; and
R 4 is phenyl or pyridyl substituted with 1-3 substituents selected from —CF 3 , —OCHF 2 , —OH, fluoro, and chloro.
39 . A method of treating mild cognitive impairment in a subject in need thereof, comprising administering an effective amount of a compound selected from the compounds of Table 1A and pharmaceutically acceptable salts thereof.
40 . The method of any one of the preceding claims , wherein the method slows progression of dementia in the subject.
41 . The method of any one of the preceding claims , wherein the method improves cognitive function or slows progression of cognitive dysfunction in the subject.
42 . The method of any one of the preceding claims , wherein the compound is administered by oral or intravenous administration.