US2023150998A1PendingUtilityA1
Compounds as glp-1r agonists
Est. expirySep 27, 2041(~15.2 yrs left)· nominal 20-yr term from priority
A61P 3/04A61P 9/00A61P 3/10A61P 1/16A61K 31/4545C07D 417/14
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Claims
Abstract
The present application provides compounds that may be used as a glucagon-like peptide-1 receptors (GLP-1R) agonist, or pharmaceutically acceptable salts thereof. Also provided are pharmaceutical compositions containing such compounds, or pharmaceutically acceptable salts thereof. Methods of preparing these compounds and compositions, and methods of using these compounds and compositions to treat or prevent a disease or a condition mediated by GLP-1R, are also provided.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is N or CH;
Y is N or CR 4 ;
n is 0 or 1;
R is hydrogen;
R 1 is —C 1 -C 6 alkylene-R 5 ;
R 2 is hydrogen, oxo, or C 1 -C 6 alkyl;
R 3 is hydrogen, oxo, or C 1 -C 6 alkyl and R 4 is hydrogen, OH, or C 1 -C 6 alkyl;
or R 3 and R 4 are taken together with the carbon atoms to which they are attached to form C 3 -C 6 cycloalkyl optionally substituted by halo or C 1 -C 3 alkyl;
R 5 is 5-membered heterocyclyl or 5-membered heteroaryl, each of which comprises 1, 2, or 3 heteroatoms independently selected from O, N, and S, wherein at least one heteroatom of R 5 is S, and further wherein R 5 is optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl;
Ring A is 5- to 12-membered heterocyclyl or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH;
L is a bond, —O—, C 1 -C 6 alkylene, *—O—C 1 -C 6 alkylene-**, *—C 1 -C 6 alkylene-O—**, or *—NR 6 —C 1 -C 6 alkylene-**, wherein * represents the point of attachment to ring A and ** represents the point of attachment to ring B;
when L is *—O—C 1 -C 6 alkylene-**, the C 1 -C 6 alkylene of L is optionally substituted by R L , wherein each R L is independently C 1 -C 6 alkyl or halo, or two R L are taken together with the carbon atom or atoms to which they are attached to form C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl; and
when L is C 1 -C 6 alkylene, the C 1 -C 6 alkylene is optionally substituted by R L1 , wherein each R L1 is independently halo, OH, oxo, or C 1 -C 6 alkyl, or two R L1 are taken together with the carbon atom or atoms to which they are attached to form C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl;
R 6 is hydrogen or C 1 -C 6 alkyl; and
Ring B is C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, each of which is independently optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 , and phenyl.
2 . The compound of claim 1 , wherein X is N.
3 . The compound of claim 1 , wherein X is CH.
4 . The compound of claim 1 , wherein Y is N.
5 . The compound of claim 1 , wherein Y is CR 4 .
6 . The compound of claim 1 , wherein Y is CR 4 , and R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a cyclopropyl group.
7 . The compound of claim 1 , wherein n is 0.
8 . The compound of claim 1 , wherein n is 1.
9 . The compound of claim 1 , wherein R 1 is —CH 2 —R 5 .
10 . The compound of claim 1 , wherein R 5 is 5-membered heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from O, N, and S, wherein at least one heteroatom of R 5 is S, and further wherein R 5 is optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
11 . The compound of claim 1 , wherein R 5 is 5-membered heteroaryl comprising 1 or 2 heteroatoms selected from S and N, wherein one heteroatom of R 5 is S, and further wherein R 5 is optionally substituted by halo, —O—C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
12 . The compound of claim 1 , wherein R 5 is thiazolyl or isothiazolyl, each optionally substituted by halo, —O—C 1-6 alkyl, C 1 -C 6 alkyl, C 1-6 alkenyl, or C 1 -C 6 haloalkyl.
13 . The compound of claim 12 , wherein R 5 is a thiazole optionally substituted by methyl, bromo, vinyl, ethyl, methoxy, chloro, or fluoro.
14 . The compound of claim 1 , wherein R 5 is
15 . The compound of claim 14 , wherein R 5 is
16 . The compound of claim 1 , wherein Ring A is 5- to 6-membered heteroaryl optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH.
17 . The compound of claim 1 , wherein Ring A is 6-membered heteroaryl optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH.
18 . The compound of claim 1 , wherein Ring A is benzodioxolyl, pyridyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted by halo, CN, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by halo or OH.
19 . The compound of claim 1 , wherein Ring A is benzodioxolyl, pyridyl, pyrimidinyl, or pyrazinyl.
20 . The compound of claim 1 , wherein Ring A is
21 . The compound of claim 1 , wherein Ring A is
22 . The compound of claim 1 , wherein L is *—O—C 1 -C 6 alkylene-** optionally substituted by R L .
23 . The compound of claim 22 , wherein L is *—O—CH 2 —** or *—O—CD 2 -**.
24 . The compound of claim 1 , wherein:
L is —O—; L is a bond; or L is *—C(O)—CH 2 —**.
25 - 26 . (canceled)
27 . The compound of claim 1 , wherein Ring B is C 6 -C 14 aryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
28 . The compound of claim 1 , wherein Ring B is phenyl optionally substituted by one to three substituents each independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
29 . The compound of claim 1 , wherein Ring B is phenyl optionally substituted by one to three substituents each independently selected from the group consisting of halo, CN, and —CONH 2 .
30 . The compound of claim 1 , wherein Ring B is
31 . The compound of claim 1 , wherein Ring B is 4- to 12-membered heterocyclyl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
32 . The compound of claim 1 , wherein Ring B is tetrahydroisoquinolinyl optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
33 . The compound of claim 1 , wherein Ring B is
optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
34 . The compound of claim 1 , wherein Ring B is
optionally substituted by one to three substituents independently selected from the group consisting of halo, and CN.
35 . The compound of claim 1 , wherein Ring B is
36 . The compound of claim 1 , wherein Ring B is a 5- to 12-membered heteroaryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
37 . The compound of claim 1 , wherein Ring B is a 9-membered heteroaryl, which is optionally substituted by one to three substituents independently selected from the group consisting of halo, CN, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —COCH 3 , —CONH 2 , —S(O) 2 CH 3 and phenyl.
38 . The compound of claim 1 , wherein Ring B is a 9-membered heteroaryl, which is optionally substituted by one to two substituents independently selected from the group consisting of halo and CN.
39 . The compound of claim 38 , wherein Ring B is
40 . The compound of claim 1 , wherein the compound is of Formula VIII
or a pharmaceutically acceptable salt thereof, wherein:
R 7 is hydrogen, chloro, bromo, fluoro, methyl, or vinyl; and
R 8 is
41 . The compound of claim 40 , wherein R 7 is hydrogen.
42 . The compound of claim 1 , wherein the compound is a meglumine salt.
43 . A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of Compounds 1-31 as listed in Table 1.
44 . The compound of claim 43 , wherein the compound is a meglumine salt.
45 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable excipient.
46 . A method of treating a disease mediated by glucagon-like peptide-1 receptor (GLP-1R) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 45 .
47 . The method of claim 46 , wherein the disease is a liver disease.
48 . The method of claim 47 , wherein the liver disease is primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), graft versus host disease, transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or oti-antitrypsin deficiency.
49 . The method of claim 46 , wherein the disease is diabetes, cardiometabolic disease, or obesity.
50 - 52 . (canceled)
53 . A method of decreasing food intake or increasing glucose tolerance in an individual in need thereof, comprising administering to the individual a compound, or pharmaceutically acceptable salt thereof, of claim 1 or the pharmaceutical composition of claim 45 .
54 . (canceled)Join the waitlist — get patent alerts
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