Lpa receptor antagonists and uses thereof

Patent metadata

Field	Value
Publication number	US-2021380561-A1
Application number	US-202117319471-A
Country	US
Kind code	A1
Filing date	May 13, 2021
Priority date	Jun 3, 2020
Publication date	Dec 9, 2021
Grant date	—

Abstract

The present disclosure relates generally to compounds that bind to Lysophosphatidic Acid Receptor 1 (LPAR1) and act as antagonists of LPAR1. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of LPAR1, including fibrosis and liver diseases such as non alcoholic steatohepatitis (NASH).

First claim

1 . A compound of Formula (I):

or pharmaceutically acceptable salt thereof,
wherein:
R 1 is hydrogen or C 1-6 alkyl optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from halogen, cyano, C 1-4 alkoxy, and C 3-10 cycloalkyl; or
R 1 is C 3-6 cycloalkyl optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from halogen, cyano, C 1-4 alkoxy, and C 1-6 alkyl;
each R 2 , which can be the same or different, is independently selected from hydrogen, halogen, cyano, oxo, C 1-4 alkyl, C 3-10 cycloalkyl, 3 to 10 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6 to 10 membered aryl, 5 to 10 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, —N(R 2A1 )(R 2A2 ), O—R 2A1 , —S—R 2A1 , —C(O)N(R 2A1 )(R 2A2 ), —NR 2A1 C(O)R 2A2 , —NR 2A1 C(O)N(R 2A2 )(R 2A3 ), —S(O) 0-2 R 2A1 , —S(O) 2 N(R 2A1 )(R 2A2 ), and —NR 2AA S(O) 2 R 2A2 , wherein each R 2A1 , R 2A2 , and R 2A3 is independently hydrogen or C 1-6 alkyl, wherein each R 2 alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl is optionally substituted with 1 to 4 R 2B , which can be the same or different, wherein each R 2B is independently C 1-4 alkyl, C 1-4 alkoxy, hydroxy, halogen, or cyano;
each R 3 , which can be the same or different, is independently selected from deuterium, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or C 1-4 alkoxy, wherein each C 1-6 alkyl and C 3-10 cycloalkyl, is optionally substituted with 1 to 3 halogens;
R 4 is C 1-6 alkyl optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from halogen, cyano, C 1-4 alkoxy, —C(O)N(R 4A1 ), and —N(R 4A1 )(R 4A2 ) wherein each R 4A1 and R 4A2 is independently H, C 1-6 alkyl, or C 3-10 cycloalkyl; or
R 4 is C 3-6 cycloalkyl or 3 to 6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl or heterocyclyl are optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy;
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, or 3;
o is 0, 1, 2, or 3;
each of X 1 , X 2 , and X 3 is independently selected from CH and N;
each U is independently —CH═, —CH 2 —, —N═, —NH—, or —O—;
each Y 1 and Y 2 is independently hydrogen, deuterium, or C 1-6 alkyl optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from deuterium, halogen, cyano, C 2-3 alkynyl, C 1-4 alkoxy, and —C(O)NH—(C 1-4 H 3-9 ); and
Z is C 1-8 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-12 aryl, 3 to 12 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5 to 12 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl are each optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl, wherein the C 1-4 alkyl is optionally substituted with 1 to 3 substituents, which can be the same or different, each selected from C 1-4 alkoxy and halogen; or
Y 1 and Z together with the carbon to which they are attached form C 3-6 cycloalkyl, C 6-12 aryl, 3 to 12 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5 to 12 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl are each optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from cyano, C 1-4 alkyl, C 1-4 alkoxy, C 6-10 aryl and halogen, wherein the C 1-4 alkyl is optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from C 1-4 alkoxy and halogen, and wherein the C 6-10 aryl is optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from C 1-4 alkyl, C 1-4 alkoxy, and halogen, and Y 2 is hydrogen or deuterium.

2 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (Ia):

3 .- 10 . (canceled)

11 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (IIIa):

wherein:
m is 0, 1, or 2; and
o is 0, 1, 2, or 3.

12 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (IIIb):

wherein:
m is 0, 1, 2, 3, or 4; and
o is 0, 1, 2, or 3.

13 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (IIIc):

wherein:
m is 0, 1 or 2; and
o is 0, 1, 2, or 3.

14 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (IIId):

wherein:
m is 0, 1, or 2; and
o is 0, 1, 2, or 3.

15 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (IIIe)

wherein:
m is 0, 1, or 2; and
o is 0, 1, 2, or 3.

16 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (IIIf):

wherein:
m is 0, 1, 2, or 3; and
o is 0, 1, 2, or 3.

17 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (IIIg):

wherein:
m is 0, 1, 2, 3, or 4; and
o is 0, 1, 2, or 3.

18 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (IVa):

wherein
m is 0, 1, or 2; and
is 0, 1, 2, or 3.

19 . The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (IVb):

wherein
m is 0, 1, 2, 3, or 4; and
o is 0, 1, 2, or 3.

20 . The compound or pharmac

Assignees

• Gilead Sciences Inc

Inventors

• Phillips Barton W
• Tang Doris T
• Venkataramani Chandrasekar
• Yang Kin S
• Zagorska Anna

Classifications

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title