IP Library › Granted Patent US 12,539,294
Granted Patent B2
US 12,539,294 · App. 17/782,530 · Granted Feb 3, 2026

Combination of an azetidine LPA1 receptor antagonist with pirfenidone and/or nintedanib for use in the treatment of fibrotic diseases

Inventors: Magdalena Birker (Allschwil, CH); Cyrille Lescop (Allschwil, CH)
Assignee: Idorsia Pharmaceuticals Ltd
A61K31/4427A61K31/44A61K31/496
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Quick Facts
Patent No.
US 12,539,294
App. No.
17/782,530
Granted
Feb 3, 2026
Kind
B2
Abstract

The present invention concerns the compounds of formula (I) wherein R 1 , R 2 , R 3 , X, and Y are as described in the description, and their use as antagonists of the LPA 1 receptor, in combination with one or more therapeutically active ingredients acting as anti-fibrotic agent(s); such as especially pirfenidone and/or nintedanib, in the prevention and/or treatment of fibrotic diseases. The invention further relates to pharmaceutical compositions comprising the compounds of formula (I) in combination with one or more therapeutically active ingredients acting as anti-fibrotic agent(s) such as pirfenidone or nintedanib.

Claims (107)

1 . A method for prophylaxis or treatment of a fibrotic disease in a subject in need thereof, wherein the method comprises administering to the subject a compound of Formula (I):

wherein

X is CH; Y is N; and R 2 is methyl, ethyl, or isopropyl; or

X is N; Y is CH; and R 2 is methyl, ethyl, or isopropyl, or difluoromethyl;

R 1 is fluoro, chloro, bromo, or methyl; and

R 3 represents

—(CH 2 ) 2-3 —C(CH 3 ) 2 —COOH;

—CO—(CH 2 ) 1-2 —C(CH 3 ) 2 —COOH; or

—SO 2 —NH 2 ;

or a pharmaceutically acceptable salt thereof;

wherein said compound of formula (I) is administered in combination with:

pirfenidone, or a pharmaceutically acceptable salt thereof;

nintedanib, or a pharmaceutically acceptable salt thereof; or

both pirfenidone, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof.

2 . The method according to claim 1 , wherein X is CH; Y is N; and R 2 is methyl, ethyl, or isopropyl.

3 . The method according to claim 2 , wherein R 1 is fluoro, chloro, or bromo.

4 . The method according to claim 1 , wherein X is N; Y is CH; and R 2 is difluoromethyl.

5 . The method according to claim 4 , wherein R 1 is methyl.

6 . The method according to claim 1 , wherein R 3 represents

—CH 2 —CH 2 —C(CH 3 ) 2 —COOH;

—CO—CH 2 —C(CH 3 ) 2 —COOH; or

—SO 2 —NH 2 .

7 . The method according to claim 3 , wherein R 3 represents-SO 2 —NH 2 .

8 . The method according to claim 1 , wherein the compound is

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylbutanoic acid;

5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylpentanoic acid;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethyl-5-oxopentanoic acid;

N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide;

3-(2-isopropylphenyl)-N-(2-methoxy-6-methylpyridin-3-yl)-1-sulfamoylazetidine-3-carboxamide;

N-(2-ethoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide;

N-(2-isopropoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide;

4-(3-((6-chloro-4-methoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylbutanoic acid;

4-(3-((6-chloro-4-ethoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylbutanoic acid;

4-(3-((6-chloro-4-isopropoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylbutanoic acid;

4-(3-((6-bromo-4-methoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylbutanoic acid;

5-(3-((6-chloro-4-methoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylpentanoic acid;

5-(3-((6-chloro-4-ethoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylpentanoic acid;

4-(3-((6-chloro-4-methoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

4-(3-((6-bromo-4-methoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

4-(3-((6-chloro-4-ethoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

N-(6-fluoro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide;

N-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide;

N-(6-chloro-4-ethoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide;

N-(6-chloro-4-isopropoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide;

N-(6-bromo-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; or

3-(2-isopropylphenyl)-N-(4-methoxy-6-methylpyridin-3-yl)-1-sulfamoylazetidine-3-carboxamide;

or a pharmaceutically acceptable salt thereof.

9 . The method according to claim 1 , wherein the compound is

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylbutanoic acid;

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; or

N-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide;

or a pharmaceutically acceptable salt thereof.

10 . The method according to claim 1 , wherein said compound of formula (I), or pharmaceutically acceptable salt thereof, is administered in combination with pirfenidone, or a pharmaceutically acceptable salt thereof.

11 . The method according to claim 10 , wherein pirfenidone, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical unit dosage form suitable for the oral administration of a total of about 2403 mg per day or below.

12 . The method according to claim 1 ; wherein said fibrotic disease is:

pulmonary fibrosis;

renal fibrosis; or

liver fibrosis.

13 . The method according to claim 1 ; wherein said fibrotic disease is:

idiopathic pulmonary fibrosis;

pulmonary fibrosis secondary to systemic inflammatory disease;

pulmonary fibrosis secondary to sarcoidosis;

radiation-induced fibrosis;

silicosis-induced pulmonary fibrosis; or

asbestos-induced pulmonary fibrosis.

14 . A pharmaceutical composition comprising, as active principles, a compound of formula (I):

wherein

X is CH; Y is N; and R 2 is methyl, ethyl, or isopropyl; or

X is N; Y is CH; and R 2 is methyl, ethyl, or isopropyl, or difluoromethyl;

R 1 is fluoro, chloro, bromo, or methyl; and

R 3 represents

—(CH 2 ) 2-3 —C(CH 3 ) 2 —COOH;

—CO—(CH 2 ) 1-2 —C(CH 3 ) 2 —COOH; or

—SO 2 —NH 2 ;

or a pharmaceutically acceptable salt thereof; in combination with one or more therapeutically active ingredients acting as anti-fibrotic agent(s); wherein said anti-fibrotic agent(s) is/are pirfenidone and/or nintedanib; or a pharmaceutically acceptable salt thereof; as well as at least one pharmaceutically acceptable excipient.

15 . The method according to claim 1 , wherein said fibrotic disease is:

pulmonary fibrosis; wherein said pulmonary fibrosis is selected from idiopathic pulmonary fibrosis; pulmonary fibrosis secondary to systemic inflammatory disease; pulmonary fibrosis secondary to sarcoidosis; iatrogenic pulmonary fibrosis; silicosis-induced pulmonary fibrosis; asbestos-induced pulmonary fibrosis; and pleural fibrosis;

renal fibrosis; wherein said renal fibrosis is selected from renal fibrosis associated with CKD, chronic renal failure, tubulointerstitial nephritis, and a chronic nephropathy selected from primary glomerulonephritis and glomerulonephritis secondary to a systemic inflammatory disease, diabetes, focal segmental glomerular sclerosis, IgA nephropathy, hypertension, renal allograft, or Alport syndrome; or

liver fibrosis; wherein said liver fibrosis is selected from cirrhosis, alcohol-induced liver fibrosis, nonalcoholic steatohepatitis, biliary duct injury, primary biliary cirrhosis, infection-induced liver fibrosis, viral-induced liver fibrosis, and autoimmune hepatitis.

16 . The method according to claim 1 , wherein said compound of formula (I), or pharmaceutically acceptable salt thereof, is administered in combination with nintedanib, or a pharmaceutically acceptable salt thereof.

17 . The method according to claim 1 , wherein said compound of formula (I), or pharmaceutically acceptable salt thereof, is administered in combination with both pirfenidone, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof.

18 . The method according to claim 9 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered in combination with pirfenidone, or a pharmaceutically acceptable salt thereof.

19 . The method according to claim 1 , wherein the compound is

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylbutanoic acid;

or a pharmaceutically acceptable salt thereof.

20 . The method according to claim 1 , wherein the compound is

4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid;

or a pharmaceutically acceptable salt thereof.

21 . The method according to claim 1 , wherein the compound is

N-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide;

or a pharmaceutically acceptable salt thereof.

22 . The method according to claim 21 ; wherein said fibrotic disease is:

pulmonary fibrosis;

renal fibrosis; or

liver fibrosis.

23 . The method according to claim 21 ; wherein said fibrotic disease is pulmonary fibrosis.

24 . The method according to claim 21 ; wherein said fibrotic disease is:

idiopathic pulmonary fibrosis;

pulmonary fibrosis secondary to systemic inflammatory disease;

pulmonary fibrosis secondary to sarcoidosis;

radiation-induced fibrosis;

silicosis-induced pulmonary fibrosis; or

asbestos-induced pulmonary fibrosis.

25 . The method according to claim 23 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered in combination with pirfenidone, or a pharmaceutically acceptable salt thereof.

26 . The method according to claim 24 , wherein the compound, or pharmaceutically acceptable salt thereof, is administered in combination with pirfenidone, or a pharmaceutically acceptable salt thereof.

27 . A method for treatment of pulmonary fibrosis in a subject in need thereof, wherein the method comprises administering to the subject N-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide, or a pharmaceutically acceptable salt thereof, in combination with pirfenidone, or a pharmaceutically acceptable salt thereof.

Assignments (2)
PATENT SECURITY AGREEMENT Recorded Jun 25, 2026
From: IDORSIA PHARMACEUTICALS LTD
To: BIOPHARMA CREDIT PLC, AS COLLATERAL AGENT
Reel/Frame 076038/0461 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 3, 2022
From: BIRKER, MAGDALENA; LESCOP, CYRILLE
To: IDORSIA PHARMACEUTICALS LTD
Reel/Frame 060711/0773 →
Continuity (1)
Related Publication 20230000846A1 · Jan 5, 2023
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