IP Library › Granted Patent US 12,378,200

Granted Patent B2

US 12,378,200 · App. 18/232,198 · Granted Aug 5, 2025

Oxopyridine derivatives useful as aminocarboxymuconate semialdehyde decarboxylase (ACMSD) inhibitors

Inventors: Taisuke Takahashi (Tsukuba, JP); Nan Ji (Arlington, MA)

Assignee: OrsoBio, Inc.

C07D213/85 C07D401/04 C07D401/12

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 12,378,200
App. No.: 18/232,198
Granted: Aug 5, 2025
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention is related to a compound represented by the following structural formula: The present invention is also related a method of treating a subject with a disease which can be ameliorated by inhibition of aminocarboxymuconate semialdehyde decarboxylase (ACMSD).

Claims (116)

1. A method of treating acute kidney injury in a subject comprising administering to the subject in need thereof an effective amount of a compound of structural formula

or a pharmaceutically acceptable salt thereof wherein:

R 1 is —H, —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN;

R 2 is -halo, (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, monocyclic heteroaryl, —CN, —NO 2 , —OR c , —NR a R b , S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R b , wherein:

the (C 1 -C 5 )alkyl group represented by R 2 is optionally substituted with —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , —C(═O)R a , (C 3 -C 6 )cycloalkyl, monocyclic heteroaryl, or phenyl, wherein the (C 3 -C 6 )cycloalkyl, monocyclic heteroaryl and phenyl substituents on the (C 1 -C 5 )alkyl group represented by R 2 are optionally and independently substituted with —CH 3 , halomethyl, halo, methoxy or halomethoxy;

the (C 3 -C 6 )cycloalkyl, phenyl and monocyclic heteroaryl groups represented by R 2 are optionally and independently substituted with (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, halo, —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R a ;

each R a and each R b are independently selected from —H and (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R a or R b is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

R c is —H, halo(C 1 -C 5 )alkyl, or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R c is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

each i is independently 0, 1, or 2;

each R 3 is independently —H, —CH 3 , or F;

A is absent, —CH 2 —, a phenylene group or a pyridylene group, wherein the phenylene group and the pyridylene group represented by A are optionally and independently substituted with 1 or 2 groups represented by R 4 ;

each R 4 is independently —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN; and

B is —COOH or tetrazolyl.

2. The method of claim 1 , wherein the compound is represented by the following structural formula:

3. The method of claim 1 , wherein the compound is represented by the following structural formula:

4. The method of claim 1 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.

5. The method of claim 1 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.

6. The method of claim 1 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1.

7. The method of claim 1 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1.

8. The method of claim 1 , wherein R 2 is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, furanyl, pyrimidyl, pyridyl, benzyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 —, or pyrimidyl-CH 2 —, wherein i) the (C 1 -C 5 )alkyl represented by R 2 is optionally substituted with halo, (C 1 -C 5 )alkoxy, or (C 3 -C 6 )cycloalkyl; ii) the phenyl or benzyl group represented by R 2 is optionally and independently substituted with —CH 3 , halomethyl, —OCH 3 , halomethoxy, or —CN; and iii) the thienyl, furanyl, pyridyl, pyrimidyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 —, or pyrimidyl-CH 2 — group represented by R 2 is optionally and independently substituted with —CH 3 .

9. The method of claim 1 , wherein:

R 1 is —H, —CH 3 , —OCH 3 , —F, —C 1 , or —CN;

R 2 is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, pyridyl, or benzyl, wherein the (C 1 -C 5 )alkyl represented by R 2 is optionally substituted with halo, (C 1 -C 5 )alkoxy, or (C 3 -C 6 )cycloalkyl; the phenyl or benzyl group represented by R 2 is optionally and independently substituted with —CH 3 ;

R 3 is —H, —F, or —CH 3 ; and

R 4 is —F, —C—, —CH 3 , or methoxy.

10. A method of treating acute kidney injury in a subject comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of structural formula

or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent wherein:

R 1 is —H, —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN;

R c is —H, halo(C 1 -C 5 )alkyl, or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R c is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

each i is independently 0, 1, or 2;

each R 3 is independently —H, —CH 3 , or F;

each R 4 is independently —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN; and

B is —COOH or tetrazolyl.

11. The method of claim 10 , wherein the compound is represented by the following structural formula:

12. The method of claim 10 , wherein the compound is represented by the following structural formula:

13. The method of claim 10 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.

14. The method of claim 10 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.

15. The method of claim 10 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1.

16. The method of claim 10 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1.

17. The method of claim 10 , wherein R 2 is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, furanyl, pyrimidyl, pyridyl, benzyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 —, or pyrimidyl-CH 2 —, wherein i) the (C 1 -C 5 )alkyl represented by R 2 is optionally substituted with halo, (C 1 -C 5 )alkoxy, or (C 3 -C 6 )cycloalkyl; ii) the phenyl or benzyl group represented by R 2 is optionally and independently substituted with —CH 3 , halomethyl, —OCH 3 , halomethoxy, or —CN; and iii) the thienyl, furanyl, pyridyl, pyrimidyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 —, or pyrimidyl-CH 2 — group represented by R 2 is optionally and independently substituted with —CH 3 .

18. The method of claim 10 , wherein:

R 1 is —H, —CH 3 , —OCH 3 , —F, —Cl, or —CN;

R 3 is —H, —F, or —CH 3 ; and

R 4 is —F, —C—, —CH 3 , or methoxy.

19. A method of treating non-alcoholic fatty liver disease in a subject comprising administering to the subject in need thereof an effective amount of a compound of structural formula

or a pharmaceutically acceptable salt thereof wherein:

R 1 is —H, —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN;

R c is —H, halo(C 1 -C 5 )alkyl, or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R c is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

each i is independently 0, 1, or 2;

each R 3 is independently —H, —CH 3 , or F;

each R 4 is independently —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN; and

B is —COOH or tetrazolyl.

20. The method of claim 19 , wherein the compound is represented by the following structural formula:

21. The method of claim 19 , wherein the compound is represented by the following structural formula:

22. The method of claim 19 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.

23. The method of claim 19 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.

24. The method of claim 19 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1.

25. The method of claim 19 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1.

26. The method of claim 19 , wherein R 2 is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, furanyl, pyrimidyl, pyridyl, benzyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 —, or pyrimidyl-CH 2 —, wherein i) the (C 1 -C 5 )alkyl represented by R 2 is optionally substituted with halo, (C 1 -C 5 )alkoxy, or (C 3 -C 6 )cycloalkyl; ii) the phenyl or benzyl group represented by R 2 is optionally and independently substituted with —CH 3 , halomethyl, —OCH 3 , halomethoxy, or —CN; and iii) the thienyl, furanyl, pyridyl, pyrimidyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 —, or pyrimidyl-CH 2 — group represented by R 2 is optionally and independently substituted with —CH 3 .

27. The method of claim 19 , wherein:

R 1 is —H, —CH 3 , —OCH 3 , —F, —C 1 , or —CN;

R 3 is —H, —F, or —CH 3 ; and

R 4 is —F, —C—, —CH 3 , or methoxy.

28. A method of treating non-alcoholic fatty liver disease in a subject comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of structural formula

or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent wherein:

R 1 is —H, —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN;

the (C 3 -C 6 )cycloalkyl, phenyl and monocyclic heteroaryl groups represented by R 2 are optionally and independently substituted with (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, halo, —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR, —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R a ;

R c is —H, halo(C 1 -C 5 )alkyl, or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R c is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

each i is independently 0, 1, or 2;

each R 3 is independently —H, —CH 3 , or F;

each R 4 is independently —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN; and

B is —COOH or tetrazolyl.

29. The method of claim 19 , wherein the compound is represented by the following structural formula:

30. The method of claim 28 , wherein the compound is represented by the following structural formula:

31. The method of claim 28 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.

32. The method of claim 28 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.

33. The method of claim 28 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1.

34. The method of claim 28 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1.

35. The method of claim 28 , wherein R 2 is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, furanyl, pyrimidyl, pyridyl, benzyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 —, or pyrimidyl-CH 2 —, wherein i) the (C 1 -C 5 )alkyl represented by R 2 is optionally substituted with halo, (C 1 -C 5 )alkoxy, or (C 3 -C 6 )cycloalkyl; ii) the phenyl or benzyl group represented by R 2 is optionally and independently substituted with —CH 3 , halomethyl, —OCH 3 , halomethoxy, or —CN; and iii) the thienyl, furanyl, pyridyl, pyrimidyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 —, or pyrimidyl-CH 2 — group represented by R 2 is optionally and independently substituted with —CH 3 .

36. The method of claim 28 , wherein:

R 1 is —H, —CH 3 , —OCH 3 , —F, —Cl, or —CN;

R 3 is —H, —F, or —CH 3 ; and

R 4 is —F, —C—, —CH 3 , or methoxy.

Assignments (5)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 3, 2024

From: JI, NAN

To: MITOBRIDGE, INC.

Reel/Frame 066992/0761 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 3, 2024

From: TAKAHASHI, TAISUKE

To: ASTELLAS PHARMA INC.

Reel/Frame 066992/0845 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 3, 2024

From: ASTELLAS PHARMA INC.

To: MITOBRIDGE, INC.

Reel/Frame 066993/0354 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 3, 2024

From: MITOBRIDGE, INC.

To: THE LIVER COMPANY

Reel/Frame 066993/0406 →

CHANGE OF NAME Recorded Apr 3, 2024

From: THE LIVER COMPANY INC.

To: ORSOBIO INC.

Reel/Frame 068390/0989 →

Continuity (4)

Division 17119343 · Dec 11, 2020

Continuation 16473474

Provisional Application 62440601 · Dec 30, 2016

Related Publication 20240059657A1 · Feb 22, 2024

References Cited (17)

Yang, Y.; Sauve, A. A. “NAD+ metabolism: bioenergetics, signaling and manipulation for therapy.” Biochim. Biophys. Acta, Proteins Proteomics 2016, 1864, 1787-1800. [cited by examiner]

Katsyuba “De novo NAD+ synthesis enhances mitochondrial function and improves health” Nature 2018, vol. 563, p. 354-359. [cited by examiner]

Vickers “The utility of animal models to evaluate novel anti-obesity agents” British Journal of Pharmacology (2011) 164 1248-1262. [cited by examiner]

Lutz “Overview of Animal Models of Obesity” Curr Protoc Pharmacol. Sep. 2012 ; Chapter: Unit 5.61. 1-22. [cited by examiner]

Bae, Cancer Targeted Drug Delivery, Springer: New York, 2013, p. v. [cited by examiner]

Hayat, M.A. Autophagy Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging vol. 5 Academic Press: Sand Diego, 2015. [cited by examiner]

Carlo C. Maley and Mel Greaves Frontiers in Cancer Research Springer: 2016, pp. 18-19. [cited by examiner]

Damia “Contemporary pre-clinical development of anticancer agents—What are the optimal preclinical models?” European Journal of Cancer 2009, 45, 2768-2781. [cited by examiner]

Sharma “Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents” Nature Reviews Cancer Apr. 2010, vol. 10, 241-253. [cited by examiner]

Ocana, A. “Preclinical development of molecular targeted agents for cancer” Nat. Rev. Clin. Oncol. 2011, 8, 200-209. [cited by examiner]

Johnson, et al. “Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials.” British Journal of Cancer 2001, 84, 1424-1431. [cited by examiner]

Badawy “Tryptophan metabolism and disposition in cancer biology and immunotherapy” Bioscience Reports (2022), 42, 1-22. [cited by examiner]

K. Thirtamara-Rajamani et al. “Is the Enzyme ACMSD a Novel Therapeutic Target in PD?” Journal of Parkinson's Disease 7 (2017) 577-587. [cited by examiner]

C. Lutz “Mouse models of ALS: Past, present and future” Brain Research 1693 (2018) 1-10. [cited by examiner]

Petrov “ALS Clinical Trials Review: 20 Years of Failure. Are we any Closer to Registering a New Treatment?” Frontiers in Aging Neuroscience Mar. 2017 | vol. 9 | Article 68, 1-11. [cited by examiner]

Cernak, M.; Nogova, L. “Current antiangiogenic agents in oncology and ophthalmology” Neoplasma (2016), 63(1), 10-17. [cited by examiner]

Adams “The Kynurenine Pathway in Brain Tumor Pathogenesis” Cancer Res (2012) 72 (22): 5649-5657. [cited by examiner]