Aryl hydrocarbon receptor antagonists and uses thereof

• US 10,351,572 B2
• Filed: 02/08/2019
• Issued: 07/16/2019
• Est. Priority Date: 04/12/2017
• Status: Active Grant

• Current Assignee: Edigene Biotechnology Incorporated
• Original Assignee: Magenta Therapeutics, Inc.
• Inventors: Romero, Arthur Glenn
• Primary Examiner(s): Shameem, Golam M
• Application Number:
  US16/271,376
• Publication Number:
  US 20190177330A1
• Time in Patent Office: 158 Days
• CPC Class Codes: A61K 2035/124 the cells being hematopoietic, bone marrow derived or blood cells
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 519/00 : Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• CPC Class Codes: C12N 2501/999 : Small molecules not provided for elsewhere
• CPC Class Codes: C12N 5/0647 : Haematopoietic stem cells; Uncommitted or multipotent progenitors
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The disclosure relates to aryl hydrocarbon receptor antagonists, such as substituted imidazopyridines and imidazopyrazines, as well as methods of expanding hematopoietic stem cells by culturing hematopoietic stem or progenitor cells in the presence of these agents. Additionally, the disclosure provides methods of treating various pathologies in a patient by administration of expanded hematopoietic stem cells. The disclosure further provides methods of synthesizing aryl hydrocarbon receptor antagonists, such as substituted imidazopyridines and imidazopyrazines, as well as kits containing aryl hydrocarbon receptor antagonists that can be used for the expansion of hematopoietic stem cells.

Claims

1. A compound represented by formula (II-f)

2. The compound of claim 1, wherein A is 1H-indol-3-yl.

3. The compound of claim 1, wherein each Z is independently selected from the group consisting of ethoxycarbonyl, methoxy, cyano, methyl, methylsulfonyl, fluoro, chloro, trifluoromethyl, ethylnyl, and cyclopropyl.

4. The compound of claim 1, wherein q is 1.

5. The compound of claim 1, wherein Z is methyl.

6. The compound of claim 1, wherein Z is cyano.

7. The compound of claim 1, wherein Z is fluoro.

8. The compound of claim 1, wherein R₅ is selected from the group consisting of isopropyl, methyl, ethyl, isobutyl, cyclohexyl, hydroxypropan-2-yl and sec-butyl.

9. The compound of claim 1, wherein R₅ is sec-butyl.

10. The compound of claim 1, wherein R₅ is (ii).

11. The compound of claim 10, wherein R₅ is (ii), n is an integer from 1 to 3, and m is an integer from 0 to 2.

12. The compound of claim 1, wherein R₅ is hydroxypropan-2-yl.

13. The compound of claim 1, wherein R₅ is 3-ethoxy-1-methylpropyl.

14. The compound of claim 1, wherein R₅ is 1-methoxy-3-butyl.

15. The compound of claim 1, wherein said compound is represented by formula (II-g)

16. The compound of claim 15, wherein A is 1H-indol-3-yl.

17. The compound of claim 15, wherein Z is methyl.

18. The compound of claim 15, wherein Z is cyano.

19. The compound of claim 15, wherein Z is fluoro.

20. The compound of claim 15, wherein R₅ is sec-butyl.

21. The compound of claim 15, wherein R₅ is (ii).

22. The compound of claim 21, wherein R₅ is (ii), n is an integer from 1 to 3, and m is an integer from 0 to 2.

23. The compound of claim 15, wherein R₅ is hydroxypropan-2-yl.

24. The compound of claim 15, wherein R₅ is 3-ethoxy-1-methylpropyl.

25. The compound of claim 15, wherein R₅ is 1-methoxy-3-butyl.

26. The compound of claim 1, wherein said compound is selected from the group consisting of

27. The compound of claim 1, wherein said compound is selected from the group consisting of

28. The compound of claim 1, wherein said compound is selected from the group consisting of