US-12624030-B2 - 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one derivatives and salts thereof

Abstract

The present disclosure relates to 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one variants or derivatives, and salts thereof, for use as agonists and antagonists. The disclosure further relates to compositions, methods of preparing, and methods of treatment.

Inventors

• Catherine Arabeyre
• Patricia Moliner
• Sabine BOISNARD
• Damien Sallaberry
• Serge Perard
• Sebastien Roy

Assignees

• PRINCIPIA BIOPHARMA INC.

Dates

Publication Date

20260512

Application Date

20211222

Claims (20)

1. 1 . A compound of Formula Ia: or a salt thereof, wherein the compound or salt thereof is about 90% pure.
2. 2 . The compound of claim 1 , wherein the compound or salt thereof is about 95% pure.
3. 3 . The compound of claim 1 , wherein the compound or salt thereof is about 98% pure.
4. 4 . A compound of Formula Ib: or a salt thereof, wherein the compound or salt thereof is about 90% pure.
5. 5 . The compound of claim 4 , wherein the compound or salt thereof is about 95% pure.
6. 6 . The compound of claim 4 , wherein the compound or salt thereof is about 98% pure.
7. 7 . The compound of claim 4 , the compound or salt thereof is about 99% pure.
8. 8 . A compound of Formula II or salt thereof, wherein the compound or salt thereof is about 99.6% pure.
9. 9 . The compound of claim 8 , wherein the compound is or salt thereof, wherein the compound or salt thereof is about 90% pure.
10. 10 . The compound of claim 9 , wherein the compound of Formula IIa or salt thereof is about 95% pure.
11. 11 . The compound of claim 9 , wherein the compound of Formula IIa or salt thereof is about 98% pure.
12. 12 . The compound of claim 8 , wherein the compound is or salt thereof, wherein the compound or salt thereof is about 90% pure.
13. 13 . The compound of claim 12 , wherein the compound of Formula IIb or salt thereof is about 95% pure.
14. 14 . The compound of claim 12 , wherein the compound of Formula IIb or salt thereof is about 98% pure.
15. 15 . A composition comprising a pharmaceutically acceptable excipient and at least one compound chosen from: or salts thereof.
16. 16 . The composition of claim 15 , wherein at least one compound is a compound of Formula Ia or a salt thereof, and wherein the compound of Formula Ia or a salt thereof is at least about 98% pure.
17. 17 . The composition of claim 15 , wherein at least one compound is a compound of Formula Ib or a salt thereof, and wherein the compound of Formula Ib or salt thereof is at least about 99% pure.
18. 18 . The composition of claim 15 , wherein the composition is in the form of a capsule, tablet, or pill.
19. 19 . A method of preparing the compound of Formula Ia of claim 1 or salt thereof, the method comprising reacting a compound of Formula VIa with acryloyl chloride.
20. 20 . The method of claim 19 , wherein the method further comprises preparing a compound of Formula VIa from a compound of Formula IX by acid-based deprotection.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a national phase entry pursuant to 35 U.S.C. § 371 of International Application No. PCT/US2021/064800, filed Dec. 22, 2021, which claims the benefit of priority of U.S. Provisional Application No. 63/130,010, filed Dec. 23, 2020, and U.S. Provisional Application No. 63/245,288, filed Sep. 17, 2021, the entire contents of each of which are incorporated by reference herein in their entirety. This application claims priority of U.S. Provisional Application No. 63/130,010, filed Dec. 23, 2020, and U.S. Provisional Application No. 63/245,288, filed Sep. 17, 2021. FIELD The present disclosure relates to 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one variants or derivatives, and salts thereof, for use as agonists and antagonists. The disclosure further relates to pharmaceutical compositions, methods of preparing, and methods of treatment. BACKGROUND Small molecule drugs have found utility in a wide range of diseases and conditions. Some act as antagonists by blocking or dampening a biological response. Some act as agonists by activating a biological response. Others can function as both. While many small molecule drugs are known, there is a need for new and different therapeutic agents. For example, according to National Center for Complementary and Integrative Health, about 2.5 million people world-wide, including some 400,000 people in the United States, suffer from multiple sclerosis (“MS”). While there are some drugs that are available for the treatment of MS, not everyone responds well to the available medications. Other examples of diseases or conditions where a need exists include autoimmune disorders such as lupus, pemphigus vulgaris, myasthenia gravis, Sjogren's syndrome, dry eye, multiple sclerosis, Wegener's granulomatosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Granulomatosis with Polyangiitis, or rheumatoid arthritis. The present disclosure provides compounds that are tyrosine kinase inhibitors, in particular Bruton tyrosine kinase (“BTK”) inhibitors, and are therefore useful for the treatment of diseases such as cancer, autoimmune, inflammatory, and thromboembolic diseases. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds. BTK, a member of the Tec family non-receptor tyrosine kinases, is essential for B cell signaling downstream from the B-cell receptor. It is expressed in B cells and other hematopoietic cells such as monocytes, macrophages and mast cells. It functions in various aspects of B cell function that maintain the B cell repertoire (see Gauld S. B. et al., B cell antigen receptor signaling: roles in cell development and disease. Science, 296:1641-2. 2002). B cells play a role in rheumatoid arthritis (see Perosa F., et al., CD20-depleting therapy in autoimmune diseases: from basic research to the clinic. J Intern Med. 267:260-77. 2010 and Dörner T, et al. Targeting B cells in immune-mediated inflammatory disease: a comprehensive review of mechanisms of action and identification of biomarkers. Pharmacol Ther. 125:464-75. 2010 and Honigberg, L., et. al., The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen-induced arthritis. Clin. Immunol 127 S1:S111. 2008) and in other autoimmune diseases such as systemic lupus erythematosus and cancers (see Shlomchik M. J., et. al., The role of B cells in lpr/lpr-induced autoimmunity. J. Exp Med. 180:1295-1306. 1994; Honigberg L. A., The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc. Natl. Acad. Sci. 107:13075-80. 2010; and Mina-Osorio P, et al., Suppression of glomerulonephritis in lupus-prone NZB×NZW mice by RN486, a selective inhibitor of Bruton's tyrosine kinase. Arthritis Rheum. 65: 2380-91. 2013). There is also potential for BTK inhibitors for treating allergic diseases (see Honigberg, L., et. al, The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen induced arthritis. Clin. Immunol 127 S1:S111. 2008). It was noted that the irreversible inhibitor suppresses passive cutaneous anaphylaxis (PCA) induced by IgE antigen complex in mice. These findings are in agreement with those noted with BTK-mutant mast cells and knockout mice and suggest that BTK inhibitors may be useful for the treatment of asthma, an IgE-dependent allergic disease of the airway. Accordingly, compounds that inhibit BTK would be useful in treatment for diseases such as autoimmune diseases, inflammatory diseases, and cancer. It has been surprisingly discovered that certain 4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one derivatives act as agonists, antagonists, or both on a number of receptors that are implicated in many of the diseases and disorders, including those listed above. SUMMARY Des