Search

US-12624018-B1 - Inhibitors of RIPK2 and medical uses thereof

US12624018B1US 12624018 B1US12624018 B1US 12624018B1US-12624018-B1

Abstract

The present disclosure relates to RIPK2 inhibitors represented by structural formula (I): The disclosure further relates to pharmaceutical composition comprising the RIPK2 inhibitors and methods of treatment of conditions such as inflammatory diseases, autoimmune diseases, granulomatous disease, neurodegenerative disease, and cancer.

Inventors

  • Chad VANHUIS
  • Shifeng Pan
  • Dominik K. KOELMEL
  • Robert AVERSA
  • Clarke Taylor
  • Marta WLODARSKA

Assignees

  • ODYSSEY THERAPEUTICS, INC.

Dates

Publication Date
20260512
Application Date
20250902

Claims (11)

  1. 1 . A compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof.
  2. 2 . The compound of claim 1 , wherein the compound is an HCl salt of the compound represented by the following structural formula:
  3. 3 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  4. 4 . A method of treating inflammatory bowel disease (IBD), comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof.
  5. 5 . The method of claim 4 , wherein the compound is an HCl salt of the compound represented by the following structural formula:
  6. 6 . The method of claim 4 , wherein the IBD is selected from ulcerative colitis, Crohn's disease, early-onset IBD, and extraintestinal IBD.
  7. 7 . The method of claim 4 , wherein the IBD is ulcerative colitis.
  8. 8 . The method of claim 4 , further comprising administering a therapeutically effective amount of an anti-integrin agent.
  9. 9 . The method of claim 8 , wherein the anti-integrin agent is vedolizumab.
  10. 10 . The method of claim 4 , further comprising administering a therapeutically effective amount of a Janus kinase (JAK) inhibitor.
  11. 11 . The method of claim 10 , wherein the JAK inhibitor is tofacitinib.

Description

RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 19/131,704, filed May 21, 2025, which is the U.S. National Stage of International Application No. PCT/US2023/080859, filed Nov. 22, 2023, which claims the benefit of priority to U.S. Provisional Patent Application No. 63/544,884, filed Oct. 19, 2023; U.S. Provisional Patent Application No. 63/468,591, filed May 24, 2023; U.S. Provisional Patent Application No. 63/443,760, filed Feb. 7, 2023; and U.S. Provisional Patent Application No. 63/427,317, filed Nov. 22, 2022. The entire teachings of the above applications are incorporated herein by reference. BACKGROUND OF THE INVENTION Autoinflammatory disorders are diseases characterized by systemic and organ-specific inflammation due to abnormalities in the innate immune system. These abnormalities are associated with numerous inflammatory disorders such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), sarcoidosis, inflammatory arthritis, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener's granulomatosis. These disorders affect millions of people. NOD1 and NOD2 (nucleotide-binding oligomerization domains 1 and 2) are members of the NOD-like receptor (NLR) family, which represent important components of the mammalian innate immune system, serving as intracellular receptors for peptidoglycan (PGN), a component of bacterial cell walls. NOD1 and NOD2 detect the presence of intracellular bacteria by binding to PGN fragments. Heredity polymorphisms in the genes encoding NOD1 and NOD2 have been associated with inflammatory disorders. Once activated, NOD signaling leads to activation of NF-kB and MAP kinases, resulting in the transcription of pro-inflammatory kinases and the induction of autophagy. NOD1 and NOD2 require RIPK2 as a common scaffolding (adaptor) protein to propagate downstream signals that lead to aberrant proinflammatory innate immune activation. In particular, RIPK2 is needed for NF-kB activation and subsequent cytokine production. Inhibition of RIPK2 resolves abnormal inflammation states such as intestinal inflammation. Accordingly, inhibitors of RIPK2 have potential to act as therapeutic agents, for example, to reduce or resolve inflammation for inflammatory disorders such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), sarcoidosis, inflammatory arthritis, peritonitis, multiple sclerosis, rheumatoid arthritis, and Wegener's granulomatosis. In the context of malignant transformation, knockdown of RIPK2 downregulated RNA expression of E-cadherin and vimentin, proteins involved in epithelial-to-mesenchymal transition (EMT) and the promotion of the metastatic phenotype indicating that RIPK2 is involved in cell migration and metastasis. Accordingly inhibitors of RIPK2 activity which can block RIPK2-dependent pro-inflammatory signaling and thereby provide a therapeutic benefit in auto-inflammatory diseases and other disorders characterized by increased and/or dysregulated RIPK2 activity are needed. A description of example embodiments of the invention follows. SUMMARY OF THE INVENTION In a first embodiment, the present invention relates a compound represented by structural formula (I): or a pharmaceutically acceptable salt thereof: wherein: R1a, R1b, and R1c are each independently selected from H, halogen, CN, and C1-6 alkyl;R2 is H or C1-3 alkyl;R3 is selected from halogen, 4- to 10-membered heterocyclyl, 5-12 membered heteroaryl, S(═O)2R5, S(═O)(═NR6)(R7), QR7, C(═O)NR8R9, NH(C═O)R5, CN, NR8R9, P(═O)R8aR9a;R4 is selected from H, halogen, C1-6 alkyl, and C1-6 alkoxy;R5 is selected from NR10R11, C1-6 alkyl, C3-6 cycloalkyl, and 4- to 10-membered heterocyclyl;R6 is selected from H, CN, and C1-6 alkyl;R7 is selected from C1-6 alkyl, C3-6 cycloalkyl, and 4- to 10-membered heterocyclyl, 5-12 membered heteroaryl, orR6 and R7 taken together with the nitrogen and sulfur atoms to which they are attached form 4- to 10-membered heterocyclyl;Q is selected from O, S, —S(═O)—, and —C(═O)—;R8 and R9 are each independently selected from H, C1-6 alkyl, C1-6 deuteroalkyl, C3-6 cycloalkyl, and 4- to 10-membered heterocyclyl, orR8 and R9 taken together with the nitrogen atom to which they are attached form 4- to 10-membered heterocyclyl;R8a and R9b are each independently C1-6 alkyl, orR8a and R9a taken together with the phosphorus atom to which they are attached form 4- to 10-membered heterocyclyl;R10 and R11 are each independently H or C1-6 alkyl, orR10 and R11 taken together with the nitrogen to which they are attached form 4- to 10-membered heterocyclyl;W is selected from O, NR2, O(C1-2 alkylene), NH(C1-2 alkylene), C1-2 alkylene, C3-6 cycloalkylene, and a bond;X is a moiety represented by one of the following structural formulas: Y1 is CH or N;Y2 and Y3 are each independently CR4 or N;U is CR12b or N;Z is CR1b or N;L, M, and J are each independently selected from N, O, or S, provided that two of L, M, and J