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EP-4739694-A2 - MACROCYCLIC COMPOUNDS AND USE AS TYK2 INHIBITORS

EP4739694A2EP 4739694 A2EP4739694 A2EP 4739694A2EP-4739694-A2

Abstract

The present disclosure relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat disease, such as autoimmune disease or an inflammatory disease.

Inventors

  • CUI, JINGRONG JEAN
  • RUI, EUGENE YUANJIN
  • ROGERS, EVAN, W.
  • ZHAI, DAYONG

Assignees

  • Blossomhill Therapeutics, Inc.

Dates

Publication Date
20260513
Application Date
20240702

Claims (20)

  1. 1. A compound of the formula I, or a pharmaceutically acceptable salt thereof, wherein X is -O- or -NR 5 -; R 1 and R 1a are each independently H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10- -P(O)NR a R b , -P(O) 2 NR a R b , -P(O)OR a , -P(0)20R a , -CN, or -NO 2 , wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -P(0)20R e , -CN, orNO 2 ; R 2 is H, deuterium, C 1 -C 6 alkyl, or -OC 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl and -OC 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S^NRRf, -S(O> 2 NR e R f , -NRR f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(0) 2 R f , -NR'SfOJNRRf, -NR^CO^NRRf, -C(O)R e , C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(0) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 ; each of R 2a , R 5 , R 8 , R 9 , and R 11 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C2- Cs alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaiyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OSfOJNR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 ; each of R 3 , R 4 , R 3a , R 4a , R 3b , and R 4b is independently H, deuterium, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -OR e , -OC(O)R e , -OC(O)NR c R d , -OC(=N)NR c R d , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR°R d , -OS(O) 2 NR c R d , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR c R d , -S(O) 2 NR c R d , -NR c R d , -NR c C(O)R d , -N(C(O)R c )(C(O)R d ), -NR c C(O)OR d -NR c C(O)NR°R d , -NR c C(=N)NR c R d , -NR c S(O)R d , -NR c S(O) 2 R d , -NR c S(O)NR c R d , -NR c S(O) 2 NR c R d , -C(O)R e , C(O)OR e , -C(O)NR c R d , -C(=N)NR c R d , -PR c R d , -P(O)R°R d , -P(O) 2 R c R d , -P(O)NR=R d , -P(O) 2 NR c R d , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 ; wherein each hydrogen atom in Cj-Cs alkyl, Cz-C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , - OC(O)NR e R, f -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(0)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR’R 1 , -P^R^, -P(O) 2 R e R f , P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO2; each of R 6 , R 6a , and R 7 is independently H, deuterium, halogen, or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e , f -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R 1 , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f -P(O> 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 ; R 10 is hydrogen or deuterium; and each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkyl-C 6 -C 10 aiyl, and 5- to 10-membered heteroaryl; provided that when X is -O-, then R 2 is: deuterium; C 1 -C 6 alkyl, wherein at least one hydrogen atom is substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR e R f -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(0) 2 R^, -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 ; or -OC 1 -C 6 alkyl, wherein each hydrogen atom in -OC 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or -NO 2 .
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is O.
  3. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 is deuterium.
  4. 4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 6 alkyl, wherein at least one hydrogen atom is optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , --OC(O)NR e R, f -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(0) 2 R f , -NR e S(O)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O) 2 R e R f , -P(O)NR e R f , -P(O) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO 2 .
  5. 5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 is OC 1 -C 6 alkyl, wherein each hydrogen atom in -OC 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P^OR e , -CN, or -NO 2 .
  6. 6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is -NR 3 -.
  7. 7. The compound of any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein R 2 is H.
  8. 8. The compound any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein R 2 is deuterium.
  9. 9. The compound any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P(0) 2 OR e , -CN, or -NO 2 .
  10. 10. The compound any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein R 2 is -OC 1 -C 6 alkyl, wherein each hydrogen atom in -OC 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -P(O)OR e , -P(0) 2 OR e , -CN, or -NO 2 .
  11. 11. The compound of any one of claims 1, 2, 5, 6, or 10, or a pharmaceutically acceptable salt thereof, wherein R 2 is unsubstituted -OC 1 -C 6 alkyl.
  12. 12. The compound of any one of claims 1, 2, 5, 6, 10, or 11, or a pharmaceutically acceptable salt thereof, wherein R 2 is -OCH 3 , -OCH2CH3, or -OCH2(CH3)2.
  13. 13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 1 is H, halogen, or C 1 -C 6 alkyl.
  14. 14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 1 is H, deuterium, fluoro, or methyl.
  15. 15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R ,a is H or deuterium.
  16. 16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 2a is C 1 -C 6 alkyl.
  17. 17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 2a is methyl.
  18. 18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein one of R 3 , R 4 , R 3a , R 4a , R 3b , or R* is C 1 -C 6 alkyl wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR e , -OC(O)R e , --OC(O)NR e R, f -OS(O)R e , -OS(O) 2 R e , -OS(O)NR e R f , -OS(O) 2 NR e R f , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR e R f , -S(O) 2 NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O) 2 R f , -NR e S(0)NR e R f , -NR e S(O) 2 NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P^RT^, -P(O) 2 R e R f , -P(O)NR e R f , -P(0) 2 NR e R f , -P(O)OR e , -P(O) 2 OR e , -CN, or -NO2, and the remaining of R 3 , R 4 , R 3a , R 48 , R 3b , and R 4b are each H.
  19. 19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3a is C 1 -C 6 alkyl.
  20. 20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3a is methyl.

Description

MACROCYCLIC COMPOUNDS AND USE AS TYK2 INHIBITORS RELATED APPLICATIONS [001] This application claims the benefit of U.S. Provisional Application No. 63/524,781, filed July 3, 2023, the entire disclosure of which are incorporated herein by reference. TECHNICAL FIELD [002] The present disclosure relates to macrocyclic compounds, pharmaceutical compositions containing macrocyclic compounds, and methods of using macrocyclic compounds to treat disease, such as human autoimmune diseases or inflammatory diseases. BACKGROUND [003] Protein kinases are tightly regulated signaling proteins that orchestrate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning G, et al The protein kinase complement of the human genome. Science. 2002, 298:1912-34). Dysregulation of kinase activity is associated with many diseases, including autoimmune diseases, and cardiovascular, degenerative, immunological, infectious, inflammatory, and metabolic diseases (Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res. 2003, 36:462-469). The molecular bases leading to various diseases include kinase gain- and loss-of-function mutations, gene amplifications and deletions, splicing changes, and translocations (Wilson LJ, et al New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Autoimmune disease Res. 2018, 78:15-29). The critical role of kinases in autoimmune disease and other diseases makes them attractive targets for drug inventions with 52 small molecule kinase inhibitors have been approved and 46 of them for autoimmune disease targeted therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2020 Update. Pharmacol Res 2020, 152:104609). Cytokine signaling is essential for cell growth, hematopoiesis, and immune system function. Cytokine-mediated receptor dimerization induces intracellular activation of receptor-bound Janus kinases (JAKs), which then induce downstream transcriptional responses. The Janus Kinase Signal Transducer and Activator of Transcription (JAK-STAT) pathway plays a significant role in both normal and pathological states of immune-mediated inflammatory diseases (O’Shea JJ, et al The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015, 66:311-28). Targeting JAK-associated pathways by JAK inhibitors has achieved clinical success for a wide array of diseases, including ruxolitinib and fedratinib for myeloproliferative neoplasms, and tofacitinib, upadacitinib, and baricitinib for rheumatoid arthritis and other immune-mediated inflammatory disease (McLoman DP, et al Lancet. 2021, 398:803-816). However, it is challenging to achieve isoform selective JAK inhibitors and almost all these approved kinase domain ATP competitive JAK inhibitors display significant undesirable adverse effects due to inhibition of multiple JAK family members. The JAK kinases are large multidomain protein including the PER domain [JH6- JH7] and the SH2 domain [JH3-JH5], both mediating receptor interactions, the pseudokinase domain [JH2] with regulatory function, and the kinase catalytic domain [JH1] (Ganido-Trigo A and Salas, A., Journal of Crohn's and Colitis, 2020, S713-S724). The pseudokinase domain regulates the kinase domain by steric inhibition of ATP binding and/or a reduction in flexibility of the kinase active site required for catalysis (Patrick J, et al PNAS 2014 111: 8025-8030). Although JAK family members have high sequence homology within the catalytic domains, the distinguishing pseudokinase domain (JH2) in the JAK family could provide an ideal “allosteric” site for the development of highly selective JAK inhibitors. TYK2, a member of JAK family, play important role in regulating the signaling of a wide range of proinflammatory cytokines including IL12, IL23, and type 1 interferons (IFNa). A highly selective TYK2 inhibitor is needed for an optimal benefit-safety balance for the treatment of human autoimmune diseases including multiple sclerosis, Crohn’s disease, psoriasis, etc. (Leitner, N. R., et al Tyrosine kinase 2- surveillant of tumours and bona fide oncogene. Cytokine 2017, 89, 209-218). [004] Therefore, the discoveiy and development of highly selective inhibitors of the JAK family, such as TYK2 inhibitors targeting the TYK2 JH2 pseudokinase domain represents a new therapeutic invention for the treatment of human autoimmune diseases including multiple sclerosis, Crohn’s disease, psoriasis, and the like. SUMMARY [005] In one aspect, the disclosure relates to a compound of the formula I or a pharmaceutically acceptable salt thereof, I [006] wherein [007] X is -O- or -NR5-; [008] R1 and R1a are each independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 8-membered heterocycloalkyl, C6-C10 aiyl, 5- to 10-