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KR-20260065743-A - TYK2 inhibitor

KR20260065743AKR 20260065743 AKR20260065743 AKR 20260065743AKR-20260065743-A

Abstract

In exemplary embodiments, a tyrosine kinase 2 inhibitor (TYK2), a pharmaceutical formulation comprising these compounds, and a method of using these compounds to inhibit tyrosine kinase 2 and treat diseases such as autoimmune diseases and inflammatory diseases are provided.

Inventors

  • 모르테자에이, 샤합

Assignees

  • 뉴메리온 랩스 인코포레이티드

Dates

Publication Date
20260511
Application Date
20240603
Priority Date
20230602

Claims (20)

  1. Compound of chemical formula I: In the above formula, X 1 is selected from N and CR 1 , and R1 is a member selected from H, a halogen, a substituted or unsubstituted straight-chain or branched-chain C1 - C6 alkyl, and a substituted or unsubstituted straight-chain or branched-chain C1 - C6 alkoxy; X and X2 are independently selected from N and CH; R 2 is a member selected from the following, and Here, R5 is a C1 - C6 alkyl; R 5' , R 6 , and R 6' are members independently selected from H and C 1 -C 6 alkyls; X 3 is selected from N and CR 7 ; X 4 is selected from N and CR 8 ; X 5 is selected from N and CR 9 ; R7 , R8 , R9 , and R10 are independently selected from H, substituted or unsubstituted C1 - C6 alkyl, and substituted or unsubstituted C1 - C6 aminoalkyl, and R7 and R8 or R8 and R9 are optionally connected with the carbon atoms to which they are bonded to form a ring selected from substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl, and Here, When R7 and R8 and R8 and R9 are not connected with the carbon to which they are attached to form a ring, one or fewer members selected from R7 , R8 , and R9 are not H; R 9 does not include the following moiety Here, z is 0 or 1 and; When at least one member selected from R7 , R8 , and R9 is Me, R2 is lim.
  2. In paragraph 1, the compound, wherein X3 , X4 , and X5 are CR7 , CR8 , and CR9 , respectively.
  3. A compound according to claim 1 or 2, wherein at least one of CR 7 , CR 8 , and CR 9 comprises a ring system selected from a monocyclic or dicyclic ring system having one or two heteroatoms and four, five, six, or seven carbon atoms.
  4. In paragraph 3, the above-mentioned ring system is a compound comprising oxygen and nitrogen.
  5. In any one of paragraphs 1 through 4, R7 , R8 , and R9 are independently H, Compound selected from: in the above formula, One or more carbon atoms of the ring in Formula II or Formula III are optionally substituted with a halogen and a member independently selected from substituted or unsubstituted alkyls; a is selected from integers 0 and 1; R 10 and R 11 are independently selected from H, halogens, and substituted or unsubstituted C 1 -C 6 alkyls; c and d are independently selected from integers 0, 1, 2, 3, and 4, and the sum c+d is selected from integers 3, 4, 5, and 6; A is a ring system selected from substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl; X 6 is selected from O, NR 12 and CR 12 R 13 ; R 12 and R 13 are independently selected from H and substituted or unsubstituted alkyls.
  6. In any one of claims 1 to 5, a compound according to Formula IV: In the above formula, Ring group B is a cycloalkyl substituted with at least one moiety selected from Formula II and Formula III.
  7. In paragraph 6, cyclic group B is a compound selected from substituted or unsubstituted cyclopentylamine and substituted or unsubstituted cyclohexylamine.
  8. In any one of claims 1 to 7, R7 , R8 , and R9 are compounds independently selected from the following:
  9. A compound according to any one of claims 1 to 8, wherein R 2 is S(O) 2 Me.
  10. A compound according to any one of claims 1 to 9, wherein X is N; X 1 and X 2 are CH; and X 3 and X 4 are CR 7 and CR 8 , respectively.
  11. In any one of claims 1 to 10, a compound according to chemical formula V: .
  12. Compound according to chemical formula VI: In the above formula, X is selected from N and CH; R 2 is selected from the following and Here, R5 is a C1 - C6 alkyl; R 5' , R 6 , and R 6' are members independently selected from H and C 1 -C 6 alkyls; X 3 and X 4 are CR 7 and CR 8 , respectively; Here, R 7 and R 8 are independently selected from H and below, and Here, One or more carbon atoms of the ring in Formula II or Formula III are optionally substituted with a halogen and a member independently selected from substituted or unsubstituted alkyls; a is selected from integers 0 and 1; R 10 and R 11 are independently selected from H, halogens, and substituted or unsubstituted C 1 -C 6 alkyls; c and d are independently selected from integers 0, 1, 2, 3, and 4, and the sum c+d is selected from integers 3, 4, 5, and 6; A is a ring system selected from substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl; X 6 is selected from O, NR 12 and CR 12 R 13 ; R 12 and R 13 are independently selected from H and substituted or unsubstituted alkyls.
  13. In paragraph 12, a compound in which one of R 10 or R 11 is CF 3 .
  14. A compound according to any one of paragraphs 1 to 13, wherein R1 is F.
  15. In paragraph 12, R 9 is a compound that does not include the following moiety: In the above formula, z is selected from 0 and 1.
  16. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for the manufacture of a drug for the treatment or prevention of a TYK2-mediated disease or condition in subjects requiring treatment or prevention.
  17. A pharmaceutical formulation comprising a compound of any one of claims 1 to 15, a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier.
  18. A pharmaceutical formulation comprising a compound of any one of claims 1 to 15, a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof, and a pharmaceutically acceptable carrier, wherein the formulation is formulated for parenteral or oral administration.
  19. A pharmaceutical formulation comprising a compound of any one of claims 1 to 15, a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier, wherein the formulation is formulated for intravenous, subcutaneous or intraperitoneal injection.
  20. A method for treating a subject requiring treatment for a TYK2-mediated disease, comprising the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the autoimmune disease is susceptible to treatment with a TYK2 inhibitor.

Description

TYK2 inhibitor Cross-reference of related applications This U.S. patent application claims priority to Provisional Patent Application No. 63/505,969 filed June 2, 2023 and Provisional Patent Application No. 63/618,980 filed January 9, 2024, the entire contents of which are incorporated herein by way of all purposes. Technology field The present invention relates to potent and selective small molecule inhibitors of tyrosine kinase 2 (TYK2), pharmaceutical formulations containing these compounds, and methods of using these compounds to treat or prevent diseases involving TYK2. TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. Cytokines involved in TYK2 activation include interferons and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, L-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotropin 1, cardiotropin-like cytokines, and LIF). Activated TYK2 subsequently phosphorylates additional signaling proteins, such as members of the STAT family including STAT1, STAT2, STAT4, and STAT6. These cytokines are involved in the pathogenesis of numerous autoimmune diseases, such as psoriasis, inflammatory bowel disease (IBD), and lupus. Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transmit cytokine signals from membrane receptors to STAT transcription factors. Four members of the JAK family—JAK1, JAK2, JAK3, and TYK2—are recognized. When a cytokine binds to its receptor, the JAK family members undergo mutual autophosphorylation and/or transphosphorylation, and after STAT is phosphorylated, they translocate into the nucleus to regulate transcription. Intracellular JAK-STAT signaling is applicable to interferons, most interleukins, and various cytokines and endocrine factors, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, and PRL. TYK2 is important for the signaling of type I interferons (IFNa, INFb), IL-6, IL-10, IL-12, and IL-23. Therefore, TYK2 signals with other members of the JAK kinase family in combinations such as TYK2/JAK1, TYK2/JAK2, and TYK2/JAK1/JAK2. TYK2 has demonstrated importance in the differentiation and function of numerous cell types critical to inflammatory and autoimmune diseases, including natural killer cells and B and T helper cell types. Certain autoimmune diseases are believed to be mediated by TYK2 signaling of certain pro-inflammatory cytokines (e.g., see [JS Tokarski, et al., J. Biol. Chem ., vol. 290(17):11061-11074 (2015)]; and see [L. Marroqui, et al., Diabetes , vol. 64: 3808-3817 (2015)]). Other autoimmune diseases, such as psoriasis and diabetes, are believed to be mediated by TYK2 signaling of certain pro-inflammatory cytokines. TYK2 is implicated as a therapeutic target for psoriasis-like skin inflammation (Ishizaki, et al., Int Immunol . 2014 26(5):257-67]), psoriatic arthritis (Mease et al., Ann Rheum Dis . 2022 81(6):815-822]), and inflammatory bowel disease (IBD) (Nielsen, et al., Trends Pharmacol Sci. 2022 43(5):424-436]). TYK2 mediates signaling through IL-12 family receptors (IL-12R and IL23R). Interleukin-23 (IL-23) cytokines have been shown to play a crucial role in the pathogenesis of autoimmune inflammation and related diseases and disorders such as multiple sclerosis, asthma, rheumatoid arthritis, psoriasis, and inflammatory bowel diseases (IBD) like ulcerative colitis and Crohn's disease. Studies in acute and chronic mouse IBD models have revealed the key roles of IL-23R and downstream effector cytokines in the pathogenesis of the disease. IL-12 and IL-23, containing the subunits p40/p35 and p40/p19, respectively, signal through receptor complexes of IL-12Rβ1/IL-12Rβ2 and IL-12Rβ1/IL-23R, respectively. IL-12 is essential for the differentiation of IFN-γ-producing T helper (Th) 1 cells and the development of the TH1 immune response, whereas IL-23 maintains the survival, expansion, and effector function of Th17 cells. Activated Th17 cells produce various effector cytokines, including IL-17A and IL17F. Inhibiting the IL-23 pathway has been shown to be effective in treating IL-23-related diseases and disorders. Numerous antibodies binding to IL-23 or IL-23R have been approved for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, moderate to severe active Crohn's disease, and moderate to severe active ulcerative colitis. Clinical trials in Crohn's disease or psoriasis with briakinumab (which also targets the common p40 subunit) and tildrakizumab, guselkumab, MEDI2070, and BI-655066 (which target the unique p19 subunit of IL-23) highlight the potential of IL-23 signaling blockade in the treatment of human inflamm