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US-20260125379-A1 - PRODRUG OF JAK KINASE INHIBITOR

US20260125379A1US 20260125379 A1US20260125379 A1US 20260125379A1US-20260125379-A1

Abstract

The present invention relates to a prodrug containing a JAK inhibitor, a composition, and use thereof. In particular, the present invention relates to a compound represented by formula (II), a pharmaceutical composition containing the compound of the present invention, and use thereof as a JAK inhibitor prodrug in treating inflammatory diseases and tumor-related diseases.

Inventors

  • Pengfei Liu
  • Wang Shen
  • Rujun Bai
  • Yue DING
  • Shizhe DING

Assignees

  • E-NITIATE BIOPHARMACEUTICALS (HANGZHOU) CO., LTD

Dates

Publication Date
20260507
Application Date
20230824
Priority Date
20220825

Claims (20)

  1. 1 . A compound of formula II, or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate, a metabolite or a pharmaceutically acceptable salt thereof: wherein, X is selected from the group consisting of CR a and N; W and Z are each independently selected from the group consisting of O, N, S, NR b , and CR c ; W and Z are not CR c at the same time; R 1 is selected from the group consisting of H, halogen, CN, C 1-6 -alkyl, C 1-6 -alkoxy, and C 1-6 -haloalkyl; the C 1-6 -alkyl, C 1-6 -alkoxy, and C 1-6 -haloalkyl are optionally substituted by one or more R d ; R 1 ′ is selected from the group consisting of H, halogen, amino, hydroxyl, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, and C 1-6 -haloalkoxy; L 1 is absent or a C 1-14 divalent saturated or unsaturated, linear or branched hydrocarbon group, and 1, 2, or 3 methylene groups in the hydrocarbon group are optionally and independently replaced by: —CH(R e )—, —C(R e ) 2 —, C 3-5 -cycloalkylene, —N(R e )—, —N(R e )C(═O)—, —C(═O)N(R e )—, —N(R e )S(═O) 2 —, —S(═O) 2 N(R e )—, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —S—, —S(═O)—, or —S(═O) 2 —; ring A is absent or is selected from the group consisting of C 6-14 -aryl, 5-14-membered heteroaryl, 3-14-membered heterocyclyl, and 3-14-membered carbocyclyl; the C 6-14 -aryl, 5-14-membered heteroaryl, 3-14-membered heterocyclyl, and 3-14-membered carbocyclyl are each optionally substituted by one or more R f ; L 2 is selected from the group consisting of H, OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, —C 0-6 -alkylene-NH(C 1-6 -alkyl), and —C 0-6 -alkylene-N(C 1-6 -alkyl) 2 ; the C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, —C 0-6 -alkylene-NH(C 1-6 -alkyl), and —C 0-6 -alkylene-N(C 1-6 -alkyl) 2 are optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, —CN, C 1-6 -alkyl, C 1-6 -haloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, —OR g , —NR g R h , —ONO 2 , —NO 2 , —S(═O) 2 OR g , —N═CR g R h , —COOR g , —CONHR g , —C 0-6 -alkylene-NHC(═O)R g , —C 0-6 -alkylene-C(═O)NHR g , and —C(═O)NR g R h ; R a , R b , and R c are each independently selected from the group consisting of H, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, and C 1-6 -haloalkoxy; each R d is independently selected from the group consisting of H, halogen, CN, —NO 2 , OH, NH 2 , —NH(C 1-6 -alkyl), —N(C 1-6 -alkyl) 2 , oxo, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, C 2-6 -alkynyl, —S—C 1-6 -alkyl, —S(═O)—C 1-6 -alkyl, —S(═O) 2 —C 1-6 -alkyl, —S(═O)NH 2 , —S(═O)NHC 1-6 -alkyl, —S(═O)N(C 1-6 -alkyl) 2 , —C 0-6 -alkylene-NHS(═O) 2 —C 1-6 -alkyl, —C(═O)—C 1-6 -alkyl, —C(═O)—C 2-6 -alkenyl, —C 0-6 -alkylene-C 6-14 -aryl, —C 0-6 -alkylene-5-14-membered heteroaryl, —C 0-6 -alkylene-C 3-14 -carbocyclyl, and —C 0-6 -alkylene-3-14-membered heterocyclyl; the —OH, NH 2 , —NH(C 1-6 -alkyl), —N(C 1-6 -alkyl) 2 , C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, C 2-6 -alkynyl, —S—C 1-6 -alkyl, —S(═O)—C 1-6 -alkyl, —S(═O) 2 —C 1-6 -alkyl, —S(═O)NH 2 , —S(═O)NHC 1-6 -alkyl, —S(═O)N(C 1-6 -alkyl) 2 , —C 0-6 -alkylene-NHS(═O) 2 —C 1-6 -alkyl, —C(═O)—C 1-6 -alkyl, —C(═O)—C 2-6 -alkenyl, —C 0-6 -alkylene-C 6-14 -aryl, —C 0-6 -alkylene-5-14-membered heteroaryl, —C 0-6 -alkylene-C 3-14 -carbocyclyl, and —C 0-6 -alkylene-3-14-membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of H, halogen, CN, —NO 2 , OH, NH 2 , —COOH, oxo, C 1-6 -alkyl, C 1-6 -haloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, —NH(C 1-6 -alkyl), —N(C 1-6 -alkyl) 2 , —COO(C 1-6 -alkyl), —CONH(C 1-6 -alkyl), —C 0-6 -alkylene-NHC(═O) C 1-6 -alkyl, —C 0-6 -alkylene-NHC(═O) C 1-6 -haloalkyl, —C 0-6 -alkylene-NHC(═O)C 2-6 -alkenyl, and —CON(C 1-6 -alkyl) 2 ; and R e , R f , R g , and R h are each independently selected from the group consisting of H, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, C 2-6 -alkynyl, —C 0-6 -alkylene-NHS(═O) 2 —C 1-6 -alkyl, —C(═O)—C 1-6 -alkyl, —C(═O)—C 2-6 -alkenyl, —C 0-6 -alkylene-C 6-14 -aryl, —C 0-6 -alkylene-5-14-membered heteroaryl, —C 0-6 -alkylene-C 3-14 -carbocyclyl, and —C 0-6 -alkylene-3-14-membered heterocyclyl; wherein the C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, C 2-6 -alkynyl, —C 0-6 -alkylene-NHS(═O) 2 —C 1-6 -alkyl, —C(═O)—C 1-6 -alkyl, —C(═O)—C 2-6 -alkenyl, —C 0-6 -alkylene-C 6-14 -aryl, —C 0-6 -alkylene-5-14-membered heteroaryl, —C 0-6 -alkylene-C 3-14 -carbocyclyl, and —C 0-6 -alkylene-3-14-membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of H, halogen, CN, —NO 2 , OH, NH 2 , —COOH, oxo, C 1-6 -alkyl, C 1-6 -haloalkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, —NH(C 1-6 -alkyl), —N(C 1-6 -alkyl) 2 , —COO(C 1-6 -alkyl), —CONH(C 1-6 -alkyl), —C 0-6 -alkylene-NHC(═O) C 1-6 -alkyl, —C 0-6 -alkylene-NHC(═O) C 1-6 -haloalkyl, —C 0-6 -alkylene-NHC(═O) C 2-6 -alkenyl, and —CON(C 1-6 -alkyl) 2 .
  2. 2 . The compound or the stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof according to claim 1 , wherein X is selected from the group consisting of CH and N; W is selected from the group consisting of O, N, S, NH, and CH; and/or Z is selected from the group consisting of N, NR b , and CR c .
  3. 3 . The compound or the stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof according to claim 1 or 2 , wherein W is CH; and/or Z is selected from the group consisting of N, NH, and CH.
  4. 4 . (canceled)
  5. 5 . The compound or the stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof according to claim 1 , wherein Z is NH.
  6. 6 . The compound or the stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof according to claim 1 , wherein R a is selected from the group consisting of H, OH, halogen, amino, CN, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, and —NHS(═O) 2 —C 1-6 -alkyl; wherein the C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, —NHS(═O) 2 —C 1-6 -alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , —NH(C 1-6 -alkyl), and —N(C 1-6 -alkyl) 2 ; R e is selected from the group consisting of H, amino, C 1-4 -alkyl, C 1-4 -haloalkyl, and C 1-4 -alkoxy; R g and R h are each independently selected from the group consisting of H, C 1-6 -alkyl, amino, and —COOH; and/or R f is selected from the group consisting of H and C 1-3 -alkyl.
  7. 7 . The compound or the stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is selected from the group consisting of H and C 1-4 -alkyl, and the C 1-4 -alkyl is optionally substituted with one or more substituents selected from the group consisting of CN, C 1-6 -alkoxy, —S—C 1-6 -alkyl, and —NHS(═O) 2 C 1-6 -alkyl-CN; and/or R 1 ′ is selected from the group consisting of H and C 1-3 -alkyl.
  8. 8 . The compound or the stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is selected from the group consisting of H, —CH 2 —CN, —CH 2 —S—CH 3 , and and/or R 1 ′ is selected from the group consisting of H and CH 3 .
  9. 9 - 11 . (canceled)
  10. 12 . The compound or the stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof according to claim 1 , wherein R e is selected from the group consisting of H, methyl, ethyl, n-propyl, and isopropyl.
  11. 13 . The compound or the stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof according to claim 1 , wherein L 1 is absent or a C 1-14 divalent saturated or unsaturated, liner or branched hydrocarbon group; 1, 2, or 3 methylene groups of the hydrocarbon group are optionally and independently replaced by: —CH(R e )—, —C(R e ) 2 —, C 3-5 -cycloalkylene, —N(R e )—, —N(R e )C(═O)—, —C(═O)N(R e )—, —O—, —C(═O)—, —OC(═O)—, or —C(═O)O—; and/or L 2 is selected from the group consisting of hydrogen, OH, C 1-6 -alkyl, C 2-6 -alkenyl, —C 0-6 -alkylene-NH(C 1-6 -alkyl), and —C 0-6 -alkylene-N(C 1-6 -alkyl) 2 ; the C 1-6 -alkyl, C 2-6 -alkenyl, —C 0-6 -alkylene-NH(C 1-6 -alkyl), and —C 0-6 -alkylene-N(C 1-6 -alkyl) 2 are optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, CN, OH, NH 2 , —ONO 2 , —COOH, —S(═O) 2 OH, —N═C(NH 2 ) 2 , C 1-6 -alkyl, and —COO(C 1-6 -alkyl).
  12. 14 . The compound or the stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof according to claim 1 , wherein L 1 is absent or is selected from the group consisting of —C 1-6 -alkylene-, —C 1-6 -alkylene-O—C 1-6 -alkylene-, —C 1-6 -alkylene-OC(═O) C 1-6 -alkylene-, —C 1-6 -alkylene-OC(═O)OC 1-6 -alkylene-, —C 1-6 -alkylene-OC(═O) C 1-6 -alkylene-O—, —C 1-6 -alkylene-OC(═O)—NR a C 1-6 -alkylene-, and —C 1-6 -alkylene-OC(═O)—NR a —; wherein each C 1-6 alkylene is optionally substituted with 1-6 R e ; and/or L 2 is selected from the group consisting of OH, CH 3 ,
  13. 15 . The compound or the stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof according to claim 1 , wherein L 1 is absent or is selected from the group consisting of, —CH 2 —, —CH 2 CH 2 —, and/or L 2 is selected from the group consisting of CH 3 ,
  14. 16 - 20 . (canceled)
  15. 21 . The compound or the stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof according to claim 1 , wherein L 2 is selected from the group consisting of
  16. 22 . (canceled)
  17. 23 . The compound or the stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof according to claim 1 , wherein ring A is absent or C 6-14 -aryl; the C 6-14 -aryl is optionally substituted by one or more R f .
  18. 24 . (canceled)
  19. 25 . The compound or the stereoisomer, geometric isomer, tautomer, hydrate, solvate, metabolite or pharmaceutically acceptable salt thereof according to claim 1 , wherein ring A is absent or C 6-10 -aryl.
  20. 26 . (canceled)

Description

TECHNICAL FIELD The present application relates to the field of medicinal chemistry, in particular to a prodrug of a JAK enzyme inhibitor, a preparation method therefor and use thereof. BACKGROUND Inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD), has a significant adverse effect on the quality of life of patients. In an active stage of the disease, common symptoms of IBD include diarrhea, rectal bleeding, abdominal bleeding and pain, weight loss, fatigue, nausea, and vomiting. In 2018, there were 12.6 million cases of ulcerative colitis and 6.1 million cases of Crohn's disease worldwide. It is estimated that by 2027, the numbers will increase to 13.5 million and 6.5 million respectively. Although there are many therapeutic schemes to induce and maintain disease remission in patients with IBD, they all have their limitations. Aminosalicylic acids are usually effective in mild diseases, but they are not effective in moderate and severe diseases. Further, long-term steroid maintenance therapy has safety problems (such as osteoporosis, muscular atrophy, neuropsychiatric disorders, etc.). Systemic immunosuppressants, such as azathioprine, mercaptopurine and methotrexate, and the like are mediocre effective in moderate and severe patients, and there is an increased risk of infection and lymphoma after long-term use. Anti-tumor necrosis factor (TNF) antibodies (such as, infliximab and adalimumab) need to be administrated by subcutaneous injection or intravenous injection, and up to a third of the patients who are first treated don't fully respond, while another third of patients who respond lose their response due to drug resistance. At present, the clinical demand is still unsatisfied, and an effective oral therapy is needed to induce and maintain the remission of IBD and avoid the safety problems caused by chronic systemic immunosuppression. Direct action of medicaments on intestinal mucosa is the way to achieve this goal. A compound or formulation with appropriate physical and chemical properties can achieve targeted delivery to the intestine, and another option is an inactive prodrug that is cleaved by an enzyme during gastrointestinal transport to generate the active parent drug. Because the increase of many proinflammatory cytokines in ulcerative colitis (such as IL-6, IL-13, IL-15, IL-23 and IFNγ) and Crohn's disease (such as IL-13, IL-15, IL-22, IL-24 and IL-27) depends on the signal transduction of Janus kinase (JAK) tyrosine kinase family, inhibition of JAK may be beneficial to the treatment of ulcerative colitis and Crohn's disease. At present, FDA and EMA have approved tofacitinib for the treatment of moderate to severe active ulcerative colitis, and Upadacitinib was also approved for the treatment of moderate to severe active ulcerative colitis in March 2022, and has shown a good therapeutic effect on Crohn's disease in clinical trials. However, because these drugs increase the risk of cancer, thrombosis, serious heart events and death, FDA issued a black box warning for these JAK inhibitors. If selective intestinal JAK inhibition is sufficient to achieve clinical efficacy, it may separate the beneficial anti-inflammatory activity of JAK inhibitors from potentially harmful systemic exposure. Thus, it is urgent to develop a new JAK inhibitor in clinic to be used to treat local inflammation or local immune diseases, which can not only achieve good therapeutic effect, but also avoid the above toxicity caused by systemic exposure. Specifically, there is a strong need to develop JAK inhibitors for treating inflammatory enteritis (e.g., Crohn's disease, ulcerative colitis) with targeted oral administration and minimal systemic exposure. SUMMARY OF THE INVENTION The present application provides a prodrug of JAK inhibitors that can be cleaved by enzymes produced by microorganisms in the gastrointestinal tract. The cleavage releases the JAK inhibitors in the gastrointestinal tract in a targeted or topical manner, thereby increasing the level of JAK inhibitors at the site of gastrointestinal inflammation to improve the curative effect and minimizing systemic exposure to other sites to reduce side effects. In one aspect, the present application provides a compound of formula I, or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate, a metabolite, or a pharmaceutically acceptable salt thereof: wherein,X is selected from the group consisting of CRa and N;W and Z are each independently selected from the group consisting of O, N, S, NRb, and CRc;W and Z cannot be CRc at the same time;R1 is selected from the group consisting of H, halogen, CN, C1-6-alkyl, C1-6-alkoxy, and C1-6-haloalkyl; the C1-6-alkyl, C1-6-alkoxy, and C1-6-haloalkyl are optionally substituted by one or more Rd;R1′ is selected from the group consisting of H, halogen, amino, hydroxyl, C1-6-alkyl, C1-6-haloalkyl, C1-6-alkoxy, and C1-6-haloalkoxy;R2 is selected from the group consisting of -L1-