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US-12617770-B2 - IRAK inhibitor and preparation method therefor and use thereof

US12617770B2US 12617770 B2US12617770 B2US 12617770B2US-12617770-B2

Abstract

A compound represented by formula I are provided. The stereoisomer, racemate, tautomer, isotopic label, prodrug or a pharmaceutically acceptable salt of the compound, and a pharmaceutical composition containing the compound, a preparation method, and medical use of the compound are further provided. The structure is as shown in formula I.

Inventors

  • Guozhong YE
  • Chenli DING
  • Yawen DING
  • Qian He
  • Chaodong Wang

Assignees

  • WUHAN CREATERNA SCIENCE AND TECHNOLOGY CO., LTD.

Dates

Publication Date
20260505
Application Date
20200923
Priority Date
20190924

Claims (20)

  1. 1 . A compound of formula I, or a stereoisomer, a racemate, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: ring A is 5-14 membered heteroaryl or 5-12 heterocyclyl containing at least one N; R 1 and R 3 are each independently selected from the group consisting of hydrogen, halogen, CN, OH, and the following groups optionally substituted with one, two, or more R: (C 1 -C 12 ) aliphatic hydrocarbyl, (C 1 -C 12 ) aliphatic hydrocarbyl optionally comprising one, two, or more heteroatoms, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -20 aryl or 5-14 membered heteroaryl, and —NR a R b ; R 2 is selected from the group consisting of halogen, CN, OH, and the following groups optionally substituted with one, two, or more R: (C 1 -C 12 ) aliphatic hydrocarbyl, (C 1 -C 12 ) aliphatic hydrocarbyl optionally comprising one, two, or more heteroatoms, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-20 aryl or 5-14 membered heteroaryl, and —NR a R b ; W is selected from the group consisting of O, S, NH, and a single bond; Ra and R b are each independently selected from the group consisting of H and (C 1 -C 12 ) aliphatic hydrocarbyl; each R is independently selected from the group consisting of halogen, CN, OH, SH, NR a R b , and the following groups optionally substituted with one, two, or more R′: (C 1 -C 12 )aliphatic hydrocarbyl, (C 1 -C 12 ) aliphatic hydrocarbyl optionally comprising one, two, or more heteroatoms, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, and C 6 -20 aryl or 5-14 membered heteroaryl; each R′ is independently selected from the group consisting of halogen, CN, OH, SH, and NR a R b ; n is selected from the group consisting of 1, 2, and 3; and m is selected from the group consisting of 1, 2, 3, 4, 5, and 6.
  2. 2 . The compound of claim 1 , wherein: each “(C 1 -C 12 ) aliphatic hydrocarbyl optionally comprising one, two, or more heteroatoms” is independently selected from the group consisting of (C 1 -C 12 ) aliphatic hydrocarbyloxy, (C 1 -C 12 ) aliphatic hydrocarbylthio, (C 1 -C 6 ) aliphatic hydrocarbyloxy (C 1 -C 6 ) aliphatic hydrocarbyl, (C 1 -C 6 ) aliphatic hydrocarbylthio(C 1 -C 6 ) aliphatic hydrocarbyl, N—(C 1 -C 3 ) aliphatic hydrocarbylamino (C 1 -C 6 ) aliphatic hydrocarbyl, and N, N-di-(C 1 -C 3 ) aliphatic hydrocarbylamino (C 1 -C 6 ) aliphatic hydrocarbyl; ring A is selected from the group consisting of pyridine, pyrrole, piperidine, and tetrahydropyrrole; each “(C 1 -C 12 ) aliphatic hydrocarbyl” is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, and (C 2 -C 6 )alkynyl; each “halogen” is independently selected from the group consisting of F, Cl, Br, and I; and each “C 3-12 cycloalkyl” is independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  3. 3 . The compound of claim 1 , wherein: R 1 , R 2 , and R 3 are each independently selected from the group consisting of the following groups optionally substituted with one, two, or more R: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 1-ethylethenyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxyl, propoxy, butoxy, pentyloxy, methoxymethyl, ethoxylmethyl, propoxymethyl, methoxyethyl, ethoxylethyl, propoxyethyl, methoxypropyl, ethoxylpropyl, propoxypropyl, N-methylaminomethyl, N-methylaminoethyl, N-ethylaminoethyl, N,N-dimethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, amino, N,N-dimethylamino, N,N-diethylamino, tetrahydropyrrolyl, piperidinyl, pyridyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, and the “ ” denotes the connection site of the group.
  4. 4 . The compound of claim 1 , which is a compound of formula Ia, formula Ib, formula Ic, formula Id, or formula Ie: or a stereoisomer, a racemate, a tautomer, or a pharmaceutically acceptable salt thereof.
  5. 5 . A compound selected from the group consisting of the following structures: or a stereoisomer, a racemate, a tautomer, or a pharmaceutically acceptable salt thereof.
  6. 6 . A pharmaceutical composition comprising the compound of claim 1 .
  7. 7 . The compound of claim 1 , wherein ring A is 5-14 membered heteroaryl containing at least one N.
  8. 8 . The compound of claim 1 , wherein ring A is pyridine ring.
  9. 9 . The compound of claim 1 , wherein W is O.
  10. 10 . The compound of claim 1 , wherein R 1 is C 3-12 cycloalkyl optionally substituted with one, two, or more R.
  11. 11 . The compound of claim 1 , wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; each of which is optionally substituted with one or two R.
  12. 12 . The compound of claim 1 , wherein R 1 is or a stereoisomer thereof.
  13. 13 . The compound of claim 1 , wherein R 2 is (C 1 -C 6 ) aliphatic hydrocarbyl, optionally substituted with one, two, or more R.
  14. 14 . The compound of claim 1 , wherein each instance of R 3 is independently (C 1 -C 6 ) aliphatic hydrocarbyl, optionally substituted with one, two, or more R.
  15. 15 . The compound of claim 1 , wherein each of R 2 and R 3 is independently methyl or ethyl; each of which is optionally substituted with one, two, or more R.
  16. 16 . The compound of claim 1 , wherein each instance of R is independently halogen, CN, OH, NR a R b , (C 1 -C 6 ) aliphatic hydrocarbyl, C 3-6 cycloalkyl, (C 1 -C 6 ) aliphatic hydrocarbyl comprising one or two heteroatoms, 3-6 membered heterocyclyl, C 6 aryl, or 5-6 membered heteroaryl; each of which is independently optionally substituted with one, two, or more R′.
  17. 17 . The compound of claim 4 , which is a compound of formula Ie: or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof.
  18. 18 . A compound, which is: or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof.
  19. 19 . The compound of claim 18 , which is:
  20. 20 . A pharmaceutical composition comprising the compound of claim 18 .

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. national entry of PCT International Application No. PCT/CN2020/117093, filed Sep. 23, 2020, which claims priority to Chinese Patent Application No. 201910906833.7 filed with China National Intellectual Property Administration on Sep. 24, 2019 and entitled “IRAK INHIBITOR AND PREPARATION METHOD THEREFOR AND USE THEREOF”. the content of which is incorporated herein by reference in its entirety. TECHNICAL FIELD The present invention relates to the field of pharmaceutical chemistry, particularly to a compound suitable for treatment of cancer and inflammatory diseases related to interleukin-1 receptor-associated kinase (IRAK), and more particularly to a compound for regulating a function of IRAK-4. BACKGROUND Interleukin-1 receptor-associated kinase (IRAK) family are intracellular serine-threonine protein kinases, including: IRAK1, IRAK2, IRAK-M and IRAK4. A common feature of these four members is the typical N-terminal death domain that mediates the interaction between the MyD88 family adapter and the central kinase domain, wherein IRAK1 and IRAK4 have activity. IRAK4 is a key factor downstream of the Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R)-mediated inflammatory signaling pathway. When the binding of ligand to a pathogen-specific molecule (e.g., lipopolysaccharide, polypeptide and viral DNA) recognized by the extracellular portion of TLR, the intracellular portion recruits MyD88 and other factors to form complexes and initiate IRAK1 autophosphorylation, thereby activating downstream serine-threonine kinase TAK1, promoting NF-κB and MAPK signaling pathways, producing proinflammatory cytokines, chemokines and destructive enzymes, and ultimately leading to inflammatory responses that mediate innate immunity. IL-1R is involved in host defense and hematopoiesis and serves as a bridge connecting the innate immunity and acquired immunity. (Flannery, et. al, Biochem. Pharmacol., 2010, 80 (12):1981-1991). Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease prominently characterized by non-suppurative inflammation in joints and joint tissues. RA is mainly manifested by synovitis of joints, which eventually causes damage to various tissues (such as cartilages of joints, ligaments and tendons) and multiple organs. Studies have shown that a variety of immune cells participate and mediate the autoimmune inflammation in RA patients, including T/B lymphocytes, macrophages, neutrophils, and the like. Meanwhile, a large number of researches have demonstrated the direct association between cytokines and RA, such as interleukins (IL-1/IL-6) and TNF-α. Studies have shown that IRAK4 inhibitors can effectively block the production of the proinflammatory cytokine tumor necrosis factor (TNF) in LPS or CpG-induced human leukocytes; in mice with collagen-induced arthritis, IRAK4 inhibitors can significantly inhibit the release of TNF, thereby controlling disease progression; in mice with MyD88-dependent inflammatory gout, IRAK4 inhibitors are able to dose-dependently block leukocyte infiltration (Priscilla N. et. al., J. Exp. Med., 2015, 13 (212):2189-2201). Therefore, it is believed that the excessive activation of IRAK4-dependent TLR/IL-1R signaling pathway is closely related to the development and progression of rheumatoid arthritis. It has been confirmed in various studies that IRAK4 activation is closely related to the onset and progression of diseases such as tumors, gout, systemic lupus erythematosus, multiple sclerosis, metabolic syndrome, atherosclerosis, myocardial infarction, sepsis, inflammatory bowel disease, asthma, and allergy (Chaudhary D, et. al., J. Med. Chem. 2015, 58 (1):96-110). SUMMARY In order to solve the problems in the prior art, the present invention provides a compound of formula I or a stereoisomer, a racemate, a tautomer, an isotopically labeled compound, a prodrug or a pharmaceutically acceptable salt thereof, wherein,ring A is 5-14 membered heteroaryl or 5-12 heterocyclyl containing at least one of N;R1, R2 and R3 are each independently selected from hydrogen, halogen, CN, OH and the following groups optionally substituted with one, two or more R: (C1-C12)aliphatic hydrocarbyl, (C1-C12)aliphatic hydrocarbyl optionally comprising one, two or more heteroatoms, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-20 aryl or 5-14 membered heteroaryl, and —NRaRb;W is selected from O, S, NH and is a single bond;Ra and Rb, are each independently selected from H and (C1-C12)aliphatic hydrocarbyl; each R is independently selected from halogen, CN, OH, SH, NRaRb, and the following groups optionally substituted with one, two or more R′: (C1-C12)aliphatic hydrocarbyl, (C1-C12)aliphatic hydrocarbyl optionally comprising one, two or more heteroatoms, C3-12 cycloalkyl, 3-12 membered heterocyclyl, and C6-20 aryl or 5-14 membered heteroaryl;each R′ is independently selected from halogen, CN, OH, SH and NRaRb; and n