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EP-4741379-A1 - CLASS OF PROGRAMMED CELL DEATH INHIBITORS, PREPARATION METHOD THEREFOR AND USE THEREOF

EP4741379A1EP 4741379 A1EP4741379 A1EP 4741379A1EP-4741379-A1

Abstract

The present invention provides a class of programmed cell death inhibitors, a preparation method therefor and a use thereof. Specifically, the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, the compound being as shown in Formula I. The present invention also provides a method for preparing the compound and a pharmaceutical composition comprising the compound or a use thereof in treating or preventing diseases or conditions associated with programmed cell death and/or human receptor-interacting protein 1 kinase (RIPK1).

Inventors

  • TAN, LI
  • YUAN, JUNYING
  • LI, YING
  • XIANG, Huaijiang
  • QIN, Ying

Assignees

  • SHANGHAI INSTITUTE OF ORGANIC CHEMISTRY, CHINESE ACADEMY OF SCIENCES

Dates

Publication Date
20260513
Application Date
20240704

Claims (10)

  1. A compound, or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, wherein the compound is represented by Formula I: wherein: X 1 is selected from the group consisting of: CH, N and a chemical bond; X 2 , X 3 , X 4 and X 5 are each independently selected from the group consisting of: CH, and N; with a proviso that a ring formed by X 1 , X 2 , X 3 , X 4 and X 5 is an aromatic ring; M is selected from the group consisting of: O, S, NR 3 , CHR 3 and C(R 3 ) 2 ; W and U are each independently selected from the group consisting of: O, S, NR 4 , CHR 4 and C(R 4 ) 2 ; ring A and ring B are each independently selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted 5-12 membered heteroaryl; R 1 and R 2 are each independently selected from the group consisting of: none, H, substituted or unsubstituted C1-C6 alkyl, and halogen; and when M is NR 3 , CHR 3 or C(R 3 ) 2 , R 2 , R 3 can form a substituted or unsubstituted 5-7 membered ring together with the C or N atoms they are connected to, as well as -C-C(O)-; R 3 and R 4 are selected from the group consisting of: H, substituted or unsubstituted C1-C6 alkyl, and halogen; R 6 is selected from the group consisting of: H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and -CH≡CR 5 ; wherein, R 5 is selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, and a substituted or unsubstituted 4-12 membered heterocyclic group; R 7 is selected from the group consisting of: H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, and -CH≡CR 8 ; wherein, R 8 is selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, and a substituted or unsubstituted 4-12 membered heterocyclic group; wherein, said substituted refers to the hydrogen atoms on the group are replaced by one or more (such as 2, 3, 4 and the like) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 hydroxyalkyl, methylsulfonyl, -S(=O) 2 NH 2 , oxo (=O), -CN, hydroxy, -NH 2 , carboxyl, C2-C6 acylamino (-C(=O)-N(Rc) 2 or -NH-C(=O) (Rc), Rc is H or C1-C5 alkyl), C1-C6 alkyl-(C2-C6 acylamino), C1-C6 amino, deuterated C1-C6 amino, -NHRd (Rd is C3-C8 cycloalkyl, a 4-7 membered heterocyclic group or a heterocyclic group substituted with C1-C6 alkyl), C6-C10 aryl, a 5-7 membered heteroaryl group having 1-3 heteroatoms selected from N, S and O, a 4-8 membered heterocyclic group having 1-3 heteroatoms selected from N, S and O, and a 4-7 membered heterocyclic group substituted with 1 or 2 Re (Re is halogen, C1-C6 alkyl, C1-C6 amino, -CN, C1-C6 alkoxy or a 4-7 membered heterocyclic group).
  2. The compound according to claim 1, or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, wherein the compound is represented by Formula II: wherein M, W, U, A, B, R 1 , R 6 , R 7 are as defined according to claim 1.
  3. The compound according to claim 1, or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, wherein the ring A and ring B are each independently selected from the group consisting of: substituted or unsubstituted phenyl, and substituted or unsubstituted 5-7 membered heteroaryl; wherein said substituted is as defined according to claim 1.
  4. The compound according to claim 1, or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, wherein the ring A and ring B are each independently selected from the group consisting of:
  5. The compound according to claim 1, or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, wherein, in Formula I, M is NR 3 , and/or W is CHR 4 ; R 6 is selected from the group consisting of: H, halogen, CN, and substituted or unsubstituted C1-C6 alkyl; R 7 is selected from the group consisting of: H, halogen, CN, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkynyl, and -CH≡CR 8 ; wherein, R 8 is selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, and a substituted or unsubstituted 4-12 membered heterocyclic group; R 3 , R 4 , and said substituted are as defined according to claim 1.
  6. The compound according to claim 1, or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, wherein the compound is represented by Formula III: wherein M, W, U, A, B, X 5 , R 1 , R 2 , R 3 , R 6 , R 8 are as defined according to claim 1.
  7. The compound according to claim 1, wherein the compound is selected from the compounds listed in the following Table: Compound No. Chemical structure Compound No. Chemical structure QY-17-24 QY-17-25 QY-18-15 QY-18-25 QY-18-26 QY-18-27 QY-18-28 QY-18-41 QY-18-42 QY-18-43 QY-18-44 QY-18-47 QY-18-49 QY-18-63 QY-18-77 QY-18-102 QY-19-53 QY-19-54 QY-19-55 QY-19-56 QY-19-60 QY-19-62 SYL-30-52 SYL-30-56 SYL-30-58 SYL-30-62 SYL-30-65 QY-20-1 QY-20-2 QY-20-5 QY-20-18 QY-20-53 QY-20-54 QY-20-55 QY-20-67 QY-20-72 QY-20-73 QY-20-74 QY-20-76 QY-20-80 QY-20-81 QY-20-82 IRCBC-002 IRCBC-003 IRCBC-004 IRCBC-005 IRCBC-006 IRCBC-010 IRCBC-007 IRCBC-016 IRCBC-033 IRCBC-050 IRCBC-043 IRCBC-054 IRCBC-041 IRCBC-046 IRCBC-049 IRCBC-048 IRCBC-052 IRCBC-067 IRCBC-032 IRCBC-053 IRCBC-051 IRCBC-058 IRCBC-059 IRCBC-071 IRCBC-072 IRCBC-095 IRCBC-096 IRCBC-094 IRCBC-093 IRCBC-101 IRCBC-057 IRCBC-102 IRCBC-091 IRCBC-105 IRCBC-099 IRCBC-106 IRCBC-100 IRCBC-119 IRCBC-098 IRCBC-122 IRCBC-120 IRCBC-131 IRCBC-121 IRCBC-103 IRCBC-125 IRCBC-104 IRCBC-145 IRCBC-129 IRCBC-097 IRCBC-146 IRCBC-134 IRCBC-124 IRCBC-123 IRCBC-149 IRCBC-150 IRCBC-036 IRCBC-152 IRCBC-154 IRCBC-153 IRCBC-159 IRCBC-155 IRCBC-156 IRCBC-157 IRCBC-161 IRCBC-158 IRCBC-008 IRCBC-259 IRCBC-260 IRCBC-258 IRCBC-160 IRCBC-261 IRCBC-257 IRCBC-262 IRCBC-256 IRCBC-276 IRCBC-269 IRCBC-271 IRCBC-265 IRCBC-266 IRCBC-267 IRCBC-268 IRCBC-270 IRCBC-272 IRCBC-273 IRCBC-274 IRCBC-275 IRCBC-277 IRCBC-279 IRCBC-280 IRCBC-281 IRCBC-282 IRCBC-283 IRCBC-284 IRCBC-285 IRCBC-286 IRCBC-287 IRCBC-288 IRCBC-289 IRCBC-290 IRCBC-291 IRCBC-292 IRCBC-293 IRCBC-294 IRCBC-295 . IRCBC-296
  8. A pharmaceutical composition comprising (a) a therapeutically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and (b) a pharmaceutically acceptable carrier.
  9. Use of the compound according to claim 1, or the pharmaceutical composition according to claim 8 in the manufacture of drugs for treating or preventing a disease or condition associated with programmed cell necrosis and/or human receptor-interacting protein kinase 1 (RIPK1).
  10. Use according to claim 9, wherein the disease or condition is one or more selected from the group consisting of: degenerative diseases, inflammation, ischemia-reperfusion injury, pathogenic infections, Parkinson's disease (PD), age-related macular degeneration, autoimmune diseases, retinal detachment induced photoreceptor necrosis, glaucoma, cisplatin-induced kidney injury and traumatic brain injury, atherosclerosis caused by hyperlipidemia, other diseases associated with RIPK1-dependent apoptosis, necrosis, or cytokine production, bacterial infections, viral infections, and lysosomal storage disorders.

Description

Technical Field The present disclosure belongs to the field of small molecule compounds, and specifically relates to a class of inhibitors of programmed cell necrosis (necroptosis), as well as a method for preparing the same and use thereof. Background Art A human body is always accompanied by dynamic regulation of cell proliferation and death during development and aging. Programmed cell death is indispensable in physiological activities such as normal development, resisting pathogen invasion, and maintaining homeostasis, and its dysregulation often leads to developmental abnormalities, immune system diseases, neurodegenerative diseases, cancers, etc., and even the death of an individual. Therefore, intervening in programmed cell death is of great significance for disease treatment research. Apoptosis is the first elucidated mechanism of programmed cell death. In recent years, programmed cell necrosis has become a new focus in the field of cell death. Numerous studies have reported that in various degenerative diseases (such as Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), retinal degenerative diseases, etc.), ischemia-reperfusion injuries (such as cerebral infarction, myocardial infarction, etc.), as well as pathogen infections, programmed cell necrosis occurs as an important pathological feature. On the other hand, the activation of programmed cell necrosis pathways is often accompanied by inflammation. Persistent inflammation can cause irreversible damage to human tissues or organs and also promote the progression of various diseases such as cardiovascular diseases, diabetes, cancers, non-alcoholic fatty liver diseases, degenerative diseases, metabolic syndromes, etc., and is described as the root of all diseases. Various chronic inflammatory diseases, such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis, or hepatitis, not only severely affect patients' health and quality of life but may also trigger fatal heart attacks or cancers; and acute inflammatory storms caused by infections, such as sepsis or severe pneumonia caused by COVID-19 infection, can directly threaten life. Tumor immunotherapies using CAR-T cells or PD-1/PD-L1 antibodies often also have acute inflammatory side effects of varying degrees, seriously affecting patients' quality of life or safety. In addition, programmed cell necrosis and inflammation are also involved in regulating tumor microenvironments: lung cancer cells can induce programmed cell necrosis in specific cells of vascular wall to facilitate metastasis through the circulatory system; high expression of main components of necrosome in pancreatic cancer can induce the expression of chemokine CXCL1, thereby suppressing body immune response. Therefore, inhibiting the occurrence of programmed cell necrosis is widely recognized as beneficial for the treatment and alleviation of various diseases. Researches have shown that tumor necrosis factor α (TNF-α) is one of the main pathways to stimulate programmed cell necrosis and inflammation in the body, and its downstream signaling pathway is also the necrosis signaling pathway with the most clear mechanism at present. In this pathway, RIPK1 plays a crucial regulatory role: by forming signaling Complex I with TNFα receptor protein TNFR1 and other regulatory factors (TRADD, TRAF2, cIAP1/2, etc.), it activates IKK complex and NF-κB inflammatory pathway; after the kinase activity is activated, it enters the cytoplasm and forms Complex IIa with apoptotic factors (FADD, Caspase-3, etc.) to mediate apoptosis; or it activates RIPK3 and polymerizes with it to form necrosome Complex IIb, ultimately inducing necroptosis. During necroptosis, the cell membrane structure is destroyed and a large number of inflammatory factors are released, which in turn triggers a chain reaction of inflammation and cell death. Studies have shown that genetic mutations in RIPK1 gene (D324V, D324H) lead to abnormal accumulation and activation of RIPK1 protein, and can cause the occurrence of autoimmune diseases; during aging, mutations and inactivation of upstream inhibitory regulatory factors (such as OPTN, TBK1, TAK1, A20, CYLD, etc.) also lead to RIPK1 activation, further aggravating degenerative diseases and inflammatory conditions; in various fungal or viral infections and organ ischemia-reperfusion injuries, RIPK1 is also abnormally activated, inducing inflammatory cell death. In the treatment of central nervous system diseases, antibody drugs have the disadvantages of poor blood-brain barrier penetration and immunogenicity, while many existing targeted small molecule drugs may affect normal functions of neurons; meanwhile, inhibition of certain key immune pathways inevitably affects normal immune functions of the human body, posing a risk of severe infections. Therefore, RIPK1 kinase is recognized as a highly promising therapeutic target for various degenerative or inflammatory diseases. The p