WO2023131116A1 - 羰基桥连杂环类化合物、及其组合物与应用 - Google Patents

羰基桥连杂环类化合物、及其组合物与应用 Download PDF

Info

Publication number
WO2023131116A1
WO2023131116A1 PCT/CN2023/070093 CN2023070093W WO2023131116A1 WO 2023131116 A1 WO2023131116 A1 WO 2023131116A1 CN 2023070093 W CN2023070093 W CN 2023070093W WO 2023131116 A1 WO2023131116 A1 WO 2023131116A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
substituted
compound
methyl
membered heteroalicyclic
Prior art date
Application number
PCT/CN2023/070093
Other languages
English (en)
French (fr)
Inventor
张强
杨磊夫
Original Assignee
北京赛特明强医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京赛特明强医药科技有限公司 filed Critical 北京赛特明强医药科技有限公司
Priority to KR1020247026065A priority Critical patent/KR20240131425A/ko
Priority to AU2023204840A priority patent/AU2023204840A1/en
Publication of WO2023131116A1 publication Critical patent/WO2023131116A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a class of carbonyl bridged heterocyclic compounds, their stereoisomers, pharmaceutically acceptable salts, pharmaceutical compositions thereof and their therapeutic effect on receptor-interacting protein 1 kinase ( RIPK1)-related autoimmune diseases, tumors, inflammatory diseases and applications in the preparation of medicines for neurodegenerative diseases.
  • RIPK1 receptor-interacting protein 1 kinase
  • Apoptosis is the autonomous and orderly death of cells controlled by genes in order to maintain the stability of the internal environment of the body. It plays an important role in the evolution of organisms, the stability of the internal environment and the development of the system.
  • Cell necrosis is the pathological process of cell death caused by the influence of physical, chemical and other environmental factors, such as mechanical damage, poisons, microorganisms, radiation, etc.
  • necroptosis also known as programmed necrosis
  • TNF- ⁇ , FasL or TRAIL stimulate death receptors to produce programmed cell necrosis, morphologically showing cell swelling, cell volume increase, organelle dysfunction, damage to cell membrane integrity, release of cell content and ROS mass production etc.
  • Cell necroptosis was initially considered to be a defense method evolved by the host to resist anti-apoptotic viruses, but it was later found that the occurrence of necroptosis would lead to an imbalance of inflammatory factors, causing acute or chronic Inflammatory diseases.
  • Receptor-interacting protein 1 kinase belongs to the TKL family of serine/threonine protein kinases. Members of the RIPK serine/threonine kinase family share the same N-terminal kinase domain, but different binding domains. Studies have found that receptor interacting protein 1 can regulate the process of apoptosis.
  • the death domain of RIPK-1 binds to death receptors such as TNFR1, Fas, TRAILR1, TRAILR2, etc. They can also bind to other proteins containing death domains, such as TRADD, FADD, etc., binding to the latter activates caspase-8 and Necessary for induction of apoptosis.
  • the RIPK-1 intermediate structure is the RIPK homotype interaction target, through which RIPK-1 can interact with RIPK-3.
  • Kelliher et al. found that RIPK-1 congenitally deficient mice died less than 3 days after birth due to massive apoptosis of cells, which indicated that RIPK-1 was also involved in the regulation of apoptosis.
  • cells congenitally deficient in RIPK-1 are quite sensitive to TNF-induced cell death, perhaps because such cells cannot effectively activate NF-kB.
  • RIPK-1 and RIPK-3 are also involved in the process of cell necroptosis.
  • the death receptors TNFR1, Fas, and TRAILR mediate apoptosis.
  • Activation of TNFR1 can trigger the ubiquitination of RIPK-1 through cIAP1 and cIAP2, and the ubiquitinated RIPK-1 determines whether the next step of the cell is to continue to survive or to die.
  • the pan-caspase inhibitor z-VAD-fmk the cell death will go to necroptosis.
  • the activity of RIPK-1 is a key factor, which is regulated by FasL, TNF and TRAIL death receptors.
  • necroptosis is associated with a variety of diseases, including tumors, autoimmune diseases, neurodegenerative diseases, inflammatory diseases and so on. It can be seen that RIP family kinases are closely related to the occurrence of various diseases such as tumors, autoimmune diseases, neurodegenerative diseases, and inflammatory diseases.
  • RIPK-1 inhibitors improve learning and memory in an Alzheimer-like rat model.
  • RIPK-1 inhibitors are also expected to be used in a variety of other neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease.
  • RIPK-1 inhibitors that can penetrate the blood-brain barrier are even less studied.
  • the ability of a drug to penetrate the blood-brain barrier is critical to the efficacy of the treatment.
  • the application provides a class of carbonyl-bridged heterocyclic compounds, which exhibit good RIPK-1 inhibitory activity and the ability to penetrate the blood-brain barrier. It is worth emphasizing that such compounds not only have strong inhibitory activity on human RIPK-1, but also have strong inhibitory activity on mouse RIPK-1.
  • the compound of the present application has a certain similarity and adaptability to human diseases when extrapolated from the results of animal experiments, which is conducive to the development of drugs through animal experiments, and is expected to be used as a RIPK-1 inhibitor for the treatment of tumors, autoimmune In the preparation of drugs for immune diseases, neurodegenerative diseases and inflammatory diseases.
  • the present invention provides the compound represented by formula (I), its pharmaceutically acceptable salt, or stereoisomer, which can be used to prepare medicines for treating or preventing diseases related to RIPK1.
  • X is CH or N
  • L is O, S, NH, carbonyl, sulfone or sulfoxide
  • R 1 is C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered heteroalicyclic group, or 1 to 3 members selected from hydroxyl, C 1 -C 6 alkoxy, cyano , -NR a R b , C 3 -C 8 cycloalkyloxy, -CONH-R 5 , C 3 -C 8 cycloalkyl, hydroxyl and/or C 1 -C 4 alkyl substituted C 3 -C 8 Cycloalkyl, carboxyl, halogen, halogenated C 1 -C 6 alkoxy, -SO 2 -R 5 , -SO-R 5 , -CO-R 5 , C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, C 1 -C 4 alkoxy C 1 -C 6 alkoxy, 4-8 membered heteroalicyclic group, oxo-substituted 4-8 membered
  • the 4-8 membered heteroalicyclic group is a 4-8 membered heteroalicyclic group containing 1-2 atoms selected from N, O, and S as ring atoms,
  • R 5 is hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, hydroxyl substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, A 4-8 membered heteroalicyclic group is substituted for a C 1 -C 6 alkyl group,
  • R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy substituted C 1 -C 6 alkyl, hydroxy substituted C 1 - C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, 4-8 membered heteroalicyclic substituted C 1 -C 6 alkyl, C 1 -C 3 alkylthio substituted C 1 - C 6 alkyl, mono or double C 1 -C 3 alkyl substituted or unsubstituted amino substituted C 1 -C 6 alkyl;
  • R 2 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen;
  • R 3 and R 4 are each independently hydrogen, halogen, or methyl.
  • the compound has the structure of formula (II):
  • R 1 is C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered heteroalicyclic group, or 1 to 3 members selected from hydroxyl, C 1 -C 6 alkoxy, cyano , -NR a R b , C 3 -C 8 cycloalkyloxy, -CONH-R 5 , C 3 -C 8 cycloalkyl, hydroxyl and/or C 1 -C 4 alkyl substituted C 3 -C 8 Cycloalkyl, carboxyl, halogen, halogenated C 1 -C 6 alkoxy, -SO 2 -R 5 , -SO-R 5 , -CO-R 5 , C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, C 1 -C 4 alkoxy C 1 -C 6 alkoxy, 4-8 membered heteroalicyclic group, oxo-substituted 4-8 membered
  • the 4-8 membered heteroalicyclic group is a 4-8 membered heteroalicyclic group containing 1-2 atoms selected from N, O, and S as ring atoms,
  • R 5 is hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, hydroxyl substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, A 4-8 membered heteroalicyclic group is substituted for a C 1 -C 6 alkyl group,
  • R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy substituted C 1 -C 6 alkyl, hydroxy substituted C 1 - C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, 4-8 membered heteroalicyclic substituted C 1 -C 6 alkyl, C 1 -C 3 alkylthio substituted C 1 - C 6 alkyl, mono or double C 1 -C 3 alkyl substituted or unsubstituted amino substituted C 1 -C 6 alkyl;
  • R 2 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen;
  • R 3 and R 4 are each independently hydrogen, halogen, or methyl.
  • R 1 is C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heteroalicyclic group, or 1 to 3 members selected from hydroxyl, C 1 -C 3 alkoxy, cyano, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkyl, hydroxyl and/or C 1 -C 4 alkyl substituted C 3 -C 6 cycloalkyl , halogen, 4-6 membered heteroalicyclic group, oxo-substituted 4-6 membered heteroalicyclic group, hydroxyl and/or C 1 -C 4 alkyl substituted 4-6 membered heteroalicyclic group, C 1 -C 3 C 1 -C 8 alkyl substituted by substituents in alkylthio,
  • the 4-6 membered heteroalicyclic group is a 4-6 membered heteroalicyclic group containing 1-2 atoms selected from N, O and S as ring atoms.
  • R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, octyl, cyclobutyl Base, cyclopentyl, cyclohexyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, or by 1 to 3 selected from hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, cyano, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclobutyl, cyclo Pentyl, cyclohexyl, 4-hydroxycyclohexyl, 4-hydroxy-4-methylcyclo
  • pyrrolidin-1-yl pyrrolidin-2-yl
  • piperidin-1-yl piperidin-4-yl
  • morpholinyl morpholinyl
  • thiomorpholinyl 1-methyl-pyrrolidinyl-2- C 1 -C 8 alkyl substituted by substituents in radical, 1-methyl-piperidin-4-yl, methylthio, ethylthio, propylthio, isopropylthio.
  • R is methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methyl Oxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, tetrahydropyran-4-yl, 4-methyl-4-hydroxypentyl, tetrahydro Pyran-4-ylethyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-4-ylpropyl, tetrahydropyran-4-ylbutyl, 3-methyl-3-hydroxy Butyl, 2-methyl-2-hydroxypropyl, 5-methyl-5-hydroxyhexyl, fluoropropyl, fluoroethyl, 2,2-difluoro-3-hydroxy-propyl.
  • R is C 1 -C 8 alkyl substituted by 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, or 1-hydroxycyclohexyl;
  • R 1 is 1-hydroxycyclopropylmethyl, 1-hydroxycyclobutylmethyl.
  • R 1 is hydroxyl and/or halogen substituted C 1 -C 6 alkyl; most preferably, R 1 is hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, Hydroxyhexyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, 4-methyl-4-hydroxypentyl, 5-methyl-5-hydroxyhexyl, fluoropropyl, Fluoroethyl, 2,2-difluoro-3-hydroxy-propyl.
  • R is hydrogen, methyl, methoxy, fluoro, chloro, bromo;
  • R2 is fluoro
  • R 3 and R 4 are each independently hydrogen, fluorine, chlorine, methyl;
  • R 3 and R 4 are each independently fluorine.
  • the compound has the structure of formula (III):
  • X is CH or N
  • L is O, S, NH, carbonyl, sulfone or sulfoxide
  • R 1 is C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, 4-8 membered heteroalicyclic group, or 1 to 3 members selected from hydroxyl, C 1 -C 6 alkoxy, cyano , -NR a R b , C 3 -C 8 cycloalkyloxy, -CONH-R 5 , C 3 -C 8 cycloalkyl, hydroxyl and/or C 1 -C 4 alkyl substituted C 3 -C 8 Cycloalkyl, carboxyl, halogen, halogenated C 1 -C 6 alkoxy, -SO 2 -R 5 , -SO-R 5 , -CO-R 5 , C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, C 1 -C 4 alkoxy C 1 -C 6 alkoxy, 4-8 membered heteroalicyclic group, oxo-substituted 4-8 membered
  • the 4-8 membered heteroalicyclic group is a 4-8 membered heteroalicyclic group containing 1-2 atoms selected from N, O, and S as ring atoms,
  • R 5 is hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, hydroxyl substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, A 4-8 membered heteroalicyclic group is substituted for a C 1 -C 6 alkyl group,
  • R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy substituted C 1 -C 6 alkyl, hydroxy substituted C 1 - C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, 4-8 membered heteroalicyclic substituted C 1 -C 6 alkyl, C 1 -C 3 alkylthio substituted C 1 - C 6 alkyl or C 1 -C 6 alkyl substituted by mono or double C 1 -C 3 alkyl or unsubstituted amino;
  • R 2 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen;
  • R 3 and R 4 are each independently hydrogen, halogen, or methyl.
  • the compound has the structure of formula (IV):
  • R 1 is a C 1 -C 10 alkyl group, a C 3 -C 8 cycloalkyl group, a 4-8 membered heteroalicyclic group, or 1 to 3 members selected from hydroxyl, C 1 -C 6 alkoxy, Cyano, -NR a R b , C 3 -C 8 cycloalkyloxy, -CONH-R 5 , C 3 -C 8 cycloalkyl, hydroxyl and/or C 1 -C 4 alkyl substituted C 3 - C 8 cycloalkyl, carboxyl, halogen, halogenated C 1 -C 6 alkoxy, -SO 2 -R 5 , -SO-R 5 , -CO-R 5 , C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, C 1 -C 4 alkoxy C 1 -C 6 alkoxy, 4-8 membered heteroalicyclic group, oxo-
  • the 4-8 membered heteroalicyclic group is a 4-8 membered heteroalicyclic group containing 1-2 atoms selected from N, O, and S as ring atoms,
  • R 5 is hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, hydroxyl substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, A 4-8 membered heteroalicyclic group is substituted for a C 1 -C 6 alkyl group,
  • R a and R b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy substituted C 1 -C 6 alkyl, hydroxy substituted C 1 - C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl, 4-8 membered heteroalicyclic substituted C 1 -C 6 alkyl, C 1 -C 3 alkylthio substituted C 1 - C 6 alkyl or C 1 -C 6 alkyl substituted by mono or double C 1 -C 3 alkyl or unsubstituted amino;
  • R 2 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen;
  • R 3 and R 4 are each independently hydrogen, halogen, or methyl.
  • R 1 is C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heteroalicyclic group, or 1 to 3 members selected from hydroxyl, C 1 -C 3 alkoxy, cyano, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkyl, hydroxyl and/or C 1 -C 4 alkyl substituted C 3 -C 6 cycloalkyl , halogen, 4-6 membered heteroalicyclic group, oxo-substituted 4-6 membered heteroalicyclic group, hydroxyl and/or C 1 -C 4 alkyl substituted 4-6 membered heteroalicyclic group, C 1 -C 3 C 1 -C 8 alkyl substituted by substituents in alkylthio,
  • the 4-6 membered heteroalicyclic group is a 4-6 membered heteroalicyclic group containing 1-2 atoms selected from N, O and S as ring atoms.
  • R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, octyl, cyclobutyl Base, cyclopentyl, cyclohexyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, or by 1 to 3 selected from hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, cyano, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclobutyl, cyclo Pentyl, cyclohexyl, 4-hydroxycyclohexyl, 4-hydroxy-4-methylcyclo
  • R is methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methyl Oxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, tetrahydropyran-4-yl, 4-methyl-4-hydroxypentyl, tetrahydro Pyran-4-ylethyl, tetrahydropyran-4-ylmethyl, tetrahydropyran-4-ylpropyl, tetrahydropyran-4-ylbutyl, 3-methyl-3-hydroxy Butyl, 2-methyl-2-hydroxypropyl, 5-methyl-5-hydroxyhexyl, fluoropropyl, fluoroethyl, 2,2-difluoro-3-hydroxy-propyl.
  • R is C 1 -C 8 alkyl substituted by 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, or 1-hydroxycyclohexyl;
  • R 1 is 1-hydroxycyclopropylmethyl, 1-hydroxycyclobutylmethyl.
  • R 1 is hydroxyl and/or halogen substituted C 1 -C 6 alkyl; most preferably, R 1 is hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, Hydroxyhexyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, 4-methyl-4-hydroxypentyl, 5-methyl-5-hydroxyhexyl, fluoropropyl, Fluoroethyl, 2,2-difluoro-3-hydroxy-propyl.
  • R is hydrogen, methyl, methoxy, fluoro, chloro, bromo;
  • R2 is fluoro
  • R 3 and R 4 are each independently hydrogen, fluorine, chlorine, methyl;
  • R 3 and R 4 are each independently fluorine.
  • the compound of the present application is a deuterated compound of the aforementioned compounds, more preferably a compound in which the 5-position of pyrazolyl in any one of the aforementioned structural formulas (I)-(IV) is deuterated.
  • the pharmaceutically acceptable salt of the compound is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, Phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, dextrose salt, benzoate, mandelate, methanesulfonate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclo Hexamate, Salicylate, Hexose, Trifluoroacetate, Aluminum, Calcium, Chloroprocaine, Choline, Diethanolamine, Ethylenediamine, Lithium , one or more of magnesium salt, potassium salt, sodium salt and zinc salt.
  • Another aspect of the present invention relates to the application of the compound, its pharmaceutically acceptable salt, stereoisomer, solvate, or deuterated compound in the preparation of a drug for treating diseases related to RIPK1, wherein the RIPK1-related Associated diseases include fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis Hepatic fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, Endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid
  • Another aspect of the present invention provides a pharmaceutical composition, which includes the amido-bridged heterocyclic compound of the present application, its stereoisomer, solvate, pharmaceutically acceptable salt or deuterated compound , and one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition may also include one or more other therapeutic agents.
  • the present invention also relates to a method for treating a disease or disorder mediated by RIPK1 kinase, which comprises administering a therapeutically effective amount of a compound of formula (I) or a salt thereof to a patient in need (human or other mammal, especially human) , the RIPK1 kinase-mediated disease or disorder includes those mentioned above.
  • Figure 1 shows the Western Blot picture of the compound of Example 40 inhibiting RIPK1 phosphorylation
  • Figure 2 shows the ratio of the phosphorylation of RIPK1 relative to the total protein expression of RIPK1 by the compound of Example 40.
  • alkyl refers to a saturated straight-chain or branched chain hydrocarbon group with the specified number of carbon atoms
  • C 1 -C 10 alkyl refers to an alkyl moiety containing 1 to 10 carbon atoms
  • C 1 -C 3 Alkyl means an alkyl moiety containing 1 to 3 carbon atoms
  • C 1 -C 6 alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl base, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methyl pentyl, etc.
  • substituent terms such as “alkyl” are used in combination with other substituent terms, such as in the terms “C 1 -C 3 alkoxy C 1 -C 6 alkylthio” or “hydroxyl substituted C 1 -C 10 alkyl
  • the linking substituent term eg, alkyl or alkylthio
  • C 1 -C 3 alkoxy C 1 -C 6 alkylthio include, but are not limited to, methoxymethylthio, methoxyethylthio, ethoxypropylthio and the like.
  • hydroxyl-substituted C 1 -C 10 alkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxyisopropyl and the like.
  • Alkoxy is an alkyl-O- group formed from a straight or branched chain alkyl previously described and -O-, eg, methoxy, ethoxy, and the like.
  • alkylthio is an alkyl-S- group formed from a straight or branched chain alkyl and -S- previously described, eg, methylthio, ethylthio, and the like.
  • Alkenyl and alkynyl include straight-chain, branched-chain alkenyl or alkynyl, and the term C 2 -C 6 alkenyl or C 2 -C 6 alkynyl denotes a straight-chain or branched hydrocarbon group having at least one alkenyl or alkynyl group.
  • halogenated C 1 -C 10 alkyl means a group having one or more halogen atoms which may be the same or different on one or more carbon atoms of an alkyl moiety comprising 1 to 10 carbon atoms.
  • halogenated C 1 -C 10 alkyl may include, but are not limited to -CF 3 (trifluoromethyl), -CCl 3 (trichloromethyl), 1,1-difluoroethyl, 2,2 , 2-trifluoroethyl and hexafluoroisopropyl, etc.
  • halogenated C 1 -C 10 alkoxy means a haloalkyl-O- group formed by said halogenated C 1 -C 10 alkyl and -O-, which can be, for example, trifluoromethane Oxygen, trichloromethoxy, etc.
  • C 1 -C 3 acyl includes formyl (-CHO), acetyl (CH 3 CO-), acetyl (C 2 H 5 CO-).
  • Cycloalkyl means a non-aromatic, saturated, cyclic hydrocarbon group containing the indicated number of carbon atoms.
  • (C3-C6)cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having 3-6 ring carbon atoms.
  • Exemplary "(C3-C6)cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aryl denotes a group or moiety comprising an aromatic monocyclic or bicyclic hydrocarbon radical containing 6 to 12 carbon ring atoms and having at least one aromatic ring.
  • aryl are phenyl, naphthyl, indenyl and dihydroindenyl (indanyl).
  • aryl is phenyl.
  • heteroalicyclic group used herein, unless otherwise specified, represents an unsubstituted or substituted stable 4 to 8 membered non-aromatic monocyclic saturated ring system consisting of carbon atoms and from N, O, S selected from 1 to 3 heteroatoms, wherein N, S heteroatoms can be freely oxidized, and N heteroatoms can also be optionally quaternized.
  • heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazole Alkyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, 1,3-dioxolyl, piperidinyl, piperazinyl, tetrahydrofuryl Hydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3 -Oxathiolanyl, 1,3-Dithianyl, 1,4-Oxathiolanyl, 1,4-Ox
  • heteroaryl denotes a group or moiety comprising an aromatic monocyclic or bicyclic radical containing 5 to 10 ring atoms comprising 1 to 3 atoms independently selected from nitrogen, oxygen and sulfur of heteroatoms.
  • the term also includes bicyclic heterocyclic aryl groups which contain an aryl ring moiety fused to a heterocycloalkyl ring moiety, or which contain a heteroaryl ring moiety fused to a cycloalkyl ring moiety.
  • heteroaryl groups can be linked to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl examples include, but are not limited to, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazole base, thiadiazolyl, isothiazolyl, pyridyl, oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuryl, iso Benzofuryl, 2,3-dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl , indolyl, isoindolyl, indolinyl, benzimidazolyl, dihydrobenz
  • carbonyl refers to a -C(O)- group.
  • Hydroxo is intended to mean a -OH radical.
  • cyano as used herein refers to the group -CN.
  • each independently means that when more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • solvated form may be a water soluble form.
  • the invention includes all such solvated and unsolvated forms.
  • the compounds of the present invention may have asymmetric carbon atoms. According to their physicochemical differences, this diastereoisomeric mixture can be separated by known and well-established methods, for example, by chromatography or fractional crystallization. into single diastereoisomers.
  • the separation of enantiomers can be carried out by first reacting with an appropriate optically active compound, converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereoisomers, and then converting the single diastereomeric Enantiomers are converted (hydrolyzed) into the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered part of this invention.
  • the compounds of the present invention may be used for therapy in free form or, where appropriate, in the form of pharmaceutically acceptable salts or other derivatives.
  • pharmaceutically acceptable salt refers to the organic and inorganic salts of the compounds of the present invention, which are suitable for humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and have a reasonable Benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. Such salts can be formed by reacting a compound of the invention with a suitable free base or acid.
  • salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, Alternatively, these salts can be obtained by using methods well known in the art, such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, citrate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconic acid Salt, hemisulfate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, methane Sulfonate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Palmitate, Pamoate, Pectate, Persulfate, Per-3-Phenylpropionate, Phosphate, picrate, propionate, stearate, s
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Other pharmaceutically acceptable salts include suitable non-toxic ammonium, quaternary ammonium, and use such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates Amine cations formed from acid salts.
  • the pharmaceutical composition of the present invention comprises the compound of structural formula (I) described herein or its pharmaceutically acceptable salt, kinase inhibitor (small molecule, polypeptide, antibody etc.), immunosuppressant, anticancer drug, antiviral agent, anticancer agent an inflammatory, antifungal, antibiotic or additional active agent of an antivascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • kinase inhibitor small molecule, polypeptide, antibody etc.
  • immunosuppressant anticancer drug
  • antiviral agent antiviral agent
  • anticancer agent an inflammatory, antifungal, antibiotic or additional active agent of an antivascular hyperproliferative compound
  • any pharmaceutically acceptable carrier, adjuvant or vehicle any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the compounds of the invention may be used alone or in combination with one or more other compounds of the invention or with one or more other agents.
  • the therapeutic agents can be formulated to be administered simultaneously or sequentially at different times, or the therapeutic agents can be administered as a single composition.
  • “combination therapy” is meant the use of a compound of the invention in combination with another agent, either at the same time as co-administration of each agent or sequentially of each agent, in either case for the purpose of to achieve the best effect of the drug.
  • Co-administration includes simultaneous delivery of dosage forms, as well as separate separate dosage forms for each compound.
  • the administration of the compounds of the present invention can be used concurrently with other therapies known in the art, for example, in cancer treatment using radiation therapy or additional therapy such as cytostatics, cytotoxic agents, other anticancer agents to improve cancer symptoms.
  • additional therapy such as cytostatics, cytotoxic agents, other anticancer agents to improve cancer symptoms.
  • the invention is not limited by the order of administration; the compounds of the invention may be administered previously, concurrently, or after other anticancer or cytotoxic agents.
  • one or more compounds or salts of the molecular formula (I) as its active ingredient can be closely mixed with a pharmaceutical carrier, which is carried out according to traditional pharmaceutical ingredient technology,
  • the carrier therein can take various forms according to the preparation forms designed for different administration modes (for example, oral or parenteral administration).
  • Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients, a joint publication of the American Pharmaceutical Association and the British Pharmaceutical Society.
  • the pharmaceutical composition of the present invention can be in the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injections such as clear liquids, suspensions, Emulsion; or for topical application as ointment, cream; or as a suppository for rectal administration.
  • the pharmaceutical composition may also be in unit dosage form suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a traditional pharmaceutical carrier or excipient and the compound as the active ingredient prepared according to the present invention. In addition, it may also include other medical or pharmaceutical preparations, carriers, adjuvants, and so on.
  • Therapeutic compounds can also be administered to mammals rather than humans.
  • the dose of drug administered to a mammal will depend on the species of the animal and its disease state or disorder.
  • Therapeutic compounds can be given to animals in the form of capsules, boluses, tablet drops.
  • Therapeutic compounds can also be administered to animals by injection or infusion. We prepare these pharmaceutical forms in a conventional manner consistent with the standards of veterinary practice.
  • pharmaceutical compositions can be mixed with animal feed and fed to animals, thus, concentrated feed additives or premixes can be prepared for mixing with normal animal feed.
  • Yet another object of the present invention is to provide a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of the present invention.
  • the present invention also includes the use of the compound of the present invention or a pharmaceutically acceptable derivative thereof, manufactured for the treatment of diseases related to RIPK1 including fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid Arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer , glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid Cancer, chronic myelogenous leukemia, acute myeloid leukemia, non-Hodgkin's lymphom
  • the present invention also provides a method for preparing the corresponding compound.
  • Various synthetic methods can be used to prepare the compound described herein, including the methods involved in the following examples.
  • the compound of the present invention or its pharmaceutically acceptable salt, isomer The body or hydrate can be synthesized by using the following methods and synthetic methods known in the field of organic chemical synthesis, or by changing methods understood by those skilled in the art. Preferred methods include but are not limited to the following methods.
  • Step 1) 3-bromo-4-fluorophenol (330mg, 1.73mmol), potassium carbonate (718.98mg, 5.20mmol), 1-bromo-3-methoxypropane (540mg, 3.50mmol) were placed in DMF ( 5 mL), react at 80°C for 2 hours.
  • Step 2) 2-Bromo-1-fluoro-(4-methoxypropyl)phenyl ether (421mg, 1.60mmol), pinacol ester (815mg, 3.21mmol), KOAc (472mg, 4.81mmol), Pd(dppf)Cl 2 (235mg, 321umol) was added to 1,4-dioxane (10mL), and reacted at 100°C for 16 hours under the protection of argon.
  • Step 1) 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (24g, 105mmol), intermediate A-1(5-(3,5-difluorophenyl)-4,5- Dihydro-1H-pyrazole) (21.9g, 120mmol), HATU (39.9g, 105mmol), DIEA (27.1g, 210mmol) were added to DMF (150mL), and reacted at 25°C for 1 hour under the protection of argon.
  • Step 2): tert-butyl 4-[3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidine-1-carboxylate (26g, 66.09mmol) Dissolved in 1,4-dioxane (60mL), then added hydrochloric acid (4M 1,4-dioxane solution system, 82.61mL) solution, stirred overnight at room temperature, suction filtered after the reaction was completed, and the solid was dissolved in In methanol, then add solid sodium carbonate, adjust the pH to 8, stir for 30 minutes, then add ethyl acetate to dilute, filter with suction, wash the solid twice with ethyl acetate, spin the filtrate to dry, and purify by column chromatography (dichloromethane /methanol/triethylamine 500/100/5) to obtain 15.5g, yield 80%. MS:294[M+H] + ;
  • Step 3) (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperidin-4-yl)methanone (3.0g, 10mmol ), 2-fluoro-4-bromopyridine (3.5g, 20mmol) and triethylamine (3.05g, 30mmol) in DMSO (20ml) were heated to 80°C for 16 hours, diluted with ethyl acetate after cooling, washed with water, Drying, concentration, and purification by column chromatography yielded 3.93 g of a yellow solid product with a yield of 88%, MS: 449,451[M+H] + ;
  • Step 4) (1-(4-bromopyridin-2-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole- 1-yl)methanone (450mg, 1mmol), intermediate B-2(2-(3-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborane) (250mg, 1mmol), potassium carbonate (210mg, 2mmol) and Pd(PPh 3 ) 4 (58mg, 0.05mmol) were dissolved in 1,4-dioxane (8mL) and In a mixed solvent of water (0.8 mL), the temperature was raised to 80°C under the protection of argon, and the reaction was stirred for 5 hours.
  • Example 8 (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(3-((4-hydroxyl-4 -Methylpentyl)oxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone
  • Example 12 (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(3-(3-hydroxypropoxy )phenyl)pyridin-2-yl)piperidin-4-yl)methanone
  • Example 15 (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(5-(3-hydroxypropoxy )-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)methanone
  • Example 16 (1-(4-(2-chloro-5-(2-methoxyethoxy)phenyl)pyridin-2-yl)piperidin-4-yl)(5-(3,5 -Difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone
  • Example 17 (1-(4-(2-chloro-5-(3-hydroxypropoxy)phenyl)pyridin-2-yl)piperidin-4-yl)(5-(3,5-di Fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone
  • Example 24 (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-((4 -Hydroxy-4-methylpentyl)oxy))phenyl)pyridin-2-yl)piperidin-4-yl)methanone
  • Example 25 (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-((5 -Hydroxypentyl)oxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone
  • Example 28 (1-(4-(5-(2-methoxyethoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)(5-phenyl- 4,5-dihydro-1H-pyrazol-1-yl)methanone was prepared by a method similar to Example 1, except that intermediate A-3 was used to replace intermediate A-1 in step 1, In step 4, intermediate B-20 was used instead of intermediate B-2 for the reaction.
  • Example 31 (1-(4-(5-(3-hydroxypropoxy)-2-methylphenyl)pyridin-2-yl)piperidin-4-yl)(5-phenyl-4, 5-dihydro-1H-pyrazol-1-yl)methanone is prepared by a method similar to that of Example 1, the difference is that the difference is that intermediate A-3 is used in step 1 instead of intermediate A -1, use intermediate B-24 instead of intermediate B-2 in step 4 to react.
  • reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to obtain 3-(3-(2-chloropyrimidin-4-yl)-4- Fluorophenoxy) propyl-1-alcohol 1.48g, yield 78%;
  • the reaction solution was diluted with dichloromethane, washed with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 907 mg of the product with a yield of 85.71%.
  • Step 3) ethyl 1-(4-(2-fluoro-5-(3-hydroxypropoxy)phenyl)pyrimidin-2-yl)piperidine-4-carboxylate (650 mg, 1.61 mmol), NaOH (321mg, 8.03mmol) was added to MeOH (10mL) and H 2 O (2mL), and the reaction was stirred at room temperature for 3 hours; the pH value was adjusted to 3 with hydrochloric acid (2N concentration) at 0°C, and the reaction solution was diluted with dichloromethane Washed with saturated brine, then dried the organic phase with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to finally obtain 1-(4-(2-fluoro-5-(3-hydroxypropoxy)phenyl)pyrimidine-2- Base) piperidine-4-carboxylic acid 532mg, yield 87.92%; MS: 376[M+H] + ;
  • reaction solution was diluted with dichloromethane and washed with saturated brine, then the organic phase was dried with anhydrous sodium sulfate, then filtered and concentrated under reduced pressure, and the obtained product was further purified by column chromatography to finally obtain 78 mg of the product, with a yield of 29% .
  • racemates obtained in Examples 18, 21, 23 and 24 were separated and purified by chiral column. Separation is carried out using a chromatograph (Shimadzu LC-20A), and the separation conditions are as follows:
  • Step 1) Methyl 2-bromoacetate (14.42g, 94.24mmol), 3-bromo-4-fluorophenol (6g, 31.41mmol), potassium carbonate (13.03g, 94.24mmol) were placed in DMF (30mL) , under the protection of argon, react at 80°C for 12 hours.
  • the reaction solution was diluted with ethyl acetate, then washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by column chromatography to finally obtain 2-(3-bromo-4-fluoro -6 grams of methyl phenoxy)acetate, yield 73%.
  • Step 2) Methyl 2-(3-bromo-4-fluoro-phenoxy)acetate (1 g, 3.80 mmol) was dissolved in tetrahydrofuran, and ethylmagnesium bromide ( 2.0 M tetrahydrofuran solution) (5.7 mL), react at this temperature for 2 hours.
  • the reaction was quenched by adding saturated ammonium chloride aqueous solution, the reaction solution was suction filtered through diatomaceous earth, the filtrate was extracted with ethyl acetate, the organic phase was washed with water and saturated brine, then dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, The crude product was purified by column chromatography to finally obtain 800 mg of 3-[(3-bromo-4-fluoro-phenoxy)methyl]pentan-3-ol with a yield of 72%.
  • reaction solution was diluted with ethyl acetate, washed with water and saturated brine, the organic phase was taken and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography to finally obtain [5-(3,5-di Fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl]-[1-[4-[5-(2-ethyl-2-hydroxybutoxy)-2-fluorophenyl ]pyridin-2-yl]piperidin-4-yl]methanone 40 mg, yield 31%.
  • Step 1) Methyl 2-(3-bromo-4-fluoro-phenoxy)acetate (500mg, 1.80mmol) was dissolved in THF (8mL), and ethyl bromide was added dropwise under argon protection at 0°C Magnesium chloride (2M solution in tetrahydrofuran, 0.9 ml, 1.80 mmol), reacted at this temperature for 30 minutes, then slowly raised to 25°C, and continued to react for 16 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution, and the filtrate obtained by filtration was extracted with dichloromethane.
  • Step 2) Mix 1-[(3-bromo-4-fluoro-phenoxy)methyl]cyclopropanol (180mg, 689.42 ⁇ mol), pinacol ester (370.63mg, 1.46mmol), potassium acetate (238.73 mg, 2.43mmol), Pd(dppf)Cl 2 (88.99mg, 121.63 ⁇ mol) were placed in 1,4-dioxane (10mL), and reacted at 100°C for 3 hours under the protection of argon, and the reaction solution was concentrated Purified by column chromatography to finally obtain 1-[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy] -2-methyl-cyclopropan-2-ol 170 mg, yield 80%.
  • 1,4-dioxane 3 mL
  • water 0.4 mL
  • reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by column chromatography to finally obtain [5-(3,5-difluorophenyl)- 4,5-Dihydro-1H-pyrazol-1-yl]-[1-[4-[2-fluoro-5-[(1-hydroxycyclopropyl)methoxy]phenyl]pyridin-2-yl ]piperidin-4-yl]methanone 28 mg, yield 29%.
  • Example 46 (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-((1 -Hydroxycyclobutyl)methoxy)phenyl)pyridin-2-yl)piperidin-4-yl)methanone
  • Step 1) Dissolve 1-hydroxycyclobutanecarboxylic acid (500mg, 4.31mmol) in THF (10mL), under the protection of argon, add lithium aluminum hydride (490.25mg, 12.92mmol) in batches at room temperature, rise to 80°C, the reaction was continued for 1 hour. In an ice bath, add 0.5ml of water, 1.5mL of 20% NaOH aqueous solution, and 0.5mL of water successively. After quenching, filter and collect the filtrate, and concentrate the filtrate under reduced pressure to finally obtain the crude product 1-(hydroxymethyl)cyclobutanol 400 mg, the yield was 91%.
  • Step 2) Mix 1-(hydroxymethyl)cyclobutanol (400mg, 3.92mmol), p-toluenesulfonyl chloride (1.12g, 5.87mmol), triethylamine (1.19g, 11.75mmol, 1.64mL), DMAP (47.85 mg, 391.65 ⁇ mol) was placed in dichloromethane (20 mL) and reacted at 25° C. for 16 hours under the protection of argon.
  • reaction solution was added with saturated aqueous sodium carbonate solution and stirred for 30 minutes, then extracted three times with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain (1-hydroxyl Cyclobutyl)methyl 4-p-toluenesulfonate 430 mg, yield 43%.
  • Step 3) (1-hydroxycyclobutyl)methyl 4-p-toluenesulfonate (430mg, 1.68mmol), 3-bromo-4-fluoro-phenol (106.81mg, 559.20 ⁇ mol), potassium carbonate (231.86 mg, 1.68mmol) was added into DMF (10mL), under the protection of argon, heated and stirred at 80°C for 16 hours.
  • Step 4) Mix 1-[(3-bromo-4-fluoro-phenoxy)methyl]cyclobutanol (150 mg, 545.23 ⁇ mol), 4,4,5,5-tetramethyl-2-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolin-2-yl)-1,3,2-dioxaborinane (179.99mg, 708.80 ⁇ mol), Pd(dppf )Cl 2 (23.94mg, 32.71 ⁇ mol), potassium acetate (107.02mg, 1.09mmol) were dissolved in 1,4-dioxane (10mL), under the protection of argon, slowly raised to 100°C, and reacted for 8 hours .
  • Step 5) (1-(4-bromopyridin-2-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole -1-yl)methanone (100mg, 222.57 ⁇ mol), 1-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2 -yl)phenoxy]methyl]cyclobutanol (107.56mg, 333.86 ⁇ mol), potassium carbonate (61.52mg, 445.15 ⁇ mol), Pd(dppf)Cl 2 (16.29mg, 22.26 ⁇ mol) dissolved in 1,4- In a mixed solvent of dioxane (5 mL) and water (0.5 mL), under the protection of argon, slowly raise the temperature to 100° C., and react for 8 hours.
  • reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration and decompression, the solvent was concentrated and purified by column chromatography to obtain (5-(3,5-difluorophenyl)- 4,5-Dihydro-1H-pyrazol-1-yl)(1-(4-(2-fluoro-5-((1-hydroxycyclobutyl)methoxy)phenyl)pyridin-2-yl )piperidin-4-yl)methanone (40 mg, 32% yield).
  • Step 1) 3,5-difluorobenzaldehyde (800mg, 5.63mmol) was placed in THF (18mL), NaBH 4 (354mg) was added to the solution in batches at 0°C, and reacted at 0°C for 2 hours. The reaction solution was quenched by adding 0.5 mL of acetone, concentrated under reduced pressure, and purified by a silica gel column to finally obtain 800 mg of diduterium-(3,5-difluorophenyl)methanol with a yield of 97.24%.
  • Step 2) Put diduterium-(3,5-difluorophenyl)methanol (800mg, 5.47mmol) in dichloromethane (54mL), add MnO 2 (2.38g) to the solution, and react at 25°C for 20 Hour. The reaction solution was collected by filtration and then concentrated under reduced pressure to finally obtain 600 mg of crude deuterated 3,5-difluorobenzaldehyde with a yield of 77%.
  • Step 3 Put deuterated 3,5-difluorobenzaldehyde (143mg, 999.24 ⁇ mol) and acetaldehyde (66.03mg, 1.50mmol) in water, under the protection of argon, add 1N Aqueous NaOH solution (1.1 mL) was reacted at 25°C for 16 hours.
  • Step 4) Add hydrazine hydrate (17.05 mg, 532.08 ⁇ mol) into ethanol (2 mL), add acetic acid (36.21 mg, 603.03 ⁇ mol, 34.49 ⁇ L) under stirring, raise the temperature to 40°C, and slowly add (E) -3-Deuterium-3-(3,5-difluorophenyl)prop-2-enal (60 mg, 354.72 ⁇ mol), heated at 80°C with sealed tube and reacted overnight.
  • Step 5) 1-[4-[2-fluoro-5-(2-hydroxy-2-methyl-propoxy)phenyl]-2-pyridyl]piperidinyl-4-carboxylic acid (178.13mg ,458.58 ⁇ mol), 5-deuterium-5-(3,5-difluorophenyl)-4,5-dihydropyrazole (70mg, 382.15 ⁇ mol), HATU (174.36mg, 458.58 ⁇ mol), DIEA (148.17mg , 1.15mmol, 199.68 ⁇ L) were placed in DMF (5mL) and reacted at 25°C for 16 hours under the protection of argon.
  • reaction solution was diluted with dichloromethane and washed with saturated brine, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the obtained product was further purified by HPLC to finally obtain (5-(3,5- Difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl-5-deuterium)(1-(4-(2-fluoro-5-(2-hydroxy-2-methylpropoxy yl) phenyl) pyridin-2-yl) piperidin-4-yl) ketone 50 mg, yield 24%.
  • the first step 3-bromo-4-fluoro-phenol (5g, 26.18mmol), 2,2-dimethyloxirane (5.66g, 78.54mmol), potassium carbonate (10.85g, 78.54mmol) In DMF (50 mL), react at 100° C. for 16 hours under the protection of argon.
  • the reaction solution was diluted with dichloromethane and washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to finally obtain 1-(3-bromo-4-fluoro-phenoxy)-2-methyl yl-propan-2-ol (5 g, 19.00 mmol, yield 72.6%).
  • the second step 1-(3-bromo-4-fluoro-phenoxy)-2-methyl-propan-2-ol (30g, 114.02mmol), pinacol ester (34.75g, 136.83mmol), Potassium acetate (22.38g, 228.05mmol), Pd(dppf)Cl 2 (4.17g, 5.70mmol) were placed in 1,4-dioxane (300mL), and reacted at 90°C for 16 hours under the protection of argon .
  • reaction liquid was filtered and concentrated under reduced pressure, and the crude product was purified by column chromatography to finally obtain 1-[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)phenoxy]-2-methyl-propan-2-ol (25 g, 80.60 mmol, yield 70.7%).
  • reaction solution was lowered to room temperature, it was diluted with water, extracted twice with ethyl acetate, the organic phases were combined, washed three times with saturated brine, then dried and concentrated, and the residue was purified by silica gel column chromatography to obtain the product 1-(4-bromo- 2-pyridyl)piperidinyl-4-carboxylic acid methyl ester (5.1g, 17.05mmol, yield 85.2%)
  • the first step 1-[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolin-2-yl)phenoxy]-2- Methyl-propan-2-ol (372.20mg, 1.2mmol) and 1-(4-bromo-2-pyridyl)piperidinyl-4-carboxylic acid methyl ester (299.16mg, 1.00mmol) were dissolved in 1,4- Add Pd(dppf)Cl 2 (878.04mg, 1.20mmol) to dioxane (10mL), replace the nitrogen atmosphere, raise the temperature to 80°C for 1 hour, cool the system down to room temperature, filter with diatomaceous earth, and concentrate the filtrate to obtain the crude product , purified on a silica gel plate to obtain 1-[4-[2-fluoro-5-(2-hydroxyl-2-methyl-propoxy)phenyl]-2-pyridyl]piperidinyl-4-carboxylic acid methyl
  • HT29 cells in good condition, resuspend and count them with McCoy's 5A complete medium, plant the cells in a 12-well plate at a cell density of 1 ⁇ 10 6 /1 mL/well, and place them overnight in a cell culture incubator at 37°C.
  • A Fluorescence intensity value of phosphorylated target protein in drug-dosed group/fluorescence intensity value of target protein in drug-added group
  • Example 40 The compound of Example 40 was tested by the above method, and the results are shown in Figure 1 and Figure 2.
  • Figure 1 is a Western Blot picture of the total protein and phosphorylated protein of RIPK1 under different concentrations of the compound, and Figure 2 is based on the bands in the above figure.
  • the ratio of RIPK1 phosphorylation relative to the total protein expression of RIPK1 was obtained by quantitative calculation of the fluorescence intensity value.
  • the experimental results showed that the compound of Example 40 directly inhibited the phosphorylation activity of RIPK1 in a dose-dependent manner, but had no obvious inhibitory effect on RIPK1.
  • TNF- ⁇ the initial concentration is 100 ⁇ g/mL
  • Z-VAD-FMK dissolved in DMSO to make 10mM solution
  • AT-406 Dissolve in DMSO to make 10mM solution.
  • HT29 was cultured in McCOY's5A medium containing 10% fetal bovine serum, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin; L929 was cultured in 10% horse serum, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin cultured in MEM medium.
  • Table 5 lists the assay results of some compounds in the present invention inhibiting HT29 and L929 cell necrosis, wherein A indicates that IC50 is less than or equal to 10nM, B indicates that IC50 is greater than 10nM but less than or equal to 50nM, and C indicates that IC50 is greater than 50nM but less than Or equal to 100nM, D means IC50 is greater than 100nM but less than or equal to 400nM, E means IC50 is greater than 400nM but less than or equal to 4000nM, F means IC50 is greater than 4000nM.
  • the compound of the present application has excellent inhibitory activity on human HT29 cells and mouse L929 cells, and the inhibitory activity on human HT29 cells is better than that on mouse L929 cells. Inhibitory activity, but the difference is small.
  • the compounds of Comparative Example 1 and Comparative Example 2 have significantly inferior inhibitory activity to human HT29 cells than the compound of the present application. At the same time, the two have almost no inhibitory activity on mouse L929 cells, and no meaningful test results have been obtained.
  • IV group Weigh an appropriate amount of the compound to be tested, completely dissolve it in an appropriate volume of solvent, and perform stirring, vortexing and/or sonication. After obtaining the solution, gradually increase the solvent to the final volume to achieve the target concentration, vortex and sonicate to obtain a homogeneous solution, and filter it with a 0.22 ⁇ m PVDF membrane.
  • Oral administration (PO) group Weigh an appropriate amount of the compound to be tested, completely dissolve it in an appropriate volume of solvent, and perform stirring, vortexing and/or sonication. After obtaining the solution, gradually increase the solvent to the final volume to achieve the target concentration, vortex, and sonicate to obtain a homogeneous solution.
  • the animals were randomly divided into groups according to their body weights, and the weights of the animals in each group were equal (not more than ⁇ 20% of the average body weight) after grouping. At the same time, the IV group did not fast, and the PO group fasted overnight (>12 hours), and food was given 2 hours after administration. All animals had free access to water. Table 10 and Table 11 below give the dosing schedule and pharmacokinetic sampling schedule, respectively.
  • Rats were administered according to the above scheme, and blood and brain tissue samples were collected and processed at predetermined time points (collection and processing
  • mice were administered according to the above scheme, and blood and brain tissue samples were collected and processed at predetermined time points (collection and processing were performed according to conventional methods in the art).
  • Brains were weighed and homogenized by adding 4 times ultrapure water. Add 6 times the volume of acetonitrile to the whole blood sample and brain homogenate (add 20 times the volume of acetonitrile to the whole blood sample of mouse PK), vortex for 1 min, and centrifuge at 4500 rpm for 15 min at 4°C. According to the response of the instrument, the supernatant is used The diluent was diluted and samples were analyzed by LC/MS.
  • Pharmacokinetic parameter calculations will be performed with WinNonlin software. When plasma/whole blood drug concentration-time data are available, the following pharmacokinetic parameters will be calculated: CL (clearance); V d (apparent volume of distribution); T 1/2 (elimination half-life); C max (peak concentration); T max (peak time); AUC (area under the plasma concentration-time curve); MRT (mean residence time); F% (bioavailability).
  • test results are shown in the following tables 12-14, which respectively provide the blood drug concentrations of the compounds 18, 40 and 42 of the examples of the present application at various time points, and the values of each pharmacokinetic parameter, and at the same time provide the results of the implementation of the present application.
  • the biological data provided by the present invention indicate that the compounds of the present invention are beneficial for the treatment or prevention of diseases caused by RIPK1 kinase abnormality. Therefore, the compounds of the present invention are beneficial for the treatment of diseases related to RIPK1 including fundus diseases, dry eye syndrome, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Rohn's disease, atherosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, Cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, stomach cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leuk

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Obesity (AREA)
  • Ophthalmology & Optometry (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Oncology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Orthopedic Medicine & Surgery (AREA)

Abstract

提供具有式（I）结构的羰基桥连杂环类化合物、立体异构体或其药学上可接受的盐，以及含有这些化合物的药物组合物和这些化合物或组合物在药物制备中的应用。所述化合物、立体异构体及其药学上可接受的盐等可用于与受体相互作用蛋白1激酶（RIPK1）相关的自身免疫性疾病、肿瘤以及神经退行性疾病的治疗或预防。

Description

羰基桥连杂环类化合物、及其组合物与应用 技术领域
本发明属于药物化学领域，具体涉及一类羰基桥连杂环类化合物、其立体异构体、药学上可接受的盐，及其药物组合物和它们在治疗与受体相互作用蛋白1激酶(RIPK1)相关的自身免疫性疾病、肿瘤、炎症性疾病以及神经退行性疾病的药物制备中的应用。
背景技术
早期，人们认为细胞的死亡方式主要有两种，细胞凋亡(apoptosis)与细胞坏死(necrosis)。细胞凋亡是细胞为维持机体内环境稳定，由基因所控制的细胞自主有序的死亡，在生物体的进化、内环境的稳定以及系统发育中起着重要的作用。细胞坏死则是细胞受到物理、化学等环境因素的影响，如机械损伤、毒物、微生物、辐射等，引起的细胞死亡的病理过程。2005年，Degterev A等首次发现并报道了一种通过一系列生化分子调控的有序的细胞坏死过程，并命名为坏死性凋亡(Necroptosis，也称程序性坏死)，该过程是一种用TNF-α、FasL或者TRAIL等刺激死亡受体产生的程序性的细胞坏死，形态学上表现出细胞肿胀、细胞体积增大、细胞器功能紊乱、细胞膜完整性受破坏、细胞内容物释放以及ROS的大量产生等。细胞坏死性凋亡最初被认为是宿主为了抵抗具有抗凋亡作用的病毒而进化产生的一种防御方式，但是后期发现伴随着坏死性凋亡的发生会导致炎性因子失衡，引起急性或慢性炎症性疾病。
受体相互作用蛋白1激酶(RIPK1)属于TKL家族丝氨酸/苏氨酸蛋白激酶。RIPK丝氨酸/苏氨酸激酶家族成员具有相同的N-末端激酶结构域，但是具有不同的结合结构域。研究发现，受体相互作用蛋白1可调控细胞凋亡过程。RIPK-1的死亡结构域与TNFR1、Fas、TRAILR1、TRAILR2等死亡受体结合，它们也能与含有死亡结构域的其他蛋白结合，比如TRADD、FADD等，与后者结合是激活caspase-8以及诱导凋亡的必备条件。RIPK-1中间结构为RIPK同型相互作用靶点，通过该位置RIPK-1能够与RIPK-3相互作用。Kelliher等研究发现RIPK-1先天缺陷的小鼠因细胞的大量凋亡，出生后不到3天便死亡，这说明RIPK-1也参与调节细胞凋亡。另外，先天RIPK-1缺陷的细胞对TNF诱导的细胞死亡相当敏感，或许是因为该种细胞不能有效的激活NF-kB。
另一方面，研究也发现RIPK-1以及RIPK-3也参与细胞的坏死性凋亡过程。大多数细胞类型中，死亡受体TNFR1、Fas以及TRAILR介导细胞凋亡。激活TNFR1能够通过cIAP1以及cIAP2触发RIPK-1的泛素化，泛素化的RIPK-1决定细胞下一步的去向是继续存活还是走向死亡。当细胞凋亡通路被泛caspase抑制剂z-VAD-fmk阻断后，细胞的死亡便走向坏死性凋亡。在该过程中，RIPK-1的活性是关键因素，它受FasL、TNF以及TRAIL死亡受体调控。
最近的研究表面，坏死性凋亡过程与多种疾病相关，包括肿瘤、自身免疫性疾病、神经退行性疾病、炎症性疾病等等。由此可知，RIP家族激酶与肿瘤、自身免疫性疾病、神经退行性疾病、炎症性疾病等多种疾病的发生有着密切的关系。
例如，在针对阿尔兹海默病的研究中，Claudia Balducci等人研究发现，活化的小神经胶质细胞在阿 尔兹海默病的演化中扮演了重要的角色(Pharmacological Research.2018；130：402-413)。同时，小神经胶质细胞高度表达RIPK-1，RIPK-1抑制剂在体外可以保护Aβ诱导的神经元死亡并降低小神经胶质细胞的增殖。而且，在阿尔兹海默样的大鼠模型中，RIPK-1抑制剂可以改善其学习和记忆能力。除阿尔兹海默病外，RIPK-1抑制剂也有望用于其他多种神经退行性疾病包括帕金森病、肌萎缩侧索硬化症和Huntington病等。
目前关于RIPK-1抑制剂的研究不是很多，只有少量进入了临床阶段的研究。亟需更多基于RIPK-1抑制剂的药品的研究和开发。另一方面，能够穿透血脑屏障的RIPK-1抑制剂更是少有研究。对于上文提及的阿尔兹海默病以及许多其他神经退行性疾病来说，药物穿透血脑屏障的能力对治疗效果至关重要。
另外，在现代的药物研发中，临床前动物试验是非常重要的一环，在研究初期通常通过大鼠或者小鼠进行试验。从转换医学的角度来看，动物模型及其结果与相应的人类疾病的病理生理和治疗，应该具有相应性和适应性。因此，需要开发的化合物在人与鼠之间的生物活性最好有较小的种属差异。GSK在专利申请WO018/092089中公开了大量具有一定RIPK-1抑制活性的化合物，但是这些化合物对于鼠源细胞的抑制活性较差，不利于通过动物实验进行药物开发。
本申请提供了一类羰基桥连杂环类化合物，表现出良好的RIPK-1抑制活性以及穿透血脑屏障的能力。值得强调的是此类化合物，不仅对人源RIPK-1具有极强的抑制活性，同时对鼠源RIPK-1也具有极强的抑制活性。换句话说，本申请的化合物用动物实验的结果外推至人的疾病有一定的相似性和适应性，有利于通过动物实验进行药物开发，有望作为RIPK-1抑制剂应用于治疗肿瘤、自身免疫性疾病、神经退行性疾病和炎症性疾病的药物的制备中。
发明内容
本发明所提供式(I)表示的化合物，其药学上可接受的盐，或立体异构体，其可用于制备治疗或预防与RIPK1相关的疾病的药物。
Figure PCTCN2023070093-appb-000001
式(I)中，
式(I)中，X为CH或者N；
L为O、S、NH、羰基、砜基或者亚砜基；
R 1为C 1-C 10烷基、C 3-C 8环烷基、4-8元杂脂环基、或者由1至3个选自羟基、C 1-C 6烷氧基、氰基、-NR aR b、C 3-C 8环烷基氧基、-CONH-R 5、C 3-C 8环烷基、羟基和/或C 1-C 4烷基取代C 3-C 8环烷基、羧基、卤素、卤代C 1-C 6烷氧基、-SO 2-R 5、-SO-R 5、-CO-R 5、C 2-C 6炔基、C 2-C 6烯基、C 1-C 4烷氧基C 1-C 6烷氧基、4-8元杂脂环基、氧代取代4-8元杂脂环基、羟基和/或C 1-C 4烷基取代4-8元杂脂环基、C 1-C 6烷硫基中的取代基所取代的C 1-C 10烷基，
所述4-8元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-8元杂脂环基，
R 5为氢、羟基、C 1-C 6烷基、C 1-C 6烷氧基C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基、4-8元杂脂环基取代C 1-C 6烷基，
R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 8环烷基、C 1-C 6烷氧基取代C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基C 1-C 6烷基、4-8元杂脂环基取代C 1-C 6烷基、C 1-C 3烷硫基取代C 1-C 6烷基、单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基；
R 2为氢、C 1-C 3烷基、C 1-C 3烷氧基、卤素；
R 3、R 4各自独立地为氢、卤素、甲基。
在一些实施方案中，优选地，所述化合物具有如下式(II)的结构：
Figure PCTCN2023070093-appb-000002
式(II)中，
R 1为C 1-C 10烷基、C 3-C 8环烷基、4-8元杂脂环基、或者由1至3个选自羟基、C 1-C 6烷氧基、氰基、-NR aR b、C 3-C 8环烷基氧基、-CONH-R 5、C 3-C 8环烷基、羟基和/或C 1-C 4烷基取代C 3-C 8环烷基、羧基、卤素、卤代C 1-C 6烷氧基、-SO 2-R 5、-SO-R 5、-CO-R 5、C 2-C 6炔基、C 2-C 6烯基、C 1-C 4烷氧基C 1-C 6烷氧基、4-8元杂脂环基、氧代取代4-8元杂脂环基、羟基和/或C 1-C 4烷基取代4-8元杂脂环基、C 1-C 6烷硫基中的取代基所取代的C 1-C 10烷基，
所述4-8元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-8元杂脂环基，
R 5为氢、羟基、C 1-C 6烷基、C 1-C 6烷氧基C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基、4-8元杂脂环基取代C 1-C 6烷基，
R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 8环烷基、C 1-C 6烷氧基取代C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基C 1-C 6烷基、4-8元杂脂环基取代C 1-C 6烷基、C 1-C 3烷硫基取代C 1-C 6烷基、单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基；
R 2为氢、C 1-C 3烷基、C 1-C 3烷氧基、卤素；
R 3、R 4各自独立地为氢、卤素、甲基。
在一些实施方案中，优选地，R 1为C 1-C 8烷基、C 3-C 6环烷基、4-6元杂脂环基、或者由1至3个选自羟基、C 1-C 3烷氧基、氰基、C 3-C 6环烷基氧基、C 3-C 6环烷基、羟基和/或C 1-C 4烷基取代C 3-C 6环烷基、卤素、4-6元杂脂环基、氧代取代4-6元杂脂环基、羟基和/或C 1-C 4烷基取代4-6元杂脂环基、C 1-C 3烷硫基中的取代基所取代的C 1-C 8烷基，
所述4-6元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-6元杂脂环基。
在一些实施方案中，优选地，R 1为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、己基、辛基、环丁基、环戊基、环己基、四氢呋喃-2-基、四氢呋喃-3-基、四氢吡喃-2-基、四氢吡喃-3-基、四氢吡喃-4-基、或者由1至3个选自羟基、甲氧基、乙氧基、丙氧基、异丙氧基、氰基、环丁基氧基、环戊基氧基、环己基氧基、环丁基、环戊基、环己基、4-羟基环己基、4-羟基-4-甲基环己基、氟、氯、四氢呋喃-2-基、四氢呋喃-3-基、四氢吡喃-2-基、四氢吡喃-3-基、四氢吡喃-4-
基、吡咯烷-1-基、吡咯烷-2-基、哌啶-1-基、哌啶-4-基、吗啉基、硫代吗啉基、1-甲基-吡咯烷-2-基、1-甲基-哌啶-4-基、甲硫基、乙硫基、丙硫基、异丙硫基中的取代基所取代的C 1-C 8烷基。
在一些实施方案中，更优选地，R 1为甲基、乙基、丙基、丁基、戊基、己基、羟乙基、羟丙基、羟丁基、羟戊基、羟己基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、四氢吡喃-4-基、4-甲基-4-羟基戊基、四氢吡喃-4-基乙基、四氢吡喃-4-基甲基、四氢吡喃-4-基丙基、四氢吡喃-4-基丁基、3-甲基-3-羟基丁基、2-甲基-2-羟基丙基、5-甲基-5-羟基己基、氟丙基、氟乙基、2,2-二氟-3-羟基-丙基。
在一些实施方案中，R 1为被1-羟基环丙基、1-羟基环丁基、1-羟基环戊基或1-羟基环己基所取代的C 1-C 8烷基；
更优选地，R 1为1-羟基环丙基甲基、1-羟基环丁基甲基。
在一些实施方案中，更优选地，R 1为羟基和/或卤素取代C 1-C 6烷基；最优选地，R 1为羟乙基、羟丙基、羟丁基、羟戊基、羟己基、2-甲基-2-羟基丙基、3-甲基-3-羟基丁基、4-甲基-4-羟基戊基、5-甲基-5-羟基己基、氟丙基、氟乙基、2,2-二氟-3-羟基-丙基。
在一些实施方案中，优选地，R 2为氢、甲基、甲氧基、氟、氯、溴；
更优选地，R 2为氟。
在一些实施方案中，优选地，R 3、R 4各自独立地为氢、氟、氯、甲基；
更优选地，R 3、R 4各自独立地为氟。
在一些实施方案中，优选地，所述化合物具有如下式(III)的结构：
Figure PCTCN2023070093-appb-000003
式(III)，
其中，X为CH或者N；
L为O、S、NH、羰基、砜基或者亚砜基；
R 1为C 1-C 10烷基、C 3-C 8环烷基、4-8元杂脂环基、或者由1至3个选自羟基、C 1-C 6烷氧基、氰基、-NR aR b、C 3-C 8环烷基氧基、-CONH-R 5、C 3-C 8环烷基、羟基和/或C 1-C 4烷基取代C 3-C 8环烷基、羧基、卤素、卤代C 1-C 6烷氧基、-SO 2-R 5、-SO-R 5、-CO-R 5、C 2-C 6炔基、C 2-C 6烯基、C 1-C 4烷氧基C 1-C 6烷氧基、4-8元杂脂环基、氧代取代4-8元杂脂环基、羟基和/或C 1-C 4烷基取代4-8元杂脂环基、C 1-C 6烷硫基中的取代基所取代的C 1-C 10烷基，
所述4-8元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-8元杂脂环基，
R 5为氢、羟基、C 1-C 6烷基、C 1-C 6烷氧基C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基、4-8元杂脂环基取代C 1-C 6烷基，
R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 8环烷基、C 1-C 6烷氧基取代C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基C 1-C 6烷基、4-8元杂脂环基取代C 1-C 6烷基、C 1-C 3烷硫基取代C 1-C 6烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基；
R 2为氢、C 1-C 3烷基、C 1-C 3烷氧基、卤素；
R 3、R 4各自独立地为氢、卤素、甲基。
在一些实施方案中，优选地，所述化合物具有如下式(IV)的结构：
Figure PCTCN2023070093-appb-000004
式(IV)，
其中，R 1为C 1-C 10烷基、C 3-C 8环烷基、4-8元杂脂环基、或者由1至3个选自羟基、C 1-C 6烷氧基、氰基、-NR aR b、C 3-C 8环烷基氧基、-CONH-R 5、C 3-C 8环烷基、羟基和/或C 1-C 4烷基取代C 3-C 8环烷基、羧基、卤素、卤代C 1-C 6烷氧基、-SO 2-R 5、-SO-R 5、-CO-R 5、C 2-C 6炔基、C 2-C 6烯基、C 1-C 4烷氧基C 1-C 6烷氧基、4-8元杂脂环基、氧代取代4-8元杂脂环基、羟基和/或C 1-C 4烷基取代4-8元杂脂环基、C 1-C 6烷硫基中的取代基所取代的C 1-C 10烷基，
所述4-8元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-8元杂脂环基，
R 5为氢、羟基、C 1-C 6烷基、C 1-C 6烷氧基C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基、4-8元杂脂环基取代C 1-C 6烷基，
R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 8环烷基、C 1-C 6烷氧基取代C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基C 1-C 6烷基、4-8元杂脂环基取代C 1-C 6烷基、C 1-C 3烷硫基取代C 1-C 6烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基；
R 2为氢、C 1-C 3烷基、C 1-C 3烷氧基、卤素；
R 3、R 4各自独立地为氢、卤素、甲基。
在一些实施方案中，优选地，R 1为C 1-C 8烷基、C 3-C 6环烷基、4-6元杂脂环基、或者由1至3个选自羟基、C 1-C 3烷氧基、氰基、C 3-C 6环烷基氧基、C 3-C 6环烷基、羟基和/或C 1-C 4烷基取代C 3-C 6环烷基、卤素、4-6元杂脂环基、氧代取代4-6元杂脂环基、羟基和/或C 1-C 4烷基取代4-6元杂脂环基、C 1-C 3烷硫基中的取代基所取代的C 1-C 8烷基，
所述4-6元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-6元杂脂环基。
在一些实施方案中，优选地，R 1为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、己基、辛基、环丁基、环戊基、环己基、四氢呋喃-2-基、四氢呋喃-3-基、四氢吡喃-2-基、四氢吡喃-3-基、四氢吡喃-4-基、或者由1至3个选自羟基、甲氧基、乙氧基、丙氧基、异丙氧基、氰基、环丁基氧基、环戊基氧基、环己基氧基、环丁基、环戊基、环己基、4-羟基环己基、4-羟基-4-甲基环己基、氟、氯、四氢呋喃-2-基、四氢呋喃-3-基、四氢吡喃-2-基、四氢吡喃-3-基、四氢吡喃-4-基、吡咯烷-1-基、吡咯烷-2-基、哌啶-1-基、哌啶-4-基、吗啉基、硫代吗啉基、1-甲基-吡咯烷-2-基、1-甲基-哌啶-4-基、甲硫基、乙硫基、丙硫基、异丙硫基中的取代基所取代的C 1-C 8烷基。
在一些实施方案中，更优选地，R 1为甲基、乙基、丙基、丁基、戊基、己基、羟乙基、羟丙基、羟丁基、羟戊基、羟己基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、四氢吡喃-4-基、4-甲基-4-羟基戊基、四氢吡喃-4-基乙基、四氢吡喃-4-基甲基、四氢吡喃-4-基丙基、四氢吡喃-4-基丁基、3-甲基-3-羟基丁基、2-甲基-2-羟基丙基、5-甲基-5-羟基己基、氟丙基、氟乙基、2,2-二氟-3-羟基-丙基。
在一些实施方案中，R 1为被1-羟基环丙基、1-羟基环丁基、1-羟基环戊基或1-羟基环己基所取代的C 1-C 8烷基；
更优选地，R 1为1-羟基环丙基甲基、1-羟基环丁基甲基。
在一些实施方案中，更优选地，R 1为羟基和/或卤素取代C 1-C 6烷基；最优选地，R 1为羟乙基、羟丙基、羟丁基、羟戊基、羟己基、2-甲基-2-羟基丙基、3-甲基-3-羟基丁基、4-甲基-4-羟基戊基、5-甲基-5-羟基己基、氟丙基、氟乙基、2,2-二氟-3-羟基-丙基。
在一些实施方案中，优选地，R 2为氢、甲基、甲氧基、氟、氯、溴；
更优选地，R 2为氟。
在一些实施方案中，优选地，R 3、R 4各自独立地为氢、氟、氯、甲基；
更优选地，R 3、R 4各自独立地为氟。
在一些实施方案中，本申请的化合物为前述化合物的氘代化合物，更优选地为前述结构式(I)-(IV)中任一项中吡唑基5位被氘代的化合物。
本申请的典型化合物如下所示：
Figure PCTCN2023070093-appb-000005
Figure PCTCN2023070093-appb-000006
Figure PCTCN2023070093-appb-000007
Figure PCTCN2023070093-appb-000008
根据本申请的一些实施方案，所述化合物的药学上可接受的盐为选自所述化合物的盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、羟基乙酸盐、乳酸盐、琥珀酸盐、马来酸盐、酒石酸盐、苹果酸盐、柠檬酸盐、富马酸盐、葡萄糖酸盐、安息香酸盐、扁桃酸盐、甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、草酸盐、棕榈酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己氨基磺酸盐、水杨酸盐、己糖酸盐、三氟乙酸盐、铝盐、钙盐、氯普鲁卡因盐、胆碱盐、二乙醇胺盐、乙二胺盐、锂盐、镁盐、钾盐、钠盐和锌盐中的一种或多种。
本发明的另一方面涉及所述的化合物、其药学上可接受的盐、立体异构体、溶剂化物、或氘代物在制备治疗与RIPK1相关疾病的药物中的应用，其中，所述与RIPK1相关的疾病包括眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌、炎性肠病、溃疡性结肠炎、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、脊椎关节炎、痛风、SoJIA、干燥综合征、全身性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬化性胆管炎、肾炎、乳糜泻、自身免疫ITP、移植排斥、实体器官的缺血再灌注损伤、败血症、全身性炎症反应综合征、脑血管意外、心肌梗死、亨廷顿氏病、阿尔茨海默氏病、帕金森氏病、变应性疾病、哮喘、特应性皮炎、多发性硬化症、I型糖尿病、韦格纳肉芽肿、肺结节病、白塞氏病、白细胞介素-1转换酶相关的发热综 合征、慢性阻塞性肺病、肿瘤坏死因子受体相关的周期性综合症和牙周炎。
本发明的又一方面提供了一种药物组合物，该药物组合物包括本申请的酰胺基桥连杂环类化合物、其立体异构体、溶剂化物、药学上可接受的盐或氘代化合物，以及一种或多种药学上可接受的载体或赋形剂。
根据本申请的一些实施方案，该药物组合物还可以包括一种或多种其他治疗剂。
本发明还涉及一种治疗RIPK1激酶介导的疾病或病症的方法，其包括对有需要的患者(人或其他哺乳动物，尤其是人)给药治疗有效量的式(I)化合物或其盐，所述RIPK1激酶介导的疾病或病症包括前述提及的那些。
附图说明
图1示出了实施例40的化合物对RIPK1磷酸化抑制的Western Blot图片；
图2示出了实施例40的化合物对RIPK1磷酸化相对于RIPK1总蛋白的表达占比。
具体实施方式
除非另有说明，在本申请(包括说明书和权利要求书)中使用的以下术语具有下面给出的定义。在本申请中，除非另外说明，使用“或”或“和”意味着“和/或”。此外，术语“包括”以及其它形式的使用，例如“包含”、“含有”和“具有”，不是限制性的。本文使用的章节标题仅仅是为了组织的目的，而不应解释为对所述的主题的限制。
发明详述
除非有特殊说明，烷基表示具有指定数目碳原子的饱和直链、支链烃基，术语C 1-C 10烷基表示含有1至10个碳原子的烷基部分，同理C 1-C 3烷基表示含有1至3个碳原子的烷基部分，比如，C 1-C 6烷基包括甲基、乙基、丙基、异丙基、n-丁基、异丁基、仲-丁基、叔-丁基、n-戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、n-己基、2-己基和2-甲基戊基等。
当取代基术语例如“烷基”与其它取代基术语组合使用时，例如在术语“C 1-C 3烷氧基C 1-C 6烷硫基”或“羟基取代C 1-C 10烷基”中，该连接取代基术语(例如烷基或烷硫基)旨在包含二价的部分，其中连接点通过所述连接取代基。“C 1-C 3烷氧基C 1-C 6烷硫基”的实例包括但不限于甲氧基甲硫基、甲氧基乙硫基和乙氧基丙硫基等。“羟基取代C 1-C 10烷基”的实例包括但不限于羟基甲基、羟基乙基和羟基异丙基等。
烷氧基由先前描述的直链或支链烷基与-O-形成的烷基-O-基团，例如，甲氧基、乙氧基等等。类似的，烷硫基由先前描述的直链或支链烷基与-S-形成的烷基-S-基团，例如，甲硫基，乙硫基等等。
烯基和炔基包括直链、支链烯基或炔基，术语C 2-C 6烯基或者C 2-C 6炔基表示具有至少一个烯基或炔基的直链或支链烃基。
术语“卤代C 1-C 10烷基”表示在包括1到10个碳原子的烷基部分的一个或多个碳原子上具有一个或多个可以相同或不同的卤素原子的基团。“卤代C 1-C 10烷基”的实例可以包括但不限于-CF 3(三氟甲基)、-CCl 3(三氯甲基)、1,1-二氟乙基、2,2,2-三氟乙基和六氟异丙基等。类似的，术语“卤代C 1-C 10烷氧基”表示由所述的卤代C 1-C 10烷基与-O-形成的卤代烷基-O-基团，可以为例如三氟甲氧基、三氯甲氧基等等。
术语“C 1-C 3酰基”包括甲酰基(-CHO)、乙酰基(CH 3CO-)、乙酰基(C 2H 5CO-)。
术语“-CO-R 5、-SO 2-R 5、-SO-R 5、-CONH-R 5”分别表示
Figure PCTCN2023070093-appb-000009
“环烷基”表示含有指定数目碳原子的非芳香的、饱和的、环状的烃基。例如，术语“(C3-C6)环烷基”指的是具有3-6个环碳原子的非芳香的环状烃环。示例性的“(C3-C6)环烷基”包括环丙基、环丁基、环戊基和环己基。
术语“芳基”表示包含芳香的单环或双环烃原子团的基团或部分，其含有6到12个碳环原子且具有至少一个芳香环。“芳基”的实例为苯基、萘基、茚基和二氢茚基(茚满基)。通常，在本发明化合物中，芳基为苯基。
在这里使用的术语“杂脂环基”，除非有特殊说明，代表未被取代的或已被取代的稳定的4至8元非芳香的单环饱和环体系，它们由碳原子以及从N，O，S中选的1至3个杂原子组成，其中N，S杂原子可以被随意氧化，N杂原子还可以被随意季铵化。这类杂环的例子包括但不限于氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、吡咯啉基、吡唑烷基、吡唑啉基、咪唑烷基、咪唑啉基、噁唑啉基、噻唑啉基、四氢呋喃基、二氢呋喃基、四氢噻吩基、1,3-二氧杂环戊烷基、哌啶基、哌嗪基、四氢吡喃基、二氢吡喃基、四氢噻喃基、1,3-二噁烷基、1,4-二噁烷基、1,3-氧硫杂环戊烷基、1,3-氧硫杂环己烷基、1,3-二噻烷基、1,4-氧硫杂环戊烷基、1,4-氧硫杂环己烷基、1,4-二噻烷基、吗啉基、硫吗啉基。
在这里使用的术语“杂芳基”表示包含芳香的单环或双环原子团(其含有5到10个环原子)的基团或部分，其包括1到3个独立地选自氮、氧和硫的杂原子。该术语还包括双环杂环芳基，其中含有与杂环烷基环部分稠合的芳基环部分，或者含有与环烷基环部分稠合的杂芳基环部分。除非有特别说明，代表未被取代或已被取代的稳定的5或6元单环芳香环体系，也可以代表未被取代或已被取代的9或10个环原子的苯稠杂芳环体系或二环杂芳环体系，它们由碳原子和由1至3个从N，O，S中选择的杂原子组成，其中N、S杂原子可以被氧化，N杂原子还可以被季铵化。杂芳基可以和任何杂原子或碳原子连接组成一个稳定的结构。杂芳基的示例性实例包括但不限于呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、异噻唑基、吡啶基、氧代-吡啶基(吡啶基-N-氧化物)、哒嗪基、吡嗪基、嘧啶基、三嗪基、苯并呋喃基、异苯并呋喃基、2,3-二氢苯并呋喃基、1,3-苯并二氧杂环戊烯基、二氢苯并二氧杂环己烯基、苯并噻吩基、吲嗪基、吲哚基、异吲哚基、二氢吲哚基、苯并咪唑基、二氢苯并咪唑基、苯并噁唑基、二氢苯并噁唑基、苯并噻唑基、苯并异噻唑基、二氢苯并异噻唑基、吲唑基、咪唑并吡啶基、吡唑并吡啶基、苯并三唑基、三唑并吡啶基、嘌呤基、喹啉基、四氢喹啉基、异喹啉基、四氢异喹啉基、喹喔啉基、噌啉基、酞嗪基、喹唑啉基、1,5-二氮杂萘基、1,6-二氮杂萘基、1,7-二氮杂萘基、1,8-二氮杂萘基和蝶啶基。
术语“羰基”指的是-C(O)-基。术语“卤素”和“卤”表示氯、氟、溴或碘取代基。“氧代”表示双键的氧部分；例如，如果直接连接到碳原子上形成一个羰基部分(C＝O)。“羟基”旨在表示-OH原子团。本文所用术语“氰基”是指基团-CN。
术语“各自独立地”是指当一个以上的取代基选自许多可能的取代基时，那些取代基可以相同或不同。
很清楚，式I的化合物、异构体、晶型或前药及其可药用盐可以存在溶剂化形式和非溶剂化形式。例如溶剂化形式可以是水溶形式。本发明包括所有这些溶剂化的和未溶剂化的形式。
本发明的化合物可能有不对称的碳原子，根据它们的理化差异，通过已知技术上已成熟的方法，比如，通过色谱或分步结晶法，这种非对映异构的混合物可以被分离成单一的非对映异构体。对映异构体 的分离可通过先用适当有旋光活性的化合物进行反应，把对映异构的混合物转化成非对映异构的混合物，分离非对映异构体，再把单一非对映异构体转化(水解)成相应的纯的对映异构体。所有这样的异构体，包括非对映异构体混合物和纯对映体被认为是该发明的一部分。
作为活性成分的本发明的化合物，以及制备该化合物的方法，都是本发明的内容。而且，一些化合物的晶型形式可以作为多晶体存在，这种形式也可以被包括在目前的发明里。另外，一些化合物可以和水(即水合物)或普通的有机溶剂一起形成溶剂化物，这种溶剂化物也被包括在此项发明的范畴内。
本发明的化合物可以以游离的形式用于治疗，或者在适当情况下以药学上可接受的盐或其它衍生物的形式用于治疗。如本文所用，术语“药学上可接受的盐”是指本发明的化合物的有机盐及无机盐，此盐适用于人类和低等动物，无过度毒性、刺激性、过敏反应等，具有合理的利益/风险比。胺，羧酸，膦酸盐，和其它类型的化合物的药学上可接受的盐在所属领域中是众所周知的。该盐可以由本发明的化合物与合适的游离碱或酸反应而成。包括但不限于，与无机酸如盐酸、氢溴酸、磷酸、硫酸、高氯酸或与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸、丙二酸形成的盐，或通过使用本领域熟知的方法，例如离子交换法，来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、己酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、过3-苯基丙酸盐、磷酸盐、苦味酸盐、丙酸盐、硬脂酸盐、硫酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐等。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁等。其他药学上可接受的盐包括适当的无毒的铵、季铵，和使用诸如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根，低级烷基磺酸盐和芳基磺酸盐形成的胺基阳离子。
本发明的药物组合物包含本文所述结构式(I)化合物或其药学上可接受的盐、激酶抑制剂(小分子，多肽，抗体等)、免疫抑制剂、抗癌药、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增生化合物的另外的活性剂；以及任何药学上可接受的载体、佐剂或赋形剂。
本发明的化合物可以作为单独使用，也可以与一种或多种其它本发明的化合物或与一种或多种其它药剂联合使用。当联合给药时，治疗剂可以配制成同时给药或顺序地在不同的时间给药，或者所述治疗剂可以作为单一组合物给药。所谓“组合疗法”，指的是使用本发明的化合物与另一种药剂一起使用，给药方式为每种药剂同时共同给药或每种药剂顺序给药，无论哪种情况，目的都是要达到药物的最佳效果。共同给药包括同时递送剂型，以及每种化合物分别的单独剂型。因此，本发明的化合物的给药可以与已知的本领域的其他疗法同时使用，例如，在癌症治疗中使用放射治疗或细胞生长抑制剂、细胞毒性剂、其它抗癌剂等附加疗法来改善癌症状。本发明并不限于给药的顺序；本发明的化合物可以先前施用，同时施用，或在其他抗癌剂或细胞毒性剂之后施用。
为了制备这一发明的药学成分，作为其活性成分的分子式(I)的一种或多种化合物或盐类可紧密的与药学载体混合在一起，这是根据传统的制药配料技术而进行的，其中的载体可根据按不同的给药方式(例如，口服或肠外给药)设计好的制备形式而采用多种多样的形式。适当的药学上可接受的载体在技术上是众所周知的。对一些这类药学可接受的载体的描述可以在《药学赋形剂手册》里找到，该书由 美国药学会和英国药学社联合出版。
本发明药物组合物可以有以下形式，比如说，适合口服给药，例如药片，胶囊，药丸，药粉，持续释放的形式，溶液或悬浮液；用于胃肠外注射如透明液，悬浮液，乳状液；或者用于局部用药如膏，霜；亦或作为栓剂用于直肠给药。药学成分也可以单位剂量的形式适合用于精确剂量的一次性给药。该药学成分将包括一种传统的药学载体或赋形剂以及根据目前的发明制成的作为活性成分的化合物，另外，也可以包括其他的医学或药学制剂，载体，辅助剂，等等。
治疗性化合物也可给于哺乳动物而非人类。给一个哺乳动物所用的药物剂量将取决于该动物的种类以及它的疾病状况或其所处的失调状态。治疗性化合物可以以胶囊，大丸药，药片药水的形式喂给动物。也可以通过注射或灌输的方式让治疗性化合物进入动物体内。我们根据符合兽医实践标准的传统的方式制备好这些药物形式。作为一种可选择的方式，药学合成药可以同动物饲料混合在一起喂给动物，因此，浓缩的饲料添加剂或预拌和料可以备以混合普通的动物饲料。
本发明的又一目的是在于提供一种用于治疗有需要的受试者中癌症的方法，其包括给受试者施用含本发明的化合物的组合物的治疗有效量的一种方法。
本发明还包括本发明的化合物或其药学上可接受的衍生物的使用，制造用于治疗与RIPK1相关的疾病包括眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌、炎性肠病、溃疡性结肠炎、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、脊椎关节炎、痛风、SoJIA、干燥综合征、全身性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬化性胆管炎、肾炎、乳糜泻、自身免疫ITP、移植排斥、实体器官的缺血再灌注损伤、败血症、全身性炎症反应综合征、脑血管意外、心肌梗死、亨廷顿氏病、阿尔茨海默氏病、帕金森氏病、变应性疾病、哮喘、特应性皮炎、多发性硬化症、I型糖尿病、韦格纳肉芽肿、肺结节病、白塞氏病、白细胞介素-1转换酶相关的发热综合征、慢性阻塞性肺病、肿瘤坏死因子受体相关的周期性综合症和牙周炎。
本发明还提供了制备相应化合物的方法，可以使用多种合成方法制备本文所述的化合物，包括下述实施例中所涉及的方法，本发明的化合物或者其药学上可接受的盐，异构体或水合物可以使用下述方法与有机化学合成领域已知的合成方法，或通过本领域技术人员理解对这些方法的变化方法合成，优选方法包括但不限于下述方法。
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合具体实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。下面提供的实施例可以更好的说明本发明，除非特别说明，所有的温度为℃。本申请部分化合物的命名采用chemdraw生成后翻译为中文所得。
缩写
HATU–N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲
DIEA–N,N-二异丙基乙胺
DMF–N,N-二甲基甲酰胺
DMSO–二甲基亚砜
PE–石油醚(沸点60-90℃)
EA–乙酸乙酯
化合物的合成
中间体A的制备
中间体A-1的合成
Figure PCTCN2023070093-appb-000010
步骤1)：将3,5-二氟苯甲醛(30g，211.1mmol)溶于DMF中，常温搅拌下分批加入(三苯基亚正膦基)乙醛(CAS号2136-75-6)(70.7g,232.2mmol)，加热至80℃反应15小时。降至室温，加水和乙酸乙酯萃取，有机相用饱和食盐水洗涤后干燥浓缩，柱层析(洗脱剂：PE/EtOAc＝100:0至100:10)纯化得到3-(3,5-二氟苯基)丙烯醛25.1g,收率71％，MS:169[M+H] +；
步骤2)：把N 2H 4.H 2O(7.15g,223.03mmol)加入到乙醇(300mL)中，搅拌状态下，加入醋酸(14.5mL，252mmol)，升温至40℃后缓慢滴加3-(3,5-二氟苯基)丙烯醛(25g，149mmol)的乙醇(20mL)溶液，80℃反应过夜。浓缩后由柱层析(洗脱剂：PE/EtOAc＝100:0至3:1)纯化得到产物20g,收率74％，MS：183[M+H] +；
由同样的方法合成如下中间体A-2和A-3：
Figure PCTCN2023070093-appb-000011
表1.中间体A-2和A-3的结构、名称和表征数据
中间体B-1的合成：2-(2-氟-5-(3-甲氧基丙氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷
Figure PCTCN2023070093-appb-000012
步骤1)：将3-溴-4-氟苯酚(330mg,1.73mmol)、碳酸钾(718.98mg,5.20mmol)、1-溴-3-甲氧基丙烷(540mg,3.50mmol)置于DMF(5mL)中，80℃反应2小时。反应液加入水，EA萃取三次，有机相经饱和食 盐水洗涤后用无水硫酸钠干燥，过滤浓缩，粗产物经薄层色谱纯化(以PE:EA＝5:1为流动相)，得到2-溴-1-氟-(4-甲氧基丙基)苯醚(421mg,93％yield)；
步骤2)：将2-溴-1-氟-(4-甲氧基丙基)苯醚(421mg,1.60mmol)、频哪醇酯(815mg,3.21mmol)、KOAc(472mg,4.81mmol)、Pd(dppf)Cl 2(235mg,321umol)加于1,4-二氧六环(10mL)中，氩气保护条件下，100℃反应16小时。反应液加水稀释后用乙酸乙酯萃取，有机相经饱和食盐水洗后用无水硫酸钠干燥，过滤减压浓缩，柱层析纯化(以PE:EA＝5:1为流动相)，得到2-(2-氟-5-(3-甲氧基丙氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷395mg,收率80％。
由同样的方法合成如下中间体B-2——B-30：
Figure PCTCN2023070093-appb-000013
Figure PCTCN2023070093-appb-000014
Figure PCTCN2023070093-appb-000015
表2.中间体B-2——B-30的结构和名称
实施例
实施例1：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(3-(2-甲氧基乙氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮
Figure PCTCN2023070093-appb-000016
步骤1)：将1-(叔丁氧基羰基)哌啶-4-羧酸(24g,105mmol)、中间体A-1(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑)(21.9g,120mmol)、HATU(39.9g,105mmol)、DIEA(27.1g,210mmol)加入DMF(150mL)中，氩气保护条件下，25℃反应1小时。反应液使用二氯甲烷稀释，经饱和食盐水洗涤后用无水硫酸钠干燥，之后过滤减压浓缩，得到的产物进一步用柱层析纯化，最终得到33.0g,收率80％。MS:394[M+H] +；
步骤2)：将4-[3-(3,5-二氟苯基)-3,4-二氢吡唑-2-羰基]哌啶-1-羧酸叔丁酯(26g,66.09mmol)溶于1,4-二氧六环(60mL)中，然后加入盐酸(4M的1,4-二氧六环溶液体系,82.61mL)溶液，室温搅拌过夜，反应完成后抽滤，固体溶于甲醇中，然后加入碳酸钠固体，调至pH为8，搅拌30分钟，然后加乙酸乙酯稀释，抽滤，固体用乙酸乙酯洗两次，滤液旋干，柱层析纯化(二氯甲烷/甲醇/三乙胺＝500/100/5)得15.5g,收率80％。MS:294[M+H] +；
步骤3)：将(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(哌啶-4-基)甲酮(3.0g,10mmol)，2-氟-4-溴吡啶(3.5g,20mmol)和三乙胺(3.05g,30mmol)的DMSO(20ml)溶液加热至80℃反应16小时，冷却后加入乙酸乙酯稀释，水洗，干燥，浓缩，柱层析纯化得到黄色固体产物3.93g,收率88％，MS:449,451[M+H] +；
步骤4)：(1-(4-溴吡啶-2-基)哌啶-4-基)(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)甲酮(450mg,1mmol)、中间体B-2(2-(3-(2-甲氧基乙氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼烷)(250mg,1mmol)、碳酸钾(210mg,2mmol)和Pd(PPh 3) 4(58mg,0.05mmol)溶于1,4-二氧六环(8mL)和水(0.8mL)的混合溶剂中，氩气保护条件下升温至80℃搅拌反应5小时。反应液过滤，浓缩，柱层析纯化(流动相：PE/EtOAc)最终得到黄色固体产物130mg。 1H NMR(400MHz,DMSO-d 6)δ8.14(d,J＝5.2Hz,1H),7.38(t,J＝7.9Hz,1H),7.33–7.22(m,3H),7.12-7.10(m,1H),7.05(s,1H),7.01(d,J＝8.1Hz,1H),6.93–6.80(m,3H),5.34(dd,J＝11.9,4.9Hz,1H),4.50–4.41(m,2H),4.23–4.14(m,2H),3.71-3.68(m,2H),3.57–3.42(m,2H),3.32(s,3H),3.00–2.87(m,2H),2.74(dd,J＝19.0,5.0Hz,1H),1.90(d,J＝12.8Hz,1H),1.76(d,J＝13.0Hz,1H),1.58-1.54(m,2H).MS:521[M+H] +。
实施例2：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(3-(3-甲氧基丙氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-4代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.14(d,J＝5.2Hz,1H),7.38(t,J＝7.9Hz,1H),7.27(d,J＝19.0Hz,3H),7.11(t,J＝9.4Hz,1H),7.06–6.96(m,2H),6.92–6.80(m,3H),5.34(dd,J＝12.0,5.0Hz,1H),4.45(d,J＝13.0Hz,2H),4.10(t,J＝6.4Hz,2H),3.50–3.48(m,4H),3.26(s,3H),2.92(dd,J＝12.7,9.5Hz,2H),2.74(dd,J＝19.0,5.1Hz,1H),2.03–1.86(m,3H),1.76(d,J＝12.7Hz,1H),1.65–1.48(m,2H).MS:535[M+H] +。
Figure PCTCN2023070093-appb-000017
实施例3：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(3-((四氢-2H-吡喃-4-基)氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-8代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.14(d,J＝5.2Hz,1H),7.38(dd,J＝8.9,7.2Hz,1H),7.32–7.22(m,3H),7.16–7.00(m,3H),6.92–6.79(m,3H),5.34(dd,J＝11.9,4.9Hz,1H),4.69(dt,J＝8.7,4.5Hz,1H),4.45(d,J＝11.8Hz,2H),3.86(dt,J＝11.6,4.4Hz,2H),3.55–3.39(m,4H),2.93(dt,J＝13.0,10.3Hz,2H),2.75(dd,J＝19.1,5.0Hz,1H),2.00–1.98(m,3H),1.90(d,J＝12.5Hz,1H),1.76(d,J＝13.0Hz,1H),1.67–1.43(m,3H).MS:547[M+H] +。
实施例4：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(5-(2-甲氧基乙氧基)-2-甲基苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-20代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.27–7.07(m,3H),6.92–6.72(m,5H),6.59(d,J＝5.1Hz,1H),5.34(dd,J＝12.1,5.0Hz,1H),4.43–4.34(m,2H),4.13–4.05(m,2H),3.68–3.60(m,2H),3.51–3.49(m,2H),3.30(s,3H),3.00–2.86(m,2H),2.80–2.68(m,1H),2.16(s,3H),1.88(d,J＝12.9Hz,1H),1.74(d,J＝13.0Hz,1H),1.53–1.50(m,2H).MS:535[M+H] +。
Figure PCTCN2023070093-appb-000018
实施例5：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(5-(3-甲氧基丙氧基)-2-甲基苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-21代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.27–7.06(m,3H),6.91–6.79(m,3H),6.78–6.71(m,2H),6.57(dd,J＝5.1,1.2Hz,1H),5.34(dd,J＝12.0,5.0Hz,1H),4.39(d,J＝12.0Hz,2H),4.01(t,J＝6.4Hz,2H),3.55–3.41(m,4H),3.24(s,3H),2.99–2.85(m,2H),2.74(dd,J＝19.0,5.0Hz,1H),2.15(s,3H),1.98–1.84(m,3H),1.74(d,J＝12.8Hz,1H),1.64–1.43(m,2H).MS:549[M+H] +。
实施例6：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-甲基-5-((四氢-2H-吡喃-4-基))氧基)苯基)吡 啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-23代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.27–7.06(m,3H),6.96–6.77(m,4H),6.73(s,1H),6.57(dd,J＝5.1,1.2Hz,1H),5.34(dd,J＝12.0,5.0Hz,1H),4.57(dt,J＝8.7,4.5Hz,1H),4.39(d,J＝13.0Hz,2H),3.83(dt,J＝11.6,4.4Hz,2H),3.55–3.41(m,4H),2.92(q,J＝11.2Hz,2H),2.74(dd,J＝19.0,5.0Hz,1H),2.15(s,3H),2.02–1.84(m,4H),1.73(d,J＝13.0Hz,1H),1.63–1.46(m,3H).MS:561[M+H] +。
Figure PCTCN2023070093-appb-000019
实施例7：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(3-(4-羟基丁氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-5代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.14(d,J＝5.2Hz,1H),7.38(t,J＝7.9Hz,1H),7.32–7.21(m,3H),7.16–7.07(m,1H),7.06–6.95(m,2H),6.93–6.80(m,3H),5.34(dd,J＝12.0,5.0Hz,1H),4.51–4.41(m,3H),4.06(t,J＝6.5Hz,2H),3.51–3.42(m,4H),2.93(q,J＝11.5Hz,2H),2.74(dd,J＝19.1,5.1Hz,1H),1.90(d,J＝12.9Hz,1H),1.83–1.71(m,3H),1.65–1.45(m,4H).MS:535[M+H] +。
实施例8：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(3-((4-羟基-4-甲基戊基)氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-7代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.14(d,J＝5.2Hz,1H),7.38(t,J＝7.9Hz,1H),7.31–7.20(m,3H),7.12(tt,J＝9.3,2.3Hz,1H),7.06–6.95(m,2H),6.92–6.79(m,3H),5.39–5.30(m,1H),4.45(d,J＝13.4Hz,2H),4.20(s,1H),4.04(t,J＝6.5Hz,2H),3.54–3.36(m,2H),2.93(td,J＝12.6,9.4Hz,2H),2.75(dd,J＝19.0,5.0Hz,1H),2.06–1.84(m,2H),1.84–1.72(m,3H),1.64–1.46(m,3H),1.11(s,6H).MS:563[M+H] +。
Figure PCTCN2023070093-appb-000020
实施例9：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(5-(4-羟基丁氧基)-2-甲基苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-22代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.0Hz,1H),7.27–7.07(m,3H),6.86–6.84(m,3H),6.78–6.70 (m,2H),6.57(d,J＝5.1Hz,1H),5.39–5.29(m,1H),4.48–4.34(m,3H),3.97(t,J＝6.5Hz,2H),3.54–3.39(m,4H),2.92(q,J＝11.0,10.6Hz,2H),2.81–2.68(m,1H),2.15(s,3H),2.06–1.95(m,1H),1.88(d,J＝12.9Hz,1H),1.75–1.65(mp,3H),1.63–1.43(m,3H).MS:549[M+H] +。
实施例10：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(5-((4-羟基-4-甲基戊基)氧基)-2-甲基苯基))吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-25代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.27–7.06(m,3H),6.87–6.84(m,3H),6.77–6.70(m,2H),6.57(dd,J＝5.1Hz,1H),5.34(dd,J＝12.1,4.9Hz,1H),4.39(d,J＝12.9Hz,2H),4.17(s,1H),3.95(t,J＝6.6Hz,2H),3.54–3.39(m,2H),2.99–2.88(m,2H),2.74(dd,J＝19.1,5.0Hz,1H),2.15(s,3H),2.05–1.99(m,1H),1.88(d,J＝12.9Hz,1H),1.80–1.68(m,3H),1.61–1.42(m,3H),1.10(s,6H).MS:577[M+H] +。
Figure PCTCN2023070093-appb-000021
实施例11：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-甲基)-5-(2-(四氢-2H-吡喃-4-基)乙氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-28代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.27–7.06(m,3H),6.91–6.79(m,3H),6.79–6.71(m,2H),6.58(d,J＝5.1Hz,1H),5.34(dd,J＝12.0,5.0Hz,1H),4.38(d,J＝11.8Hz,2H),4.01(t,J＝6.3Hz,2H),3.87–3.78(m,2H),3.49–3.48(m,2H),3.27–3.25(m,4H),2.92(q,J＝11.1,10.6Hz,2H),2.74(dd,J＝19.1,5.1Hz,1H),2.15(s,3H),1.99(t,J＝7.4Hz,1H),1.88(d,J＝12.9Hz,1H),1.78–1.43(m,7H).MS:589[M+H] +。
实施例12：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(3-(3-羟基丙氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-3代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.14(d,J＝5.2Hz,1H),7.38(t,J＝7.9Hz,1H),7.32–7.22(m,3H),7.12(tt,J＝9.4,2.3Hz,1H),7.06–6.97(m,2H),6.92–6.79(m,3H),5.34(dd,J＝11.9,5.0Hz,1H),4.57(t,J＝5.1Hz,1H),4.45(d,J＝13.4Hz,2H),4.11(t,J＝6.4Hz,2H),3.63–3.42(m,4H),2.93(dt,J＝13.2,9.9Hz,2H),2.74(dd,J＝19.0,5.0Hz,1H),1.89(p,J＝6.2Hz,3H),1.76(d,J＝13.2Hz,1H),1.65–1.48(m,2H).MS:521[M+H] +。
Figure PCTCN2023070093-appb-000022
Figure PCTCN2023070093-appb-000023
实施例13：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(3-(4-甲氧基丁氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-6代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.14(d,J＝5.2Hz,1H),7.38(t,J＝7.9Hz,1H),7.32–7.21(m,3H),7.11(t,J＝9.4Hz,1H),7.06–6.96(m,2H),6.92–6.79(m,3H),5.34(dd,J＝11.9,5.0Hz,1H),4.49–4.40(m,2H),4.06(t,J＝6.3Hz,2H),3.54–3.36(m,4H),3.24(s,3H),2.93(dt,J＝12.9,9.8Hz,2H),2.74(dd,J＝19.0,5.0Hz,1H),1.90(d,J＝12.5Hz,1H),1.81–1.64(m,5H),1.55(dt,J＝20.8,12.2Hz,2H).MS:549[M+H] +。
实施例14：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(3-((四氢-2H-吡喃-4-基)甲氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-9代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.14(d,J＝5.2Hz,1H),7.38(t,J＝7.9Hz,1H),7.32–7.21(m,3H),7.12(t,J＝9.3Hz,1H),7.06–6.97(m,2H),6.93–6.80(m,3H),5.34(dd,J＝11.9,4.9Hz,1H),4.49–4.41(m,2H),3.95–3.84(m,4H),3.55–3.40(m,4H),2.93(td,J＝12.6,9.4Hz,2H),2.75(dd,J＝19.0,4.9Hz,1H),2.06–1.95(m,1H),1.90(d,J＝12.7Hz,1H),1.80–1.66(m,3H),1.55(dd,J＝21.9,12.5Hz,2H),1.36-1.32(m,2H).MS:561[M+H] +。
Figure PCTCN2023070093-appb-000024
实施例15：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(5-(3-羟基丙氧基)-2-甲基苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-24代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.27–7.22(m,1H),7.19(d,J＝8.5Hz,1H),7.12(t,J＝9.3Hz,1H),6.91–6.80(m,3H),6.78–6.70(m,2H),6.57(d,J＝5.1Hz,1H),5.34(dd,J＝11.9,5.0Hz,1H),4.53(t,J＝5.2Hz,1H),4.38(dd,J＝13.2,3.8Hz,2H),4.02(t,J＝6.4Hz,2H),3.59–3.41(m,4H),2.92(dt,J＝12.8,9.5Hz,2H),2.74(dd,J＝19.0,5.0Hz,1H),2.15(s,3H),1.92–1.79(m,3H),1.74(d,J＝12.9Hz,1H),1.64–1.44(m,2H).MS:535[M+H] +。
实施例16：(1-(4-(2-氯-5-(2-甲氧基乙氧基)苯基)吡啶-2-基)哌啶-4-基)(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-10代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.15(d,J＝5.1Hz,1H),7.45(d,J＝8.7Hz,1H),7.25(s,1H),7.17–7.07(m, 1H),7.06–6.95(m,2H),6.88–6.80(m,3H),6.66(d,J＝5.1Hz,1H),5.39–5.29(m,1H),4.39(d,J＝13.1Hz,2H),4.18–4.10(m,2H),3.69–3.62(m,2H),3.50-3.48(m,2H),3.30(s,3H),2.95-2.92(m,2H),2.74(dd,J＝18.9,5.0Hz,1H),1.89(d,J＝12.9Hz,1H),1.74(d,J＝13.0Hz,1H),1.61–1.43(m,2H).MS:555[M+H] +。
Figure PCTCN2023070093-appb-000025
实施例17：(1-(4-(2-氯-5-(3-羟基丙氧基)苯基)吡啶-2-基)哌啶-4-基)(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-11代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.15(d,J＝5.1Hz,1H),7.44(d,J＝8.8Hz,1H),7.27–7.23(m,1H),7.13-7.11(m,1H),7.04–6.92(m,2H),6.85-6.82(m,3H),6.65(d,J＝5.1Hz,1H),5.39–5.29(m,2H),4.38(d,J＝12.2Hz,2H),3.59–3.41(m,4H),2.93(d,J＝11.9Hz,2H),2.74(dd,J＝19.0,5.0Hz,1H),2.0-1.97(m,2H),1.88-1.85(m,3H),1.74(d,J＝13.0Hz,1H),1.61–1.43(m,2H).MS:555[M+H] +。
实施例18：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-(3-羟基丙氧基)苯基)吡啶-2-基))哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-12代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.15(d,J＝5.1Hz,1H),7.27–7.19(m,2H),7.16–7.04(m,2H),6.99(d,J＝9.0Hz,1H),6.93(s,1H),6.86–6.82(m,2H),6.76(d,J＝5.1Hz,1H),5.34(dd,J＝12.0,5.0Hz,1H),4.56(t,J＝5.2Hz,1H),4.40(d,J＝11.9Hz,2H),4.06(t,J＝6.4Hz,2H),3.60–3.40(m,4H),2.93(q,J＝10.8Hz,2H),2.74(dd,J＝19.0,5.0Hz,1H),1.87–1.85(m,3H),1.74(d,J＝13.0Hz,1H),1.63–1.42(m,2H).MS:539[M+H] +。
Figure PCTCN2023070093-appb-000026
实施例19：(5-(2-氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(5-(2-甲氧基乙氧基)-2-甲基苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在步骤1中用中间体A-2代替中间体A-1，在步骤4中用中间体B-20代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.0Hz,1H),7.34–7.24(m,2H),7.23–7.10(m,3H),7.05(t,J＝7.7Hz,1H),6.88(d,J＝8.4Hz,1H),6.80–6.71(m,2H),6.58(d,J＝5.1Hz,1H),5.45(dd,J＝12.1,5.1Hz,1H),4.38(d,J＝13.0Hz,2H),4.12–4.05(m,2H),3.67–3.60(m,2H),3.54–3.50(m,2H),3.30(s,3H),2.92(td,J＝12.9,7.5Hz,2H),2.71(dd,J＝19.0,5.2Hz,1H),2.15(s,3H),1.86 (d,J＝12.9Hz,1H),1.73(d,J＝12.5Hz,1H),1.58–1.46(m,2H).MS:517[M+H] +。
实施例20：(5-(2-氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(5-(3-羟基丙氧基)-2-甲基苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在步骤1中用中间体A-2代替中间体A-1，在步骤4中用中间体B-24代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.34–7.25(m,2H),7.22–7.12(m,3H),7.05(t,J＝7.7Hz,1H),6.87(d,J＝8.4Hz,1H),6.75(s,1H),6.72(s,1H),6.57(d,J＝5.1Hz,1H),5.45(dd,J＝12.0,5.1Hz,1H),4.53(t,J＝5.2Hz,1H),4.38(d,J＝13.2Hz,2H),4.02(t,J＝6.4Hz,2H),3.59–3.51(m,2H),3.32(br,2H),2.91(q,J＝11.1,10.6Hz,2H),2.77–2.64(m,1H),2.15(s,3H),2.08-2.00(m,1H),1.85(q,J＝6.4Hz,2H),1.73(d,J＝13.0Hz,1H),1.62–1.42(m,2H).MS:517[M+H] +。
Figure PCTCN2023070093-appb-000027
实施例21：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-(3-羟基-3-甲基丁氧基)苯基)吡啶)-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-13代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝5.1Hz,1H),7.30–7.19(m,2H),7.18–7.03(m,2H),7.00(t,J＝9.0Hz,1H),6.93(s,1H),6.89–6.79(m,2H),6.76(d,J＝5.0Hz,1H),5.34(dd,J＝12.0,4.9Hz,1H),4.47–4.31(m,3H),4.11(t,J＝7.2Hz,2H),3.48-3.40(m,2H),2.93(dt,J＝12.7,10.3Hz,2H),2.74(dd,J＝19.0,5.0Hz,1H),1.95–1.80(m,3H),1.75(d,J＝12.7Hz,1H),1.55-1.52(m,2H),1.16(s,6H).MS:567[M+H] +。
实施例22：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-(2-羟基乙氧基)苯基)吡啶-2-基))哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-14代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝5.1Hz,1H),7.29–7.19(m,2H),7.18–6.96(m,3H),6.93(s,1H),6.89–6.73(m,3H),5.34(dd,J＝12.0,4.9Hz,1H),4.90(br,1H),4.45–4.36(m,2H),4.03(t,J＝5.0Hz,2H),3.72(t,J＝4.9Hz,2H),3.55–3.29(m,2H),3.01–2.86(m,2H),2.74(dd,J＝19.0,5.0Hz,1H),1.89(d,J＝12.2Hz,1H),1.75(d,J＝12.5Hz,1H),1.56-1.53(m,2H).MS:525[M+H] +。
Figure PCTCN2023070093-appb-000028
实施例23：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-(2-羟基-2-甲基丙氧基)苯基)吡啶)-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-15代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝5.1Hz,1H),7.28–7.18(m,2H),7.17–6.96(m,3H),6.93(s,1H),6.88–6.80(m,2H),6.77(dd,J＝5.2,1.7Hz,1H),5.34(dd,J＝12.0,4.9Hz,1H),4.64(s,1H),4.40(d,J＝12.9Hz,2H),3.76(s,2H),3.48–3.40(m,2H),2.94(q,J＝10.7Hz,2H),2.74(dd,J＝19.0,5.0Hz,1H),1.89(d,J＝12.8Hz,1H),1.75(d,J＝12.8Hz,1H),1.63–1.43(m,2H),1.20(s,6H).MS:553[M+H] +。
实施例24：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-((4-羟基-4-甲基戊基)氧基))苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-16代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝5.2Hz,1H),7.28–7.18(m,2H),7.18–6.94(m,3H),6.93(s,1H),6.89–6.73(m,3H),5.34(dd,J＝12.0,4.9Hz,1H),4.45–4.36(m,2H),4.20(s,1H),3.99(t,J＝6.5Hz,2H),3.48–3.40(m,2H),2.93(dt,J＝13.4,10.0Hz,2H),2.74(dd,J＝19.0,5.0Hz,1H),1.94–1.85(m,1H),1.82–1.69(m,3H),1.64–1.44(m,4H),1.10(s,6H).MS:581[M+H] +。
Figure PCTCN2023070093-appb-000029
实施例25：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-((5-羟基戊基)氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-17代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.15(d,J＝5.1Hz,1H),7.28–7.18(m,2H),7.18–6.95(m,3H),6.93(s,1H),6.89–6.73(m,3H),5.34(dd,J＝12.0,4.9Hz,1H),4.42-4.38(m,3H),4.00(t,J＝6.5Hz,2H),3.55–3.30(m,4H),2.93(q,J＝11.4Hz,2H),2.74(dd,J＝19.0,5.0Hz,1H),1.89(d,J＝12.9Hz,1H),1.76-1.70(m,3H),1.62–1.39(m,6H).MS:567[M+H] +。
实施例26：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-((5-羟基-5-甲基己基)氧基))苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-18代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝5.1Hz,1H),7.28–7.18(m,2H),7.18–6.95(m,3H),6.93(s,1H),6.88–6.80(m,2H),6.77(d,J＝5.0Hz,1H),5.34(dd,J＝12.0,5.0Hz,1H),4.45–4.39(m,2H),4.11(s,1H),4.00(t,J＝6.4Hz,2H),3.48–3.40(m,2H),2.93(q,J＝11.2Hz,2H),2.74(dd,J＝19.0,5.0Hz,1H),1.94–1.85(m,1H),1.79–1.65(m,3H),1.62–1.34(m,6H),1.07(s,6H).MS:595[M+H] +。
Figure PCTCN2023070093-appb-000030
实施例27：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-(3-氟丙氧基)苯基)吡啶-2-基))哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-19代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝5.2Hz,1H),7.29–7.21(m,2H),7.17–6.98(m,3H),6.94(s,1H),6.87–6.80(m,2H),6.77(dt,J＝5.1,1.7Hz,1H),5.34(dd,J＝12.0,5.0Hz,1H),4.68(t,J＝5.9Hz,1H),4.56(t,J＝5.9Hz,1H),4.40(dd,J＝13.3,3.5Hz,2H),4.12(t,J＝6.2Hz,2H),3.55–3.36(m,2H),2.93(dt,J＝12.9,9.9Hz,2H),2.74(ddd,J＝19.0,5.0,1.8Hz,1H),2.18–2.04(m,2H),1.94–1.85(m,1H),1.75(d,J＝12.2Hz,1H),1.64–1.43(m,2H).MS:541[M+H] +。
实施例28：(1-(4-(5-(2-甲氧基乙氧基)-2-甲基苯基)吡啶-2-基)哌啶-4-基)(5-苯基-4,5-二氢-1H-吡唑-1-基)甲酮采用与实施例1相似的方法进行制备，不同之处在于在步骤1中用中间体A-3代替中间体A-1，在步骤4中用中间体B-20代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.36–7.15(m,5H),7.13–7.10(m,2H),6.88(d,J＝8.4Hz,1H),6.80–6.70(m,2H),6.58(d,J＝5.0Hz,1H),5.34–5.29(m,1H),4.42–4.33(m,2H),4.12–4.05(m,2H),3.68–3.60(m,2H),3.42–3.36(m,2H),3.30(s,3H),2.94–3.88(m,2H),2.67(dd,J＝18.9,4.7Hz,1H),2.15(s,3H),1.91–1.82(m,1H),1.73(d,J＝13.0Hz,1H),1.55–1.51(m,2H).MS:499[M+H] +。
Figure PCTCN2023070093-appb-000031
实施例29：(5-(2-氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(5-(3-羟基丙氧基)-2-甲基苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在步骤1中用中间体A-2代替中间体A-1，在步骤4中用中间体B-24代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.34–7.24(m,2H),7.22–7.12(m,3H),7.10–7.01(m,1H),6.87(d,J＝8.4Hz,1H),6.78–6.70(m,2H),6.57(d,J＝4.9Hz,1H),5.43–5.38(m,1H),4.53(s,1H),4.37(d,J＝13.2Hz,2H),4.02(t,J＝6.4Hz,2H),3.58–3.46(m,4H),2.92(d,J＝9.1Hz,2H),2.71(dd,J＝19.0,5.1Hz,1H),2.15(s,3H),2.07–1.95(m,1H),1.87-1.81(m,2H),1.73(d,J＝12.9Hz,1H),1.63–1.45(m,2H).MS:517[M+H] +。
实施例30：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-(3-甲氧基丙氧基)苯基)吡啶-2-基)哌 啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-1代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.15(d,J＝5.2Hz,1H),7.29–7.19(m,2H),7.17–7.04(m,2H),7.00(d,J＝9.0Hz,1H),6.93(s,1H),6.86–6.82(m,2H),6.79–6.73(m,1H),5.34(dd,J＝12.0,4.9Hz,1H),4.40(d,J＝13.0Hz,2H),4.05(t,J＝6.3Hz,2H),3.55–3.41(m,4H),3.24(s,3H),2.93(dt,J＝13.3,10.5Hz,2H),2.74(dd,J＝19.1,5.0Hz,1H),2.01–1.84(m,3H),1.75(d,J＝13.1Hz,1H),1.58–1.52(m,2H).MS:553[M+H] +。
Figure PCTCN2023070093-appb-000032
实施例31：(1-(4-(5-(3-羟基丙氧基)-2-甲基苯基)吡啶-2-基)哌啶-4-基)(5-苯基-4,5-二氢-1H-吡唑-1-基)甲酮采用与实施例1相似的方法进行制备，不同之处在于，不同之处在于在步骤1中用中间体A-3代替中间体A-1，在步骤4中用中间体B-24代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.36–7.27(m,2H),7.27–7.14(m,3H),7.14–7.07(m,2H),6.87(dd,J＝8.4,2.7Hz,1H),6.78–6.69(m,2H),6.57(dd,J＝5.1,1.3Hz,1H),5.34–5.29(m,2H),4.38(d,J＝12.8Hz,2H),4.02(t,J＝6.4Hz,2H),3.59–3.43(m,2H),2.98–2.88(m,2H),2.74–2.62(m,1H),2.15(s,3H),2.02–1.96(m,3H),1.85(q,J＝6.4Hz,2H),1.73(d,J＝12.7Hz,1H),1.66–1.38(m,2H).MS:499[M+H] +。
实施例32：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(5-(4-甲氧基丁氧基)-2-甲基苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-26代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.27–7.07(m,3H),6.85(dd,J＝11.4,8.4Hz,3H),6.78–6.71(m,2H),6.58(d,J＝5.3Hz,1H),5.34(dd,J＝12.0,5.0Hz,1H),4.38(dd,J＝13.2,3.6Hz,2H),3.97(t,J＝6.4Hz,2H),3.60–3.41(m,4H),3.22(s,3H),3.00–2.85(m,2H),2.74(dd,J＝18.9,5.0Hz,1H),2.15(s,3H),1.88(d,J＝12.8Hz,1H),1.79–1.44(m,7H).MS:563[M+H] +。
Figure PCTCN2023070093-appb-000033
实施例33：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-甲基-5-((四氢-2H-吡喃-4-基))甲氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-27代替中间体B-2进行反 应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.27–7.06(m,3H),6.85(dd,J＝15.5,8.4Hz,3H),6.78–6.70(m,2H),6.57(d,J＝5.1Hz,1H),5.34(dd,J＝12.0,5.0Hz,1H),4.38(d,J＝12.5Hz,2H),3.91–3.79(m,4H),3.54–3.41(m,4H),2.92(q,J＝10.7Hz,2H),2.74(dd,J＝19.0,5.0Hz,1H),2.15(s,3H),1.99(br,1H),1.88(d,J＝12.8Hz,1H),1.70(dd,J＝27.6,12.7Hz,3H),1.61–1.46(m,2H),1.31(qd,J＝12.2,4.5Hz,2H).MS:575[M+H] +。
实施例34：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(5-(4-甲氧基丁氧基)-2-甲基苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-26代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.27–7.06(m,3H),6.88–6.82(m,3H),6.78–6.70(m,2H),6.57(d,J＝5.0Hz,1H),5.34(dd,J＝12.0,5.0Hz,1H),4.43–4.34(m,2H),3.97(t,J＝6.3Hz,2H),3.50–3.40(m,2H),3.36(t,J＝6.3Hz,2H),3.22(s,3H),2.92(q,J＝11.2Hz,2H),2.74(ddd,J＝18.9,5.0,1.8Hz,1H),2.15(s,3H),1.88(d,J＝13.1Hz,1H),1.78–1.46(m,7H).MS:563[M+H] +。
Figure PCTCN2023070093-appb-000034
实施例35：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(5-(4-羟基丁氧基)-2-甲基苯基)吡啶-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-22代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.1Hz,1H),7.27–7.07(m,3H),6.88–6.81(m,3H),6.77–6.70(m,2H),6.57(d,J＝5.2Hz,1H),5.35–5.31(m,2H),4.47–4.34(m,2H),3.96(t,J＝6.5Hz,2H),3.56–3.46(m,2H),2.92(q,J＝11.0Hz,2H),2.80–2.68(m,1H),2.15(s,3H),2.03-1.98(m,4H),1.88(d,J＝13.2Hz,1H),1.75–1.69(m,2H),1.58–1.50(m,3H).MS:549[M+H] +。
实施例36：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-(4-羟基丁氧基)苯基)吡啶)-2-基)哌啶-4-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于，不同之处在于在步骤4中用中间体B-29代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝5.1Hz,1H),7.28–7.18(m,2H),7.17–6.95(m,3H),6.93(s,1H),6.89–6.73(m,3H),5.34(dd,J＝12.0,5.0Hz,1H),4.49–4.35(m,4H),4.01(t,J＝6.5Hz,2H),3.55–3.42(m,3H),3.01–2.86(m,2H),2.74(ddd,J＝19.1,5.0,1.8Hz,1H),1.94–1.85(m,1H),1.78-1.71(m,3H),1.64–1.43(m,4H).MS:553[M+H] +。
Figure PCTCN2023070093-appb-000035
实施例37：(1-(4-(5-(2,2-二氟-3-羟基丙氧基)-2-氟苯基)吡啶)-2-基)哌啶-4-基)(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)甲酮
采用与实施例1相似的方法进行制备，不同之处在于在第4步中用中间体B-30代替中间体B-2进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝5.1Hz,1H),7.33–7.05(m,5H),6.95(s,1H),6.89–6.75(m,3H),5.67(t,J＝6.2Hz,1H),5.34(dd,J＝12.0,5.0Hz,1H),4.39(t,J＝12.9Hz,4H),3.76(td,J＝13.8,6.2Hz,2H),3.48(m,2H),2.94(dt,J＝12.7,10.4Hz,2H),2.74(dd,J＝19.1,5.0Hz,1H),1.90(d,J＝12.7Hz,1H),1.76(d,J＝12.9Hz,1H),1.64–1.44(m,2H).MS:575[M+H] +。
实施例38：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-(3-羟基丙氧基)苯基)嘧啶-2-基))哌啶-4-基)甲酮
Figure PCTCN2023070093-appb-000036
步骤1)：将2,4-二氯嘧啶(1.00g,6.71mmol)、中间体B-12的3-(4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基)丙-1-醇(2.58g,8.73mmol)、碳酸钾(1.86g,13.4mmol)、Pd[PPh 3] 4(776mg,0.671mmol)加入乙醇(12mL)和甲苯(6mL)的混合溶剂中，氩气保护条件下，升温至55℃反应8小时。反应液用乙酸乙酯稀释后经饱和食盐水洗涤，然后经无水硫酸钠干燥后过滤浓缩，粗产物柱层析纯化得到3-(3-(2-氯嘧啶-4-基)-4-氟苯氧基)丙基-1-醇1.48g,收率78％；
步骤2)：将3-(3-(2-氯嘧啶-4-基)-4-氟苯氧基)丙基-1-醇(741mg,2.62mmol)、哌啶-4-羧酸乙酯(412.35mg,2.62mmol)、碳酸铯(1.71g,5.25mmol)加入DMF(8mL)，氩气置换后在85℃下反应3小时。反应液用二氯甲烷稀释，经饱和食盐水洗涤后用无水硫酸钠干燥有机相，过滤减压浓缩，得到产品907mg，收率85.71％。MS:404[M+H] +；
步骤3)：将1-(4-(2-氟-5-(3-羟基丙氧基)苯基)嘧啶-2-基)哌啶-4-甲酸乙酯(650mg,1.61mmol)、NaOH(321mg,8.03mmol)加入MeOH(10mL)和H 2O(2mL)中，室温搅拌反应3小时；0℃条件下用盐酸(2N 浓度)调节pH值至3，反应液用二氯甲烷稀释后经饱和食盐水洗涤，然后用无水硫酸钠干燥有机相，经过滤减压浓缩最终得到1-(4-(2-氟-5-(3-羟基丙氧基)苯基)嘧啶-2-基)哌啶-4-甲酸532mg,收率87.92％；MS:376[M+H] +；
步骤4)：将1-(4-(2-氟-5-(3-羟基丙氧基)苯基)嘧啶-2-基)哌啶-4-甲酸(190mg,0.5mmol)、中间体A-1(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑)(100mg,0.55mmol)、HATU(190mg,0.5mmol)、DIEA(129mg,1mmol)加入DMF(3mL)中，氩气保护条件下，25℃反应2小时。反应液用二氯甲烷稀释后经饱和食盐水洗涤，然后用无水硫酸钠干燥有机相，再经过滤减压浓缩，得到的产物进一步用柱层析纯化，最终得到产物78mg,收率29％。 1H NMR(400MHz,DMSO-d 6)δ8.44(d,J＝5.1Hz,1H),7.48(d,J＝6.2Hz,1H),7.32–7.19(m,2H),7.18–7.05(m,2H),7.00(d,J＝5.1Hz,1H),6.88–6.81(m,2H),5.34(dd,J＝12.0,5.0Hz,1H),4.75(d,J＝13.1Hz,2H),4.60(t,J＝5.0Hz,1H),4.08(t,J＝6.3Hz,2H),3.55(q,J＝6.4Hz,2H),3.51–3.35(m,2H),3.04(td,J＝12.5,9.7Hz,2H),2.75(dd,J＝19.0,5.0Hz,1H),1.98–1.76(m,4H),1.56–1.49(m,2H).MS:540[M+H] +。
实施例39：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-(3-羟基-3-甲基丁氧基)苯基)嘧啶)-2-基)哌啶-4-基)甲酮
Figure PCTCN2023070093-appb-000037
采用与实施例38相似的方法进行制备，不同之处在于在第1步中用中间体B-13代替中间体B-12进行反应。 1H NMR(400MHz,DMSO-d 6)δ8.44(d,J＝5.1Hz,1H),7.49(d,J＝6.2Hz,1H),7.31–7.21(m,2H),7.17–7.04(m,2H),7.00(d,J＝5.1Hz,1H),6.88–6.80(m,2H),5.34(dd,J＝12.0,5.0Hz,1H),4.79–4.71(m,2H),4.41(s,1H),4.13(t,J＝7.2Hz,2H),3.55–3.35(m,2H),3.04(td,J＝12.5,8.5Hz,2H),2.75(dd,J＝19.1,5.0Hz,1H),1.97–1.75(m,4H),1.51(dd,J＝17.4,12.0Hz,2H),1.16(s,6H).MS:568[M+H] +。
立体异构体的分离
对实施例18、21、23和24所得的外消旋体通过手性柱进行了分离纯化。分离采用色谱仪(岛津LC-20A)进行，分离条件如下：
Figure PCTCN2023070093-appb-000038
在分离出来的两个峰中，收集保留时间更长的那一个峰，旋转蒸发除去溶剂，得到对映异构体的纯品。将上述活性对映异构体的绝对构型指定为(S)。
Figure PCTCN2023070093-appb-000039
Figure PCTCN2023070093-appb-000040
实施例44：[5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基]-[1-[4-[5-(2-乙基-2-羟基丁氧基)-2-氟苯基]吡啶-2-基]哌啶-4-基]甲酮
Figure PCTCN2023070093-appb-000041
步骤1)：将2-溴乙酸甲酯(14.42g,94.24mmol)、3-溴-4-氟苯酚(6g,31.41mmol)、碳酸钾(13.03g,94.24mmol)置于DMF(30mL)中，氩气保护条件下，80℃反应12小时。反应液用乙酸乙酯稀释，然后用水和饱和食盐水洗涤，有机相用无水硫酸钠干燥，之后过滤减压浓缩，粗产物柱层析纯化，最终得到2-(3-溴-4-氟-苯氧基)乙酸甲酯6克，收率73％。
步骤2)：将2-(3-溴-4-氟-苯氧基)乙酸甲酯(1g,3.80mmol)溶于四氢呋喃中，0℃氩气保护条件下，滴加乙基溴化镁(2.0M的四氢呋喃溶液)(5.7mL)，此温度下反应2小时。加入饱和氯化铵水溶液淬灭反应，反应液经硅藻土抽滤，滤液用乙酸乙酯萃取，有机相经水和饱和食盐水洗涤，然后用无水硫酸钠干燥，后过滤减压浓缩，粗产物经柱层析纯化，最终得到3-[(3-溴-4-氟-苯氧基)甲基]戊-3-醇800毫克,收率72％。
步骤3)：将3-[(3-溴-4-氟-苯氧基)甲基]戊-3-醇(800mg,2.75mmol)，频哪醇酯(907.06mg,3.57mmol)，Pd(dppf)Cl 2(120.63mg,164.86μmol)和醋酸钾(539.31mg,5.50mmol)溶于1,4-二氧六环(15mL)中，氩气保护条件下，缓慢升至100℃，反应8小时，冷却至室温，反应液加硅藻土抽滤，后用乙酸乙酯稀释，然后用水和饱和食盐水洗涤，经无水硫酸钠干燥后，过滤减压浓缩溶剂，粗产物柱层析纯化，最终得到3-[[4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基]甲基]戊-3-醇800毫克，收率90％。
步骤4)：将(1-(4-溴吡啶-2-基)哌啶-4-基)(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)甲酮(100mg,222.57μmol)、3-[[4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基]甲基]戊-3-醇(112.92mg,333.86μmol)、碳酸钾(61.52mg,445.15μmol)、Pd(dppf)Cl 2(16.29mg,22.26μmol)溶于1,4-二氧六环(5mL)和水(0.5mL)的混合溶剂中，氩气保护条件下，缓慢升至100℃，反应8小时。反应液用乙酸乙酯稀释后用水和饱和食盐水洗涤，取有机相用无水硫酸钠干燥，后过滤减压浓缩溶剂，经硅胶柱层析纯化，最终得到[5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基]-[1-[4-[5-(2-乙基-2-羟基丁氧基)-2-氟苯基]吡啶-2-基]哌啶-4-基]甲酮40毫克，收率31％。
1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝5.1Hz,1H),7.27–7.18(m,2H),7.17–6.97(m,3H),6.93(s,1H),6.89–6.80(m,2H),6.76(d,J＝5.2Hz,1H),5.34(dd,J＝12.0,4.9Hz,1H),4.44–4.32(m,3H),3.77(s,2H),3.48(dd,J＝18.8,12.1Hz,1H),3.37(dd,J＝11.7,3.9Hz,1H),3.00–2.87(m,2H),2.80–2.66(m,1H),1.89(d,J＝13.3Hz,1H),1.75(d,J＝12.8Hz,1H),1.59–1.47(m,6H),0.83(t,J＝7.5Hz,6H).MS:581[M+H] +
实施例45：[5-(3,5-二氟苯基)-4,5-二氢-1H吡唑-1-基]-[1-[4-[2-氟-5-[(1-羟基环丙基)甲氧基]苯基]吡啶-2-基]哌啶-4-基]甲酮
Figure PCTCN2023070093-appb-000042
步骤1)：将2-(3-溴-4-氟-苯氧基)乙酸甲酯(500mg,1.80mmol)溶于THF(8mL)中，0℃氩气保护条件下，滴加乙基溴化镁(2M的四氢呋喃溶液，0.9毫升,1.80mmol)，此温度下反应30分钟后，缓慢升至25℃，继续反应16小时。加入饱和氯化铵水溶液淬灭反应，过滤得滤液用二氯甲烷萃取，有机相用饱 和食盐水洗涤后经无水硫酸钠干燥，过滤减压浓缩，硅胶柱层析纯化最终得到1-[(3-溴-4-氟-苯氧基)甲基]环丙醇180毫克，收率38％。
步骤2)：将1-[(3-溴-4-氟-苯氧基)甲基]环丙醇(180mg,689.42μmol)、频哪醇酯(370.63mg,1.46mmol)、醋酸钾(238.73mg,2.43mmol)、Pd(dppf)Cl 2(88.99mg,121.63μmol)置于1,4-二氧六环(10mL)中，氩气保护条件下，100℃反应3小时，反应液浓缩后经柱层析纯化，最终得到1-[4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基]-2-甲基-环丙-2-醇170毫克，收率80％。
步骤3)：将(1-(4-溴吡啶-2-基)哌啶-4-基)(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)甲酮(80mg,178.06μmol)、1-[4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基]-2-甲基-环丙-2-醇(71.33mg,231.48μmol)、碳酸钾(49.22mg,356.12μmol)、Pd(dppf)Cl 2(13.03mg,17.81μmol)溶于1,4-二氧六环(3mL)和水(0.4mL)的混合溶剂中，氩气保护条件下，缓慢升至80℃，反应6小时。反应液用乙酸乙酯稀释，后用饱和食盐水洗涤，无水硫酸钠干燥后过滤减压浓缩溶剂，粗产物柱层析纯化，最终得到[5-(3,5-二氟苯基)-4,5-二氢-1H吡唑-1-基]-[1-[4-[2-氟-5-[(1-羟基环丙基)甲氧基]苯基]吡啶-2-基]哌啶-4-基]甲酮28毫克，收率29％。 1H NMR(400MHz,DMSO-d 6)δ8.15(d,J＝5.3Hz,1H),7.30–7.20(m,2H),7.18–7.05(m,2H),7.03–6.94(m,2H),6.89–6.76(m,3H),5.34(dd,J＝12.0,5.0Hz,1H),4.90(s,2H),4.38(d,J＝13.0Hz,2H),3.55–3.32(m,2H),2.99(d,J＝12.0Hz,2H),2.75(dd,J＝19.0,5.0Hz,1H),2.55(d,J＝7.3Hz,1H),1.91(d,J＝12.9Hz,1H),1.76(d,J＝13.1Hz,1H),1.63–1.46(m,2H),0.97(t,J＝7.3Hz,4H).MS:551[M+H] +
实施例46：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-((1-羟基环丁基)甲氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮
Figure PCTCN2023070093-appb-000043
步骤1)：将1-羟基环丁烷羧酸(500mg,4.31mmol)溶于THF(10mL)中，氩气保护条件下，室温分批加入氢化铝锂(490.25mg,12.92mmol)，升至80℃，继续反应1小时。冰浴中，依次加入0.5ml水，1.5mL 20％NaOH水溶液，0.5mL水，淬灭完毕后，过滤并收集滤液，滤液减压浓缩，最终得到粗品1-(羟甲基)环丁醇400毫克,收率91％。
步骤2)：将1-(羟甲基)环丁醇(400mg,3.92mmol)、对甲基苯磺酰氯(1.12g,5.87mmol)、三乙胺(1.19g,11.75mmol,1.64mL)、DMAP(47.85mg,391.65μmol)置于二氯甲烷(20mL)中，氩气保护条件下，25℃反应16小时。反应液加入饱和碳酸钠水溶液搅拌30分钟，再用乙酸乙酯萃取三次，有机相经饱和食盐水洗涤后用无水硫酸钠干燥，过滤减压浓缩，粗产物柱层析纯化得到(1-羟基环丁基)甲基4-对甲苯磺酸酯430毫克，收率43％。
步骤3)：将(1-羟基环丁基)甲基4-对甲苯磺酸酯(430mg,1.68mmol)、3-溴-4-氟-苯酚(106.81mg,559.20μmol)、碳酸钾(231.86mg,1.68mmol)加入DMF(10mL)中，氩气保护条件下，80℃加热搅拌反应16小时。反应体系加入水，用乙酸乙酯萃取三次，有机相经饱和食盐水洗涤后用无水硫酸钠干燥，过滤减压浓缩，柱层析纯化最终得到1-[(3-溴-4-氟-苯氧基)甲基]环丁醇150毫克，收率98％。
步骤4)：将1-[(3-溴-4-氟-苯氧基)甲基]环丁醇(150mg,545.23μmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1,3,2-二氧杂硼烷(179.99mg,708.80μmol)、Pd(dppf)Cl 2(23.94mg,32.71μmol)、醋酸钾(107.02mg,1.09mmol)溶于1,4-二氧六环(10mL)中，氩气保护条件下，缓慢升至100℃，反应8小时。反应液冷却至室温后加硅藻土抽滤，滤液用乙酸乙酯稀释，后用水和饱和食盐水洗涤，经无水硫酸钠干燥后过滤减压浓缩溶剂，粗产物柱层析纯化(洗脱剂：PE:EA＝3:1)，最终得到1-[[4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基]甲基]环丁醇(150mg,486.77μmol,产率：89.28％)。
步骤5)：将(1-(4-溴吡啶-2-基)哌啶-4-基)(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)甲酮(100mg,222.57μmol)、1-[[4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基]甲基]环丁醇(107.56mg,333.86μmol)、碳酸钾(61.52mg,445.15μmol)、Pd(dppf)Cl 2(16.29mg,22.26μmol)溶于1,4-二氧六环(5mL)和水(0.5mL)的混合溶剂中，氩气保护条件下，缓慢升至100℃，反应8小时。反应液用乙酸乙酯稀释，经水和饱和食盐水洗涤后再用无水硫酸钠干燥，过滤减压后浓缩溶剂，柱层析纯化得到(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基)(1-(4-(2-氟-5-((1-羟基环丁基)甲氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮(40毫克，收率32％)。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝5.1Hz,1H),7.29–7.19(m,2H),7.17–7.00(m,3H),6.94(s,1H),6.88–6.74(m,3H),5.34(dd,J＝12.0,5.0Hz,1H),5.25(s,1H),4.40(dd,J＝13.4,3.7Hz,2H),3.95(s,2H),3.48(dd,J＝19.1,12.0Hz,1H),3.40–3.35(m,1H),3.01–2.87(m,2H),2.74(dd,J＝18.9,4.9Hz,1H),2.11(t,J＝9.1Hz,2H),2.00(dt,J＝12.5,9.5Hz,2H),1.89(d,J＝13.0Hz,1H),1.75(d,J＝12.9Hz,1H),1.66–1.49(m,4H).MS:565[M+H] +
实施例47：(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基-5-氘)(1-(4-(2-氟-5-(2-羟基-2-甲基丙氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮
Figure PCTCN2023070093-appb-000044
步骤1)：将3,5-二氟苯甲醛(800mg,5.63mmol)置于THF(18mL)中，0℃下向溶液中分批加入NaBH 4(354mg)，0℃反应2小时。反应液加0.5mL丙酮淬灭后减压浓缩，经硅胶柱纯化最终得到二氘-(3,5-二氟苯基)甲醇800毫克，收率97.24％。
步骤2)：将二氘-(3,5-二氟苯基)甲醇(800mg,5.47mmol)置于二氯甲烷(54mL)中，向溶液中加入MnO 2(2.38g)，25℃反应20小时。反应液过滤收集滤液后减压浓缩，最终得到粗品氘代3,5-二氟苯甲醛600毫克，收率77％.
步骤3)：将氘代3,5-二氟苯甲醛(143mg,999.24μmol)、乙醛(66.03mg,1.50mmol)置于水中，氩气保护，0℃下向反应液中滴加1N的NaOH水溶液(1.1mL)，25℃下反应16小时。TLC显示没有原料后，向反应液中加入水，用乙酸乙酯萃取三次，有机相用饱和食盐水洗涤，后用无水硫酸钠干燥，过滤减压浓缩后柱层析(PE:EA＝20:1)纯化，最终得到(E)-3-氘-3-(3,5-二氟苯基)丙-2-烯醛60毫克，收率36％。
步骤4)：把水合肼(17.05mg,532.08μmol)加入到乙醇(2mL)中，搅拌状态下，加入乙酸(36.21mg,603.03μmol,34.49μL)，升温至40℃，缓慢滴加(E)-3-氘-3-(3,5-二氟苯基)丙-2-烯醛(60mg,354.72μmol)，于80℃封管加热并反应过夜。将反应液浓缩，经硅胶板纯化(PE/EtOAc＝3:1)得到产物5-氘-5-(3,5-二氟苯基)-4,5-二氢吡唑20毫克，收率31％。
步骤5)：将1-[4-[2-氟-5-(2-羟基-2-甲基-丙氧基)苯基]-2-吡啶基]哌啶基-4-甲酸(178.13mg,458.58μmol)、5-氘-5-(3,5-二氟苯基)-4,5-二氢吡唑(70mg,382.15μmol)、HATU(174.36mg,458.58μmol)、DIEA(148.17mg,1.15mmol,199.68μL)置于DMF(5mL)中，氩气保护条件下，25℃反应16小时。反应液用二氯甲烷稀释后经饱和食盐水洗涤，有机相用无水硫酸钠干燥，后过滤减压浓缩，得到的产物进一步用高效制备液相纯化，最终得到(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-基-5-氘)(1-(4-(2-氟-5-(2-羟基-2-甲基丙氧基)苯基)吡啶-2-基)哌啶-4-基)甲酮50毫克，收率24％。
1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝5.1Hz,1H),7.28–7.18(m,2H),7.17–6.97(m,3H),6.93(s,1H), 6.88–6.80(m,2H),6.85–6.73(m,1H),4.63(s,1H),4.44–4.36(m,2H),3.76(s,2H),3.48(dd,J＝19.1,1.7Hz,1H),3.37(dt,J＝7.5,3.6Hz,1H),3.01–2.87(m,2H),2.74(dd,J＝19.0,1.8Hz,1H),1.90(d,J＝12.9Hz,1H),1.76(d,J＝12.9Hz,1H),1.65–1.44(m,2H),1.21(s,6H).MS:554[M+H] +
1-[4-[2-氟-5-(2-羟基-2-甲基-丙氧基)苯基]-2-吡啶基]哌啶基-4-甲酸的合成：
(一)1-[4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基]-2-甲基-丙-2-醇的合成
Figure PCTCN2023070093-appb-000045
第一步：将3-溴-4-氟-苯酚(5g,26.18mmol)、2,2-二甲基环氧乙烷(5.66g,78.54mmol)、碳酸钾(10.85g,78.54mmol)置于DMF(50mL)中，氩气保护条件下，于100℃反应16小时。反应液用二氯甲烷稀释后经饱和食盐水洗涤，有机相用无水硫酸钠干燥，然后过滤减压浓缩，最终得到1-(3-溴-4-氟-苯氧基)-2-甲基-丙-2-醇(5g,19.00mmol,收率72.6％)。
第二步：将1-(3-溴-4-氟-苯氧基)-2-甲基-丙-2-醇(30g,114.02mmol)、频哪醇酯(34.75g,136.83mmol)、醋酸钾(22.38g,228.05mmol)、Pd(dppf)Cl 2(4.17g,5.70mmol)置于1,4-二氧六环(300mL)中，氩气保护条件下，于90℃反应16小时。反应液过滤减压浓缩，粗产物柱层析纯化，最终得到1-[4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基]-2-甲基-丙-2-醇(25g,80.60mmol,收率70.7％)。
(二)1-(4-溴-2-吡啶基)哌啶基-4-甲酸甲酯的合成
Figure PCTCN2023070093-appb-000046
将2-氟-4-溴-吡啶(3.52g,20mmol)和哌啶基-4-甲酸甲酯(2.86g,20.00mmol)溶于DMF(50mL)，加入三乙胺(4.05g,40.00mmol,5.58mL)，加热至80℃反应3小时。反应液降至室温后加水稀释，用乙酸乙酯萃取两次，将有机相合并，并用饱和食盐水洗涤三次，然后干燥浓缩，剩余物用硅胶柱层析纯化得到产品1-(4-溴-2-吡啶基)哌啶基-4-甲酸甲酯(5.1g,17.05mmol,收率85.2％)
(三)1-[4-[2-氟-5-(2-羟基-2-甲基-丙氧基)苯基]-2-吡啶基]哌啶基-4-甲酸的合成
Figure PCTCN2023070093-appb-000047
第一步：将1-[4-氟-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基]-2-甲基-丙-2-醇(372.20mg,1.2mmol)和1-(4-溴-2-吡啶基)哌啶基-4-甲酸甲酯(299.16mg,1.00mmol)溶解在1,4-二氧六环(10mL)中，加入Pd(dppf)Cl 2(878.04mg,1.20mmol)，置换氮气环境，升温80℃反应1小时，体系降至室温，垫硅藻土过滤，滤液浓缩得粗品，硅胶板纯化得到1-[4-[2-氟-5-(2-羟基-2-甲基-丙氧基)苯基]-2-吡啶基]哌啶基-4-甲酸甲酯(400mg,993.89μmol,收率82.8％)
第二步：将1-[4-[2-氟-5-(2-羟基-2-甲基-丙氧基)苯基]-2-吡啶基]哌啶基-4-甲酸甲酯(400mg,993.89μmol)溶解在MeOH(5mL)中，加入LiOH.H 2O(83.41mg,1.99mmol)，常温反应1小时，反应液浓缩后加水，以及盐酸调节至pH＝6，收集析出的固体，干燥得产品1-[4-[2-氟-5-(2-羟基-2-甲基-丙氧基)苯基]-2-吡啶基]哌啶基-4-甲酸(350mg,901.06μmol,收率90.66％)
对照例
参照WO2018/092089公开的内容，合成了如下两个化合物作为对照。
Figure PCTCN2023070093-appb-000048
实验例1.化合物对HT29细胞中RIPK1磷酸化抑制的Western Blot检测
本实验通过Western blot检测诱导HT29细胞程序性坏死过程中待测化合物对胞内RIPK1及其磷酸化的影响，以验证化合物对RIPK1磷酸化的抑制作用。
一.主要实验试剂/仪器
Figure PCTCN2023070093-appb-000049
Figure PCTCN2023070093-appb-000050
表3.实验例1所用主要试剂与仪器
二.实验过程
1.细胞收集及蛋白样品提取
a)收集状态良好的HT29细胞，用McCoy's 5A完全培养基重悬计数，以1×10 6/1mL/孔的细胞密度将细胞种植于12孔板中，在37℃细胞培养箱中过夜。
b)向上述12孔板中先加Z-VAD-FMK(终浓度为20μM)，30分钟后再加入诱导剂(其中TNF-α终浓度为20ng/mL，AT-406终浓度为100nM)以及不同浓度的待测化合物，在37℃细胞培养箱中孵育7小时。
c)完全裂解液的配制：取一管分装好的RIPA裂解液，解冻后分别加入磷酸酶抑制剂、Roche蛋白酶抑制剂(磷酸酶抑制剂：RIPA＝1:100；Roche蛋白酶抑制剂：RIPA＝4:100)，放在冰上待用。
d)弃细胞培养液上清，用PBS洗2遍后于每孔中加入配制好的完全细胞裂解液100μL，冰上裂解15分钟，裂解过程中间歇摇晃；
e)裂解完全后转移至提前标记好的1.5mL离心管中于4℃，14000rpm下离心20分钟；
f)取上清，转移至做好标记的600μL离心管中，置于冰上。
g)用BCA试剂盒检测并计算蛋白浓度；
2.预制胶每孔加入待测蛋白样品或者预染双色蛋白分子量标准品，蛋白上样量为40～50ug/孔。
3.恒压100V条件下电泳，当凝胶上预染双色蛋白分子量标准品条带跑出泳道下边缘时，停止电泳。
4.电泳结束后，取下凝胶夹，用剥胶铲轻轻撬起短玻璃板，弃去上层浓缩胶，轻轻剥下分离胶后置于转膜液中。
5.根据凝胶大小剪一块大小适中的NC膜，先用纯水浸湿，然后浸入预冷过的转膜液中；同时将滤纸浸泡在转膜缓冲液中。
6.在转印匣中按照滤纸、NC膜、凝胶、滤纸的顺序组装，然后将转印匣放入
Figure PCTCN2023070093-appb-000051
Turbo内，调取仪器自带的“Standard SD”程序完成转膜。
7.用去离子水稍加漂洗载有蛋白的NC膜，根据Marker条带指示按所需检测蛋白的分子量大小裁剪膜，加入封闭液使膜浸没，于室温下在摇床上缓慢摇动封闭1小时。
8.封闭完成后将NC膜放入抗体孵育盒中，加入稀释好的一抗后于室温下摇床上轻摇孵育1小时。
9.孵育完成后用TBST洗膜3次，每次10分钟。
10.根据一抗来源选择二抗，按1:10000～1:15000比例用二抗稀释液稀释二抗，加入抗体孵育盒后将膜浸没于其中，于室温下摇床上轻摇孵育1小时。
11.孵育完成后用TBST洗膜3次，每次10分钟。
12.用纯水漂洗膜一次，用Odyssey CLX红外荧光扫描成像系统扫描膜获取图像，并采用其系统自带的灰度读取功能读取条带的荧光信号值。
三.典型实验结果及分析
根据荧光强度值计算目标蛋白其磷酸化相对于目标蛋白的表达占比，进而以对照组为基准计算给药组中目标蛋白磷酸化的标准化表达倍数，计算方法如下：
目标蛋白磷酸化的标准化表达倍数＝A/B
A:加药组目标蛋白磷酸化的荧光强度值/加药组目标蛋白的荧光强度值
B:不加药组目标蛋白磷酸化的荧光强度值/不加药组目标蛋白的荧光强度值
通过上述方法对实施例40的化合物进行了测试，结果如图1和图2所示，图1是不同浓度化合物下RIPK1总蛋白和磷酸化蛋白的Western Blot图片，图2是根据上图条带荧光强度值进行定量计算得到的RIPK1磷酸化相对于RIPK1总蛋白的表达占比。实验结果显示实施例40的化合物直接抑制了RIPK1的磷酸化活性并呈现剂量依赖关系，而对RIPK1无明显的抑制作用。
实验例2.化合物抑制细胞坏死的实验方法(CCK8法)
本实验例2在诱导HT29和L929细胞系细胞程序性坏死的条件下，加入不同浓度的待测化合物，测试待测化合物对程序性坏死的拯救效果的IC 50。
一 主要实验试剂、仪器及材料
Figure PCTCN2023070093-appb-000052
Figure PCTCN2023070093-appb-000053
表4.试验例2所用主要试剂与仪器
化合物：溶于DMSO配成10mM溶液；
TNF-α：初始浓度为100μg/mL；
Z-VAD-FMK：溶于DMSO配成10mM溶液；
AT-406：溶于DMSO配成10mM溶液。
细胞系：HT29用含10％胎牛血清、100U/mL青霉素、100μg/mL链霉素的McCOY's5A培养基培养，L929用含10％马血清、100U/mL青霉素、100μg/mL链霉素的MEM培养基培养。
二 具体实验方法：
1.用DMSO溶解待测化合物形成储藏液并进行梯度稀释，然后再用相应培养基稀释得到10倍工作浓度溶液。
2.将处于对数生长期的细胞用培养液稀释调整至特定细胞浓度，添加80μL细胞悬液至96孔板中，使得HT29和L929的细胞密度分别为1.2*10 4cells/孔和2.0*10 4cells/孔。置于37℃、5％二氧化碳气体培养箱中培养过夜。
3.在已接种细胞的96孔板中每孔加入10μL化合物溶液。待测化合物最高浓度为10μM，9个浓度，4倍梯度稀释，双复孔。同时设置不加化合物的对照组。
4.细胞继续培养30分钟后，于每孔中加入10μL诱导剂混合液，其中HT29细胞中Human TNF-α、AT-406和Z-VAD-FMK的终浓度分别为20ng/mL，1μM和20μM；L929细胞中Murine TNF-α和Z-VAD-FMK的终浓度分别为20ng/mL和25μM。
5.将已加化合物和诱导剂的96孔板置于37℃、5％二氧化碳气体培养箱中继续培养，其中HT29细胞培养16小时，L929细胞培养4-8小时后，用CCK8检测细胞活力，并用GraphPad Prism软件制作量效曲线并计算IC 50。
表5列出了本发明中部分化合物抑制HT29和L929细胞坏死的测定结果，其中A表示IC 50小于或等于10nM，B表示IC 50大于10nM但小于或等于50nM，C表示IC 50大于50nM但小于或等于100nM，D表示IC 50大于100nM但小于或等于400nM，E表示IC 50大于400nM但小于或等于4000nM，F表示IC 50大于4000nM。
由下表所示的结果可以发现，本申请的化合物对于人源HT29细胞和鼠源L929细胞均表现出非常优异的抑制活性，其中对于人源HT29细胞的抑制活性优于对于鼠源L929细胞的抑制活性，但是差异较小。而对照例1和对照例2的化合物，对于人源HT29细胞的抑制活性显著劣于本申请的化合物，同时，二者对于鼠源L929细胞几乎没有抑制活性，没有得到有意义的测试结果。
表5、本发明部分化合物抑制HT29细胞坏死的测定结果
Figure PCTCN2023070093-appb-000054
实验例3.小分子化合物药代动力学试验
本实验通过对SD大鼠、CD-1小鼠或比格犬单次口服及静脉注射给予本申请部分化合物后，研究了本申请化合物的药代动力学特征，及本申请化合物穿透血脑屏障的能力。
(一)所用试剂、仪器以及动物
表6.试验试剂
Figure PCTCN2023070093-appb-000055
表7.试验仪器
Figure PCTCN2023070093-appb-000056
表8.试验动物
Figure PCTCN2023070093-appb-000057
(二)样品制剂配制
1.静脉注射(IV)组：称取适当数量的待测化合物，完全溶解于适当体积的溶媒中，进行搅拌、涡流和/或超声处理。得到溶液后，将逐渐增加溶媒至终体积以达到目标浓度，涡旋、超声，得到均一溶液，用0.22μm的PVDF滤膜过滤。
2.口服(PO)组：称取适当数量的待测化合物，完全溶解于适当体积的溶媒中，进行搅拌、涡流和/或超声处理。得到溶液后，将逐渐增加溶媒至终体积以达到目标浓度，涡旋、超声，得到均一溶液。
表9.测试化合物所进行的药代动力学试验及溶媒配制
Figure PCTCN2023070093-appb-000058
Figure PCTCN2023070093-appb-000059
(三)给药及取样
根据动物体重对动物随机分组，分组后各组动物体重相当(不超过平均体重的±20％)。同时，IV组不禁食，PO组禁食过夜(>12小时)，并于给药后2小时给予食物。所有动物自由饮水。以下表10和表11分别给出了给药方案和药代动力学采样方案。
表10-1.实施例18、实施例40和实施例42大鼠PK给药方案
Figure PCTCN2023070093-appb-000060
表10-2.实施例40小鼠PK给药方案
Figure PCTCN2023070093-appb-000061
表10-3.实施例18比格犬PK给药方案
Figure PCTCN2023070093-appb-000062
表10-4.实施例42比格犬PK给药方案
Figure PCTCN2023070093-appb-000063
Figure PCTCN2023070093-appb-000064
表11-1.大鼠药代动力学采样方案
Figure PCTCN2023070093-appb-000065
按照上述方案对大鼠进行给药，并在预定的时间点进行血液和脑组织样品的采集和处理(采集和处理
按本领域常规方法进行)。
表11-2.小鼠药代动力学采样方案
Figure PCTCN2023070093-appb-000066
按照上述方案对小鼠进行给药，并在预定的时间点进行血液和脑组织样品的采集和处理(采集和处理按本领域常规方法进行)。
表11-3.实施例18的比格犬药代动力学采样方案
Figure PCTCN2023070093-appb-000067
表11-4.实施例42的比格犬药代动力学采样方案
Figure PCTCN2023070093-appb-000068
Figure PCTCN2023070093-appb-000069
(五)样品分析
脑称重，加入4倍的超纯水匀浆。全血样品和脑匀浆液分别加入6倍体积的乙腈(小鼠PK的全血样品加入20倍体积的乙腈)，涡旋1min后，4℃，4500rpm离心15min，根据仪器响应，上清液用稀释液稀释，用LC/MS分析样品。
(六)数据分析：
将用WinNonlin软件进行药代动力学参数计算。如有适用的血浆/全血的药物浓度-时间数据，将计算以下药代动力学参数：CL(清除率)；V d(表观分布容积)；T 1/2(消除半衰期)；C max(达峰浓度)；T max(达峰时间)；AUC(血药浓度-时间曲线下面积)；MRT(平均滞留时间)；F％(生物利用度)。
测试结果示于下表12-14中，分别给出了本申请实施例化合物18、40和42在各时间点的血药浓度，以及各药代动力学参数值，同时给出了本申请实施例化合物18、40和42在大鼠或小鼠的脑和血液中的浓度及其比值。由上面的结果可知，本申请实施例18、40和42的化合物表现出了优异的药代动力学性质以及穿透血脑屏障的能力。
表12-1.本申请实施例18的化合物的大鼠/比格犬试验的血药浓度(ng/mL)
Figure PCTCN2023070093-appb-000070
表12-2.本申请实施例40的化合物的小鼠/大鼠试验的血药浓度(ng/mL)
Figure PCTCN2023070093-appb-000071
Figure PCTCN2023070093-appb-000072
表12-3.本申请实施例42的化合物的大鼠/比格犬试验的血药浓度(ng/mL)
Figure PCTCN2023070093-appb-000073
表13-1.本申请实施例18的化合物的大鼠/比格犬试验的药代参数
Figure PCTCN2023070093-appb-000074
表13-2.本申请实施例40的化合物的小鼠/大鼠试验的药代参数
Figure PCTCN2023070093-appb-000075
Figure PCTCN2023070093-appb-000076
表13-1.本申请实施例42的化合物的大鼠/比格犬试验的药代参数
Figure PCTCN2023070093-appb-000077
表14.本申请实施例18、40和42的化合物在脑和全血中的浓度及比值(采样时间，给药后2h)
Figure PCTCN2023070093-appb-000078
本发明所提供的生物学数据表明，本发明的化合物有利于治疗或预防由于RIPK1激酶异常而引起的疾病。因此，本发明的化合物有利于治疗与RIPK1相关的疾病包括眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、 肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌、炎性肠病、溃疡性结肠炎、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、脊椎关节炎、痛风、SoJIA、干燥综合征、全身性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬化性胆管炎、肾炎、乳糜泻、自身免疫ITP、移植排斥、实体器官的缺血再灌注损伤、败血症、全身性炎症反应综合征、脑血管意外、心肌梗死、亨廷顿氏病、阿尔茨海默氏病、帕金森氏病、变应性疾病、哮喘、特应性皮炎、多发性硬化症、I型糖尿病、韦格纳肉芽肿、肺结节病、白塞氏病、白细胞介素-1转换酶相关的发热综合征、慢性阻塞性肺病、肿瘤坏死因子受体相关的周期性综合症和牙周炎。本发明的化合物可以作为单一疗法或联合疗法，可以与多个本发明的化合物联合用药或与本发明以外的其他药物联合用药。
以上所述仅为本发明的较佳实施方式而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (15)

  1. 式(I)表示的化合物、立体异构体、或其药学上可接受的盐、或其氘代物，
    Figure PCTCN2023070093-appb-100001
    式(I)中，X为CH或者N；
    L为O、S、NH、羰基、砜基或者亚砜基；
    R 1为C 1-C 10烷基、C 3-C 8环烷基、4-8元杂脂环基、或者由1至3个选自羟基、C 1-C 6烷氧基、氰基、-NR aR b、C 3-C 8环烷基氧基、-CONH-R 5、C 3-C 8环烷基、羟基和/或C 1-C 4烷基取代C 3-C 8环烷基、羧基、卤素、卤代C 1-C 6烷氧基、-SO 2-R 5、-SO-R 5、-CO-R 5、C 2-C 6炔基、C 2-C 6烯基、C 1-C 4烷氧基C 1-C 6烷氧基、4-8元杂脂环基、氧代取代4-8元杂脂环基、羟基和/或C 1-C 4烷基取代4-8元杂脂环基、C 1-C 6烷硫基中的取代基所取代的C 1-C 10烷基，
    所述4-8元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-8元杂脂环基，
    R 5为氢、羟基、C 1-C 6烷基、C 1-C 6烷氧基C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基、4-8元杂脂环基取代C 1-C 6烷基，
    R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 8环烷基、C 1-C 6烷氧基取代C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基C 1-C 6烷基、4-8元杂脂环基取代C 1-C 6烷基、C 1-C 3烷硫基取代C 1-C 6烷基、单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基；
    R 2为氢、C 1-C 3烷基、C 1-C 3烷氧基、卤素；
    R 3、R 4各自独立地为氢、卤素、甲基。
  2. 根据权利要求1所述的化合物、立体异构体、或其药学上可接受的盐，其中，所述化合物具有如下式(II)的结构：
    Figure PCTCN2023070093-appb-100002
    式(II)中，
    R 1为C 1-C 10烷基、C 3-C 8环烷基、4-8元杂脂环基、或者由1至3个选自羟基、C 1-C 6烷氧基、氰基、-NR aR b、C 3-C 8环烷基氧基、-CONH-R 5、C 3-C 8环烷基、羟基和/或C 1-C 4烷基取代C 3-C 8环烷基、羧基、卤素、卤代C 1-C 6烷氧基、-SO 2-R 5、-SO-R 5、-CO-R 5、C 2-C 6炔基、C 2-C 6烯基、C 1-C 4烷氧基C 1-C 6烷氧基、4-8元杂脂环基、氧代取代4-8元杂脂环基、羟基和/或C 1-C 4烷基取代4-8元杂脂环基、C 1-C 6烷硫基中的取代基所取代的C 1-C 10烷基，
    所述4-8元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-8元杂脂环基，
    R 5为氢、羟基、C 1-C 6烷基、C 1-C 6烷氧基C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基、4-8元杂脂环基取代C 1-C 6烷基，
    R a和R b各自独立地为氢、C 1-C 6烷基、C 3-C 8环烷基、C 1-C 6烷氧基取代C 1-C 6烷基、羟基取代C 1-C 6烷基、C 3-C 8环烷基C 1-C 6烷基、4-8元杂脂环基取代C 1-C 6烷基、C 1-C 3烷硫基取代C 1-C 6烷基、单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基；
    R 2为氢、C 1-C 3烷基、C 1-C 3烷氧基、卤素；
    R 3、R 4各自独立地为氢、卤素、甲基。
  3. 根据权利要求1或2所述的化合物、立体异构体、或其药学上可接受的盐，其中，
    R 1为C 1-C 8烷基、C 3-C 6环烷基、4-6元杂脂环基、或者由1至3个选自羟基、C 1-C 3烷氧基、氰基、C 3-C 6环烷基氧基、C 3-C 6环烷基、羟基和/或C 1-C 4烷基取代C 3-C 6环烷基、卤素、4-6元杂脂环基、氧代取代4-6元杂脂环基、羟基和/或C 1-C 4烷基取代4-6元杂脂环基、C 1-C 3烷硫基中的取代基所取代的C 1-C 8烷基，
    所述4-6元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-6元杂脂环基。
  4. 根据权利要求3所述的化合物、立体异构体、或其药学上可接受的盐，其中，R 1为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、己基、辛基、环丁基、环戊基、环己基、四氢呋喃-2-基、四氢呋喃-3-基、四氢吡喃-2-基、四氢吡喃-3-基、四氢吡喃-4-基、或者由1至3个选自羟基、甲氧基、乙氧基、丙氧基、异丙氧基、氰基、环丁基氧基、环戊基氧基、环己基氧基、环丁基、环戊基、环己基、4-羟基环己基、4-羟基-4-甲基环己基、氟、氯、四氢呋喃-2-基、四氢呋喃-3-基、四氢吡喃-2-基、四氢吡喃-3-基、四氢吡喃-4-基、吡咯烷-1-基、吡咯烷-2-基、哌啶-1-基、哌啶-4-基、吗啉基、硫代吗啉基、1-甲基-吡咯烷-2-基、1-甲基-哌啶-4-基、甲硫基、乙硫基、丙硫基、异丙硫基中的取代基所取代的C 1-C 8烷基；
    更优选地，R 1为甲基、乙基、丙基、丁基、戊基、己基、羟乙基、羟丙基、羟丁基、羟戊基、羟己基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、四氢吡喃-4-基、4-甲基-4-羟基戊基、四氢吡喃-4-基乙基、四氢吡喃-4-基甲基、四氢吡喃-4-基丙基、四氢吡喃-4-基丁基、3-甲基-3-羟基丁基、2-甲基-2-羟基丙基、5-甲基-5-羟基己基、氟丙基、氟乙基、2,2-二氟-3-羟基-丙基。
  5. 根据权利要求3所述的化合物、立体异构体、或其药学上可接受的盐，其中，R 1为被1-羟基环丙基、1-羟基环丁基、1-羟基环戊基或1-羟基环己基所取代的C 1-C 8烷基；
    更优选地，R 1为1-羟基环丙基甲基、1-羟基环丁基甲基。
  6. 根据权利要求1-4中任一项所述的化合物、立体异构体、或其药学上可接受的盐，其中，R 2为氢、甲基、甲氧基、氟、氯、溴。
  7. 根据权利要求1-4中任一项所述的化合物、立体异构体、或其药学上可接受的盐，其中，R 3、R 4各自独立地为氢、氟、氯、甲基。
  8. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，所述化合物具有如下式(III)的结构：
    Figure PCTCN2023070093-appb-100003
  9. 根据权利要求2所述的化合物或其药学上可接受的盐，其中，所述化合物具有如下式(IV)的结构：
    Figure PCTCN2023070093-appb-100004
  10. 根据权利要求1所述的化合物、立体异构体、或其药学上可接受的盐，其中，所述化合物选自如下结构：
    Figure PCTCN2023070093-appb-100005
    Figure PCTCN2023070093-appb-100006
    Figure PCTCN2023070093-appb-100007
    Figure PCTCN2023070093-appb-100008
    Figure PCTCN2023070093-appb-100009
  11. 权利要求2至10中任一项所述化合物的氘代物。
  12. 权利要求1至11中任一项所述的化合物、立体异构体、或其药学上可接受的盐、或其氘代物在制备治疗与RIPK1相关疾病的药物中的应用。
  13. 权利要求12所述的应用，其中，所述与RIPK1相关的疾病包括：眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌、炎性肠病、溃疡性结肠炎、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、脊椎关节炎、痛风、SoJIA、干燥综合征、全身性硬皮病、抗磷脂综合征、血管炎、骨关节炎、非酒精性脂肪性肝炎、酒精性脂肪性肝炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬化性胆管炎、肾炎、乳糜泻、自身免疫ITP、移植排斥、实体器官的缺血再灌注损伤、败血症、全身性炎症反应综合征、脑血管意外、心肌梗死、亨廷顿氏病、阿尔茨海默氏病、帕金森氏病、变应性疾病、哮喘、特应性皮炎、多发性硬化症、I型糖尿病、韦格纳肉芽肿、肺结节病、白塞氏病、白细胞介素-1转换酶相关的发热综合征、慢性阻塞性肺病、肿瘤坏死因子受体相关的周期性综合症和牙周炎。
  14. 一种药物组合物，包括权利要求1至11中任一项所述的化合物、立体异构体、或其药学上可接受的盐、或其氘代物，以及一种或多种药学上可接受的载体或赋形剂。
  15. 权利要求14所述的药物组合物，还包括一种或多种其他治疗剂。
PCT/CN2023/070093 2022-01-04 2023-01-03 羰基桥连杂环类化合物、及其组合物与应用 WO2023131116A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
KR1020247026065A KR20240131425A (ko) 2022-01-04 2023-01-03 카르보닐 가교된 헤테로시클릭 화합물, 및 이의 조성물 및 적용
AU2023204840A AU2023204840A1 (en) 2022-01-04 2023-01-03 Carbonyl bridged heterocyclic compound, and composition and application thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202210003492.4 2022-01-04
CN202210003492 2022-01-04
CN202211582187 2022-12-09
CN202211582187.1 2022-12-09

Publications (1)

Publication Number Publication Date
WO2023131116A1 true WO2023131116A1 (zh) 2023-07-13

Family

ID=87073187

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/070093 WO2023131116A1 (zh) 2022-01-04 2023-01-03 羰基桥连杂环类化合物、及其组合物与应用

Country Status (5)

Country Link
KR (1) KR20240131425A (zh)
CN (1) CN116496256A (zh)
AU (1) AU2023204840A1 (zh)
TW (1) TWI827429B (zh)
WO (1) WO2023131116A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107624111A (zh) * 2015-05-19 2018-01-23 葛兰素史密斯克莱知识产权发展有限公司 作为激酶抑制剂的杂环酰胺
WO2018092089A1 (en) 2016-11-18 2018-05-24 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
WO2019224773A1 (en) * 2018-05-23 2019-11-28 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as rip1 kinase inhibitors
CN113767092A (zh) * 2019-05-09 2021-12-07 劲方医药科技(上海)有限公司 双杂环羰基取代的二氢吡唑类化合物,其制法与医药上的用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230026425A1 (en) * 2019-01-25 2023-01-26 Beijing Scitech-Mq Pharmaceuticals Limited Acylamino bridged heterocyclic compound, and composition and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107624111A (zh) * 2015-05-19 2018-01-23 葛兰素史密斯克莱知识产权发展有限公司 作为激酶抑制剂的杂环酰胺
WO2018092089A1 (en) 2016-11-18 2018-05-24 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
WO2019224773A1 (en) * 2018-05-23 2019-11-28 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as rip1 kinase inhibitors
CN113767092A (zh) * 2019-05-09 2021-12-07 劲方医药科技(上海)有限公司 双杂环羰基取代的二氢吡唑类化合物,其制法与医药上的用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Excipients", AMERICAN PHARMACEUTICAL ASSOCIATION
HARRIS, PHILIP A. ET AL.: "Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono- Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase", JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, 23 April 2019 (2019-04-23), pages 5096 - 5110, XP055616358, DOI: 10.1021/acs.jmedchem.9b00318 *
PHARMACOLOGICAL RESEARCH., vol. 130, 2018, pages 402 - 413

Also Published As

Publication number Publication date
CN116496256A (zh) 2023-07-28
AU2023204840A1 (en) 2024-08-01
KR20240131425A (ko) 2024-08-30
TWI827429B (zh) 2023-12-21
TW202328104A (zh) 2023-07-16

Similar Documents

Publication Publication Date Title
US10428080B2 (en) TBK/IKK inhibitor compounds and uses thereof
CN104370828B (zh) 用作raf激酶抑制剂的嘧啶衍生物
CN109195972A (zh) 作为ret激酶抑制剂的杂环化合物
CN111601799A (zh) 作为Il-17调节剂的稠合咪唑衍生物
ES2954152T3 (es) Moduladores del receptor de piperidina CXCR7
TW202128653A (zh) 作為parp7抑制劑的嗒酮
CN112778276A (zh) 作为shp2抑制剂的化合物及其应用
CN103702990A (zh) 2-(2,4,5-取代苯胺)嘧啶衍生物作为egfr调谐子用于治疗癌症
CN101675041A (zh) 用作激酶抑制剂的氨基嘧啶类化合物
CN114423753A (zh) 作为cd38抑制剂的杂双环酰胺
WO2023246656A1 (zh) Sos1蛋白降解靶向嵌合体及其组合物、制剂和用途
WO2021197452A1 (zh) 含氮杂芳类衍生物自由碱的晶型
TWI724753B (zh) 醯胺基橋連雜環類化合物、及其組合物與應用
CN115368373A (zh) 螺环类化合物及其用途
JP2016514709A (ja) ヤヌスキナーゼ阻害剤としてのジェミナル置換シアノエチルピラゾロピリドン
TWI822666B (zh) Ｊａｎｕｓ激酶抑制劑之結晶型
JP2020537671A (ja) ピリミジンＴＢＫ／ＩＫＫεインヒビター化合物およびそれらの使用
WO2020169058A1 (zh) Pd-l1拮抗剂化合物
WO2023131116A1 (zh) 羰基桥连杂环类化合物、及其组合物与应用
WO2022194265A1 (zh) 一种喹唑啉类化合物、组合物及其应用
CN116194103A (zh) 细胞周期蛋白依赖性激酶7（cdk7）非共价抑制剂
CN116783183A (zh) 作为vhl抑制剂用于治疗贫血和癌症的1-(2-(4-环丙基-1h-1,2,3-三唑-1-基)乙酰基)-4-羟基-n-(苄基)吡咯烷-2-甲酰胺衍生物
JP2021522165A (ja) ２，６−ジアミノ−３，４−ジヒドロピリミジン−４−オン誘導体および治療におけるその使用
CN111247134A (zh) 嘧啶ΤΒΚ/ΙΚΚε抑制剂化合物及其用途
WO2021238908A1 (zh) 杂芳类衍生物的盐、晶型及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23736981

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: AU2023204840

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2023736981

Country of ref document: EP

Effective date: 20240711

ENP Entry into the national phase

Ref document number: 20247026065

Country of ref document: KR

Kind code of ref document: A

Ref document number: 2023204840

Country of ref document: AU

Date of ref document: 20230103

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE