WO2021238817A1 - 大环jak抑制剂及其应用 - Google Patents

大环jak抑制剂及其应用 Download PDF

Info

Publication number
WO2021238817A1
WO2021238817A1 PCT/CN2021/095329 CN2021095329W WO2021238817A1 WO 2021238817 A1 WO2021238817 A1 WO 2021238817A1 CN 2021095329 W CN2021095329 W CN 2021095329W WO 2021238817 A1 WO2021238817 A1 WO 2021238817A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
aryl
independently selected
cycloalkyl
membered
Prior art date
Application number
PCT/CN2021/095329
Other languages
English (en)
French (fr)
Inventor
吕志俭
李佳
苏明波
高安慧
Original Assignee
百极弘烨（广东）医药科技有限公司
百极弘烨(南通)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 百极弘烨（广东）医药科技有限公司, 百极弘烨(南通)医药科技有限公司 filed Critical 百极弘烨（广东）医药科技有限公司
Priority to US17/999,743 priority Critical patent/US20230167114A1/en
Priority to EP21812993.0A priority patent/EP4159735A1/en
Publication of WO2021238817A1 publication Critical patent/WO2021238817A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • 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
    • 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
    • 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
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P37/02—Immunomodulators
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a macrocyclic JAK inhibitor and its application.
  • Protein kinases are a group of enzymes that regulate a variety of important biological processes, which constitute one of the largest human enzyme families.
  • the biological processes especially include cellular kinases that catalyze protein, lipid, sugar, nucleoside and other cellular metabolism
  • the phosphorylation of substances plays a key role in all aspects of eukaryotic cell physiology. It has been shown that abnormal kinase activity is involved in many human diseases, including cancer, autoimmune diseases and inflammatory diseases.
  • Janus kinase is a cytoplasmic tyrosine kinase that transduces cytokine signals from membrane receptors to STAT transcription factors. It plays an important role in the process of cytokine signal transmission.
  • the JAK family includes four members: JAK1, JAK2, JAK3 and Tyrosine Kinase 2 (TYK2). JAK usually associates with cytokine receptors in pairs as homodimers or heterodimers. The cytokine binds to its receptor, causing the dimerization of the receptor molecule, and the JAKs coupled to the receptor approach each other and are activated by the phosphorylation of interacting tyrosine residues.
  • the JAK family transmits cytokine-mediated signals to cells through the JAK-STAT (signal transducer and activator of transcription) pathway.
  • STAT Signal Transducer and Activator of Transcription
  • JAKs As the downstream substrate of JAKs, STATs can be activated by tyrosine phosphorylation under the stimulation of external signals, and then transferred to the nucleus to regulate gene transcription.
  • JAK family members When cytokines bind to their receptors, JAK family members autophosphorylate and/or transphosphorylate each other, and then STATs are phosphorylated and then migrate to the nucleus to regulate transcription.
  • autoimmune diseases such as allergies, asthma, (allo) transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, myelodysplastic disorders, leukemia and lymphoma
  • hematological malignancies their regulation is related to the JAK/STAT signaling pathway.
  • JAK kinase has been marketed; and Incyte's Ruxotinib, which is used to treat myelofibrosis and acute graft-versus-host disease.
  • JAK enzyme inhibitors also have some obvious side effects.
  • some JAK inhibitors are easy to cause the following side effects: infection, including pneumonia, viral infection (such as herpes zoster infection), bacterial infection, actinomycetes Infections (mycobacterial infections), fungal infections, decreased immunity (such as decreased NK cells), and anemia.
  • infection including pneumonia, viral infection (such as herpes zoster infection), bacterial infection, actinomycetes Infections (mycobacterial infections), fungal infections, decreased immunity (such as decreased NK cells), and anemia.
  • infections including pneumonia, viral infection (such as herpes zoster infection), bacterial infection, actinomycetes Infections (mycobacterial infections), fungal infections, decreased immunity (such as decreased NK cells), and anemia.
  • black box warnings are given for some serious side effects.
  • These serious side effects include, for example, acute tuberculosis, invasive fungal infections, bacterial infections, and some lymphomas or other tumors.
  • JAKs family kinases are responsible for regulating many signal pathways. Since JAK1 and JAK3 are common components of the ⁇ -chain cytokine receptor complex, it is very difficult to develop inhibitors with high selectivity to JAK1.
  • JAK1 plays a key role in biological response regulation, and JAK1 is widely expressed and is associated with several major cytokine receptor families. It participates in the passage of IL-2 receptor ⁇ subunit family (IL-2, IL-4, IL-7R, IL-9R, IL-15R and IL-21R), IL-4 receptor family (IL-4R, IL -13R), the signaling of members of the gp130 receptor family and type II cytokine receptors (including the IL-10 receptor family and both the type I and type II IFN receptor families).
  • IL-2 receptor ⁇ subunit family IL-2, IL-4, IL-7R, IL-9R, IL-15R and IL-21R
  • IL-4 receptor family IL-4 receptor family
  • type II cytokine receptors including the IL-10 receptor family and both the type I and type II IFN receptor families.
  • the present invention provides an inhibitor of JAK or related kinases, especially an inhibitor with high selectivity to JAK1.
  • Ring C is independently selected from the following group of substituted or unsubstituted groups: 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • X is independently selected from the following group: N, CR d ;
  • Z is independently selected from the following group: bond, NR b , O, S, C(R c ) 2 ;
  • R b is independently selected from the group consisting of H, C1-C6 alkyl
  • Each R c is independently selected from the following group: H, halogen, amino, nitro, hydroxyl, cyano, carboxy, sulfone, sulfoxide, amide, sulfonamide, ester, C1-C6 alkyl, C1 -C6 alkoxy, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and Rd are each independently selected from the following group: H, D, halogen, amino, nitro, hydroxyl, cyano, carboxy, sulfone Group, sulfoxide group, amide group, sulfonamide group, ester group, formyl group, formamide group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- 10-membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • R 1 and R 2 together with the atoms to which they are connected form a substituted or unsubstituted group: 5-6 membered aryl heteroaryl, 3-10 membered heterocyclyl, C3-C10 cycloalkyl;
  • substitution refers to substitution by one or more (such as 2, 3, 4, 5) groups selected from the following group: D, halogen, amino, nitro, hydroxyl, cyano, carboxy, sulfone, sulfide Sulfone group, amide group, sulfonamide group, ester group, formyl group, formamide group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3-10 membered hetero Cycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • each R a is independently selected from the group consisting of: halogen, amino, nitro, hydroxyl, mercapto group, a cyano group, a carboxyl group, a sulfone group, a sulfoxide group, an amide group, sulfonamide Group, ester group, formyl group, carboxamido group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3-10 membered heterocycloalkyl group, C3-C10 ring Alkyl, 5-12 membered heteroaryl, C6-C12 aryl
  • n 1, 2, 3, 4, 5 or 6;
  • n 0, 1, 2, 3.
  • the compound or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates have the structure shown in Formula II:
  • A, B, C, W, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and m are as described above.
  • Z is a bond
  • Y is NH
  • the compound or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates have the structure shown in Formula III:
  • A, B, C, W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and m are defined as described above.
  • heterocycloalkyl, cycloalkyl, aryl, heteroaryl, aryl groups may be further optionally substituted with one or more (e.g. 2,3,4,5) substituted with R a, wherein each R a is independently selected from From the following group: halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxy, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • R b , R c and n are as described above.
  • L 1 and Y are connected.
  • R 3 is halogen
  • A is NR b ; wherein R b is independently selected from the following group: H, C1-C6 alkyl.
  • B is a bond.
  • ring C is independently selected from the following group of substituted or unsubstituted groups: 6-membered heterocycloalkyl, C6 cycloalkyl, 6-membered heteroaryl, C6 aryl; wherein, the Substitution refers to substitution by one or more groups selected from the following group: D, halogen, amino, nitro, hydroxyl, sulfhydryl, cyano, carboxy, sulfhydryl, sulfone, sulfoxide, amide, sulfonamide , Ester group, formyl group, carboxamido group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3-10 membered heterocycloalkyl group, C3-C10 cycloalkane Group, 5-12 membered heteroaryl group, C6-C12 aryl group;
  • each R a is independently selected from the group consisting of: halogen, amino, nitro, hydroxyl, mercapto group, a cyano group, a carboxyl group, a sulfone group, a sulfoxide group, an amide group, a sulfonamide group, an ester group, a formyl group, formamide Group, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl , C6-C12 aryl.
  • the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate is characterized in that ring C is selected from the following group:
  • X 1, X 2, X 3 , X 4, X '1 and X' 2 are each independently selected from the group consisting of: N, CR d; and X 1, X 2, X 3 and X 4 have 0,1, 2. Three are N;
  • R d The definition of R d is as described above.
  • X '1 and X' 2 are both N.
  • ring C is selected from:
  • R d are each independently selected from the following group: H, D, halogen, amino, nitro, hydroxyl, cyano, carboxy, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide Group, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl , C6-C12 aryl;
  • e 0, 1, 2, 3;
  • f 0, 1, 2, 3, or 4.
  • the compound has the structure shown in formula IV-1 and IV-2:
  • E 1 and E 2 are each independently N or CR d ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R d and m are as described above.
  • E 1 is N.
  • E 2 is N.
  • n 1, 2, 3, 4.
  • n 1
  • the compound of formula I has one or more of the following characteristics:
  • B is the key, NR b ;
  • Ring C is independently selected from the following group of substituted or unsubstituted groups: 6-membered heterocycloalkyl, C6 cycloalkyl, 6-membered heteroaryl, C6 aryl; preferably, ring C is
  • X 1, X 2, X 3 , X 4, X '1 and X' 2 are each independently selected from the group consisting of: N, CR d; and X 1, X 2, X 3 and X 4 have 0,1, 2. Three are N;
  • substitution refers to substitution by one or more groups selected from the following group: D, halogen, amino, nitro, hydroxyl, sulfhydryl, cyano, carboxyl, sulfhydryl, sulfone, sulfoxide, amide Group, sulfonamide group, ester group, formyl group, formamide group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3-10 membered heterocycloalkyl group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • X is N
  • Y is NR b ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and Rd are each independently selected from the following group: H, D, halogen, amino, nitro, hydroxyl, cyano, carboxy, sulfone Group, sulfoxide group, amide group, sulfonamide group, ester group, formyl group, formamide group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3- 10-membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • Each R c is independently selected from the following group: H, halogen, amino, nitro, hydroxyl, cyano, carboxy, sulfone, sulfoxide, amide, sulfonamide, ester, C1-C6 alkyl, C1 -C6 alkoxy, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • alkyl, alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heteroaryl, and aryl groups may be further optionally substituted by one or more (such as 2, 3, 4, 5 ) R a substituents, wherein each R a is independently selected from the group consisting of: halogen, amino, nitro, hydroxyl, mercapto group, a cyano group, a carboxyl group, a sulfone group, a sulfoxide group, an amide group, a sulfonamide group, an ester group, Formyl, carboxamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5- 12-membered heteroaryl, C6-C12 aryl.
  • Y is NH
  • W is independently selected from the following group: CH 2 , substituted phenyl; wherein, the substitution refers to substitution by 1-3 groups selected from the following group: halogen, amino, hydroxyl, Mercapto group, cyano group, carboxyl group, sulfone group, sulfoxide group, amide group, sulfonamide group, ester group, formyl group, formamide group, C1-C6 alkyl group, C1-C6 alkoxy group.
  • R 6 and R 7 are each independently selected from the following group: H, D, halogen, and C1-C6 alkyl.
  • R d is selected from the group consisting of H, D, halogen, C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, R m NR p , R m SO 2 -,- COOR p , -CONR y R z , -NR y COR m ;
  • R m is independently selected from: C1-C6 alkyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl Group, C6-C12 aryl;
  • R p is independently selected from: H, C1-C6 alkyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 Aryl;
  • R y and R z are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered heterocycl
  • A, B, C, W, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m are specific compounds in the embodiment The corresponding specific group.
  • the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, and the compound is selected from the following group:
  • the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate is selected from the compounds shown in the embodiment.
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the first aspect or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates; and pharmaceutically acceptable Accepted carrier.
  • the pharmaceutical composition further includes:
  • the pharmaceutical composition further includes a drug selected from the following group:
  • PD-1 inhibitors such as nivolumab, pembrolizumab, pidilizumab, cemipilimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10 , BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.
  • PD-L1 inhibitors such as duvacizumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biosimilars of the above drugs, etc.
  • CD20 antibodies such as rituximab, obin utuzumab, Ofatumumab, veltuzumab, tositumomab, 131I-
  • MEK inhibitors such as simetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, Pi masertib (AS-703026), PD184352 (CI-1040), etc.
  • mTOR inhibitors such as Vistusertib, etc.
  • SHP2 inhibitors such as RMC-4630, JAB-3068,
  • a method for preparing a pharmaceutical composition which includes the step of combining a pharmaceutically acceptable carrier with the compound or its stereoisomers or optical isomers according to the first aspect of the present invention.
  • Pharmaceutically acceptable salts, prodrugs or solvates are mixed to form a pharmaceutical composition.
  • the compound of the present invention can be prepared into powders, tablets, granules, capsules, solutions, emulsions, suspensions and the like.
  • the pharmaceutical composition is used to treat or prevent diseases related to the activity or expression of JAK kinase.
  • the disease is selected from the following group: cancer, myeloproliferative disease, inflammation, immune disease, organ transplantation, viral disease, cardiovascular disease or metabolic disease, human or animal autoimmune disease , Rheumatoid arthritis, skin disorders, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, psoriasis.
  • the third aspect of the present invention provides a use of the compound described in the first aspect or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates for the preparation of therapeutic or prophylactic and Drugs or pharmaceutical compositions for diseases related to the activity or expression of JAK kinase.
  • the disease is selected from the following group: cancer, myeloproliferative disease, inflammation, immune disease, organ transplantation, viral disease, cardiovascular disease or metabolic disease, human or animal autoimmune disease , Rheumatoid arthritis, skin disorders, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, psoriasis.
  • the cancer is selected from the following group: prostate cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, giant lymphoprolosis, pancreatic cancer, leukemia, lymphoma or multiple Myeloma.
  • the disease related to the activity or expression of JAK kinase is a disorder related to JAK1.
  • JAK1-related disorders are selected from the following group: type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative Colitis, Crohn's disease and alopecia areata.
  • the inventors unexpectedly discovered for the first time a new JAK inhibitor with a novel structure, good biological activity and extremely excellent selectivity. Specifically, the selectivity of the compound of the present invention represented by the ratio of JAK2/JAK1 or the selectivity represented by the ratio of JAK3/JAK1 is increased by about 12 times on average. Therefore, the side effects of the compound of the present invention and the inhibition of JAK3 are extremely significantly reduced, and the safety will be significantly improved.
  • the present invention has been completed on this basis.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH 2 O- is equivalent to -OCH 2 -.
  • the term “about” means that the value can vary from the recited value by no more than 1%.
  • the expression “about 100” includes all values between 99 and 101 (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the term “comprising” or “including (including)” can be open, semi-closed, and closed. In other words, the term also includes “substantially composed of” or “consisting of”.
  • alkyl includes straight-chain or branched alkyl groups.
  • C 1 -C 6 alkyl means a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.
  • the alkyl group may be optionally substituted or unsubstituted, and the substituted alkyl group includes haloalkyl, benzyl and the like.
  • alkenyl includes linear or branched alkenyl.
  • C 2 -C 6 alkenyl refers to a linear or branched alkenyl group having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -Butenyl, or similar groups.
  • alkynyl includes straight-chain or branched alkynyl groups.
  • a C 2 -C 6 alkynyl group refers to a linear or branched alkynyl group having 2-6 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, or the like.
  • cycloalkyl refers to a cyclic alkyl group containing a specific number of C atoms, such as "C3-C10 cycloalkyl” refers to having 3-10 (preferably 3, 4, 5, 6, 7 Or 8) cycloalkyl of carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. It can also be in the form of a bicyclic ring, such as a bridged ring or a spiro ring. In the present invention, cycloalkyl is intended to include substituted cycloalkyl.
  • C1-C6 alkoxy refers to a linear or branched alkoxy group having 1 to 6 carbon atoms; it has the formula C1-C6 alkyl-O- or -C1-C5 alkyl Group -O-C1-C5 alkyl (e.g., -CH 2 -O-CH 2 CH 3 , -CH 2 -O-(CH 2 ) 2 CH 3 , -CH 2 CH 2 -O-CH 2 CH 3 ) Structure, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.
  • heterocyclyl refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S, and O
  • heterocyclyl refers to A saturated or partially saturated cyclic group having 3-10 atoms in which 1-3 atoms are heteroatoms selected from the group consisting of N, S, and O. It may be in the form of a single ring or a double ring, such as a bridged ring or a spiro ring.
  • the 3-10 membered heterocyclic group is preferably a 3-8 membered heterocyclic group, more preferably a 3-6 membered heterocyclic group, and more preferably a 6-8 membered heterocyclic group.
  • heterocycloalkyl or heterocyclic group may be optionally substituted or unsubstituted.
  • aryl refers to an aromatic ring group that does not contain heteroatoms on the ring
  • C6-C12 aryl refers to an aromatic ring group with 6 to 12 carbon atoms that does not contain heteroatoms on the ring
  • the aryl group can be fused on a heteroaryl, heterocyclic or cycloalkyl ring, and the ring connected to the parent structure is an aryl ring.
  • phenyl ie six-membered aromatic ring
  • naphthyl etc.
  • six-membered aryl also means to include six-membered aryl and 5-6 membered cycloalkyl and six-membered aryl and 5-6 membered heterocycloalkyl .
  • the C6-C12 aryl group is preferably a C6-C10 aryl group.
  • Aryl groups can be optionally substituted or unsubstituted.
  • heteroaryl refers to a cyclic aromatic group having 1-3 atoms selected from the group consisting of N, S and O heteroatoms
  • heteroaryl refers to having 5-12 Atomic cyclic aromatic group in which 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a monocyclic ring or a condensed ring form.
  • heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, and the ring connected to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , Alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, amide, sulfonamide, Formyl group, formamide group, carboxyl group and carboxylate group, etc.
  • groups which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , Alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, ary
  • halogen or "halogen atom” refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br.
  • amide group refers to a group with the structure -CONRR', wherein R and R'can independently represent hydrogen, alkyl, cycloalkyl, aryl, heterocyclic group, as above Defined. R and R'may be the same or different in the dialkylamine segment.
  • sulfonamide group refers to a group with the structure -SO 2 NRR', wherein R and R'can independently represent hydrogen, alkyl, cycloalkyl, aryl, heterocyclic group, As defined above. R and R'may be the same or different in the dialkylamine segment.
  • carboxamido means to include The carboxamido group is also meant to include substituted carboxamido groups, having the formula Wherein, R each independently represents hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic group, as defined above. Each R may be the same or different.
  • amino means having the structure -N-RR', and R and R'each independently represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, as defined above , R and R'can be the same or different.
  • sulfoxide group means having -S(O)-R, R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, as defined above.
  • sulfone group means having -S(O) 2 -R, R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, as defined above.
  • ester group means having a -C(O)-OR or RC(O)-O- structure, where R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl , Heterocyclic group, as defined above.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the groups of the present invention can be substituted by substituents selected from the following group: deuterium, halogen, cyano, nitro, hydroxyl , Amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl Group, C6-C12 aryl group.
  • the term "plurality” means 2, 3, 4, 5 independently.
  • the structural formula described in the present invention is intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, containing asymmetry The R and S configuration of the center, the (Z) and (E) isomers of the double bond, etc. Therefore, a single stereochemical isomer of the compound of the present invention or a mixture of its enantiomers, diastereomers or geometric isomers (or conformational isomers) all belong to the scope of the present invention.
  • tautomers means that structural isomers with different energies can exceed the low energy barrier to convert into each other.
  • proton tautomers ie, proton transfer
  • Valence tautomers include interconversion through some bond-forming electron recombination.
  • solvate refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • the compound of the present invention refers to the compound represented by formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compound of formula I.
  • the compound of formula I has the following structure:
  • the compound of formula I has the structure shown in formula II:
  • A, B, C, W, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and m are as described above.
  • Z is a bond
  • Y is NH
  • the compound of formula I has the structure shown in formula III:
  • A, B, C, W, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and m are defined as described above.
  • ring C is independently selected from the following group of substituted or unsubstituted groups: 6-membered heterocycloalkyl, C6 cycloalkyl, 6-membered heteroaryl, C6 aryl; wherein, the The substitution refers to substitution by one or more groups selected from the following group: D, halogen, amino, nitro, hydroxyl, sulfhydryl, cyano, carboxyl, sulfhydryl, sulfone, sulfoxide, amide, sulfonamide Group, ester group, formyl group, carboxamido group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3-10 membered heterocycloalkyl group, C3-C10 ring Alkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • each R a is independently selected from the group consisting of: halogen, amino, nitro, hydroxyl, mercapto group, a cyano group, a carboxyl group, a sulfone group, a sulfoxide group, an amide group, a sulfonamide group, an ester group, a formyl group, formamide Group, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl , C6-C12 aryl.
  • ring C is selected from the following group:
  • X 1, X 2, X 3 , X 4, X '1 and X' 2 are each independently selected from the group consisting of: N, CR d; and X 1, X 2, X 3 and X 4 have 0,1, 2. Three are N;
  • R d The definition of R d is as described above.
  • W is independently selected from the following group: C(R c ) 2 , 6-membered heterocycloalkyl, C6 cycloalkyl, 6-membered aryl or heteroaryl, L 1 -(CH 2 ) n -L 2 ;
  • W is independently 6-membered aryl or heteroaryl; wherein, L 1 is independently selected from the following group: none, 6-membered heterocycloalkyl, C6 cycloalkyl, 6-membered aromatic Group or heteroaryl group,
  • heterocycloalkyl, cycloalkyl, aryl, heteroaryl, aryl groups may be further optionally substituted with one or more of R a, wherein each R a is independently selected from the group consisting of: halogen, amino, nitro, , Hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 Alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • R b , R c and n are as described above.
  • R 3 is halogen
  • A is NR b ; wherein, R b is independently selected from the following group: H, C1-C6 alkyl.
  • B is a bond.
  • m is 1, 2, 3, 4.
  • pharmaceutically acceptable salt refers to a salt formed by a compound of the present invention and an acid or base suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of this invention with acids.
  • Acids suitable for salt formation include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 150°C, preferably 10°C to 100°C).
  • the reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.
  • the compound of the present invention can be prepared with the following steps
  • a 1 is selected from the following group: carboxyl group, sulfonic acid group, CO-OR", -CO-NH-R"; wherein, R" is selected from the following group of substituted or unsubstituted groups: C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • substitution refers to substitution by one or more groups selected from the following group: D, halogen, amino, amine, nitro, hydroxyl, sulfhydryl, cyano, carboxy, sulfone, sulfoxide, amide , Sulfonamide group, ester group, formyl group, formamide group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, 3-10 membered heterocyclic group, C3- C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • a 2 is selected from the following group: amino, hydroxyl
  • A, B, C, W, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and m are as described above.
  • the starting materials and reagents used in the compound synthesis method of the present invention can be purchased commercially or synthesized by methods reported in the literature.
  • the compound of the present invention has excellent JAK kinase inhibitory activity
  • the compound of the present invention or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, and containing the compound of the present invention are the main activity
  • the pharmaceutical composition of the components can be used to prevent and/or treat (stabilize, reduce or cure) JAK kinase-related diseases (for example, skin diseases, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriatic arthritis, juvenile arthritis) , Crohn's disease, myasthenia gravis, cancer (including prostate cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, giant lymphoprolosis, pancreatic cancer, leukemia, lymphoma or multiple Myeloma, etc.)).
  • JAK kinase-related diseases for example, skin diseases, rheumatoid arthritis, multiple sclerosis, type I diabetes,
  • the pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per agent, and more preferably, contains 10-200 mg of the compound of the present invention per agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that each component of the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc.
  • antioxidants
  • the administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular, or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and g
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as JAK inhibitors).
  • other pharmaceutically acceptable compounds such as JAK inhibitors.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., JAK inhibitor).
  • one or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used simultaneously, separately or sequentially with the compound of the present invention Prevent and/or treat diseases related to the activity or expression of JAK kinase.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the dosage is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are all within the skill range of a skilled physician.
  • the compound of the present invention has a novel structure and excellent JAK kinase inhibitory effect
  • the compound of the present invention can be used as JAK kinase inhibitor, especially as a highly selective inhibitor of JAK1.
  • the synthetic methods of the compounds of the present invention are shown in the following schemes, methods and examples.
  • the starting materials are commercially available or can be prepared according to known methods in the art or described herein.
  • the compound of the present invention can be illustrated by the specific examples shown below. However, these specific embodiments should not be construed as the only kind of the present invention. These examples further illustrate the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of conditions and procedures can be used to prepare these compounds. All temperatures are in degrees Celsius, unless otherwise stated.
  • PTLC thin layer chromatography
  • LCMS chromatogram adopts Agilent Technologies 1200 series or 6120 quadrupole spectrometer.
  • For the LC mobile phase is acetonitrile (A) and water (B) and 0.01% formic acid, eluent gradient: 6.0 minutes 5-95% A, 5.0 minutes 60-95% A, 5.0 minutes 80-100% A and 10 minutes 85-100% A, using SBC1850 mm x 4.6 mm x 2.7 micron capillary column.
  • MS Mass spectrometry
  • ESI electrospray ionization mass spectrometry
  • MS mass range 150-750amu; positive ion electrospray ionization
  • MS mass range 150-750amu; positive ion electrospray ionization
  • MS mass range 150-750amu; positive ion electrospray ionization
  • Alk is an alkyl group
  • AR is aryl
  • MgSO 4 magnesium sulfate
  • Na 2 SO 4 sodium sulfate
  • PE petroleum ether
  • the first step 3-amino-5-bromo-2-fluoropyridine (A1-2)
  • 3-amino-5-bromo-2-fluoropyridine (A1-2, 300mg, 1.57mmol), p-methoxycarbonylphenylboronic acid (282.7mg, 1.57mmol) and potassium carbonate (542.7mg, 3.93mmol)
  • 1,4-dioxane (12ml) and water (3ml)
  • tetrakis(triphenylphosphine) palladium 54.5mg, 0.03mmol
  • the third step tert-butyl 5-((2-chloro-5-methylpyrimidine-4-)amino)pentylamine carboxylate (A1-5)
  • the fourth step 4-(5-((4-(5-tert-butoxycarbonylamino)pentyl)-5-methylpyrimidine-2-)amino)-6-fluoropyridine-3-)methyl benzoate (A1-6)
  • methyl 4-(5-amino-6-fluoropyridine-3-)benzoate (A1-3, 141mg, 0.57mmol), 5-((2-chloro-5-methylpyrimidine-4- ) Amino) tert-butyl amylamine formate (A1-5, 179mg, 0.55mmol) and potassium carbonate (150mg, 1.1mmol) were added to 1,4-dioxane (10ml), stirred for 5min, and then added three at a time (Dibenzylideneacetone) two palladium (50mg, 0.05mmol) and 2-dicyclohexylphosphorus-2',4',6'-triisopropylbiphenyl (52mg, 0.11mmol), heated to 100°C, Stir for 5h.
  • the fifth step 4-(5-((4-(5-tert-butoxycarbonylamino)pentyl-5-methylpyrimidine-2-)amino)-6-fluoropyridine-3-)benzoic acid (A1 -7)
  • the sixth step 4-(5-((4-(5-aminopentylamino)-5-methylpyrimidine-2-)amino)-6-fluoropyridine-3-)benzoic acid (A1-8)
  • the seventh step 2 6 -fluoro-4 5 -methyl-3,5,11-triaza-4(2,4)-pyrimidine hetero-2(3,5)-pyridine hetero-1(1,4 )-Benzene heterocyclic dodecanophen-12-one (A1)
  • the JAK kinase activity measurement method uses homogeneous time-resolved fluorescence technology.
  • the reaction of this method is in a 384 shallow-well plate, and the total reaction volume is 10 ⁇ L.
  • the mixture of kinase protein, compound, ATP and substrate in the reaction buffer of 50mM Hepes (pH7.0), NaN 3 0.02%, BSA 0.01%, 0.1mM orthovanadate (Orthocanadate), 5mM MgCl 2, 1mM DTT After reacting for 1 hour, add an antibody capable of recognizing the phosphorylation of the substrate, the dye XL-615, and a detection buffer (Cisbio) containing EDTA into the system.
  • the reaction signal of kinase is detected by PE company's multi-well plate detector.
  • the parameter settings are excitation light 320nm, emission light 615nm and 665nm.
  • the signal ratio of 665nm and 615nm indirectly reflects the activity of JAK.
  • a background hole without enzyme and a full enzyme activity hole without compound are set up in the reaction.
  • IC 50 values of compounds to inhibit protein by the equation: Y 100 / (1 + 10 ⁇ ((LogIC50-X) * HillSlope)) is obtained.
  • the concentration of ATP is 2 ⁇ M and the concentration of JAK1 protein is 0.2ng/ ⁇ L.
  • the concentration of ATP is 2 ⁇ M and the concentration of JAK2 protein is 0.01ng/ ⁇ L.
  • the concentration of ATP is 2 ⁇ M and the concentration of JAK3 protein is 0.04ng/ ⁇ L.
  • the concentration of ATP is 2 ⁇ M, and the concentration of TYK2 protein is 0.2ng/ ⁇ L.
  • test data is divided into the following types: A: IC 50 ⁇ 10nM; B: IC 50 11-100nM; C: IC 50 101-1000nM; D: IC 50 1001-10000nM; E: IC 50 >10000nM.
  • the compound of formula I of the present invention exhibits very excellent JAK inhibitory activity, especially JAK1 activity.
  • the IC50 value of the compound of the present invention can be as low as 10 nM or lower, so for a subject weighing about 70 kg (such as a patient, especially a patient with rheumatoid arthritis or psoriasis), the daily dosage is usually 10 mg-30 mg. Very effective in inhibiting JAK, especially JAK1.
  • the compound of formula I of the present invention exhibits very excellent JAK1 selectivity, that is, the IC50 ratio of JAK3/JAK1 and/or the IC50 ratio of JAK2/JAK1 is better than the currently marketed drugs.

Abstract

本发明涉及一种大环JAK抑制剂及其应用。具体地，本发明涉及如式I所示的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，也涉及所述化合物的药物组合物以及其作为JAK抑制剂，以及在制备预防和/或治疗与JAK，尤其是JAK1相关疾病的药物中的医药用途。

Description

大环JAK抑制剂及其应用 技术领域
本发明属于药物化学领域，具体涉及一种大环JAK抑制剂及应用。
背景技术
蛋白激酶(PK)是调控多种重要生物过程的一组酶，其构成了人最大的酶家族之一，所述生物过程尤其包括细胞激酶催化蛋白质、脂质、糖、核苷和其他细胞代谢物的磷酸化并在真核细胞生理学的所有方面起关键作用。已经表明在许多人类疾病中涉及激酶活性异常，这些疾病包括癌症、自身免疫性疾病和炎性疾病。
Janus激酶(JAK)是转导细胞因子信号从膜受体到STAT转录因子的细胞质酪氨酸激酶，其在细胞因子信号传递过程中起重要作用。JAK家族包括四个成员JAK1、JAK2、JAK3及酪氨酸激酶2(TYK2)。JAK通常与细胞因子受体成对缔合作为均二聚体或杂二聚体。细胞因子与其受体结合，引起受体分子的二聚化，与受体偶联的JAKs相互接近并通过交互的酪氨酸残基磷酸化作用而活化。JAK家族通过JAK-STAT(信号转导与转录活化因子)通路将细胞因子介导的信号传递至细胞中。
信号转导和转录激活子(Signal Transducer and Activator of Transcription,STAT)是一组能与靶基因调控区DNA结合的胞质蛋白。作为JAKs的下游底物，STATs可以在外界信号的刺激下，发生酪氨酸磷酸化从而被激活，随后转入细胞核调节基因的转录。当细胞因子与其受体结合时，JAK家族成员自磷酸化和/或彼此转磷酸化，随后STATs磷酸化，然后迁移至细胞核内以调节转录。
许多异常的免疫应答，如过敏、哮喘、(异体)移植排斥、类风湿性关节炎、肌萎缩性脊髓侧索硬化症和多发性硬化症等自身免疫性疾病，骨髓增生失调，白血病和淋巴瘤等血液系统恶性肿瘤，它们的调节都与JAK/STAT信号通路有关。
研究表明，在JAK激酶水平下的阻断信号转导为炎性疾病、自身免疫病、骨髓增殖性疾病和癌症的治疗方法的开发提供了前景。JAK激酶的抑制也有助于皮肤免疫疾病如银屑病和皮肤敏化的治疗。已经上市的有辉瑞的托伐替尼(Toficitinib)，用于治疗类风湿性关节炎；以及Incyte的鲁索替尼，用于治疗骨髓纤维化以及急性移植物抗宿主病。
然而，目前已有的一些JAK酶抑制剂也存在一些明显的毒副作用，例如一些JAK抑制剂容易引起以下副作用：感染，包括肺炎、病毒感染(如带状疱疹感染)、细菌感染、放线菌感染(分枝杆菌感染)、真菌感染、免疫力下降(如NK细胞减少)以及贫血。在美国，甚至因为部分严重的副作用而得到黑框警示(Black box)，这些严重的副作用包括，例如急性肺结核、侵入性真菌感染、细菌感染、以及部分淋巴瘤或其它肿瘤。研究表明，目前已有的JAK抑制剂往往对JAK1和JAK3均有抑制活性，大多数的这些副作用的产生与JAK3的活性受抑制有关。
然而，研究表明，JAKs家族激酶负责调节众多信号通路。由于JAK1和JAK3是常见的γ-链细胞因子受体复合物的组成部分，这导致开发对JAK1具有高选择性的抑制剂存在很大的难度。
JAK1在生物反应调节中起关键作用，且JAK1被广泛表达并与几种主要的细胞因子受体家族相关联。它参与通过IL-2受体γ亚单位家族(IL-2、IL-4、IL-7R、IL-9R、IL-15R和IL-21R)、IL-4受体家族(IL-4R、IL-13R)、gp130受体家族和II类细胞因子受体(包括IL-10受体家族以及I型和II型IFN受体家族两者)的成员的信号传导。
综上所述，目前本领域迫切需要研发出Janus激酶或相关激酶的抑制剂，尤其是对JAK1具有高选择性的抑制剂。
发明内容
本发明提供了一种JAK或相关激酶的抑制剂，尤其是对JAK1具有高选择性的抑制剂。
本发明的第一方面，提供一种式I所示的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，
Figure PCTCN2021095329-appb-000001
式中，
A独立地选自下组：C(＝O)、-C(＝O)O-、C(＝O)NH、N-R b、O、S、SO、SO 2；
B独立地选自下组：键、C(＝O)、N-R b、C(R c) 2、C(＝O)O-、O、S、SO、SO 2；
环C独立地选自取代或未取代的下组基团：3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
X独立地选自下组：N、CR d；
Y独立地选自下组：C(＝O)、N-R b、C(R c) 2、C(＝O)O-、O、S、SO、SO 2；
Z独立地选自下组：键、N-R b、O、S、C(R c) 2；
W独立地选自下组：C(R c) 2、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基、L 1-(CH 2) n-L 2；其中，L 1独立地选自下组：无、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基，L 2独立地选自下组：N-R b、C(＝O)O-、O、S、SO、SO 2；
R b独立地选自下组：H、C1-C6烷基；
各R c独立地选自下组：H、卤素、氨基、硝基、羟基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、C1-C6烷基、C1-C6烷氧基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
R 1、R 2、R 3、R 4、R 5、R 6、R 7和R d各自独立地选自下组：H、D、卤素、氨基、硝基、羟基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
或者，R 1和R 2与它们连接的原子一起构成取代或未取代的下组基团：5-6元芳基杂芳基、3-10元杂环基、C3-C10环烷基；
-(CH 2) m-和-(CH 2) n-中的H原子可以任选地被一个或多个R a取代；
所述的取代是指被选自下组的一个或多个(如2、3、4、5)基团取代：D、卤素、氨基、硝基、羟基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
如无特别说明，上述的烷基、烷氧基、烯基、炔基、杂环烷基、环烷基、杂芳基、芳基可进一步任选地被1个或多个(如2、3、4、5)R a取代，其中，各R a独立地选自下组：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
m为1、2、3、4、5或6；
n为0、1、2、3。
在另一优选例中，所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其具有式II所示的结构：
Figure PCTCN2021095329-appb-000002
A、B、C、W、Y、Z、R 1、R 2、R 3、R 4、R 5、R 6、R 7、m的定义如上所述。
在另一优选例中，Z为键。
在另一优选例中，Y为NH。
在另一优选例中，所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其具有式III所示的结构：
Figure PCTCN2021095329-appb-000003
式中，A、B、C、W、R 1、R 2、R 3、R 4、R 5、R 6、R 7、m的定义如上所述。
在另一优选例中，所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，W独立地选自下组：C(R c) 2、6元杂环烷基、C6环烷基、6元芳基或杂芳基、L 1-(CH 2) n-L 2；其中，L 1独立地选自下组：无、6元杂环烷基、C6环烷基、6元芳基或杂芳基，L 2独立地选自下组：N-R b、C(＝O)O-、O、S、SO、SO 2；
上述的杂环烷基、环烷基、杂芳基、芳基可进一步任选地被1个或多个(如2、3、4、5)R a取代，其中，各R a独立地选自下组：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
R b、R c和n的定义如上所述。
在另一优选例中，L 1与Y连接。
在另一优选例中，R 3为卤素。
在另一优选例中，A为C(＝O)。
在另一优选例中，A为N-R b；其中，R b独立地选自下组：H、C1-C6烷基。
在另一优选例中，A为-C(＝O)NH-，B为键。
在另一优选例中，环C独立地选自取代或未取代的下组基团：6元杂环烷基、C6环烷基、6元杂芳基、C6芳基；其中，所述的取代是指被选自下组的一个或多个基团取代：D、卤素、氨基、硝基、羟基、巯基、氰基、羧基、巯基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
如无特别说明，上述的烷基、烷氧基、烯基、炔基、杂环烷基、环烷基、杂芳基、芳基可进一步任选地被1个或多个R a取代，其中，各R a独立地选自下组：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基。
在另一优选例中，所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，环C选自下组：
Figure PCTCN2021095329-appb-000004
其中，
Figure PCTCN2021095329-appb-000005
表示单键或双键；
X 1、X 2、X 3、X 4、X' 1和X' 2各自独立地选自下组：N、C-R d；且X 1、X 2、X 3和X 4中有0、1、2、3个为N；
R d的定义如上所述。
在另一优选例中，X' 1和X' 2均为N。
在另一优选例中，环C选自：
Figure PCTCN2021095329-appb-000006
Figure PCTCN2021095329-appb-000007
R d各自独立地选自下组：H、D、卤素、氨基、硝基、羟基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
e为0、1、2、3；
f为0、1、2、3或4。
在另一优选例中，所述化合物具有式IV-1和IV-2所示的结构：
Figure PCTCN2021095329-appb-000008
其中，
E 1和E 2各自独立地为N或CR d；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R d、m的定义如上所述。
在另一优选例中，E 1为N。
在另一优选例中，E 2为N。
在另一优选例中，m为1、2、3、4。
在另一优选例中，n为1。
在另一优选例中，所述式I化合物具有如下一个或多个特征：
A为C(＝O)、C(＝O)NH或N-R b；其中，R b独立地选自下组：H、C1-C6烷基；
B为键、N-R b；
环C独立地选自取代或未取代的下组基团：6元杂环烷基、C6环烷基、6元杂芳基、C6芳基；优选地，环C为
Figure PCTCN2021095329-appb-000009
其中，
Figure PCTCN2021095329-appb-000010
表示单键或双键；
X 1、X 2、X 3、X 4、X' 1和X' 2各自独立地选自下组：N、C-R d；且X 1、X 2、X 3和X 4中有0、1、2、3个为N；
其中，所述的取代是指被选自下组的一个或多个基团取代：D、卤素、氨基、硝基、羟基、巯基、氰基、羧基、巯基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
W独立地选自下组：C(R c) 2、6元杂环烷基、C6环烷基、6元芳基或杂芳基、L 1-(CH 2) n-L 2；其中，L 1独立地选自下组：无、6元杂环烷基、C6环烷基、6元芳基或杂芳基，L 2独立地选自下组：N-R b、C(＝O)O-、O、S、SO、SO 2；
X为N；
Y为N-R b；
Z为键；
R 1、R 2、R 3、R 4、R 5、R 6、R 7和R d各自独立地选自下组：H、D、卤素、氨基、硝基、羟基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
各R c独立地选自下组：H、卤素、氨基、硝基、羟基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、C1-C6烷基、C1-C6烷氧基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
上述的烷基、烷氧基、烯基、炔基、杂环烷基、环烷基、杂芳基、芳基可进一步任选地被1个或多个(如2、3、4、5)R a取代，其中，各R a独立地选自下组：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲 酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基。
在另一优选例中，-A-B-为-C(＝O)NH-。
在另一优选例中，Y为NH。
在另一优选例中，W独立地选自下组：CH 2、取代的苯基；其中，所述取代是指被选自下组的1-3个基团取代：卤素、氨基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基。
在另一优选例中，R 6和R 7各自独立地选自下组：H、D、卤素、C1-C6烷基。
在另一优选例中，R d选自下组：H、D、卤素、C1-C6烷基、C1-C6烷氧基、氨基、硝基、R mNR p、R mSO 2-、-COOR p、-CONR yR z、-NR yCOR m；R m独立地选自：C1-C6烷基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；R p独立地选自：H、C1-C6烷基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；R y和R z各自独立地选自：H、C1-C6烷基、C1-C6烷氧基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；其中，烷基、烷氧基、烯基、炔基、杂环烷基、环烷基、杂芳基、芳基可进一步任选地被1个或多个R a取代，其中，各R a独立地选自下组：卤素、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基。
在另一优选例中，A、B、C、W、X、Y、Z、R 1、R 2、R 3、R 4、R 5、R 6、R 7、m为实施例中各具体化合物相对应的具体基团。
在另一优选例中，所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，所述化合物选自下组：
Figure PCTCN2021095329-appb-000011
Figure PCTCN2021095329-appb-000012
Figure PCTCN2021095329-appb-000013
在另一优选例中，所述化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，选自实施例中所示的化合物。
本发明第二方面，提供一种药物组合物，包含第一方面所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物；和药学上可接受的载体。
在另一优选例中，所述药物组合物还包括：
在另一优选例中，所述药物组合物还包括选自下组的药物：
PD-1抑制剂(如纳武单抗、派姆单抗、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如度伐单抗、阿特珠单抗、阿维鲁 单抗(avelumab)、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、veltuzumab,托西莫单抗、131I-托西莫单抗、替伊莫单抗、90Y-替伊莫单抗、90In-替伊莫单抗、替伊莫单抗(ibritumomab tiuxetan)等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、阿卡替尼、赞布替尼、Vecabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼、沙普替尼、Naquotinib、吡咯替尼、罗乐替尼、奥希替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞戈非尼、司曲替尼、Ningetinib、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、伏立诺他、Fimepinostat、Droxinostat、恩替诺特、达西司特、Quisinostat、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib、Milciclib、Trilaciclib、Lerociclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等)，或其组合。
在另一优选例中，提供一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述第一方面所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物进行混合，从而形成药物组合物。
在另一优选例中，本发明化合物可以制备成散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂等。
在另一优选例中，所述的药物组合物用于治疗或预防与JAK激酶的活性或表达量相关的疾病。
在另一优选例中，所述的疾病选自下组：癌症、骨髓增殖性疾病、炎症、免疫性疾病、器官移植、病毒性疾病、心血管疾病或代谢性疾病、人或动物自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化，类风湿关节炎、银屑性关节炎、炎性肠病、重症肌无力、牛皮癣。
本发明第三方面，提供一种第一方面所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物的用途，用于制备治疗或预防与JAK激酶的活性或表达量相关的疾病的药物或药物组合物。
在另一优选例中，所述的疾病选自下组：癌症、骨髓增殖性疾病、炎症、免疫性疾病、器官移植、病毒性疾病、心血管疾病或代谢性疾病、人或动物自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化，类风湿关节炎、银屑性关节炎、炎性肠病、重症肌无力、牛皮癣。
在另一优选例中，癌症选自下组：前列腺癌、肾癌、肝癌、乳腺癌、肺癌、甲状腺癌、卡波济氏肉瘤、巨大淋巴增生症、胰腺癌、白血病、淋巴癌或多发性骨髓瘤。
在另一优选例中，JAK激酶的活性或表达量相关的疾病为JAK1相关的障碍。
在另一优选例中，JAK1相关的障碍选自下组：1型糖尿病、狼疮、多发性硬化症、类风湿性关节炎、牛皮癣、哮喘、特应性皮炎、自身免疫性甲状腺疾病、溃疡性结肠炎、克罗恩病和斑秃。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人通过广泛而深入的研究，首次意外地发现一种新的JAK抑制剂，结构新颖，并且具有很好的生物活性及极其优异的选择性。具体地，本发明化合物，以JAK2/JAK1之比为代表的选择性或以JAK3/JAK1之比为代表的选择性平均提高约12倍。因此，本发明化合物与JAK3受抑制相关的副作用极其显著下降，而安全性将显著提高。在此基础上完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
如本文所用，术语“烷基”包括直链或支链的烷基。例如C 1-C 6烷基表示具有1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。本发明中，烷基可以是任选取代的或未取代的，取代的烷基包括卤代烷基、苄基等。
如本文所用，术语“烯基”包括直链或支链的烯基。例如C 2-C 6烯基指具有2-6个碳原子的直链或支链的烯基，例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用，术语“炔基”包括直链或支链的炔基。例如C 2-C 6炔基是指具有2-6个碳原子的直链或支链的炔基，例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用，术语“环烷基”是指包含特定数目的C原子的环状烷基，如“C3-C10环烷基”指具有3-10个(优选3、4、5、6、7或8个)碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。本发明中，环烷基意在包含取代环烷基。
如本文所用，术语“C1-C6烷氧基”是指具有1-6个碳原子的直链或支链的烷氧基；其具有式C1-C6烷基-O-或-C1-C5烷基-O-C1-C5烷基(如，-CH 2-O-CH 2CH 3、-CH 2-O-(CH 2) 2CH 3、-CH 2CH 2-O-CH 2CH 3)结构，例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用，“杂环(烷)基(heterocyclyl)”是指具有选自N、S和O的杂原子的饱和或部分饱和的环状基团，“3-10元杂环基”是指具有3-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环，也可以是双环形式，例如桥环或螺环形式。3-10元杂环基优选3-8元杂环基，更优选地为3-6元杂环基，更优选地为6-8元杂环基。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、哌嗪基、四氢呋喃基、吗啉基和吡咯烷基等。杂环烷基或杂环基可以是任选取代的或未取代的。
如本文所用，“芳基”是指环上不含杂原子的芳香族环基，“C6-C12芳基”是指在环上不含杂原子的具有6至12个碳原子的芳香族环基，所述芳基可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。如苯基(即六元芳环)、萘基等，其中六元芳基还意在包含六元芳基并5-6元环烷基和六元芳基并5-6元杂环烷基。C6-C12芳基优选C6-C10芳基。芳基可以是任选取代的或未取代的。
如本文所用，“杂芳基”指具有1-3个原子为选自下组N、S和O的杂原子的环状芳香基，“5-12元杂芳基”指具有5-12个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、酰胺基、磺酰胺基、甲酰基、甲酰胺基、羧基和羧酸酯基等。
如本文所用，“卤素”或“卤原子”指F、Cl、Br和I。更佳地，卤素或卤原子选自F、Cl和Br。
在本发明中，术语“酰胺基”是指带有结构-CONRR'的基团，其中，R和R'可以独立的代表氢、烷基、环烷基、芳基、杂环基，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。
在本发明中，术语“磺酰胺基”是指带有结构-SO 2NRR'的基团，其中R和R'可以独立的代表氢、烷基、环烷基、芳基、杂环基，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。
在本发明中，术语“甲酰基”是指包含-CHO的基团。
在本发明中，术语“甲酰胺基”是指包含
Figure PCTCN2021095329-appb-000014
的基团，甲酰胺基还意在包含取代的甲酰胺基，具有式
Figure PCTCN2021095329-appb-000015
其中，R各自独立地代表氢、烷基、环烷基、环烯基、芳基、杂芳基、杂环基，如上文所定义。各R可以相同或不同。
在本发明中，“氨基”是指具有-N-RR'结构，R和R'各自独立地代表氢、烷基、环烷基、芳基、杂芳基、杂环基，如上文所定义，R和R'可以相同或不同。
在本发明中，“亚砜基”是指具有-S(O)-R，R独立地代表氢、烷基、环烷基、芳基、杂芳基、杂环基，如上文所定义。
在本发明中，“砜基”是指具有-S(O) 2-R，R独立地代表氢、烷基、环烷基、芳基、杂芳基、杂环基，如上文所定义。
在本发明中，“酯基”是指具有-C(O)-O-R或R-C(O)-O-结构，其中，R独立地代表氢、烷基、环烷基、芳基、杂芳基、杂环基，如上文所定义。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。
本发明所述的基团除非特别说明是“取代的或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基。
在本发明中，术语“多个”独立指2、3、4、5个。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用，术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
活性成分
如本文所用，“本发明化合物”指式I所示的化合物，并且还包括及式I化合物的立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物。
所述式I化合物具有如下结构：
Figure PCTCN2021095329-appb-000016
其中，A、B、C、W、X、Y、Z、R 1、R 2、R 3、R 4、R 5、R 6、R 7、m的定义如上所述。
优选地，所述式I化合物具有式II所示的结构：
Figure PCTCN2021095329-appb-000017
其中，A、B、C、W、Y、Z、R 1、R 2、R 3、R 4、R 5、R 6、R 7、m的定义如上所述。
优选地，上述各式中，Z为键。
优选地，上述各式中，Y为NH。
优选地，所述式I化合物具有式III所示的结构：
Figure PCTCN2021095329-appb-000018
式中，A、B、C、W、R 1、R 2、R 3、R 4、R 5、R 6、R 7、m的定义如上所述。
优选地，上述各式中，环C独立地选自取代或未取代的下组基团：6元杂环烷基、C6环烷基、6元杂芳基、C6芳基；其中，所述的取代是指被选自下组的一个或多个基团取代：D、卤素、氨基、硝基、羟基、巯基、氰基、羧基、巯基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
如无特别说明，上述的烷基、烷氧基、烯基、炔基、杂环烷基、环烷基、杂芳基、芳基可进一步任选地被1个或多个R a取代，其中，各R a独立地选自下组：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基。
优选地，上述各式中，环C选自下组：
Figure PCTCN2021095329-appb-000019
其中，
Figure PCTCN2021095329-appb-000020
表示单键或双键；
X 1、X 2、X 3、X 4、X' 1和X' 2各自独立地选自下组：N、C-R d；且X 1、X 2、X 3和X 4中有0、1、2、3个为N；
R d的定义如上所述。
优选地，上述各式中，W独立地选自下组：C(R c) 2、6元杂环烷基、C6环烷基、6元芳基或杂芳基、L 1-(CH 2) n-L 2；优选地，W独立地为6元芳基或杂芳基；其中，L 1独立地选自下组：无、6元杂环烷基、C6环烷基、6元芳基或杂芳基，L 2独立地选自下组：N-R b、C(＝O)O-、O、S、SO、SO 2；
上述的杂环烷基、环烷基、杂芳基、芳基可进一步任选地被1个或多个R a取代，其中，各R a独立地选自下组：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
R b、R c和n的定义如上所述。
优选地，上述各式中，R 3为卤素。
优选地，上述各式中，A为C(＝O)。
优选地，上述各式中，A为N-R b；其中，R b独立地选自下组：H、C1-C6烷基。
优选地，上述各式中，A为-C(＝O)NH-，B为键。
优选地，上述各式中，m为1、2、3、4。
如本文所用，“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
化合物的制备方法
以下方案和实例中描述了制备式I的化合物的方法。原料和中间体从商业来源购买，由已知步骤制备，或以其他方式说明。在某些情况下，可以改变执行反应方案的步骤的顺序，以促进反应或避免不需要的副反应产物。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～150℃，优选10℃～100℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。
优选地，本发明化合物可同如下步骤制得
在惰性溶剂中，催化剂存在下，化合物A 8发生反应，得到化合物I。
Figure PCTCN2021095329-appb-000021
式中，
A 1选自下组：羧基、磺酸基、CO-O-R”、-CO-NH-R”；其中，R”选自取代或未取代的下组基团：C1-C6烷基、C2-C6烯基、C2-C6炔基、3-10元杂环基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
所述的取代是指被选自下组的一个或多个基团取代：D、卤素、氨基、胺基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
A 2选自下组：氨基、羟基；
A、B、C、W、X、Y、Z、R 1、R 2、R 3、R 4、R 5、R 6、R 7和m的定义如上所述。
本发明化合物合成方法中所用起始原料和试剂均可商业购买或通过文献报道的方法合成。
药物组合物和施用方法
由于本发明化合物具有优异的JAK激酶的抑制活性，因此本发明化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)JAK激酶相关疾病(例如，皮肤病、类风湿性关节炎、多发性硬化、I型糖尿病、牛皮癣关节炎、少年关节炎、克罗恩氏病、重症肌无力、癌症(包括前列腺癌、肾癌、肝癌、乳腺癌、肺癌、甲状腺癌、卡波济氏肉瘤、巨大淋巴增生症、胰腺癌、白血病、淋巴癌或多发性骨髓瘤等))。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2021095329-appb-000022
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物(例如JAK抑制剂)联合给药。
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物(例如例如JAK抑制剂)。该其他药学上可接受的化合物(例如JAK抑制剂)中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗JAK激酶的活性或表达量相关的疾病。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点在于：
1.本发明的化合物结构新颖且具有优异的JAK激酶抑制作用；
2.本发明的化合物可以作为JAK激酶抑制剂，尤其是作为JAK1的高择性抑制剂。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例
通用材料及测试方法：
本发明的化合物的合成方法示于下面的方案、方法和实施例。起始原料是市售的或可以根据本领域或本文所描述的已知方法制备。本发明的化合物可通过以下所示的具体实施例来说明。然而，这些具体实施例不应被解释为是本发明的唯一种类。这些实施例进一步详细说明本发明化合物的制备。本领域的技术人员将容易理解，条件和过程的已知变化可用于制备这些化合物。所有的温度均为摄氏度，除非另有说明。
薄层色谱(PTLC)的制备是在20×20cm的板(500微米厚的硅胶)上进行。硅胶层析法用Biotage快速色谱系统。
1H NMR用Bruker AscendTM400光谱仪，400MHz，298°K，并且将残余质子在氘化试剂中的化学位移(ppm)给出参考：
CHCl3δ＝7.26ppm，CH3OH或CH3ODδ＝3.30ppm，DMSO-d 6δ＝2.50ppm
LCMS色谱采用安捷伦科技1200系列或6120四极谱仪。对于LC流动相为乙腈(A)和水(B)和0.01％甲酸，洗脱剂梯度：6.0分钟5-95％A，5.0分钟60-95％A，5.0分钟80-100％A和10分钟85-100％A，用SBC1850毫米×4.6毫米×2.7微米的毛细管柱。
质谱(MS)通过电喷雾离子质谱法(ESI)进行测定。
HPLC质谱分析条件：
LC1：
柱：SB-C18 50mm×4.6mm×2.7μm
温度：50℃
洗脱液：5:95至95:5体积/体积乙腈/水+0.01％甲酸，6分钟。
流量：1.51.5mL/min，注射5μL
检测：PDA，200-600nm
MS：质量范围150-750amu；正离子电喷雾电离
LC2：
柱：SB-C18 50mm×4.6mm×2.7μm
温度：50℃
洗脱液：5:95至95:5体积/体积乙腈/水+0.05％TFA梯度，超过3.00分钟。
流量：1.51.5mL/min，注射5μL
检测：PDA，200-600nm
MS：质量范围150-750amu；正离子电喷雾电离
LC3：
柱：SB-C18 50mm×4.6mm×2.7μm
温度：50℃
洗脱液：10:90至98:2体积/体积乙腈/水+0.05％TFA梯度，超过3.75分钟。
流速：1.0mL/min，注射10μL
检测：PDA，200-600nm
MS：质量范围150-750amu；正离子电喷雾电离
缩略语表：
AcOH＝乙酸
Alk为烷基
AR为芳基
Boc＝叔丁氧羰基
bs＝宽峰
CH 2Cl 2＝二氯甲烷
d＝双峰
dd＝双二重峰
DBU＝1,8-二氮杂双环[5.4.0]十一-7-烯
DCM＝二氯甲烷
DEAD＝偶氮二甲酸二乙酯
DMF＝N，N-二甲基甲酰胺
DMSO＝二甲基亚砜
EA＝乙酸乙酯
ESI＝电喷雾电离
Et＝乙基
EtOAc＝乙酸乙酯
EtOH＝乙醇
h＝小时
HOAc＝乙酸
LiOH＝氢氧化锂
m＝多重
Me＝甲基
MeCN＝乙腈
MeOH＝甲醇
MgSO 4＝硫酸镁
min＝分钟
MS＝质谱
NaCl＝氯化钠
NaOH＝氢氧化钠
Na 2SO 4＝硫酸钠
NMR＝核磁共振光谱
PE＝石油醚
PG＝保护基
Ph＝苯基
rt＝室温
s＝单峰
t＝三重峰
TFA＝三氟乙酸
THF＝四氢呋喃
TS＝对甲苯磺酰基(甲苯磺酰基)
实施例1 A1的合成路线：
Figure PCTCN2021095329-appb-000023
第一步：3-氨基-5-溴-2-氟吡啶(A1-2)
5-溴-2-氟-3-硝基吡啶(A1-1，3.00g，13.6mmol)加入甲醇(30ml)中，室温搅拌5min，加入雷尼镍(150mg)，反应体系通入氢气反应6h。TLC确认反应完全后，过滤，浓缩甲醇，残余物经柱层析纯化，得到淡黄色固体3-氨基-5-溴-2-氟吡啶(A1-2，1.879g，收率72.5％)。
第二步：4-(5-氨基-6-氟吡啶-3-)苯甲酸甲酯(A1-3)
氮气保护下，3-氨基-5-溴-2-氟吡啶(A1-2，300mg，1.57mmol)、对甲氧羰基苯硼酸(282.7mg，1.57mmol)和碳酸钾(542.7mg，3.93mmol)加入1,4-二氧六环(12ml)和水(3ml)中，搅拌5min，再加入四(三苯基膦)钯(54.5mg，0.03mmol)，升温至80℃，搅拌反应4h。TLC 确认反应完全后，浓缩1,4-二氧六环，加入EA和去离子水，萃取分层，收集有机层，无水硫酸钠干燥，浓缩EA，残余物经柱层析纯化，得到类白色固体4-(5-氨基-6-氟吡啶-3-)苯甲酸甲酯(A1-3，368.2mg，收率95.2％)。 1H NMR(400MHz,CDCl 3)δ8.15(t,J＝8.3Hz,2H),7.81(s,1H),7.72(d,J＝8.3Hz,1H),7.61(d,J＝8.3Hz,1H),7.33(dd,J＝10.2,2.0Hz,1H),3.98(d,J＝2.0Hz,3H)。
第三步：5-((2-氯-5-甲基嘧啶-4-)氨基)戊胺甲酸叔丁酯(A1-5)
2,4-二氯-5-甲基嘧啶(A1-4，300mg，1.84mmol)、N-叔丁氧羰基尸胺(744.6mg，3.68mmol)和N，N-二异丙基乙胺(475.6mg，3.68mmol)加入1，4-二氧六环(3ml)中，升温至50℃，搅拌16h后。浓缩1,4-二氧六环，加入EA和去离子水，萃取分层，收集有机层，无水硫酸钠干燥，浓缩EA，残余物经柱层析纯化得到淡黄色油状物5-((2-氯-5-甲基嘧啶-4-)氨基)戊胺甲酸叔丁酯(A1-5，595.5mg，收率98.4％)。 1H NMR(400MHz,CDCl 3)δ7.79(s,1H),3.51(dd,J＝12.9,6.6Hz,2H),3.13(d,J＝6.2Hz,2H),2.00(s,3H),1.71–1.61(m,2H),1.54(dt,J＝14.5,7.0Hz,2H),1.43(m,11H)。
第四步：4-(5-((4-(5-叔丁氧羰基氨基)戊基)-5-甲基嘧啶-2-)氨基)-6-氟吡啶-3-)苯甲酸甲酯(A1-6)
氮气保护下，4-(5-氨基-6-氟吡啶-3-)苯甲酸甲酯(A1-3，141mg，0.57mmol)，5-((2-氯-5-甲基嘧啶-4-)氨基)戊胺甲酸叔丁酯(A1-5，179mg，0.55mmol)和碳酸钾(150mg，1.1mmol)加入1,4-二氧六环(10ml)中，搅拌5min，再一次性加入三(二亚苄基丙酮)二钯(50mg，0.05mmol)和2-二环己基磷-2',4',6'-三异丙基联苯(52mg，0.11mmol)，升温至100℃，搅拌5h。TLC确认反应完全后，浓缩1,4-二氧六环，加入EA和去离子水，萃取分层，收集有机层，无水硫酸钠干燥，浓缩EA，残余物经柱层析纯化得到白色固体4-(5-((4-(5-叔丁氧羰基氨基)戊基)-5-甲基嘧啶-2-)氨基)-6-氟吡啶-3-)苯甲酸甲酯(A1-6，150mg，收率48.7％)。 1H NMR(400MHz,CDCl 3)δ9.35(d,J＝9.7Hz,1H),8.15(d,J＝7.9Hz,2H),7.95(s,1H),7.80(s,1H),7.69(d,J＝7.9Hz,2H),3.98(s,3H),3.53(dd,J＝12.8,6.4Hz,2H),3.11(d,J＝6.1Hz,2H),2.01(s,3H),1.45(s,10H),1.39–1.26(m,5H)。
第五步：4-(5-((4-(5-叔丁氧基羰基氨基)戊基-5-甲基嘧啶-2-)氨基)-6-氟吡啶-3-)苯甲酸(A1-7)
4-(5-((4-(5-叔丁氧羰基氨基)戊基)-5-甲基嘧啶-2-)氨基)-6-氟吡啶-3-)苯甲酸甲酯(A1-6，150mg，0.28mmol)加入四氢呋喃(9ml)和水(3ml)中，再加入氢氧化锂一水合物(58mg，1.4mmol),室温搅拌16h。TLC确认反应完全后，滴加1mol/L HCl调节pH＝5～6，浓缩四氢呋喃，加入去离子水，抽滤，收集滤饼，减压抽干，得到类白色固体4-(5-((4-(5-叔丁氧基羰基氨基)戊基-5-甲基嘧啶-2-)氨基)-6-氟吡啶-3-)苯甲酸(A1-7，127mg，收率87％)。
第六步：4-(5-((4-(5-氨基戊氨)-5-甲基嘧啶-2-)氨基)-6-氟吡啶-3-)苯甲酸(A1-8)
4-(5-((4-(5-叔丁氧基羰基氨基)戊基-5-甲基嘧啶-2-)氨基)-6-氟吡啶-3-)苯甲酸(A1-7， 127mg，0.24mmol)加入1,4-二氧六环(2ml)中，滴加4mol/L HCl的Dioxane溶液(2ml)，室温搅拌2h。LCMS确认反应完全后，直接浓缩除掉1,4-二氧六环，得到类白色固体4-(5-((4-(5-氨基戊氨)-5-甲基嘧啶-2-)氨基)-6-氟吡啶-3-)苯甲酸(A1-8，114mg，crude)，未纯化直接用于下一步。
第七步：2 6-氟-4 5-甲基-3,5,11-三氮杂-4(2,4)-嘧啶杂-2(3,5)-吡啶杂-1(1,4)-苯杂环十二蕃-12-酮(A1)
2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(95mg，0.25mmol)和N，N-二异丙基乙胺(161.6mg，1.25mmol)加入DCM中，搅拌5min。缓慢滴加4-(5-((4-(5-氨基戊氨)-5-甲基嘧啶-2-)氨基)-6-氟吡啶-3-)苯甲酸(A1-8，53mg，0.125mmol)的DCM(10ml)和N，N-二甲基甲酰胺(1ml)混合溶液，滴毕室温搅拌4h。LCMS确认反应完全后，加入去离子水淬灭反应，萃取分层，收集有机层。浓缩DCM，残余物经反相柱纯化，冻干后得到白色固体A1(2.3mg，收率4.5％)。MS(ESI)m/z:calcd 407.20(M+H),found 407.36； 1H NMR(400MHz,DMSO- d6)δ8.90(s,1H),8.74(s,1H),7.96(d,J＝27.7Hz,2H),7.67(d,J＝31.8Hz,3H),7.47(s,2H),6.48(s,1H),2.88(s,2H),2.74(s,2H),1.90(s,3H),1.37-1.18(m,6H)。
参照实施例1的实验步骤制备，以不同起始原料，得到实施例2-48，如下表1所示。
表1
Figure PCTCN2021095329-appb-000024
Figure PCTCN2021095329-appb-000025
Figure PCTCN2021095329-appb-000026
Figure PCTCN2021095329-appb-000027
Figure PCTCN2021095329-appb-000028
Figure PCTCN2021095329-appb-000029
Figure PCTCN2021095329-appb-000030
Figure PCTCN2021095329-appb-000031
实施例49：生物测试
生物测试方法
JAK激酶的测活方法是利用均相时间分辨荧光技术。该方法的反应是在384浅孔板中，反应总体积是10μL。激酶蛋白、化合物、ATP和底物的混合液在50mM Hepes(pH7.0)、NaN 3 0.02％、BSA 0.01％、0.1mM原钒酸盐(Orthocanadate)、5mM MgCl 2、1mM DTT的反应缓冲液中进行，反应1小时后，向体系中加入能够识别底物磷酸化的抗体和染料XL-615以及含有EDTA的检测缓冲液(Cisbio)。激酶的反应信号通过PE公司的多孔板检测仪进行检测。参数设置是激发光320nm，发射光615nm和665nm。通过665nm和615nm的信号比值间接反映JAK的活力。反应中设置不加酶的背景孔和不含化合物的全酶活 性孔。
化合物抑制蛋白IC 50的值通过公式：Y＝100/(1+10^((LogIC50-X)*HillSlope))获得。
在JAK1反应体系中，ATP的浓度为2μM，JAK1蛋白浓度是0.2ng/μL。
在JAK2反应体系中，ATP的浓度为2μM，JAK2蛋白浓度是0.01ng/μL。
在JAK3反应体系中，ATP的浓度为2μM，JAK3蛋白浓度是0.04ng/μL。
在TYK2反应体系中，ATP的浓度为2μM，TYK2蛋白浓度是0.2ng/μL。
测试数据分为以下几种：A:IC 50<10nM；B:IC 50 11-100nM；C:IC 50 101-1000nM；D:IC 50 1001-10000nM；E:IC 50>10000nM。
测试结果如表2所示。
表2
Figure PCTCN2021095329-appb-000032
Figure PCTCN2021095329-appb-000033
讨论:
上述实验结果提示：
(1)本发明的式I化合物表现出非常优异的抑制JAK的活性，尤其是JAK1活性。本发明化合物IC50值可以低至10nM级或更低，这样对于体重约70kg的对象(如病人，尤其是风湿性关节炎或银屑病患者)而言，日服用剂量通常为10mg-30mg就可极其有效抑制JAK，尤其是JAK1。
(2)本发明的式I化合物表现出非常优异的JAK1选择性，即JAK3/JAK1的IC50之比和/或JAK2/JAK1的IC50之比优于目前已上市的药物。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 式I所示的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，
    Figure PCTCN2021095329-appb-100001
    式中，
    A独立地选自下组：C(＝O)、-C(＝O)O-、C(＝O)NH、N-R b、O、S、SO、SO 2；
    B独立地选自下组：键、C(＝O)、N-R b、C(R c) 2、C(＝O)O-、O、S、SO、SO 2；
    环C独立地选自取代或未取代的下组基团：3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
    X独立地选自下组：N、CR d；
    Y独立地选自下组：C(＝O)、N-R b、C(R c) 2、C(＝O)O-、O、S、SO、SO 2；
    Z独立地选自下组：键、N-R b、O、S、C(R c) 2；
    W独立地选自下组：C(R c) 2、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基、L 1-(CH 2) n-L 2；其中，L 1独立地选自下组：无、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基，L 2独立地选自下组：N-R b、C(＝O)O-、O、S、SO、SO 2；
    R b独立地选自下组：H、C1-C6烷基；
    各R c独立地选自下组：H、卤素、氨基、硝基、羟基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、C1-C6烷基、C1-C6烷氧基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7和R d各自独立地选自下组：H、D、卤素、氨基、硝基、羟基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
    或者，R 1和R 2与它们连接的原子一起构成取代或未取代的下组基团：5-6元芳基杂芳基、3-10元杂环基、C3-C10环烷基；
    -(CH 2) m-和-(CH 2) n-中的H原子可以任选地被一个或多个R a取代；
    所述的取代是指被选自下组的一个或多个基团取代：D、卤素、氨基、硝基、羟基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
    如无特别说明，上述的烷基、烷氧基、烯基、炔基、杂环烷基、环烷基、杂芳基、芳基可进一步任选地被1个或多个R a取代，其中，各R a独立地选自下组：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
    m为1、2、3、4、5或6；
    n为0、1、2、3。
  2. 如权利要求1所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，其具有式II所示的结构：
    Figure PCTCN2021095329-appb-100002
    其中，A、B、C、W、Y、Z、R 1、R 2、R 3、R 4、R 5、R 6、R 7、m的定义如权利要求1所述。
  3. 如权利要求1所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，环C选自下组：
    Figure PCTCN2021095329-appb-100003
    其中，
    Figure PCTCN2021095329-appb-100004
    表示单键或双键；
    X 1、X 2、X 3、X 4、X' 1和X' 2各自独立地选自下组：N、C-R d；且X 1、X 2、X 3和X 4中有0、1、2、3个为N；
    R d的定义如权利要求1所述。
  4. 如权利要求1所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，其具有式III所示的结构：
    Figure PCTCN2021095329-appb-100005
    式中，A、B、C、W、R 1、R 2、R 3、R 4、R 5、R 6、R 7、m的定义如权利要求1所述。
  5. 如权利要求1-4中任一项所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，环C选自：
    Figure PCTCN2021095329-appb-100006
    Figure PCTCN2021095329-appb-100007
    R d各自独立地选自下组：H、D、卤素、氨基、硝基、羟基、氰基、羧基、砜基、亚砜基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
    e为0、1、2、3；
    f为0、1、2、3或4。
  6. 如权利要求1-5中任一项所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，其具有式IV-1和IV-2所示的结构：
    Figure PCTCN2021095329-appb-100008
    其中，
    E 1和E 2各自独立地为N或CR d；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R d、m的定义如权利要求1所述。
  7. 如权利要求1所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，W独立地选自下组：C(R c) 2、6元杂环烷基、C6环烷基、6元芳基或杂芳基、L 1-(CH 2) n-L 2；其中，L 1独立地选自下组：无、6元杂环烷基、C6环烷基、6元芳基或杂芳基，L 2独立地选自下组：N-R b、C(＝O)O-、O、S、SO、SO 2；
    上述的杂环烷基、环烷基、杂芳基、芳基可进一步任选地被1个或多个R a取代，其中，各R a独立地选自下组：卤素、氨基、硝基、羟基、巯基、氰基、羧基、砜基、亚砜 基、酰胺基、磺酰胺基、酯基、甲酰基、甲酰胺基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、3-10元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；
    R b、R c和n的定义如权利要求1所述。
  8. 如权利要求1所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，其特征在于，所述化合物选自下组：
    Figure PCTCN2021095329-appb-100009
    Figure PCTCN2021095329-appb-100010
    Figure PCTCN2021095329-appb-100011
  9. 一种药物组合物，其特征在于，包含权利要求1-8中任一项所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物；和药学上可接受的载体。
  10. 如权利要求7所述的药物组合物，其特征在于，所述的药物组合物用于治疗或预防与JAK激酶的活性或表达量相关的疾病。
  11. 一种权利要求1-8任一所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物的用途，其特征在于，用于制备治疗或预防与JAK激酶的活性或表达量相关的疾病的药物或药物组合物。
  12. 如权利要求11所述的用途，其特征在于，所述的疾病选自下组：癌症、骨髓增殖性疾病、炎症、免疫性疾病、器官移植、病毒性疾病、心血管疾病或代谢性疾病、人或动物自身免疫疾病、类风湿性关节炎、皮肤病症、多发性硬化，类风湿关节炎、银屑性关节炎、炎性肠病、重症肌无力、牛皮癣。
PCT/CN2021/095329 2020-05-29 2021-05-21 大环jak抑制剂及其应用 WO2021238817A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US17/999,743 US20230167114A1 (en) 2020-05-29 2021-05-21 Macrocyclic jak inhibitor and use thereof
EP21812993.0A EP4159735A1 (en) 2020-05-29 2021-05-21 Macrocyclic jak inhibitor and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010477110.2 2020-05-29
CN202010477110.2A CN113735856A (zh) 2020-05-29 2020-05-29 大环jak抑制剂及其应用

Publications (1)

Publication Number Publication Date
WO2021238817A1 true WO2021238817A1 (zh) 2021-12-02

Family

ID=78724768

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/095329 WO2021238817A1 (zh) 2020-05-29 2021-05-21 大环jak抑制剂及其应用

Country Status (4)

Country Link
US (1) US20230167114A1 (zh)
EP (1) EP4159735A1 (zh)
CN (1) CN113735856A (zh)
WO (1) WO2021238817A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022240978A1 (en) * 2021-05-11 2022-11-17 Theseus Pharmaceuticals, Inc. Macrocyclic compounds and uses thereof
WO2023046030A1 (zh) * 2021-09-23 2023-03-30 河南晟翔医药科技有限公司 一种egfr小分子抑制剂、含其的药物组合物及其用途

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023229430A1 (ko) * 2022-05-27 2023-11-30 보로노이 주식회사 헤테로아릴 유도체 화합물 및 이의 용도
WO2024078263A1 (zh) * 2022-10-09 2024-04-18 药雅科技(上海)有限公司 大环杂环类化合物作为egfr抑制剂的制备及其应用

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1675225A (zh) * 2002-08-21 2005-09-28 舍林股份公司 大环嘧啶化合物、其制备方法以及作为药物的应用
EP1803723A1 (de) * 2006-01-03 2007-07-04 Bayer Schering Pharma Aktiengesellschaft (2,4,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononaphan-3^4-yl)-sulfoximid derivate als selektive inhibitoren der aurora kinase zur behandlung von krebs
WO2009112439A1 (en) * 2008-03-10 2009-09-17 Janssen Pharmaceutica Nv 4-aryl-2-anilino-pyrimidines as plk kinase inhibitors
WO2009132202A2 (en) * 2008-04-24 2009-10-29 Incyte Corporation Macrocyclic compounds and their use as kinase inhibitors
CN102143750A (zh) * 2008-09-08 2011-08-03 默克专利有限公司 用作蛋白激酶抑制剂的大环嘧啶
CN102498113A (zh) * 2009-09-21 2012-06-13 弗·哈夫曼-拉罗切有限公司 Jak的大环抑制剂
CN102617599A (zh) * 2012-04-10 2012-08-01 江苏先声药物研究有限公司 大环类化合物及其应用
WO2012125603A1 (en) * 2011-03-16 2012-09-20 Cephalon, Inc. Macrocyclic compounds as alk, fak and jak2 inhibitors
CN102757448A (zh) * 2011-04-26 2012-10-31 中南大学 大环类激酶抑制剂化合物、制备方法及其作为药物的应用
CN106164075A (zh) * 2014-04-03 2016-11-23 詹森药业有限公司 大环嘧啶衍生物
CN106715445A (zh) * 2014-09-02 2017-05-24 皮埃尔法布雷医药公司 作为ftl3和jak抑制剂的大环n‑芳基‑三环嘧啶‑2‑胺聚醚的衍生物
CN106795173A (zh) * 2014-09-02 2017-05-31 皮埃尔法布雷医药公司 作为ftl3和jak抑制剂的大环n‑芳基‑2‑氨基‑4‑芳基‑嘧啶聚醚的衍生物
CN107735399A (zh) * 2015-07-02 2018-02-23 Tp生物医药公司 作为蛋白质激酶的调节剂的手性二芳基大环
WO2019126122A1 (en) * 2017-12-19 2019-06-27 Tp Therapeutics, Inc. Macrocyclic kinase inhibitors and their use

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1675225A (zh) * 2002-08-21 2005-09-28 舍林股份公司 大环嘧啶化合物、其制备方法以及作为药物的应用
EP1803723A1 (de) * 2006-01-03 2007-07-04 Bayer Schering Pharma Aktiengesellschaft (2,4,9-triaza-1(2,4)-pyrimidina-3(1,3)-benzenacyclononaphan-3^4-yl)-sulfoximid derivate als selektive inhibitoren der aurora kinase zur behandlung von krebs
WO2009112439A1 (en) * 2008-03-10 2009-09-17 Janssen Pharmaceutica Nv 4-aryl-2-anilino-pyrimidines as plk kinase inhibitors
WO2009132202A2 (en) * 2008-04-24 2009-10-29 Incyte Corporation Macrocyclic compounds and their use as kinase inhibitors
CN102143750A (zh) * 2008-09-08 2011-08-03 默克专利有限公司 用作蛋白激酶抑制剂的大环嘧啶
CN102498113A (zh) * 2009-09-21 2012-06-13 弗·哈夫曼-拉罗切有限公司 Jak的大环抑制剂
WO2012125603A1 (en) * 2011-03-16 2012-09-20 Cephalon, Inc. Macrocyclic compounds as alk, fak and jak2 inhibitors
CN102757448A (zh) * 2011-04-26 2012-10-31 中南大学 大环类激酶抑制剂化合物、制备方法及其作为药物的应用
CN102617599A (zh) * 2012-04-10 2012-08-01 江苏先声药物研究有限公司 大环类化合物及其应用
CN106164075A (zh) * 2014-04-03 2016-11-23 詹森药业有限公司 大环嘧啶衍生物
CN106715445A (zh) * 2014-09-02 2017-05-24 皮埃尔法布雷医药公司 作为ftl3和jak抑制剂的大环n‑芳基‑三环嘧啶‑2‑胺聚醚的衍生物
CN106795173A (zh) * 2014-09-02 2017-05-31 皮埃尔法布雷医药公司 作为ftl3和jak抑制剂的大环n‑芳基‑2‑氨基‑4‑芳基‑嘧啶聚醚的衍生物
CN107735399A (zh) * 2015-07-02 2018-02-23 Tp生物医药公司 作为蛋白质激酶的调节剂的手性二芳基大环
WO2019126122A1 (en) * 2017-12-19 2019-06-27 Tp Therapeutics, Inc. Macrocyclic kinase inhibitors and their use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHENG-QING NING ET AL.: "Macrocyclic compounds as anti-cancer agents: Design and synthesis of multi-acting inhibitors against HDAC, FLT3 and JAK2", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 95, 17 March 2015 (2015-03-17), pages 104 - 115, XP055438200, DOI: 10.1016/j.ejmech.2015.03.034 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022240978A1 (en) * 2021-05-11 2022-11-17 Theseus Pharmaceuticals, Inc. Macrocyclic compounds and uses thereof
WO2023046030A1 (zh) * 2021-09-23 2023-03-30 河南晟翔医药科技有限公司 一种egfr小分子抑制剂、含其的药物组合物及其用途

Also Published As

Publication number Publication date
CN113735856A (zh) 2021-12-03
US20230167114A1 (en) 2023-06-01
EP4159735A1 (en) 2023-04-05

Similar Documents

Publication Publication Date Title
WO2021238817A1 (zh) 大环jak抑制剂及其应用
RU2633694C2 (ru) Дейтерированный фениламинопиримидин и фармацевтическая композиция, содержащая такое соединение
AU2015266453C1 (en) Alk kinase inhibitor, and preparation method and use thereof
KR20170143026A (ko) 중수소화된 디아미노피리미딘 화합물 및 이 화합물을 함유하는 약물 조성물
CN113563309A (zh) 吡啶类衍生物及其制备方法和用途
CN109721600B (zh) 一类含氮稠环化合物及其制备方法和用途
CN112457308B (zh) 新型三环芳香杂环化合物，及其制备方法、药物组合物和应用
CN114746414A (zh) 氮杂-喹啉化合物及其用途
EP4006031A1 (en) Dihydro-pyrrolo-pyrimidine selective jak2 inhibitor
WO2022095909A1 (zh) 用作ntrk激酶抑制剂的化合物及其应用
WO2021228000A1 (zh) 联芳环链接芳杂环衍生物作为免疫调节剂的制备及其应用
CN111718332B (zh) 2-取代吡唑氨基-4-取代氨基-5-嘧啶甲酰胺类化合物、组合物及其应用
JP7349750B2 (ja) キナーゼ阻害活性を有する芳香族複素環式化合物
WO2018133875A1 (zh) Jak酶抑制剂及其制备方法和用途
CN110938070A (zh) 一类具有激酶抑制活性的芳香杂环类化合物
CN110938071A (zh) 一类具有激酶抑制活性的芳香杂环类化合物
CN113735879B (zh) 一种大环jak抑制剂及其应用
WO2022117012A1 (zh) 螺环jak抑制剂、含其的药物组合物及其应用
CN113583020B (zh) 一种jak2抑制剂及应用
TWI820414B (zh) 喹唑啉類化合物、製備方法及其應用
WO2021233454A1 (zh) 新型三环芳香杂环化合物，及其制备方法、药物组合物和应用
WO2023155900A1 (zh) 一类五元并六元杂环化合物及其作为蛋白激酶抑制剂的用途
WO2023046030A1 (zh) 一种egfr小分子抑制剂、含其的药物组合物及其用途
WO2022222911A1 (zh) 嘧啶酮化合物及其用途
WO2020200154A1 (zh) 一类噻吩并氮杂环类化合物、制备方法和用途

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: 21812993

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021812993

Country of ref document: EP

Effective date: 20230102