WO2021238818A1 - 一种大环jak抑制剂及其应用 - Google Patents

一种大环jak抑制剂及其应用 Download PDF

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WO2021238818A1
WO2021238818A1 PCT/CN2021/095332 CN2021095332W WO2021238818A1 WO 2021238818 A1 WO2021238818 A1 WO 2021238818A1 CN 2021095332 W CN2021095332 W CN 2021095332W WO 2021238818 A1 WO2021238818 A1 WO 2021238818A1
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group
membered
aryl
cycloalkyl
amino
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PCT/CN2021/095332
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French (fr)
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吕志俭
李佳
苏明波
高安慧
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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
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Priority to EP21813815.4A priority Critical patent/EP4159738A1/en
Priority to JP2022573606A priority patent/JP2023528394A/ja
Priority to US18/000,016 priority patent/US20230203059A1/en
Publication of WO2021238818A1 publication Critical patent/WO2021238818A1/zh

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    • C07D498/02—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 two hetero rings
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    • A—HUMAN NECESSITIES
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    • 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
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    • C—CHEMISTRY; METALLURGY
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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 difficult to develop inhibitors with high selectivity to JAK3.
  • the present invention provides an inhibitor of JAK or related kinases, especially an inhibitor with high selectivity to JAK3.
  • X 1 , X 2 , X 3 and X 4 are each independently selected from the following group: N, C or CR d ; and among X 1 , X 2 , X 3 and X 4 , 0, 1, 2, and 3 are N ;
  • R d and X 2 are fused to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;
  • R d is fused with X 1 to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;
  • R d is fused with X 4 to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;
  • R d is fused with X 3 to form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;
  • R b is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R d are each independently selected from the following group: H, D, halogen, amino, amine, nitro, hydroxyl, mercapto, cyano, carboxyl , Sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group , C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl or -OR 11 ; wherein R 11 is selected from 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
  • R 5 and R 6 together with the C atom to which they are attached form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;
  • R 8 and R 9 together with the C atom to which they are attached form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;
  • R 9 and R 10 together with the C atom to which they are attached form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;
  • (CH 2) n and (CH 2) H m atoms may be optionally substituted with one or more (e.g. 2,3,4,5) R a substituent;
  • n 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • substitution refers to substitution by one or more (such as 2, 3, 4, 5) groups selected from the following group: D, halogen, amino, amine, 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 heterocyclic group, C3-C10 cycloalkyl group, 5-12 membered heteroaryl group, C6-C12 aryl group;
  • each R a is independently selected from the group consisting of: halogen, amino, amino, nitro, hydroxy, a mercapto group, a cyano group, a carboxyl group, a sulfone group, a sulfoxide group, an 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
  • the compound of formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate is characterized in that it has the formula I' structure:
  • Q is selected from the following group of substituted or unsubstituted groups: (CH 2 )m-R'-, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, 5-12 membered heteroarylene, C6 -C12 arylene; wherein, R'is independently selected from the following group of substituted or unsubstituted groups: 5-12 membered heteroarylene, C6-C12 arylene;
  • substitution refers to substitution by one or more (such as 2, 3, 4, 5) groups selected from the following group: D, halogen, amino, amine, 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 heterocyclic group, C3-C10 cycloalkyl group, 5-12 membered heteroaryl group, C6-C12 aryl group;
  • X, m, n, A, X 1 , X 2 , X 3 , X 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are as defined above.
  • the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, X 2 is CR d , and R d is selected from the following group: H , Amino, amine, C1-C6 alkyl, hydroxyl, mercapto, the alkyl group may be optionally substituted with one or more groups selected from the group consisting of halogen, amino, nitro, hydroxyl, mercapto, 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, C2-C6 alkenyl group, C2-C6 Alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl.
  • R d is
  • the compound represented by formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate has the structure represented by formula II:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the following group: H, D, halogen, amino, amino, nitro , Hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkyne Group, 3-10 membered heterocyclic group, C3-C10 cycloalkyl group, 5-12 membered heteroaryl group, C6-C12 aryl group or -OR 11 ; wherein R 11 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
  • R 1 and R 2 together with the C atom to which they are attached form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group;
  • R 3 and R 4 together with the C atom to which they are attached form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;
  • R 5 and R 6 together with the C atom to which they are attached form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;
  • R 8 and R 9 together with the C atom to which they are attached form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;
  • R 9 and R 10 together with the C atom to which they are attached form a substituted or unsubstituted 5-6 membered cycloalkyl, heterocyclic, aryl or heteroaryl group;
  • (CH 2) m and (CH 2) H n atoms may be optionally substituted with one or more substituents R a;
  • substitution refers to substitution by one or more (such as 2, 3, 4, 5) groups selected from the following group: D, halogen, amino, amine, nitro, hydroxyl, cyano, carboxyl, 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 heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • each R a is independently selected from the group consisting of: halogen, amino, amino, nitro, hydroxy, a mercapto group, a cyano group, a carboxyl group, a sulfone group, a sulfoxide group, an 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
  • the compound represented by formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate has the structure represented by formula III:
  • B is selected from the following group of substituted or unsubstituted groups: bond, (CH 2 )m-R'-, C3-C10 cycloalkylene, 3-10 membered heterocyclylene, 5-12 membered heteroarylene , C6-C12 arylene; wherein, R'is independently selected from the following group of substituted or unsubstituted groups: 5-12 membered heteroarylene, C6-C12 arylene;
  • substitution refers to substitution by one or more (such as 2, 3, 4, 5) groups selected from the following group: D, halogen, amino, amine, 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 heterocyclic group, C3-C10 cycloalkyl group, 5-12 membered heteroaryl group, C6-C12 aryl group;
  • B is selected from the following group of substituted or unsubstituted groups: 5-12 membered heteroarylene, C6-C12 arylene; wherein, the substitution refers to being selected from the following group One or more (such as 2, 3, 4, 5) group substitutions: D, halogen, amino, amine, nitro, hydroxyl, cyano, carboxy, 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 heterocyclic group, C3-C10 cycloalkyl group , 5-12 membered heteroaryl, C6-C12 aryl; n is 0 or 1.
  • R b is selected from the following group: H.
  • R b is selected from the following group: H, substituted or unsubstituted C1-C
  • the compound of formula I or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates have the structure shown in formula IV:
  • Q is selected from the following group of substituted or unsubstituted: (CH 2 )m-R'-, 5-12 membered heteroarylene, C6-C12 arylene; wherein R'is independently selected from substituted or unsubstituted Substitution of the following group: 5-12 membered heteroarylene, C6-C12 arylene; said substitution refers to one or more (such as 2, 3, 4, 5) groups selected from the group Group substitution: D, halogen, amino, amine, 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 heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aromatic base;
  • X, m, R 1 , R 2 , R 5 , R 6 , R 8 , and R 9 are as defined above.
  • the compound of formula I or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates have the structure shown in formula V
  • R 5 , R 6 , R 8 , R 9 , X, n, R 1 , and R 2 are as defined above.
  • c , R b and m are as described above.
  • X is C(R c ) 2 , O or S, wherein the definition of R c is as described above.
  • the compound of formula I or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates have the structure shown in formula VI
  • R 1 , R 2 , R 5 , R 6 , R 8 , R 9 and n are as defined above.
  • the compound of formula I or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates have the structure shown in formula VII
  • R 1 , R 2 , R 5 , R 6 , R 8 , R 9 and Q are as defined above.
  • R 2 is selected from the following group: H, amino, amino, C1-C6 alkyl group, hydroxyl group, mercapto group, the alkyl group may be optionally substituted by one or more (such as 2, 3, 4, 5) groups 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 2 is selected from the following group: H, amino, amino, C1-C6 alkyl group, hydroxyl group, mercapto group, the alkyl group may be optionally substituted
  • the compound of formula I or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates have the structure shown in formula VIII
  • R 1 , R 5 , R 6 , R 8 , R 9 , X and n are as defined above.
  • the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, R 8 is selected from the following group: H, halogen, amino, amine Group, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl or- OR 11 ;
  • R 11 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 (such as 2, 3, 4, 5) groups selected from the following group: D, halogen, amino, amine, hydroxyl, cyano, amide, C1-C6 Alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl ;
  • the alkyl group, alkenyl group, alkynyl group, heterocyclic group, cycloalkyl, heteroaryl, aryl groups may be further optionally substituted with one or more (e.g. 2,3,4,5) R a substituent, wherein each R a is independently selected from the group consisting of: halogen, amino, amino, nitro, hydroxy, a 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, Carboxamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl Group, C6-C12 aryl group.
  • R a substituent
  • R 8 is selected from the following group: C1-C6 alkyl, C3-C10 cycloalkyl, 3-10 membered heterocyclic group or -OR 11 ;
  • R 11 is selected from the following group of substituted or unsubstituted groups: C1-C6 alkyl, 3-10 membered heterocyclic group, 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, amine, hydroxyl, cyano, amide, C1-C6 Alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl ;
  • alkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, aryl groups may be further optionally substituted with one or more (e.g. 2,3,4,5) R a substituted , wherein each R a is independently selected from the group consisting of: halogen, amino, amino, nitro, hydroxy, a mercapto group, a cyano group, a carboxyl group, a sulfone group, a sulfoxide group, an amide group, a sulfonamide group, an ester group, A Acyl, carboxamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, 5-12 member Heteroaryl, C6-C12 aryl.
  • R a substituted wherein each
  • the compound of formula I or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates have the structure shown in formula IX
  • R 1 , R 2 , R 5 and R 6 are each independently selected from: H, halogen, OH, amino, amino, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy Group, halogenated C1-C3 alkoxy, 3-6 membered heterocyclic group, C3-C6 cycloalkyl;
  • R 11 and n are as described above.
  • R 11 is selected from substituted or unsubstituted groups: C1-C3 alkyl, 3-6 membered heterocyclyl, C3-C6 cycloalkyl, 5-6 membered heteroaryl, Phenyl;
  • substitution refers to substitution by one or more groups selected from the following group: D, halogen, amino, amino, hydroxyl, cyano, amide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl; wherein, the alkyl, alkenyl , an alkynyl group, a heterocyclic group, cycloalkyl, heteroaryl, aryl groups may be further optionally substituted with one or more (e.g.
  • R a is independently Selected from the following group: halogen, amino, amine, 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 heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aromatic base.
  • the compound of formula I or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates have the structure represented by formula X
  • R 1 , R 2 , R 5 and R 6 are each independently selected from: H, halogen, OH, amino, amino, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy Group, halogenated C1-C3 alkoxy, 3-6 membered heterocyclic group, C3-C6 cycloalkyl;
  • R 11 and Q are as described above.
  • Q is a substituted or unsubstituted group of the following groups: phenylene, -phenylene CH 2 -, -5- 6-membered heteroarylene, and -5- 6-membered heteroarylene CH 2 -;
  • the substitution refers to substitution by one or more groups selected from the following group: D, halogen, amino, amine, hydroxyl, cyano, amide, C1-C6 alkyl, C1-C6 Alkoxy.
  • the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, R 9 is selected from the following group: H, C1-C6 alkyl , C1-C6 alkoxy, 3-10 membered heterocyclyl, C3-C10 cycloalkyl; wherein, the alkyl, alkoxy, heterocycloalkyl, and cycloalkyl may be further optionally substituted by 1 one or more (e.g.
  • each R a is independently selected from the group consisting of: halogen, amino, amino, nitro, hydroxyl, mercapto, 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 is selected from the group consisting of H and halogen.
  • B is a bond
  • R 7 is H.
  • R 3 is H.
  • R 4 is H.
  • R 5 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered heterocyclic group, C3-C10 cycloalkyl group, the alkyl group, alkoxy group, alkenyl group, alkynyl group, heterocycloalkyl group, cycloalkyl group, heteroaryl group, aryl group may be further optionally composed of 1 or more ( the 2,3,4,5) substituted with R a, wherein each R a is independently selected from the group consisting of: halogen, amino, amino, nitro, hydroxy, a mercapto group, a cyano group, a carboxyl group, a sulfone group, a sulfoxide group , Amide group, sulfonamide group, ester group, formyl group, formamide group, C1-C6 alkyl,
  • R 6 is H.
  • R 10 is H.
  • the compound of formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate has one or more characteristics selected from the following group:
  • B is selected from the following group of substituted or unsubstituted groups: bond, 5-12 membered heteroarylene, C6-C12 arylene, (CH 2 )m-R'-;R'is independently selected from substituted or unsubstituted Substitution of the following group: 5-12 membered heteroarylene, C6-C12 arylene; the substitution refers to substitution by one or more groups selected from the following group: D, halogen, amino, amine , 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 heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl;
  • X 1 , X 2 , X 3 and X 4 are each independently N or CR d ; preferably, X 2 is CH, C-NH 2, CN(R b )2, C-OH, C-SH; preferably , X 1 is CH, C-halogen; preferably, X 3 is CH; preferably, X 4 is CH;
  • R 5 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered heterocyclic group, C3-C10 cycloalkyl,
  • R 6 is H
  • R 7 is H
  • R 8 is selected from the following group: H, halogen, amino, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, 5 -12-membered heteroaryl, C6-C12 aryl or -OR 11 ; wherein R 11 is selected from substituted or unsubstituted groups: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl , 3-10 membered heterocyclic group, C3-C10 cycloalkyl group, 5-12 membered heteroaryl group, C6-C12 aryl group;
  • R 9 is selected from the following group: H, C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered heterocyclyl, C3-C10 cycloalkyl;
  • R 10 is H
  • X is C(R c ) 2 , (CH 2 )mO-, O or S;
  • n 0, 1, 2, 3, 4 or 5;
  • R b is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl;
  • Each Rd is independently selected from the following group: H, D, halogen, amino, amine, nitro, hydroxyl, sulfhydryl, cyano, carboxy, sulfone, sulfoxide, amide, sulfonamide, ester, Formyl, carboxamido, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6- C12 aryl or -OR 11 ; wherein R 11 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;
  • each R a is independently selected from the group consisting of: halogen, amino, amino, nitro, hydroxy, a 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 , Carboxamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 member Heteroaryl, C6-C12 aryl.
  • X, n, A, B, X 1 , X 2 , X 3 , X 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are specific The specific group corresponding to the compound.
  • 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 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 biological analogues 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 biological analogues of the above drugs, etc.
  • CD20 antibodies such as rituximab, obin utuzumab, Ofatumumab, veltuzumab, tositumomab,
  • MEK inhibitors such as smetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, Pim asertib (AS-703026), PD184352 (CI-1040), etc.
  • mTOR inhibitors such as Vistusertib, etc.
  • SHP2 inhibitors such as RMC-4630, JAB-30
  • 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 third aspect of the present invention provides a compound according to the first aspect or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate or the pharmaceutical composition according to the second aspect Is used to prepare drugs or pharmaceutical compositions for treating or preventing diseases related to the activity or expression of JAK kinase.
  • the disease related to the activity or expression of JAK kinase is a JAK3-related disorder.
  • the disease related to JAK3 activity or expression is selected from the following group: organ transplant rejection, xenotransplant rejection, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis) , Cancer, asthma, atopic dermatitis, type I diabetes and diabetic complications, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, alopecia areata, mast cell-mediated allergic reactions , Thromboembolic, allergic complications and vitiligo.
  • the cancer is selected from the following group: leukemia, lymphoma, and multiple myeloma.
  • the fourth aspect of the present invention provides a method for preparing the compound or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates as described in the first aspect, which comprises 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, X 1 , X 2 , X 3 , X 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and n are as described above.
  • compound A 8 reacts to obtain compound I.
  • the inert solvent is DCM.
  • the catalyst or condensing agent is selected from: EDCI, DMAP, DCC and the like.
  • 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 JAK3/JAK1 or the selectivity represented by the ratio of JAK3/JAK2 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.
  • 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.
  • the cycloalkyl group can be fused to an aryl, heteroaryl, or heterocyclyl ring, and the ring connected to the parent structure is a cycloalkyl group, such as Wait.
  • 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 )
  • the structure is preferably C1-C6 alkyl-O-, 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.
  • heterocyclic group may be fused to a heteroaryl, aryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, such as Wait.
  • 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 aryl
  • naphthyl etc.
  • six-membered aryl also means to include six-membered aryl and 5-6-membered cycloalkyl (such as ) And six-membered aryl and 5-6 membered heterocyclic groups (such as Wait).
  • 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 refers to NH 2 .
  • amino group refers to having the structure -N-RR', and R and R'each independently represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, as described above
  • R and R' can be the same or different, and are not hydrogen at the same time.
  • 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 heterocyclyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl , C6-C12 aryl.
  • 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 or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate has the structure described in formula I':
  • X 2 is CR d
  • R d is selected from the following group: H, amino, amino, C1-C6 alkyl, hydroxyl, sulfhydryl, and the alkyl may be optionally selected from the following group Substitution of one or more groups: 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 heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 Aryl.
  • X 1 , X 2 , X 3 and X 4 are each independently N or CR d ; preferably, X 2 is CH, C-NH 2, CN(R b )2, C-OH , C-SH; preferably, X 1 is CH, C-halogen; preferably, X 3 is CH; preferably, X 4 is CH.
  • the compound represented by formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate has the structure represented by formula II:
  • A, B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and n are as described above.
  • the compound represented by Formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, has the structure represented by Formula III:
  • B is selected from the following group of substituted or unsubstituted groups: bond, 5-12 membered heteroarylene, C6-C12 arylene; wherein, the substitution refers to being selected from One or more group substitutions of the group: D, halogen, amino, amine, nitro, hydroxyl, cyano, carboxy, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, methyl Amido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl , C6-C12 aryl; n is 0 or 1.
  • the compound or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates have the structure shown in formula IV:
  • the compound of formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate which has the structure shown in formula V
  • R 5 , R 6 , R 8 , R 9 , X, n, R 1 , and R 2 are as defined above.
  • X is C(Rc)2, O or S, wherein Rc is defined as described above.
  • the compound of formula I or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates have the structure shown in formula VI
  • R 1 , R 2 , R 5 , R 6 , R 8 , R 9 and n are as defined above.
  • the compound of formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate which has the structure shown in formula VII
  • R 1 , R 2 , R 5 , R 6 , R 8 , R 9 and Q are as defined above.
  • the compound of formula I or its stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates have the structure shown in formula VIII
  • R 1 , R 5 , R 6 , R 8 , R 9 , X and n are as defined above.
  • R 2 is selected from the group consisting of H, amino, amino, C1-C6 alkyl, hydroxyl, and mercapto;
  • R 3 is H.
  • R 4 is H.
  • R 5 is H, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered heterocyclic group, C3-C10 cycloalkyl, alkyl, alkoxy, alkenyl group, alkynyl group, a heterocyclic group, a cycloalkyl group may be further optionally substituted with one or more of said R a, wherein each R a Independently selected from the following group: halogen, amino, amine, nitro, hydroxyl, sulfhydryl, cyano, carboxy, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, formamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3-C
  • R 6 is H.
  • R 7 is H.
  • R 8 is selected from the following group: H, halogen, amino, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3 -C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl or -OR 11 ; wherein R 11 is selected from substituted or unsubstituted groups: C1-C6 alkyl, C2-C6 alkene Group, C2-C6 alkynyl, 3-10 membered heterocyclic group, C3-C10 cycloalkyl group, 5-12 membered heteroaryl group, C6-C12 aryl group.
  • R 9 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered heterocyclic group, and C3-C10 cycloalkyl.
  • R 10 is H.
  • n 1, 2, 3, 4 or 5.
  • alkyl group, alkoxy group, alkenyl group, alkynyl group, heterocyclic group, cycloalkyl, heteroaryl, aryl groups may be further optionally substituted with one or more of R a, wherein each R a is independently Ground is selected from the following group: halogen, amino, amine, 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 heterocyclic group, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 Aryl.
  • 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 preparation of the compound of the present invention includes the 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, X 1 , X 2 , X 3 , X 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and n are as described above.
  • the compound of formula A of the present invention can be obtained through the following steps:
  • R 1 , R 2 , R 5 , R 6 , R 8 , and R 9 are as defined above;
  • formula A-6 is hydrolyzed under alkaline (lithium hydroxide monohydrate) conditions to obtain formula A-7;
  • a condensing agent such as O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • compound A-8 undergoes a condensation reaction to obtain a compound of formula A.
  • 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 ), 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 emulsifiers
  • wetting agents such as sodium lauryl sulfate
  • 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 JAK3.
  • 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
  • Example 1 4 4 -morpholine-6-oxa-3,11-diaza-2(4,2)-pyrimidine hetero-1(1,4),4(1,3)-diphenyl heterocycle Preparation of dodecane-12-one (A1)
  • the first step 2-morpholine-5-nitrobenzyl alcohol (A1-1)
  • 2-Fluoro-5-nitrobenzyl alcohol (10.0g, 58mmol) and equivalent morpholine were added to DMSO (100ml), heated to 100°C and stirred for 2h. After TLC confirms that the reaction is complete, pour it into water, extract with EA, wash with deionized water three times, dry with anhydrous sodium sulfate, concentrate EA, and purify the residue by column chromatography to obtain 2-morpholine-5-nitrobenzyl alcohol as a yellow solid (A1-1, 13.0g, yield 94%).
  • 2-morpholine-5-nitrobenzyl alcohol (A1-1, 10.00g, 42mmol) and triphenylphosphine (22.03g, 84mmol) were added to DCM (100ml), stirred for 10min, cooled to 0°C in an ice bath, dropped Add a solution of carbon tetrabromide (27.84g, 84mmol) in DCM (50ml), and stir at room temperature for 1h after dropping.
  • the seventh step 4-(2-((3-((4-((tert-butoxycarbonylamine)butoxy)methyl)-4-morpholinophenyl)amino)pyrimidine-4-)benzoic acid ( A1-7)
  • Step 8 4-(2-((3-((4-Aminobutoxy)methyl)-4-morpholinophenyl)amino)pyrimidine-4-)benzoic acid (A1-8)
  • the ninth step 4 4 -morpholine-6-oxa-3,11-diaza-2(4,2)-pyrimidine hetero-1(1,4),4(1,3)-diphenyl hetero Cyclododecane-12-one (A1)
  • Example 2 1 2 -Fluoro- 4 4 -cyclopropyl-6-oxa-3,11-diaza-2(4,2)-pyrimidinheter-1(1,4),4(1,3 )-Diphenyl heterocyclododecane-12-one (A2) preparation
  • A2-3 400mg, 1.0mmol
  • cyclopropylboronic acid 129mg, 1.5mmol
  • potassium phosphate 637mg, 3.0mmol
  • tricyclohexylphosphine were added Tetrafluoroborate (147.3mg, 0.40mmol) and palladium acetate (45mg, 0.20mmol) were heated to 100°C and stirred for 3h.
  • the fourth step 1 2 -fluoro- 4 4 -cyclopropyl-6-oxa-3,11-diaza-2(4,2)-pyrimidinhe-1(1,4),4(1, 3)-Diphenyl heterocyclododecane-12-one (A2)
  • Example 3-94 was obtained, as shown in Table 1 below.
  • the fourth step 4-(2-((3-((4-((tert-butoxycarbonyl)amino)-2-methylbutoxy)methyl)-4-cyclopropoxyphenyl)amino Pyrimidine-4-yl)-3-nitrobenzoic acid methyl ester (95-d)
  • methyl 4-(2-chloropyrimidin-4-yl)-3-nitrobenzoate (435mg, 1.48mmol), tert-butyl (4-((5-amino-2-cyclopropoxybenzyl) Yl)oxy)-3-methylbutyl)carbamate (95-c, 300mg, 0.822mmol) was added to 1,4-dioxane (20mL), and then three (dibenzylidene Acetone) two palladium (150mg, 0.164mmol) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (156mg, 0.328mmol), potassium carbonate (227mg, 1.64mmol), react at 100°C for 8h .
  • Step 5 4-(2-((3-((4-((tert-butoxycarbonyl)amino)-2-methylbutoxy)methyl)-4-cyclopropoxyphenyl)amino )Pyrimidin-4-yl)-3-nitrobenzoic acid (95-e)
  • the sixth step 4-(2-((3-((4-amino-2-methylbutoxy)methyl)-4-cyclopropoxyphenyl)amino)pyrimidin-4-yl)-3 -Nitrobenzoic acid (95-f)
  • the seventh step 44-cyclopropoxy-8-methyl-12-nitro-6-oxa-3,11-diaza 2(4,2)-pyrimidinheter-1(1,4), 4(1,3)-Diphenyl heterocyclododecane-12-one (95-g)
  • the eighth step 12-amino-44-cyclopropoxy-8-methyl-6-oxa-3,11-diaza 2(4,2)-pyrimidine-1(1,4),4( 1,3)-Diphenylcyclododecane-12-one (95)
  • tert-butyl (4-((5-amino-2-((tetrahydro-2H-pyran-3-yl)oxy)benzyl)oxy)phenyl)carbamate (197- c, 1.1g, 2.6mmol) and methyl 4-(2-chloropyrimidin-4-yl)-3-nitrobenzoate (914mg, 3.12mmol) were added to 1,4-dioxane (20ml) , Add potassium carbonate (718mg, 5.2mmol), three (dibenzylideneacetone) two palladium (238mg, 0.26mmol) and 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (242mg, 0.52mmol), heated to 100°C and stirred for 16h.
  • the fifth step 4-(2-((3-((4-((tert-butoxycarbonyl)amino)phenoxy)methyl)-4-((tetrahydro-2H-pyran-3-yl )Oxy)phenyl)amino)pyrimidin-4-yl)-3-nitrobenzoic acid (197-e)
  • the sixth step 4-(2-((3-((4-aminophenoxy)methyl)-4-((tetrahydro-2H-pyran-3-yl)oxy)phenyl)amino) Pyrimidine-4-yl)-3-nitrobenzoic acid (197-f)
  • the seventh step 12-nitro-44-((tetrahydro-2H-pyran-3-yl)oxy)-6-oxa-3,8-diaza-2(4,2)-pyrimidine Hetero-1,7(1,4),4(1,3)-triphenyl heterocyclic ninepin-9-one (197-g)
  • the eighth step 12-amino-44-((tetrahydro-2H-pyran-3-yl)oxy)-6-oxa-3-8-diaza-2(4,2)-pyrimidine hetero -1,7(1,4),4(1,3)-Triphenylcyclonin-9-one(197)
  • Example 197 using commercially available compounds or the preparation methods of the intermediate compounds shown in the reference, the following example compounds in Table 3 were prepared.
  • methyl 4-bromo-3-hydroxybenzoate (1.00g, 4.35mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.45g, 8.70mmol) were added to anhydrous DCM ( 20ml), cooled to 0°C in an ice bath, stirred for 10min, slowly added N,N-diisopropylethylamine (2.25g, 17.39mmol) dropwise, slowly rose to room temperature and continued stirring for 5h after the addition was completed.
  • Step 6 Methyl 4-(2-((3-((4-((tert-butoxycarbonyl)amino)phenoxy)methyl)-4-(cyclopentyloxy)phenyl)amino) Pyrimidine-4-yl)-3-((2-(trimethylsilyl)ethoxy)methoxy)benzoate (215-f)
  • the seventh step 4-(2-((3-((4-aminophenoxy)methyl)-4-(cyclopentyloxy)phenyl)amino)pyrimidin-4-yl)-3-hydroxybenzene Methyl formate (215-g)
  • the eighth step 4-(2-((3-((4-aminophenoxy)methyl)-4-(cyclopentyloxy)phenyl)amino)pyrimidin-4-yl)-3-hydroxybenzene Formic acid (215-h)
  • the ninth step 44-(cyclopentyloxy)-12-hydroxy-6-oxa-3,8-diaza 2(4,2)-pyrimidine-1,7(1,4),4(1 ,3)-Triphenylcyclonin-9-one (215)
  • 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 is carried out in the reaction buffer of 50 mM Hepes (pH 7.0), NaN3 0.02%, BSA 0.01%, 0.1 mM Orthocanadate, 5 mM Mgcl 2 , and 1 mM DTT.
  • 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.
  • concentration of ATP 2 ⁇ M
  • 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 JAK3 inhibitory activity, and it has good selectivity to JAK1, JAK2 and TYK2.
  • 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 JAK3.
  • the compound of formula I of the present invention exhibits very excellent JAK selectivity, that is, the IC50 ratio of JAK1/JAK3 and/or the IC50 ratio of JAK2/JAK3 is far superior to 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JAK3相关疾病的药物中的医药用途。

Description

一种大环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。不同于其他JAKs的广泛表达，JAK3只表 达在造血系统中，因此人们通常认为选择性抑制JAK3的功能能够达到安全有效的免疫效果。
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JAK3具有高选择性的抑制剂存在很大的难度。
因此，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JAK3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JAK3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 PCTCN2021095332-appb-000001
式中，
X 1、X 2、X 3和X 4各自独立地选自下组：N、C或C-R d；且X 1、X 2、X 3和X 4中有0、1、2、3个为N；
或者，当X 1为C-R d时，R d与X 2稠合形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
或者，当X 2为C-R d时，R d与X 1稠合形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
或者，当X 3为C-R d时，R d与X 4稠合形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
或者，当X 4为C-R d时，R d与X 3稠合形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
A选自下组：-C(＝O)N-R b、-C(＝O)O-、-SO 2N(R b)-、-C(＝O)N-R b-SO 2-、O、S；其中，R b选自下组：H、取代或未取代C1-C6烷基；
B选自取代或未取代的下组基团：键、C(R c) 2、C3-C10亚环烷基、3-10元亚杂环基、5-12元亚杂芳基、C6-C12亚芳基、(CH 2)m-R'-；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'独立地选自取代或未取代的下组基团：5-12元亚杂芳基、C6-C12亚芳基；
X选自取代或未取代的下组基团：键、C(R c) 2、(CH 2)m-O-、C(＝O)O-、O、N-R b、S、SO、SO 2、C3-C10亚环烷基、3-10元亚杂环基、5-12元亚杂芳基、C6-C12亚芳基；
R 5、R 6、R 7、R 8、R 9、R 10和R d各自独立地选自下组：H、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、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芳基或-OR 11；其中，R 11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；
或者R 5和R 6与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
或者R 8和R 9与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
或者R 9和R 10与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
(CH 2)n和(CH 2)m中的H原子可以任选地被一个或多个(如2、3、4、5)R a取代；
m为1、2、3、4或5；
n为0、1、2、3、4、5、6、7或8；
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、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；
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、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，所述的式I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I'所述的结构：
Figure PCTCN2021095332-appb-000002
Figure PCTCN2021095332-appb-000003
式中，
Q选自取代或未取代的下组基团：(CH 2)m-R'-、C3-C10亚环烷基、3-10元亚杂环基、5-12元亚杂芳基、C6-C12亚芳基；其中，R'独立地选自取代或未取代的下组基团：5-12元亚杂芳基、C6-C12亚芳基；
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、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；
X、m、n、A、X 1、X 2、X 3、X 4、R 5、R 6、R 7、R 8、R 9、R 10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，X 2为C-R d，R d选自下组：H、氨基、胺基、C1-C6烷基、羟基、巯基，所述烷基可任选地被选自下组的一个或多个基团取代：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，其具有式II所示的结构：
Figure PCTCN2021095332-appb-000004
式中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10各自独立地选自下组：H、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、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芳基或-OR 11；其中，R 11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；
或者R 1和R 2与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
或者R 3和R 4与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
或者R 5和R 6与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
或者R 8和R 9与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
或者R 9和R 10与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
(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；
A、B、m、n和X的定义如上所述；
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、胺基、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、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，其具有式III所示的结构：
Figure PCTCN2021095332-appb-000005
式中，
B选自取代或未取代的下组基团：键、(CH 2)m-R'-、C3-C10亚环烷基、3-10元亚杂环基、5-12元亚杂芳基、C6-C12亚芳基；其中，R'独立地选自取代或未取代的下组基团：5-12元亚杂芳基、C6-C12亚芳基；
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、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；
m、n、R 5、R 6、R 8、R 9、R 1、R 2的定义如上所述。
在另一优选例中，B选自取代或未取代的下组基团：5-12元亚杂芳基、C6-C12亚芳基；其中，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、胺基、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元杂环基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；n为0或1。
在另一优选例中，A选自下组：-C(＝O)N-R b、-C(＝O)O-、-SO 2N(R b)-，其中，R b选自下组：H、取代或未取代C1-C6烷基，其中，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、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。
在另一优选例中，A为-C(＝O)N-R b，其中，R b选自下组：H、取代或未取代C1-C6烷基，其中，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、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。
在另一优选例中，当A为-C(＝O)N-R b时，羰基部分与
Figure PCTCN2021095332-appb-000006
相连，其中，R b的定义如上所述。
在另一优选例中，所述的式I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IV所示的结构：
Figure PCTCN2021095332-appb-000007
式中，
Q选自取代或未取代的下组基团：(CH 2)m-R'-、5-12元亚杂芳基、C6-C12亚芳基；其中，R'独立地选自取代或未取代的下组基团：5-12元亚杂芳基、C6-C12亚芳基；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、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；
X、m、R 1、R 2、R 5、R 6、R 8、R 9定义如上所述。
在另一优选例中，所述的式I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V所示的结构
Figure PCTCN2021095332-appb-000008
其中，R 5、R 6、R 8、R 9、X、n、R 1、R 2的定义如上所述。
在另一优选例中，X选自下组：键、C(R c) 2、(CH 2)m-O-、C(＝O)O-、O、N-R b、S、SO、SO 2；R c、R b和m的定义如上所述。
在另一优选例中，X为C(R c) 2、O或S，其中，R c的定义如上所述。
在另一优选例中，所述的式I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VI所示的结构
Figure PCTCN2021095332-appb-000009
其中，R 1、R 2、R 5、R 6、R 8、R 9和n的定义如上所述。
在另一优选例中，所述的式I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VII所示的结构
Figure PCTCN2021095332-appb-000010
其中，R 1、R 2、R 5、R 6、R 8、R 9和Q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，R 2选自下组：H、氨基、胺基、C1-C6烷基、羟基、巯基，所述烷基可任选地被选自下组的一个或多个(如2、3、4、5)基团取代：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，所述的式I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VIII所示的结构
Figure PCTCN2021095332-appb-000011
其中，R 1、R 5、R 6、R 8、R 9、X和n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，R 8选自下组：H、卤素、氨基、胺基、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芳基或-OR 11；
其中，R 11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(如2、3、4、5)基团取代：D、卤素、氨基、胺基、羟基、氰基、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；
上述烷基、烯基、炔基、杂环基、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、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。
在另一优选例中，R 8选自下组：C1-C6烷基、C3-C10环烷基、3-10元杂环基或-OR 11；
R 11选自取代或未取代的下组基团：C1-C6烷基、3-10元杂环基、C3-C10环烷基；
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、胺基、羟基、氰基、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；
其中，上述烷基、烯基、炔基、杂环基、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、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。
在另一优选例中，所述的式I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IX所示的结构
Figure PCTCN2021095332-appb-000012
式中，R 1、R 2、R 5和R 6各自独立地选自：H、卤素、OH、氨基、胺基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基、3-6元杂环基、C3-C6环烷基；
R 11和n的定义如上所述。
在另一优选例中，R 11选自取代或未取代的下组基团：C1-C3烷基、3-6元杂环基、C3-C6环烷基、5-6元杂芳基、苯基；
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、羟基、氰基、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；其中，所述烷基、烯基、炔基、杂环基、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、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。
在另一优选例中，所述的式I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X所示的结构
Figure PCTCN2021095332-appb-000013
式中，R 1、R 2、R 5和R 6各自独立地选自：H、卤素、OH、氨基、胺基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基、3-6元杂环基、C3-C6环烷基；
R 11和Q的定义如上所述。
在另一优选例中，Q为取代或未取代的下组基团：亚苯基、-亚苯基CH 2-、-5-6元亚杂芳基、-5-6元亚杂芳基CH 2-；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、羟基、氰基、酰胺基、C1-C6烷基、C1-C6烷氧基。
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，R 9选自下组：H、C1-C6烷基、C1-C6烷氧基、3-10元杂环基、C3-C10环烷基；其中，所述的烷基、烷氧基、杂环烷基、环烷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、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元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基。
在另一优选例中，R 1选自下组：H、卤素。
在另一优选例中，B为键。
在另一优选例中，R 7为H。
在另一优选例中，R 3为H。
在另一优选例中，R 4为H。
在另一优选例中，R 5为H、卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、3-10元杂环基、C3-C10环烷基，所述的烷基、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、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元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基。
在另一优选例中，R 6为H。
在另一优选例中，R 10为H。
在另一优选例中，所述的式I化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物具有选自下组的一个或多个特征：
A选自下组：-C(＝O)N-R b、-C(＝O)O-、-SO 2N(R b)-，优选地为-C(＝O)N-R b；
B选自取代或未取代的下组基团：键、5-12元亚杂芳基、C6-C12亚芳基、(CH 2)m-R'-；R'独立地选自取代或未取代的下组基团：5-12元亚杂芳基、C6-C12亚芳基；所述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；
X 1、X 2、X 3和X 4各自独立地为N或C-R d；优选地，X 2为CH、C-NH 2、C-N(R b)2、C-OH、C-SH；优选地，X 1为CH、C-卤素；优选地，X 3为CH；优选地，X 4为CH；
R 5为H、卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、3-10元杂环基、C3-C10环烷基，
R 6为H；
R 7为H；
R 8选自下组：H、卤素、氨基、胺基、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芳基或-OR 11；其中，R 11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；
R 9选自下组：H、C1-C6烷基、C1-C6烷氧基、3-10元杂环基、C3-C10环烷基；
R 10为H；
X为C(R c) 2、(CH 2)m-O-、O或S；
n为0、1、2、3、4或5；
R b选自下组：H、取代或未取代C1-C6烷基；
各R d独立地选自下组：H、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、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芳基或-OR 11；其中，R 11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；
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、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元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基。
在另一优选例中，X、n、A、B、X 1、X 2、X 3、X 4、R 5、R 6、R 7、R 8、R 9、R 10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 PCTCN2021095332-appb-000014
Figure PCTCN2021095332-appb-000015
Figure PCTCN2021095332-appb-000016
Figure PCTCN2021095332-appb-000017
Figure PCTCN2021095332-appb-000018
Figure PCTCN2021095332-appb-000019
Figure PCTCN2021095332-appb-000020
Figure PCTCN2021095332-appb-000021
Figure PCTCN2021095332-appb-000022
Figure PCTCN2021095332-appb-000023
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。
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、前药或溶剂化物或第二方面所述的药物组合物的用途，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，JAK激酶的活性或表达量相关的疾病为JAK3相关的障碍。
在另一优选例中，所述与JAK3活性或表达量相关的疾病选自下组：器官移植排斥、异种移植排斥、红斑狼疮、多发性硬化、类风湿性关节炎、银屑病(牛皮癣)、癌症、哮喘、特应性皮炎、I型糖尿病与糖尿病并发症、自体免疫性甲状腺障碍、溃疡性结肠炎、克罗恩氏病、阿尔茨海默病、斑秃、肥大细胞介导的过敏反应、血栓栓塞性、过敏性并发症和白癜风等。
在另一优选例中，所述的癌症选自下组：白血病、淋巴瘤、多发性骨髓瘤。
本发明第四方面，提供一种如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、前药或溶剂化物的制备方法，包括如下步骤：
在惰性溶剂中，催化剂存在下，化合物A 8发生成环反应，从而得到式I化合物；
Figure PCTCN2021095332-appb-000024
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、X 1、X 2、X 3、X 4、R 5、R 6、R 7、R 8、R 9、R 10、X和n的定义如上所述。
在惰性溶剂中，催化剂或缩合剂存在下，化合物A 8发生反应，得到化合物I。
在另一优选例中，所述的惰性溶剂为DCM。
在另一优选例中，催化剂或缩合剂选自：EDCI、DMAP、DCC等。
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JAK3/JAK1之比为代表的选择性或以JAK3/JAK2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。
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。
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。所述环烷基可以稠合于芳基、杂芳基、杂环基环上，其中与母体结构连接在一起的环为环烷基，如
Figure PCTCN2021095332-appb-000025
等。
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，优选地为C1-C6烷基-O-，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3-6元，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。所述杂环基可以稠合于杂芳基、芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，如
Figure PCTCN2021095332-appb-000026
Figure PCTCN2021095332-appb-000027
等。
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(即六元芳基)、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(如
Figure PCTCN2021095332-appb-000028
)和六元芳基并5-6元杂环基(如
Figure PCTCN2021095332-appb-000029
等)。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 PCTCN2021095332-appb-000030
的基团，甲酰胺基还意在包含取代的甲酰胺基，具有式
Figure PCTCN2021095332-appb-000031
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NH 2。
在本发明中，“胺基”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，且不同时为氢。
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。
Figure PCTCN2021095332-appb-000032
式中，
X、n、A、B、X 1、X 2、X 3、X 4、R 5、R 6、R 7、R 8、R 9、R 10的定义如上所述。
优选地，所述的式I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I'所述的结构：
Figure PCTCN2021095332-appb-000033
式中，
Q、X、n、A、X 1、X 2、X 3、X 4、R 5、R 6、R 7、R 8、R 9、R 10的定义如上所述。
优选地，上述化合物中，X 2为C-R d，R d选自下组：H、氨基、胺基、C1-C6烷基、羟基、巯基，所述烷基可任选地被选自下组的一个或多个基团取代：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元杂环基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基。
当A为-C(＝O)N-R b时，羰基部分与
Figure PCTCN2021095332-appb-000034
相连，其中，R b的定义如上所述。
优选地，上述化合物中，X 1、X 2、X 3和X 4各自独立地为N或C-R d；优选地，X 2为CH、C-NH 2、C-N(R b)2、C-OH、C-SH；优选地，X 1为CH、C-卤素；优选地，X 3为CH；优选地，X 4为CH。
优选地，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，其具有式II所示的结构：
Figure PCTCN2021095332-appb-000035
式中，
A、B、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、n的定义如上所述。
优选地，所述的式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，其具有式III所示的结构：
Figure PCTCN2021095332-appb-000036
式中，
B、m、n、R 1、R 2、R 5、R 6、R 8、R 9的定义如上所述。
优选地，上述化合物中，B选自取代或未取代的下组基团：键、5-12元亚杂芳基、C6-C12亚芳基；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、胺基、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元杂环基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基；n为0或1。
优选地，上述化合物中，A选自下组：-C(＝O)N-R b、-C(＝O)O-、-SO 2N(R b)-(优选地为-C(＝O)N-R b)，Rb的定义如上所述。
优选地，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IV所示的结构：
Figure PCTCN2021095332-appb-000037
式中，
Q、X、m、R 1、R 2、R 5、R 6、R 8、R 9定义如上所述。
优选地，所述的式I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V所示的结构
Figure PCTCN2021095332-appb-000038
其中，R 5、R 6、R 8、R 9、X、n、R 1、R 2的定义如上所述。
优选地，上述化合物中，X为C(Rc)2、O或S，其中，Rc的定义如上所述。
优选地，所述的式I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VI所示的结构
Figure PCTCN2021095332-appb-000039
其中，R 1、R 2、R 5、R 6、R 8、R 9和n的定义如上所述。
优选地，所述的式I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VII所示的结构
Figure PCTCN2021095332-appb-000040
其中，R 1、R 2、R 5、R 6、R 8、R 9和Q的定义如上所述。
优选地，所述的式I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VIII所示的结构
Figure PCTCN2021095332-appb-000041
其中，R 1、R 5、R 6、R 8、R 9、X和n的定义如上所述。
优选地，上述化合物中，R 2选自下组：H、氨基、胺基、C1-C6烷基、羟基、巯基；
优选地，上述化合物中，R 3为H。
优选地，上述化合物中，R 4为H。
优选地，上述化合物中，R 5为H、卤素、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、3-10元杂环基、C3-C10环烷基，所述的烷基、烷氧基、烯基、炔基、杂环基、环烷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、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。
优选地，上述化合物中，R 6为H。
优选地，上述化合物中，R 7为H。
优选地，上述化合物中，R 8选自下组：H、卤素、氨基、胺基、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芳基或-OR 11； 其中，R 11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。
优选地，上述化合物中，R 9选自下组：H、C1-C6烷基、C1-C6烷氧基、3-10元杂环基、C3-C10环烷基。
优选地，上述化合物中，R 10为H。
优选地，上述化合物中，n为1、2、3、4或5。
上述的烷基、烷氧基、烯基、炔基、杂环基、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、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。
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。
本发明化合物的制备包括步骤：
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 PCTCN2021095332-appb-000042
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、X 1、X 2、X 3、X 4、R 5、R 6、R 7、R 8、R 9、R 10、X和n的定义如上所述。
优选地，本发明的式A化合物可通过如下步骤得到：
Figure PCTCN2021095332-appb-000043
式中，R 1、R 2、R 5、R 6、R 8、R 9的定义如上所述；
(i)在惰性溶剂(如DCM)中，式A-1与卤化剂(如四溴化碳、三苯基膦)反应，得到A-2；
(ii)在惰性溶剂(如DMF)中，碱(如氢化钠)存在下，式A-2与和
Figure PCTCN2021095332-appb-000044
反应，得到A-3；
(iii)在惰性溶剂(如乙醇)中，还原剂(如钯/碳)存在下，式A-3发生还原反应，得到A-4；
(iv)在惰性溶剂(如DMF和/或1,4-二氧六环和/水)中，碱性(如碳酸钠、碳酸钾等)条件下，催化剂(如双三苯基磷二氯化钯)存在下，
Figure PCTCN2021095332-appb-000045
与
Figure PCTCN2021095332-appb-000046
偶联，得到化合物A-5；
(v)在惰性溶剂(如1,4-二氧六环)中，碱性(如碳酸钠、碳酸钾等)条件下，催化剂(如三(二亚苄基丙酮)二钯/2-二环己基磷-2,4,6-三异丙基联苯)存在下，式A-5与式A-4偶联，得到A-6；
(vi)在惰性溶剂(如THF和水)中，碱性(氢氧化锂一水合物)条件下，式A-6水解，得到式A-7；
(vii)在惰性溶剂(如EA)中，酸性(如氯化氢)条件下，式A-7脱保护基团(如Boc)，得到化合物A-8；
(viii)在惰性溶剂(如DCM)中，缩合剂(如O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐/N,N-二异丙基乙胺)存在下，化合物A-8发生缩合反应，得到式A化合物。
上述合成步骤中，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
Figure PCTCN2021095332-appb-000047
Figure PCTCN2021095332-appb-000048
)、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JAK3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。
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)
化合物A1-A94合成路线：
Figure PCTCN2021095332-appb-000049
实施例1 4 4-吗啉-6-氧杂-3,11-二氮杂-2(4,2)-嘧啶杂-1(1,4),4(1,3)-二苯杂环十二蕃-12-酮(A1)制备
Figure PCTCN2021095332-appb-000050
第一步：2-吗啉-5-硝基苯甲醇(A1-1)
2-氟-5-硝基苄醇(10.0g,58mmol)与等当量吗啉加入到DMSO(100ml)中，加热至100℃搅拌2h。TLC确认反应完全后，倒入水中，EA萃取，去离子水洗涤三次，无水硫酸钠干燥，浓缩EA，残余物经柱层析纯化，得到黄色固体2-吗啉-5-硝基苯甲醇(A1-1,13.0g,收率94％)。MS(ESI)m/z:calcd 239.10(M+H),found 239.23； 1H NMR(400MHz,DMSO):δ8.34(d,J＝2.7Hz,1H),8.10(dd,J＝8.9,2.8Hz,1H),7.17(d,J＝8.9Hz,1H),5.54(t,J＝5.7Hz,1H),4.55(d,J＝5.7Hz,2H),3.76(t,J＝4.0Hz,4H),3.01(t,J＝4.0Hz,4H)。
第二步：4-(2-溴甲基-4-硝基苯基)吗啉(A1-2)
2-吗啉-5-硝基苯甲醇(A1-1，10.00g，42mmol)和三苯基膦(22.03g，84mmol)加入DCM(100ml)中，搅拌10min，冰浴冷却到0℃，滴加四溴化碳(27.84g，84mmol)的DCM(50ml)溶液，滴毕室温搅拌1h。TLC确认反应完全后，去离子水洗涤，无水硫酸钠干燥，浓缩DCM，残余物经柱层析纯化得到黄色固体4-(2-溴甲基-4-硝基苯基)吗啉(A1-2，10.05g，收率79％)。MS(ESI)m/z:calcd 301.02(M+H),found 301.1； 1H NMR(400MHz,CDCl 3):δ8.38(s,1H),8.17(d,J＝8.8Hz,1H),7.16(d,J＝8.8Hz,1H),4.65(s,2H),3.92(t,J＝4.8Hz,4H),3.13(t,J＝4.8Hz,4H)。
第三步：4-((2-吗啉基-5-硝基)苄氧)丁胺-1-羧酸叔丁酯(A1-3)
氮气保护，4-(N-叔丁氧羰基氨基)-1-丁醇(189mg,1.0mmol)加入到无水DMF(4ml)中，冰浴冷至0℃，加入氢化钠(53mg,1.33mmol,60％)，冰浴下继续搅拌30min，后慢慢加入4-(2-溴甲基-4-硝基苯基)吗啉(A1-2,200mg,0.67mmol)的DMF(4ml)溶液，慢慢升至室温继 续搅拌1h。TLC确认反应完全后，置冰浴下加饱和氯化铵溶液淬灭，EA萃取，去离子水洗涤三次，无水硫酸钠干燥，浓缩EA溶液，残余物经柱层析纯化得到A1-3(180mg,收率66％)。MS(ESI)m/z:calcd 410.23(M+H),found 410.35； 1H NMR(400MHz,CDCl 3):δ8.36(d,J＝2.6Hz,1H),8.16(dd,J＝8.9,2.7Hz,1H),7.08(d,J＝8.0Hz,1H),4.55(s,2H),3.90(t,J＝4.0Hz,4H),3.58(t,J＝6.2Hz,2H),3.22-3.12(m,2H),3.08(t,J＝4.0Hz,4H),1.80–1.55(m,4H),1.46(s,9H)。
第四步：4-((5-氨基-2-吗啉)苄氧)丁胺-1-羧酸叔丁酯(A1-4)
4-((2-吗啉基-5-硝基)苄氧)丁胺-1-羧酸叔丁酯(A1-3,180mg,0.44mmol)加入到无水乙醇(7ml)中，后分别加入甲酸铵(277mg,4.4mmol)和钯/碳(47mg,0.044mmol,10％on carbon(wetted with ca.55％Water))，室温搅拌2h。TLC和LCMS确认反应完毕后，抽滤，浓缩滤液，残余物经柱层析纯化得到黄色油状物4-((5-氨基-2-吗啉)苄氧)丁胺-1-羧酸叔丁酯(A1-4,166mg,收率99％)。MS(ESI)m/z:计算值380.25(M+H),实测值380.17；
第五步：4-(2-氯嘧啶-4-)苯甲酸甲酯(A1-5)
氮气保护，2,4-二氯嘧啶(3.00g,20.3mmol)和4-甲氧羰基苯硼酸(4.38g,24.3mmol)加入到混合溶剂DMF、1,4-二氧六环、水(24ml,15ml,6ml)中，再加入碳酸钠(6.45g,60.9mmol)，然后加入双三苯基磷二氯化钯(1.42g,2.03mmol)，加热至80℃搅拌16h。TLC确认反应完全后，浓缩1,4-二氧六环，EA萃取，去离子水洗涤有机相三次，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-(2-氯嘧啶-4-)苯甲酸甲酯(A1-5,4.27g,收率85％)。MS(ESI)m/z:计算值249.04(M+H),实测值249.12； 1H NMR(400MHz,CDCl 3):δ8.73(d,J＝5.2Hz,1H),8.24–8.16(m,4H),7.73(d,J＝5.2Hz,1H),3.99(s,3H)。
第六步：4-(2-((3-((4-((叔丁氧羰基胺)丁氧)甲基)-4-吗啉苯基)胺基)嘧啶-4-)苯甲酸甲酯(A1-6)
氮气保护，4-(2-氯嘧啶-4-)苯甲酸甲酯(A1-5,119mg,0.48mmol)和4-((5-氨基-2-吗啉)苄氧)丁胺-1-羧酸叔丁酯(A1-4,166mg,0.44mmol)加入到1,4-二氧六环(5ml)中，加入碳酸钾(121mg,0.88mmol)、三(二亚苄基丙酮)二钯(20mg,0.022mmol)和2-二环己基磷-2,4,6-三异丙基联苯(23mg,0.048mmol)，加热至100℃搅拌16h。TLC确认反应完全后，浓缩1,4-二氧六环，加入去离子水和二氯甲烷，分液，有机相用去离子水洗涤三次，无水硫酸钠干燥，浓缩二氯甲烷，残余物经柱层析纯化得到黄色固体4-(2-((3-((4-((叔丁氧羰基胺)丁氧)甲基)-4-吗啉苯基)胺基)嘧啶-4-)苯甲酸甲酯(A1-6,145mg,收率56％)。MS(ESI)m/z:calcd592.72(M+H),found 592.95； 1H NMR(400MHz,DMSO-d6):δ9.68(s,1H),8.59(d,J＝5.1Hz,1H),8.32(d,J＝8.4Hz,2H),8.12(d,J＝8.1Hz,2H),7.91(s,1H),7.70(d,J＝8.4Hz,1H),7.46(d,J＝5.2Hz,1H),7.11(d,J＝8.7Hz,1H),6.77(s,1H),4.53(s,2H),3.91(s,3H),3.74(m,4H),3.50(t,J＝4.0Hz,2H),2.91(d,J＝6.0Hz,2H),2.84(s,4H),1.49(m,4H),1.35(s,9H)。
第七步：4-(2-((3-((4-((叔丁氧羰基胺)丁氧)甲基)-4-吗啉苯基)胺基)嘧啶-4-)苯甲酸(A1-7)
4-(2-((3-((4-((叔丁氧羰基胺)丁氧)甲基)-4-吗啉苯基)胺基)嘧啶-4-)苯甲酸甲酯(A1-6,145mg,0.24mmol)加入到THF和水(6ml/2ml)的混合溶液中，再加入氢氧化锂一水合物(51mg,1.23mmol)，室温搅拌16h。TLC确认反应完全后，加1M HCl调节体系PH至7.0，浓缩溶剂，加入EA和水分液萃取，去离子水洗涤，无水硫酸钠干燥，浓缩EA得到黄色固体4-(2-((3-((4-((叔丁氧羰基胺)丁氧)甲基)-4-吗啉苯基)胺基)嘧啶-4-)苯甲酸(A1-7,124mg,收率88％)，直接进行下步反应。
第八步：4-(2-((3-((4-氨基丁氧)甲基)-4-吗啉苯基)胺基)嘧啶-4-)苯甲酸(A1-8)
4-(2-((3-((4-((叔丁氧羰基胺)丁氧)甲基)-4-吗啉苯基)胺基)嘧啶-4-)苯甲酸(A1-7,124mg,0.21mmol)加入EA(2ml)中，滴入氯化氢/EA溶液(1mol/L,1ml)，室温搅拌1h。TLC确认反应结束后，浓缩反应液得到黄色固体4-(2-((3-((4-氨基丁氧)甲基)-4-吗啉苯基)胺基)嘧啶-4-)苯甲酸(A1-8,120mg,收率100％)。MS(ESI)m/z:calcd 478.25(M+H),found 478.33。
第九步：4 4-吗啉-6-氧杂-3,11-二氮杂-2(4,2)-嘧啶杂-1(1,4),4(1,3)-二苯杂环十二蕃-12-酮(A1)
O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(143mg,0.36mmol)和N,N-二异丙基乙胺(162mg,1.2mmol)加入到DCM(10ml)中，室温搅拌。缓慢滴加4-(2-((3-((4-氨基丁氧)甲基)-4-吗啉苯基)胺基)嘧啶-4-)苯甲酸(A1-8,60mg,0.11mmol)的DCM和DMF(3ml/7ml)的混合溶液，持续1h，加毕继续室温搅拌16h。LCMS确认反应完全后，浓缩反应液，残余物经柱层析纯化得到黄色固体4 4-吗啉-6-氧杂-3,11-二氮杂-2(4,2)-嘧啶杂-1(1,4),4(1,3)-二苯杂环十二蕃-12-酮(A1,15mg,收率30％)。MS(ESI)m/z:calcd 460.23(M+H),found 460.52； 1H NMR(400MHz,DMSO-d6):δ9.59(s,1H),8.55(d,J＝5.0Hz,1H),8.41(d,J＝2.0Hz,1H),7.94(d,J＝8.0Hz,3H),7.52(d,J＝7.9Hz,2H),7.27(d,J＝5.0Hz,1H),7.04(dd,J＝10.4,5.3Hz,2H),4.48(s,2H),3.78–3.63(m,4H),3.24(t,J＝4.0Hz,2H),2.83–2.75(m,4H),2.69(m,2H),1.40-1.34(m,2H),1.20–1.10(m,2H)。
实施例2 1 2-氟-4 4-环丙基-6-氧杂-3,11-二氮杂-2(4,2)-嘧啶杂-1(1,4),4(1,3)-二苯杂环十二蕃-12-酮(A2)的制备
Figure PCTCN2021095332-appb-000051
第一步：1-溴-2-溴甲基-4-硝基苯(A2-2)
2-溴-5-硝基苄醇(A2-1,928mg，4.0mmol)和三苯基膦(1.98g，6.0mmol)加入DCM(40ml)中，搅拌10min，冰浴冷却到0℃，滴加四溴化碳(1.57g，6.0mmol)的DCM(5ml)溶液，滴毕室温搅拌2h。TLC确认反应完全后，浓缩DCM，残余物经柱层析纯化得到黄色固体A2-2(647mg，收率55％)。 1H NMR(400MHz,CDCl 3):8.36(s,1H),8.05(d,J＝8.8Hz,1H),7.81(d,J＝8.8Hz,1H),4.66(s,2H)。
第二步：4-((2-溴-5-硝基)苄氧)丁胺-1-羧酸叔丁酯(A2-3)
氮气保护，4-(N-叔丁氧羰基氨基)-1-丁醇(547mg,2.9mmol)加入到无水DMF(10ml)中，冰浴冷至0℃，加入氢化钠(132mg,3.3mmol,60％)，冰浴下继续搅拌30min，后慢慢加入A2-2(647mg,2.2mmol)的DMF(5ml)溶液，冰浴下继续搅拌1h。TLC确认反应完全后，置于冰浴下加饱和氯化铵溶液淬灭，EA萃取，去离子水洗涤三次，无水硫酸钠干燥，浓缩EA溶液，残余物经柱层析纯化得到A2-3(440mg,收率50％)。MS(ESI)m/z:calcd 347.08(M+H-56),found 346.90。
第三步：4-((2-环丙基-5-硝基)苄氧)丁胺-1-羧酸叔丁酯(A2-4)
氮气保护，A2-3(400mg,1.0mmol)和环丙基硼酸(129mg,1.5mmol)溶于甲苯(16mL)和水(2ml)中，加入磷酸钾(637mg,3.0mmol)，三环己基膦四氟硼酸盐(147.3mg,0.40mmol)和醋酸钯(45mg，0.20mmol)，加热至100℃搅拌3h。TLC确认反应完全后，浓缩甲苯，EA萃取，去离子水洗涤有机相三次，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A2-4(360mg,收率98％)。MS(ESI)m/z:calcd 365.20(M+H),found 365.14。
第四步：1 2-氟-4 4-环丙基-6-氧杂-3,11-二氮杂-2(4,2)-嘧啶杂-1(1,4),4(1,3)-二苯杂环十二蕃-12-酮(A2)
由A2-4经过五步反应(类似于A1)得到黄色固体A2(30mg)。MS(ESI)m/z:calcd 433.20(M+H),found 433.30； 1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.58(d,J＝5.0Hz,1H),8.22(d,J＝2.3Hz,1H),8.07-8.03(m,1H),7.88-7.84(m,1H),7.41-7.37(m,2H),7.16(dd,J＝5.0,2.1Hz,1H),6.97(dd,J＝8.3,2.3Hz,1H),6.87(d,J＝8.3Hz,1H),4.55(s,2H),3.23(t,J＝6.4Hz,2H),2.81-2.75(m,2H),1.86–1.77(m,1H),1.38-1.32(m,2H),1.25-1.22(m,2H),0.88-0.77(m,2H),0.57-0.53(m,2H).
参照实施例1和2的实验步骤，以不同起始原料，得到实施例3-94，如下表1所示。
表1
Figure PCTCN2021095332-appb-000052
Figure PCTCN2021095332-appb-000053
Figure PCTCN2021095332-appb-000054
Figure PCTCN2021095332-appb-000055
Figure PCTCN2021095332-appb-000056
Figure PCTCN2021095332-appb-000057
Figure PCTCN2021095332-appb-000058
Figure PCTCN2021095332-appb-000059
Figure PCTCN2021095332-appb-000060
Figure PCTCN2021095332-appb-000061
Figure PCTCN2021095332-appb-000062
Figure PCTCN2021095332-appb-000063
Figure PCTCN2021095332-appb-000064
Figure PCTCN2021095332-appb-000065
实施例95 12-氨基-44-环丙氧基-8-甲基-6-氧杂-3,11-二氮杂2(4,2)-嘧啶-1(1,4),4(1,3)-二苯杂环十二蕃-12-酮(95)的制备
Figure PCTCN2021095332-appb-000066
第一步：(4-((2-氟-5-硝基苄基)氧基)-3-甲基丁基)氨基甲酸叔丁酯(95-a)
2-氟-5-硝基苄溴(660mg，2.82mmol)溶于Tol(15mL)，向其中加入50％氢氧化钠水溶液(15mL)，搅拌片刻，再加入(4-羟基-3-甲基丁基)氨基甲酸叔丁酯(800mg，3.95mmol)，反应5～10min，称取TBAHS(130mg，0.394mmol)加入反应液中，室温反应1h。TLC确认反应完全后，加入EA和水萃取，去离子水洗涤，无水硫酸钠干燥，浓缩EA，残余物经柱层析纯化得到黄色油状物(4-((2-氟-5-硝基苄基)氧基)-3-甲基丁基)氨基甲酸叔丁酯(95-a,440mg,收率44％)。 1H NMR(400MHz,CDCl 3):δ8.39(d,J＝3.0Hz,1H),8.25–8.17(m,1H),7.21(t,J＝8.8Hz,1H),4.62(s,2H),3.46–3.40(m,2H),3.27–3.12(m,2H),1.92–1.85(m,1H),1.68–1.61(m,2H),1.46(s,9H),1.02(d,J＝6.7Hz,3H).
第二步：叔丁基(4-((2-环丙氧基-5-硝基苄基)氧基)-3-甲基丁基)氨基甲酸酯(95-b)
(4-((2-氟-5-硝基苄基)氧基)-3-甲基丁基)氨基甲酸叔丁酯(95-a,440mg，1.24mmol)，环丙醇(432mg，7.44mmol)溶于DMF(10mL)，搅拌片刻，冰浴下向其中缓慢加入叔丁醇钠(594mg，6.18mmol)，加完移至室温反应2h。TLC确认反应完全后，加入EA和水萃取，去离子水洗涤，无水硫酸钠干燥，浓缩EA得黄色油状物叔丁基(4-((2-环丙氧基-5-硝基苄基)氧基)-3-甲基丁基)氨基甲酸酯(95-b,400mg,收率80％)，直接进行下步反应。
第三步：叔丁基(4-((5-氨基-2-环丙氧基苄基)氧基)-3-甲基丁基)氨基甲酸酯(95-c)
叔丁基(4-((2-环丙氧基-5-硝基苄基)氧基)-3-甲基丁基)氨基甲酸酯(95-b,400mg，1.01mmol)溶于甲醇(20mL)，向其中加入适量Raney Ni，H 2保护，室温反应2h。TLC确认反应完全后，抽滤，滤液浓缩，残余物经柱层析纯化得到无色油状物叔丁基(4-((5-氨基-2-环丙氧基苄基)氧基)-3-甲基丁基)氨基甲酸酯(95-c,300mg,收率81％)。MS(ESI)m/z:calcd 365.24(M+H),found 365.30.
第四步：4-(2-((3-((4-((叔丁氧基羰基)氨基)-2-甲基丁氧基)甲基)-4-环丙氧基苯基)氨基嘧啶-4-基)-3-硝基苯甲酸甲酯(95-d)
氮气保护，4-(2-氯嘧啶-4-基)-3-硝基苯甲酸甲酯(435mg，1.48mmol)，叔丁基(4-((5-氨基-2-环丙氧基苄基)氧基)-3-甲基丁基)氨基甲酸酯(95-c,300mg，0.822mmol)加入到1,4-二氧六环(20mL)中，再加入三(二亚苄基丙酮)二钯(150mg,0.164mmol)和2-二环己基磷-2,4,6-三异丙基联苯(156mg,0.328mmol)，碳酸钾(227mg,1.64mmol)，100℃反应8h。TLC确认反应完全后，浓缩1,4-二氧六环，加入去离子水和二氯甲烷，分液，有机相用去离子水洗涤三次，无水硫酸钠干燥，浓缩二氯甲烷，残余物经柱层析纯化得到黄色固体4-(2-((3-((4-((叔丁氧基羰基)氨基)-2-甲基丁氧基)甲基)-4-环丙氧基苯基)氨基嘧啶-4-基)-3-硝基苯甲酸甲酯(95-d,250mg,收率49％)。MS(ESI)m/z:calcd 622.28(M+H),found 622.30； 1H NMR(400MHz,CDCl 3)δ8.61–8.54(m,1H),8.54–8.44(m,1H),8.33(d,J＝7.8Hz,1H),7.74(d,J＝7.9Hz,1H),7.56(d,J＝8.3Hz,1H),7.42(s,1H),7.22(d,J＝8.8Hz,1H),7.15(dd,J＝9.2,5.3Hz,1H),6.87(d,J＝4.3Hz,1H),4.49(s,2H),4.03(s,3H),3.58–3.48(m,1H),3.39–3.31(m,2H),3.20(ddd,J＝8.3,4.2,2.3Hz,2H),1.78(s,1H),1.61(dd,J＝5.5,1.2Hz,2H),1.45(s,9H),0.96(d,J＝6.8Hz,3H),0.78(dd,J＝8.5,7.7Hz,4H).
第五步：4-(2-((3-((4-((叔丁氧基羰基)氨基)-2-甲基丁氧基)甲基)-4-环丙氧基苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸(95-e)
4-(2-((3-((4-((叔丁氧基羰基)氨基)-2-甲基丁氧基)甲基)-4-环丙氧基苯基)氨基嘧啶-4-基)-3-硝基苯甲酸甲酯(95-d,250mg,0.403mmol)加入到THF和水(10ml/3ml)的混合溶液中，再加入氢氧化锂一水合物(85mg,2.01mmol)，室温搅拌16h。TLC确认反应完全后，加1M HCl调节体系PH至5～6，浓缩溶剂，加入EA和水分液萃取，去离子水洗涤，无水硫酸钠干燥，浓缩EA得到黄色固体4-(2-((3-((4-((叔丁氧基羰基)氨基)-2-甲基丁氧基)甲基)-4-环丙氧基苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸(95-e,210mg,收率86％)，直接进行下步反应。MS(ESI)m/z:calcd 608.26(M+H),found 608.30。
第六步：4-(2-((3-((4-氨基-2-甲基丁氧基)甲基)-4-环丙氧基苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸(95-f)
4-(2-((3-((4-((叔丁氧基羰基)氨基)-2-甲基丁氧基)甲基)-4-环丙氧基苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸(95-d,210mg,0.345mmol)加入EA(6ml)中，滴入氯化氢/EA溶液(3mol/L,3ml)，40℃搅拌3h。TLC确认反应结束后，滤出固体，烘干后得黄色固体4-(2-((3-((4-氨基-2-甲基丁氧基)甲基)-4-环丙氧基苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸(95-f,100mg,收率57％)，直接进行下步反应。MS(ESI)m/z:calcd 508.21(M+H),found 508.30。
第七步：44-环丙氧基-8-甲基-12-硝基-6-氧杂-3,11-二氮杂2(4,2)-嘧啶杂-1(1,4),4(1,3)-二苯杂环十二蕃-12-酮(95-g)
O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(150mg,0.394mmol)和N,N-二异丙基乙胺(102mg,0.789mmol)加入到DCM(30ml)中，室温搅拌。缓慢滴加4-(2-((3-((4- 氨基-2-甲基丁氧基)甲基)-4-环丙氧基苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸(95-f,100mg,0.197mmol)的DCM和DMF(10ml/5ml)的混合溶液，持续0.5h，加毕继续室温搅拌4h。LCMS确认反应完全后，浓缩反应液，残余物经柱层析纯化得到黄色固体44-环丙氧基-8-甲基-12-硝基-6-氧杂-3,11-二氮杂2(4,2)-嘧啶杂-1(1,4),4(1,3)-二苯杂环十二蕃-12-酮(95-g,50mg,收率52％)。MS(ESI)m/z:calcd 490.20(M+H),found 490.20； 1H NMR(400MHz,DMSO-d6):δ9.59(s,1H),8.62(d,J＝4.7Hz,1H),8.17(d,J＝15.7Hz,2H),7.94(s,1H),7.80(d,J＝7.8Hz,2H),7.19(d,J＝4.6Hz,1H),7.13(d,J＝8.7Hz,1H),7.05(d,J＝6.4Hz,1H),4.30(q,J＝12.5Hz,2H),3.79(s,1H),3.13(s,1H),2.93(d,J＝7.4Hz,4H),1.25(s,2H),1.17(s,2H),0.75–0.68(m,5H),0.61(s,2H).
第八步：12-氨基-44-环丙氧基-8-甲基-6-氧杂-3,11-二氮杂2(4,2)-嘧啶-1(1,4),4(1,3)-二苯杂环十二蕃-12-酮(95)
环丙氧基-8-甲基-12-硝基-6-氧杂-3,11-二氮杂2(4,2)-嘧啶杂-1(1,4),4(1,3)-二苯杂环十二蕃-12-酮(95-g,50mg,0.102mmol)溶于乙醇(10mL)，加入氯化亚锡(185mg,0.818mmol)，氯化氢水溶液(0.5mL,1mol/mL)，室温反应16h。TLC确认反应完全后，浓缩乙醇，用饱和碳酸氢钠水溶液调节体系PH至8.0，加入EA和水分液萃取，去离子水洗涤，无水硫酸钠干燥，浓缩EA后反相纯化冻干得白色固体12-氨基-44-环丙氧基-8-甲基-6-氧杂-3,11-二氮杂2(4,2)-嘧啶-1(1,4),4(1,3)-二苯杂环十二蕃-12-酮(95,10mg,收率22％)。MS(ESI)m/z:calcd 460.23(M+H),found 460.30； 1H NMR(400MHz,DMSO-d6):δ9.45(s,1H),8.51(d,J＝4.7Hz,1H),8.14(s,1H),7.72(s,1H),7.43(d,J＝7.7Hz,1H),7.16(d,J＝8.6Hz,1H),7.06(s,2H),6.74(s,1H),6.56(d,J＝7.9Hz,1H),5.93(s,2H),4.38(dd,J＝29.8,14.2Hz,2H),3.80(s,1H),2.99(d,J＝7.6Hz,1H),2.74(d,J＝50.1Hz,2H),1.27(d,J＝15.5Hz,4H),0.78(t,J＝27.1Hz,5H),0.62(s,3H).
依据与上述实施例95相同的方法，使用市售化合物或参考所示的中间体化合物的制备方法而制备以下表2的实施例化合物。
表2
Figure PCTCN2021095332-appb-000067
Figure PCTCN2021095332-appb-000068
Figure PCTCN2021095332-appb-000069
Figure PCTCN2021095332-appb-000070
Figure PCTCN2021095332-appb-000071
Figure PCTCN2021095332-appb-000072
Figure PCTCN2021095332-appb-000073
Figure PCTCN2021095332-appb-000074
Figure PCTCN2021095332-appb-000075
Figure PCTCN2021095332-appb-000076
Figure PCTCN2021095332-appb-000077
Figure PCTCN2021095332-appb-000078
Figure PCTCN2021095332-appb-000079
Figure PCTCN2021095332-appb-000080
Figure PCTCN2021095332-appb-000081
Figure PCTCN2021095332-appb-000082
实施例197 12-氨基-44-((四氢-2H-吡喃-3-基)氧基)-6-氧杂-3-8-二氮杂-2(4,2)-嘧啶杂-1,7(1,4),4(1,3)-三苯环九蕃-9-酮(197)的制备
Figure PCTCN2021095332-appb-000083
第一步：叔丁基(4-((2-氟-5-硝基苄基)氧基)苯基)氨基甲酸酯(197-a)
2-氟-5-硝基苄溴(5.0g,21mmol)溶于甲苯(25ml)中，冰浴下缓慢加入50％的NaOH溶液(50ml)，然后在加入氧羰酰-4-羟基苯胺(4.7g，22mmol)的甲苯(25ml)溶液，室温搅拌2h。TLC确认反应完全后，EA萃取，去离子水洗涤三次，无水硫酸钠干燥，浓缩 EA，残余物经柱层析纯化，得到黄色固体叔丁基(4-(((2-氟-5-硝基苄基)氧基)苯基)氨基甲酸酯(197-a,6.01g,收率78％)。MS(ESI)m/z:calcd 234.00(M+H)。
第二步：叔丁基(4-((5-硝基-2-((四氢-2H-吡喃-3-基)氧基)苄基)氧基)苯基)氨基甲酸酯(197-b)
叔丁基(4-((2-氟-5-硝基苄基)氧基)苯基)氨基甲酸酯(197-a，1g，2.8mmol)和3-羟基四氢吡喃(572mg，5.6mmol)溶于DMF(10ml)中，冰浴下缓慢加入叔丁醇钠(333mg，3.36mmol)，0℃搅拌1h。TLC确认反应完全后，加水稀释，EA萃取，去离子水洗涤三次，无水硫酸钠干燥，浓缩EA，得到黄色油状物叔丁基(4-((5-硝基-2-((四氢-2H-吡喃-3-基)氧基)苄基)氧基)苯基)氨基甲酸酯(197-b,1.20g,收率97％)。MS(ESI)m/z:calcd 445.20(M+H)。
第三步：叔丁基(4-((5-氨基-2-((四氢-2H-吡喃-3-基)氧基)苄基)氧基)苯基)氨基甲酸酯(197-c)
叔丁基(4-((5-硝基-2-((四氢-2H-吡喃-3-基)氧基)苄基)氧基)苯基)氨基甲酸酯(197-b,1.2g,2.7mmol)溶于甲醇(20ml)中，加入Raney Ni(120mg，10％wt)，用氢气包置换氢气三次，室温搅拌2h。TLC确认反应完全后，用硅藻土过滤，旋干滤液得到黄色油状物叔丁基(4-((5-氨基-2-((四氢-2H-吡喃-3-基)氧基)苄基)氧基)苯基)氨基甲酸酯(197-c,1.10g,收率98％)。MS(ESI)m/z:calcd 415.20(M+H)。
第四步：甲基4-(2-((3-((4-((叔丁氧基羰基)氨基)苯氧基)甲基)-4-((四氢-2H-吡喃-3-基)氧基)苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸酯(197-d)
氮气保护，叔丁基(4-((5-氨基-2-((四氢-2H-吡喃-3-基)氧基)苄基)氧基)苯基)氨基甲酸酯(197-c,1.1g,2.6mmol)和4-(2-氯嘧啶-4-基)-3-硝基苯甲酸甲酯(914mg,3.12mmol)加入到1,4-二氧六环(20ml)中，加入碳酸钾(718mg,5.2mmol)、三(二亚苄基丙酮)二钯(238mg,0.26mmol)和2-二环己基磷-2,4,6-三异丙基联苯(242mg,0.52mmol)，加热至100℃搅拌16h。TLC确认反应完全后，浓缩1,4-二氧六环，加入去离子水和乙酸乙酯，分液，有机相用去离子水洗涤三次，无水硫酸钠干燥，浓缩乙酸乙酯，残余物经柱层析纯化得到黄色固体甲基4-(2-((3-((4-((叔丁氧基羰基)氨基)苯氧基)甲基)-4-((四氢-2H-吡喃-3-基)氧基)苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸酯(197-d,900mg,收率50％)。MS(ESI)m/z:calcd 672.30(M+H)。
第五步：4-(2-((3-((4-((叔丁氧基羰基)氨基)苯氧基)甲基)-4-((四氢-2H-吡喃-3-基)氧基)苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸(197-e)
甲基4-(2-((3-((4-((叔丁氧基羰基)氨基)苯氧基)甲基)-4-((四氢-2H-吡喃-3-基)氧基)苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸酯(197-d,900mg,1.3mmol)加入到THF和水(16ml/4ml)的混合溶液中，再加入氢氧化锂一水合物(273mg,6.5mmol)，室温搅拌2h。TLC确认反应完全后，加1M HCl调节体系PH至7.0，浓缩溶剂，加入EA和水分液萃取，去离子水洗涤，无水硫酸钠干燥，浓缩EA得到黄色固体4-(2-((3-((4-((叔丁氧基羰基)氨基)苯氧基) 甲基)-4-((四氢-2H-吡喃-3-基)氧基)苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸(197-e,769mg,收率90％)，MS(ESI)m/z:calcd 658.20(M+H)，直接进行下步反应。
第六步：4-(2-((3-((4-氨基苯氧基)甲基)-4-((四氢-2H-吡喃-3-基)氧基)苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸(197-f)
4-(2-((3-((4-((叔丁氧基羰基)氨基)苯氧基)甲基)-4-((四氢-2H-吡喃-3-基)氧基)苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸(197-e,769mg,1.17mmol)加入EA(8ml)中，滴入氯化氢/EA溶液(3mol/L,8ml)，室温搅拌1h。TLC确认反应结束后，过滤后得到黄色固体4-(2-((3-((4-氨基苯氧基)甲基)-4-((四氢-2H-吡喃-3-基)氧基)苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸(197-f，750mg,收率100％)。MS(ESI)m/z:calcd 478.25(M+H),found 558.20。
第七步：12-硝基-44-((四氢-2H-吡喃-3-基)氧基)-6-氧杂-3,8-二氮杂-2(4,2)-嘧啶杂-1,7(1,4),4(1,3)-三苯杂环九蕃-9-酮(197-g)
O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(1.03g,2.70mmol)和N,N-二异丙基乙胺(871mg,6.75mmol)加入到DCM(10ml)中，室温搅拌。缓慢滴加4-(2-((3-((4-氨基苯氧基)甲基)-4-((四氢-2H-吡喃-3-基)氧基)苯基)氨基)嘧啶-4-基)-3-硝基苯甲酸(197-f，750mg,1.35mmol)的DCM和DMF(7ml/7ml)的混合溶液，加完后继续室温搅拌1h。LCMS确认反应完全后，浓缩反应液，倒入冰水中，析出固体，过滤烘干得到黄色固体12-硝基-44-((四氢-2H-吡喃-3-基)氧基)-6-氧杂-3,8-二氮杂-2(4,2)-嘧啶杂-1,7(1,4),4(1,3)-三苯杂环九蕃-9-酮(197-g,530mg,收率73％)。MS(ESI)m/z:calcd 540.20(M+H)； 1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.58(s,1H),8.58(d,J＝4.8Hz,1H),7.76(d,J＝2.7Hz,1H),7.72(m,1H),7.62(d,J＝7.8Hz,1H),7.43(d,J＝1.5Hz,1H),7.13(d,J＝4.8Hz,1H),7.09(d,J＝2.4Hz,1H),7.03(d,J＝9.0Hz,1H),6.78(s,4H),5.13(s,2H),4.32(m,1H),3.81(m,2H),3.55(m,2H),2.17-1.43(m,4H)。
第八步：12-氨基-44-((四氢-2H-吡喃-3-基)氧基)-6-氧杂-3-8-二氮杂-2(4,2)-嘧啶杂-1,7(1,4)，4(1,3)-三苯环九蕃-9-酮(197)
12-硝基-44-((四氢-2H-吡喃-3-基)氧基)-6-氧杂-3,8-二氮杂-2(4,2)-嘧啶杂-1,7(1,4),4(1,3)-三苯杂环九蕃-9-酮(197-g,50mg,0.09mmol)溶于甲醇(5ml)中，加入Raney Ni(120mg，10％wt)，用氢气包置换氢气三次，室温搅拌2h。TLC确认反应完全后，用硅藻土过滤，旋干滤液得到黄色色固体12-氨基-44-((四氢-2H-吡喃-3-基)氧基)-6-氧杂-3-8-二氮杂-2(4,2)-嘧啶杂-1,7(1,4)，4(1,3)-三苯环九蕃-9-酮(197,26g,收率57％)。MS(ESI)m/z:calcd 510.20(M+H)； 1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),9.43(s,1H),8.46(d,J＝5.1Hz,1H),7.93(d,J＝2.7Hz,1H),7.08(m,1H),7.05–7.01(m,2H),6.97(d,J＝5.1Hz,1H),6.76–6.69(m,2H),6.65–6.57(m,2H),6.41–6.30(m,2H),5.13(d,J＝2.8Hz,2H),4.34(m,1H),3.82(m,2H),3.60–3.54(m,2H),2.08–1.49(m,4H)。
依据与上述实施例197相同的方法，使用市售化合物或参考所示的中间体化合物的制备方法而制备以下表3的实施例化合物。
表3
Figure PCTCN2021095332-appb-000084
Figure PCTCN2021095332-appb-000085
Figure PCTCN2021095332-appb-000086
实施例215 44-(环戊氧基)-12-羟基-6-氧杂-3,8-二氮杂2(4,2)-嘧啶-1,7(1,4),4(1,3)-三苯环九蕃-9-酮(215)的制备
Figure PCTCN2021095332-appb-000087
第一步：4-溴-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯甲酸甲酯(215-a)
氮气保护，4-溴-3-羟基苯甲酸甲酯(1.00g,4.35mmol)和2-(三甲基硅烷基)乙氧甲基氯(1.45g,8.70mmol)，加入到无水DCM(20ml)中,冰浴冷至0℃后搅拌10min，缓慢滴加N,N-二异丙基乙胺(2.25g,17.39mmol)，滴加完毕后慢慢升至室温继续搅拌5h。TLC确认反应完毕后，抽滤，浓缩滤液，残余物经柱层析纯化得到黄色油状物4-溴-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯甲酸甲酯(215-a,1.52g,收率97％)。
第二步：4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯甲酸甲酯(215-b)
氮气保护，4-溴-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯甲酸甲酯(215-a,1.52g,4.2mmol)，联硼酸频那醇酯(1.60g,6.3mmol)，1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.30g,0.42mmol)以及乙酸钾(1.24g,12.6mmol)加入到1,4-二氧六环中(20ml)，加热至80℃搅拌16h。TLC确认反应完全后，抽滤，浓缩滤液，残余物经柱层析纯化得到无色油状物4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯甲酸甲酯(215-b,1.46g,收率85％)。 1H NMR(400MHz,DMSO-d6)：δ7.65(d,J＝7.5Hz,1H),7.60–7.56(m,2H),5.29(s,2H),3.86(s,3H),3.74(dd,J＝10.7,5.6Hz,2H),1.30(s,12H),0.94–0.84(m,2H),-0.04(s,9H).
第三步：4-(2-氯嘧啶-4-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯甲酸甲酯(215-c)
氮气保护，2,4-二氯嘧啶(0.46g,4.30mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯甲酸甲酯(215-b,1.46g,3.58mmol)加入到混合 溶剂1,4-二氧六环、水(20ml,4ml)中，再加入碳酸钠(0.76g,7.16mmol)，然后加入双三苯基磷二氯化钯(0.50g,0.72mmol)，加热至80℃搅拌16h。TLC确认反应完全后，浓缩1,4-二氧六环，EA萃取，去离子水洗涤有机相三次，无水硫酸钠干燥，浓缩EA，残余物经柱层析纯化得到无色油状物4-(2-氯嘧啶-4-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯甲酸甲酯(215-c,1.21g,收率86％)。 1H NMR(400MHz,CDCl 3)：δ8.66(d,J＝5.2Hz,1H),8.12(d,J＝8.1Hz,1H),7.97(d,J＝5.2Hz,1H),7.93(s,1H),7.82(d,J＝8.1Hz,1H),5.39(s,2H),3.96(s,3H),3.76(t,2H),1.01–0.92(m,2H),0.01(s,9H).
第四步：叔丁基(4-((2-(环戊氧基)-5-硝基苄基)氧基)苯基)氨基甲酸酯(215-d)
叔丁基(4-((2-氟-5-硝基苄基)氧基)苯基)氨基甲酸酯(197-a,500mg,1.38mmol)和环戊醇(238mg,2.76mmol)加入到DMF(10ml)中，冰浴搅拌5分钟后，再加入叔丁醇钠(397mg,4.14mmol),缓慢恢复至室温搅拌2h后，再40℃加热1h，LCMS显示反应完全，加入饱和氯化铵溶液淬灭反应，加水和EA萃取，去离子水洗涤有机相三次，无水硫酸钠干燥，浓缩EA，得到黄色油状物叔丁基(4-((2-(环戊氧基)-5-硝基苄基)氧基)苯基)氨基甲酸酯(215-d,586mg，收率99％)。MS(ESI)m/z:calcd 429.19(M+H),found 429.20； 1H NMR(400MHz,CDCl 3)δ8.40(d,J＝2.8Hz,1H),8.20(dd,J＝8.8,2.8Hz,1H),7.31-7.26(m,2H),6.97-6.94(m,3H),6.49(s,1H),5.05(s,2H),4.97-4.93(m,1H),2.03-1.88(m,4H),1.86-1.80(m,2H),1.74-1.66(m,2H),1.54(s,9H).
第五步：叔丁基(4-((5-氨基-2-(环戊氧基)苄基)氧基)苯基)氨基甲酸酯(215-e)
叔丁基(4-((2-(环戊氧基)-5-硝基苄基)氧基)苯基)氨基甲酸酯(215-d,460mg,1.074mmol)加入到混合溶剂甲醇、水(20ml,5ml)中，加入Fe粉(300mg,5.37mmol)和氯化铵(285mg,5.37mmol)，80℃加热搅拌3h。LCMS显示反应完全。用硅藻土滤除固体后，将甲醇旋干，用EA萃取，无水硫酸钠干燥，浓缩EA，残余物经柱层析纯化得到黄色油状物叔丁基(4-((5-氨基-2-(环戊氧基)苄基)氧基)苯基)氨基甲酸酯(215-e,400mg，收率93％)。MS(ESI)m/z:calcd 399.22(M+H),found 399.30。
第六步：甲基4-(2-((3-((4-((叔丁氧基羰基)氨基)苯氧基)甲基)-4-(环戊氧基)苯基)氨基)嘧啶-4-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯甲酸酯(215-f)
氮气保护，4-(2-氯嘧啶-4-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯甲酸甲酯(215-c,238mg，0.602mmol)，叔丁基(4-((5-氨基-2-(环戊氧基)苄基)氧基)苯基)氨基甲酸酯(215-e,200mg，0.502mmol)加入到1,4-二氧六环(10mL)中，再加入三(二亚苄基丙酮)二钯(46mg,0.0502mmol)和2-二环己基磷-2,4,6-三异丙基联苯(48mg,0.1004mmol)，碳酸钾(139mg,1.004mmol)，100℃反应4h。TLC确认反应完全后，浓缩1,4-二氧六环，加入去离子水和二氯甲烷，分液，有机相用去离子水洗涤三次，无水硫酸钠干燥，浓缩二氯甲烷，残余物经柱层析纯化得到黄色固体甲基4-(2-((3-((4-((叔丁氧基羰基)氨基)苯氧基)甲基)-4-(环戊氧基)苯基)氨基)嘧啶-4-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯甲酸酯(215-f,141mg，收率37％)。MS(ESI)m/z:calcd 757.36(M+H),found 757.30。
第七步：4-(2-((3-((4-氨基苯氧基)甲基)-4-(环戊氧基)苯基)氨基)嘧啶-4-基)-3-羟基苯甲酸甲酯(215-g)
冰浴下，甲基4-(2-((3-((4-((叔丁氧基羰基)氨基)苯氧基)甲基)-4-(环戊氧基)苯基)氨基)嘧啶-4-基)-3-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯甲酸酯(215-f,120mg，0.158mmol)加到二氯甲烷(4mL)，再加入三氟乙酸(1mL)，室温搅拌反应2h，LCMS显示反应完全，将二氯甲烷和三氟乙酸浓缩后得到4-(2-((3-((4-氨基苯氧基)甲基)-4-(环戊氧基)苯基)氨基)嘧啶-4-基)-3-羟基苯甲酸甲酯(215-g，82mg，收率98％)直接用于下一步反应。MS(ESI)m/z:calcd 527.22(M+H),found 527.3。
第八步：4-(2-((3-((4-氨基苯氧基)甲基)-4-(环戊氧基)苯基)氨基)嘧啶-4-基)-3-羟基苯甲酸(215-h)
4-(2-((3-((4-氨基苯氧基)甲基)-4-(环戊氧基)苯基)氨基)嘧啶-4-基)-3-羟基苯甲酸甲酯(215-g,82mg,0156mmol)加入到四氢呋喃、水(5mL,1mL)中，再加入氢氧化锂一水合物(33mg，0.779mmol)，室温搅拌反应过夜，LCMS显示反应完全。浓缩四氢呋喃后，中压制备纯化冻干得到4-(2-((3-((4-氨基苯氧基)甲基)-4-(环戊氧基)苯基)氨基)嘧啶-4-基)-3-羟基苯甲酸(215-h,20mg，收率25％)。MS(ESI)m/z:calcd 513.21(M+H),found 513.20。
第九步：44-(环戊氧基)-12-羟基-6-氧杂-3,8-二氮杂2(4,2)-嘧啶-1,7(1,4),4(1,3)-三苯环九蕃-9-酮(215)
O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(30mg,0.078mmol)和N,N-二异丙基乙胺(50mg,0.39mmol)加入到DMF(2ml)中，室温搅拌。缓慢滴加4-(2-((3-((4-氨基苯氧基)甲基)-4-(环戊氧基)苯基)氨基)嘧啶-4-基)-3-羟基苯甲酸(215-h,20mg,0.039mmol)的DMF(2ml)溶液，持续0.5h，加毕继续室温搅拌3h。LCMS反应完全，中压制备纯化冻干得到黄色固体44-(环戊氧基)-12-羟基-6-氧杂-3,8-二氮杂2(4,2)-嘧啶-1,7(1,4),4(1,3)-三苯环九蕃-9-酮(215,0.75mg，收率3.8％)。MS(ESI)m/z:calcd 495.20(M+H),found 495.20。
依据与上述实施例215相同的方法，使用市售化合物或参考所示的中间体化合物的制备方法而制备以下表4的实施例化合物。
表4
Figure PCTCN2021095332-appb-000088
Figure PCTCN2021095332-appb-000089
实施例218：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10ìL。激酶蛋白、化合物、ATP和底物的混合液在50mM Hepes(pH7.0)，NaN3 0.02％，BSA 0.01％，0.1mM 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2ìM，JAK1蛋白浓度是0.2ng/ìL。
在JAK2反应体系中，ATP的浓度为2ìM，JAK2蛋白浓度是0.01ng/ìL。
在JAK3反应体系中，ATP的浓度为2ìM，JAK3蛋白浓度是0.04ng/ìL。
在TYK2反应体系中，ATP的浓度为2ìM，TYK2蛋白浓度是0.2ng/ìL。
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4所示
表4
Figure PCTCN2021095332-appb-000090
Figure PCTCN2021095332-appb-000091
Figure PCTCN2021095332-appb-000092
Figure PCTCN2021095332-appb-000093
Figure PCTCN2021095332-appb-000094
Figure PCTCN2021095332-appb-000095
Figure PCTCN2021095332-appb-000096
讨论:
上述实验结果提示：
(1)本发明的式I化合物表现出JAK3抑制活性，其对JAK1、JAK2和TYK2均有较好的选择性。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JAK3。
(2)本发明的式I化合物表现出非常优异的JAK选择性，即JAK1/JAK3的IC50之比和/或JAK2/JAK3的IC50之比远远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 (15)

  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 PCTCN2021095332-appb-100001
    式中，
    X 1、X 2、X 3和X 4各自独立地选自下组：N、C或C-R d；且X 1、X 2、X 3和X 4中有0、1、2、3个为N；
    或者，当X 1为C-R d时，R d与X 2稠合形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
    或者，当X 2为C-R d时，R d与X 1稠合形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
    或者，当X 3为C-R d时，R d与X 4稠合形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
    或者，当X 4为C-R d时，R d与X 3稠合形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
    A选自下组：-C(＝O)N-R b、-C(＝O)O-、-SO 2N(R b)-、-C(＝O)N-R b-SO 2-、O、S；其中，R b选自下组：H、取代或未取代C1-C6烷基；
    B选自取代或未取代的下组基团：键、C(R c) 2、C3-C10亚环烷基、3-10元亚杂环基、5-12元亚杂芳基、C6-C12亚芳基、(CH 2)m-R'-；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'独立地选自取代或未取代的下组基团：5-12元亚杂芳基、C6-C12亚芳基；
    X选自取代或未取代的下组基团：键、C(R c) 2、(CH 2)m-O-、C(＝O)O-、O、N-R b、S、SO、SO 2、C3-C10亚环烷基、3-10元亚杂环基、5-12元亚杂芳基、C6-C12亚芳基；
    R 5、R 6、R 7、R 8、R 9、R 10和R d各自独立地选自下组：H、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、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芳基或-OR 11；其中，R 11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；
    或者R 5和R 6与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
    或者R 8和R 9与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
    或者R 9和R 10与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
    (CH 2)n和(CH 2)m中的H原子可以任选地被一个或多个R a取代；
    m为1、2、3、4或5；
    n为0、1、2、3、4、5、6、7或8；
    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；
    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、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元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基。
  2. 如权利要求1所述的式I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I'所述的结构：
    Figure PCTCN2021095332-appb-100002
    式中，
    Q选自取代或未取代的下组基团：(CH 2)m-R'-、C3-C10亚环烷基、3-10元亚杂环基、5-12元亚杂芳基、C6-C12亚芳基；其中，R'独立地选自取代或未取代的下组基团：5-12元亚杂芳基、C6-C12亚芳基；
    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；
    X、m、n、A、X 1、X 2、X 3、X 4、R 5、R 6、R 7、R 8、R 9、R 10定义如权利要求1所述。
  3. 如权利要求1所述的式I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 PCTCN2021095332-appb-100003
    式中，
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9和R 10各自独立地选自下组：H、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、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芳基或-OR 11；其中，R 11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；
    或者R 1和R 2与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
    或者R 3和R 4与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
    或者R 5和R 6与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
    或者R 8和R 9与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
    或者R 9和R 10与它们连接的C原子一起形成取代或未取代的5-6元环烷基、杂环基、芳基或杂芳基；
    (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；
    A、B、m、n和X的定义如权利要求1所述；
    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、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；
    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、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元杂环烷基、C3-C10环烷基、5-12元杂芳基、C6-C12芳基。
  4. 如权利要求1所述的式I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 PCTCN2021095332-appb-100004
    式中，
    B选自取代或未取代的下组基团：键、(CH 2)m-R'-、C3-C10亚环烷基、3-10元亚杂环基、5-12元亚杂芳基、C6-C12亚芳基；其中，R'独立地选自取代或未取代的下组基团：5-12元亚杂芳基、C6-C12亚芳基；
    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；
    m、n、R 5、R 6、R 8、R 9的定义如权利要求1所述，R 1、R 2的定义如权利要求3所述。
  5. 如权利要求1所述的式I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所示的结构：
    Figure PCTCN2021095332-appb-100005
    式中，
    Q选自取代或未取代的下组基团：(CH 2)m-R'-、5-12元亚杂芳基、C6-C12亚芳基；其中，R'独立地选自取代或未取代的下组基团：5-12元亚杂芳基、C6-C12亚芳基；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；
    X、m、R 1、R 2、R 5、R 6、R 8、R 9定义如权利要求1所述。
  6. 如权利要求1所述的式I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V所示的结构
    Figure PCTCN2021095332-appb-100006
    其中，R 5、R 6、R 8、R 9、X和n的定义如权利要求1所述；R 1、R 2的定义如权利要求3所述。
  7. 如权利要求1所述的式I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VI所示的结构
    Figure PCTCN2021095332-appb-100007
    其中，R 1、R 2各自独立地选自：H、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、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芳基或-OR 11；其中，R 11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；所述烷基、烷氧基、烯基、炔基、杂环基、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、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；
    R 5、R 6、R 8、R 9和n的定义如权利要求1所述。
  8. 如权利要求1所述的式I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VII所示的结构
    Figure PCTCN2021095332-appb-100008
    其中，
    Q选自取代或未取代的下组基团：(CH 2)m-R'-、C3-C10亚环烷基、3-10元亚杂环基、5-12元亚杂芳基、C6-C12亚芳基；其中，R'独立地选自取代或未取代的下组基团：5-12元亚杂芳基、C6-C12亚芳基；
    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；所述烷基、烷氧基、烯基、炔基、杂环基、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、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；
    m、R 5、R 6、R 8、R 9的定义如权利要求1所述。
  9. 如权利要求1所述的式I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VIII所示的结构
    Figure PCTCN2021095332-appb-100009
    其中，R 1选自：H、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、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芳基或-OR 11；其中，R 11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；所述烷基、烷氧基、烯基、炔基、杂环基、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、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；
    R 5、R 6、R 8、R 9、X和n的定义如权利要求1所述。
  10. 如权利要求1-9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，R 8选自下组：H、卤素、氨基、胺基、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芳基或-OR 11；
    其中，R 11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、羟基、氰基、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；
    上述烷基、烯基、炔基、杂环基、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、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。
  11. 如权利要求1-10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，R 8选自下组：C1-C6烷基、C3-C10环烷基、3-10元杂环基或-OR 11；
    R 11选自取代或未取代的下组基团：C1-C6烷基、3-10元杂环基、C3-C10环烷基；
    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、羟基、氰基、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；
    上述烷基、烯基、炔基、杂环基、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、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。
  12. 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 PCTCN2021095332-appb-100010
    Figure PCTCN2021095332-appb-100011
    Figure PCTCN2021095332-appb-100012
    Figure PCTCN2021095332-appb-100013
    Figure PCTCN2021095332-appb-100014
    Figure PCTCN2021095332-appb-100015
    Figure PCTCN2021095332-appb-100016
    Figure PCTCN2021095332-appb-100017
    Figure PCTCN2021095332-appb-100018
    Figure PCTCN2021095332-appb-100019
  13. 一种药物组合物，其特征在于，包含权利要求1-12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。
  14. 一种权利要求1-12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、前药或溶剂化物或权利要求13所述的药物组合物的用途，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。
  15. 一种如权利要求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、前药或溶剂化物的制备方法，包括如下步骤：
    在惰性溶剂中，催化剂存在下，化合物A 8发生成环反应，从而得到式I化合物；
    Figure PCTCN2021095332-appb-100020
    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、X 1、X 2、X 3、X 4、R 5、R 6、R 7、R 8、R 9、R 10、X和n的定义如权利要求1所述。
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