WO2022199676A1 - Composé tétracyclique fusionné, son procédé de préparation et son utilisation en médecine - Google Patents

Composé tétracyclique fusionné, son procédé de préparation et son utilisation en médecine Download PDF

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WO2022199676A1
WO2022199676A1 PCT/CN2022/082894 CN2022082894W WO2022199676A1 WO 2022199676 A1 WO2022199676 A1 WO 2022199676A1 CN 2022082894 W CN2022082894 W CN 2022082894W WO 2022199676 A1 WO2022199676 A1 WO 2022199676A1
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Prior art keywords
alkyl
cancer
alkoxy
haloalkyl
heteroaryl
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PCT/CN2022/082894
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English (en)
Chinese (zh)
Inventor
李心
沈峰
董怀德
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202280021238.5A priority Critical patent/CN116981666A/zh
Publication of WO2022199676A1 publication Critical patent/WO2022199676A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a condensed tetracyclic compound, a preparation method thereof and its application in medicine.
  • the present disclosure relates to a fused tetracyclic compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and its use in the preparation of a medicament for inhibiting HPK1.
  • Anticancer therapy has entered the era of immunotherapy from chemoradiotherapy, targeted therapy, and immunotherapy.
  • the targets of tumor immunotherapy mainly include immune checkpoints, immune agonists, Treg, macrophages, tumor microenvironment metabolites such as IDO, A2AR pathway, and so on.
  • hematopoietic progenitor kinase 1 Hematopoietic Progenitor Kinase1, referred to as HPK1; also known as mitogen-activated protein kinase kinase kinase 1 (Mitogen-activated protein kinase kinase kinase 1), referred to as MAP4K1
  • HPK1 hematopoietic Progenitor Kinase 1
  • mitogen-activated protein kinase kinase kinase 1 Mitogen-activated protein kinase kinase kinase 1
  • MAP4K1 mitogen
  • TCR activation After TCR activation, it functions as a negative feedback regulation, which is related to T cell exhaustion.
  • the well-studied signaling pathway is: after TCR binds to MHC-peptide, LAT is phosphorylated, recruiting GADS-SLP76 complex, resulting in phosphorylation and pathway activation of downstream PLC.
  • ZAP70 phosphorylates the Y381 site of HPK1, which binds to the SH2 region of SLP76, thereby phosphorylating the latter's S376 site. Phosphorylation of SLP76S376 recruits 14-3-3, which leads to ubiquitination and disassembly of the entire TCR signalosome.
  • HPK1 is considered to be a good immunotherapy target for the following three reasons: (1) HPK1 expression profile is limited to immune cells, and it is safe; (2) HPK1 has multiple functions in different stages of the "cancer-immune cycle". Inhibition of HPK1 can regulate the immunosuppressive function of NK cells, DC cells, and T cells, and can also regulate the activation of B cells, among which T cell activation is the most studied; (3) HPK1 kinase activity is involved in inhibiting anti-cancer immune responses. important in.
  • HPK1 expression is associated with T cell exhaustion signatures, including CD3E, PD1, CTLA4, TIM-3, LAG-3 and TIGIT, and high HPK1 expression is associated with shorter survival.
  • Analysis of the TCGA PanCancer database revealed a positive correlation between HPK1 (but not other MAP4K family members) expression and PD1.
  • HPK1 was upregulated in exhausted T cells, and HPK1, TIM3 and LAG3 were more expressed in PD1-high T cells than in PD1-low T cells.
  • HPK1 was down-regulated in CD4+ T cells from patients with systemic lupus erythematosus (SLE), and SLEDAI scores were negatively correlated with HPK1 mRNA levels.
  • SLE systemic lupus erythematosus
  • SLEDAI scores were negatively correlated with HPK1 mRNA levels.
  • the expression of HPK1 was also down-regulated in peripheral blood cells of patients with psoriatic arthritis (PsA).
  • HPK1 knockout mice did not have any abnormality in the resting state. Once the TCR is activated, whether it is HPK1 knockout, HPK1 kinase dead (kinase dead) knock-in, or SLP76S376A knock-in mice, the results are similar, and the immune response will be activated. HPK1-deficient mice are more susceptible to experimental autoimmune encephalomyelitis (EAE). HPK1 kinase activity modulates TCR signaling and cytokine secretion in vitro; inhibition of HPK1 alleviates PGE2- and adenosine-mediated immunosuppression.
  • EAE experimental autoimmune encephalomyelitis
  • HPK1 knockout and kinase inactivation knock-in show that HPK1 mainly acts through kinase activity, but some literatures report that its scaffold also has certain functions, so the idea of drug development to inhibit HPK1 is kinase inhibition. Agent-based, but also some PROTAC molecules.
  • the related patents disclosed so far include WO2016205942A1, WO2019238067A1, WO2021013083A1, WO2020103896A1 and WO2021000925A1 and so on.
  • Ring A is aryl or heteroaryl
  • Ring B is phenyl or 5- or 6-membered heteroaryl
  • G 1 is CR 1 or nitrogen atom
  • G 2 is CR 2 or nitrogen atom
  • G 6 is selected from C(O), CR 6a R 6b , NR 6c and oxygen atoms;
  • G 7 is selected from C(O), CR 7a R 7b , NR 7c and oxygen atoms;
  • R 6a , R 6b , R 7a and R 7b are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino , nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, Aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, substituted with one or more substituents of cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 0 , R 6c and R 7c are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group base;
  • Each R a is the same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH 2 ) r NR m R n , -OR p , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cyclic Alkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro , substituted with one or more substituents in hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl,
  • R a and ring B form a condensed ring optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino , nitro, hydroxyl, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more groups, wherein said alkyl, alkenyl, alkynyl, Alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano , amino, nitro, hydroxyl, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted with one or more substituents;
  • R', R 1 and R 2 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR d Re , -OR g , -(CO)R f , -(CO)NR d Re , -(CO)OR g , -SO 2 R f , -SO 2 NR d Re , -NR h (CO )R f , -NR h (CO)NR d Re , -NR h (CO)OR g , -NR h SO 2 R f , -NR h SO 2 NR d R e , nitro, hydroxyl, hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkyny
  • R m , R n , R p , R d , Re , R f , R g , Rh , R d2 , Re2 , R f2 , R g2 and R h2 are the same or different, and are each independently selected from hydrogen atoms , alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxy substituted with one or more substituents of alkyl, cycloalkyl, heterocyclyl, aryl and
  • heterocyclyl group optionally selected from halogen, alkyl, alkenyl, alkyne one or more of radical, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, oxo, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl substituted groups wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl , alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and one or more substitution
  • p 0, 1, 2, 3, or 4;
  • q 0, 1, 2, 3 or 4;
  • r 0, 1, 2, 3 or 4.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof:
  • G 3 is CR 3 or nitrogen atom
  • G 5 is CR 5 or nitrogen atom
  • R 3 and R 5 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycle substituted with one or more substituents in aryl, aryl and heteroaryl;
  • R 4a and R 4b are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH 2 ) r NR m R n , -OR p , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy , cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, Substituted with one or more substituents of nitro, hydroxy, oxo, hydroxyalkyl, cycloalkyl
  • Each R is the same or different and is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl substituted with one or more substituents in the radical and heteroaryl; or
  • R q is selected from hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • Rings A , G1 , G2, G6 , G7, R0, Rm, Rn, Rp , R ' , r and q are as defined in general formula (I).
  • the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (IV) or (V) or Its pharmaceutically acceptable salts:
  • Rings A , G1, G6 , G7, R0, R2, R3 , R4a , R4b , R5, Rq , R', R, q and n are of formula ( II ) or (III) ) as defined in .
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (VI) or a pharmaceutically acceptable salt thereof:
  • t 0, 1, 2 or 3;
  • Ring A , Ring B, Rd , Re , G1 , G2, G6 , G7, R0, Ra , R' and p are as defined in general formula (I ) .
  • the compound represented by the general formula (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof wherein- G7- G6- is selected from -O- CHR6a- , -CHR7a -O-, -NR7c - CHR6a- , -CHR7a - NR6c- , -C(O) -NR6c- and -NR 7c -C(O)-, R 6a , R 7a , R 6c and R 7c are as defined in general formula (I); preferably, -G 7 -G 6 - is selected from -O-CH 2 -, -CH 2 - O- , -NH-CH2-, -CH2 -NH-, -C(O)-NH- and -NH-C(O)-; more preferably, -G7 - G6- is- O-CH 2 -.
  • R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, hydroxyl and C 1-6 hydroxyalkyl;
  • R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably hydrogen atom.
  • the compound represented by the general formula (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof wherein G 1 is CR 1 , and R 1 is as defined in general formula (I); preferably, G 1 is CR 1 , and R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, hydroxyl and C 1-6 hydroxyalkyl; further preferably, G 1 is CR 1 , and R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably, G 1 is CH.
  • R 2 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, hydroxyl and C 1-6 hydroxyalkyl;
  • R 2 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably hydrogen atom.
  • R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, hydroxyl and C 1-6 hydroxyalkyl;
  • R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably hydrogen atom.
  • R 5 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, hydroxyl and C 1-6 hydroxyalkyl;
  • R 5 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; more preferably hydrogen atom or methyl.
  • the compound represented by the general formula (II) or (III) or a pharmaceutically acceptable salt thereof wherein R 5 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 alkoxy; preferably, R 5 is selected from hydrogen atom, F, methyl and methoxy.
  • the compound represented by the general formula (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof wherein each R' is the same or different, and is each independently selected from C 1-6 alkyl, C 1-6 haloalkyl or -(CO)NR d Re , where R d and Re are as defined in general formula (I);
  • R d and R e are the same or different, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group, and a C 1-6 hydroxyalkyl group, or R d and R e are combined with The nitrogen atoms to which they are attached together form a 3- to 8-membered heterocyclic group optionally selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1- Substituted with one or more groups in 6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, hydroxyl and C 1-6 hydroxyalkyl;
  • R d and R e are the same or different, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl group and a C 1-6 hydroxyalkyl group, or R d and R e together with the nitrogen atoms to which they are attached form an azetidinyl group optionally selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, hydroxy and One or more groups in the C 1-6 hydroxyalkyl group are substituted.
  • the compound represented by the general formula (I), (II), (III), (IV), (V) or (VI) or a pharmaceutically acceptable salt thereof wherein each R' is the same or different, and is each independently C 1-6 alkyl or -(CO)NR d Re , where R d and Re are as defined in general formula (I);
  • each R' is the same or different, and each is independently a C 1-6 alkyl group or -(CO)NR d Re , and R d and Re are the same or different, and each is independently selected from a hydrogen atom, C 1-6 alkyl and C 1-6 hydroxyalkyl, or R d and R e together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocyclic group optionally replaced by a or multiple hydroxyl substitutions;
  • each R' is the same or different, and each independently is C 1-6 alkyl or -(CO)NR d Re , R d and Re are the same or different, and each is independently selected from C 1- 6 alkyl and C 1-6 hydroxyalkyl, or R d and R e together with the nitrogen atom to which they are attached form an azetidinyl group optionally substituted by one or more hydroxyl groups replace.
  • the compound represented by the general formula (II) or (IV) or a pharmaceutically acceptable salt thereof wherein R 4a and R 4b are the same or different, and are each independently selected from hydrogen atoms , halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, -(CH 2 ) r NR m R n , hydroxyl and C 1-6 hydroxyalkyl, wherein said C 1-6 alkyl and C 1-6 alkoxy are each independently optionally selected from halogen, C 1-6 alkoxy, C 1-6 haloalkane substituted with one or more substituents of oxy, cyano, amino, hydroxy and C 1-6 hydroxyalkyl, R m , R n and r are as defined in general formula (II);
  • R 4a and R 4b are the same or different, and each is independently selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 haloalkyl and C 1-6 hydroxyalkyl, wherein said C 1-6 alkyl is optionally selected from C 1-6 alkoxy, C 1-6 haloalkoxy, cyano and amino substituted by one or more substituents; or R and R together with the nitrogen atom to which they are attached form a 3- to 8-membered heterocyclic group optionally selected from halogen, C One of 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, hydroxyl, oxo and C 1-6 hydroxyalkyl or Multiple group substitution; r is 0, 1 or 2;
  • one of R 4a and R 4b is -(CH 2 ) r NR m R n , the other is a hydrogen atom, R m and R n are the same or different, and are independently selected from hydrogen atoms, C 1- 6 alkyl and C 1-6 haloalkyl ; or R and R together with the nitrogen atom to which they are attached form a piperazine ring optionally selected from halogen, C 1-6 alkyl and C One or more of the 1-6 haloalkyl groups are substituted; r is 0 or 1.
  • the compound represented by general formula (II) or (IV) or a pharmaceutically acceptable salt thereof wherein one of R 4a and R 4b is -(CH 2 ) r NR m R n , the other is a hydrogen atom or a C 1-6 alkyl group, R m and R n are the same or different, and are each independently a C 1-6 alkyl group; or R m and R n together with the nitrogen atom to which they are attached A piperazine ring is formed, which is optionally substituted with one or more C1-6 alkyl groups; r is 0 or 1.
  • the compound represented by the general formula (II) or (IV) or a pharmaceutically acceptable salt thereof wherein R 4a and R 4b are the same or different, and are each independently selected from hydrogen atoms , halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, -(CH 2 ) r NR m R n , hydroxyl and C 1-6 hydroxyalkyl, wherein said C 1-6 alkyl and C 1-6 alkoxy are each independently optionally selected from halogen, C 1-6 alkoxy, C 1-6 haloalkane substituted by one or more substituents of oxy, cyano, amino, hydroxyl and C 1-6 hydroxyalkyl, and at least one of R 4a and R 4b is -(CH 2 ) r NR m R n , R m and R n are the same or different, and
  • the compound represented by the general formula (II) or (IV) or a pharmaceutically acceptable salt thereof wherein R 4a is piperazinyl, and the piperazinyl is optionally C 1 -6 alkyl substitution; and/or R 4b is a hydrogen atom.
  • the compound represented by the general formula (II) or (IV) or a pharmaceutically acceptable salt thereof wherein R 4a is 4-methylpiperazin-1-yl or 4-ethyl and/or R 4b is a hydrogen atom or a methyl group.
  • the compound represented by the general formula (III) or (V) or a pharmaceutically acceptable salt thereof wherein each R is the same or different, and is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, hydroxyl and C 1-6 hydroxyalkyl;
  • each R is the same or different, and each is independently selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl.
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein -G 7 -G 6 - is selected from -O-CH 2 -, -CH 2 -O -, -NH-CH 2 -, -CH 2 -NH-, -C(O)-NH- and -NH-C(O)-; Ring A is phenyl or pyrazolyl; G 1 is CR 1 , R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; G 2 is CR 2 , R 2 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkane group; G 3 is CR 3 , R 3 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; G 5 is CR 5 , R 5 is selected from hydrogen atom, halogen, C 1-6 Al
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein -G 7 -G 6 - is -O-CH 2 -; ring A is phenyl or Pyrazolyl; G 1 is CR 1 , R 1 is hydrogen atom; G 2 is CR 2 , R 2 is hydrogen atom; G 3 is CR 3 , R 3 is hydrogen atom; G 5 is CR 5 , and R 5 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 alkoxy; R 0 is hydrogen atom; q is 1; each R' is C 1-6 alkyl or -(CO)NR d Re , R d and R e are the same or different, and are each independently selected from a hydrogen atom, a C 1-6 alkyl group, and a C 1-6 hydroxyalkyl group, or R d and R e together with the nitrogen atom to which they are attached form 3 to 8-member
  • Typical compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a compound of formula (IA) or a salt thereof,
  • R w is an amino protecting group; preferably Ts;
  • Ring A , Ring B, G1 , G2, G6 , G7, R', Ra , p and q are as defined in general formula (I).
  • Another aspect of the present disclosure relates to a compound of general formula (IIA) or (IIIA) or a salt thereof,
  • R w is an amino protecting group; preferably Ts;
  • Rings A , G1 , G2, G3 , G5, G6 , G7 , R', R4a , R4b , Rq , R, n and q are as in general formula (II) or (III) definition.
  • Another aspect of the present disclosure relates to a compound of general formula (IVA) or (VA) or a salt thereof,
  • R w is an amino protecting group; preferably Ts;
  • Rings A , G1 , R2, R3 , R5 , G6 , G7, R', R4a , R4b , Rq , R, n and q are as in general formula (IV) or (V) definition.
  • Another aspect of the present disclosure relates to a compound of formula (VIA) or a salt thereof,
  • R w is an amino protecting group; preferably Ts;
  • Ring A , Ring B, Rd , Re , G1 , G2, G6 , G7, Ra , R', t and p are as defined in general formula (VI).
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IA) or its salt is subjected to deprotection reaction to obtain the compound of general formula (I) or its pharmaceutically acceptable salt;
  • R w is an amino protecting group; preferably Ts;
  • R 0 is a hydrogen atom
  • Ring A , Ring B, G1 , G2, G6 , G7, R', Ra , p and q are as defined in general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIA) or a salt thereof is subjected to a deprotection reaction to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof; or
  • R w is an amino protecting group; preferably Ts;
  • R 0 is a hydrogen atom
  • Rings A , G1 , G2, G3 , G5, G6 , G7 , R', R4a , R4b , Rq , R, n and q are as in general formula (II) or (III) definition.
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or (V) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IVA) or a salt thereof is subjected to a deprotection reaction to obtain a compound of general formula (IV) or a pharmaceutically acceptable salt thereof; or
  • the compound of general formula (VA) or its salt is subjected to deprotection reaction to obtain the compound of general formula (V) or its pharmaceutically acceptable salt;
  • R w is an amino protecting group; preferably Ts;
  • R 0 is a hydrogen atom
  • Rings A , G1 , R2, R3 , R5 , G6 , G7, R', R4a , R4b , Rq , R, n and q are as in general formula (IV) or (V) definition.
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (VIA) or its salt is subjected to deprotection reaction to obtain the compound of general formula (VI) or its pharmaceutically acceptable salt;
  • R w is an amino protecting group; preferably Ts;
  • R 0 is a hydrogen atom
  • Ring A , Ring B, Rd , Re , G1 , G2, G6 , G7, Ra , R', t and p are as defined in general formula (VI).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising:
  • Q is halogen or hydroxyl, preferably hydroxyl
  • Ring A , Ring B, Rd , Re , G1 , G2, G6 , G7, Ra , R0 , R', t and p are as defined in general formula (VI).
  • compositions comprising any of the formulas (I), (II), (III), (IV), (V), (VI) or Table A of the present disclosure
  • the present disclosure further relates to a compound of general formula (I), (II), (III), (IV), (V), (VI) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a medicament comprising the same Use of the composition in the manufacture of a medicament for inhibiting HPK1.
  • the present disclosure further relates to a compound of general formula (I), (II), (III), (IV), (V), (VI) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a medicament comprising the same Use of the composition in the preparation of a medicament for treating and/or preventing a disease or condition by inhibiting HPK1;
  • the disease or condition is preferably selected from cancer, autoimmune disease, inflammatory disease, infectious disease, cardiac Use in the medicament of a disease or condition of vascular disease, neurodegenerative disease, diabetes and reproductive disorders, preferably, said disease or condition is selected from cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, deficiency blood, atherosclerosis, stroke and Alzheimer's disease;
  • the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophagus cancer, stomach cancer, lung cancer, liver cancer, Kidney cancer, pancreatic cancer, bile duct cancer, colorectal
  • the present disclosure further relates to a compound of general formula (I), (II), (III), (IV), (V), (VI) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a medicament comprising the same
  • a composition in the manufacture of a medicament for the treatment and/or prevention of diseases or conditions of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders
  • the disease or condition is selected from cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke and Alzheimer's disease
  • the cancer is preferably selected from Brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophagus cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, Urothelial cancer, urethral cancer, bladder cancer, breast cancer,
  • the present disclosure further relates to a method of inhibiting HPK1, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (II), (III), (IV), (V), (VI) or Table A
  • a method of inhibiting HPK1 comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (II), (III), (IV), (V), (VI) or Table A
  • the present disclosure further relates to a method of treating and/or preventing a disease or disorder by inhibiting HPK1, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (II), (III), (IV), (V), (VI) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • said disease or condition is preferably selected from cancer, autoimmune disease, inflammatory disease, infectious disease, cardiovascular disease, neurodegenerative disease, diabetes and reproductive disorders; preferably, said disease or condition is selected from Cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke and Alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer Cancer, oral cancer, salivary gland cancer, esophagus cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer , Breast cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, leukemia, lymphoma, multiple myeloma, skin cancer, malignant lipoma, bone cancer, soft tissue sarcoma, neurofibroma
  • the present disclosure further relates to a method of treating and/or preventing a disease or condition of cancer, autoimmune disease, inflammatory disease, infectious disease, cardiovascular disease, neurodegenerative disease, diabetes, and reproductive disorders, comprising administering the A compound of general formula (I), (II), (III), (IV), (V), (VI) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a compound thereof, in a therapeutically effective amount for a patient
  • said disease or condition is selected from cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke and Alzheimer's disease; said The cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cavity cancer, salivary gland cancer, esophagus cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal cancer Tracheal stromal tumor, urothelial cancer,
  • the present disclosure further relates to a compound of general formula (I), (II), (III), (IV), (V), (VI) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a compound including the same A pharmaceutical composition for use as a medicament.
  • the present disclosure further relates to a compound of general formula (I), (II), (III), (IV), (V), (VI) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a compound including the same A pharmaceutical composition for use as a drug that inhibits HPK1.
  • the present disclosure further relates to a compound of general formula (I), (II), (III), (IV), (V), (VI) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a compound including the same
  • the disease or condition is preferably selected from cancer, autoimmune disease, inflammatory disease, infection Sexual diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders;
  • the disease or condition is selected from cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis Sclerosis, stroke and Alzheimer's disease
  • the cancer is preferably selected from brain cancer, thyroid cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophagus cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer , Cholangiocarcinoma, colorectal cancer, small bowel cancer,
  • the present disclosure further relates to a compound of general formula (I), (II), (III), (IV), (V), (VI) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a compound including the same
  • Pharmaceutical compositions for the treatment and/or prevention of diseases or conditions of cancer, autoimmune diseases, inflammatory diseases, infectious diseases, cardiovascular diseases, neurodegenerative diseases, diabetes and reproductive disorders preferably, said The disease or condition is selected from cancer, allergy, asthma, sepsis, HIV infection, hepatitis B virus infection, ischemia, atherosclerosis, stroke and Alzheimer's disease; the cancer is preferably selected from brain cancer, thyroid Cancer, head and neck cancer, throat cancer, oral cancer, salivary gland cancer, esophagus cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial cancer , urethral cancer, bladder cancer, breast cancer, ovarian cancer, endometrial
  • the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; soft tissue cancer is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyosarcoma, leiomyosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma, and synovial sarcoma; lymphoma selected from Hodgkin's disease and non-Hodgkin's lymphoma (eg, mantle cell lymphoma, diffuse large B-cell lymphoma , follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); liver cancer is preferably hepatocellular carcinoma; lung cancer is selected from non-small cell lung cancer (NSCLC) (eg squamous cell carcinoma)
  • the colorectal cancer described in the present disclosure is also called colorectal cancer, preferably colon cancer or rectal cancer; the glioma is preferably glioblastoma.
  • the active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation or insufflation.
  • the compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compound is preferably presented in a unit dose or in a form that the patient can self-administer in a single dose.
  • a unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid.
  • a suitable unit dose may be 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.
  • Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents.
  • the aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils.
  • the oily suspensions may contain thickening agents.
  • the aforementioned sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase can be vegetable oil, or mineral oil or a mixture thereof.
  • Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • a sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase.
  • the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure.
  • a continuous intravenous drug delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM.5400 IV pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used.
  • fatty acids are also available in the preparation of injectables.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • the compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension.
  • These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, severity of disease, etc.; in addition, optimal treatment mode such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (eg 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 1-12 alkyl), more preferably alkyl having 1 to 6 carbon atoms (ie C 1-6 alkyl) ).
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituent preferably being selected from the group consisting of D atom, halogen, alkyl, alkoxy, haloalkyl , one or more of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl heteroaryl indivual.
  • alkylene refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is a residue containing 1 straight or branched chain groups of up to 20 carbon atoms, preferably having 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms ( That is, a C 1-12 alkylene group), more preferably an alkylene group having 1 to 6 carbon atoms (ie, a C 1-6 alkylene group).
  • 1 to 12 eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene base (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and the like.
  • the alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from the group consisting of alkenyl, alkynyl, alkoxy, haloalkoxy, Cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy one or more of oxo, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above, preferably having 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 2-12 alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (ie C 2-6 alkenyl).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • Alkenyl can be substituted or unsubstituted, when substituted, the substituent is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl one or more of , cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkynyl refers to an alkyl group having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Preferably have 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 2-12 alkynyl), more preferably have 2 to 6 Alkynyl of carbon atoms (ie C 2-6 alkynyl).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl one or more of , cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 14 (eg 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13 and 14) carbon atoms (i.e. 3 to 14 membered cycloalkyl), preferably 3 to 8 (e.g. 3, 4, 5, 6, 7 and 8) ) carbon atoms (ie 3 to 8 membered cycloalkyl), more preferably 3 to 6 carbon atoms (ie 3 to 6 membered cycloalkyl).
  • 3 to 14 eg 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13 and 14
  • 3 to 8 e.g. 3, 4, 5, 6, 7 and 8
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of shared spiro atoms between the rings, spirocycloalkyl groups are classified as mono- or poly-spirocycloalkyl groups (eg, bis-spirocycloalkyl groups), preferably mono-spirocycloalkyl groups and bis-spirocycloalkyl groups base.
  • mono- or poly-spirocycloalkyl groups eg, bis-spirocycloalkyl groups
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • bicyclic or polycyclic (such as tricyclic, tetracyclic) fused cycloalkyl groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/membered 6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan , 6-member/3-member, 6-member/4-member, 6-member/5-member, 6-member/6-member, 6-member/7-member, 7-member/5-member or 7-member/6-membered bicyclic fused cycloalkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (eg tricyclic, tetracyclic) bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl (including monocyclic, spiro, fused and bridged) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring where it is attached to the parent structure Rings together are cycloalkyl, non-limiting examples include etc.; preferably
  • Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy One or more of hydroxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy.
  • Alkoxy can be optionally substituted or unsubstituted, when substituted, the substituent is preferably selected from D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy group, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e. 3 to 20 membered heterocyclyl), wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, so Said sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), but does not include ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms being carbon.
  • It preferably contains 3 to 14 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms (ie 3 to 14 membered heterocyclyl), of which 1 to 4 (eg 1, 2, 3 and 4) are heteroatoms; more preferably 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8) are included (ie 3 to 8 membered heterocyclyl) or 6 to 14 ring atoms (e.g. 6, 7, 8, 9, 10, 11, 12, 13 and 14) of which 1-3 are heteroatoms (e.g.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine base, homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro heterocyclyls, fused heterocyclyls and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group with one atom (called a spiro atom) shared between the monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur.
  • the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds.
  • Spiroheterocyclyls are classified into mono- or poly-spiroheterocyclyls (eg, bis-spiroheterocyclyls) according to the number of spiro atoms shared between the rings, preferably mono-spiroheterocyclyls and bis-spiroheterocyclyls base.
  • spiroheterocyclyl include:
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 membered (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (ie 6 to 14 membered fused heterocyclic group), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered fused heterocyclyl).
  • bicyclic or polycyclic such as tricyclic, tetracyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/membered 6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan , 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered/6-membered bicyclic fused heterocycl
  • bridged heterocyclyl refers to a 5- to 20-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 membered (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered) (ie 6 to 14 membered bridged heterocyclyl), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie, a 7- to 10-membered bridged heterocyclyl).
  • 6 to 14 membered eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 membered
  • 7 to 10 membered eg 7, 8, 9 or 10 membered
  • a 7- to 10-membered bridged heterocyclyl ie 6 to 14 membered bridged bridged bridged heterocyclyl
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the
  • the rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy One or more of hydroxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :
  • Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy One or more of hydroxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 1, 2, 3 and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered) (ie 5 to 10 membered heteroaryl), more preferably 5 or 6 membered (ie 5 or 6 membered) heteroaryl), for example furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl Wait.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy One or more of hydroxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent
  • residues from which atoms are derived are "divalent cycloalkyl", "divalent heterocyclyl", “arylene” and "heteroarylene”.
  • amino protecting group is used to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when the other part of the molecule is reacted.
  • Non-limiting examples include (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methylbenzenesulfonyl (Ts ) and p-methoxybenzyl, etc.
  • SEM trimethylsilyl)ethoxymethyl
  • Ts p-methylbenzenesulfonyl
  • Ts p-methoxybenzyl
  • hydroxy protecting group refers to a hydroxy derivative commonly used to block or protect a hydroxy group while reacting on other functional groups of a compound.
  • the hydroxyl protecting group can be triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl , tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitro benzoyl.
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • aryloxy refers to aryl-O-, wherein aryl is as defined above.
  • heteroaryloxy refers to heteroaryl-O-, wherein heteroaryl is as defined above.
  • alkylthio refers to alkyl-S-, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to -OH.
  • thiol refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.
  • Ts refers to p-toluenesulfonyl.
  • stereoisomer refers to isomers that are structurally identical but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in the compounds of the present disclosure may have additional asymmetric atoms.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (D)- and (+)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques (L)-isomer.
  • An isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliaries, or, when the molecule contains basic functional groups (such as amino groups) or acidic functional groups (such as carboxyl groups), with appropriate optical Active acids or bases form diastereomeric salts, which are then resolved by conventional methods known in the art to yield the pure isomers. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or both Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both Z and E forms are included.
  • tautomer or tautomeric form refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton tautomers
  • proton transfer such as keto-enol and imine-enamine, lactam-lactam isomerizations .
  • the compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof.
  • isotopic derivative refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass.
  • isotopes that can be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as 2 H (deuterium, D), respectively, 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, etc., preferably deuterium.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All transformations of the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and a partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.
  • Optionally or “optionally” means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • “optionally substituted with halogen or cyano” means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted with halogen or cyano and the alkyl is not substituted with halogen and cyano situation.
  • Substituted means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
  • a person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as pharmaceutically acceptable carriers and excipients .
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have due biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect.
  • the determination of the therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance, and the appropriate therapeutically effective amount in each case can be determined by those skilled in the art based on routine experiments.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.
  • the present disclosure provides a preparation method of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IA) or its salt is subjected to deprotection reaction under alkaline or microwave conditions to obtain the compound of general formula (I) or its pharmaceutically acceptable salt;
  • R w is an amino protecting group; preferably Ts;
  • R 0 is a hydrogen atom
  • Ring A , Ring B, G1 , G2, G6 , G7, R', Ra , p and q are as defined in general formula (I).
  • the present disclosure provides a preparation method of a compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIA) or its salt is subjected to deprotection reaction under basic or microwave conditions to obtain the compound of general formula (II) or its pharmaceutically acceptable salt; or
  • the compound of general formula (IIIA) or its salt is subjected to deprotection reaction under alkaline or microwave conditions to obtain the compound of general formula (III) or its pharmaceutically acceptable salt;
  • R w is an amino protecting group; preferably Ts;
  • R 0 is a hydrogen atom
  • Rings A , G1 , G2, G3 , G5, G6 , G7 , R', R4a , R4b , Rq , R, n and q are as in general formula (II) or (III) definition.
  • the present disclosure provides a preparation method of a compound represented by general formula (IV) or (V) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IVA) or its salt is subjected to deprotection reaction under basic or microwave conditions to obtain the compound of general formula (IV) or its pharmaceutically acceptable salt; or
  • the compound of general formula (VA) or its salt is subjected to deprotection reaction under alkaline or microwave conditions to obtain the compound of general formula (V) or its pharmaceutically acceptable salt;
  • R w is an amino protecting group; preferably Ts;
  • R 0 is a hydrogen atom
  • Rings A , G1 , R2, R3 , R5 , G6 , G7, R', R4a , R4b , Rq , R, n and q are as in general formula (IV) or (V) definition.
  • the present disclosure provides a preparation method of a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (VIA) or its salt is subjected to deprotection reaction under alkaline or microwave conditions to obtain the compound of general formula (VI) or its pharmaceutically acceptable salt;
  • R w is an amino protecting group; preferably Ts;
  • R 0 is a hydrogen atom
  • Ring A , Ring B, Rd , Re , G1 , G2, G6 , G7, Ra , R', t and p are as defined in general formula (VI).
  • the present disclosure provides a preparation method of a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (VIA') or its salt is acylated with general formula (VIB) or its salt in the presence of basic conditions and a condensing agent to obtain the compound of general formula (VI) or its pharmaceutically acceptable salt ;
  • Ring A , Ring B, Rd , Re , G1 , G2, G6 , G7, Ra , R0 , R', t and p are as defined in general formula (VI).
  • the present disclosure provides a preparation method of a compound represented by general formula (VI) or a pharmaceutically acceptable salt thereof, the method comprising:
  • Ring A , Ring B, Rd , Re , G1 , G2, G6 , G7, Ra , R0 , R', t and p are as defined in general formula (VI).
  • the reagents that provide basic conditions in the above synthesis scheme include organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, Lithium diisopropylamide, tetrahydrofuran solution of lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, bis(trimethyl) Silicon) Lithium Lithium Tetrahydrofuran solution or 1,8-diazabicycloundec-7-ene
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate , sodium hydroxide, lithium hydroxide and potassium hydroxide;
  • the reagent for deprotection reaction to provide alkaline conditions is preferably sodium hydroxide;
  • the condensing agents described in the above synthesis scheme include but are not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-hydroxybenzotriazole , 1-Hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), 2-(7-azo Nitrobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), benzotriazole-1-yloxytris(dimethylamino)phosphonium Hexafluorophosphate or be
  • the reaction of the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, Ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromo Ethane and mixtures thereof.
  • the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, Ethyl acetate, n-hex
  • the reaction temperature of the above microwave reaction is 50-180°C, preferably 100°C.
  • the reaction time of the above microwave reaction is 0.5-4 hours; preferably 2 hours.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS was measured with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • HPLC High Performance Liquid Chromatography
  • Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
  • HPLC preparations used Waters 2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the average inhibition rate and IC 50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography method include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: n-hexane/dichloromethane system, D: ethyl acetate/dichloromethane/n-hexane, the volume ratio of the solvent varies according to the polarity of the compound For adjustment, a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • the microwave was reacted at 100 ° C for 2 hours, and the reaction solution was concentrated under reduced pressure and then subjected to high performance liquid chromatography (Waters-2545, chromatographic column: SharpSil-T C18, 30*150mm, 5 ⁇ m; mobile phase: water (10mmol/L) ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 25%-50%, flow rate: 30 mL/min) was purified to give the title compound 2 (1.1 mg, yield: 5%).
  • the title compound 5e (500 mg, yield: 87.7%) was obtained by using the third to seventh steps of the synthetic route in Example 1, and replacing the starting compound 1d in the third step with compound 5d.
  • Test example 1 HPK1 enzyme activity detection (ADP-Glo method)
  • ADP-Glo Kinase Detection Kit including ADP-Glo Reagent and Kinase Detection Reagent (Promega, V9101)
  • BSA bovine serum albumin
  • MBP Dephosphorylated MBP
  • Detection buffer 40 mM Tris-HCl buffer, 7.5; 20 mM MgCl 2 ; 0.1 mg/mL BSA; 50 ⁇ M DTT;
  • HPK1 enzyme solution The detection buffer is prepared as HPK1 enzyme solution with a final concentration of 1.5ng/ ⁇ L;
  • Test Example 2 Detection of SLP76 protein phosphorylation in Jurkat cells (HTRF method)
  • FBS Fetal bovine serum
  • CD3 Antibody, anti-human, pure functional grade CD3 Antibody, anti-human, pure-functional grade
  • Jurkat E6-1 cells were purchased from the American Type Culture Collection Center (ATCC, TIB-152) and cultured in RPMI1640 medium (10% FBS). Cell culture density was maintained at 2 x 10 5 to 2 x 10 6 cells/mL, and passaged 2-3 times a week.
  • Test compounds were dissolved in DMSO to 5 mM.

Abstract

La présente invention concerne un composé tétracyclique fusionné, son procédé de préparation et son utilisation en médecine. Plus particulièrement, la présente invention concerne un composé tétracyclique fusionné tel que représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique contenant le composé, et son utilisation en tant qu'agent thérapeutique, en particulier l'utilisation de celui-ci dans la préparation d'un médicament pour l'inhibition de HPK1, les groupes dans la formule générale (I) étant tels que définis dans la description.
PCT/CN2022/082894 2021-03-26 2022-03-25 Composé tétracyclique fusionné, son procédé de préparation et son utilisation en médecine WO2022199676A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107922431A (zh) * 2015-06-25 2018-04-17 大学健康网络 Hpk1抑制剂及其使用方法
CN109923114A (zh) * 2016-09-09 2019-06-21 因赛特公司 作为hpk1调节剂的吡唑并吡啶衍生物和其用于治疗癌症的用途
WO2020103896A1 (fr) * 2018-11-22 2020-05-28 Beigene, Ltd. Pyrrolo[2,3-b]pyridines utilisés en tant qu'inhibiteur de hpk1 et leurs utilisations
WO2021000925A1 (fr) * 2019-07-04 2021-01-07 Beigene, Ltd. Pyrrolo[2, 3-b]pyrazines utilisées en tant qu'inhibiteur de hpk1 et leur utilisation
CN112239473A (zh) * 2019-07-17 2021-01-19 百济神州(北京)生物科技有限公司 作为hpk1抑制剂的三环化合物的制备方法
CN112243439A (zh) * 2018-06-13 2021-01-19 百济神州有限公司 作为hpk1抑制剂的吡咯并[2,3-b]吡啶或吡咯并[2,3-b]吡嗪及其用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107922431A (zh) * 2015-06-25 2018-04-17 大学健康网络 Hpk1抑制剂及其使用方法
CN109923114A (zh) * 2016-09-09 2019-06-21 因赛特公司 作为hpk1调节剂的吡唑并吡啶衍生物和其用于治疗癌症的用途
CN112243439A (zh) * 2018-06-13 2021-01-19 百济神州有限公司 作为hpk1抑制剂的吡咯并[2,3-b]吡啶或吡咯并[2,3-b]吡嗪及其用途
WO2020103896A1 (fr) * 2018-11-22 2020-05-28 Beigene, Ltd. Pyrrolo[2,3-b]pyridines utilisés en tant qu'inhibiteur de hpk1 et leurs utilisations
WO2021000925A1 (fr) * 2019-07-04 2021-01-07 Beigene, Ltd. Pyrrolo[2, 3-b]pyrazines utilisées en tant qu'inhibiteur de hpk1 et leur utilisation
CN112239473A (zh) * 2019-07-17 2021-01-19 百济神州(北京)生物科技有限公司 作为hpk1抑制剂的三环化合物的制备方法

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