WO2022199676A1 - 稠合四环类化合物、其制备方法及其在医药上的应用 - Google Patents

稠合四环类化合物、其制备方法及其在医药上的应用 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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alkyl
cancer
alkoxy
haloalkyl
heteroaryl
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PCT/CN2022/082894
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English (en)
French (fr)
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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/zh

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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

涉及稠合四环类化合物、其制备方法及其在医药上的应用。具体而言，涉及一种通式(I)所示的稠合四环类化合物、其制备方法及含有该类化合物的药物组合物以及其作为治疗剂的用途，特别是其在制备用于抑制HPK1的药物中的用途。其中通式(I)中各基团如说明书中所定义。

Description

稠合四环类化合物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种稠合四环类化合物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的稠合四环类化合物、其制备方法及含有该类化合物的药物组合物，以及其在制备用于抑制HPK1的药物中的用途。
背景技术
抗癌治疗已经从放化疗，靶向治疗，进入免疫治疗的年代。肿瘤免疫治疗的靶点主要包括免疫检查点，免疫激动剂，Treg，巨噬细胞，肿瘤微环境代谢物如IDO，A2AR通路，等等。而造血祖细胞激酶1(Hematopoietic Progenitor Kinase1，简称HPK1；也称有丝***原活化蛋白激酶激酶激酶激酶1(Mitogen-activated protein kinase kinase kinase kinase 1)，简称MAP4K1)是T细胞内的负调节因子，在TCR激活后起负反馈调节的功能，与T细胞耗竭有关。研究比较清楚的信号通路为：TCR与MHC-肽结合后，LAT被磷酸化，招募GADS-SLP76复合体，引起下游PLC的磷酸化和通路激活。而与此同时，ZAP70会磷酸化HPK1的Y381位点，其与SLP76的SH2区结合，从而磷酸化后者的S376位点。SLP76S376磷酸化招募14-3-3，从而导致泛素化，造成整个TCR信号小体(signalosome)的解体。
目前认为HPK1是一类较好免疫疗法靶点是基于以下3点原因：(1)HPK1表达谱局限于免疫细胞，安全性好；(2)HPK1在“癌症-免疫周期”的不同阶段具有多种负调控作用，抑制HPK1可以调节NK细胞，DC细胞，T细胞的免疫抑制功能，还能调节B细胞活化，其中以T细胞活化研究得最多；(3)HPK1激酶活性在抑制抗癌免疫反应中很重要。
研究表明HPK1表达与T细胞耗竭特征(exhaustion signature)相关，包括CD3E，PD1，CTLA4，TIM-3，LAG-3和TIGIT，并且HPK1的高表达跟生存期短相关。TCGA PanCancer数据库分析显示HPK1(而非其他MAP4K家族成员)表达与PD1之间呈正相关。HPK1在耗竭的T细胞中表达上调，HPK1，TIM3和LAG3在PD1高的T细胞中的表达高于PD1低的T细胞。与之相反，HPK1在***性红斑狼疮(SLE)患者CD4+T细胞中表达下调，且SLEDAI评分与HPK1mRNA水平呈负相关。HPK1在银屑病关节炎(PsA)患者外周血细胞中表达也下调。
HPK1基因敲除的小鼠在静息状态下没有任何异常。而一旦TCR被激活，无论是HPK1敲除，还是HPK1激酶失活(kinase dead)敲入，或SLP76S376A敲入的小鼠，得到的结果都是类似的，都会激活免疫反应。HPK1缺陷小鼠更易患实验性自身免疫性脑脊髓炎(EAE)。HPK1激酶活性在体外调节TCR信号传导和细胞因子分泌；抑制HPK1可减轻PGE2和腺苷介导的免疫抑制。HPK1激酶失活小鼠 会抑制体内肿瘤的生长，去除CD8+或CD4+T细胞后，HPK1-/-小鼠的抗肿瘤作用几乎消失，说明T细胞介导了HPK1的大部分免疫抑制作用。
上述HPK1敲除和激酶失活敲入的小鼠数据表明HPK1主要还是通过激酶活性起作用的，但是有部分文献报道其支架(scaffold)也有一定的功能，所以抑制HPK1的药物开发思路以激酶抑制剂为主，也有一些PROTAC分子。
目前已公开的相关专利有WO2016205942A1、WO2019238067A1、WO2021013083A1、WO2020103896A1和WO2021000925A1等等。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
Figure PCTCN2022082894-appb-000001
其中：
环A为芳基或杂芳基；
环B为苯基或5元或6元杂芳基；
G 1为CR 1或氮原子；
G 2为CR 2或氮原子；
G 6选自C(O)、CR 6aR 6b、NR 6c和氧原子；
G 7选自C(O)、CR 7aR 7b、NR 7c和氧原子；
R 6a、R 6b、R 7a和R 7b相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 0、R 6c和R 7c相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
各个R a相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) rNR mR n、-OR p、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、氧代、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或两个R a与环B形成稠合环，所述的稠合环任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、氧代、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、氧代、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R’、R 1和R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-NR dR e、-OR g、-(CO)R f、-(CO)NR dR e、-(CO)OR g、-SO 2R f、-SO 2NR dR e、-NR h(CO)R f、-NR h(CO)NR dR e、-NR h(CO)OR g、-NR hSO 2R f、-NR hSO 2NR dR e、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-NR d2R e2、-OR g2、-(CO)R f2、-(CO)NR d2R e2、-(CO)OR g2、-SO 2R f2、-SO 2NR d2R e2、-NR h2(CO)R f2、-NR h2(CO)NR d2R e2、-NR h2(CO)OR g2、-NR h2SO 2R f2、-NR h2SO 2NR d2R e2、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R m、R n、R p、R d、R e、R f、R g、R h、R d2、R e2、R f2、R g2和R h2相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或R m和R n、R d和R e、R d2和R e2与它们所连接的氮原子一起形成杂环基，所述杂环基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、氧代、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
p为0、1、2、3或4；
q为0、1、2、3或4；且
r为0、1、2、3或4。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐为通式(II)或(III)所示的化合物或其可药用的盐：
Figure PCTCN2022082894-appb-000002
其中
G 3为CR 3或氮原子；
G 5为CR 5或氮原子；
R 3和R 5相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 4a和R 4b相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) rNR mR n、-OR p、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、氧代、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
各个R相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；或
两个R一起形成氧代基；
R q选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
n为0、1、2、3、4、5或6；
环A、G 1、G 2、G 6、G 7、R 0、R m、R n、R p、R’、r和q如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、(II)或(III)所示的化合物或其可药用的盐为通式(IV)或(V)所示的化合物或其可药用的盐：
Figure PCTCN2022082894-appb-000003
其中：
环A、G 1、G 6、G 7、R 0、R 2、R 3、R 4a、R 4b、R 5、R q、R’、R、q和n如通式(II)或(III)中所定义。
在本公开一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐为通式(VI)所示的化合物或其可药用的盐：
Figure PCTCN2022082894-appb-000004
其中
t为0、1、2或3；
环A、环B、R d、R e、G 1、G 2、G 6、G 7、R 0、R a、R’和p如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物或其可药用的盐，其中-G 7-G 6-选自-O-CHR 6a-、-CHR 7a-O-、-NR 7c-CHR 6a-、-CHR 7a-NR 6c-、-C(O)-NR 6c-和-NR 7c-C(O)-，R 6a、R 7a、R 6c和R 7c如通式(I)中所定义；优选地，-G 7-G 6-选自-O-CH 2-、-CH 2-O-、-NH-CH 2-、-CH 2-NH-、-C(O)-NH-和-NH-C(O)-；更优选地，-G 7-G 6-为-O-CH 2-。
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物或其可药用的盐，其中环A为6-10元芳基或5元或6元杂芳基，优选为苯基或吡唑基。
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物或其可药用的盐，其中G 1为CR 1，R 1如通式(I)中所定义；
优选地，R 1选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基；
进一步优选地，R 1选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选为氢原子。
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物或其可药用的盐，其中G 1为CR 1，R 1如通式(I)中所定义；优选地，G 1为CR 1，R 1选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、 氰基、氨基、羟基和C 1-6羟烷基；进一步优选地，G 1为CR 1，R 1选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，G 1为CH。
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(VI)所示的化合物或其可药用的盐，其中G 2为CR 2，R 2如通式(I)中所定义；
优选地，R 2选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基；
进一步优选地，R 2选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选为氢原子。
在本公开一些实施方案中，所述的通式(I)、(II)、(III)或(VI)所示的化合物或其可药用的盐，其中G 2为CR 2，R 2如通式(I)中所定义；优选地，G 2为CR 2，R 2选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基；进一步优选地，G 2为CR 2，R 2选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，G 2为CH。
在本公开一些实施方案中，所述的通式(II)或(III)所示的化合物或其可药用的盐，其中G 3为CR 3，R 3如通式(II)或(III)中所定义；
优选地，R 3选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基；
进一步优选地，R 3选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选为氢原子。
在本公开一些实施方案中，所述的通式(II)或(III)所示的化合物或其可药用的盐，其中G 3为CR 3，R 3如通式(II)或(III)中所定义；优选地，G 3为CR 3，R 3选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基；进一步优选地，G 3为CR 3，R 3选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，G 3为CH。
在本公开一些实施方案中，所述的通式(II)或(III)所示的化合物或其可药用的盐，其中G 5为CR 5，R 5如通式(II)或(III)中所定义；
优选地，R 5选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基；
进一步优选地，R 5选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选为氢原子或甲基。
在本公开一些实施方案中，所述的通式(II)或(III)所示的化合物或其可药用的盐，其中G 5为CR 5，R 5如通式(II)或(III)中所定义；优选地，G 5为CR 5，R 5选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基；进一步优选地，G 5为CR 5，R 5选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，G 5为CR 5，R 5为氢原子或甲基。
在本公开一些实施方案中，所述的通式(II)或(III)所示的化合物或其可药用的 盐，其中R 5选自氢原子、卤素、C 1-6烷基和C 1-6烷氧基；优选地，R 5选自氢原子、F、甲基和甲氧基。
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物或其可药用的盐，其中R 0选自氢原子、C 1-6烷基和C 1-6卤代烷基；优选为氢原子。
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物或其可药用的盐，其中各个R’相同或不同，且各自独立地选自C 1-6烷基、C 1-6卤代烷基或-(CO)NR dR e，R d和R e如通式(I)中所定义；
优选地，R d和R e相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，或R d和R e与它们所连接的氮原子一起形成3至8元杂环基，所述3至8元杂环基任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基中的一个或多个基团取代；
进一步优选地，R d和R e相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，或R d和R e与它们所连接的氮原子一起形成氮杂环丁烷基，所述氮杂环丁烷基任选被选自卤素、C 1-6烷基、C 1-6卤代烷基、氰基、羟基和C 1-6羟烷基中的一个或多个基团取代。
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物或其可药用的盐，其中各个R’相同或不同，且各自独立地为C 1-6烷基或-(CO)NR dR e，R d和R e如通式(I)中所定义；
优选地，各个R’相同或不同，且各自独立地为C 1-6烷基或-(CO)NR dR e，R d和R e相同或不同，且各自独立地选自氢原子、C 1-6烷基和C 1-6羟烷基，或R d和R e与它们所连接的氮原子一起形成3至8元杂环基，所述3至8元杂环基任选被一个或多个羟基取代；
更优选地，各个R’相同或不同，且各自独立地为C 1-6烷基或-(CO)NR dR e，R d和R e相同或不同，且各自独立地选自C 1-6烷基和C 1-6羟烷基，或R d和R e与它们所连接的氮原子一起形成氮杂环丁烷基，所述氮杂环丁烷基任选被一个或多个羟基取代。
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物或其可药用的盐，其中各个R’相同或不同，且各自独立地为
Figure PCTCN2022082894-appb-000005
乙基、
Figure PCTCN2022082894-appb-000006
在本公开一些实施方案中，所述的通式(II)或(IV)所示的化合物或其可药用的盐，其中R 4a和R 4b相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6 烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、-(CH 2) rNR mR n、羟基和C 1-6羟烷基，其中所述的C 1-6烷基和C 1-6烷氧基各自独立地任选被选自卤素、C 1-6烷氧基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基中的一个或多个取代基所取代，R m、R n和r如通式(II)中所定义；
优选地，R 4a和R 4b中至少有一个为-(CH 2) rNR mR n，R m和R n相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基、氰基和氨基中的一个或多个取代基所取代；或R m和R n与它们所连接的氮原子一起形成3至8元杂环基，所述3至8元杂环基任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基、氧代和C 1-6羟烷基中的一个或多个基团取代；r为0、1或2；
进一步优选地，R 4a和R 4b中一个为-(CH 2) rNR mR n，另一个为氢原子，R m和R n相同或不同，且各自独立地选自氢原子、C 1-6烷基和C 1-6卤代烷基；或R m和R n与它们所连接的氮原子一起形成哌嗪环，所述哌嗪环任选被选自卤素、C 1-6烷基和C 1-6卤代烷基中的一个或多个基团取代；r为0或1。
在本公开一些实施方案中，所述的通式(II)或(IV)所示的化合物或其可药用的盐，其中R 4a和R 4b中一个为-(CH 2) rNR mR n，另一个为氢原子或C 1-6烷基，R m和R n相同或不同，且各自独立地为C 1-6烷基；或R m和R n与它们所连接的氮原子一起形成哌嗪环，所述哌嗪环任选被一个或多个C 1-6烷基取代；r为0或1。
在本公开一些实施方案中，所述的通式(II)或(IV)所示的化合物或其可药用的盐，其中R 4a和R 4b相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、-(CH 2) rNR mR n、羟基和C 1-6羟烷基，其中所述的C 1-6烷基和C 1-6烷氧基各自独立地任选被选自卤素、C 1-6烷氧基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基中的一个或多个取代基所取代，且R 4a和R 4b中至少有一个为-(CH 2) rNR mR n，R m和R n相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基、氰基和氨基中的一个或多个取代基所取代；或R m和R n与它们所连接的氮原子一起形成3至8元杂环基，所述3至8元杂环基任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基、氧代和C 1-6羟烷基中的一个或多个基团取代；r为0、1或2。
在本公开一些实施方案中，所述的通式(II)或(IV)所示的化合物或其可药用的盐，其中R 4a为哌嗪基，所述哌嗪基任选被C 1-6烷基取代；和/或R 4b为氢原子。
在本公开一些实施方案中，所述的通式(II)或(IV)所示的化合物或其可药用的盐，其中R 4a为4-甲基哌嗪-1-基或4-乙基哌嗪-1-基；和/或R 4b为氢原子或甲基。
在本公开一些实施方案中，所述的通式(II)或(IV)所示的化合物或其可药用的盐，其中R 4b为-CH 2-N(CH 3) 2；和/或R 4a为氢原子。
在本公开一些实施方案中，所述的通式(III)或(V)所示的化合物或其可药用的 盐，其中各个R相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基；
优选地，各个R相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基。
在本公开一些实施方案中，所述的通式(III)或(V)所示的化合物或其可药用的盐，其中R q选自氢原子、C 1-6烷基和C 1-6卤代烷基；优选为C 1-6烷基，更优选为甲基。
在本公开一些实施方案中，所述的通式(I)、(II)、(III)、(IV)或(V)所示的化合物或其可药用的盐，其中q为0或1；优选地，q为1。
在本公开一些实施方案中，所述的通式(III)或(V)所示的化合物或其可药用的盐，其中n为0或1。
在本公开一些实施方案中，所述的通式(I)或(VI)所示的化合物或其可药用的盐，其中p为1或2；优选地，p为1。
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中-G 7-G 6-选自-O-CH 2-、-CH 2-O-、-NH-CH 2-、-CH 2-NH-、-C(O)-NH-和-NH-C(O)-；环A为苯基或吡唑基；G 1为CR 1，R 1选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；G 2为CR 2，R 2选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；G 3为CR 3，R 3选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；G 5为CR 5，R 5选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 0选自氢原子、C 1-6烷基和C 1-6卤代烷基；各个R’相同或不同，且各自独立地选自C 1-6烷基、C 1-6卤代烷基或-(CO)NR dR e，R d和R e相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，或R d和R e与它们所连接的氮原子一起形成3至8元杂环基，所述3至8元杂环基任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基中的一个或多个基团取代；R 4a和R 4b相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、-(CH 2) rNR mR n、羟基和C 1-6羟烷基，其中所述的C 1-6烷基和C 1-6烷氧基各自独立地任选被选自卤素、C 1-6烷氧基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基中的一个或多个取代基所取代，且R 4a和R 4b中至少有一个为-(CH 2) rNR mR n，R m和R n相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基、氰基和氨基中的一个或多个取代基所取代；或R m和R n与它们所连接的氮原子一起形成3至8元杂环基，所述3至8元杂环基任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基、氧代和C 1-6羟烷基中的一个或多个基团取代；r为0、1或2；且q为0或1。
在本公开一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中-G 7-G 6-为-O-CH 2-；环A为苯基或吡唑基；G 1为CR 1，R 1为氢原子；G 2为CR 2， R 2为氢原子；G 3为CR 3，R 3为氢原子；G 5为CR 5，R 5选自氢原子、卤素、C 1-6烷基和C 1-6烷氧基；R 0为氢原子；q为1；各个R’为C 1-6烷基或-(CO)NR dR e，R d和R e相同或不同，且各自独立地选自氢原子、C 1-6烷基和C 1-6羟烷基，或R d和R e与它们所连接的氮原子一起形成3至8元杂环基，所述3至8元杂环基任选被一个或多个羟基取代；R 4a和R 4b中一个为-(CH 2) rNR mR n，另一个为氢原子或C 1-6烷基，R m和R n相同或不同，且各自独立地为C 1-6烷基；或R m和R n与它们所连接的氮原子一起形成哌嗪环，所述哌嗪环任选被一个或多个C 1-6烷基取代；且r为0或1。
表A本公开的典型化合物包括但不限于：
Figure PCTCN2022082894-appb-000007
Figure PCTCN2022082894-appb-000008
Figure PCTCN2022082894-appb-000009
Figure PCTCN2022082894-appb-000010
Figure PCTCN2022082894-appb-000011
本公开的另一方面涉及通式(IA)所示的化合物或其盐，
Figure PCTCN2022082894-appb-000012
其中：R w为氨基保护基；优选为Ts；
环A、环B、G 1、G 2、G 6、G 7、R’、R a、p和q如通式(I)中所定义。
本公开的另一方面涉及通式(IIA)或(IIIA)所示的化合物或其盐，
Figure PCTCN2022082894-appb-000013
其中：R w为氨基保护基；优选为Ts；
环A、G 1、G 2、G 3、G 5、G 6、G 7、R’、R 4a、R 4b、R q、R、n和q如通式(II)或(III)中所定义。
本公开的另一方面涉及通式(IVA)或(VA)所示的化合物或其盐，
Figure PCTCN2022082894-appb-000014
其中：R w为氨基保护基；优选为Ts；
环A、G 1、R 2、R 3、R 5、G 6、G 7、R’、R 4a、R 4b、R q、R、n和q如通式(IV)或(V)中所定义。
本公开的另一方面涉及通式(VIA)所示的化合物或其盐，
Figure PCTCN2022082894-appb-000015
其中：R w为氨基保护基；优选为Ts；
环A、环B、R d、R e、G 1、G 2、G 6、G 7、R a、R’、t和p如通式(VI)中所定义。
本公开的典型中间体化合物包括但不限于：
Figure PCTCN2022082894-appb-000016
Figure PCTCN2022082894-appb-000017
Figure PCTCN2022082894-appb-000018
本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022082894-appb-000019
通式(IA)的化合物或其盐经脱保护反应，得到通式(I)所示的化合物或其可药用的盐；
其中R w为氨基保护基；优选为Ts；
R 0为氢原子；
环A、环B、G 1、G 2、G 6、G 7、R’、R a、p和q如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(II)或(III)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022082894-appb-000020
通式(IIA)的化合物或其盐经脱保护反应，得到通式(II)所示的化合物或其可药用的盐；或
通式(IIIA)的化合物或其盐经脱保护反应，得到通式(III)所示的化合物或其可 药用的盐；
其中R w为氨基保护基；优选为Ts；
R 0为氢原子；
环A、G 1、G 2、G 3、G 5、G 6、G 7、R’、R 4a、R 4b、R q、R、n和q如通式(II)或(III)中所定义。
本公开的另一方面涉及一种制备通式(IV)或(V)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022082894-appb-000021
通式(IVA)的化合物或其盐经脱保护反应，得到通式(IV)所示的化合物或其可药用的盐；或
通式(VA)的化合物或其盐经脱保护反应，得到通式(V)所示的化合物或其可药用的盐；
其中R w为氨基保护基；优选为Ts；
R 0为氢原子；
环A、G 1、R 2、R 3、R 5、G 6、G 7、R’、R 4a、R 4b、R q、R、n和q如通式(IV)或(V)中所定义。
本公开的另一方面涉及一种制备通式(VI)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022082894-appb-000022
通式(VIA)的化合物或其盐经脱保护反应，得到通式(VI)所示的化合物或其可药用的盐；
其中R w为氨基保护基；优选为Ts；
R 0为氢原子；
环A、环B、R d、R e、G 1、G 2、G 6、G 7、R a、R’、t和p如通式(VI)中所定义。
本公开的另一方面涉及一种制备通式(VI)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022082894-appb-000023
通式(VIA’)的化合物或其盐与通式(VIB)或其盐经酰化反应，得到通式(VI)所示的化合物或其可药用的盐；
其中Q为卤素或羟基，优选为羟基；
环A、环B、R d、R e、G 1、G 2、G 6、G 7、R a、R 0、R’、t和p如通式(VI)中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、(II)、(III)、(IV)、(V)、(VI)或表A中所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I)、(II)、(III)、(IV)、(V)、(VI)或表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备用于抑制HPK1的药物中的用途。
本公开进一步涉及通式(I)、(II)、(III)、(IV)、(V)、(VI)或表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备用于通过抑制HPK1来治疗和/或预防的疾病或病症的药物中的用途；所述的疾病或病症优选选自癌症、自身免疫性疾病、炎性疾病、感染性疾病、心血管疾病、神经退行性疾病、糖尿病和生殖障碍的疾病或病症的药物中的用途，优选地，所述的疾病或病症选自癌症、过敏、哮喘、败血症、艾滋病毒感染、乙肝病毒感染、缺血、动脉粥样硬化、中风和阿尔茨海默氏病；所述的癌症优选选自脑癌、甲状腺癌、头颈癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胰腺癌、胆管癌、结肠直肠癌、小肠癌、胃肠道间质瘤、尿路上皮癌、尿道癌、膀胱癌、乳腺癌、卵巢癌、子宫内膜癌、***、输卵管癌、睾丸癌、***癌、白血病、淋巴瘤、多发性骨髓瘤、皮肤癌、恶性脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤和成神经细胞瘤。
本公开进一步涉及通式(I)、(II)、(III)、(IV)、(V)、(VI)或表A中所示的化合物或其可药用的盐、或包括其的药物组合物在制备用于治疗和/或预防癌症、自身免疫性疾病、炎性疾病、感染性疾病、心血管疾病、神经退行性疾病、糖尿病和 生殖障碍的疾病或病症的药物中的用途，优选地，所述的疾病或病症选自癌症、过敏、哮喘、败血症、艾滋病毒感染、乙肝病毒感染、缺血、动脉粥样硬化、中风和阿尔茨海默氏病；所述的癌症优选选自脑癌、甲状腺癌、头颈癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胰腺癌、胆管癌、结肠直肠癌、小肠癌、胃肠道间质瘤、尿路上皮癌、尿道癌、膀胱癌、乳腺癌、卵巢癌、子宫内膜癌、***、输卵管癌、睾丸癌、***癌、白血病、淋巴瘤、多发性骨髓瘤、皮肤癌、恶性脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤和成神经细胞瘤。
本公开进一步涉及一种抑制HPK1的方法，其包括给予所需患者治疗有效量的通式(I)、(II)、(III)、(IV)、(V)、(VI)或表A所示的化合物或其可药用的盐、或包括其的药物组合物。
本公开进一步涉及一种通过抑制HPK1来治疗和/或预防的疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)、(II)、(III)、(IV)、(V)、(VI)或表A所示的化合物或其可药用的盐、或包括其的药物组合物。其中所述的疾病或病症优选选自癌症、自身免疫性疾病、炎性疾病、感染性疾病、心血管疾病、神经退行性疾病、糖尿病和生殖障碍；优选地，所述的疾病或病症选自癌症、过敏、哮喘、败血症、艾滋病毒感染、乙肝病毒感染、缺血、动脉粥样硬化、中风和阿尔茨海默氏病；所述的癌症优选选自脑癌、甲状腺癌、头颈癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胰腺癌、胆管癌、结肠直肠癌、小肠癌、胃肠道间质瘤、尿路上皮癌、尿道癌、膀胱癌、乳腺癌、卵巢癌、子宫内膜癌、***、输卵管癌、睾丸癌、***癌、白血病、淋巴瘤、多发性骨髓瘤、皮肤癌、恶性脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤和成神经细胞瘤。
本公开进一步涉及一种治疗和/或预防癌症、自身免疫性疾病、炎性疾病、感染性疾病、心血管疾病、神经退行性疾病、糖尿病和生殖障碍的疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)、(II)、(III)、(IV)、(V)、(VI)或表A所示的化合物或其可药用的盐、或包括其的药物组合物；优选地，所述的疾病或病症选自癌症、过敏、哮喘、败血症、艾滋病毒感染、乙肝病毒感染、缺血、动脉粥样硬化、中风和阿尔茨海默氏病；所述的癌症优选选自脑癌、甲状腺癌、头颈癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胰腺癌、胆管癌、结肠直肠癌、小肠癌、胃肠道间质瘤、尿路上皮癌、尿道癌、膀胱癌、乳腺癌、卵巢癌、子宫内膜癌、***、输卵管癌、睾丸癌、***癌、白血病、淋巴瘤、多发性骨髓瘤、皮肤癌、恶性脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤和成神经细胞瘤。
本公开进一步涉及一种通式(I)、(II)、(III)、(IV)、(V)、(VI)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作药物。
本公开进一步涉及一种通式(I)、(II)、(III)、(IV)、(V)、(VI)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作抑制HPK1的药物。
本公开进一步涉及一种通式(I)、(II)、(III)、(IV)、(V)、(VI)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作治疗和/或预防通过抑制HPK1来治疗和/或预防的疾病或病症的药物；其中所述的疾病或病症优选选自癌症、自身免疫性疾病、炎性疾病、感染性疾病、心血管疾病、神经退行性疾病、糖尿病和生殖障碍；优选地，所述的疾病或病症选自癌症、过敏、哮喘、败血症、艾滋病毒感染、乙肝病毒感染、缺血、动脉粥样硬化、中风和阿尔茨海默氏病；所述的癌症优选选自脑癌、甲状腺癌、头颈癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胰腺癌、胆管癌、结肠直肠癌、小肠癌、胃肠道间质瘤、尿路上皮癌、尿道癌、膀胱癌、乳腺癌、卵巢癌、子宫内膜癌、***、输卵管癌、睾丸癌、***癌、白血病、淋巴瘤、多发性骨髓瘤、皮肤癌、恶性脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤和成神经细胞瘤。
本公开进一步涉及一种通式(I)、(II)、(III)、(IV)、(V)、(VI)或表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作治疗和/或预防癌症、自身免疫性疾病、炎性疾病、感染性疾病、心血管疾病、神经退行性疾病、糖尿病和生殖障碍的疾病或病症，优选地，所述的疾病或病症选自癌症、过敏、哮喘、败血症、艾滋病毒感染、乙肝病毒感染、缺血、动脉粥样硬化、中风和阿尔茨海默氏病；所述的癌症优选选自脑癌、甲状腺癌、头颈癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胰腺癌、胆管癌、结肠直肠癌、小肠癌、胃肠道间质瘤、尿路上皮癌、尿道癌、膀胱癌、乳腺癌、卵巢癌、子宫内膜癌、***、输卵管癌、睾丸癌、***癌、白血病、淋巴瘤、多发性骨髓瘤、皮肤癌、恶性脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤和成神经细胞瘤。
优选地，本公开中所述的脑癌选自多形性成胶质细胞瘤或成神经细胞瘤；软组织癌选自纤维肉瘤、胃肠道肉瘤、横纹肌瘤、平滑肌肉瘤、去分化脂肉瘤、多形性脂肉瘤、恶性纤维组织细胞瘤、圆细胞肉瘤和滑膜肉瘤；淋巴瘤选自霍奇金氏疾病和非霍奇金淋巴瘤(例如套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡中心淋巴瘤、边缘区B细胞淋巴瘤、淋巴浆细胞淋巴瘤和外周T细胞淋巴瘤)；肝癌优选为肝细胞癌；肺癌选自非小细胞肺癌(NSCLC)(例如鳞状细胞癌)和小细胞肺癌(SCLC)；肾癌选自肾细胞癌、透明细胞和肾嗜酸细胞瘤；白血病选自慢性淋巴细胞性白血病(CLL)、慢性粒细胞性白血病、急性成淋巴细胞性白血病(ALL)、T-细胞急性成淋巴细胞性白血病(T-ALL)、慢性髓细胞性白血病(CML)和急性骨髓性白血病(AML)；皮肤癌选自恶性黑色素瘤、鳞状细胞癌、基底细胞癌和血管肉瘤；咽喉癌选自鼻咽癌。
本公开中所述的结肠直肠癌又称结直肠癌，优选为结肠癌或直肠癌；所述的神经胶质瘤优选为胶质母细胞瘤。
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药，吸入或吹入给药的各种剂型。本公开的化合物也可以配制成例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。
作为一般性指导，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。 无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、***的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选为具有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷基(即C 1-12烷基)，更优选为具有1至6个碳原子的烷基(即C 1-6烷基)。非限制性的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以 是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基的杂芳基中的一个或多个。
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其为从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选具有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子(即C 1-12亚烷基)，更优选具有1至6个碳原子的亚烷基(即C 1-6亚烷基)。亚烷基的非限制性的实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，所述取代基优选选自烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个。
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，优选具有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子(即C 2-12烯基)，更优选具有2至6个碳原子的烯基(即C 2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述。优选具有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子(即C 2-12炔基)，更优选具有2至6个碳原子的炔基(即C 2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至14个(例如3、4、5、6、7、8、9、10、11、12、13和14个)碳原子(即3至14元环烷基)，优选包含3至8个(例如3、4、5、6、7和8个)碳原子(即3至8元环烷基)，更优选包含3至6个碳原子(即3至6元环烷基)。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯 基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指5至20元，单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基或多螺环烷基(例如双螺环烷基)，优选为单螺环烷基和双螺环烷基。更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2022082894-appb-000024
术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环或多环(例如三环、四环)稠环烷基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2022082894-appb-000025
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环或多环(例如三环、四环)桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2022082894-appb-000026
所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳 基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括
Figure PCTCN2022082894-appb-000027
等；优选为
Figure PCTCN2022082894-appb-000028
Figure PCTCN2022082894-appb-000029
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，所述取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基和丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其包含3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元杂环基)，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至14个(例如3、4、5、6、7、8、9、10、11、12、13和14个)环原子(即3至14元杂环基)，其中1～4个(例如1、2、3和4个)是杂原子；更优选包含3至8个环原子(例如3、4、5、6、7和8个)(即3至8元杂环基)或6至14个环原子(例如6、7、8、9、10、11、12、13和14个)，其中1-3是杂原子(例如1、2和3个)；更优选包含3至8个环原子，其中1-3个(例如1、2和3个)是杂原子；最优选包含5或6个环原子(即5元或6元杂环基)，其中1-3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元(例如6、7、8、9、10、11、12、13和14元)(即6至14元螺杂环基)，更优选为7至10元(例如7、8、9或10元)(即7至10元螺杂环基)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基或多螺杂环基(例如双螺杂环基)，优选为单螺杂环基和双螺杂环基。更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、 5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2022082894-appb-000030
术语“稠杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元(例如6、7、8、9、10、11、12、13和14元)(即6至14元稠杂环基)，更优选为7至10元(例如7、8、9或10元)(即7至10元稠杂环基)。根据组成环的数目可以分为双环或多环(例如三环、四环)稠杂环基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2022082894-appb-000031
术语“桥杂环基”指5至20元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元(例如6、7、8、9、10、11、12、13和14元)(即6至14元桥杂环基)，更优选为7至10元(例如7、8、9或10元)(即7至10元桥杂环基)。根据组成环的数目可以分为双环或多环(例如三环、四环)桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2022082894-appb-000032
所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2022082894-appb-000033
等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，所述取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、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，其非限制性实例包括：
Figure PCTCN2022082894-appb-000034
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个。
术语“杂芳基”指包含1至4个杂原子(例如1、2、3和4个)、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)(即5至10元杂芳基)，更优选为5元或6元(即5元或6元杂芳基)，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡 嗪基、哒嗪基、咪唑基、吡唑基、***基、四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、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，其非限制性实例包括：
Figure PCTCN2022082894-appb-000035
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，所述取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个。
上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同环原子或两个不同的环原子上除去两个氢原子所衍生的残基即“二价环烷基”、“二价杂环基”、“亚芳基”和“亚杂芳基”。
术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实施例包含(三甲基硅)乙氧基甲基(SEM)、四氢吡喃基、叔丁氧羰基、乙酰基、苄基、烯丙基、对甲基苯磺酰基(Ts)和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代；氨基保护基优选为Ts。
术语“羟基保护基”是指通常用于阻断或保护羟基而反应在化合物的其它官能团上进行的羟基衍生物。作为示例，优选地，所述的羟基保护基可以是三乙基硅基、三异丙基硅基、叔丁基二甲基硅烷基(TBS)、叔丁基二苯基硅基、甲基、叔丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氢吡喃基(THP)、甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“芳基氧基”指芳基-O-，其中芳基如上所定义。
术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。
术语“烷硫基”指烷基-S-，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”或“氧代”指“＝O”。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如上所定义。
Ts指对甲苯磺酰基。
本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。
本公开所述化合物的化学结构中，键
Figure PCTCN2022082894-appb-000036
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022082894-appb-000037
可以为
Figure PCTCN2022082894-appb-000038
或者同时包含
Figure PCTCN2022082894-appb-000039
Figure PCTCN2022082894-appb-000040
两种构型。对于所有的碳-碳双键，即使仅命名了一个构型，Z型和E型均包括在内。
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是 指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。
如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物。
Figure PCTCN2022082894-appb-000041
所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。
本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为 2H(氘，D)、 3H(氚，T)、 11C、 13C、 14C、 15N、 17O、 18O、 32p、 33p、 33S、 34S、 35S、 36S、 18F、 36Cl、 82Br、 123I、 124I、 125I、 129I和 131I等，优选氘。
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为1～6个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备盐。 通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
针对药物或药理学活性剂而言，术语“治疗有效量”是指足以达到或至少部分达到预期效果的药物或药剂的用量。治疗有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的治疗有效量可以由本领域技术人员根据常规试验确定。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开提供通式(I)所示的化合物或其可药用的盐的制备方法，该方法包括：
Figure PCTCN2022082894-appb-000042
通式(IA)的化合物或其盐在碱性或微波条件下，经脱保护反应，得到通式(I)的化合物或其可药用的盐；
其中R w为氨基保护基；优选为Ts；
R 0为氢原子；
环A、环B、G 1、G 2、G 6、G 7、R’、R a、p和q如通式(I)中所定义。
方案二
本公开提供通式(II)或(III)所示的化合物或其可药用的盐的制备方法，该方法包括：
Figure PCTCN2022082894-appb-000043
通式(IIA)的化合物或其盐在碱性或微波条件下，经脱保护反应，得到通式(II)的化合物或其可药用的盐；或
通式(IIIA)的化合物或其盐在碱性或微波条件下，经脱保护反应，得到通式(III)的化合物或其可药用的盐；
其中R w为氨基保护基；优选为Ts；
R 0为氢原子；
环A、G 1、G 2、G 3、G 5、G 6、G 7、R’、R 4a、R 4b、R q、R、n和q如通式(II)或(III)中所定义。
方案三
本公开提供通式(IV)或(V)所示的化合物或其可药用的盐的制备方法，该方法包括：
Figure PCTCN2022082894-appb-000044
通式(IVA)的化合物或其盐在碱性或微波条件下，经脱保护反应，得到通式(IV)的化合物或其可药用的盐；或
通式(VA)的化合物或其盐在碱性或微波条件下，经脱保护反应，得到通式(V)的化合物或其可药用的盐；
其中R w为氨基保护基；优选为Ts；
R 0为氢原子；
环A、G 1、R 2、R 3、R 5、G 6、G 7、R’、R 4a、R 4b、R q、R、n和q如通式(IV)或(V)中所定义。
方案四
本公开提供通式(VI)所示的化合物或其可药用的盐的制备方法，该方法包括：
Figure PCTCN2022082894-appb-000045
通式(VIA)的化合物或其盐在碱性或微波条件下，经脱保护反应，得到通式(VI)的化合物或其可药用的盐；
其中R w为氨基保护基；优选为Ts；
R 0为氢原子；
环A、环B、R d、R e、G 1、G 2、G 6、G 7、R a、R’、t和p如通式(VI)中所定义。
方案五
本公开提供通式(VI)所示的化合物或其可药用的盐的制备方法，该方法包括：
Figure PCTCN2022082894-appb-000046
通式(VIA’)的化合物或其盐与通式(VIB)或其盐在碱性条件和缩合剂存在下，经酰化反应，得到通式(VI)的化合物或其可药用的盐；
其中Q为羟基；
环A、环B、R d、R e、G 1、G 2、G 6、G 7、R a、R 0、R’、t和p如通式(VI)中所定义。
方案六
本公开提供通式(VI)所示的化合物或其可药用的盐的制备方法，该方法包括：
Figure PCTCN2022082894-appb-000047
通式(VIA’)的化合物或其盐与通式(VIB)或其盐在碱性条件下，经酰化反应，得到通式(VI)的化合物或其可药用的盐；
其中Q为卤素；
环A、环B、R d、R e、G 1、G 2、G 6、G 7、R a、R 0、R’、t和p如通式(VI)中所定义。
以上合成方案中提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、二异丙基氨基锂的四氢呋喃溶液、醋酸钠、醋酸钾、叔丁醇钠、叔丁醇钾、双(三甲基硅基)胺基锂、双(三甲基硅基)胺基锂四氢呋喃溶液或1,8-二氮杂二环十一碳-7-烯，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化锂和氢氧化钾；脱保护反应提供碱性条件的试剂优选为氢氧化钠；酰化反应提供碱性条件的试剂优选为N,N-二异丙基乙胺。
以上合成方案中所述的缩合剂包括但不限于1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N,N'-二环己基碳化二亚胺、N,N'-二异丙基碳二酰亚胺、O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯、1-羟基苯并***、1-羟基-7-偶氮苯并三氮唑、O-苯并三氮唑-N,N,N',N'-四甲脲六氟磷酸酯(HBTU)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐或六氟磷酸苯并***-1-基-氧基三吡咯烷基磷；优选为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)。
上述步骤的反应优选在溶剂中进行，所用的溶剂包括但不限于：吡啶、乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。
上述微波反应的反应温度为50-180℃，优选为100℃。
上述微波反应的反应时间为0.5-4小时；优选为2小时。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan LCQ advantage MAX)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：正己烷/二氯甲烷体系，D：乙酸乙酯/二氯甲烷/正己烷，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
N,N-二甲基-4-(7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酰胺1
Figure PCTCN2022082894-appb-000048
第一步
5-溴-4-氟-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶1b
将化合物5-溴-4-氟-1H-吡咯并[2,3-b]吡啶1a(5.0g，23.3mmol，南京药石)溶于四氢呋喃(60mL)中，冰浴下加入氢化钠(1.2g，30.2mmol，含量60％)，恢复室温反应30分钟后，加入对甲基苯磺酰氯(5.7g，30.2mmol)。搅拌反应1小时后，反应液中加入水(60mL)，用二氯甲烷萃取(50mL×3)，合并有机相，减压浓缩后，加入10mL石油醚和乙酸乙酯(V:V＝10:1)的混合溶液中，搅拌20分钟，固体析出后过滤干燥即得标题化合物1b(8.2g，产率：95％)。
MS m/z(ESI):368.9[M+1]。
第二步
4-氟-5-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶1c
将化合物1b(4.3g，11.6mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷 络合物(1.9g，2.3mmol)，联硼酸频那醇酯(5.9g，23.3mmol)，乙酸钾(3.4g，34.9mmol)溶于1,4-二氧六环(60mL)。氮气氛围下，100℃反应14小时，硅藻土过滤后，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物1c(4.3g，产率：88％)。
MS m/z(ESI):417.2[M+1]。
第三步
(2-溴-5-(4-甲基哌嗪-1-基)苯基)甲醇1f
将化合物1d(10.6g，36.9mmol，采用公知的方法“Journal of Medicinal Chemistry,2005,48,2667-2677”)溶于甲醇(200mL)中，冰浴下分批加入硼氢化钠(2.4g，63.7mmol)。恢复室温反应1小时后，反应液减压浓缩，加入水(60mL)，用二氯甲烷萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1f(6.3g，产率：60％)。MS m/z(ESI):285.2[M+1]。
第四步
(2-(4-氟-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-5-基)-5-(4-甲基哌嗪-1-基)苯基)甲醇1g
将化合物1c(4.0g，8.7mmol)，化合物1f(2.5g，8.7mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(1.4g，1.7mmol)，碳酸钠(1.9g，17.9mmol)，溶于110mL 1,4-二氧六环和水(V:V＝10:1)的混合溶液中。氮气氛围下，100℃反应6小时，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1g(3.9g，产率：90％)。
MS m/z(ESI):495.2[M+1]。
第五步
7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶1h
将化合物1g(3.9g，7.8mmol)溶于二甲亚砜(40mL)中，加入叔丁醇钾(4.5g，40.1mmol)，100℃反应1小时，反应液减压浓缩后，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1h(1.5g，产率：60％)。
MS m/z(ESI):321.2[M+1]。
第六步
3-碘-7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶1i
将化合物1h(1.3g，4.0mmol)溶于四氢呋喃(20mL)，冰浴下加入N-碘代丁二酰亚胺(960mg，4.26mmol)。反应1小时后，加入二氯甲烷(200mL)稀释，用2M氢氧化钠溶液洗涤(100mL)，收集有机相，无水硫酸钠干燥，过滤除去干燥剂后减压浓缩即得标题化合物1i(1.5g，产率：82％)。
MS m/z(ESI):447.1[M+1]。
第七步
3-碘-7-(4-甲基哌嗪-1-基)-1-对甲苯磺酰基-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶1j
将化合物1i(1.1g，2.5mmol)溶于四氢呋喃(15mL)中，冰浴下加入氢化钠(152mg，3.8mmol，含量60％)。保持温度反应30分钟后，加入对甲苯磺酰氯(616mg，3.2mmol)，搅拌反应1小时后，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1j(1.3g，产率：84％)。
MS m/z(ESI):601.2[M+1]。
第八步
N,N-二甲基-4-(7-(4-甲基哌嗪-1-基)-1-对甲苯磺酰基-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酰胺1k
将化合物1j(200mg，0.33mmol)，化合物N,N-二甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苯甲酰胺(138mg，0.50mmol，上海乐研)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(52mg，0.06mmol)，碳酸钠(68mg，0.66mmol)溶于6mL 1,4-二氧六环和水(V:V＝10:1)的混合溶液中。氮气氛围下，100℃反应12小时，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1k(80mg，产率：26％)。
MS m/z(ESI):622.2[M+1]。
第九步
N,N-二甲基-4-(7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酰胺1
将化合物1k(80mg，0.14mmol)溶于甲醇(5mL)，加入2M氢氧化钠溶液(0.75mL)，50℃反应1小时，反应液减压浓缩后用高效液相色谱法(Waters-2545，色谱柱：SharpSil-T C18,30*150mm,5μm；流动相：水(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈25％-50％，流速：30mL/min)纯化得到标题化合物1(30mg，产率：50％)。
MS m/z(ESI):468.1[M+1]。
1H NMR(500MHz,CD 3OD):δ8.50(s,1H),7.66(d,2H),7.62(d,1H),7.38-7.33(m,3H),6.94(dd,1H),6.76(d,1H),5.10(s,2H),3.18(t,4H),3.04(s,3H),3.01(s,3H)2.57(t,4H),2.29(s,3H)。
实施例2
3-(1-乙基-1H-吡唑-4-基)-7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶2
Figure PCTCN2022082894-appb-000049
将化合物1j(30mg，49.96μmol)，化合物1-乙基-4-(四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑(17mg，76.54μmol，上海毕得)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(7.8mg，9.56μmol)，碳酸钠(10.8mg，101.9μmol)溶于3mL 1,4-二氧六环和水(V:V＝10:1)的混合溶液中。氮气氛围下，微波100℃反应2小时，反应液减压浓缩后用高效液相色谱法(Waters-2545，色谱柱：SharpSil-T C18,30*150mm,5μm；流动相：水(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈25％-50％，流速：30mL/min)纯化得到标题化合物2(1.1mg，产率：5％)。
MS m/z(ESI):415.1[M+1]。
1H NMR(500MHz,CD 3OD):δ8.56(s,1H),7.97(s,1H),7.82(s,1H),7.72(d,1H),7.41(s,1H),7.06(dd,1H),6.90(d,1H),5.31(s,2H),4.25(q,2H),3.31-3.28(m,4H),2.67(t,4H),2.39(s,3H),1.53(t,3H)。
实施例3
(3-羟基氮杂环丁烷-1-基)(4-(7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯基)甲酮3
Figure PCTCN2022082894-appb-000050
第一步
4-(7-(4-甲基哌嗪-1-基)-1-对甲苯磺酰基-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b] 吡啶-3-基)苯甲酸甲酯3a
将化合物1j(20mg，33μmol)，化合物4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苯甲酸甲酯(13mg，49.5μmol，上海乐妍)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(5.6mg，6.8μmol)，碳酸钠(7.2mg，67.9μmol)溶于3mL 1,4-二氧六环和水(V:V＝10:1)的混合溶液中。氮气氛围下，100℃反应12小时，反应液减压浓缩，通过柱层析以洗脱剂体系A纯化得到标题化合物3a(20mg，产率：98.5％)。MS m/z(ESI):609.2[M+1]。
第二步
4-(7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酸3b
将化合物3a(20mg，32.8μmol)溶于4mL甲醇和四氢呋喃(V:V＝10:1)的混合溶液中，加入2M氢氧化钠水溶液(1mL)。50℃反应12小时，降至室温后中反应液用2M盐酸(1mL)调节pH至中性，减压浓缩后得到粗品标题化合物3b(14mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):441.2[M+1]。
第三步
(3-羟基氮杂环丁烷-1-基)(4-(7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯基)甲酮3
将化合物3b(14mg，31.78μmol)溶于无水N,N-二甲基甲酰胺(2mL)中，依次加入3-羟基氮杂环丁烷(8.4mg，114.9μmol)，2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(31mg，81.5μmol)，N,N-二异丙基乙胺(32.2mg，249μmol)。搅拌反应1小时，反应液减压浓缩后用高效液相色谱法(Waters-2545，色谱柱：SharpSil-T C18,30*150mm,5μm；流动相：水(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈25％-50％，流速：30mL/min)纯化得到标题化合物3(2mg，产率：13％)。MS m/z(ESI):496.1[M+1]。
1H NMR(500MHz,CD 3OD):δ8.62(s,1H),7.78(d,2H),7.74(d,1H),7.68(d,2H),7.48(s,1H),7.06(dd,1H),6.87(d,1H),5.23(s,2H),4.46(q,1H),4.25(d,2H),4.00(d,2H),3.29(t,4H),2.68(t,4H),2.40(s,3H)。
实施例4
(S)-N-(2-羟丙基)-N-甲基-4-(7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酰胺4
Figure PCTCN2022082894-appb-000051
将化合物3b(15mg，34μmol)溶于无水N,N-二甲基甲酰胺(2mL)中，依次加入(S)-1-甲基氨基丙烷-2-醇(6mg，66.6μmol)，2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(19mg，49.9μmol)，N,N-二异丙基乙胺(22mg，170.2μmol)。搅拌反应1小时，反应液减压浓缩后用高效液相色谱法(Waters-2545，色谱柱：SharpSil-T C18,30*150mm,5μm；流动相：水(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈25％-50％，流速：30mL/min)纯化得到标题化合物4(2.3mg，产率：13％)。
MS m/z(ESI):512.2[M+1]。
1H NMR(500MHz,CD 3OD):δ8.62(s,1H),7.81-7.72(m,3H),7.54-7.40(m,3H),7.06(dd,1H),6.88(d,1H),5.22(s,2H),4.04(s,1H),3.68(d,2H),3.32-3.26(m,4H),3.19(s,3H),2.68(t,4H),2.40(s,3H),1.28(d,3H)。
实施例5
N,N-二甲基-4-(6-甲基-7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酰胺5
Figure PCTCN2022082894-appb-000052
Figure PCTCN2022082894-appb-000053
第一步
2-(3-溴-2-甲基苯基)-1,3-二氧戊环烷5b
将化合物3-溴-2-甲基苯甲醛5a(10g，50.24mmol，上海毕得)溶于甲苯(200mL)，加入乙二醇(4.68g，75.36mmol)，对甲基苯磺酸(955.6mg，5.02mmol)，加热至140℃分水反应14小时，反应冷却至室温，依次用5％碳酸钠水溶液(100mL)洗涤，饱和食盐水(100mL)洗涤，收集有机相，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物5b(12g，产率：98.2％)。
第二步
2-甲基-3-(4-甲基哌嗪-1-基)苯甲醛5c
将化合物5b(11g，45.2mmol)溶于甲苯(100mL)，加入三(二亚苄基丙酮)二钯(2.07g，2.26mmol)，1,1'-联萘-2,2'-双二苯膦(1.97g，3.16mmol)，叔丁醇钾(7.1g，63.34mmol)，1-甲基哌嗪(5.9g，58.5mmol)，加热至100℃反应14小时，反应冷却至室温，加入6M盐酸(100mL)搅拌反应2小时后，用6M氢氧化钠水溶液调节PH至13左右，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物5c(5.5g，产率：49.8％)。
MS m/z(ESI):219.2[M+1]。
第三步
6-溴-2-甲基-3-(4-甲基哌嗪-1-基)苯甲醛5d
将化合物5c(0.5g，2.29mmol)溶于二氯甲烷(5mL)，冰浴下加入溴化钾(817.7mg，6.87mmol)，溴素(439.2mg，2.74mmol)，搅拌反应14小时，反应液中加入饱和碳酸氢钠水溶液(10mL)淬灭，用二氯甲烷酯萃取(5mL×3)，收集有机相，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物5d(500mg，产率：73.4％)。
MS m/z(ESI):297.9[M+1]。
第四步
3-碘-6-甲基-7-(4-甲基哌嗪-1-基)-1-对甲苯磺酰基-1,5-二氢异苯并吡喃并[3,4-d]吡咯[2,3-b]吡啶5e
采用实施例1中的合成路线第三至第七步，将第三步原料化合物1d替换为化合物5d，制得标题化合物5e(500mg，产率：87.7％)。
MS m/z(ESI):615.2[M+1]。
第五步
N,N-二甲基-4-(6-甲基-7-(4-甲基哌嗪-1-基)-1-对甲苯磺酰基-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酰胺5f
将化合物5e(50mg，81.36μmol)，化合物N,N-二甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苯甲酰胺(25mg，86.15μmol)，醋酸钯(1.83mg，8.15μmol)，1,1’-双(二叔丁基膦)二茂铁(4.1mg，8.13μmol)，磷酸钾(36mg，162.16μmol)溶于2mL1,4-二氧六环和水(V:V＝10:1)的混合溶液中。氮气氛围下，100℃反应12小时，反应液中加入5mL水稀释，用二氯甲烷萃取(5mL×3)，合并有机相，无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，得到粗品标题化合物5f(30mg)，无需纯化直接用于下步反应。
MS m/z(ESI):636.2[M+1]。
第六步
N,N-二甲基-4-(6-甲基-7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酰胺5
将化合物5f(50mg，78.6μmol)溶于甲醇(5mL)，加入2M氢氧化钠溶液(0.75mL)，80℃反应0.5小时，反应液减压浓缩后用高效液相色谱法(Waters-2545，色谱柱：SharpSil-T C18,30*150mm,5μm；流动相：水(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈25％-50％，流速：30mL/min)纯化得到标题化合物5(2.1mg，产率：5.5％)。
MS m/z(ESI):482.2[M+1]。
1H NMR(500MHz,CD 3OD):δ8.63(s,1H),7.83-7.76(m,2H),7.69(d,1H),7.48(m,3H),7.17(d,1H),5.33(s,2H),4.61(br,4H),2.61(br,4H),3.16(s,3H),3.13(s,3H),2.40(s,3H),2.28(s,3H)。
实施例6
3-(1-乙基-1H-吡唑-4-基)-6-甲基-7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶6
Figure PCTCN2022082894-appb-000054
采用实施例5中的合成路线，将第五步原料化合物N,N-二甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苯甲酰胺替换为化合物1-乙基-4-(四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑，制得标题化合物6(3mg，产率：41％)。
MS m/z(ESI):429.0[M+1]。
1H NMR(500MHz,CDCl 3):δ9.26(s,1H),8.66(s,1H),7.85(s,1H),7.79(s,1H),7.64(d,1H),7.14(d,1H),5.38(s,2H),4.27(q,2H),3.01(t,3H),2.70(m,3H),2.45(m,2H),2.30(s,3H),1.71(m,4H),1.59(t,3H)。
实施例7
1-(3-(1-乙基-1H-吡唑-4-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-8-基)-N,N-二甲基甲胺7
Figure PCTCN2022082894-appb-000055
第一步
3-溴-4-(羟甲基)-N,N-二甲基苯甲酰胺7b
将2M二甲胺的甲醇溶液(2mL)溶于四氢呋喃(5mL)中，冰浴下加入2M三甲基铝的甲苯溶液(1.5mL)，搅拌10分钟，加入化合物3-溴-4-(羟甲基)苯甲酸甲酯7a(500mg，2.0mmol，上海皓鸿)，搅拌反应3小时后，加入水(10mL)淬灭反应，用二氯甲烷萃取(50mL×3)，合并有机相，减压浓缩后，用硅胶柱色谱法以洗脱剂体系A纯化得到得标题化合物7b(400mg，产率：75％)。
MS m/z(ESI):257.9[M+1]。
第二步
(2-溴-4-((二甲氨基)甲基)苯基)甲醇7c
将化合物7b(400mg，1.55mmol)溶于四氢呋喃(5mL)中，加入硼烷二甲硫醚络合物(5.26mmol，0.5mL)70℃反应2小时后，加入甲醇(2mL)淬灭反应，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物7c(300mg，产率：79％)。
MS m/z(ESI):244.2[M+1]。
第三步
1-(3-碘-1-对甲苯磺酰基-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-8-基)-N,N-二甲基甲胺7d
采用实施例1中的合成路线第四至第七步，将第四步原料化合物1f替换为化合物7c，制得标题化合物7d(50mg，产率：26％)。
MS m/z(ESI):559.9[M+1]。
第四步
1-(3-(1-乙基-1H-吡唑-4-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-8-基)-N,N-二甲基甲胺7
将化合物7d(100mg，0.178mmol)，化合物1-乙基-4-(四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑(47mg，0.214mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(15mg，0.02mmol)，碳酸钠(38mg，0.36mmol)溶于6mL 1,4-二氧六环和水(V:V＝10:1)的混合溶液中。氮气氛围下，100℃反应12小时，反应液减压浓缩，所得黑色油状物溶于甲醇(5mL)，加入2M氢氧化钠溶液(0.75mL)，50℃反应1小时，反应液减压浓缩后用高效液相色谱法(Waters-2545，色谱柱：SharpSil-T C18,30*150mm,5μm；流动相：水(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈25％-40％，流速：30mL/min)纯化得到标题化合物7(2mg，产率：3％)。
MS m/z(ESI):374.0[M+1]。
1H NMR(500MHz,CD 3OD):δ8.69(s,1H),7.98(s,1H),7.84(d,2H),7.44(s,1H),7.28(s,2H),5.37(s,2H),4.25(q,2H),3.59(s,2H),2.32(s,6H),1.53(t,3H)。
实施例8
4-(7-(4-乙基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)-N,N-二甲基苯甲酰胺8
Figure PCTCN2022082894-appb-000056
Figure PCTCN2022082894-appb-000057
第一步
2-(3-溴苯基)-1,3-二氧环戊烷8b
将化合物3-溴苯甲醛8a(14g，75.66mmol，上海毕得)溶于甲苯(200mL)，加入乙二醇(7.04g，113.4mmol)，对甲基苯磺酸(1.4g，7.56mmol)，加热至140℃分水反应14小时，反应冷却至室温，依次用5％碳酸钠水溶液(100mL)，饱和食盐水(100mL)洗涤，收集有机相，减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物8b(17g，产率：98％)。
第二步
3-(4-乙基哌嗪-1-基)苯甲醛8c
将化合物8b(4g，17.4mmol)溶于甲苯(60mL)，加入三(二亚苄基丙酮)二钯(1.59g，1.73mmol)，1,1'-联萘-2,2'-双二苯膦(2.17g，3.48mmol)，叔丁醇钾(3.91g，34.8mmol)，1-乙基哌嗪(2.99g，26.2mmol)，加热至100℃反应14小时，反应冷却至室温，加入6M盐酸(100mL)搅拌反应2小时后，用6M氢氧化钠水溶液调节PH至13左右，乙酸乙酯萃取(100mL×3)，合并有机相，无水硫酸钠干燥，过滤除去干燥剂后减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物8c(1.9g，产率：49.8％)。
MS m/z(ESI):219.2[M+1]。
第三步
2-溴-5-(4-乙基哌嗪-1-基)苯甲醛8d
将化合物8c(1.9g，8.7mmol)溶于二氯甲烷(30mL)，冰浴下加入N-溴代丁二酰亚胺(3.09g，17.36mmol)，升至室温搅拌反应1小时，反应液用1M氢氧化钠水溶液调节PH至8左右，用二氯甲烷酯萃取(20mL×3)，收集有机相，减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物8d(1.2g，产率：46.3％)。MS m/z(ESI):297.9[M+1]。
后续采用实施例1中的合成路线第三至第九步，将第三步原料化合物1d替换 为化合物8d，制得标题化合物8(5mg，产率：18.2％)。
MS m/z(ESI):482.2[M+1]。
1H NMR(500MHz,CD 3OD):δ8.61(s,1H),7.80-7.75(m,2H),7.73(d,1H),7.50-7.44(m,3H),7.05(dd,1H),6.86(d,1H),5.21(s,2H),3.29(t,4H),3.14(d,6H),2.68(t,4H),2.53(q,2H),1.18(t,3H)。
实施例9
N,N,2-三甲基-4-(7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酰胺9
Figure PCTCN2022082894-appb-000058
采用实施例1中的合成路线，将第八步原料化合物N,N-二甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苯甲酰胺替换为化合物N,N,2-三甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苯甲酰胺，制得标题化合物9(10mg，产率：44％)。
MS m/z(ESI):482.2[M+1]。
1H NMR(500MHz,CDCl 3):δ9.31(s,1H),8.68(s,1H),7.70(d,1H),7.52(d,2H),7.22(d,1H),7.00(dd,1H),6.73(d,1H),5.18(s,2H),3.28(t,4H),3.20(s,3H),2.96(s,3H),2.62(t,4H),2.39(s,3H),2.37(s,3H)。
实施例10
N,N-二甲基-4-(8-甲基-7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酰胺10
Figure PCTCN2022082894-appb-000059
采用实施例5中的合成路线，将第一步原料化合物5a替换为化合物3-溴-4-甲基苯甲醛，制得标题化合物10(1.2mg，产率：4％)。
MS m/z(ESI):482.2[M+1]。
1H NMR(500MHz,CD 3OD):δ8.65(s,1H),7.77(d,2H),7.69(s,1H),7.50-7.43(m,3H),6.99(s,1H),5.22(s,2H),3.14(d,6H),3.08(s,4H),2.93(s,4H),2.59(s,3H),2.41(s,3H)。
实施例11
4-(6-氟-7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)-N,N-二甲基苯甲酰胺11
Figure PCTCN2022082894-appb-000060
采用实施例5中的合成路线，将第一步原料化合物5a替换为化合物3-溴-2-氟苯甲醛，制得标题化合物11(3mg，产率：13.1％)。
MS m/z(ESI):486.2[M+1]。
1H NMR(500MHz,CD 3OD):δ8.65(s,1H),7.77(d,2H),7.61(d,1H),7.51-7.46(m,3H),7.12(t,1H),5.36(s,2H),3.24-3.10(m,10H),2.67(t,4H),2.38(s,3H)。
实施例12
4-(6-甲氧基-7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)-N,N-二甲基苯甲酰胺12
Figure PCTCN2022082894-appb-000061
采用实施例5中的合成路线，将第一步原料化合物5a替换为化合物3-溴-2-甲氧基苯甲醛(上海毕得)，制得标题化合物12(6mg，产率：10％)。
MS m/z(ESI):498.2[M+1]。
1H NMR(500MHz,CD 3OD):δ8.62(s,1H),7.789(d,2H),7.57(d,1H),7.50-7.47(m,3H),7.08(d,1H),5.37(s,2H),3.90(s,3H),3.35-3.21(m,4H),3.21-3.16(m,2H),3.13(d,6H),2.76-2.72(m,2H),2.43(s,3H)。
实施例13
(S)-N-(2-羟丙基)-N-甲基-4-(6-甲基-7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酰胺13
Figure PCTCN2022082894-appb-000062
第一步
4-(6-甲基-7-(4-甲基哌嗪-1-基)-1-对甲苯磺酰基-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酸甲酯13a
将化合物5e(200mg，325μmol)，化合物4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苯甲酸甲酯(128mg，488μmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(26mg，32.5μmol)，碳酸钠(69mg，650μmol)溶于10mL 1,4-二氧六环和水(V:V＝10:1)的混合溶液中。氮气氛围下，100℃反应12小时，反应液减压浓缩，通过柱层析以洗脱剂体系A纯化得到标题化合物13a(150mg，产率：74％)。
MS m/z(ESI):623.2[M+1]。
第二步
4-(6-甲基-7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酸13b
将化合物13a(150mg，240μmol)溶于12mL甲醇和四氢呋喃(V:V＝10:1)的混合溶液中，加入2M氢氧化钠水溶液(5mL)。50℃反应12小时，降至室温后，反应液用2M盐酸调节pH至中性，减压浓缩后得到粗品标题化合物13b(100mg)，产物不经纯化直接用于下一步反应。
MS m/z(ESI):455.2[M+1]。
第三步
(S)-N-(2-羟丙基)-N-甲基-4-(6-甲基-7-(4-甲基哌嗪-1-基)-1,5-二氢异苯并吡喃并[3,4-d]吡咯并[2,3-b]吡啶-3-基)苯甲酰胺13
将化合物13b(50mg，110μmol)溶于无水N,N-二甲基甲酰胺(2mL)中，依次加入(S)-1-甲基氨基丙烷-2-醇(40mg，444μmol)，2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(105mg，275μmol)，N,N-二异丙基乙胺(57mg，440μmol)。 搅拌反应1小时，反应液减压浓缩后用高效液相色谱法(Waters-2545，色谱柱：SharpSil-T C18,30*150mm,5μm；流动相：水(10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈25％-50％，流速：30mL/min)纯化得到标题化合物13(10mg，产率：17.2％)。
MS m/z(ESI):526.2[M+1]。
1H NMR(500MHz,CD 3OD):δ8.60(s,1H),7.78-7.74(m,3H),7.66(d,1H),7.49(d,1H),7.42(s,1H),7.16(d,1H),5.31(s,2H),4.20-4.03(m,2H),3.69-3.66(m,2H),3.50-3.45(m,2H),3.33(s,3H),3.12(s,3H),2.68-2.60(m,2H),2.40(s,3H),2.22(s,3H),1.34-1.29(m,3H)。
生物学评价
测试例1.HPK1酶活性检测(ADP-Glo法)
1.试剂与仪器
1)ADP-Glo激酶检测试剂盒(包含ADP-Glo试剂和激酶检测试剂(Kinase Detection Reagent))(Promega,V9101)
2)1M Tris-HCl缓冲液pH＝7.5(索莱宝,T1140)
3)1M MgCl 2(Invitrogen,AM9530G)
4)1M DTT(Thermofisher,P2325)
5)20mg/mL牛血清白蛋白(BSA)(TAKARA 2320)
6)ATP溶液(10mM)(Thermofisher PV3227)
7)去磷酸化MBP(Sigma,13-110)(以下简称MBP)
8)HPK1(Signalchem,M23-11G)
9)96孔小体积白板(Cisbio,66PL96100)
10)PHERA star酶标仪(BMG labtech)
2.实验方法
2.1试剂准备
a.检测缓冲液:40mM Tris-HCl缓冲液，7.5；20mM MgCl 2；0.1mg/mL BSA；50μM DTT；
b.HPK1酶溶液：检测缓冲液配制为终浓度1.5ng/μL的HPK1酶溶液；
c.ATP和MBP混合底物：检测缓冲液分别配制终浓度60μM的ATP和终浓度0.6ug/μL的MBP，等体积混合配好的ATP和MBP；
d.化合物：起始浓度33.3μM，3倍稀释，9个浓度梯度。所有浓度化合物用检测缓冲液稀释33.3倍，备用。
2.2实验步骤
a.96孔板，每孔加入2μL配制好的HPK1酶溶液，第1列不加酶，加2μL的检测缓冲液。
b.每孔加2μL的化合物，第1和最后1列不加化合物，加DMSO作为对照，离心，混匀震荡2分钟，室温孵育10分钟。
c.每孔加入2μL ATP和MBP混合物底物，离心，混匀震荡2分钟，室温孵育60分钟。
d.每孔加6μL ADP-Glo试剂，离心，混匀震荡2分钟，室温孵育40分钟。
e.每孔加12μL激酶检测试剂，离心，混匀震荡2分钟，室温孵育40分钟。
f.酶标仪读板，记录RLU(相对发光单位(Relative luminescence unit))数值。
g.Graphpad软件作图，计算化合物IC 50值，见表1。
表1本公开中化合物对HPK1酶活性抑制作用IC 50值
实施例编号 HPK1/IC 50(nM)
1 0.7
2 1.5
3 1.3
4 1.5
5 2.8
6 1.3
7 4.9
8 1.7
9 3.6
10 3.0
11 7.0
13 1.5
结论：本公开化合物对HPK1酶的活性具有明显的抑制作用。
测试例2.Jurkat细胞SLP76蛋白磷酸化检测(HTRF法)
1.试剂与仪器
1)RPMI 1640培养基(Gibco,61870044)
2)胎牛血清(Gibco,10099141C)(以下简称FBS)
3)75cm 2滤盖细胞培养瓶(Corning,430641)
4)PBS,pH 7.4(Gibco,10010049)
5)CD3抗体，抗人，纯功能级(CD3Antibody,anti-human,pure-functional grade)(Miltenyi Biotec,130-093-387)
6)Phospho-SLP-76(Ser376)细胞试剂盒(Cisbio,63ADK076PEG)
7)HTRF 96孔小体积白板(Cisbio,66PL96100)
8)96孔板(Corning,3788)
9)微孔板震荡器(其林贝尔)
10)PHERA star酶标仪(BMG labtech)
11)Countstar BioMed自动细胞计数仪(上海睿钰生物科技)
12)超净工作台(Thermo,1300ALL)
13)CO 2培养箱(Thermo，I160)
2.细胞及培养方法
Jurkat E6-1细胞购买于美国模式菌种收集中心(ATCC，TIB-152)，用RPMI1640培养基(10％FBS)培养。细胞培养密度维持在2×10 5到2×10 6细胞/mL，一周传代2-3次。
3.化合物准备
a.测试化合物用DMSO溶解至5mM。
b.化合物起始浓度5mM，3倍稀释，10个浓度梯度。
c.用培养液将所有浓度化合物稀释100倍，备用。
4.实验步骤
a.Jurkat细胞计数，用新鲜培养液调整细胞密度至5×10 6/mL。
b.96孔板，每孔接种20μL细胞，37℃培养4小时。
c.每孔加入5μL化合物(第1列和12列加5μL 0.5％的DMSO)，37℃培养1小时。
d.用培养液将CD3抗体稀释至20ng/μL，每孔加入5μL(第1列加5μL培养液作为对照)，37℃培养半小时。
e.每孔加入10μL裂解液裂解细胞，室温850rpm震荡半小时。
f.取16μL细胞裂解液至新的HTRF 96孔板中，每孔加入4μL抗体混合物，室温放置过夜。
g.酶标仪读板，记录665nm和620nm信号值。
h.Graphpad软件作图，计算化合物IC 50值，见表2。
表2本公开中化合物对Jurkat细胞SLP76蛋白磷酸化抑制作用IC 50值
实施例编号 SLP76蛋白磷酸化/IC 50(nM)
1 189.0
2 173.0
5 162.6
6 107.6
11 107.5
13 144.1
结论：本公开化合物对Jurkat细胞SLP76蛋白磷酸化均具有明显的抑制作用。

Claims (20)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    Figure PCTCN2022082894-appb-100001
    其中：
    环A为芳基或杂芳基；
    环B为苯基或5元或6元杂芳基；
    G 1为CR 1或氮原子；
    G 2为CR 2或氮原子；
    G 6选自C(O)、CR 6aR 6b、NR 6c和氧原子；
    G 7选自C(O)、CR 7aR 7b、NR 7c和氧原子；
    R 6a、R 6b、R 7a和R 7b相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 0、R 6c和R 7c相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    各个R a相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) rNR mR n、-OR p、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、氧代、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或两个R a与环B形成稠合环，所述的稠合环任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、氧代、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、氧代、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所 取代；
    R’、R 1和R 2相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-NR dR e、-OR g、-(CO)R f、-(CO)NR dR e、-(CO)OR g、-SO 2R f、-SO 2NR dR e、-NR h(CO)R f、-NR h(CO)NR dR e、-NR h(CO)OR g、-NR hSO 2R f、-NR hSO 2NR dR e、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-NR d2R e2、-OR g2、-(CO)R f2、-(CO)NR d2R e2、-(CO)OR g2、-SO 2R f2、-SO 2NR d2R e2、-NR h2(CO)R f2、-NR h2(CO)NR d2R e2、-NR h2(CO)OR g2、-NR h2SO 2R f2、-NR h2SO 2NR d2R e2、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R m、R n、R p、R d、R e、R f、R g、R h、R d2、R e2、R f2、R g2和R h2相同或不同，且各自独立地选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或R m和R n、R d和R e、R d2和R e2与它们所连接的氮原子一起形成杂环基，所述杂环基任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、氧代、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个基团取代，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    p为0、1、2、3或4；
    q为0、1、2、3或4；且
    r为0、1、2、3或4。
  2. 根据权利要求1所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)或(III)所示的化合物或其可药用的盐：
    Figure PCTCN2022082894-appb-100002
    其中：
    G 3为CR 3或氮原子；
    G 5为CR 5或氮原子；
    R 3和R 5相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 4a和R 4b相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、-(CH 2) rNR mR n、-OR p、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、氧代、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    各个R相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、烯基、炔基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烯基、炔基、烷氧基、卤代烷基、卤代烷氧基、氰基、氨基、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或者两个R一起形成氧代基；
    R q选自氢原子、烷基、烯基、炔基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    n为0、1、2、3、4、5或6；
    环A、G 1、G 2、G 6、G 7、R 0、R m、R n、R p、R’、r和q如权利要求1中所定义。
  3. 根据权利要求1或2中所述的通式(I)所示的化合物或其可药用的盐，其中-G 7-G 6-选自-O-CHR 6a-、-CHR 7a-O-、-NR 7c-CHR 6a-、-CHR 7a-NR 6c-、-C(O)-NR 6c-和-NR 7c-C(O)-，R 6a、R 7a、R 6c和R 7c如权利要求1中所定义；优选地，-G 7-G 6-选自-O-CH 2-、-CH 2-O-、-NH-CH 2-、-CH 2-NH-、-C(O)-NH-和-NH-C(O)-；更优选地，-G 7-G 6-为-O-CH 2-。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其可药用的盐，其中环A为6-10元芳基或5元或6元杂芳基，优选为苯基或吡唑基。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其可药用的盐，其中G 1为CR 1，R 1如权利要求1中所定义；优选地，R 1选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，R 1为氢原子。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其可药用的盐，其中G 2为CR 2，R 2如权利要求1中所定义；优选地，R 2选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，R 2为氢原子。
  7. 根据权利要求2至6中任一项所述的通式(II)或(III)所示的化合物或其可药用的盐，其中G 3为CR 3，R 3如权利要求2中所定义；优选地，R 3选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；更优选地，R 3为氢原子。
  8. 根据权利要求2至7中任一项所述的通式(II)或(III)所示的化合物或其可药用的盐，其中G 5为CR 5，R 5如权利要求2中所定义；优选地，R 5选自氢原子、卤素、C 1-6烷基和C 1-6烷氧基。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其可药用的盐，其中R 0选自氢原子、C 1-6烷基和C 1-6卤代烷基；优选为氢原子。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其可药用的盐，其中各个R’相同或不同，且各自独立地选自C 1-6烷基、C 1-6卤代烷基和-(CO)NR dR e，R d和R e如权利要求1中所定义；优选地，R d和R e相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，或R d和R e与它们所连接的氮原子一起形成3至8元杂环基，所述3至8元杂环基任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基中的一个或多个基团取代。
  11. 根据权利要求2至10中任一项所述的通式(II)或(III)所示的化合物或其可药用的盐，其中R 4a和R 4b相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、-(CH 2) rNR mR n、羟基和C 1-6羟烷基，其中所述的C 1-6烷基和C 1-6烷氧基各自独立地任选被选自卤素、C 1-6烷氧基、C 1-6卤代烷氧基、氰基、氨基、羟基和C 1-6羟烷基中的一个或多个取代基所取代，R m、R n和r如权利要求1中所定义；
    优选地，R 4a和R 4b中至少有一个为-(CH 2) rNR mR n，R m和R n相同或不同，且各自独立地选自氢原子、C 1-6烷基、C 1-6卤代烷基和C 1-6羟烷基，其中所述的C 1-6烷基任选被选自C 1-6烷氧基、C 1-6卤代烷氧基、氰基和氨基中的一个或多个取代基所 取代；或R m和R n与它们所连接的氮原子一起形成3至8元杂环基，所述3至8元杂环基任选被选自卤素、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、氰基、氨基、羟基、氧代和C 1-6羟烷基中的一个或多个基团取代；r为0、1或2。
  12. 根据权利要求2至11中任一项所述的通式(II)或(III)所示的化合物或其可药用的盐，其中R q选自氢原子、C 1-6烷基和C 1-6卤代烷基；优选为C 1-6烷基。
  13. 根据权利要求1至9和11中任一项所述的通式(I)所示的化合物或其可药用的盐，其选自如下化合物：
    Figure PCTCN2022082894-appb-100003
    Figure PCTCN2022082894-appb-100004
  14. 一种通式(IA)所示的化合物或其盐：
    Figure PCTCN2022082894-appb-100005
    其中：R w为氨基保护基；优选为Ts；
    环A、环B、G 1、G 2、G 6、G 7、R’、R a、p和q如权利要求1中所定义。
  15. 根据权利要求14中所述的通式(IA)所示的化合物或其盐，其选自如下化合物：
    Figure PCTCN2022082894-appb-100006
  16. 一种制备根据权利要求1所述的通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
    Figure PCTCN2022082894-appb-100007
    通式(IA)的化合物或其盐经脱保护反应，得到通式(I)所示的化合物或其可药用的盐；
    其中R w为氨基保护基；优选为Ts；
    R 0为氢原子；
    环A、环B、G 1、G 2、G 6、G 7、R’、R a、p和q如权利要求1中所定义。
  17. 一种药物组合物，所述药物组合物含有根据权利要求1至13中任一项所 述的通式(I)所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  18. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求17所述的药物组合物在制备用于抑制HPK1的药物中的用途。
  19. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求17所述的药物组合物在制备用于治疗和/或预防选自癌症、自身免疫性疾病、炎性疾病、感染性疾病、心血管疾病、神经退行性疾病、糖尿病和生殖障碍的疾病或病症的药物中的用途。
  20. 根据权利要求19所述的用途，其中所述的疾病或病症选自癌症、过敏、哮喘、败血症、艾滋病毒感染、乙肝病毒感染、缺血、动脉粥样硬化、中风和阿尔茨海默氏病；所述的癌症优选选自脑癌、甲状腺癌、头颈癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胰腺癌、胆管癌、结直肠癌、小肠癌、胃肠道间质瘤、尿路上皮癌、尿道癌、膀胱癌、乳腺癌、卵巢癌、子宫内膜癌、***、输卵管癌、睾丸癌、***癌、白血病、淋巴瘤、多发性骨髓瘤、皮肤癌、恶性脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤和成神经细胞瘤。
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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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