WO2022228543A1 - 桥环类化合物、其制备方法及其在医药上的应用 - Google Patents

桥环类化合物、其制备方法及其在医药上的应用 Download PDF

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WO2022228543A1
WO2022228543A1 PCT/CN2022/090172 CN2022090172W WO2022228543A1 WO 2022228543 A1 WO2022228543 A1 WO 2022228543A1 CN 2022090172 W CN2022090172 W CN 2022090172W WO 2022228543 A1 WO2022228543 A1 WO 2022228543A1
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cancer
pharmaceutically acceptable
compound
acceptable salt
general formula
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PCT/CN2022/090172
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English (en)
French (fr)
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李心
蔡国栋
董怀德
张喆
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 CN202280028320.0A priority Critical patent/CN117203207A/zh
Publication of WO2022228543A1 publication Critical patent/WO2022228543A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • 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
    • 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a bridged ring compound, a preparation method thereof and its application in medicine.
  • the present disclosure relates to bridged ring compounds represented by general formula (I), their preparation methods and pharmaceutical compositions containing such compounds, and their use in the preparation of medicines for inhibiting KRAS G12D and/or KRAS G12V use.
  • RAS is one of the oncogenes with the highest mutation rate in tumors, and about 30% of human malignancies are associated with mutations in the RAS gene.
  • the RAS family includes KRAS, NRAS and HRAS, of which KRAS mutations are the most common, accounting for about 85%.
  • KRAS mutations are common in solid tumors, with high frequency mutations in the three most lethal human cancers—lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%).
  • KRAS gene mutations 97% are the 12th or 13th amino acid residues mutated, among which G12D and G12V are important mutations.
  • Data analysis of European and American populations showed that in pancreatic cancer, colorectal cancer, and non-small cell lung cancer, G12D mutations accounted for 36%, 12%, and 4% of patients, respectively.
  • KRAS After KRAS is activated, it regulates the functions of cell proliferation, survival, migration and metabolism through numerous downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM1-RAc. After KRAS gene mutation, the protein is continuously activated, which leads to the continuous activation of downstream signaling pathways and promotes tumorigenesis.
  • KRAS Due to the lack of traditional small-molecule binding sites on the surface of KRAS protein, and its ultra-high affinity for guanylate, it is extremely difficult to inhibit, and it has long been regarded as an undruggable drug target.
  • KRAS has been and remains a target of great interest in drug development.
  • G12D and/or G12V as a mutant that is widely and highly expressed in various tumors, has important clinical significance to develop inhibitors against it.
  • G 1 is selected from O, NR a and CR b R c ;
  • G 2 is NR d ;
  • Ring A is aryl or heteroaryl
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • L is selected from a single bond, O and NR e ;
  • R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH 2 ) u -NR f R g , hydroxy and hydroxyalkyl;
  • R 2 and R 4 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 ) v -NR h R i , hydroxy, hydroxyalkyl and cycloalkyl;
  • R 3 and R 6 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 ) w - NRjRk , nitro , hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 5 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, cyano, hydroxy, and hydroxyalkyl;
  • R b and R c 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 ) x -NR m R n , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Ra , R d , Re , R f , R g , Rh , R i , R j , R k , R m and R n are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group , alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • u, v, w and x are the same or different and are each independently selected from 0, 1, 2 and 3;
  • r 0, 1 or 2;
  • p 0, 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, 4 or 5;
  • t 0, 1, 2, 3, 4 or 5.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein G 1 is O or CR b R c , and R b and R c are as in the general formula (I) as defined in ; preferably, G 1 is O or CH 2 ; more preferably, G 1 is O.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a naphthalene ring; and/or ring B is R 6 may be substituted at any position of the ring B.
  • Another aspect of the present disclosure relates to a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:
  • G 1 , G 2 , L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , p, q, r and t are as defined in general formula (I).
  • Another aspect of the present disclosure relates to a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:
  • y is 0, 1, 2, 3, or 4;
  • G 1 , Ring A, Ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , p, r and t are as defined in general formula (I).
  • the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof wherein for Ring C is 6-membered aryl or 5-6 membered heteroaryl, z is 0, 1 or 2, and R is as defined in general formula (III); preferably, for R 3 is as defined in general formula (III).
  • the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof wherein for R 3a and R 3b are the same or different, and are each independently selected from a hydrogen atom, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, -(CH 2 ) w -NR j R k and C 1-6 hydroxyalkyl, R j and R k are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group, and w is 0 or 1; preferably, for R 3a and R 3b are the same or different, and are each independently selected from a hydrogen atom, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; more
  • the compound represented by general formula (I) or (III) or a pharmaceutically acceptable salt thereof wherein ring A is a bicyclic aryl group or a bicyclic heteroaryl group; preferably, ring A is a bicyclic aryl group or a bicyclic heteroaryl group.
  • ring A is an 8-10-membered bicyclic aryl group or an 8-10-membered bicyclic heteroaryl group; more preferably, it is a naphthyl group.
  • the compound represented by general formula (I) or (III) or a pharmaceutically acceptable salt thereof wherein for R is as defined in general formula (I); preferably, for R 6 is halogen; further preferably, for R 6 is halogen; R 6 is further preferably F.
  • the compound represented by general formula (I) or (III) or a pharmaceutically acceptable salt thereof wherein for preferably
  • the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof wherein R e is a hydrogen atom or a C 1-6 alkyl group; Preferably, Re is a hydrogen atom.
  • the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof wherein R 1 are the same or different, and each is independently selected from hydrogen Atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, amino, -(CH 2 ) u -NR f R g , hydroxy and C 1-6 hydroxyalkyl, R f and R g
  • R 1 is the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group, and u is 0 or 1;
  • R 1 is the same or different, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkane and C 1-6 haloalkyl; further preferably, R 1 is a hydrogen atom.
  • the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof wherein 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, -(CH 2 ) v -NR h R i , hydroxy and C 1-6 hydroxy Alkyl, R h and R i are the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group, and v is 0 or 1; preferably, R 2 is selected from hydrogen atom, halogen, C 1-6 alkane and C 1-6 haloalkyl; further preferably, R 2 is a hydrogen atom.
  • the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof wherein R 3 is the same or different, and each is independently selected from hydrogen Atom, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano , amino, -(CH 2 ) w -NR j R k , hydroxy and C 1-6 hydroxyalkyl, R j and R k are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group, w is 0 or 1; preferably, R 3 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, hydroxyl and C 1 -6 hydroxyalkyl; further
  • the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof wherein R 4 is selected from hydrogen atom, halogen, C 1-6 Alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, -(CH 2 ) v -NR h R i , hydroxy and C 1-6 hydroxy Alkyl, R h and R i are the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group, and v is 0 or 1; preferably, R 4 is selected from hydrogen atom, halogen, C 1-6 alkane and C 1-6 haloalkyl; further preferably, R 4 is halogen; most preferably, R 4 is F.
  • the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof wherein R 5 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy and C 1-6 hydroxyalkyl; preferably, R 5 are the same or different, and are each independently selected from hydrogen atoms, C 1-6 alkyl, hydroxy and C 1-6 hydroxyalkyl; further preferably, R 5 is a hydrogen atom.
  • the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof wherein R 6 is the same or different, and each 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, -(CH 2 ) w -NR j R k , hydroxy and C 1-6 hydroxyalkyl, R j and R k are the same or different, and each is independently a hydrogen atom or a C 1-6 alkyl group, w is 0 or 1; preferably, R 6 is the same or different, And each is independently selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; further preferably, R 6 is halogen; most preferably, R 6 is F.
  • the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof wherein q is 1, 2 or 3; preferably, q is 1 or 2; More preferably, q is 2.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein G 1 is O or CH 2 ; G 2 is NH; L is selected from a single bond, O and NR e ; R e is a hydrogen atom or a C 1-6 alkyl group; Ring A is an 8-10-membered bicyclic aryl group or an 8-10-membered bicyclic heteroaryl group; Ring B is a 3-8-membered heterocyclic group; p is 0 or 1; R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, amino, -(CH 2 ) u -NR f R g , hydroxyl and C 1-6 hydroxyl Alkyl, R f and R g are the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group, and u is 0 or 1; R 2 is selected from
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein G 1 is O or CH 2 ; G 2 is NH; L is O; p is 1; R 1 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; R 2 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; q is 1 or 2; R 3 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, hydroxyl and C 1-6 hydroxyalkyl; R 4 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; r is 0 or 1; R 5 is selected from hydrogen atom, C 1-6 alkyl, hydroxyl and C 1-6 hydroxyl alkyl; t is 1
  • the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof wherein G 1 is O or CH 2 ; G 2 is NH; L is O; p is 0; R 2 is a hydrogen atom; q is 1, 2 or 3; R 3 is the same or different, and each is independently selected from hydrogen atom, halogen, C 1-6 alkyl, C 2-6 alkynyl and hydroxyl; R 4 is halogen; r is 1; R 5 is a hydrogen atom; t is 1; and R 6 is halogen.
  • 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 is an amino protecting group; preferably Boc;
  • G 1 , Ring A, Ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , p, q, r and t are as defined in general formula (I).
  • Another aspect of the present disclosure relates to a compound of general formula (IIA) or a salt thereof,
  • R is an amino protecting group; preferably Boc;
  • G 1 , L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , p, q, r and t are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a compound of general formula (IIIA) or a salt thereof,
  • R is an amino protecting group; preferably Boc;
  • R 0 is a hydroxyl protecting group; preferably MOM;
  • G 1 , Ring A, Ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , y, p, r and t are as defined in general formula (III).
  • 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; optionally, when R 3 and/or R 6 group contains a protecting group , before or after the deprotection reaction, it also includes a step of removing the protecting group on the R3 and/or R6 group ;
  • R is an amino protecting group; preferably Boc;
  • G 2 is NH
  • G 1 , Ring A, Ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , p, q, r and t 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 (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; optionally, when R 3 and/or R 6 group contains a protecting group , before, at the same time or after the deprotection reaction, it also includes a step of removing the protecting group on the R3 and/or R6 group ;
  • R is an amino protecting group; preferably Boc;
  • G 2 is NH
  • G 1 , Ring A, Ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , p, q, r and t 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 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 ; optionally, when the R3 and/or R6 group contains a protecting group , before or after the deprotection reaction, it also includes a step of removing the protecting group on the R3 and/or R6 group ;
  • R is an amino protecting group; preferably Boc;
  • G 2 is NH
  • G 1 , L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , p, q, r and t are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) 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 ; optionally, when the R3 and/or R6 group contains a protecting group , before, at the same time or after the deprotection reaction, it also includes a step of removing the protecting group on the R3 and/or R6 group ;
  • R is an amino protecting group; preferably Boc;
  • G 2 is NH
  • G 1 , L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , p, q, r and t are as defined in general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIIA) or a salt thereof is subjected to a deprotection reaction to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof; optionally, when the R 6 group contains a protecting group, in the deprotection reaction Before or after the protection reaction, it also includes the step of removing the protecting group on the R 6 group;
  • R is an amino protecting group; preferably Boc;
  • R 0 is a hydroxyl protecting group; preferably MOM;
  • G 1 , Ring A, Ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , y, p, r and t are as defined in general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIIA) or a salt thereof is subjected to a deprotection reaction to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof; optionally, when R 3 and/or R 6 groups contain a protecting group , before, at the same time or after the deprotection reaction, it also includes a step of removing the protecting group on the R3 and/or R6 group ;
  • R is an amino protecting group; preferably Boc;
  • R 0 is a hydroxyl protecting group; preferably MOM;
  • G 1 , Ring A, Ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , y, p, r and t are as defined in general formula (III).
  • compositions comprising a compound shown in the general formula (I), (II), (III) or Table A of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to a compound of general formula (I), (II), (III) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a compound for inhibiting KRAS G12D and/or Use in medicine of KRAS G12V; wherein KRAS G12D and/or KRAS G12V is preferably KRAS G12D.
  • the present disclosure further relates to compounds of general formula (I), (II), (III) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a compound for the treatment and/or prevention of disease or the use in the medicine of the disease, the disease or disease is cancer; the disease or disease is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophagus cancer , gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial cancer, urinary tract cancer, bladder cancer, Anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma
  • the present disclosure further relates to a method of inhibiting KRAS G12D and/or KRAS G12V, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), (II), (III) or Table A, or a compound thereof.
  • the present disclosure further relates to a method of treating and/or preventing a disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III) or Table A, or a compound thereof.
  • the present disclosure further relates to a compound represented by general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.
  • the present disclosure further relates to a compound represented by the general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in inhibiting KRAS G12D and/or or KRAS G12V; wherein KRAS G12D and/or KRAS G12V is preferably KRAS G12D.
  • the present disclosure further relates to a compound represented by the general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as treatment and/or prevention
  • a medicine for a disease or condition wherein the disease or condition is cancer; the disease or condition is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, Gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anus Cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia
  • diseases or disorders described in the present disclosure are diseases or disorders that are treated and/or prevented by inhibiting KRAS G12D and/or KRAS G12V; wherein KRAS G12D and/or KRAS G12V are preferably KRAS G12D.
  • 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 (also known as bronchial lung cancer) is selected from non-small cell lung cancer (NSCLC)
  • 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 activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the health of the patient condition, behavior of the patient, diet of the patient, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the optimal mode of treatment 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-methylhe
  • 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 substituents are preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • 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 ( -CH2) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituent preferably being selected from alkenyl, alkynyl, alkoxy, haloalkoxy , cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane One or more of oxy, 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.
  • a spiro atom a carbon atom shared between the monocyclic rings, which may contain one or more double bonds.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan).
  • spirocycloalkyl groups are divided into mono-spirocycloalkyl groups, or poly-spirocycloalkyl groups (eg, double-spirocycloalkyl groups), preferably mono-spirocycloalkyl groups and double-spiro-cycloalkyl groups alkyl.
  • 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, preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxy, 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.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably selected from the group consisting of 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, haloalkane One or more of oxy, 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 (eg 1, 2, 3 and 4) heteroatoms, 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 8 to 10 membered (eg 8, 9 or 10 membered) ), more preferably 5- or 6-membered (ie, 5- or 6-membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridyl oxazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • 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, haloalkane One or more of oxy, 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, tert-butoxycarbonyl (Boc), acetyl, benzyl, allyl, p-toluenesulfonic acid Acyl (Ts) and p-methoxybenzyl, etc.
  • SEM trimethylsilyl)ethoxymethyl
  • Boc tetrahydropyranyl
  • Boc tert-butoxycarbonyl
  • acetyl benzyl
  • allyl allyl
  • These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or
  • 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; the hydroxyl protecting group is preferably MOM.
  • 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.
  • Boc refers to tert-butoxycarbonyl.
  • TIPS refers to triisopropylsilyl.
  • 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), it can be combined 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.
  • C 1-6 alkyl optionally substituted by 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 by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano substitution.
  • 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 acidic conditions to obtain the compound of general formula (I) or its pharmaceutically acceptable salt; optionally, when R 3 and/or R 6 groups When containing a protective group, the step of removing the protective group on the R3 and/or R6 group under acidic or basic conditions is also included before or after the deprotection reaction;
  • R is an amino protecting group; preferably Boc;
  • G 2 is NH
  • G 1 , Ring A, Ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , p, q, r and t are as defined in general formula (I).
  • the present disclosure provides a preparation method of a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIA) or its salt is subjected to deprotection reaction under acidic conditions to obtain the compound of general formula (II) or its pharmaceutically acceptable salt; optionally, when R 3 and/or R 6 groups When containing a protective group, the step of removing the protective group on the R3 and/or R6 group under acidic or basic conditions is also included before or after the deprotection reaction;
  • R is an amino protecting group; preferably Boc;
  • G 2 is NH
  • G 1 , L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , p, q, r and t are as defined in general formula (II).
  • the present disclosure provides a preparation method of a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIIA) or its salt is subjected to a deprotection reaction under acidic conditions to obtain the compound of general formula (III) or a pharmaceutically acceptable salt thereof; optionally, when the R 6 group contains a protecting group, Before or after the deprotection reaction, it also includes a step of removing the protecting group on the R 6 group under acidic or basic conditions;
  • R is an amino protecting group; preferably Boc;
  • R 0 is a hydroxyl protecting group; preferably MOM;
  • G 1 , Ring A, Ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , y, p, r and t are as defined in general formula (III).
  • 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 acidic conditions to obtain the compound of general formula (I) or its pharmaceutically acceptable salt; optionally, when R 3 and/or R 6 groups When containing a protecting group, the step of removing the protecting group on the R 3 and/or R 6 group under acidic or basic conditions is also included before, at the same time or after the deprotection reaction;
  • R is an amino protecting group; preferably Boc;
  • G 2 is NH
  • G 1 , Ring A, Ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , p, q, r and t are as defined in general formula (I).
  • the present disclosure provides a preparation method of a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIA) or its salt is subjected to deprotection reaction under acidic conditions to obtain the compound of general formula (II) or its pharmaceutically acceptable salt; optionally, when R 3 and/or R 6 groups When containing a protecting group, the step of removing the protecting group on the R 3 and/or R 6 group under acidic or basic conditions is also included before, at the same time or after the deprotection reaction;
  • R is an amino protecting group; preferably Boc;
  • G 2 is NH
  • G 1 , L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , p, q, r and t are as defined in general formula (II).
  • the present disclosure provides a preparation method of a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IIIA) or its salt is subjected to deprotection reaction under acidic conditions to obtain the compound of general formula (III) or its pharmaceutically acceptable salt; optionally, when R 3 and/or R 6 groups When containing a protective group, the step of removing the protective group on the R 3 and/or R 6 group under acidic or basic conditions is also included before, at the same time or after the deprotection reaction;
  • R is an amino protecting group; preferably Boc;
  • R 0 is a hydroxyl protecting group; preferably MOM;
  • G 1 , Ring A, Ring B, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , y, p, r and t are as defined in general formula (III).
  • the reagents providing acidic conditions in the above synthesis scheme include organic acids and inorganic acids, and the organic acids include but are not limited to trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me 3 SiCl and TMSOTf; the
  • the inorganic acids include, but are not limited to, hydrogen chloride, hydrochloric acid in dioxane, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; preferably hydrochloric acid in dioxane.
  • the reagents that provide alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamine Lithium propylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride in tetrahydrofuran or 1,8-diazabicycloundec-7- alkene
  • the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride and potassium hydroxide; preferably It is a solution of tetrabutylammonium fluoride in tetrahydr
  • the terminal alkyne can be protected by TIPS, and the reagent for removing TIPS is preferably a solution of tetrabutylammonium fluoride in tetrahydrofuran or cesium fluoride.
  • 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
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • MS used Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • 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, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • reaction was carried out at 100°C for 14 hours under nitrogen atmosphere, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain 1 g of the title compound (25 mg, yield: 38.4%).
  • the starting material compound 1f of the third step was replaced with 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5 - Tetramethyl-1,3,2-dioxaborolane (prepared by the method disclosed in Intermediate 21 on page 111 of the specification in patent application "WO2021/041671A1") to obtain the title compound 4 ( 5 mg, yield: 24.7%).
  • the first step starting compound 1b was replaced with 3,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester to obtain the title compound 6a ( 90 mg, yield: 70.4%).
  • the crude compound 7a (15 mg, 20.1 ⁇ mol) was dissolved in ethyl acetate (3 mL), 1 mL of 4M hydrochloric acid dioxane solution was added, and the reaction was carried out at room temperature for 1.5 hours.
  • the reaction solution was concentrated under reduced pressure and subjected to high performance liquid chromatography (Waters -2545, chromatographic column: SharpSil-T C18, 30*150mm, 5 ⁇ m; mobile phase: water (containing 10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30mL/min) Purification gave the title compound 7 (3 mg, yield: 24.8%).
  • the first step starting material compound 1b was replaced with 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester hydrochloride (Shanghai Bidder) to obtain the title compound 10 (5 mg, yield: 12.4%).
  • Test Example 1 Experimental Biological Evaluation of ERK Phosphorylation Inhibition in AGS Cells (HTRF Method)
  • AGS cells (Nanjing Kebai, CBP60476) were cultured with RPMI1640 (Hyclone, SH30809.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, AGS cells were seeded in a 96-well plate at a density of 40,000 cells/well in complete medium, 190 ⁇ L of cell suspension per well, and placed in a 37°C, 5% CO 2 cell incubator overnight.
  • lysis buffer lysis buffer, Cisbio, 64KL1FDF
  • blocking reagent Cisbio, 64KB1AAC
  • IC50 values of compound inhibitory activity were calculated according to compound concentration and ratio of phosphorylated ERK/total ERK using Graphpad Prism software, and the results are shown in Table 1 below.
  • the disclosed compounds have a good inhibitory effect on ERK phosphorylation in AGS cells.
  • Test Example 2 Experimental Biological Evaluation of GP2d Cell 3D Proliferation Inhibition
  • the inhibitory effect of the disclosed compounds on KRAS targets was evaluated by testing the 3D proliferation inhibitory effect of the disclosed compounds on GP2d cells.
  • GP2d cells (Nanjing Kebai, CBP60010) were cultured in complete medium, namely DMEM/high glucose medium (Hyclone, SH30243.01) containing 10% fetal bovine serum (Corning, 35-076-CV).
  • GP2d cells were seeded in a 96-well low-adsorption plate (Corning, CLS7007-24EA) at a density of 1000 cells/well using complete medium, 90 ⁇ L of cell suspension per well, centrifuged at 2000 rpm for 5 minutes at room temperature and placed for 37 °C, 5% CO 2 cell incubator overnight.
  • IC50 values of compound inhibitory activity were calculated using Graphpad Prism software, and the results are shown in Table 2 below.
  • the disclosed compounds have a good inhibitory effect on the 3D proliferation of GP2d cells.
  • Test Example 3 SPR method to detect the affinity of the disclosed compound with KRAS protein isoform G12D or WT
  • Biotinylated Avi-KRAS-WT or Avi-KRAS-G12D was first diluted to 20 ⁇ g/mL with 1 ⁇ HBS-P+ (Cat. #BR1006-71) buffer containing 100 mM MgCl, and then flowed through SA (Cat. .#BR1005-31) Biosensor chip channel 2 for 420s to obtain a coupling level of about 5000-7000RU.
  • the small molecule compound samples were injected sequentially from low to high for 120 s, and then dissociated for 720 s.
  • the experiments were performed in a single-cycle kinetic mode.
  • the Biacore 8K instrument detects the reaction signal in real time to obtain the binding and dissociation curve. After the experiment, Biacore 8K evaluation software was used for data analysis, and a 1:1 model was used for data fitting and affinity data.
  • Test Example 4 Inhibitory effect of the compounds of the present disclosure on the proliferation of SW620
  • SW620 cells (Nanjing Kebai Biology)
  • Fetal Bovine Serum (FBS) (Gibco)
  • PBS Phosphate Buffered Saline
  • SW620 cells are human colon cancer cells carrying the KRAS G12V mutation, and the proliferative effects of compounds on SW620 cells were evaluated. After adding the compound, it can inhibit the proliferation of SW620 cells, and the relative luminescence unit value was determined by CTG, so as to evaluate the inhibitory effect of the compound on the proliferation of SW620 cells.
  • test compound Add 10 ⁇ L of the test compound after secondary dilution to each well, the final concentration of the test compound is 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52nM; DMSO wells are blank wells, only medium is added The test wells are negative control wells.
  • Cells were cultured in a 37 °C, CO - free incubator for 5 days. On the 6th day, the 96-well cell culture plate was taken out, 50 ⁇ L of thawed CTG was added, and incubated at room temperature for 20 minutes, and the relative luminescence unit (RLU) value was read by a microplate reader.
  • RLU relative luminescence unit
  • Table 4 shows the IC50 values of the compounds of the present disclosure measured by the inhibition of human SW620 proliferation.

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Abstract

本公开涉及桥环类化合物、其制备方法及其在医药上的应用。具体而言，本公开涉及一种通式(I)所示的桥环类化合物、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KRAS G12D和/或KRAS G12V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

桥环类化合物、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，涉及一种桥环类化合物、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)所示的桥环类化合物、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KRAS G12D和/或KRAS G12V的药物中的用途。
背景技术
RAS是在肿瘤中突变率最高的致癌基因之一，约30％的人类恶性肿瘤与RAS基因的突变有关。RAS家族包括KRAS、NRAS和HRAS，其中KRAS突变最为常见，约占85％。KRAS突变常见于实体瘤，在人类三大致命性癌症——肺癌(17％)、结直肠癌(33％)和胰腺癌(61％)中均存在高频突变。在KRAS的基因突变中，97％是第12号或者第13号氨基酸残基发生了突变，其中G12D和G12V是重要突变。对欧美人群的数据分析显示：在胰腺癌、结直肠癌及非小细胞肺癌中，G12D突变分别占病人的36％、12％和4％。
KRAS被激活以后，通过以RAF-MEK-ERK，PI3K-AKT-mTOR及TIAM1-RAc为代表的众多下游信号通路，调控细胞增殖、存活、迁移及代谢等多个方面的功能。KRAS基因突变后，蛋白持续处于活化状态，导致下游信号通路持续激活而促进肿瘤发生。
由于KRAS蛋白表面缺乏传统意义上的小分子结合位点，并与鸟苷酸有着超高亲和力而极难被抑制，长久以来被认为是不可成药的药物靶点。但基于KRAS异常激活在癌症进展中的重要性和普遍性，KRAS一直并仍然是药物开发非常关注的靶点。目前除了KRAS G12C抑制剂以外，仍缺乏对其他突变有效的KRAS抑制剂，使得大部分KRAS突变的病人依然无药可治。G12D和/或G12V，作为一个在多种肿瘤中广泛高表达的突变体，开发针对它的抑制剂有着重要的临床意义。
目前已公开的相关专利申请有WO2021041671A1、WO2020146613A1、WO2017172979A1、WO2020238791A1和WO2021000885A1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 PCTCN2022090172-appb-000001
其中：
G 1选自O、NR a和CR bR c；
G 2为NR d；
环A为芳基或杂芳基；
环B选自环烷基、杂环基、芳基和杂芳基；
L选自单键、O和NR e；
R 1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) u-NR fR g、羟基和羟烷基；
R 2和R 4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) v-NR hR i、羟基、羟烷基和环烷基；
R 3和R 6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) w-NR jR k、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R 5相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、氰基、羟基和羟烷基；
R b和R c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) x-NR mR n、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
R a、R d、R e、R f、R g、R h、R i、R j、R k、R m和R n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；
u、v、w和x相同或不同，且各自独立地选自0、1、2和3；
r为0、1或2；
p为0、1、2、3、4或5；
q为0、1、2、3、4或5；且
t为0、1、2、3、4或5。
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，其中G 1为O或CR bR c，R b和R c如通式(I)中所定义；优选地，G 1为O或CH 2；更优 选地，G 1为O。
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，其中环A为萘环；和/或环B为
Figure PCTCN2022090172-appb-000002
R 6可取代在所述环B任意位置。
本公开另一方面涉及一种通式(II)所示的化合物或其可药用的盐：
Figure PCTCN2022090172-appb-000003
其中
G 1、G 2、L、R 1、R 2、R 3、R 4、R 5、R 6、p、q、r和t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)或(II)所示的化合物或其可药用的盐，其中R d为氢原子或C 1-6烷基；优选地，R d为氢原子。
本公开另一方面涉及一种通式(III)所示的化合物或其可药用的盐：
Figure PCTCN2022090172-appb-000004
其中，
y为0、1、2、3或4；
G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、p、r和t如通式(I)中所定义。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中
Figure PCTCN2022090172-appb-000005
为
Figure PCTCN2022090172-appb-000006
环C为6元芳基或5-6元杂芳基，z为0、1 或2，R 3如通式(III)中所定义；优选地，
Figure PCTCN2022090172-appb-000007
为
Figure PCTCN2022090172-appb-000008
R 3如通式(III)中所定义。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中
Figure PCTCN2022090172-appb-000009
为
Figure PCTCN2022090172-appb-000010
R 3a和R 3b相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、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) w-NR jR k和C 1-6羟烷基，R j和R k相同或不同，且各自独立地为氢原子或C 1-6烷基，w为0或1；优选地，
Figure PCTCN2022090172-appb-000011
为
Figure PCTCN2022090172-appb-000012
R 3a和R 3b相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6炔基、C 1-6卤代烷基和C 1-6羟烷基；更优选地，
Figure PCTCN2022090172-appb-000013
为
Figure PCTCN2022090172-appb-000014
R 3a为氢原子或卤素，R 3b选自卤素、C 1-6烷基和C 2-6炔基；最优选地，
Figure PCTCN2022090172-appb-000015
为
Figure PCTCN2022090172-appb-000016
R 3a为氢原子或F，R 3b选自F、乙基和乙炔基。
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 1为O或CR bR c，R b和R c如通式(I)中所定义；优选地，G 1为O或CH 2；更优选地，G 1为O。
在本公开一些实施方案中，所述的通式(I)或(II)所示的化合物或其可药用的盐， 其中G 2为NH。
在本公开一些实施方案中，所述的通式(I)或(III)所示的化合物或其可药用的盐，其中环A为双环芳基或双环杂芳基；优选地，环A为8-10元双环芳基或8-10元双环杂芳基；进一步优选为萘基。
在本公开一些实施方案中，所述的通式(I)或(III)所示的化合物或其可药用的盐，其中环B为3-8元杂环基；优选地，环B为
Figure PCTCN2022090172-appb-000017
R 6可取代在所述环B任意位置。
在本公开一些实施方案中，所述的通式(I)或(III)所示的化合物或其可药用的盐，其中
Figure PCTCN2022090172-appb-000018
为
Figure PCTCN2022090172-appb-000019
R 6如通式(I)中所定义；优选地，
Figure PCTCN2022090172-appb-000020
为
Figure PCTCN2022090172-appb-000021
R 6为卤素；进一步优选地，
Figure PCTCN2022090172-appb-000022
为
Figure PCTCN2022090172-appb-000023
R 6为卤素；R 6进一步优选为F。
在本公开一些实施方案中，所述的通式(I)或(III)所示的化合物或其可药用的盐，其中
Figure PCTCN2022090172-appb-000024
为
Figure PCTCN2022090172-appb-000025
优选为
Figure PCTCN2022090172-appb-000026
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，其中L为O。
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，其中R e为氢原子或C 1-6烷基；优选地，R e为氢原子。
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，其中R 1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卤代烷基、氰基、氨基、-(CH 2) u-NR fR g、羟基和C 1-6羟烷基，R f和R g相同或不同，且各自独立地为氢原子或C 1-6烷基，u为0或1；优选地，R 1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；进一步优选地，R 1为氢原子。
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，其中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、-(CH 2) v-NR hR i、羟基和C 1-6羟烷基，R h和R i相同或不同，且各自独立地为氢原子或C 1-6烷基，v为0或1；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；进一步优选地，R 2为氢原子。
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，其中R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6 烯基、C 2-6炔基、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) w-NR jR k、羟基和C 1-6羟烷基，R j和R k相同或不同，且各自独立地为氢原子或C 1-6烷基，w为0或1；优选地，R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6炔基、C 1-6卤代烷基、羟基和C 1-6羟烷基；进一步优选地，R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6炔基和羟基；最优选地，R 3相同或不同，且各自独立地选自卤素、乙基、乙炔基和羟基。
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，其中R 4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) v-NR hR i、羟基和C 1-6羟烷基，R h和R i相同或不同，且各自独立地为氢原子或C 1-6烷基，v为0或1；优选地，R 4选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；进一步优选地，R 4为卤素；最优选地，R 4为F。
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，其中R 5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卤代烷基、羟基和C 1-6羟烷基；优选地，R 5相同或不同，且各自独立地选自氢原子、C 1-6烷基、羟基和C 1-6羟烷基；进一步优选地，R 5为氢原子。
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，其中R 6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) w-NR jR k、羟基和C 1-6羟烷基，R j和R k相同或不同，且各自独立地为氢原子或C 1-6烷基，w为0或1；优选地，R 6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；进一步优选地，R 6为卤素；最优选地，R 6为F。
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，其中r为0或1，优选1。
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，其中p为0或1，优选1。
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，其中p为0。
在本公开一些实施方案中，所述的通式(I)或(II)所示的化合物或其可药用的盐，其中q为1、2或3；优选地，q为1或2；更优选地，q为2。
在本公开一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中y为0或1，优选1。
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，其中t为1或2，优选1。
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，其中t为0或1。
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，其中u为0或1。
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，其中v为0或1。
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，其中w为0或1。
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，其中x为0或1。
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，其中G 1为O或CH 2；G 2为NH；L选自单键、O和NR e；R e为氢原子或C 1-6烷基；环A为8-10元双环芳基或8-10元双环杂芳基；环B为3-8元杂环基；p为0或1；R 1选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、氰基、氨基、-(CH 2) u-NR fR g、羟基和C 1-6羟烷基，R f和R g相同或不同，且各自独立地为氢原子或C 1-6烷基，u为0或1；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、-(CH 2) v-NR hR i、羟基和C 1-6羟烷基，R h和R i相同或不同，且各自独立地为氢原子或C 1-6烷基，v为0或1；q为1或2；R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、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) w-NR jR k、羟基和C 1-6羟烷基，R j和R k相同或不同，且各自独立地为氢原子或C 1-6烷基，w为0或1；R 4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) v-NR hR i、羟基和C 1-6羟烷基，R h和R i相同或不同，且各自独立地为氢原子或C 1-6烷基，v为0或1；r为0或1；R 5选自氢原子、卤素、C 1-6烷基、C 1-6卤代烷基、羟基和C 1-6羟烷基；t为0或1；R 6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) w-NR jR k、羟基和C 1-6羟烷基，R j和R k相同或不同，且各自独立地为氢原子或C 1-6烷基，w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 1为O或CH 2；G 2为NH；L为O；p为1；R 1选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；R 2选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；q为1或2；R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6炔基、C 1-6卤代烷基、羟基和C 1-6羟烷基；R 4选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；r为0或1；R 5选自氢原子、C 1-6烷基、羟基和C 1-6羟烷基；t为1；且R 6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(II)所示的化合物或其可药用的盐，其中G 1为O或CH 2；G 2为NH；L为O；p为0；R 2为氢原子；q为1、2或3；R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6炔基和羟基；R 4为卤素；r为1；R 5为氢原子；t为1；且R 6为卤素。
表A本公开的典型化合物包括但不限于：
Figure PCTCN2022090172-appb-000027
Figure PCTCN2022090172-appb-000028
Figure PCTCN2022090172-appb-000029
Figure PCTCN2022090172-appb-000030
Figure PCTCN2022090172-appb-000031
Figure PCTCN2022090172-appb-000032
Figure PCTCN2022090172-appb-000033
Figure PCTCN2022090172-appb-000034
Figure PCTCN2022090172-appb-000035
Figure PCTCN2022090172-appb-000036
本公开的另一方面涉及通式(IA)所示的化合物或其盐，
Figure PCTCN2022090172-appb-000037
其中，
R为氨基保护基；优选为Boc；
G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、p、q、r和t如通式(I)中所定义。
本公开的另一方面涉及通式(IIA)所示的化合物或其盐，
Figure PCTCN2022090172-appb-000038
其中，
R为氨基保护基；优选为Boc；
G 1、L、R 1、R 2、R 3、R 4、R 5、R 6、p、q、r和t如通式(II)中所定义。
本公开的另一方面涉及通式(IIIA)所示的化合物或其盐，
Figure PCTCN2022090172-appb-000039
其中，
R为氨基保护基；优选为Boc；
R 0为羟基保护基；优选为MOM；
G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、y、p、r和t如通式(III)中所定义。
本公开的典型中间体化合物包括但不限于：
Figure PCTCN2022090172-appb-000040
Figure PCTCN2022090172-appb-000041
Figure PCTCN2022090172-appb-000042
Figure PCTCN2022090172-appb-000043
Figure PCTCN2022090172-appb-000044
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 PCTCN2022090172-appb-000045
通式(IA)的化合物或其盐经脱保护反应，得到通式(I)的化合物或其可药用的盐；任选地，当R 3和/或R 6基团上含有保护基时，在所述脱保护反应之前或之后还包括脱去R 3和/或R 6基团上的保护基的步骤；
其中R为氨基保护基；优选为Boc；
G 2为NH；
G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、p、q、r和t如通式(I)中所定义。
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 PCTCN2022090172-appb-000046
通式(IA)的化合物或其盐经脱保护反应，得到通式(I)的化合物或其可药用的盐；任选地，当R 3和/或R 6基团上含有保护基时，在所述脱保护反应之前、同时或之后还包括脱去R 3和/或R 6基团上的保护基的步骤；
其中R为氨基保护基；优选为Boc；
G 2为NH；
G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、p、q、r和t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)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022090172-appb-000047
通式(IIA)的化合物或其盐经脱保护反应，得到通式(II)的化合物或其可药用的盐；任选地，当R 3和/或R 6基团上含有保护基时，在所述脱保护反应之前或之后还包括脱去R 3和/或R 6基团上的保护基的步骤；
其中R为氨基保护基；优选为Boc；
G 2为NH；
G 1、L、R 1、R 2、R 3、R 4、R 5、R 6、p、q、r和t如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022090172-appb-000048
通式(IIA)的化合物或其盐经脱保护反应，得到通式(II)的化合物或其可药用的盐；任选地，当R 3和/或R 6基团上含有保护基时，在所述脱保护反应之前、同时或之后还包括脱去R 3和/或R 6基团上的保护基的步骤；
其中R为氨基保护基；优选为Boc；
G 2为NH；
G 1、L、R 1、R 2、R 3、R 4、R 5、R 6、p、q、r和t如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(III)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022090172-appb-000049
通式(IIIA)的化合物或其盐经脱保护反应，得到通式(III)的化合物或其可药用的盐；任选地，当R 6基团上含有保护基时，在所述脱保护反应之前或之后还包括脱去R 6基团上的保护基的步骤；
其中R为氨基保护基；优选为Boc；
R 0为羟基保护基；优选为MOM；
G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、y、p、r和t如通式(III)中所定义。
本公开的另一方面涉及一种制备通式(III)所示的化合物或其可药用的盐的方法，该方法包括：
Figure PCTCN2022090172-appb-000050
通式(IIIA)的化合物或其盐经脱保护反应，得到通式(III)的化合物或其可药用的盐；任选地，当R 3和/或R 6基团上含有保护基时，在所述脱保护反应之前、同时或之后还包括脱去R 3和/或R 6基团上的保护基的步骤；
其中R为氨基保护基；优选为Boc；
R 0为羟基保护基；优选为MOM；
G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、y、p、r和t如通式(III)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)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)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KRAS G12D和/或KRAS G12V的药物中的用途；其中KRAS G12D和/或KRAS G12V优选为KRAS G12D。本公开进一步涉及通式(I)、(II)、(III)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/或预防疾病或病症的药物中的用途，所述的疾病或病症为癌症；所述的疾病或病症优选选自脑癌、甲状腺癌、头颈癌、鼻咽癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胸膜癌、腹膜癌、胰腺癌、胆囊癌、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、肛门癌、关节癌、乳腺癌、阴道癌、卵巢癌、子宫内膜癌、宫颈癌、输卵管癌、睾丸癌、前列腺癌、血管瘤、白血病、淋巴瘤、骨髓瘤、皮肤癌、黑色素瘤、脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤和胶质母细胞瘤；进一步优选选自胰腺癌、结直肠癌和非小细胞肺癌。
本公开进一步涉及一种抑制KRAS G12D和/或KRAS G12V的方法，其包括给予所需患者治疗有效量的通式(I)、(II)、(III)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KRAS G12D和/或KRAS G12V优选为KRAS G12D。
本公开进一步涉及一种治疗和/或预防疾病或病症的方法，其包括给予所需患者治疗有效量的通式(I)、(II)、(III)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为癌症；所述的疾病或病症优选选自脑癌、甲状腺癌、头颈癌、鼻咽癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胸膜癌、腹膜癌、胰腺癌、胆囊癌、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、肛门癌、关节癌、乳腺癌、阴道癌、卵巢癌、子宫内膜癌、宫颈癌、输卵管癌、睾丸癌、前列腺癌、血管瘤、白血病、淋巴瘤、骨髓瘤、皮肤癌、黑色素瘤、脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤和胶质母细胞瘤；进一步优选选自胰腺癌、结直肠癌和非小细胞肺癌。
本公开进一步涉及一种通式(I)、(II)、(III)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)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KRAS G12D和/或KRAS G12V的药物；其中KRAS G12D和/或KRAS G12V优选为KRAS G12D。
本公开进一步涉及一种通式(I)、(II)、(III)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/或预防疾病或病症的药物，其中所述的疾病或病症为癌症；所述的疾病或病症优选选自脑癌、甲状腺癌、头颈癌、鼻 咽癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胸膜癌、腹膜癌、胰腺癌、胆囊癌、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、肛门癌、关节癌、乳腺癌、阴道癌、卵巢癌、子宫内膜癌、宫颈癌、输卵管癌、睾丸癌、前列腺癌、血管瘤、白血病、淋巴瘤、骨髓瘤、皮肤癌、黑色素瘤、脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤和胶质母细胞瘤；进一步优选选自胰腺癌、结直肠癌和非小细胞肺癌。
本公开所述的疾病或病症是通过抑制KRAS G12D和/或KRAS G12V来治疗和/或预防的疾病或病症；其中KRAS G12D和/或KRAS G12V优选为KRAS G12D。
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(又称支气管肺癌)选自非小细胞肺癌(NSCLC)、小细胞肺癌(SCLC)和鳞状细胞癌；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；骨髓瘤优选为多发性骨髓瘤；结直肠癌优选为结肠癌或直肠癌。
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、疾病的严重性、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、排泄的速率、药物的组合等；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，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上被取代，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 PCTCN2022090172-appb-000051
术语“稠环烷基”指5至20元，系统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 PCTCN2022090172-appb-000052
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 PCTCN2022090172-appb-000053
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 PCTCN2022090172-appb-000054
等；优选为
Figure PCTCN2022090172-appb-000055
Figure PCTCN2022090172-appb-000056
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“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 PCTCN2022090172-appb-000057
术语“稠杂环基”指5至20元，系统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 PCTCN2022090172-appb-000058
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 PCTCN2022090172-appb-000059
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 PCTCN2022090172-appb-000060
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“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 PCTCN2022090172-appb-000061
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(例如1、2、3和4个)杂原子、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)，进一步优选为8至10元(例如8、9或10元)，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、三唑基、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 PCTCN2022090172-appb-000062
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。
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(Boc)、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Boc。
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；羟基保护基优选为MOM。
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。
MOM指甲氧基甲基。
Boc指叔丁氧羰基。
TIPS指三异丙基硅基。
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 PCTCN2022090172-appb-000063
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022090172-appb-000064
可以为
Figure PCTCN2022090172-appb-000065
或者同时包含
Figure PCTCN2022090172-appb-000066
Figure PCTCN2022090172-appb-000067
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。
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C 1-6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 PCTCN2022090172-appb-000068
通式(IA)的化合物或其盐在酸性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；任选地，当R 3和/或R 6基团上含有保护基时，在所述脱保护反应之前或之后还包括在酸性或碱性条件下脱去R 3和/或R 6基团上的保护基的步骤；
其中R为氨基保护基；优选为Boc；
G 2为NH；
G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、p、q、r和t如通式(I)中所定义。
方案二
本公开提供通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括：
Figure PCTCN2022090172-appb-000069
通式(IIA)的化合物或其盐在酸性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；任选地，当R 3和/或R 6基团上含有保护基时，在所述脱保护反应之前或之后还包括在酸性或碱性条件下脱去R 3和/或R 6基团上的保护基的步骤；
其中R为氨基保护基；优选为Boc；
G 2为NH；
G 1、L、R 1、R 2、R 3、R 4、R 5、R 6、p、q、r和t如通式(II)中所定义。
方案三
本公开提供通式(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 PCTCN2022090172-appb-000070
通式(IIIA)的化合物或其盐在酸性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；任选地，当R 6基团上含有保护基时，在所述脱保护反应之前或之后还包括在酸性或碱性条件下脱去R 6基团上的保护基的步骤；
其中R为氨基保护基；优选为Boc；
R 0为羟基保护基；优选为MOM；
G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、y、p、r和t如通式(III)中所定义。
方案四
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 PCTCN2022090172-appb-000071
通式(IA)的化合物或其盐在酸性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；任选地，当R 3和/或R 6基团上含有保护基时，在所述脱保护反应之前、同时或之后还包括在酸性或碱性条件下脱去R 3和/或R 6基团上的保护基的步骤；
其中R为氨基保护基；优选为Boc；
G 2为NH；
G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、p、q、r和t如通式(I)中所定义。
方案五
本公开提供通式(II)所示的化合物或其可药用的盐的制备方法，该方法包括：
Figure PCTCN2022090172-appb-000072
通式(IIA)的化合物或其盐在酸性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；任选地，当R 3和/或R 6基团上含有保护基时，在所述脱保护反应之前、同时或之后还包括在酸性或碱性条件下脱去R 3和/或R 6基团上的保护基的步骤；
其中R为氨基保护基；优选为Boc；
G 2为NH；
G 1、L、R 1、R 2、R 3、R 4、R 5、R 6、p、q、r和t如通式(II)中所定义。
方案六
本公开提供通式(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 PCTCN2022090172-appb-000073
通式(IIIA)的化合物或其盐在酸性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；任选地，当R 3和/或R 6基团上含有保护基时，在所述脱保护反应之前、同时或之后还包括在酸性或碱性条件下脱去R 3和/或R 6基团上的保护基的步骤；
其中R为氨基保护基；优选为Boc；
R 0为羟基保护基；优选为MOM；
G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、y、p、r和t如通式(III)中所定义。
以上合成方案中提供酸性条件的试剂包括有机酸和无机酸，所述的有机酸包 括但不限于三氟乙酸、甲酸、乙酸、甲磺酸、对甲苯磺酸、Me 3SiCl和TMSOTf；所述的无机酸包括但不限于氯化氢、盐酸二氧六环溶液、盐酸、硫酸、硝酸和磷酸；优选为盐酸二氧六环溶液。
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、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钾、叔丁醇钠、叔丁醇钾、四丁基氟化铵、四丁基氟化铵的四氢呋喃溶液或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、醋酸钠、醋酸钾、碳酸钾、碳酸铯、氢氧化钠、氢氧化锂、氟化铯和氢氧化钾；优选为四丁基氟化铵的四氢呋喃溶液或氟化铯。
以上合成方案中，当R 3和/或R 6中含有末端炔基时，该末端炔可被TIPS保护，脱去TIPS的试剂优选为四丁基氟化铵的四氢呋喃溶液或氟化铯。
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。
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 NEO 500M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Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
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，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
4-(4-(3-氧杂-7,9-二氮杂双环[3.3.1]壬-7-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-氟萘-2-酚1
Figure PCTCN2022090172-appb-000074
Figure PCTCN2022090172-appb-000075
第一步
7-(2,7-二氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-9-羧酸叔丁酯1c
将2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶1a(400mg，1.58mol，采用专利申请“WO2021/041671A1”中说明书第80页的中间体4公开的方法制备而得)，N,N-二异丙基乙胺(248mg，7.92mmol)溶于10mL二氯甲烷中，-40℃加入3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-9-羧酸叔丁酯1b(361mg，1.58mmol，南京药石)，保持温度搅拌反应1小时后，反应液中加入10mL水，二氯甲烷萃取(10mL×3)，有机相合并，用2M盐酸溶液洗涤，有机相用无水硫酸钠干燥，过滤除去干燥剂后滤液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物1c(500mg，产率：71％)。
MS m/z(ESI):444.0[M+1]。
第二步
7-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-9-羧酸叔丁酯1e
将化合物1c(100mg，225μmol)溶于乙腈(2mL)，加入((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇1d(71mg，446μmol，药明)，N,N-二异丙基乙胺(108.5mg，839μmol)和4A分子筛(100mg)，90℃搅拌反应14小时，反应液冷却至室温后减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1e(80mg，产率：62.6％)。
MS m/z(ESI):567.1[M+1]。
第三步
7-(8-氟-7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-9-羧酸叔丁酯1g
将化合物1e(50mg，88.1μmol)，2-(8-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷1f(50mg，150.5μmol，采用专利申请“WO2021/041671A1”中说明书第522页的实施例282公开的方法制备而得)，[1,1′-双(二-叔丁基膦基)二茂铁]二氯合钯(II)(10mg，15.3μmol，adamas)，无水碳酸钾(30mg，217.0μmol)溶于3mL 1,4-二氧六环和水(V:V＝5:1)的混合溶液中。氮气氛围下，100℃反应14小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物1g(25mg，产率：38.4％)。
MS m/z(ESI):737.2[M+1]。
第四步
4-(4-(3-氧杂-7,9-二氮杂双环[3.3.1]壬-7-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-氟萘-2-酚1
将化合物1g(20mg，27.1μmol)溶于乙腈(1mL)中，加入4M的盐酸二氧六环溶液1mL，室温反应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(含有10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈38％-45％，流速：30mL/min)纯化得到标题化合物1(2mg，产率：12.4％)。
MS m/z(ESI):593.2[M+1]。
1H NMR(500MHz,CD 3OD):δ9.08(s,1H),7.58(d,1H),7.38(td,1H),7.32(t,1H),7.16(t,1H),6.91(dd,1H),5.01(q,3H),4.35-4.21(m,2H),4.02-3.87(m,8H),3.02(s,4H),2.22-2.11(m,2H),2.01(q,4H)。
实施例2
7-(7-(8-乙炔基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-氧杂-7,9-二氮杂双环[3.3.1]壬烷2
Figure PCTCN2022090172-appb-000076
Figure PCTCN2022090172-appb-000077
第一步
三异丙基((8-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)萘-1-基)乙炔基)硅烷2b
将((8-溴萘-1-基)乙炔基)三异丙基硅烷2a(5g，12.9mmol，采用专利申请“WO2021/041671A1”中说明书第301页的实施例179公开的方法制备而得)溶于50mL 1,4-二氧六环中，依次加入4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-二(1,3,2-二氧硼杂环戊烷)(6g，23.6mmol，韶远科技(上海)有限公司)，乙酸钾(2.5g，25.47mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物(1.05g，1.28mmol)，氮气保护下80℃搅拌16小时。冷却，通过硅藻土过滤，将滤液浓缩，用薄层层析以展开剂体系B纯化得到标题化合物2b(4g，产率：71.33％)。
MS m/z(ESI):435.2[M+1]。
第二步
7-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(8-((三异丙基硅基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-9-羧酸叔丁酯2c
将化合物1e(60mg，105.8μmol)，化合物2b(70mg，161.1μmol)，四(三苯基膦)钯(24mg，20.7μmol，adamas)，无水碳酸铯(68mg，208.7μmol)溶于5mL 1,4-二氧六环和水(V:V＝5:1)的混合溶液中。氮气氛围下，100℃反应14小时，反应液冷却至室温，减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物2c(80mg，产率：90.1％)。
MS m/z(ESI):839.2[M+1]。
第三步
7-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(8-((三异丙基硅基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3-氧杂-7,9-二氮杂双环[3.3.1]壬烷2d
将化合物2c(80mg，108.2μmol)溶于乙腈(2mL)中，加入4M的盐酸二氧六环溶液2mL，室温反应1小时，反应液减压浓缩后得到粗品标题化合物2d(70mg，产率：99.2％)，不经纯化直接用于下步反应。
MS m/z(ESI):739.2[M+1]。
第四步
7-(7-(8-乙炔基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-氧杂-7,9-二氮杂双环[3.3.1]壬烷2
将化合物2d(80mg，108.2μmol)溶于N,N-二甲基甲酰胺(2mL)中，加入1M四丁基氟化铵的四氢呋喃溶液2.4mL，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(含有10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)纯化得到标题化合物2(2mg，产率：3.1％)。
MS m/z(ESI):583.2[M+1]。
1H NMR(500MHz,CDCl 3):δ9.07(s,1H),7.96(d,1H),7.77-7.73(m,1H),7.62(s,1H),7.49(s,1H),7.46(s,1H),7.07(s,1H),5.35(d,2H),4.80(s,1H),4.30(d,2H),4.16(t,1H),3.95(d,3H),3.84(d,4H),3.18(s,2H),3.01-2.93(m,1H),2.62(d,1H),2.26-2.20(m,3H),2.06-2.01(m,2H),1.96-1.90(m,2H)。
实施例3
4-(4-(3-氧杂-7,9-二氮杂双环[3.3.1]壬-7-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基萘-2-酚3
Figure PCTCN2022090172-appb-000078
Figure PCTCN2022090172-appb-000079
第一步
7-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)-8-((三异丙基硅基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3-氧杂-7,9-二氮杂双环[3.3.1]壬烷-9-羧酸叔丁酯3b
将化合物1e(30mg，52.9μmol)，三异丙基((6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)萘-1-基)乙炔基)硅烷3a(26.1mg，52.9μmol，采用专利申请“WO2021/041671A1”中说明书第103页的中间体17公开的方法制备而得)，四(三苯基膦)钯(12.2mg，10.5μmol，adamas)和无水碳酸铯(51.7mg，158.7μmol)溶于3mL 1,4-二氧六环和水(V:V＝5:1)的混合溶液中。氮气氛围下，100℃反应3小时，反应液减压浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物3b(30mg，产率：38.4％)。
MS m/z(ESI):899.2[M+1]。
第二步
4-(4-(3-氧杂-7,9-二氮杂双环[3.3.1]壬-7-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-((三异丙基硅基)乙炔基)萘-2-酚3c
将化合物3b(30mg，33.6μmol)溶于乙腈(1mL)中，加入4M的盐酸二氧六环溶液1mL，反应1小时后，反应液减压浓缩后得到粗品标题化合物3c(25mg，产率：99.5％)，产品不经纯化直接用于下步反应。
MS m/z(ESI):755.2[M+1]。
第三步
4-(4-(3-氧杂-7,9-二氮杂双环[3.3.1]壬-7-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基萘-2-酚3
将粗品化合物3c(25mg，33.1μmol)溶于N,N-二甲基甲酰胺(1mL)中，加入氟 化铯(25.2mg，165.5μmol)，搅拌反应4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(含有10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈30％-45％，流速：30mL/min)纯化得到标题化合物3(5mg，产率：25.2％)。
MS m/z(ESI):599.2[M+1]。
1H NMR(500MHz,CDCl 3):δ8.96(s,1H),8.79(s,1H),7.56(d,1H),7.49(s,1H),7.17(d,1H),7.09(d,1H),7.07(s,1H),5.32(d,1H),5.20(s,1H),4.81(m,2H),4.73(m,2H),4.29(s,2H),4.25-4.20(m,2H),4.13-4.09(m,2H),3.89-3.8(m,3H),2.95(d,2H),2.19(dt,3H),2.00(d,2H),1.94-1.83(m,3H)。
实施例4
4-(4-(3-氧杂-7,9-二氮杂双环[3.3.1]壬-7-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基萘-2-酚4
Figure PCTCN2022090172-appb-000080
采用实施例1中的合成路线，将第三步原料化合物1f替换为2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷(采用专利申请“WO2021/041671A1”中说明书第111页的中间体21公开的方法制备而得)，制得标题化合物4(5mg，产率：24.7％)。
MS m/z(ESI):603.2[M+1]。
1H NMR(500MHz,CDCl 3):δ9.01(d,1H),7.57(d,1H),7.37-7.33(m,1H),7.23-7.21(m,1H),7.16(m,1H),7.07(s,1H),6.99(s,1H),5.49-5.31(m,2H),5.24(s,1H),5.02-4.60(m,2H),4.30-4.24(m,2H),3.94-3.83(m,3H),3.77-3.72(m,2H),3.33-3.30(m,2H),3.28-3.18(m,2H),3.01-2.94(m,3H),2.37-2.29(m,3H),2.26-2.23(m,2H),2.20-2.17(m,1H),1.02-0.87(t,3H)。
实施例5
4-(4-(3,9-二氮杂双环[3.3.1]壬-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-氟萘-2-酚5
Figure PCTCN2022090172-appb-000081
采用实施例1中的合成路线，将第一步原料化合物1b替换为3,9-二氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯，制得标题化合物5(6mg，产率：24.8％)。
MS m/z(ESI):591.2[M+1]。
1H NMR(500MHz,CD 3OD):δ9.12(s,1H),7.59(d,1H),7.39(td,1H),7.33(d,1H),7.17(d,1H),6.93(dd,1H),5.36(s,1H),4.34(dd,1H),4.27(d,1H),3.87(s,1H),3.28(s,3H),3.26-3.18(m,4H),3.06-2.98(m,1H),2.31-2.11(m,4H),2.00(dd,4H),1.91(s,2H),1.59(s,1H),1.34(s,1H),1.29(s,1H)。
实施例6
4-(4-(3,9-二氮杂双环[3.3.1]壬-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基萘-2-酚6
Figure PCTCN2022090172-appb-000082
第一步
3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧 啶-4-基)-3,9-二氮杂双环[3.3.1]壬烷-9-羧酸叔丁酯6a
采用实施例1中的合成路线第一步，将第一步原料化合物1b替换为3,9-二氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯，制得标题化合物6a(90mg，产率：70.4％)。
MS m/z(ESI):564.9[M+1]。
第二步
4-(4-(3,9-二氮杂双环[3.3.1]壬-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基萘-2-酚6
采用实施例3中的合成路线第一至第三步，将第一步原料化合物1e替换为化合物6a，制得标题化合物6(6mg，产率：25.2％)。
MS m/z(ESI):597.2[M+1]。
1H NMR(500MHz,CD 3OD):δ9.06(s,1H),7.80(d,1H),7.48(d,1H),7.37(t,1H),7.30(d,1H),7.16(d,1H),5.36(s,1H),4.32(dd,1H),4.25(dd,1H),3.85(t,3H),3.28(s,3H),3.26-3.18(m,3H),2.99(dd,1H),2.30-2.16(m,4H),2.00(dt,4H),1.94-1.84(m,2H),1.60(s,1H),1.34(s,1H),1.29(d,1H)。
实施例7
4-(4-(3,9-二氮杂双环[3.3.1]壬-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基萘-2-酚7
Figure PCTCN2022090172-appb-000083
第一步
3-(7-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,9-二氮杂双环[3.3.1]壬烷-9-羧酸叔丁酯7a
将化合物6a(30mg，53μmol)，2-(8-乙基-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷(27mg，78.91μmol)，四(三苯基膦)钯(9.1mg，7.8μmol，adamas)和无水碳酸铯(51mg，156.5μmol)溶于3mL 1,4-二氧六环和水(V:V＝5:1)的混合溶液中。氮气氛围下，100℃反应14小时，反应液减压浓缩，残余物中加入二氯甲烷和甲醇(V:V＝10:1)的混合溶液，过滤，滤液减压浓缩得到粗品标题化合物7a(15mg，产率：37.9％)。
MS m/z(ESI):745.2[M+1]。
第二步
4-(4-(3,9-二氮杂双环[3.3.1]壬-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基萘-2-酚7
将粗品化合物7a(15mg，20.1μmol)溶于乙酸乙酯(3mL)中，加入4M的盐酸二氧六环溶液1mL，室温反应1.5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(含有10mmol/L碳酸氢铵)和乙腈，梯度配比：乙腈35％-45％，流速：30mL/min)纯化得到标题化合物7(3mg，产率：24.8％)。
MS m/z(ESI):601.2[M+1]。
1H NMR(500MHz,CD 3OD):δ9.12(s,1H),7.63(d,1H),7.40-7.33(m,1H),7.29(d,1H),7.16(d,1H),7.03(d,1H),5.36(s,1H),4.58(s,1H),4.36(d,1H),4.29(d,1H),3.91(s,1H),3.86(d,1H),3.35(s,7H),3.05(d,1H),2.35(d,2H),2.22(dd,4H),2.05-2.01(m,4H),1.92(q,3H),0.90(td,3H)。
实施例8
4-(4-(3-氧杂7,9-二氮杂双环[3.3.1]壬-7-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚8
Figure PCTCN2022090172-appb-000084
采用实施例1中的合成路线，将第三步原料化合物1f替换为2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷(采用专利申请“WO2021/041671”中说明书第104页的中间体18公开的方法制备而得)，制得标题化合物8(5mg，产率：15.4％)。
MS m/z(ESI):621.2[M+1]。
1H NMR(500MHz,CDCl 3):δ8.65(s,1H),8.33(s,1H),7.89(d,1H),7.65(s,1H), 6.96(d,1H),5.51-5.33(m,2H),5.26(s,1H),5.04-4.62(m,2H),4.32-4.27(m,2H),3.95-3.85(m,3H),3.80-3.74(m,2H),3.33-3.32(m,2H),3.27-3.16(m,2H),3.02-2.95(m,3H),2.36-2.30(m,3H),2.27-2.24(m,2H),2.20-2.17(m,1H),1.03-0.86(t,3H)。
实施例9(对比例1)
4-(4-(3,6-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-氟萘-2-酚9
Figure PCTCN2022090172-appb-000085
采用实施例1中的合成路线，将第一步原料化合物1b替换为3,6-二氮杂双环[3.2.1]辛烷-6-甲酸叔丁酯(上海毕得)，制得标题化合物9(4mg，产率：25％)。
MS m/z(ESI):577.2[M+1]。
1H NMR(500MHz,CD 3OD):δ9.10(d,1H),7.61(d,1H),7.41(td,1H),7.35(d,1H),7.17(dd,1H),6.93(dd,1H),5.37(dd,1H),4.61-4.51(m,2H),4.35(dd,1H),4.27(t,1H),3.88-3.79(m,2H),3.68(s,1H),3.57(dd,2H),3.31-3.20(m,3H),3.07(s,2H),3.05-3.01(m,1H),2.69(s,1H),2.27-2.18(m,1H),2.22-2.11(m,3H),2.07-1.99(m,2H),1.98-1.94(m,2H)。
实施例10(对比例2)
4-(4-(9-氧杂-3,7-二氮杂双环[3.3.1]壬-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-氟萘-2-酚10
Figure PCTCN2022090172-appb-000086
采用实施例1中的合成路线，将第一步原料化合物1b替换为9-氧杂-3,7-二氮杂双环[3.3.1]壬烷-3-甲酸叔丁酯盐酸盐(上海毕得)，制得标题化合物10(5mg，产率：12.4％)。
MS m/z(ESI):593.2[M+1]。
1H NMR(500MHz,CD 3OD):δ9.15(s,1H),7.60(d,1H),7.39(td,1H),7.33(t,1H),7.17(d,1H),6.92(dd,1H),4.76(d,4H),4.40-4.28(m,3H),4.04-3.92(m,5H),3.18-3.02(m,4H),2.32-2.12(m,4H),2.02(m,3H)。
实施例11(对比例3)
4-(4-(2,5-二氮杂双环[2.2.1]庚-2-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-氟萘-2-酚11
Figure PCTCN2022090172-appb-000087
采用实施例1中的合成路线，将第一步原料化合物1b替换为2,5-氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(上海毕得)，制得标题化合物11(3.9mg，产率：13.9％)。
MS m/z(ESI):563.2[M+1]。
1H NMR(500MHz,CD 3OD):δ9.15(s,1H),7.61(d,1H),7.43-7.35(m,1H),7.35(s,1H),7.22-7.13(m,1H),6.95-6.91(m,1H),5.52-5.39(m,2H),4.44-4.23(m,4H),3.96-3.90(m,1H),3.25-3.14(m,2H),3.09-3.04(m,2H),2.39(dd,1H),2.35-2.24(m,2H),2.23-2.13(m,3H),2.07-2.02(m,3H),1.99-1.93(m,3H)。
生物学评价
测试例1：AGS细胞ERK磷酸化抑制实验生物学评价(HTRF法)
一、测试目的
本实验通过检测化合物对细胞ERK磷酸化抑制作用，根据IC 50大小评价本公开化合物对KRAS靶点的抑制作用。
二、实验方法
AGS细胞(南京科佰，CBP60476)用含有10％胎牛血清的RPMI1640(Hyclone，SH30809.01)完全培养基进行培养。实验第一天，使用完全培养基将AGS细胞以40000个/孔的密度种于96孔板，每孔190μL细胞悬液，放置37℃，5％CO 2细胞培养箱培养过夜。
第二天，每孔加入10μL用完全培养基配制的梯度稀释的待测化合物，化合物的终浓度是从10μM开始进行5倍梯度稀释的9个浓度点，设置含有0.5％DMSO的空白对照，孔板放置37℃，5％CO 2的细胞培养箱孵育1个小时。孵育完成后，取出96孔细胞培养板，吸掉培养基，每孔加入200μL PBS(上海源培生物科技股份有限公司，B320)洗一遍。吸掉PBS，每孔加入50μL含封闭液(blocking reagent，Cisbio，64KB1AAC)的裂解缓冲液(lysis buffer，Cisbio，64KL1FDF)，孔板放置振荡器上室温震荡裂解40分钟。裂解后用移液器吹打混匀，每孔各转移16μL裂解液分别至两块HTRF 96孔检测板(Cisbio，66PL96100)中，之后两块板分别 加入4μL预混的磷酸化ERK1/2抗体溶液(Cisbio，64AERPEG)或4μL预混的总ERK1/2抗体溶液(Cisbio，64NRKPEG)。微孔板用封板膜密封，在微孔板离心机中离心1分钟，室温避光孵育过夜。
第三天，使用ENVISION多功能酶标仪(PerkinElmer，ENVISION)读取337nm波长激发，665nm和620nm波长发射的荧光值。
三、数据分析
用Graphpad Prism软件根据化合物浓度和磷酸化ERK/总ERK的比值计算化合物抑制活性的IC 50值，结果参见下表1。
表1细胞ERK磷酸化抑制活性数据
实施例编号 AGS/IC 50(nM)
4 120
5 65.3
6 30.2
7 51.1
对比例1 >10000
对比例2 >10000
结论：本公开化合物对AGS细胞ERK磷酸化具有较好的抑制作用。
测试例2：GP2d细胞3D增殖抑制实验生物学评价
一、测试目的
通过测试本公开化合物对GP2d细胞的3D增殖抑制作用，评价本公开化合物对KRAS靶点的抑制作用。
二、实验方法
GP2d细胞(南京科佰，CBP60010)用完全培养基即含有10％胎牛血清(Corning，35-076-CV)的DMEM/高糖培养基(Hyclone，SH30243.01)进行培养。实验第一天，使用完全培养基将GP2d细胞以1000个细胞/孔的密度种于96孔低吸附板(Corning，CLS7007-24EA)，每孔90μL细胞悬液，2000rpm室温离心5分钟后放置37℃，5％CO 2细胞培养箱培养过夜。
第二天，每孔加入10μL用完全培养基配制的梯度稀释的待测化合物，GP2d细胞的化合物终浓度是从1μM开始进行3倍梯度稀释的9个浓度点，设置含有0.5％DMSO的空白对照。孔板放置37℃，5％CO 2的细胞培养箱培养120小时。第七天，取出96孔细胞培养板，每孔加入50μL
Figure PCTCN2022090172-appb-000088
3D试剂(Promega，G9682)，室温震荡25分钟后，吹吸混匀并取出50μL转移至白色不透底的96孔板(PE，6005290)中，使用多功能微孔板酶标仪(PerkinElmer，ENVISION)读取发光信号值。
三、数据分析
用Graphpad Prism软件计算化合物抑制活性的IC 50值，结果参见下表2。
表2细胞3D增殖抑制活性数据
实施例编号 GP2d/IC 50(nM)
5 156
6 152
对比例1 >10000
对比例2 >10000
对比例3 >10000
结论：本公开化合物对GP2d细胞3D增殖具有较好的抑制作用。
测试例3：SPR方法检测本公开化合物与KRAS蛋白亚型G12D或WT的亲和力
先将生物素化的Avi-KRAS-WT或Avi-KRAS-G12D用含有100mM MgCl 2的1×HBS-P+(Cat.#BR1006-71)缓冲液稀释至20μg/mL，然后流过SA(Cat.#BR1005-31)生物传感芯片通道2，持续420s，获得大约5000-7000RU的偶联水平。再将小分子化合物样品从低到高依次进样120s，之后解离720s。试验采用单循环动力学模式。Biacore 8K仪器实时检测反应信号获得结合解离曲线。试验结束后用Biacore 8K评价软件进行数据分析，采用1:1模型进行数据拟合并获得亲和力数据。
表3化合物与KRAS蛋白亚型G12D或WT的亲和力数据
Figure PCTCN2022090172-appb-000089
结论：本公开化合物与KRAS蛋白亚型G12D或WT具有较好的亲和力。
测试例4本公开化合物对SW620增殖的抑制作用
一.实验材料及仪器
1.SW620细胞(南京科佰生物)
2.Leibovitz's L-15培养基(Gibco)
3.胎牛血清(FBS)(Gibco)
4. 0.25％胰酶(Gibco)
5.磷酸盐缓冲液(PBS)(上海源培生物科技有限公司)
6.Cell Titer Glo(CTG)(Promega)
7.T75细胞培养瓶(Corning)
8. 15mL离心管(Corning)
9. 96孔配药板(Corning)
10. 96孔平底细胞培养板(Corning)
11.恒温细胞培养箱(Thermo scientific)
12.生物安全柜(ESCO)
13.超高速冷冻离心机(Thermo scientific)
14.多功能读板仪(PerkinElmer)
二.实验步骤
SW620细胞是携带KRAS G12V突变的人结肠癌细胞，通过评估化合物对SW620细胞的增殖作用。加入化合物后会抑制SW620细胞增殖，通过CTG测定相对发光单位值，从而评估化合物对SW620细胞增殖的抑制作用。
第0天，取生长良好、达70％-80％满的SW620细胞，消化后将细胞用含10％FBS的L-15培养调整细胞密度到1.11*10 4/mL。加90μL细胞悬液到96孔细胞培养板中，最终每孔细胞数为1000/孔。将细胞置于37℃，无CO 2培养箱中培养24小时。第1天：将溶于100％DMSO的20mM受试化合物用100％DMSO系列稀释至2000、666.67、222.22、74.07、24.69、8.23、2.74、0.91、0.30μM，空白孔为100％DMSO，再20倍稀释于含10％FBS的L-15培养基中。加10μL二级稀释后的受试化合物到每孔，受试化合物终浓度分别为10000、3333.33、1111.11、370.37、123.46、41.15、13.72、4.57、1.52nM；DMSO孔为空白孔，仅加培养基的测试孔为阴性对照孔。将细胞置于37℃，无CO 2培养箱中培养5天。第6天取出96孔细胞培养板，加入50μL融化的CTG，于室温孵育20分钟，酶标仪读取相对发光单位(Relative luminescence unit，RLU)值。使用以下公式计算抑制率：抑制率＝[RLU(空白孔)-RLU(受试化合物)]/[RLU(空白孔)-RLU(阴性对照孔)]*100％，用Graphpad Prism软件根据化合物各浓度与相应的抑制率绘出抑制曲线，并计算抑制率达到50％时化合物的浓度，即IC 50值。本公开化合物通过对人SW620增殖的抑制作用测得的IC 50值见表4。
表4化合物对SW620细胞增殖抑制活性数据
实施例编号 SW620/IC 50(nM) 最大抑制率/％
1 1016 91
2 2795 96
4 667 86
7 1785 100
8 234 92
对比例1 >10000 14
对比例2 >10000 48
结论：本公开化合物对SW620细胞增殖具有较好的抑制作用。

Claims (22)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    Figure PCTCN2022090172-appb-100001
    其中：
    G 1选自O、NR a和CR bR c；
    G 2为NR d；
    环A为芳基或杂芳基；
    环B选自环烷基、杂环基、芳基和杂芳基；
    L选自单键、O和NR e；
    R 1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) u-NR fR g、羟基和羟烷基；
    R 2和R 4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) v-NR hR i、羟基、羟烷基和环烷基；
    R 3和R 6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) w-NR jR k、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R 5相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、氰基、羟基和羟烷基；
    R b和R c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) x-NR mR n、硝基、羟基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    R a、R d、R e、R f、R g、R h、R i、R j、R k、R m和R n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；
    u、v、w和x相同或不同，且各自独立地选自0、1、2和3；
    r为0、1或2；
    p为0、1、2、3、4或5；
    q为0、1、2、3、4或5；且
    t为0、1、2、3、4或5。
  2. 根据权利要求1所述的化合物或其可药用的盐，其中G 1为O或CR bR c，R b和R c如权利要求1中所定义。
  3. 根据权利要求1或2所述的化合物或其可药用的盐，其中环A为萘环；和/或环B为
    Figure PCTCN2022090172-appb-100002
    R 6可取代在所述环B任意位置。
  4. 根据权利要求1或3所述的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
    Figure PCTCN2022090172-appb-100003
    其中，G 1、G 2、L、R 1、R 2、R 3、R 4、R 5、R 6、p、q、r和t如权利要求1中所定义。
  5. 根据权利要求1所述的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
    Figure PCTCN2022090172-appb-100004
    其中，
    y为0、1、2、3或4；
    G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、p、r和t如权利要求1中所定义。
  6. 根据权利要求1至4中任一项所述的化合物或其可药用的盐，其中G 2为NH。
  7. 根据权利要求1至6中任一项所述的化合物或其可药用的盐，其中L为O。
  8. 根据权利要求1至7中任一项所述的化合物或其可药用的盐，其中R 1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；优选地，R 1为氢原子。
  9. 根据权利要求1至8中任一项所述的化合物或其可药用的盐，其中R 2选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；优选地，R 2为氢原子。
  10. 根据权利要求1至9中任一项所述的化合物或其可药用的盐，其中R 3相同或不同，且各自独立地选自氢原子、卤素、C 1-6烷基、C 2-6炔基、C 1-6卤代烷基、羟基和C 1-6羟烷基；优选地，R 3相同或不同，且各自独立地选自卤素、乙基、乙炔基和羟基。
  11. 根据权利要求1至10中任一项所述的化合物或其可药用的盐，其中R 4选自氢原子、卤素、C 1-6烷基和C 1-6卤代烷基；优选地，R 4为卤素。
  12. 根据权利要求1至11中任一项所述的化合物或其可药用的盐，其中R 5相同或不同，且各自独立地选自氢原子、C 1-6烷基、羟基和C 1-6羟烷基；优选地，R 5为氢原子。
  13. 根据权利要求1至12中任一项所述的化合物或其可药用的盐，其中R 6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；优选地，R 6为卤素。
  14. 根据权利要求1至13中任一项所述的化合物或其可药用的盐，其为如下化合物：
    Figure PCTCN2022090172-appb-100005
    Figure PCTCN2022090172-appb-100006
  15. 一种通式(IIIA)所示的化合物或其盐：
    Figure PCTCN2022090172-appb-100007
    其中：
    R为氨基保护基；优选为Boc；
    R 0为羟基保护基；优选为MOM；
    G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、y、p、r和t如权利要求5中所定义。
  16. 选自以下的化合物：
    Figure PCTCN2022090172-appb-100008
    Figure PCTCN2022090172-appb-100009
    Figure PCTCN2022090172-appb-100010
  17. 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 PCTCN2022090172-appb-100011
    通式(IA)的化合物或其盐经脱保护反应，得到通式(I)的化合物或其可药用的盐；任选地，当R 3和/或R 6基团上含有保护基时，在所述脱保护反应之前、同时或之后还包括脱去R 3和/或R 6基团上的保护基的步骤；
    其中R为氨基保护基；优选为Boc；
    G 2为NH；
    G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、p、q、r和t如权利要求1中所定义。
  18. 一种制备根据权利要求5所述的通式(III)所示的化合物或其可药用的盐的方法，该方法包括：
    Figure PCTCN2022090172-appb-100012
    通式(IIIA)的化合物或其盐经脱保护反应，得到通式(III)的化合物或其可药用的盐；
    其中R为氨基保护基；优选为Boc；
    R 0为羟基保护基；优选为MOM；
    G 1、环A、环B、L、R 1、R 2、R 3、R 4、R 5、R 6、y、p、r和t如权利要求5中所定义。
  19. 一种药物组合物，所述药物组合物含有根据权利要求1至14中任一项所述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。
  20. 根据权利要求1至14中任一项所述的化合物或其可药用的盐或根据权利要求19所述的药物组合物在制备用于抑制KRAS G12D和/或KRAS G12V的药物中的用途。
  21. 根据权利要求1至14中任一项所述的化合物或其可药用的盐或根据权利要求19所述的药物组合物在制备用于治疗和/或预防疾病或病症的药物中的用途， 所述的疾病或病症为癌症。
  22. 根据权利要求1至14中任一项所述的化合物或其可药用的盐或根据权利要求19所述的药物组合物在制备用于治疗和/或预防疾病或病症的药物中的用途，所述的疾病或病症选自脑癌、甲状腺癌、头颈癌、鼻咽癌、咽喉癌、口腔癌、唾液腺癌、食道癌、胃癌、肺癌、肝癌、肾癌、胰腺癌、胆囊癌、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、阴道癌、卵巢癌、子宫内膜癌、宫颈癌、输卵管癌、睾丸癌、前列腺癌、血管瘤、白血病、淋巴瘤、骨髓瘤、皮肤癌、脂肪瘤、骨癌、软组织肉瘤、神经纤维瘤、神经胶质瘤、成神经细胞瘤和胶质母细胞瘤；优选选自胰腺癌、结直肠癌和非小细胞肺癌。
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