WO2023116779A1 - Composé dialcyne et son utilisation - Google Patents

Composé dialcyne et son utilisation Download PDF

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Publication number
WO2023116779A1
WO2023116779A1 PCT/CN2022/140759 CN2022140759W WO2023116779A1 WO 2023116779 A1 WO2023116779 A1 WO 2023116779A1 CN 2022140759 W CN2022140759 W CN 2022140759W WO 2023116779 A1 WO2023116779 A1 WO 2023116779A1
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alkyl
substituted
group
independently
membered
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PCT/CN2022/140759
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English (en)
Chinese (zh)
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罗会兵
王家坡
周华勇
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上海艾力斯医药科技股份有限公司
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Priority to CN202280084772.0A priority Critical patent/CN118525018A/zh
Publication of WO2023116779A1 publication Critical patent/WO2023116779A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/437—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 five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more 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 invention relates to a diacetylenic compound and its application.
  • Tumor is one of the most important problems that endanger human health, and lung cancer is one of the malignant tumors that threaten people's health and life the most.
  • Lung cancer is mainly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), of which about 80%-85% are NSCLC.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • EGFR epidermal growth factor receptor
  • EGFR inhibitors—EGFR-tyrosine kinase inhibitors (TKI) targeted drugs is one of the biggest research hotspots in the treatment of lung cancer.
  • EGFR Epidermal growth factor
  • EGFR Epidermal growth factor
  • the first-generation EGFR TKI drugs include gefitinib, erlotinib, and icotinib, which are reversible targeted drugs.
  • the second-generation EGFR TKI drugs include afatinib and dacomitinib, which are irreversible targeted drugs.
  • the first-generation and second-generation EGFR TKI drugs have good inhibitory effects on EGFR sensitive mutations (such as exon 19 deletion and exon 21 L858R point mutation), they are significantly better than conventional chemotherapy in the treatment of NSCLC , but most patients will develop drug resistance after 1-2 years of drug use, and about 50%-60% of drug resistance cases are caused by T790M gene mutations.
  • Osimertinib the third-generation EGFR TKI drug, has very good inhibitory activity against T790M mutation, thus bringing better therapeutic effect and survival benefits to patients.
  • EGFR re-mutation is a common secondary mutation of drug resistance, including C797S, G796S/R, L792F/Y /H, L718Q/V and other mutations, among which the C797S mutation is the most common, with an occurrence rate of about 21%.
  • the C797 site is the key site for the binding of EGFR TKI drugs to EGFR, and the C797S mutation will greatly reduce the binding of the third-generation EGFR TKI drugs to the EGFR target, resulting in drug resistance.
  • the technical problem to be solved by the present invention is to provide a diacetylenic compound and its application in view of the defects of existing EGFR inhibitors such as single structure and poor inhibitory effect on C797S mutation.
  • the compound of the present invention has a novel structure, and is effective against EGFR sensitive mutations (such as exon 19 deletion and exon 21 L858R point mutation), EGFR T790M mutation, and third-generation EGFR inhibitor resistance re-mutation (such as EGFR C797S mutation). With good inhibitory effect, it is expected to treat and/or prevent various diseases mediated by EGFR.
  • the present invention solves the above-mentioned technical problems through the following technical solutions.
  • the present invention provides a diacetylene compound as shown in formula I or a pharmaceutically acceptable salt thereof,
  • Each R 5 is independently H, deuterium, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5a , halogen, cyano, hydroxyl, -OC 1-6 alkyl, substituted by -OC 1-6 alkyl or -N(R 6 ) 2 substituted by one or more R 5b ;
  • two R 5 and the connected carbon atoms together form a C 3-7 cycloalkyl group, a C 3-7 cycloalkyl group substituted by one or more R 5c , a 3-10 membered heterocyclic group, or a C 3-7 cycloalkyl group substituted by one or more R 5d substituted 3-10 membered heterocyclic group;
  • Each R 5a , R 5b , R 5c and R 5d is independently deuterium, C 1-4 alkyl, -OC 1-4 alkyl, halogen, -N(R 6 ) 2 , cyano, hydroxyl, C 2-4 alkenyl or C 2-4 alkynyl;
  • R 1 is H, deuterium, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 1a , halogen, cyano, hydroxyl, -OC 1-6 alkyl, one or more -OC 1-6 alkyl or -N(R 6 ) 2 substituted by R 1b ;
  • Each R 1a and R 1b is independently deuterium, C 1-4 alkyl, -OC 1-4 alkyl, halogen, -N(R 6 ) 2 , cyano, hydroxyl, C 2-4 alkenyl or C 2-4 alkynyl;
  • Ring A is a 3-12 membered heterocyclic group, a 5-10 membered heteroaryl group, a C 3-12 cycloalkyl group or a C 6-10 aryl group;
  • Each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h is independently deuterium, C 1-4 alkyl, halogen, cyano, hydroxyl, -OC 1-4 Alkyl, -N(R 6 ) 2 , C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 2-a , 3-8 membered heterocyclic group, 3-8 membered heterocyclic group substituted by one or more R 2-b , phenyl, phenyl substituted by one or more R 2-c , 5-6 membered heteroaryl A group or a 5-6 membered heteroaryl group substituted by one or more R 2-d ;
  • Each R 2-a , R 2-b , R 2-c and R 2-d is independently deuterium, C 1-4 alkyl, -OC 1-4 alkyl, halogen, -NH 2 , cyano , hydroxyl, C 2-4 alkenyl or C 2-4 alkynyl;
  • n 0, 1, 2, 3, 4 or 5;
  • Ring B is a C 6-10 aryl group, a 3-12 membered heterocyclic group, a C 3-12 cycloalkyl group or a 5-10 membered heteroaryl group;
  • Each R 3 is independently deuterium, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3a , oxo, halogen, cyano, -OC 1-6 alkyl, substituted by One or more R 3b substituted -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl, C 2-6 alkynyl substituted by one or more R 3c , one or more C 2-6 alkynyl substituted by R 3d , hydroxyl, -N(R 6 ) 2 , C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 3e , 3-10 membered hetero Cyclic group, 3-10 membered heterocyclic group substituted by one or more R 3f , C 6-10 aryl group, C 6-10 aryl group substituted by one or more R 3g , 5-10 membered heteroaryl group or 5-10 membered heteroaryl substituted by one or
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3h is independently deuterium, C 1-4 alkyl, -OC 1-4 alkyl, halogen, -N (R 6 ) 2 , cyano, hydroxyl, C 2-4 alkenyl or C 2-4 alkynyl;
  • n 0, 1, 2, 3, 4 or 5;
  • Ring C is a 5-10 membered heteroaryl group, a 3-12 membered heterocyclic group, a C6-10 aryl group or a C3-12 cycloalkyl group;
  • Each R 4 is independently deuterium, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 4a , oxo, halogen, cyano, -OC 1-6 alkyl, substituted by -OC 1-6 alkyl, C 2-6 alkenyl substituted by one or more R 4b, C 2-6 alkenyl, C 2-6 alkynyl substituted by one or more R 4c , one or more C 2-6 alkynyl substituted by R 4d , hydroxyl, -N(R 6 ) 2 , -CON(R 6 ) 2 , C 3-7 cycloalkyl, C 3-7 substituted by one or more R 4e Cycloalkyl, 3-10 membered heterocyclic group, 3-10 membered heterocyclic group substituted by one or more R 4f , C 6-10 aryl, C 6-10 aryl substituted by one or more R 4g , 5-10 membered heteroaryl or 5-10 membered heteroary
  • R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4h is independently deuterium, C 1-4 alkyl, -OC 1-4 alkyl, halogen, -N (R 6 ) 2 , cyano, hydroxyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 4-a , 3-8 membered heterocyclic group or 3-8 membered heterocyclic group substituted by one or more R 4-b ;
  • Each R 4-a and R 4-b is independently deuterium, C 1-4 alkyl, -OC 1-4 alkyl, halogen, -NH 2 , cyano, hydroxyl, C 2-4 alkenyl or C 2-4 alkynyl;
  • p 0, 1, 2, 3, 4 or 5;
  • Each R 6 is independently H, C 1-6 alkyl or C 1-6 alkyl substituted by one or more R 6a ;
  • two R 6 form a 3-8 membered heterocyclic group together with the connected nitrogen atom;
  • Each R 6a is independently deuterium, C 1-4 alkyl, -OC 1-4 alkyl, halogen, -NH 2 , -NH-C 1-4 alkyl, -N(C 1-4 alkyl) 2. Cyano, hydroxyl, C 2-4 alkenyl or C 2-4 alkynyl;
  • At least one of the rings A, B, and C is a 5-10 membered heteroaryl group or a 3-12 membered heterocyclic group;
  • the cyclic hydrocarbon group is saturated or partially unsaturated, and the heterocyclic group is saturated or partially unsaturated;
  • heteroatoms in the heterocyclic group and heteroaryl group are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.
  • Each R 5 is independently C 1-6 alkyl, C 1-6 alkyl in C 1-6 alkyl substituted by one or more R 5a , C 1- in -OC 1-6 alkyl 6 alkyl, C 1-6 alkyl in -OC 1-6 alkyl substituted by one or more R 5b
  • R 1 is C 1-6 alkyl, C substituted by one or more R 1a 1-6 alkyl, C 1-6 alkyl in -OC 1-6 alkyl, C 1-6 alkyl in -OC 1-6 alkyl substituted by one or more R 1b
  • each R 2 is independently C 1-6 alkyl, C 1-6 alkyl in C 1-6 alkyl substituted by one or more R 2a , C 1-6 alkane in -OC 1-6 alkyl
  • each R 3 is independently deuterium, C 1-6 alkyl, and one or more R C 1-6 alkyl
  • each of R 5a , R 5b , R 5c and R 5d is independently C 1-4 alkyl, in C 1-4 alkyl in -OC 1-4 alkyl
  • each R 1a and R 1b are each independently C 1-4 alkyl, C 1-4 alkyl in -OC 1-4 alkyl
  • each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h are each independently C 1-4 alkyl, -OC 1-4 alkyl
  • each R 2-a , R 2-b , R 2- c and R 2-d are each independently C 1-4 alkyl, C 1-4 alkyl in -OC 1-4 alkyl
  • each R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3h are each independently a C 1-4 alkyl group, a C 1-4 alkyl group
  • each R 5 , R 5a , R 5b , R 5c , R 5d , R 1 , R 1a , R 1b , R 2 , R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2-a , R 2-b , R 2-c , R 2-d , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 4 , R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , R 4h , R 4-a and R 4-b are each independently halogen, so The aforementioned halogens are independently fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine.
  • each R 5 and the connected carbon atoms together form a C 3-7 cycloalkyl, a C 3-7 ring in a C 3-7 cycloalkyl substituted by one or more R 5c
  • ring A is a C 3-12 cycloalkyl group
  • each R 2 is independently a C 3-7 cycloalkyl group
  • each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h is independently a C 3-7 cycloalkyl group, substituted by one or more R 2-a
  • ring B is in the C 3-12 cycloalkyl group
  • each R 3 is independently a C 3-7 cycloalkyl group
  • each R 2 is independently a C 3-7 cycloalkyl group, and in the C 3-7 cycloalkyl group in the C 3-7 cycloalkyl group substituted by one or more R 2e , each R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h are each independently a C 3-7 cycloalkyl group, C 3- in a C 3-7 cycloalkyl group substituted by one or more R 2-a
  • each R 3 is independently a C 3-7 cycloalkyl group, and in the C 3-7 cycloalkyl group in the C 3-7 cycloalkyl group substituted by one
  • the ring A is a C 3-12 cycloalkyl group
  • the ring B is a C 3-12 cycloalkyl group
  • the ring C is a C 3-12 cycloalkyl group
  • the hydrocarbon group can be a C 3-7 cycloalkyl group
  • the C 3-7 cycloalkyl group is independently a C 3-7 cycloalkyl group or a C 3-7 cycloalkenyl group
  • the C 3-7 cycloalkyl group can be Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, such as cyclopropyl, cyclopentyl or cyclohexyl
  • the C 3-7 cycloalkenyl can be cyclopropenyl, cyclobutyl Alkenyl, cyclopentenyl, cyclohexenyl or cyclohep
  • each R 2 is independently a 3-10 membered heterocyclic group, and among the 3-10 membered heterocyclic groups in the 3-10 membered heterocyclic group substituted by one or more R 2f , each R 3 is independently a 3-10 membered heterocyclic group, and in the 3-10 membered heterocyclic group in the 3-10 membered heterocyclic group substituted by one or more R 3f , each R 4 is independently 3-10 In the 3-10 membered heterocyclic group in the 3-10 membered heterocyclic group substituted by one or more R 4f , the 3-10 membered heterocyclic group is a 3-10 membered heterocycloalkane or 3-10 membered heterocycloalkenyl groups; the 3-10 membered heterocycloalky
  • each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h is independently a 3-8 membered heterocyclyl, surrounded by one or more R 2
  • each R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g and R 4h are each independently In the 3-8 membered heterocyclic group which is a 3-8 membered heterocyclic group, which is substituted by one or more R 4-b, in the 3-8 membered heterocyclic group, two R 6 form together with the connected nitrogen atom
  • the 3-8 membered heterocyclyl is 3-8 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl; the 3-8 membered heterocyclo
  • ring A is a 3-12 membered heterocyclic group
  • ring B is a 3-12 membered heterocyclic group
  • ring C is a 3-12 membered heterocyclic group, the 3-12 membered heterocyclic group
  • the ring group is a 3-12 membered heterocycloalkyl or a 3-12 membered heterocycloalkenyl
  • the 3-12 membered heterocycloalkyl can be a 3 to 7 membered monocyclic heterocycloalkyl, a 4 to 8 membered A ring-linked heterocycloalkyl group, a 4- to 8-membered bridging ring-linked heterocycloalkyl group or a 5- to 10-membered spiro-linked heterocycloalkyl group
  • piperidinyl, piperazinyl or pyrrolidinyl and for example for
  • the 3-12 membered heterocycloalkenyl can be a 4 to 7 membered monocyclic heterocycloal
  • each R 5a , R 5b , R 5c , R 5d , R 1a , R 1b , R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2-a , R 2-b , R 2-c , R 2-d , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , R 4h , R 4-a , R 4-b and R 6a are each independently a C 2-4 alkenyl group, the C 2 -4 alkenyl is vinyl, propenyl or allyl, eg vinyl.
  • each R 2 is independently a C 2-6 alkenyl, and among the C 2-6 alkenyl in the C 2-6 alkenyl substituted by one or more R 2c , each R 3 is independently C 2-6 alkenyl, and among the C 2-6 alkenyl in C 2-6 alkenyl substituted by one or more R 3c , each R 4 is independently C 2-6 alkenyl , C 2-6 alkenyl in C 2-6 alkenyl substituted by one or more R 4c , said C 2-6 alkenyl is vinyl, propenyl or allyl, such as vinyl.
  • each R 5a , R 5b , R 5c , R 5d , R 1a , R 1b , R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2-a , R 2-b , R 2-c , R 2-d , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , R 4h , R 4-a , R 4-b and R 6a are each independently a C 2-4 alkynyl group, the C 2 -4Alkynyl is ethynyl, propynyl or propargyl, eg ethynyl.
  • each R 2 is independently a C 2-6 alkynyl group, and among the C 2-6 alkynyl groups in the C 2-6 alkynyl group substituted by one or more R 2d , each R 3 is independently C 2-6 alkynyl, in the C 2-6 alkynyl in C 2-6 alkynyl substituted by one or more R 3d , each R 4 is independently C 2-6 alkynyl , C 2-6 alkynyl in C 2-6 alkynyl substituted by one or more R 4d , said C 2-6 alkynyl is ethynyl, propynyl or propargyl, such as ethynyl .
  • ring A is a 5-10 membered heteroaryl group
  • each R 2 is independently a 5-10 membered heteroaryl group, a 5-10 membered heteroaryl group substituted by one or more R 2h
  • the ring B is a 5-10 membered heteroaryl group
  • each R 3 is independently a 5-10 membered heteroaryl group, 5 substituted by one or more R 3h -In the 5-10 membered heteroaryl group in the 10 membered heteroaryl group, in the 5-10 membered heteroaryl group
  • each R4 is independently a 5-10 membered heteroaryl group, surrounded by one or more R
  • the 5-10 membered heteroaryl group is and for
  • another example
  • each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g and R 2h is independently a 5-6 membered heteroaryl group or replaced by one or more In the 5-6 membered heteroaryl group in the 5-6 membered heteroaryl group substituted by R 2-d , the 5-6 membered heteroaryl group is For example
  • ring A is a C 6-10 aryl group
  • each R 2 is independently a C 6-10 aryl group, and in a C 6-10 aryl group substituted by one or more R 2g
  • ring B is in the C 6-10 aryl group
  • each R 3 is independently a C 6-10 aryl group, and in the C 6-10 aryl group substituted by one or more R 3g
  • the ring C is in the C 6-10 aryl group
  • each R 4 is independently a C 6-10 aryl group, and in the C 6-10 aryl group substituted by one or more R 4g
  • the C 6-10 aryl group is phenyl or naphthyl.
  • X is -C(R 5 ) 2 -.
  • each R 5 is independently H or C 1-6 alkyl; or two R 5 and the carbon atoms connected together form a C 3-7 cyclohydrocarbon group or are replaced by one or more C 3-7 cycloalkyl substituted by R 5c .
  • each R 5c is independently deuterium, C 1-4 alkyl, -OC 1-4 alkyl, halogen, -N(R 6 ) 2 , cyano or hydroxyl.
  • R 1 is H, deuterium, C 1-6 alkyl, halogen, hydroxyl or -N(R 6 ) 2 .
  • Ring A is a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group.
  • each R 2 is independently oxo, halogen, cyano, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 2a , C 2 -6 alkynyl, C 2-6 alkynyl substituted by one or more R 2d , C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 2e , 3-10 membered heterocycle group, 3-10 membered heterocyclic group substituted by one or more R 2f , C 6-10 aryl group, C 6-10 aryl group substituted by one or more R 2g , 5-10 membered heteroaryl group or 5-10 membered heteroaryl substituted by one or more R 2h .
  • each of R 2a , R 2d , R 2e , R 2f , R 2g and R 2h is independently halogen, C 1-4 alkyl, C 3-7 cycloalkyl, One or more R 2-a substituted C 3-7 cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heterocyclic group substituted by one or more R 2-b , 5-6 membered heterocyclic group Aryl or 5-6 membered heteroaryl substituted by one or more R 2-d .
  • each of R 2-a , R 2-b and R 2-d is independently C 1-4 alkyl or -NH 2 .
  • n 0, 1, 2 or 3.
  • Ring B is C 6-10 aryl or 5-10 membered heteroaryl.
  • each R 3 is independently deuterium, C 1-6 alkyl, cyano, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -N(R 6 ) 2 , halogen or hydroxy.
  • m is 0, 1, 2 or 3.
  • ring C is a 5-10 membered heteroaryl group or a C 6-10 aryl group.
  • each R 4 is independently oxo, halogen, cyano, hydroxyl, -N(R 6 ) 2 , -CON(R 6 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 4a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 4b , C 2-6 alkynyl, by one or C 2-6 alkynyl substituted by R 4d , C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 4e , 3-10 membered heterocyclyl, one or more R 4f substituted 3-10 membered heterocyclic group, 5-10 membered heteroaryl group or 5-10 membered heteroaryl group substituted by one or more R 4h , and oxo, halogen, cyano, hydroxyl, -N(R 6 ) 2 , -CON(R 6 ) 2 , C
  • each of R 4a , R 4b , R 4d , R 4e and R 4f is independently C 1-4 alkyl, halogen, cyano, hydroxyl, -N(R 6 ) 2 , 3-8 membered heterocyclic group or 3-8 membered heterocyclic group substituted by one or more R 4-b .
  • each of R 4a , R 4b , R 4d , R 4e , R 4f and R 4h is independently C 1-4 alkyl, halogen, cyano, hydroxyl, -N(R 6 ) 2 , 3-8 membered heterocyclic group or 3-8 membered heterocyclic group substituted by one or more R 4-b .
  • each R 4-b is independently deuterium, C 1-4 alkyl, -OC 1-4 alkyl, halogen, -NH 2 , cyano, hydroxyl, C 2-4 Alkenyl or C 2-4 alkynyl.
  • p is 0, 1, 2 or 3.
  • each R 6 is independently H, C 1-6 alkyl or C 1-6 alkyl substituted by one or more R 6a ; or, two R 6 are connected to The nitrogen atoms together form a 3-8 membered heterocyclic group.
  • each R 6a is independently C 1-4 alkyl, -OC 1-4 alkyl, halogen, -NH 2 , -NH-C 1-4 alkyl, -N( C 1-4 alkyl) 2 or hydroxyl.
  • X is -(CH 2 )-, -C(CH 3 ) 2 - or
  • R 1 is -OH, H or -NH 2 .
  • Ring A is
  • each R 2 is independently methyl, ethyl, oxo, F, Cl, Br, -CN, ethynyl, -CF 3 ,
  • ring B is
  • each R 3 is independently F, Cl or hydroxyl.
  • ring C is
  • X is -C(R 5 ) 2 -;
  • Each R 5 is independently H or C 1-6 alkyl; or two R 5 and the carbon atoms connected together form a C 3-7 cycloalkyl or a C 3-7 ring substituted by one or more R 5c hydrocarbon group;
  • Each R 5c is independently deuterium, C 1-4 alkyl, -OC 1-4 alkyl, halogen, -N(R 6 ) 2 , cyano or hydroxyl;
  • R 1 is H, deuterium, C 1-6 alkyl, halogen, hydroxyl or -N(R 6 ) 2 ;
  • Ring A is a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group
  • Each R 2 is independently oxo, halogen, cyano, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 2a , C 2-6 alkynyl, one or more C 2-6 alkynyl substituted by R 2d , C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 2e , 3-10 membered heterocyclyl, one or more R 2f Substituted 3-10 membered heterocyclic group, C 6-10 aryl, C 6-10 aryl substituted by one or more R 2g , 5-10 membered heteroaryl or substituted by one or more R 2h 5-10 membered heteroaryl;
  • Each of R 2a , R 2d , R 2e , R 2f , R 2g and R 2h is independently halogen, C 1-4 alkyl, C 3-7 cycloalkyl, substituted by one or more R 2-a C 3-7 cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heterocyclic group substituted by one or more R 2-b , 5-6 membered heteroaryl group or one or more R 2-d substituted 5-6 membered heteroaryl;
  • Each R 2-a , R 2-b and R 2-d is independently C 1-4 alkyl or -NH 2 ;
  • Ring B is C 6-10 aryl or 5-10 membered heteroaryl
  • Each R 3 is independently deuterium, C 1-6 alkyl, cyano, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -N(R 6 ) 2 , halogen or hydroxyl;
  • Ring C is 5-10 membered heteroaryl or C6-10 aryl
  • Each R 4 is independently oxo, halogen, cyano, -N(R 6 ) 2 , hydroxyl, -CON(R 6 ) 2 , C 1-6 alkyl, substituted by one or more R 4a C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 4b , C 2-6 alkynyl, C 2 substituted by one or more R 4d -6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 4e , 3-10 membered heterocyclyl or 3-10 membered heterocyclyl substituted by one or more R 4f ring group;
  • R 4a , R 4b , R 4d , R 4e and R 4f is independently C 1-4 alkyl, halogen, cyano, hydroxyl, -N(R 6 ) 2 , 3-8 membered heterocyclic group or A 3-8 membered heterocyclic group substituted by one or more R 4-b ;
  • Each R 4-b is independently deuterium, C 1-4 alkyl, -OC 1-4 alkyl, halogen, -NH 2 , cyano, hydroxyl, C 2-4 alkenyl or C 2-4 alkynyl ;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3;
  • Each R 6 is independently H, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 6a ; or, two R 6 form a 3-8 member together with the attached nitrogen atom Heterocyclyl;
  • Each R 6a is independently C 1-4 alkyl, -OC 1-4 alkyl, halogen, -NH 2 , -NH-C 1-4 alkyl, -N(C 1-4 alkyl) 2 or hydroxyl.
  • X is -C(R 5 ) 2 -;
  • Each R 5 is independently H or C 1-6 alkyl; or two R 5 and the carbon atoms connected together form a C 3-7 cycloalkyl or a C 3-7 ring substituted by one or more R 5c hydrocarbon group;
  • Each R 5c is independently deuterium, C 1-4 alkyl, -OC 1-4 alkyl, halogen, -N(R 6 ) 2 , cyano or hydroxyl;
  • R 1 is H, deuterium, C 1-6 alkyl, halogen, hydroxyl or -N(R 6 ) 2 ;
  • Ring A is a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group
  • Each R 2 is independently oxo, halogen, cyano, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 2a , C 2-6 alkynyl, one or more C 2-6 alkynyl substituted by R 2d , C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 2e , 3-10 membered heterocyclyl, one or more R 2f Substituted 3-10 membered heterocyclic group, C 6-10 aryl, C 6-10 aryl substituted by one or more R 2g , 5-10 membered heteroaryl or substituted by one or more R 2h 5-10 membered heteroaryl;
  • Each of R 2a , R 2d , R 2e , R 2f , R 2g and R 2h is independently halogen, C 1-4 alkyl, C 3-7 cycloalkyl, substituted by one or more R 2-a C 3-7 cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered heterocyclic group substituted by one or more R 2-b , 5-6 membered heteroaryl group or one or more R 2-d substituted 5-6 membered heteroaryl;
  • Each R 2-a , R 2-b and R 2-d is independently C 1-4 alkyl or -NH 2 ;
  • Ring B is C 6-10 aryl or 5-10 membered heteroaryl
  • Each R 3 is independently deuterium, C 1-6 alkyl, cyano, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -N(R 6 ) 2 , halogen or hydroxyl;
  • Ring C is 5-10 membered heteroaryl or C6-10 aryl
  • Each R 4 is independently oxo, halogen, cyano, -N(R 6 ) 2 , hydroxyl, -CON(R 6 ) 2 , C 1-6 alkyl, substituted by one or more R 4a C 1-6 alkyl, -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 4b , C 2-6 alkynyl, C 2 substituted by one or more R 4d -6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 4e , 3-10 membered heterocyclyl, 3-10 membered heterocyclyl substituted by one or more R 4f Cyclic group, 5-10 membered heteroaryl or 5-10 membered heteroaryl substituted by one or more R 4h ;
  • R 4a , R 4b , R 4d , R 4e , R 4f and R 4h is independently C 1-4 alkyl, halogen, cyano, hydroxyl, -N(R 6 ) 2 , 3-8 membered hetero Cyclic group or 3-8 membered heterocyclic group substituted by one or more R 4-b ;
  • Each R 4-b is independently deuterium, C 1-4 alkyl, -OC 1-4 alkyl, halogen, -NH 2 , cyano, hydroxyl, C 2-4 alkenyl or C 2-4 alkynyl ;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3;
  • Each R 6 is independently H, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 6a ; or, two R 6 form a 3-8 member together with the attached nitrogen atom Heterocyclyl;
  • Each R 6a is independently C 1-4 alkyl, -OC 1-4 alkyl, halogen, -NH 2 , -NH-C 1-4 alkyl, -N(C 1-4 alkyl) 2 or hydroxyl.
  • diacetylenic compound shown in formula I is any of the following structures:
  • the diacetylenic compound shown in formula I or a pharmaceutically acceptable salt thereof can be synthesized by a method similar to a well-known method in the field of chemistry, and its steps and conditions can refer to the steps of similar reactions in the art and conditions, in particular, were synthesized according to the instructions herein.
  • Starting materials are generally from commercial sources or can be readily prepared using methods well known to those skilled in the art (available through SciFinder, Reaxys online database).
  • the diacetylenic compound shown in formula I or a pharmaceutically acceptable salt thereof can also be obtained by the prepared diacetylenic compound shown in formula I or a pharmaceutically acceptable salt thereof.
  • other diacetylenic compounds represented by formula I or pharmaceutically acceptable salts thereof can be obtained through peripheral modification using conventional methods in the art.
  • the necessary raw materials or reagents for the preparation of the diacetylenic compounds represented by formula I or pharmaceutically acceptable salts thereof are commercially available or prepared by synthetic methods known in the art.
  • the compounds of the present invention can be prepared as free bases or as salts with addition of acids, as described in the experimental section below.
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein and possesses all the effects of the parent compound.
  • the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises:
  • substance A which is a diacetylenic compound represented by formula I as described above or a pharmaceutically acceptable salt thereof
  • said EGFR inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly as experimental purposes, for example: as a standard sample or control sample to provide comparison, or to prepare according to conventional methods in the art Into a kit to provide rapid detection of the effect of EGFR inhibition.
  • the present invention also provides the application of a substance A or the pharmaceutical composition as described above in the preparation of medicines, and the medicines can be used for the treatment and/or prevention of EGFR (sensitivity or drug-resistant mutants) Drugs for mediating diseases;
  • the substance A is the above-mentioned diacetylenic compound shown in formula I or a pharmaceutically acceptable salt thereof; the substance A is in a therapeutically effective amount.
  • the present invention also provides the application of a substance A or the pharmaceutical composition as described above in the preparation of medicines, and the medicines can be used for the treatment and/or prevention of cancer;
  • the substance A is the above-mentioned
  • the substance A is in a therapeutically effective amount.
  • the present invention also provides a method for inhibiting EGFR (sensitivity or drug-resistant mutant), which includes administering a therapeutically effective amount of substance A or the aforementioned pharmaceutical composition to the patient; the substance A is the above-mentioned Diyne compounds as shown in formula I or pharmaceutically acceptable salts thereof.
  • the present invention also provides a method for treating and/or preventing diseases mediated by EGFR (sensitivity or drug-resistant mutants), which comprises administering to a patient a therapeutically effective amount of substance A or a pharmaceutical combination as described above
  • the substance; the substance A is the above-mentioned diacetylenic compound shown in formula I or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for treating and/or preventing cancer, which includes administering a therapeutically effective amount of substance A or the aforementioned pharmaceutical composition to the patient; Diacetylenic compounds or pharmaceutically acceptable salts thereof.
  • the diseases mediated by EGFR as mentioned above can be diseases resistant to the first, second and third generation EGFR inhibitors, and the first, second and third generation EGFR inhibitors can be selected from gefitinib, erlotinib , icotinib, afatinib, dacomitinib, osimertinib, amitinib, or furumetinib.
  • the diseases mediated by EGFR as mentioned above can be caused by EGFR sensitive mutations (such as deletion of exon 19 and L858R point mutation of exon 21), EGFR T790M mutation, and re-mutation of resistance to third-generation EGFR inhibitors (such as EGFR C797S mutation)-mediated disease, such as EGFR Del19/T790M/C797S mutation, EGFR L858R/T790M/C797S mutation-mediated disease.
  • EGFR sensitive mutations such as deletion of exon 19 and L858R point mutation of exon 21
  • EGFR T790M mutation re-mutation of resistance to third-generation EGFR inhibitors (such as EGFR C797S mutation)-mediated disease, such as EGFR Del19/T790M/C797S mutation, EGFR L858R/T790M/C797S mutation-mediated disease.
  • a disease mediated by EGFR as described above may be cancer.
  • Cancer as mentioned above may be selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer Carcinoma, liver cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, glioma, glioblastoma, gastric cancer One or more of intestinal stromal tumor, cholangiocarcinoma, endometrial cancer, multiple myeloma, leukemia and melanoma.
  • the diyne compounds represented by formula I of the present invention may contain one or more chiral centers and exist in different optically active forms.
  • the compound contains enantiomers.
  • the present invention includes both these isomers and mixtures of isomers, such as racemic mixtures. Enantiomers may be resolved by methods known in the art, such as crystallization and chiral chromatography.
  • diastereoisomers may exist.
  • the present invention includes resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereoisomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • stereoisomer includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds of the present invention may exist in the form of stereoisomers, and thus encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, Atropisomers, etc., the compound of the present invention can also be in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesoform, racemate, atropisomer equivalent mixture, etc.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • Diyne compounds as shown in Formula I or pharmaceutically acceptable salts thereof are intended to encompass any isotopically labeled (or "radiolabeled”" Diyne compounds as shown in Formula I or pharmaceutically acceptable salts thereof )Variants.
  • This variant can be that one or more atoms in the diacetylenic compound shown in formula I or a pharmaceutically acceptable salt thereof are different from the atomic mass or mass number usually found in nature. obtained by atomic replacement.
  • the radionuclide used will depend on the particular application of the radiolabeled variant. For example, for in vitro receptor labeling and competition assays, 3H or14C are often useful. For radiographic applications, 11C or18F are often useful.
  • isotopic variants of the compounds of the invention may be useful, for example, to investigate the mechanism of action or the distribution of the active ingredient in vivo; due to the relative ease of preparation and Detectability, compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose.
  • the incorporation of isotopes such as deuterium may confer particular therapeutic benefit due to better metabolic stability of the compound, e.g. increasing half-life in vivo or lowering the effective dose required; case constitutes a preferred embodiment of the invention.
  • Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example by the methods described below and in the working examples, by using corresponding isotopically modified specific reagents and/or starting compounds .
  • pharmaceutical composition refers to a formulation comprising a compound of the present invention and a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
  • pharmaceutically acceptable refers to substances (such as pharmaceutical excipients) that do not affect the biological activity or properties of the compounds of the present invention, and are relatively non-toxic, that is, the substances can be administered to individuals without causing adverse effects Biologically react or interact in an undesirable manner with any component contained in the composition.
  • pharmaceutical excipient or “pharmaceutically acceptable carrier” refers to the excipients and additives used in the production of drugs and formulation of prescriptions, and refers to all substances contained in pharmaceutical preparations except active ingredients.
  • Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method for the subject to dissolve the active ingredient at a desired rate after administration, or to promote the activity of the subject after administration of the composition. The ingredients are effectively absorbed.
  • the pharmaceutical excipients can be inert fillers, or provide certain functions, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredients of the composition.
  • Described pharmaceutical adjuvant can comprise one or more in the following adjuvant: binding agent, suspending agent, emulsifying agent, diluent, filler, granulating agent, adhesive, disintegrating agent, lubricant, antiadhesive Glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
  • compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, milling, encapsulating, entrapping or freeze-drying processes.
  • the diacetylenic compound shown in formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable may be administered in any form of pharmaceutical composition.
  • These compositions may be prepared according to methods well known in the art of pharmacy and may be administered by various routes depending upon the need for local or systemic treatment and the area to be treated.
  • Administration can be topical (including epidermal and transdermal, ocular and mucosal, including intranasal, vaginal, and rectal delivery), pulmonary (eg, by powder or aerosol inhalation or insufflation, including by nebulizer; intratracheal or intranasal) , oral (solid and liquid preparations) or parenteral administration forms.
  • solid oral formulations include, but are not limited to, powders, capsules, caplets, gelcaps, and tablets.
  • liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
  • topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations.
  • formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in pharmaceutically acceptable carriers, suspensions for injection, and emulsions for injection.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, salves, emulsions, ointments, gels, drops, suppositories, sprays, liquids and powders.
  • Oral administration may include dosage forms formulated for once-daily or twice-daily (BID) administration.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, eg, intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or it can be by a continuous infusion pump.
  • Conventional pharmaceutical carriers, water, powder or oil bases, thickeners and the like may be necessary or desired.
  • Pharmaceutical compositions comprising the present invention may also be in controlled or delayed release dosage forms (eg liposomes or microspheres).
  • prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient.
  • a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by those skilled in the art.
  • patient refers to any animal that is about to or has received the administration of the compound or composition according to the embodiments of the present invention, preferably a mammal, and most preferably a human.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.
  • pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base.
  • base addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like.
  • acid addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • a pharmaceutically acceptable acid include inorganic acids and organic acids.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left.
  • C 1 -C 4 alkyl or C 1-4 alkyl refers to an alkyl group as defined below having a total of 1, 2, 3 or 4 carbon atoms.
  • the total number of carbon atoms in the abbreviated notation does not include carbons that may be present in substituents of the stated group.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • substituted means that one or more hydrogen atoms in a given structure have been replaced by a particular substituent.
  • the substituents are independent of each other, that is, the one or more substituents may be different from each other or the same of.
  • a substituent may substitute at each substitutable position of the substituent. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently.
  • C 1 -C 6 alkyl or "C 1-6 alkyl” specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkane
  • C 1-4 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl (ie propyl, including n-propyl and isopropyl), C 4 alkyl (ie butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl).
  • moiety As used herein, the terms “moiety”, “structural moiety”, “chemical moiety”, “group”, “chemical group” refer to a specific segment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities embedded or attached to molecules.
  • any variable (such as R 1-a ) appears multiple times in the definition of a compound, the definition at each position of the variable has nothing to do with the definitions at other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted by 1, 2 or 3 R 1-a groups, that is to say, the group may be substituted by up to 3 R 1-a groups, in which a certain position R 1-a The definition of is independent of the definition of the remaining positions R 1-a . Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • linking substituents are described.
  • the Markush variables recited for that group are to be understood as linking groups.
  • the Markush group definition for that variable recites “alkyl,” it is understood that “alkyl” represents a linking alkylene group.
  • alkyl group when an alkyl group is clearly indicated as a linking group, then the alkyl group represents a linked alkylene group, for example, the group "halo-C 1-4 alkyl "C 1-4 alkyl in " should be understood as C 1-4 alkylene.
  • halogen means fluorine, chlorine, bromine or iodine, especially F, Cl or Br.
  • alkyl as a group or part of another group (such as used in haloalkyl, deuterated alkyl, etc. groups), is meant to include branched and straight chains with the specified number of carbon atoms.
  • Chain saturated aliphatic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, most preferably 1 to 4) carbon atoms, and through a single bond
  • the propyl group is a C3 alkyl group (including isomers, such as n-propyl or isopropyl);
  • the butyl group is a C4 alkyl group (including isomers, such as n-butyl, sec-butyl, isobutyl or tert-butyl);
  • pentyl is C 5 alkyl (including isomers, such as n-pentyl, 1-methyl-butyl, 1-ethyl
  • Examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2- Dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, nonyl, decyl and similar alkyl groups.
  • alkylene means a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched chain hydrocarbon group; i.e. One hydrogen in the alkyl group is substituted, the definition of alkyl group is as above.
  • alkylene groups include methylene (-CH 2 -), ethylene ⁇ including -CH 2 CH 2 - or -CH(CH 3 )- ⁇ , isopropylidene ⁇ including -CH(CH 3 )CH 2 -or -C(CH 3 ) 2 - ⁇ and so on.
  • alkoxy as a group or part of another group, means -O-alkyl, the definition of alkyl is as above.
  • alkenyl refers to a straight or branched hydrocarbon chain having at least one double bond, consisting only of carbon atoms and hydrogen atoms, having, for example 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms and is linked to the rest of the molecule by a single bond, for example including but not limited to vinyl, 1-propene group, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl or pent-1,4-dienyl, etc.
  • alkynyl refers to a straight or branched hydrocarbon chain radical having at least one triple bond, consisting only of carbon and hydrogen atoms, having, for example 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms and are linked to the rest of the molecule by a single bond, for example including but not limited to ethynyl, 1-propane Alkynyl, n-propargyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl or pent-1,4-diynyl and the like.
  • cyclohydrocarbyl means a group having a specified number of carbon atoms (such as having 3 to 15 carbon atoms, preferably having 3 to 12 carbon atoms, more preferably Having 3 to 7 carbon atoms), saturated or partially unsaturated monocyclic or polycyclic (e.g. bicyclic, tricyclic or multicyclic bridged rings, and ring (fused ring) or spiro ring systems) non-aromatic carbon Ring substituents, and which may be single bonded to the rest of the molecule via any suitable carbon atom; include, for example, "cycloalkyl", “cycloalkenyl”.
  • cycloalkyl as a group or part of another group, means a saturated monocyclic or polycyclic (such as bicyclic, tricyclic or more ) or spiro ring system) and it may be attached to the rest of the molecule by a single bond via any suitable carbon atom; such as a C 3-15 cycloalkyl having 3 to 15 carbon atoms, preferably having C 3-12 cycloalkyl with 3 to 12 carbon atoms, more preferably C 3-7 cycloalkyl with 3 to 7 carbon atoms, most preferably C 3-6 membered cycloalkane with 3 to 6 carbon atoms base.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
  • cycloalkenyl as a group or part of another group, means a partially unsaturated monocyclic or polycyclic (eg bicyclic, Non-aromatic carbocyclic substituents of tricyclic or higher ring bridged rings, fused rings (fused rings) or spiro ring systems) and which may be attached to the rest of the molecule by a single bond via any suitable carbon atom; such as C 3-15 cycloalkenyl having 3 to 15 carbon atoms, preferably C 3-12 cycloalkenyl having 3 to 12 carbon atoms, more preferably C 3-7 cycloalkenyl having 3 to 7 carbon atoms , most preferably a C 3-6 membered cycloalkenyl group having 3 to 6 carbon atoms.
  • cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl (e.g. ), cyclopentadienyl (for example ), cyclohexenyl (for example ), cycloheptenyl, cyclohexadienyl, etc.
  • the C 3-7 cycloalkyl is C 3-7 cycloalkyl or C 3-7 cycloalkenyl
  • the C 3-7 cycloalkyl can be cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl or cycloheptyl, such as cyclopropyl, cyclopentyl or cyclohexyl
  • the C 3-7 cycloalkenyl can be cyclopropenyl, cyclobutenyl, cyclopentenyl , cyclohexenyl or cycloheptenyl, for example cyclopentenyl or cyclohexenyl.
  • heterocyclyl refers to a group consisting of carbon atoms and 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O and S
  • ring-joint (fused ring) heterocyclic group When it is a bicyclic, tricyclic or more ring-joint (fused ring) heterocyclic group, it may also include a ring-joint (fused ring) group formed with a cycloalkyl, aryl, heteroaryl as defined herein. ), provided that the heterocyclyl is attached to the remainder of the molecule via a single bond from any suitable atom in the saturated or partially unsaturated heterocyclic ring.
  • heterocyclyl includes "heterocycloalkyl” and “heterocycloalkenyl”.
  • Heterocycloalkyl refers to carbon atoms and 1, 2, 3, 4, 5 or 6 Stable saturated monocyclic or polycyclic (e.g.
  • Heterocycloalkenyl refers to a stable partially unsaturated monocyclic ring or Non-aromatic cyclic groups that are polycyclic (eg, bicyclic, tricyclic or multicyclic bridged rings, fused rings (fused rings) or spiro ring systems).
  • the 3-10 membered heterocyclyl is 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl.
  • heterocycloalkyl is 3 to 7 membered monocyclic heterocycloalkyl, 4 to 8 membered ring-linked heterocycloalkyl, 4 to 8 membered bridged ring linked heterocycloalkyl Or a 5- to 10-membered spiro-linked heterocycloalkyl.
  • Exemplary 3-membered heterocycloalkyl groups include, but are not limited to, aziridinyl, oxiranyl, and thiiridine, or stereoisomers thereof;
  • exemplary 4-membered heterocycloalkyl groups Groups include, but are not limited to, azetidinyl, oxirane, thietanyl, or isomers and stereoisomers thereof;
  • exemplary 5-membered heterocycloalkyl groups Including but not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl (For example ), thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolanyl, oxathiofuranyl, dithiofuranyl, or other Isomers and Stereoisomers.
  • Exemplary 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl (For example ), tetrahydropyranyl, cyclopentylsulfide, morpholinyl (for example (For example )), thiomorpholinyl, dithianyl, dioxanyl, piperazinyl (For example ), triazinyl group, (For example ), or its isomers and stereoisomers.
  • Exemplary 7-membered heterocycloalkyl groups include, but are not limited to, (For example ), (For example ), (For example )or (For example ), or its isomers and stereoisomers.
  • Exemplary 8-membered heterocycloalkyl groups include, but are not limited to, (For example ), (For example ), (For example another example ), (For example )or (For example ), or its isomers and stereoisomers.
  • Exemplary 9-membered heterocycloalkyl groups include, but are not limited to, (For example )or (For example ), or its isomers and stereoisomers.
  • Exemplary 10-membered heterocycloalkyl groups include, but are not limited to, (For example )or (For example ), or its isomers and stereoisomers.
  • heterocycloalkenyl is 4 to 7 membered monocyclic heterocycloalkenyl, 5 to 9 membered ring-linked heterocycloalkenyl, 5 to 9 membered bridged ring linked heterocycloalkenyl Or a 6- to 10-membered spiro-linked heterocycloalkenyl.
  • heterocyclenyl include, but are not limited to, pyranyl, 2,3-dihydropyrrolyl, 2,3-dihydrofuryl, 1,2,3,4-tetrahydropyridyl, 1,2,3 ,6-tetrahydropyridyl, 3,4-dihydro-2H-pyran, For example
  • aryl refers to an aromatic group composed of carbon atoms satisfying the 4n+2 rule of conjugated hydrocarbon ring system, each ring has an aromatic sex.
  • aryl refers to an aromatic group having 6 to 18 (preferably 6 to 10) carbon atoms. Examples of aryl groups include, but are not limited to, phenyl or naphthyl, and the like.
  • heteroaryl as a group or part of another group, means a conjugated ring system group having carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur in the ring .
  • the heteroaryl group can be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and when it is a bicyclic, tricyclic or multicyclic ring (fused ring), its Fusions with cycloalkyl or heterocyclyl as defined herein may also be included, provided that the heteroaryl is attached to the rest of the molecule via a single bond via an atom on the aromatic ring.
  • a 5-10 membered heteroaryl group preferably comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, more preferably comprising 1, 2, 3 or 4 heteroatoms selected from N, 5-6 membered heteroaryl with O and S heteroatoms.
  • heteroaryl include, but are not limited to Thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, diazolyl, oxadiazolyl, isoxazolyl, pyridyl pyrimidinyl Pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl Furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazolyl, isoxazolyl, thiadiazolyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinoline Base, iso
  • a "-" at the end of a group means that the group is attached to other fragments in the molecule through this site.
  • the present invention adopts traditional methods of mass spectrometry and elemental analysis, and the steps and conditions can refer to the conventional operating steps and conditions in the art.
  • the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry and optics. In some cases, standard techniques were used for chemical synthesis, chemical analysis.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is: the diacetylenic compound provided by the present invention is novel in structure, sensitive to EGFR mutation (such as exon 19 deletion and L858R point mutation of exon 21), EGFR T790M mutation and the third generation EGFR Inhibitor-resistant re-mutation (such as EGFR C797S mutation) has a good inhibitory effect and is expected to treat and/or prevent various diseases mediated by EGFR.
  • EGFR mutation such as exon 19 deletion and L858R point mutation of exon 21
  • EGFR T790M mutation EGFR T790M mutation
  • the third generation EGFR Inhibitor-resistant re-mutation such as EGFR C797S mutation
  • PMB p-methoxybenzyl
  • Boc tert-butoxycarbonyl
  • TIPS triisopropylsilyl
  • Bn benzyl
  • TMS trimethylsilyl
  • SEM (trimethylsilyl)ethoxymethyl DMSO: dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • Tos p-toluenesulfonyl
  • THP tetrahydropyranyl.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the determination of nuclear magnetic resonance is carried out with a Bruker AVANCE-400 nuclear magnetic instrument, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ) or deuterated chloroform (CDCl 3 ), and the internal standard is tetramethylsilane.
  • the determination of mass spectrometry was performed with an Agilent (Agilent) 1260-6125B single quadrupole liquid mass spectrometer, and an electrospray ionization source (ESI) was used.
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification used is 0.15mm-0.20mm, and the specification used for preparative thin-layer chromatography is 0.4mm-0.5mm.
  • Preparative high-performance liquid chromatography used an AutoPurification LC preparative system equipped with an ACQUITY QDa mass spectrometer detector produced by Waters (Waters).
  • the preparative chromatographic column used was SunFire C18 5 ⁇ m 19x250mm OBD preparative column.
  • the mobile phase used different gradients of water (with 0.1% formic acid)-acetonitrile to elute the compounds.
  • 3-Bromo-1-methylpyridin-2(1H)-one (3.3g, 17.6mmol) was dissolved in tetrahydrofuran (100mL), and 1.3M tetrahydrofuran solution of isopropylmagnesium chloride-lithium chloride (13mL , 16.8mmol), after stirring at room temperature for 1 hour, 2,5-difluoro-N-methoxy-N-methylbenzamide (0.84g, 4.2mmol) was added, and the reaction was continued at room temperature for 16 hours.
  • Step 2 3-(1-(2,5-Difluorophenyl)-1-hydroxy-4-(trimethylsilyl)but-3-yn-1-yl)-1-methylpyridine-2 (1H)-Kone
  • Step 3 3-(1-(2,5-Difluorophenyl)-1-hydroxybut-3-yn-1-yl)-1-methylpyridin-2(1H)-one
  • Step 4 3-(4-Bromo-1-(2,5-difluorophenyl)-1-hydroxybut-3-yn-1-yl)-1-methylpyridin-2(1H)-one
  • Step 2 3-(1-(3,5-Difluorophenyl)-1-hydroxy-4-(trimethylsilyl)but-3-yn-1-yl)-1,6-dimethyl Pyridin-2(1H)-one
  • Zinc powder (1.2 g, 15.2 mmol), 3-bromo-1-trimethylsilyl-1-propyne (1.75 g, 7.6 mmol) were added to 25 mL of tetrahydrofuran. Under nitrogen protection, the reaction was stirred at 55°C for 30 minutes. The reaction solution was cooled to room temperature, and 3-(3,5-difluorobenzoyl)-1,6-dimethylpyridin-2(1H)-one (1.0g, 3.8mmol) was added to the reaction system, and The reaction was stirred for 30 minutes.
  • Step 3 3-(1-(3,5-Difluorophenyl)-1-hydroxybut-3-yn-1-yl)-1,6-lutidine-2(1H)-one
  • Step 4 3-(4-Bromo-1-(3,5-difluorophenyl)-1-hydroxybut-3-yn-1-yl)-1,6-lutidine-2(1H) -ketone
  • Step 1 N-((2,5-difluorophenyl)(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methylene)-2-methylpropane- 2-sulfinamide
  • Step 2 N-(1-(2,5-difluorophenyl)-1-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-4-(trimethyl Silyl)but-3-yn-1-yl)-2-methylpropane-2-sulfinamide
  • Zinc powder (1.3g, 20mmol) was added into 5mL of tetrahydrofuran, and after nitrogen replacement, 3-bromo-1-trimethylsilyl-1-propyne (1.9g, 10mmol) was added, heated to 55°C and stirred for 30 minutes , cooled to about 25°C, N-((2,5-difluorophenyl)(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)methylene)-2 -Methylpropane-2-sulfinamide (1.05 g, 3 mmol) was added to the reaction system, and the reaction was continued for 30 minutes after the addition was completed.
  • Step 3 N-(1-(2,5-difluorophenyl)-1-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)but-3-yne- 1-yl)-2-methylpropane-2-sulfinamide
  • N-(1-(2,5-difluorophenyl)-1-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-4-(trimethylsilyl yl)but-3-yn-1-yl)-2-methylpropane-2-sulfinamide (1300 mg, 2.8 mmol) was dissolved in 20 mL THF.
  • a 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (3 mL) was added and reacted at 20° C. for 30 minutes.
  • Step 4 3-(1-Amino-4-bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-1-methylpyridin-2(1H)-one
  • Step 3 3-(1-(2,5-Difluorophenyl)-4-(trimethylsilyl)but-3-yn-1-yl)-1-methylpyridine-2(1H)- ketone
  • Step 4 3-(1-(2,5-Difluorophenyl)but-3-yn-1-yl)-1-methylpyridin-2(1H)-one
  • reaction solution was diluted with ethyl acetate, washed three times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (1.45 g, 99%), ESI-MS m/z: 274[M+1] + .
  • Step 5 3-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-1-methylpyridin-2(1H)-one
  • 2-Bromo-6-methoxypyridine (25.3g, 134.4mmol) was dissolved in tetrahydrofuran (200mL), cooled to -70°C under nitrogen protection, and a 2.5M hexane solution of n-butyllithium (53.8mL, 134.4mmol), stirred at -70°C for 30 minutes, added dropwise 2-(3-bromopropoxy)tetrahydro-2H-pyran (20g, 89.6mmol), stirred at -70°C for 1 hour, and then naturally Return to room temperature and stir for 2 hours.
  • Step 4 6-((2,5-Difluorophenyl)(hydroxy)methyl)-2,3-indolinazin-5(1H)-one
  • 6-((2,5-Difluorophenyl)(hydroxy)methyl)-2,3-dihydroindorazin-5(1H)-one (2.0 g, 7.2 mmol) was dissolved in trifluoroacetic acid ( 40 mL), triethylsilane (1.67 mg, 14.4 mmol) was added, and the reaction was stirred at 50° C. for 2.0 hours.
  • Step 6 6-(1-(2,5-Difluorophenyl)-4-(trimethylsilyl)but-3-yn-1-yl)-2,3-dihydroindorazine-5 (1H)-Kone
  • Step 7 6-(1-(2,5-Difluorophenyl)but-3-yn-1-yl)-2,3-indolinazin-5(1H)-one
  • Step 8 6-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-2,3-indolinazin-5(1H)-one
  • intermediate A10 was prepared according to the experimental procedure for the synthesis of intermediate A8.
  • Step 1 3-((5-fluoro-2-hydroxyphenyl)(hydroxy)methyl)-1-methylpyridin-2(1H)-one
  • Step 4 3-(1-(5-Fluoro-2-(methoxymethoxy)phenyl)-4-(trimethylsilyl)but-3-yn-1-yl)-1-methan ylpyridin-2(1H)-one
  • Step 5 3-(1-(5-Fluoro-2-(methoxymethoxy)phenyl)but-3-yn-1-yl)-1-methylpyridin-2(1H)-one
  • Step 6 3-(4-Bromo-1-(5-fluoro-2-(methoxymethoxy)phenyl)but-3-yn-1-yl)-1-methylpyridine-2(1H )-ketone
  • intermediate A12 was prepared according to the experimental procedure for the synthesis of intermediate A8.
  • intermediate A13 was prepared according to the experimental procedure for the synthesis of intermediate A8.
  • intermediate A14 was prepared according to the experimental procedure for the synthesis of intermediate A8.
  • Step 6 1-Cyclopropyl-3-(1-(2,5-difluorophenyl)-4-(trimethylsilyl)but-3-yn-1-yl)pyridine-2(1H) -ketone
  • Step 7 1-Cyclopropyl-3-(1-(2,5-difluorophenyl)but-3-yn-1-yl)pyridin-2(1H)-one
  • Step 8 3-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-1-cyclopropylpyridin-2(1H)-one
  • magnesium chips (982 mg, 40.93 mmol) were suspended in tetrahydrofuran (150 mL), 2-bromo-1,4-difluorobenzene (6.7 g, 35.08 mmol) was added dropwise at room temperature, and the reaction was stirred for 1 hour.
  • the reactant was cooled to 0°C, a solution of 6-chloro-2-methoxynicotinaldehyde (5.0 g, 29.23 mmol) in tetrahydrofuran (50 mL) was added dropwise, and the reaction was stirred at room temperature for 1 hour.
  • 6-Chloro-3-(2,5-difluorobenzyl)-2-methoxypyridine (1.0g, 3.71mmol)
  • cyclopropylboronic acid (1.27g, 14.86mmol)
  • [1,1'-bis (Diphenylphosphino)ferrocene]palladium dichloride (543 mg, 0.74 mmol)
  • cesium fluoride 1.4 g, 9.27 mmol
  • Step 4 6-Cyclopropyl-3-(2,5-difluorobenzyl)pyridin-2-ol
  • 6-cyclopropyl-3-(2,5-difluorobenzyl)-2-methoxypyridine (1.0g, 3.63mmol) was dissolved in 48% hydrobromic acid aqueous solution (10mL), stirred at 100°C for 1.5 hours .
  • 6-cyclopropyl-3-(2,5-difluorobenzyl)pyridin-2-ol 910mg, 3.48mmol
  • iodomethane 742mg, 5.22mmol
  • potassium carbonate 962mg, 6.96mmol
  • Step 6 6-Cyclopropyl-3-(1-(2,5-difluorophenyl)-4-(trimethylsilyl)but-3-yn-1-yl)-1-methylpyridine -2(1H)-one
  • 6-cyclopropyl-3-(2,5-difluorobenzyl)-1-methylpyridin-2(1H)-one 139 mg, 0.50 mmol was dissolved in tetrahydrofuran (10 mL), dry ice - Cool to -70°C in an acetone bath, slowly add n-butyllithium (0.7 mL, 1.11 mmol, 1.6M n-heptane solution) dropwise, and stir for 0.5 hours.
  • 3-Bromo-1-trimethylsilyl-1-propyne 212 mg, 1.11 mmol
  • was slowly added at -70°C and the reaction was stirred for 0.5 hours.
  • Step 7 6-Cyclopropyl-3-(1-(2,5-difluorophenyl)but-3-yn-1-yl)-1-methylpyridin-2(1H)-one
  • Step 8 3-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-6-cyclopropyl-1-methylpyridine-2(1H)- ketone
  • 6-cyclopropyl-3-(1-(2,5-difluorophenyl)but-3-yn-1-yl)-1-methylpyridin-2(1H)-one (50mg, 0.16mmol) , N-bromosuccinimide (30mg, 0.16mmol), silver nitrate (3mg, 0.01mmol) were dissolved in acetone (5mL), and stirred at 0°C for 1 hour.
  • 6-Chloro-3-(2,5-difluorobenzyl)-2-methoxypyridine (5.3g, 19.7mmol) was dissolved in 48% hydrobromic acid aqueous solution (50mL), and stirred at 100°C for 1.5 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to 3-4 with 2N sodium hydroxide solution.
  • Step 3 6-Chloro-3-(1-(2,5-difluorophenyl)-4-(trimethylsilyl)but-3-yn-1-yl)-1-methylpyridine-2 (1H)-Kone
  • Step 4 6-Chloro-3-(1-(2,5-difluorophenyl)but-3-yn-1-yl)-1-methylpyridin-2(1H)-one
  • Step 5 3-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-6-chloro-1-methylpyridin-2(1H)-one
  • Step 1 3-(2,5-Difluorobenzyl)-1-methyl-6-((triisopropylsilyl)ethynyl)pyridin-2(1H)-one
  • 6-Chloro-3-(2,5-difluorobenzyl)-1-methylpyridin-2(1H)-one 700 mg, 2.6 mmol
  • triisopropylsilylacetylene 1.89 g, 10.4 mmol
  • Tetrakistriphenylphosphine palladium 600mg, 0.52mmol
  • cuprous iodide 197mg, 1.04mmol
  • triethylamine (2mL) were dissolved in dioxane (20mL), under the protection of argon, the reaction was stirred at 110°C for 16 hours .
  • Step 2 3-(1-(2,5-difluorophenyl)-4-(trimethylsilyl)but-3-yn-1-yl)-1-methyl-6-((triiso Propylsilyl)ethynyl)pyridin-2(1H)-one
  • Step 3 3-(1-(2,5-Difluorophenyl)but-3-yn-1-yl)-1-methyl-6-((triisopropylsilyl)ethynyl)pyridine- 2(1H)-keto
  • Step 4 3-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-1-methyl-6-((triisopropylsilyl)acetylene Base) pyridin-2(1H)-one
  • Step 1 2-(1-(2,5-Difluorophenyl)but-3-yn-1-yl)-4-fluoroisoindolin-1-one
  • Step 2 2-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-4-fluoroisoindolin-1-one
  • Step 1 2-(1-(2,5-Difluorophenyl)-4-(trimethylsilyl)but-3-yn-1-yl)isoindolin-1-one
  • Step 2 2-(1-(2,5-Difluorophenyl)but-3-yn-1-yl)isoindolin-1-one
  • Step 3 2-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)isoindolin-1-one
  • Methyl 3-pyrrolidine acrylate (5.0 g, 32.2 mmol) and diazonium p-nitrobenzenetetrafluoroborate (7.6 g, 32.2 mmol) were dissolved in acetonitrile (640 mL), and stirred at room temperature for 1 hour.
  • Triethylamine (8.95 mL, 64.4 mmol) was added to the reaction system, and the reaction was stirred at 80° C. for 2 hours.
  • Step 6 N-(1-(6,7-Dihydro-5H-pyrrole[1,2-a]imidazol-3-yl)-4-(trimethylsilyl)but-3-yne-1- base)-2-methylpropane-2-sulfinamide
  • Zinc powder (2.05 g, 31.6 mmol) and 3-(trimethylsilyl)propargyl bromide (3 g, 15.8 mmol) were dispersed in tetrahydrofuran solution (20 mL).
  • the reaction was stirred at 55° C. for 30 minutes under nitrogen protection.
  • the reaction solution was cooled to room temperature, and N-((6,7-dihydro-5H-pyrrole[1,2-a]imidazol-3-yl)methylene)-2-methylpropane-2-sulfinic acid was added dropwise
  • a solution of amide (3 g, 12.5 mmol) in tetrahydrofuran (20 mL) was stirred for 30 minutes.
  • Step 7 1-(6,7-Dihydro-5H-pyrrole[1,2-a]imidazol-3-yl)-4-(trimethylsilyl)but-3-yn-1-amine
  • Step 8 2-(1-(6,7-Dihydro-5H-pyrrole[1,2-a]imidazol-3-yl)-4-(trimethylsilyl)but-3-yne-1- Base) -4-fluoroisoindolin-1-one
  • Step 9 2-(1-(6,7-Dihydro-5H-pyrrole[1,2-a]imidazol-3-yl)but-3-yn-1-yl)-4-fluoroisoindoline -1-one
  • Step 1 2-(1-(2,5-Difluorophenyl)but-3-yn-1-yl)-7-fluoroisoindolin-1-one
  • Step 2 2-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-4-fluoroisoindolin-1-one
  • Step 1 4-Chloro-6-(1-(2,5-difluorophenyl)-4-(triisopropylsilyl)but-3-yn-1-yl)-5,6-dihydro -7H-Pyrrole[3,4-b]pyridin-7-one
  • Step 2 4-Chloro-6-(1-(2,5-difluorophenyl)but-3-yn-1-yl)-5,6-dihydro-7H-pyrrole[3,4-b] Pyridin-7-one
  • Step 3 6-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-4-chloro-5,6-dihydro-7H-pyrrole[3, 4-b]pyridin-7-one
  • Step 1 6-Bromo-2-(1-(2,5-difluorophenyl)-4-(trimethylsilyl)butyl-3-yn-1-yl)-4-fluoroisoindole Lin-1-one
  • Step 2 2-(1-(2,5-difluorophenyl)-4-(trimethylsilyl)butyl-3-yn-1-yl)-4-fluoro-6-((triiso Propylsilyl)ethynyl)isoindolin-1-one
  • 6-bromo-2-(1-(2,5-difluorophenyl)-4-(trimethylsilyl)butyl-3-yn-1-yl)-4-fluoroisoindoline- 1-ketone 600 mg, 1.29 mmol was dissolved in 1,4-dioxane (10 mL), triisopropylsilylacetylene (703.9 mg, 3.86 mmol), triethylamine (390.5 mg, 3.86 mmol) were added, Add cuprous iodide (122.5 mg, 0.64 mmol) and tetrakistriphenylphosphine palladium (148.7 mg, 0.13 mmol) under argon atmosphere, and stir at 80°C for 1 hour.
  • Step 3 2-(1-(2,5-Difluorophenyl)butyl-3-yn-1-yl)-4-fluoro-6-((triisopropylsilyl)ethynyl)isoindyl Indolin-1-one
  • Step 4 2-(4-Bromo-1-(2,5-difluorophenyl)butyl-3-yn-1-yl)-4-fluoro-6-((triisopropylsilyl)acetylene base) isoindolin-1-one
  • Intermediate A27 was prepared according to the method of intermediate A26. Simply replacing the starting material 5-bromo-2-(bromomethyl)-3-fluorobenzoic acid methyl ester in step 1 with 4-bromo-2-(bromomethyl)-6-fluorobenzoic acid methyl ester. ESI-MS m/z: 574 [M+1] + .
  • 2-Amino-5-chloro-3-fluorobenzoic acid (6.5 g, 34.39 mmol) was dissolved in 130 mL of hydrobromic acid and 15 mL of dioxane. The temperature was lowered to 0°C, sodium nitrite (2.73g, 39.55mmol) was dissolved in 5mL of water, added dropwise to the reaction system, and stirred at 0°C for 2 hours. The prepared diazonium salt reactant was slowly added dropwise to cuprous bromide (7.4 g, 51.5 mmol) dissolved in 150 mL of hydrobromic acid solution, and reacted at 0° C. for 10 minutes. The reaction was then heated to 50°C and stirred for 1.5 hours.
  • Methyl 2-bromo-5-chloro-3-fluorobenzoate (2g, 7.52mmol), methylboronic acid (676mg, 11.28mmol), potassium carbonate (2.07g, 15mmol), 1,1'-bis(di Phenylphosphino)ferrocenepalladium chloride (550 mg, 0.07 mmol) was dissolved in a mixed solvent of 1,4-dioxane (35 mL) and water (5 mL). Under nitrogen protection, react at 110°C for 10 hours.
  • Step 6 6-Chloro-2-(1-(2,5-difluorophenyl)-4-(trimethylsilyl)but-3-yn-1-yl)-4-fluoroisoindoline -1-one
  • Methyl 2-(bromomethyl)-5-chloro-3-fluorobenzoate (1.3g, 4.64mmol), 1-(2,5-difluorophenyl)-4-(trimethylsilyl) But-3-yn-1-amine (1.17g, 4.64mmol) and triethylamine (1.41g, 13.93mmol) were dissolved in 10mL of n-butanol, and stirred at 140°C for 1 hour.
  • Step 6 6-Chloro-2-(1-(2,5-difluorophenyl)but-3-yn-1-yl)-4-fluoroisoindolin-1-one
  • White solid (232 mg, 66%), ESI-MS m/z: 350 [M+1] + .
  • Step 7 2-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-6-chloro-4-fluoroisoindolin-1-one
  • Step 1 2-(2,5-Difluorobenzyl)-2H-indazole and 1-(2,5-difluorobenzyl)-1H-indazole
  • Step 4 2-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-2H-indazole
  • Intermediate A30 was prepared referring to step 2 to step 4 of intermediate A29, except that the raw material 2-(2,5-difluorobenzyl)-2H-indazole in step 2 was replaced by 1-(2,5-difluoro Benzyl)-1H-indazole.
  • Intermediate A31 was prepared according to the method of intermediate A29, except that the raw material indazole was replaced by 7-bromoindazole.
  • Step 2 4-Chloro-2-(2,5-difluorobenzyl)-6-((triisopropylsilyl)ethynyl)-2H-indazole
  • Step 3 4-Chloro-2-(1-(2,5-difluorophenyl)-4-(trimethylsilyl)but-3-yn-1-yl)-6-(triisopropyl Silyl)ethynyl)-2H-indazole
  • Step 4 4-Chloro-2-(1-(2,5-difluorophenyl)but-3-yn-1-yl)-6-((triisopropylsilyl)ethynyl)-2H- Indazole
  • Step 5 2-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-4-chloro-6-((triisopropylsilyl)ethynyl )-2H-indazole
  • Intermediate A33 was prepared according to the method of intermediate A29, except that the raw material indazole was replaced by 7-trifluoromethyl indazole.
  • Step 3 6-Bromo-2-(1-(2,5-difluorophenyl)-4-(triisopropylsilyl)but-3-yn-1-yl)-4-fluoroisoindole Lin-1-one
  • Step 4 2-(1-(2,5-Difluorophenyl)-4-(triisopropylsilyl)but-3-yn-1-yl)-4-fluoro-6-(4-( 1-Methylpiperidin-4-yl)phenyl)isoindolin-1-one
  • Step 5 2-(1-(2,5-Difluorophenyl)but-3-yn-1-yl)-4-fluoro-6-(4-(1-methylpiperidin-4-yl) Phenyl)isoindolin-1-one
  • Step 6 2-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-4-fluoro-6-(4-(1-methylpiperidine- 4-yl)phenyl)isoindolin-1-one
  • Step 1 2-(1-(2,5-Difluorophenyl)-4-(triisopropylsilyl)but-3-yn-1-yl)-4-fluoro-6-(4-( 4-Methylpiperazin-1-yl)phenyl)isoindolin-1-one
  • Step 2 2-(1-(2,5-Difluorophenyl)but-3-yn-1-yl)-4-fluoro-6-(4-(4-methylpiperazin-1-yl) Phenyl)isoindolin-1-one
  • Step 3 2-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-4-fluoro-6-(4-(4-methylpiperazine- 1-yl)phenyl)isoindolin-1-one
  • Step 1 4-(4-(2-(1-(2,5-difluorophenyl)-4-(triisopropylsilyl)but-3-yn-1-yl)-7-fluoro- tert-butyl 3-oxoisoindolin-5-yl)phenyl)piperidine-1-carboxylate
  • Step 2 4-(4-(2-(1-(2,5-difluorophenyl)but-3-yn-1-yl)-7-fluoro-3-oxoisoindoline-5- Base) phenyl) piperidine-1-carboxylate tert-butyl ester
  • Step 3 4-(4-(2-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-7-fluoro-3-oxoisoindole (Phenyl-5-yl)phenyl)piperidine-1-carboxylate tert-butyl ester
  • Step 1 4-(4-(2-(1-(2,5-difluorophenyl)-4-(triisopropylsilyl)but-3-yn-1-yl)-7-fluoro- tert-butyl 3-oxoisoindolin-5-yl)phenyl)piperazine-1-carboxylate
  • Step 2 4-(4-(2-(1-(2,5-difluorophenyl)but-3-yn-1-yl)-7-fluoro-3-oxoisoindoline-5- Base) phenyl) piperazine-1-carboxylate tert-butyl ester
  • Step 3 4-(4-(2-(4-Bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-7-fluoro-3-oxoisoindole (Phenyl-5-yl)phenyl)piperazine-1-carboxylate tert-butyl ester
  • Step 1 N-((2,5-difluorophenyl)(1-((trimethylsilyl)ethynyl)cyclopropyl)methyl)-2-methylpropane-2-sulfinamide
  • Step 2 (2,5-Difluorophenyl)(1-((trimethylsilyl)ethynyl)cyclopropyl)methanamine
  • Step 3 N-((2,5-difluorophenyl)(1-((trimethylsilyl)ethynyl)cyclopropyl)methyl)-1-(2-nitrophenyl)methyl imine
  • Step 4 2-((2,5-Difluorophenyl)(1-((trimethylsilyl)ethynyl)cyclopropyl)methyl)-2H-indazole
  • Step 5 2-((2,5-Difluorophenyl)(1-ethynylcyclopropyl)methyl)-2H-indazole
  • Step 1 N-(((R)-6-fluoro-6,7-dihydro-5H-pyrrole[1,2-c]imidazol-1-yl)methylene)-2-methylpropane-2 -sulfenamide
  • Step 2 N-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrole[1,2-c]imidazol-1-yl)-4-(trimethylsilyl )but-3-yn-1-yl)-2-methylpropane-2-sulfinamide
  • Step 4 N-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrole[1,2-c]imidazol-1-yl)-4-(trimethylsilyl )but-3-yn-1-yl)-1-(2-nitrophenyl)methanimine
  • Step 5 2-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrole[1,2-c]imidazol-1-yl)-4-(trimethylsilyl )but-3-yn-1-yl)-2H-indazole
  • Step 5 2-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrole[1,2-c]imidazol-1-yl)but-3-yn-1-yl) -2H-indazole
  • Step 1 1-(2-Chloro-6-nitrophenyl)-N-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrole[1,2-c]imidazole -1-yl)-4-(trimethylsilyl)but-3-yn-1-yl)methimine
  • Step 2 4-Chloro-2-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrole[1,2-c]imidazol-1-yl)-4-(trimethyl ylsilyl)but-3-yn-1-yl)-2H-indazole
  • Step 3 4-Chloro-2-(1-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)but-3-yne- 1-yl)-2H-indazole
  • Step 4 2-(4-Bromo-1-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)but-3-yne- 1-yl)-4-chloro-2H-indazole
  • Step 1 N-(3-((4-methoxybenzyl)oxy)-2,2-dimethylpropylene)-2-methylpropane-2-sulfinamide
  • Step 2 N-(1-(2,5-difluorophenyl)-3-((4-methoxybenzyl)oxy)-2,2-dimethylpropyl)-2-methyl Propane-2-sulfinamide
  • Step 4 1-(2,5-Difluorophenyl)-3-((4-methoxybenzyl)oxy)-2,2-dimethyl-N-(2-nitrobenzylidene ) propane-1-amine
  • Step 5 2-(1-(2,5-Difluorophenyl)-3-(4-methoxybenzyl)oxy)-2,2-dimethylpropyl)-2H-indazole
  • Step 7 3-(2,5-Difluorophenyl)-3-(2H-indazol-2-yl)-2,2-dimethylpropanal
  • Step 8 2-(1-(2,5-Difluorophenyl)-2,2-Dimethyl-3-yn-1-yl)-2H-indazole
  • tert-butyl 3-formyl-3-methylpiperidine-1-carboxylate 870mg, 3.8mmol
  • dimethyl (1-diazo-2-oxopropyl)phosphonate 1.1g, 5.7 mmol
  • potassium carbonate 1.58 g, 11.5 mmol
  • Step 4 tert-butyl 3-((2-(1-(2,5-difluorophenyl)-4-(trimethylsilyl)but-3-yn-1-yl)-2H-indazole -6-yl)ethynyl)-3-methylpiperidine-1-carboxylate
  • Step 5 tert-butyl 3-((2-(1-(2,5-difluorophenyl)but-3-yn-1-yl)-2H-indazol-6-yl)ethynyl)-3 -Methylpiperidine-1-carboxylate
  • Step 6 tert-butyl 3-((2-(4-bromo-1-(2,5-difluorophenyl)but-3-yn-1-yl)-2H-indazol-6-yl)ethyne base)-3-methylpiperidine-1-carboxylate
  • Step 4 Methyl 4-((triisopropylsilyl)ethynyl)pyrazolo[1,5-a]pyridine-5-carboxylate
  • Methyl 4-bromopyrazol[1,5-a]pyridine-5-carboxylate 500mg, 1.9mmol
  • triisopropylsilylacetylene 1.0g, 5.9mmol
  • tetrakistriphenylphosphine palladium 226mg, 0.19mmol
  • cuprous iodide 74mg, 0.39mmol
  • triethylamine 1mL
  • Step 5 4-((Triisopropylsilyl)ethynyl)pyrazolo[1,5-a]pyridine-5-carboxamide
  • Step 1 Methyl 3-iodo-4-((triisopropylsilyl)ethynyl)pyrazolo[1,5-a]pyridine-5-carboxylate
  • Step 1 4-((Triisopropylsilyl)ethynyl)-1H pyrrolo[2,3-b]pyridine-5-carboxamide
  • Step 2 3-Ethyl 6-methyl 4-bromopyrazol[1,5-a]pyridine-3,6-dicarboxylate and 3-ethyl 4-methyl 6-bromopyrazol[1, 5-a]pyridine-3,4-dicarboxylate
  • N,N-Diisopropylethylamine (1.97g, 15.3mmol) and ethyl acrylate (2.1g, 21mmol) were added to N-dimethylformamide (17mL) solution, and stirred at -30°C for 2 hours.
  • the above reaction liquid was added dropwise to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.2 g, 14.1 mmol) in N,N-dimethylformamide ( 15 mL) solution, the reaction was stirred at 0°C for 1 hour, water (50 mL) and saturated sodium carbonate (20 mL) were added, stirred for 15 minutes, filtered, and the solid was collected to obtain a crude product.
  • Step 3 Methyl 4-bromopyrazol[1,5-a]pyridine-6-carboxylate and methyl 6-bromopyrazol[1,5-a]pyridine-4-carboxylate

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Abstract

La présente invention concerne un composé dialcyne et son utilisation. L'invention concerne un composé dialcyne tel que représenté dans la formule I ou un sel pharmaceutiquement acceptable de celui-ci. Le composé dialcyne ou le sel pharmaceutiquement acceptable de celui-ci a un bon effet inhibiteur sur une mutation sensible à l'EGFR (telle qu'une mutation de délétion d'exon 19 et une mutation ponctuelle d'exon 21 L858R), une mutation T790M d'EGFR, et une remutation de résistance à un médicament d'un inhibiteur d'EGFR de troisième génération (tel qu'une mutation C797S d'EGFR), et est censé traiter et/ou prévenir diverses maladies médiées par EGFR.
PCT/CN2022/140759 2021-12-21 2022-12-21 Composé dialcyne et son utilisation WO2023116779A1 (fr)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
JPS62207234A (ja) * 1986-03-07 1987-09-11 Rikagaku Kenkyusho ジイン化合物を含む制癌剤
CN102060786A (zh) * 2011-01-20 2011-05-18 天津大学 4-(取代-1,3-二炔基)-4-(三氟甲基)-3,4-二氢取代喹唑啉-2-酮类化合物及其制备方法和应用
CN102329285A (zh) * 2011-09-14 2012-01-25 帕潘纳(北京)科技有限公司 环氧炔醇类化合物及其制剂和用途
US20200102299A1 (en) * 2017-06-02 2020-04-02 Hoffmann-La Roche Inc. Compounds
CN112839937A (zh) * 2018-08-16 2021-05-25 韩国化学研究院 异吲哚啉-1-酮衍生物、其制备方法、和包含其作为有效组分的用于预防或治疗癌症的药物组合物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62207234A (ja) * 1986-03-07 1987-09-11 Rikagaku Kenkyusho ジイン化合物を含む制癌剤
CN102060786A (zh) * 2011-01-20 2011-05-18 天津大学 4-(取代-1,3-二炔基)-4-(三氟甲基)-3,4-二氢取代喹唑啉-2-酮类化合物及其制备方法和应用
CN102329285A (zh) * 2011-09-14 2012-01-25 帕潘纳(北京)科技有限公司 环氧炔醇类化合物及其制剂和用途
US20200102299A1 (en) * 2017-06-02 2020-04-02 Hoffmann-La Roche Inc. Compounds
CN112839937A (zh) * 2018-08-16 2021-05-25 韩国化学研究院 异吲哚啉-1-酮衍生物、其制备方法、和包含其作为有效组分的用于预防或治疗癌症的药物组合物

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Title
DATABASE REGISTRY ANONYMOUS : "- 3,5-Hexadiyn-1-ol, 6-(9-anthryl)-1,1-diphenyl- (8CI) (CA INDEX NAME) ", XP093074384, retrieved from STN *

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