WO2023143312A1 - Nitrogen-containing heterocyclic compound, and preparation method therefor and use thereof - Google Patents

Nitrogen-containing heterocyclic compound, and preparation method therefor and use thereof Download PDF

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WO2023143312A1
WO2023143312A1 PCT/CN2023/072929 CN2023072929W WO2023143312A1 WO 2023143312 A1 WO2023143312 A1 WO 2023143312A1 CN 2023072929 W CN2023072929 W CN 2023072929W WO 2023143312 A1 WO2023143312 A1 WO 2023143312A1
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substituted
membered
alkyl
independently
fluoro
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PCT/CN2023/072929
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French (fr)
Chinese (zh)
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罗会兵
姜佳俊
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上海艾力斯医药科技股份有限公司
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Publication of WO2023143312A1 publication Critical patent/WO2023143312A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to a nitrogen-containing heterocyclic compound, its preparation method and application.
  • the RAS protein When the RAS protein binds to GDP, it is in an "inactive" state; when stimulated by specific upstream cell growth factors, the guanine nucleotide exchange factor (GEF) catalyzes the RAS protein to release GDP, binds to GTP, and is in an "activated” state. "state.
  • the RAS protein combined with GTP can activate downstream proteins and activate downstream signaling pathways.
  • RAS protein itself has weak GTPase activity, which can hydrolyze GTP to GDP, thereby realizing the conversion from activated state to inactive state. In this hydrolysis process, GTPase-activating protein (GAP) is also required to participate, which can interact with RAS protein and greatly promote its ability to hydrolyze GTP to GDP.
  • GAP GTPase-activating protein
  • RAS protein Any mutation in a RAS protein that affects its own GTPase activity or its interaction with GAP or its ability to hydrolyze GTP to GDP will result in a prolonged active state of the RAS protein that continues to be administered Downstream protein growth signals, causing cells to grow and differentiate continuously, which may eventually lead to cancer.
  • RAS gene family There are three members of the RAS gene family: KRAS, NRAS and HRAS.
  • the KRAS G12D inhibitor MRTX1133 developed by Mitati Therapeutics, Inc. has been disclosed in WO2021041671. Its structure is as follows, and preclinical data have been published so far.
  • KRAS G12D and/or KRAS G12V mutations Although some progress has been made in this field, there is currently no approved treatment for KRAS G12D and/or KRAS G12V mutations, so there is still a need to continue to develop effective, stable, and safe small-molecule KRAS G12D and/or KRAS G12V inhibitors. Yu Zhi Treatment of diseases, such as cancer, mediated by KRAS G12D and/or KRAS G12V mutations.
  • the technical problem to be solved by the present invention is the problem of single structure of KRAS G12D and KRAS G12V inhibitors in the prior art, and a kind of nitrogen-containing heterocyclic compound, its preparation method and application are provided, which are effective for KRAS G12D and/or KRAS G12V Has a good inhibitory effect.
  • the present invention provides compounds as shown in formula I, stereoisomers thereof or pharmaceutically acceptable salts thereof:
  • Ring A is 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkenyl; said 4-10 membered heterocycloalkyl and The number of heteroatoms in the 4-10 membered heterocycloalkenyl is 1 or 2, wherein the heteroatoms are selected from one or both of N, O and S;
  • n 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • R 1a , R 1b , R 1c and R 1d is independently deuterium, -CN, halogen or -OH;
  • L is -(CR 6a R 6b ) n1 - * , -O-(CR 6a R 6b ) n2 - * , -S-(CR 6a R 6b ) n3 - * or -N(R 5 )(CR 6a R 6b ) n4- * ; * represents one end connected with R 2 ;
  • Each Q is independently a connecting single bond or -O-;
  • R 2-a and R 2-b are independently deuterium, -CN, halogen or -OH;
  • R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4-f is independently -OH, deuterium, halogen, -(CH 2 ) n6 N(R 5 ) 2 , -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl -S-, C 2 -C 6 alkenyl, C 2 -C 6 Alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heterocycloalkenyl, Aryl, C 1 -C 6 alkyl substituted by one or more R 4-a-1 , C 1 -C 6 alkyl substituted by one or more R 4-a-2 -O-, by one or C 1 -
  • R 4-a-1 to R 4-a-11 and R 4-g-1 to R 4-g-11 is independently deuterium, halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S- or 3-7 membered cycloalkyl;
  • R 4b is H, deuterium, -N(R 5 ) 2 , halogen, -OH, C 1 -C 6 alkyl, -CN, C 1 -C 6 alkane substituted by one or more R 4-b-1 C 1 -C 6 alkyl-O-, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
  • Each R 4-b-1 is independently deuterium, halogen, -CN or -OH;
  • n1, n2, n3, n4, n5, n6, n7, n8 and n9 are independently 0, 1, 2, 3, 4 or 5;
  • Each R 6a and R 6b are independently H, deuterium, halogen, -CN, -OH, C 1 -C 6 alkyl or deuterated C 1 -C 6 alkyl;
  • R 7 is independently H, deuterium, C 1 -C 6 alkyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl , C 6 -C 10 aryl or 5 to 14 membered heteroaryl;
  • R 8 is independently H, deuterium, -OH or C 1 -C 6 alkyl.
  • the compound shown in formula I is not any of the following compounds:
  • Each R 4-b is independently -OH, deuterium, -(CH 2 ) n6 N(R 5 ) 2 , -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkene radical, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 4-a-1 , one or more R 4-a-2 Substituted C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S- substituted by one or more R 4-a-3 , substituted by one or more R 4-a-4 C 2 -C 6 alkenyl, C 2 -C 6 alkyn
  • Each R 4-f is independently -OH, halogen, -(CH 2 ) n6 N(R 5 ) 2 or C 2 -C 6 alkynyl;
  • R 4a is 5 to 14 membered heteroaryl substituted by one or more R 4-k , C 6 -C 10 aryl substituted by one or more R 4-f , C 6 - C 10 aryl or 5 to 14 membered heteroaryl;
  • Each R 4-f is independently halogen, -OH or C 2 -C 6 alkynyl
  • Each R 4-k is independently halogen, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , -(CH 2 ) n6 N(R 5 ) 2 , C 1 -C 6 Alkyl or -CN.
  • n is 0 or 1, preferably 0.
  • each R 1 is independently halogen, -CN, -OH, -N(R 5 ) 2 , C 1 -C 6 alkyl, or C 1 -C substituted by one or more R 1a 6 alkyl.
  • each of R 1a , R 1b , R 1c , and R 1d is independently —CN, halogen, or —OH.
  • L is -O-(CR 6a R 6b ) n2 - * , and * represents the end connected to R 2 .
  • R is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted by one or more R 2e , preferably 4-10 membered substituted by one or more R 2e Heterocycloalkyl.
  • each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2j is independently halogen or C 1 -C 6 alkyl; preferably halogen.
  • R 3 is halogen, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 6 -C 10 aryl substituted by one or more R 3j or substituted by one or more R 3k substituted 5- to 14-membered heteroaryl; preferably halogen or C 6 -C 10 aryl substituted by one or more R 3j .
  • each of R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j and R 3k is independently halogen, -OH, -N (R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl or C 2 -C 6 alkynyl substituted by one or more R 3-a ; preferably halogen, -OH or C 2 - C 6 alkynyl.
  • each of R 3-a , R 3-b , R 3-c , R 3-d , R 3-e , R 3-f , R 3-g , R 3-h , R 3- i , R 3-j and R 3-k are each independently halogen, -CN or -OH.
  • R 4a is 4-10 membered heterocycloalkenyl substituted by one or more R 4-j , 5 to 14 membered heteroaryl substituted by one or more R 4-k , substituted by one C 6 -C 10 aryl, C 6 -C 10 aryl or 5 to 14 membered heteroaryl substituted by or multiple R 4- f ; preferably 5 to 14 membered by one or more R 4-k Heteroaryl, C 6 -C 10 aryl substituted by one or more R 4-f , C 6 -C 10 aryl or 5 to 14 membered heteroaryl.
  • each of R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4-f is independently -OH, halogen, -(CH 2 ) n6 N(R 5 ) 2 , —CN or C 2 -C 6 alkynyl; preferably OH, halogen or C 2 -C 6 alkynyl.
  • each R 4-a is independently -OH, -(CH 2 ) n6 N(R 5 ) 2 , -CN or C 2 -C 6 alkynyl; preferably -OH, -(CH 2 ) n6 N(R 5 ) 2 or -CN, more preferably -OH.
  • each of R 4-a-1 to R 4-a-11 and R 4-g-1 to R 4-g-11 is independently halogen.
  • R 4b is halogen
  • n1, n2, n3, n4, n5, n6, n7, n8 and n9 are each independently 0 or 1.
  • Ring A is a 4-10 membered heterocycloalkyl
  • n 0;
  • L is -O-(CR 6a R 6b ) n2 - * , * represents one end connected to R 2 ;
  • R 2 is a 4-10 membered heterocycloalkyl group or a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
  • each R 2e is independently halogen
  • R 4a is a 5- to 14-membered heteroaryl group substituted by one or more R 4-k , a C 6 -C 10 aryl group substituted by one or more R 4-f , a C 6 -C 10 aryl group, 5 to 14-membered heteroaryl or C 1 -C 6 alkyl substituted by one or more R 4-a ;
  • Each R 4-k is independently halogen, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , -(CH 2 ) n6 N(R 5 ) 2 or C 1 -C 6 alkyl;
  • Each R 4-g-1 is independently halogen
  • R 4b is halogen
  • n2 1;
  • n6 is 0
  • Each R 6a and R 6b are each independently H.
  • L is -O-(CR 6a R 6b ) n2 - * , * represents one end connected to R 2 ;
  • R 2 is a 4-10 membered heterocycloalkyl group or a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
  • each R 2e is independently halogen
  • R 3 is halogen or C 6 -C 10 aryl substituted by one or more R 3j ;
  • R 4a is a 5- to 14-membered heteroaryl group substituted by one or more R 4-k , a C 6 -C 10 aryl group substituted by one or more R 4-f , a C 6 -C 10 aryl group, 5 to 14-membered heteroaryl or C 1 -C 6 alkyl substituted by one or more R 4-a ;
  • Each R 4-a is independently -OH
  • Each R 4-f is independently -OH, halogen or C 2 -C 6 alkynyl
  • Each R 4-k is independently halogen, -CN, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , -(CH 2 ) n6 N(R 5 ) 2 or C 1 -C 6 alkyl;
  • Each R 4-g-1 is independently halogen
  • R 4b is halogen
  • Each R 5 is independently H or C 1 -C 6 alkyl
  • n6 is 0
  • Each R 6a and R 6b are each independently H.
  • Ring A is a 4-10 membered heterocycloalkyl
  • n 0;
  • L is -O-(CR 6a R 6b ) n2 - * , * represents one end connected to R 2 ;
  • R 2 is a 4-10 membered heterocycloalkyl group or a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
  • Each R 2e is independently halogen or C 1 -C 6 alkyl
  • R 3j and R 3k is independently halogen, -OH, -N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 3-a , or C 2 -C 6 alkynyl;
  • Each R 3-a is independently halogen, -CN or -OH;
  • Each R 4-a is independently -OH, -(CH 2 ) n6 N(R 5 ) 2 or -CN;
  • Each R 4-f is independently -OH, halogen or C 2 -C 6 alkynyl
  • Each R 4-g-1 is independently halogen
  • R 4b is halogen
  • Each R 5 is independently H or C 1 -C 6 alkyl
  • n2 1;
  • n6 is 0
  • n7 is 0;
  • Each R 6a and R 6b are each independently H.
  • each of the "4-10 membered heterocycloalkyl groups” is independently a 5-8 membered heterocycloalkyl group, for example (preferred ),
  • each of the "4-10 membered heterocycloalkyl" is independently which stated for
  • each of said halogens is independently fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • each "C 6 -C 10 aryl” is independently phenyl or naphthyl.
  • each of the "C 1 -C 6 alkyl groups” is independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
  • each of the "C 2 -C 6 alkynyl groups” is independently a C 2 -C 3 alkynyl group, such as ethynyl, propynyl or propargyl, preferably ethynyl.
  • each of the "5- to 14-membered heteroaryl groups” is independently "a 5-10-membered heteroaryl group whose heteroatom is N or S, and the number of heteroatoms is 1 or 2", for example Pyrazolyl, pyridyl, quinolinyl, isoquinolyl, quinazolinyl, indolyl, indazolyl, pyrazolopyridyl, pyrimidinyl or benzothienyl, for example
  • each of the "4-10 membered heterocycloalkenyl groups” is independently a 5-8 membered heterocycloalkenyl group, for example
  • each of the "3-7 membered cycloalkyl groups" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • each of the "3-7 membered cycloalkenyl groups" is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.
  • each of the "C 2 -C 6 alkenyl” is independently vinyl, 1-propenyl, n-allyl, but-1-ene but-2-enyl, pent-1-enyl or pent-1,4-dienyl.
  • the "4-10 membered heterocycloalkyl” and “4-10 membered heterocycloalkyl” in “4-10 membered heterocycloalkyl substituted by one or more R 2e " are independently 5-8 membered heterocycloalkyl, for example (preferred
  • the halogens are each independently fluorine, chlorine, bromine or iodine.
  • the “C 6 -C 10 aryl” in “C 6 -C 10 aryl substituted by R 4-f " is independently phenyl or naphthyl.
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , R 4a , R 4 -g , R 4- h , R 4- i , R 4-j , R 4-k and R 5 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the "5 to 14 membered heteroaryl” in the “5 to 14 membered heteroaryl” and “5 to 14 membered heteroaryl substituted by one or more R 4-k “"Aryl” is independently "the heteroatom is N or S, and the number of heteroatoms is 1 or 2 5-10 membered heteroaryl", such as pyrazolyl, pyridyl, quinolinyl, isoquinolyl , quinazolinyl, indolyl, indazolyl, pyrazolopyridyl, pyrimidinyl or benzothienyl, and for example
  • R 4a in “4-10 membered heterocycloalkenyl” in “4-10 membered heterocycloalkenyl substituted by one or more R 4-j " is independently 5-8 membered heterocycloalkenyl, such as
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • n 0.
  • L is -O-CH 2 - * , and * represents the end connected to R 2 .
  • R is preferred
  • R 4b is F.
  • R 3 is or Cl.
  • R 4a is preferred more preferred
  • the compound shown in formula I is any one of the following compounds:
  • the pharmaceutically acceptable salt of the compound shown in formula I is any of the following compounds: of trifluoroacetate.
  • the present invention also provides a compound (intermediate) as shown below:
  • the present invention also provides the hydrochloride salt of any of the following compounds:
  • the present invention also provides a preparation method of the compound shown in formula I, its stereoisomer or a pharmaceutically acceptable salt thereof, which can be the following route:
  • P is an amino protecting group, such as Boc, PMB, Bn, Cbz, Fmoc, etc.,
  • R 2 , R 3 and R 4a are as defined above;
  • Step 1 In a solvent, in the presence of a base and a catalyst, the compound shown in formula SM-1 is subjected to Suzuki reaction to obtain the compound shown in formula SM-2;
  • Step 3 deprotection reaction [substituents R 3a and R 3b (such as -OH, -NH 2 , C 2 -C 6 alkynyl) in R 3 are protected by a protecting group, and a deprotection reaction can be performed to obtain a compound of formula I ];
  • Step 1 In a solvent, in the presence of a base and a catalyst, the compound shown in formula SM-1 is subjected to a Suzuki reaction to obtain a compound shown in formula SM-4;
  • the present invention also provides a pharmaceutical composition, which comprises substance A and pharmaceutical excipients (or pharmaceutically acceptable carrier); said substance A is the above-mentioned compound shown in formula I, its stereoisomer or a pharmaceutically acceptable salt thereof. Said substance A may be in a therapeutically effective amount.
  • the present invention also provides an application of substance A in the preparation of RAS inhibitors, wherein said substance A is the above-mentioned compound represented by formula I, its stereoisomer or a pharmaceutically acceptable salt thereof.
  • the RAS inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample to provide comparison, or to prepare according to conventional methods in the art A kit is developed to provide rapid detection of the effect of inhibiting RAS.
  • the present invention also provides the application of a substance A in the preparation of medicines, and the medicine is used for treating and/or preventing RAS-mediated diseases;
  • the substance A is the above-mentioned compound shown in formula I, its Stereoisomers or pharmaceutically acceptable salts thereof; said substance A is in a therapeutically effective amount.
  • the present invention also provides the application of a substance A in the preparation of medicines, and the medicine is used for treating and/or preventing cancer;
  • the substance A is the above-mentioned compound shown in formula I and its stereoisomers or a pharmaceutically acceptable salt thereof; the substance A is in a therapeutically effective amount.
  • the present invention also provides a method for inhibiting RAS, which comprises administering a therapeutically effective amount of substance A to a patient; said substance A is the above-mentioned compound represented by formula I, its stereoisomer or its pharmaceutically acceptable Accepted salt.
  • the present invention also provides a method for treating and/or preventing cancer, which comprises administering a therapeutically effective amount of substance A to a patient; said substance A is the above-mentioned compound represented by formula I, its stereoisomer or its pharmaceutically acceptable salt.
  • the RAS as described above may be KRAS or a KRAS mutation; eg KRAS G12D, KRAS G12V.
  • RAS mediated diseases such as cancer as described above.
  • 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 Cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • the base addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts.
  • acid addition can be achieved by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a pharmaceutically acceptable acid include inorganic acids (such as hydrochloric acid), organic acids (such as trifluoroacetic acid, formic acid).
  • inorganic acids such as hydrochloric acid
  • organic acids such as trifluoroacetic acid, formic acid.
  • 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.
  • pharmaceutical composition refers to a preparation comprising a compound of the present invention and a vehicle generally accepted in the art for delivering 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 a substance (such as a pharmaceutical excipient) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological effects. 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 compound shown in formula I, its stereoisomer or pharmaceutically acceptable salt thereof can be formulated as Any form of administration of the compound.
  • 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.
  • Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, gelcaps, and tablets.
  • Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
  • Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations.
  • Examples of 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.
  • compositions and formulations for topical administration may include transdermal patches, salves, emulsions, ointments, gels, drops, suppositories, sprays, liquids and powders.
  • suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants.
  • 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 desirable.
  • Pharmaceutical compositions comprising the present invention may also be in controlled or delayed release dosage forms (eg liposomes or microspheres).
  • treatment refers to therapeutic therapy or palliative measures.
  • treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.
  • Treatment can also refer to prolonging survival as compared to expected survival if not receiving treatment.
  • 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.
  • substituted or "substituent” is a group in which a hydrogen atom is replaced by the designated group.
  • substitutions are at any position, but are permitted only if they result in a stable or chemically viable chemical. Examples are as follows: The structure indicates that the hydrogen atom on ring A is replaced by p R4 .
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with at least one R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • alkyl refers to a saturated linear or branched monovalent hydrocarbon group.
  • C 1 -C 6 alkyl means having 1-6 carbon atoms
  • An alkyl group, preferably an alkyl group having 1 to 4 carbon atoms, is specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • phenylene refers to a group obtained by removing two hydrogen atoms from a benzene ring, that is, one hydrogen in the phenyl is replaced.
  • heterocycloalkyl refers to a group formed by replacing at least one carbon atom in a cycloalkyl group with a heteroatom selected from N, O and S.
  • the 4-10 membered heterocycloalkyl group can specifically be 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl group.
  • Examples of heterocycloalkyl include, but are not limited to (preferred
  • aryl refers to an aromatic group in which each ring is aromatic, such as phenyl or naphthyl.
  • heteroaryl refers to an aromatic group containing heteroatoms, preferably containing 1, 2 or 3 aromatic 5-6-membered monocyclic or 9-membered rings independently selected from nitrogen, oxygen and sulfur -10-membered bicyclic ring, when bicyclic, each ring has aromaticity, such as pyrazolyl, pyridyl, quinolinyl, isoquinolyl, quinazolinyl, indolyl, indazolyl, pyrazolyl, Azolopyridyl, pyrimidinyl or benzothienyl, and for example wait.
  • aromaticity such as pyrazolyl, pyridyl, quinolinyl, isoquinolyl, quinazolinyl, indolyl, indazolyl, pyrazolyl, Azolopyridyl, pyrimidinyl or benzothienyl, and for example wait.
  • alkynyl refers to a straight-chain or branched chain hydrocarbon group (such as C 2 -C 6 alkynyl, another example C 2 -C 3 alkynyl) having one or more triple bonds with a specific number of carbon atoms ).
  • the one or more carbon-carbon triple bonds may be internal or terminal, such as propynyl with a triple bond internal or propynyl with a triple bond at the end wait.
  • heterocycloalkenyl means a cyclic alkenyl linked through a heteroatom or a heteroatom group.
  • alkenyl refers to a straight or branched hydrocarbon chain group 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 are attached to the rest of the molecule by a single bond, examples including but not limited to vinyl, 1-propenyl, n-allyl, but-1-ene group, but-2-enyl, pent-1-enyl or pent-1,4-dienyl, etc.
  • cycloalkyl means a carbocyclic substituent of a saturated monocyclic or polycyclic ring (such as a bicyclic, tricyclic or more ring-bridged ring, a ring (fused ring) or a spiro ring system), and it may be attached to the remainder of the molecule by a single bond via any suitable carbon atom; such as having 3 to 3-15 membered cycloalkyl group with 15 carbon atoms, preferably 3-12 membered cycloalkyl group with 3 to 12 carbon atoms, more preferably 3-7 membered cycloalkyl group with 3 to 7 carbon atoms, most preferably 3-6 membered cycloalkyl having 3 to 6 carbon atoms.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
  • cycloalkenyl means a partially unsaturated monocyclic or polycyclic (such as a bicyclic, tricyclic or more ring-bridged ring, an acyclic ring) having at least one double bond (such as a carbon-carbon double bond) (fused ring) or spiro ring system) and which may be attached to the rest of the molecule by a single bond via any suitable carbon atom; e.g.
  • Cycloalkenyl preferably 3-12 membered cycloalkenyl having 3 to 12 carbon atoms, more preferably 3-7 membered cycloalkenyl having 3 to 7 carbon atoms, most preferably 3 to 6 carbon atoms -6 membered cycloalkenyl.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl (e.g. ), cyclopentadienyl (for example ), cyclohexenyl (for example ), cycloheptenyl, cyclohexadienyl, etc.
  • halogen means fluorine, chlorine, bromine or iodine, especially F or Cl.
  • the positive and progressive effect of the present invention is that the nitrogen-containing heterocyclic compound is expected to treat and/or prevent various diseases mediated by KRAS, especially various diseases mediated by KRAS G12D and/or KRAS G12V.
  • Boc tert-butoxycarbonyl
  • TIPS triisopropylsilyl
  • MOM methoxymethyl (CH 3 OCH 2 -)
  • FA formic acid
  • MEOH methanol
  • EtOH ethanol
  • DMSO dimethyl sulfoxide
  • ACN acetonitrile
  • CDCl 3 deuterated chloroform.
  • Step 2 tert-Butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro-3-fluoropyridin-4-yl)aminomethyl ester
  • 2,6-Dichloro-3-fluoropyridin-4-amine (4.2g, 23.21mmol, 1eq) was dissolved in dichloromethane (40mL), BOC anhydride (10.29g, 47.15mmol, 2.03eq) was added, 4 -Dimethylaminopyridine (457.28mg, 3.74mmol, 0.16eq), react at room temperature for 16 hours. LCMS monitored the reaction to be complete.
  • reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 0-20%) to obtain tert-butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro- 3-fluoropyridin-4-yl)aminomethyl ester (7.0 g, yield: 79.13%), white solid.
  • tert-Butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro-3-fluoropyridin-4-yl)aminomethyl ester (5.84g, 15.32mmol, 1eq) was dissolved in In tetrahydrofuran (30mL), lithium diisopropylamide (2M, 15.32mL, 2eq) was added dropwise at -78°C and warmed to room temperature for 2 hours. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Step 6 Ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotine ester
  • reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 20-50%) to obtain ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2- Trichloroacetyl)ureido)nicotine ester (1.5 g, yield: 76.14%), white solid.
  • Ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotine ester (3.0 g, 6.80 mmol, 1 eq) was dissolved in methanol ( 40mL), add ammonia methanol solution (7M, 2.77mL, 2.85eq), and react at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was slurried with methyl tert-butyl ether to obtain 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (1.8g, yield: 100%), white solid.
  • Step 9 (1R,5S)-tert-butyl-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diaze Heterobicyclo[3.2.1]octane-8-carboxylate
  • Step 10 (1R,5S)-tert-butyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazine-7a -yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • reaction solution was slowly poured into a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Step 1 (1R,5S)-tert-butyl-3-(5,7-bis(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylate
  • Mobile phase A water (ammonia hydroxide v/v)
  • mobile phase B ACN; gradient B%: 36%-76%; retention time: 9min.
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H -pyrazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidine- 7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; gradient B%: 29%-69%; retention time: 9min.
  • Step 1 (1R,5S)-tert-butyl-3-(5-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-8-fluoro-7-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H -pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ester
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; gradient B%: 25%-65%; retention time: 9min.
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-fluoropyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; gradient B%: 35%-75%; retention time: 9min.
  • Embodiment 5 Compound 5
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(3-fluorophenyl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(3-fluorophenyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A water (ammonia hydroxide v/v)
  • mobile phase B ACN; gradient B%: 50%-70%; retention time: 10min.
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(naphthalen-1-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(naphthalen-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; gradient B%: 43%-83%, retention time: 9min.
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H -indol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 37%-77%, retention time: 9min.
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane Alkane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 40%-60%, retention time: 11min.
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrazolo[1, 5-a]pyridin-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrazolo[1,5-a]pyridin-3-yl)pyrido[4,3-d] Pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A water (ammonia hydroxide v/v)
  • mobile phase B ACN
  • gradient B% 31%-51%
  • retention time 13min
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-3-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrimidin-5-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrimidin-5-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; Gradient B%: 29%-69%, retention time 9min
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methoxypyridine -3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methoxypyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl )-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 40%-60%, retention time: 13min
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methylpyridine- 3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl) -6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A water (ammonia hydroxide v/v)
  • mobile phase B ACN
  • Step 1 (1R,5S)-tert-butyl-3-(5-(5-cyanopyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy )-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3- Hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-5-yl)nicotinenitrile hydrochloride
  • Mobile phase A Water (FA)
  • mobile phase B ACN
  • Gradient B% 1%-41%, retention time: 9min
  • Step 1 (1R,5S)-tert-butyl-3-(5-(5-(dimethylamino)pyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxy Methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazine-7a -yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(5-(dimethylamino)pyridine-3 -yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-7 -yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Step 3 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(5-(dimethylamino)pyridine-3 -yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-7 -yl)-5-ethynyl-6-fluoronaphthalene-2-ol
  • Mobile phase A [Water (0.1% ammonia v/v)-ACN] mobile phase B: ACN; Gradient: 40%-60% (v/v), 10min
  • Step 1 (1R,5S)-tert-butyl-3-(5-(5-chloropyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy) -8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazin-7a-yl)methyl Oxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(5-chloropyridin-3-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 38%-78%, retention time: 9min
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2S,7aR)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-morpholinopyridine -3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-(trifluoromethyl)pyridin-3-yl)pyrido[4,3-d]pyrimidine- 7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 40%-80%, retention time: 9min
  • Step 3 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(isoquinolin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5 -Trifluoroacetate of ethynyl-6-fluoronaphthalen-2-ol
  • Step 2 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3- Hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-5-yl)nicotinamide hydrochloride
  • Step 3 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3 -Hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3- d] pyrimidin-5-yl) nicotinamide
  • Mobile phase A Water (0.05% ammonia water, v/v)
  • Mobile phase B ACN; gradient: 38%-58% (v/v), retention time: 10min.
  • Step 1 (1R,5S)-tert-Butyl-3-(5-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-8-fluoro-7-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H -pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester
  • Step 2 4-(5-(6-aminopyridin-3-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN, gradient B%: 31%-71%, retention time: 9min
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-4-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 50%-70%, retention time: 15min
  • Step 1 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-2-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Step 1 Methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro- 7-(7-fluoro-3-(methoxy methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazine- 7a-yl)methoxy)pyrido[4,3-d]pyrimidine-5-carboxylate
  • Diisobutylaluminum hydride (1M, 1.04mL, 5eq) was slowly added dropwise at -70°C. After the dropwise addition was completed, it was slowly raised to room temperature and reacted at room temperature overnight. The completion of the reaction was monitored by LCMS, and the reaction solution was quenched with sodium sulfate decahydrate.
  • Mobile phase A Water (NH3H2O+NH4HCO3)
  • mobile phase B ACN
  • Gradient B% 24%-64%
  • retention time 9min
  • Step 1 (1R,5S)-tert-butyl-3-(5-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-Diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 (1R,5S)-tert-butyl-3-(5-(aminomethyl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1- Base)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4- base)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 45%-65%, retention time: 10min
  • Step 1 (1R,5S)-tert-butyl-3-(5-aminocarbonyl-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-Diazabicyclo[3.2.1]octane-8-carboxylate
  • Mobile phase A Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; Gradient B%: 34%-64% Retention time: 10min
  • Step 1 (1R,5S)-tert-butyl-3-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl ylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-((Z)-N' -Hydroxyaminocarbaimidoyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 3 (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-oxoylidene- 4,5-dihydro-1,2,4-oxadiazol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate
  • Mobile phase A Water (FA), mobile phase: ACN; Gradient B%: 46%-76%, retention time: 10min
  • Step 4 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3- Hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-5-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride
  • Mobile phase A Water (FA)
  • mobile phase B ACN
  • gradient B% 0%-40%
  • retention time 9min
  • Step 1 tert-butyl-(1R,5S)-3-(7-chloro-8-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl Silyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidazin-7a(5H)-yl)methoxy)pyrido[ 4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 tert-butyl-(1R,5S)-3-(8-fluoro-5,7-bis(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethyl Silyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 3 4,4'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5,7-diyl)bis(6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol) hydrochloride
  • Embodiment 29 Compound 29
  • Step 1 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)-6-fluoro-5- ((Triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN, gradient B%: 25%-65%; retention time: 9min.
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%: 24%-64%; retention time: 10min
  • Step 1 (1R,5S)-tert-butyl-3-(5-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl )-7-chloro-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Heterobicyclo[3.2.1]octane-8-carboxylate
  • Step 1 (1R,5S)-tert-butyl-3-(7-chloro-5-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] Octane-8-carboxylate
  • Step 2 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-chloro-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)pyrido[ 4,3-d] pyrimidine hydrochloride
  • Step 3 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-chloro-5-(8-ethynylnaphthalen-1-yl )-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine
  • Mobile phase A Water (0.05% ammonia water, v/v)
  • Mobile phase B ACN; Gradient B%: 34%-74% (v/v), retention time: 11min
  • Step 1 (1R,5S)-tert-butyl-3-(7-chloro-5-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Hexahydro-1H-pyrrolidinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate
  • Mobile phase A Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 40%-80%, retention time: 9min
  • Test Example 1 Proliferation inhibitory activity on Ba/F3KRAS-G12D, Ba/F3KRAS-G12V stably transfected cell lines and AGS tumor cell lines containing KRAS G12D mutation:
  • This test example 1 is used to determine the Ba/F3KRAS-G12D and Ba/F3KRAS-G12V cells that the compound of the present invention stably expresses the KRAS G12D/V mutant protein in the original B cell Ba/F3 of the mouse in vitro, and expresses the KRAS G12D mutant protein Proliferation inhibitory activity of gastric cancer AGS cells.
  • Ba/F3KRAS-G12D and Ba/F3KRAS-G12V were purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd., product numbers KC-1259 and KC-1261, respectively; AGS was purchased from Shanghai Baili Biotechnology Co., Ltd.
  • the details are as follows: take the stock solution (10mM) of the compound dissolved in DMSO in advance, dilute it to 10 gradient concentrations by doubling ratio (4 times), and dilute it to 10 times of the target concentration in another 96-well plate with medium, and then in Add 10 ⁇ l/well of the compound solution to the 96-well plate inoculated with cells to reach the target concentration (10000, 2500, 625, 156, 39, 10, 2.5, 0.6, 0.15, 0.04 nM). Three replicate wells were set up for each concentration, and a blank control was set up.
  • Cell proliferation inhibition rate (%) [(luminous intensity 72 hours containing cell medium control group -luminous intensity 72 hours compound group )/(luminous intensity 72 hours containing cell medium control group -luminous intensity 72 hours no cell medium control group )] ⁇ 100%.
  • test results show that the compounds of the present invention (especially compound 4, compound 6, compound 10, compound 13, compound 18, compound 21, compound 22, compound 24, compound 29) are effective against Ba/F3KRAS-G12D containing KRAS G12D/V mutation, Ba/F3KRAS-G12V and AGS cells have good proliferation inhibitory activity.

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Abstract

Disclosed are a nitrogen-containing heterocyclic compound as represented by formula I, and a preparation method therefor and the use thereof. The compound as represented by formula I, and a stereoisomer thereof or a pharmaceutically acceptable salt thereof has a good inhibitory effect on KRAS G12D and/or KRAS G12V.

Description

一种含氮杂环化合物、其制备方法及应用A nitrogen-containing heterocyclic compound, its preparation method and application
本申请要求申请日为2022/1/28的中国专利申请2022101085764的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of the Chinese patent application 2022101085764 with a filing date of 2022/1/28. This application cites the full text of the above-mentioned Chinese patent application.
技术领域technical field
本发明涉及一种含氮杂环化合物、其制备方法及应用。The invention relates to a nitrogen-containing heterocyclic compound, its preparation method and application.
背景技术Background technique
RAS蛋白是一种位于细胞膜上的分子量为21kDa的鸟嘌呤三核苷酸磷酸(GTP)结合蛋白，由188或189个氨基酸构成。RAS蛋白的活性状态对细胞的生长、分化、细胞骨架、蛋白质运输和分泌等都具有影响，其活性则是通过与GTP或鸟嘌呤二核苷酸磷酸(GDP)的结合进行调节。当RAS蛋白与GDP结合时，处于“失活”状态；当有上游特定的细胞生长因子刺激时，鸟嘌呤核苷酸交换因子(GEF)催化RAS蛋白释放出GDP，与GTP结合，处于“活化”状态。与GTP结合的RAS蛋白能够活化下游的蛋白，激活下游信号通路。RAS蛋白本身具有弱的GTP酶活性，能够水解GTP到GDP，从而实现从活化状态到失活状态的转化。在这个水解过程中，还需要GTP酶激活蛋白(GAP)参与，它能与RAS蛋白相互作用并大大促进其水解GTP到GDP的能力。任何在RAS蛋白中的影响其自身的GTP酶活性或其与GAP相互作用或其水解GTP到GDP的能力的突变，将会导致所述RAS蛋白处于延长的活化状态，延长活化的RAS蛋白继续给予下游蛋白生长信号，导致细胞不停的生长和分化，最终可能导致癌症。RAS基因家族三个成员：KRAS、NRAS和HRAS。RAS protein is a guanine trinucleotide phosphate (GTP) binding protein with a molecular weight of 21 kDa located on the cell membrane, consisting of 188 or 189 amino acids. The active state of RAS protein has an influence on cell growth, differentiation, cytoskeleton, protein transport and secretion, etc., and its activity is regulated by combining with GTP or guanine dinucleotide phosphate (GDP). When the RAS protein binds to GDP, it is in an "inactive" state; when stimulated by specific upstream cell growth factors, the guanine nucleotide exchange factor (GEF) catalyzes the RAS protein to release GDP, binds to GTP, and is in an "activated" state. "state. The RAS protein combined with GTP can activate downstream proteins and activate downstream signaling pathways. RAS protein itself has weak GTPase activity, which can hydrolyze GTP to GDP, thereby realizing the conversion from activated state to inactive state. In this hydrolysis process, GTPase-activating protein (GAP) is also required to participate, which can interact with RAS protein and greatly promote its ability to hydrolyze GTP to GDP. Any mutation in a RAS protein that affects its own GTPase activity or its interaction with GAP or its ability to hydrolyze GTP to GDP will result in a prolonged active state of the RAS protein that continues to be administered Downstream protein growth signals, causing cells to grow and differentiate continuously, which may eventually lead to cancer. There are three members of the RAS gene family: KRAS, NRAS and HRAS.
KRAS突变是最常见的致癌驱动因子，存在于多种肿瘤中：肺腺癌(32％)、结直肠癌(41％)、胰腺癌(86％)。KRAS突变又以第12位密码子的G12突变最为常见，例如，在KRAS突变的肺腺癌、结直肠癌及胰腺癌中，G12突变又分别占85％、68％及91％；G12突变包括G12C、G12D、G12V、G12R等突变形式。在KRAS G12突变的肺腺癌、结直肠癌、胰腺癌患者中，KRAS G12D突变患者分别占比17％、45％、45％，KRAS G12V突变患者分别占比23％、30％、35％(例如，参见Moore,A.R.et al.Nat Rev Drug Discov 19,533(2020))。KRAS mutations are the most common oncogenic driver, present in a variety of tumors: lung adenocarcinoma (32%), colorectal cancer (41%), pancreatic cancer (86%). The KRAS mutation is the most common G12 mutation at the 12th codon. For example, in KRAS-mutated lung adenocarcinoma, colorectal cancer, and pancreatic cancer, G12 mutations accounted for 85%, 68%, and 91% respectively; G12 mutations include G12C, G12D, G12V, G12R and other mutant forms. Among patients with KRAS G12 mutations in lung adenocarcinoma, colorectal cancer, and pancreatic cancer, patients with KRAS G12D mutations accounted for 17%, 45%, and 45%, respectively, and patients with KRAS G12V mutations accounted for 23%, 30%, and 35% ( See, eg, Moore, A.R. et al. Nat Rev Drug Discov 19, 533 (2020)).
由Mitati Therapeutics,Inc.公司开发的KRAS G12D抑制剂MRTX1133已在WO2021041671公开，其结构如下，目前已公开临床前数据。
The KRAS G12D inhibitor MRTX1133 developed by Mitati Therapeutics, Inc. has been disclosed in WO2021041671. Its structure is as follows, and preclinical data have been published so far.
MRTX1133MRTX1133
虽然在该领域取得了一定进展，但目前还没有针对KRAS G12D和/或KRAS G12V突变的批准治疗，因此仍需要继续开发有效、稳定、安全的小分子KRAS G12D和/或KRAS G12V抑制剂，用于治 疗由KRAS G12D和/或KRAS G12V突变介导的疾病，例如癌症。Although some progress has been made in this field, there is currently no approved treatment for KRAS G12D and/or KRAS G12V mutations, so there is still a need to continue to develop effective, stable, and safe small-molecule KRAS G12D and/or KRAS G12V inhibitors. Yu Zhi Treatment of diseases, such as cancer, mediated by KRAS G12D and/or KRAS G12V mutations.
发明内容Contents of the invention
本发明所要解决的技术问题是现有技术中KRAS G12D和KRAS G12V抑制剂结构单一的问题，而提供了一种含氮杂环化合物、其制备方法及应用，其对KRAS G12D和/或KRAS G12V具有较好的抑制作用。The technical problem to be solved by the present invention is the problem of single structure of KRAS G12D and KRAS G12V inhibitors in the prior art, and a kind of nitrogen-containing heterocyclic compound, its preparation method and application are provided, which are effective for KRAS G12D and/or KRAS G12V Has a good inhibitory effect.
本发明提供了如式I所示的化合物、其立体异构体或其药学上可接受的盐：
The present invention provides compounds as shown in formula I, stereoisomers thereof or pharmaceutically acceptable salts thereof:
其中，环A为3-7元环烷基、3-7元环烯基、4-10元杂环烷基或4-10元杂环烯基；所述4-10元杂环烷基和4-10元杂环烯基里的杂原子个数为1或2个，其中所述杂原子选自N、O和S中的一种或两种；Wherein, Ring A is 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkenyl; said 4-10 membered heterocycloalkyl and The number of heteroatoms in the 4-10 membered heterocycloalkenyl is 1 or 2, wherein the heteroatoms are selected from one or both of N, O and S;
n为0、1、2、3、4、5、6、7、8、9或10；n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
各R1分别独立地为氘、卤素、-CN、-OH、-N(R5)2、硝基、C1-C6烷基、被一个或多个R1a取代的C1-C6烷基、C1-C6烷基-O-、被一个或多个R1b取代的C1-C6烷基-O-、C2-C6烯基、被一个或多个R1c取代的C2-C6烯基、C2-C6炔基、被一个或多个R1d取代的C2-C6炔基、-C(＝O)H、-CO2R5、-C(＝O)N(R5)2、5至14元杂芳基或氧代基(＝O)；所述的5至14元杂芳基中杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；Each R 1 is independently deuterium, halogen, -CN, -OH, -N(R 5 ) 2 , nitro, C 1 -C 6 alkyl, C 1 -C 6 substituted by one or more R 1a Alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-O- substituted by one or more R 1b , C 2 -C 6 alkenyl, substituted by one or more R 1c C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkynyl substituted by one or more R 1d , -C(=O)H, -CO 2 R 5 , -C (=O)N(R 5 ) 2 , 5 to 14-membered heteroaryl or oxo group (=O); the heteroatom in the 5 to 14-membered heteroaryl is selected from one of N, O and S One or more kinds, the number of heteroatoms is 1, 2 or 3;
各R1a、R1b、R1c和R1d分别独立地为氘、-CN、卤素或-OH；Each of R 1a , R 1b , R 1c and R 1d is independently deuterium, -CN, halogen or -OH;
L为-(CR6aR6b)n1-*、-O-(CR6aR6b)n2-*、-S-(CR6aR6b)n3-*或-N(R5)(CR6aR6b)n4-*；*表示与R2连接的一端；L is -(CR 6a R 6b ) n1 - * , -O-(CR 6a R 6b ) n2 - * , -S-(CR 6a R 6b ) n3 - * or -N(R 5 )(CR 6a R 6b ) n4- * ; * represents one end connected with R 2 ;
R2为H、-COOH、-N(R5)2、C1-C6烷基、C1-C6烷基-O-、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、-NHC(＝NH)NH2，-C(O)N(R5)2、-CH(CH2OR5)[(CH2)n5OR5]、-N(R5)C(＝O)-(C6-C10芳基)、-C(＝O)O-(C1-C6烷基)、被一个或多个R2a取代的C1-C6烷基、被一个或多个R2b取代的C1-C6烷基-O-、被一个或多个R2c取代的3-7元环烷基、被一个或多个R2d取代的3-7元环烯基、被一个或多个R2e取代的4-10元杂环烷基、被一个或多个R2f取代的-C(＝O)O-(C1-C6烷基)、被一个或多个R2g取代的C6-C10芳基、被一个或多个R2h取代的5至14元杂芳基、-N(R5)C(＝O)-(被一个或多个R2i取代的C6-C10芳基)或被一个或多个R2j取代的4-10元杂环烯基；所述“4-10元杂环烷基”和“被一个或多个R2e取代的4-10元的杂环烷基”中的“4-10元杂环烷基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烯基”和“被一个或多个R2j取代的4-10元杂环烯基”中的“4-10元杂环烯基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“5至14元杂芳基”和“被一个或多个R2h 取代的5至14元杂芳基”中的“5至14元杂芳基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；R 2 is H, -COOH, -N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl , 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, -NHC(=NH)NH 2 , -C(O)N (R 5 ) 2 , -CH(CH 2 OR 5 )[(CH 2 ) n5 OR 5 ], -N(R 5 )C(=O)-(C 6 -C 10 aryl), -C(= O)O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted by one or more R 2a , C 1 -C 6 alkyl substituted by one or more R 2b -O- , 3-7 membered cycloalkyl substituted by one or more R 2c , 3-7 membered cycloalkenyl substituted by one or more R 2d , 4-10 membered heterocycle substituted by one or more R 2e Alkyl, -C(=O)O-(C 1 -C 6 alkyl) substituted by one or more R 2f , C 6 -C 10 aryl substituted by one or more R 2g , by one or A 5- to 14-membered heteroaryl group substituted by multiple R 2h , -N(R 5 )C(=O)-(C 6 -C 10 aryl substituted by one or more R 2i ) or by one or more A 4-10 membered heterocycloalkenyl group substituted by R 2j ; "4 in the "4-10 membered heterocycloalkyl group" and "4-10 membered heterocycloalkyl group substituted by one or more R 2e " The heteroatoms in -10-membered heterocycloalkyl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the "4-10-membered heterocycloalkenyl The heteroatoms in the "4-10-membered heterocyclenyl" in "and "4-10-membered heterocyclenyl substituted by one or more R 2j " are selected from one or more of N, O and S species, the number of heteroatoms is 1, 2 or 3; the "5 to 14 membered heteroaryl" and "by one or more R 2h The heteroatoms in the "5- to 14-membered heteroaryl" in the "substituted 5- to 14-membered heteroaryl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3 indivual;
各R2a、R2b、R2c、R2d、R2e、R2f和R2j分别独立地为卤素、-OH、氘、-CN、-C(＝O)H、C1-C6烷基、被一个或多个R2-a取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷基-O-、被一个或多个R2- b取代的C1-C6烷基-O-、苯基-Q-、FO2S-亚苯基-Q-、苯基-C(＝O)NH-、-N(R5)2、(Cl-C6烷基)-O-(C1-C6烷基)-、(Cl-C6烷基)-C(＝O)-、氧代基(＝O)、(被一个或多个卤素取代的Cl-C6烷基)-C(＝O)-、-SO2F、(Cl-C6烷基)-SO2-、(Cl-C6烷基)-O-(Cl-C6烷基)-O-、-CH2OC(＝O)N(R5)2、(Cl-C6烷基)-O-C(＝O)-NHCH2-、-CH2NHC(＝O)N(R5)2、(Cl-C6烷基)-C(＝O)NHCH2-、(吡唑基)-CH2-、(Cl-C6烷基)-SO2-NHCH2-、(4-10元杂环烷基)-C(＝O)-OCH2-、(R5)2N-C(＝O)-O-、(Cl-C6烷基)-O-(Cl-C6烷基)-NH-C(＝O)-O-、苯基-(Cl-C6烷基)-NH-C(＝O)-O-、(4-10元杂环烷基)-C(＝O)-O-或(4-10元杂环烷基)-CH2-；所述“苯基-C(＝O)NH-”和“苯基-(Cl-C6烷基)-NH-C(＝O)-O-”里的“苯基”任选被-C(＝O)H、卤素、CN或OH取代；所述“(4-10元杂环烷基)-C(＝O)-OCH2-”、“(4-10元杂环烷基)-C(＝O)-O-”和“(4-10元杂环烷基)-CH2-”里的“4-10元杂环烷基”任选被0、1或2个氧代基(＝O)取代；所述“(4-10元杂环烷基)-C(＝O)-OCH2-”、“(4-10元杂环烷基)-C(＝O)-O-”和“(4-10元杂环烷基)-CH2-”里的“4-10元杂环烷基”中的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；Each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2j is independently halogen, -OH, deuterium, -CN, -C(=O)H, C 1 -C 6 alkyl , C 1 -C 6 alkyl, C 2 -C 6 alkenyl , C 2 -C 6 alkynyl, C 1 -C 6 alkyl-O- substituted by one or more R 2-a , by one or C 1 -C 6 alkyl -O-, phenyl-Q-, FO 2 S-phenylene-Q-, phenyl-C(=O)NH-, -N( R 5 ) 2 , (C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl) -C(=O)-, oxo (= O), (C l -C 6 alkyl substituted by one or more halogens) -C(=O)-, -SO 2 F, (C l -C 6 alkyl) -SO 2 -, (C l -C 6 alkyl) -O-(C l -C 6 alkyl) -O-, -CH 2 OC(=O)N(R 5 ) 2 , (C l -C 6 alkyl) -OC(= O)-NHCH 2 -, -CH 2 NHC(=O)N(R 5 ) 2 , (C 1 -C 6 alkyl)-C(=O)NHCH 2 -, (pyrazolyl)-CH 2 - , (C 1 -C 6 alkyl)-SO 2 -NHCH 2 -, (4-10 membered heterocycloalkyl)-C(=O)-OCH 2 -, (R 5 ) 2 NC(=O)- O-, (C l -C 6 alkyl) -O-(C l -C 6 alkyl) -NH-C(=O) -O-, phenyl - (C l -C 6 alkyl) -NH -C(=O)-O-, (4-10 membered heterocycloalkyl)-C(=O)-O- or (4-10 membered heterocycloalkyl)-CH 2 -; said "phenyl "Phenyl" in -C(=O)NH-" and "phenyl-(C 1 -C 6 alkyl)-NH-C(=O)-O-" is optionally replaced by -C(=O) Substituted by H, halogen, CN or OH; said "(4-10 membered heterocycloalkyl)-C(=O)-OCH 2 -", "(4-10 membered heterocycloalkyl)-C(=O )-O-" and "(4-10-membered heterocycloalkyl)-CH 2 -" in "4-10-membered heterocycloalkyl" are optionally replaced by 0, 1 or 2 oxo groups (=O) Substitution; the "(4-10 membered heterocycloalkyl)-C(=O)-OCH 2 -", "(4-10 membered heterocycloalkyl)-C(=O)-O-" and " The heteroatoms in the "4-10 membered heterocycloalkyl" in (4-10 membered heterocycloalkyl)-CH 2 -" are selected from one or more of N, O and S, and the number of heteroatoms 1, 2 or 3;
各Q分别独立地为连接单键或-O-；Each Q is independently a connecting single bond or -O-;
各R2-a和R2-b分别独立地为氘、-CN、卤素或-OH；Each R 2-a and R 2-b are independently deuterium, -CN, halogen or -OH;
各R2g、R2h和R2i分别独立地为卤素、-OH、-C(＝O)H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷基-O-、被一个或多个卤素或OH取代的C1-C6烷基或-N(R5)2；Each of R 2g , R 2h and R 2i is independently halogen, -OH, -C(=O)H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl substituted by one or more halogens or OH, or -N(R 5 ) 2 ;
R3为卤素、-OH、氘、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、硝基、-(CH2)n6N(R5)2、-NHC(＝NH)NH2、-(CH2)n7C(＝O)N(R5)2、-(CH2)n8C(＝O)R5、-N(R5)C(＝O)-(C6-C10芳基)、-(CH2)n9C(＝O)O-(C1-C6烷基)、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R3a取代的C1-C6烷基、被一个或多个R3b取代的C1-C6烷基-O-、被一个或多个R3c取代的C1-C6烷基-S-、被一个或多个R3d取代的C2-C6烯基、被一个或多个R3e取代的C2-C6炔基、被一个或多个R3f取代的3-7元环烷基、被一个或多个R3g取代的3-7元环烯基、被一个或多个R3h取代的4-10元杂环烷基、被一个或多个R3i取代的4-10元杂环烯基、被一个或多个R3j取代的C6-C10芳基或被一个或多个R3k取代的5至14元杂芳基；所述“5至14元杂芳基”和“被一个或多个R3k取代的5至14元杂芳基”中的“5至14元杂芳基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烷基”和“被一个或多个R3h取代的4-10元杂环烷基”中的“4-10元杂环烷基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烯基”和“被一个或多个R3i取代的4-10元杂环烯基”中的“4-10元杂环烯基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；R 3 is halogen, -OH, deuterium, -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl , C 2 -C 6 alkynyl, nitro, -(CH 2 ) n6 N(R 5 ) 2 , -NHC(=NH)NH 2 , -(CH 2 ) n7 C(=O)N(R 5 ) 2 , -(CH 2 ) n8 C(=O)R 5 , -N(R 5 )C(=O)-(C 6 -C 10 aryl), -(CH 2 ) n9 C(=O)O -(C 1 -C 6 alkyl), 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6 -C 10 Aryl, 5- to 14-membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 3a , C 1 -C 6 alkyl substituted by one or more R 3b -O-, one C 1 -C 6 alkyl-S- substituted by one or more R 3c , C 2 -C 6 alkenyl substituted by one or more R 3d , C 2 -C 6 alkyne substituted by one or more R 3e group, 3-7 membered cycloalkyl substituted by one or more R 3f , 3-7 membered cycloalkenyl substituted by one or more R 3g , 4-10 membered heterogeneous substituted by one or more R 3h Cycloalkyl, 4-10 membered heterocycloalkenyl substituted by one or more R 3i , C 6 -C 10 aryl substituted by one or more R 3j or 5 to 10 substituted by one or more R 3k 14-membered heteroaryl; the heteroaryl in the "5- to 14-membered heteroaryl" in the "5- to 14-membered heteroaryl" and "5 to 14-membered heteroaryl substituted by one or more R3k " Atoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the "4-10 membered heterocycloalkyl" and "substituted by one or more R 3h The heteroatoms in the "4-10 membered heterocycloalkyl" in "4-10 membered heterocycloalkyl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the hetero in the "4-10-membered heterocyclenyl" in the "4-10-membered heterocyclenyl" and "4-10-membered heterocyclenyl substituted by one or more R3i " Atoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
各R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j和R3k分别独立地为氘、卤素、-OH、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、-N(R5)2、-(CH2)-C(＝O)N(R5)2、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R3-a取代的C1-C6烷基、被一个或多个R3-b取代的C1-C6烷基-O-、被一个或多个R3-c取 代的C1-C6烷基-S-、被一个或多个R3-d取代的C2-C6烯基、被一个或多个R3-e取代的C2-C6炔基、被一个或多个R3-f取代的3-7元环烷基、被一个或多个R3-g取代的4-10元杂环烷基、被一个或多个R3-h取代的5至14元杂芳基、被一个或多个R3-i取代的3-7元环烯基、被一个或多个R3-j取代的4-10元杂环烯基或被一个或多个R3-k取代的C6-C10芳基；所述“4-10元杂环烷基”和“被一个或多个R3-g取代的4-10元杂环烷基”中的“4-10元杂环烷基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烯基”和“被一个或多个R3-j取代的4-10元杂环烯基”中的“4-10元杂环烯基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“5至14元杂芳基”和“被一个或多个R3-h取代的5至14元杂芳基”中的“5至14元杂芳基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；Each of R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j and R 3k is independently deuterium, halogen, -OH, -CN, C 1 - C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -N(R 5 ) 2 , -(CH 2 )-C(=O)N(R 5 ) 2 , 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycle Alkenyl, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 3-a , C substituted by one or more R 3-b 1 -C 6 alkyl-O-, taken by one or more R 3-c Substituted C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl substituted by one or more R 3-d , C 2 -C 6 alkynyl substituted by one or more R 3-e , 3-7 membered cycloalkyl substituted by one or more R 3-f , 4-10 membered heterocycloalkyl substituted by one or more R 3-g , substituted by one or more R 3-h 5 to 14-membered heteroaryl, 3-7-membered cycloalkenyl substituted by one or more R 3-i , 4-10-membered heterocycloalkenyl substituted by one or more R 3-j or by one or multiple R 3-k substituted C 6 -C 10 aryl; said "4-10 membered heterocycloalkyl" and "4-10 membered heterocycloalkyl substituted by one or more R 3-g "The heteroatoms in the "4-10 membered heterocycloalkyl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the "4-10 The heteroatoms in the "4-10 membered heterocyclenyl" in "heterocyclenyl" and "4-10 membered heterocyclenyl substituted by one or more R 3-j " are selected from N, O and One or more of S, the number of heteroatoms is 1, 2 or 3; the "5 to 14 membered heteroaryl" and "5 to 14 membered heteroaryl substituted by one or more R 3-h The heteroatoms in the "5- to 14-membered heteroaryl" in "aryl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
各R3-a、R3-b、R3-c、R3-d、R3-e、R3-f、R3-g、R3-h、R3-i、R3-j和R3-k分别独立地为氘、卤素、-CN、-OH、C1-C6烷基、C1-C6烷基-O-或3-7元环烷基；Each of R 3-a , R 3-b , R 3-c , R 3-d , R 3-e , R 3-f , R 3-g , R 3-h , R 3-i , R 3-j and R 3-k are independently deuterium, halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O- or 3-7 membered cycloalkyl;
R4a为氘、-OH、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、-(CH2)n7C(＝O)N(R5)2、-C(＝O)OR7、-C[N(R5)2](＝NR8)、C2-C6烯基、C2-C6炔基、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a取代的C1-C6烷基、被一个或多个R4-b取代的C1-C6烷基-O-、被一个或多个R4-c取代的C1-C6烷基-S-、被一个或多个R4-d取代的C2-C6烯基、被一个或多个R4-e取代的C2-C6炔基、被一个或多个R4-f取代的C6-C10芳基、被一个或多个R4-g取代的3-7元环烷基、被一个或多个R4-h取代的3-7元环烯基、被一个或多个R4-i取代的4-10元杂环烷基、被一个或多个R4-j取代的4-10元杂环烯基或被一个或多个R4-k取代的5至14元杂芳基；所述“5至14元杂芳基”和“被一个或多个R4-k取代的5至14元杂芳基”中的“5至14元杂芳基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烷基”和“被一个或多个R4-i取代的4-10元杂环烷基”中的“4-10元杂环烷基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烯基”和“被一个或多个R4-j取代的4-10元杂环烯基”中的“4-10元杂环烯基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；R 4a is deuterium, -OH, -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl -S-, -(CH 2 ) n7 C(= O)N(R 5 ) 2 , -C(=O)OR 7 , -C[N(R 5 ) 2 ](=NR 8 ), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 4-a , C 1 -C 6 alkyl-O- substituted by one or more R 4-b , one or more R 4-c Substituted C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl substituted by one or more R 4-d , C 2 -C 6 alkynyl substituted by one or more R 4-e , C 6 -C 10 aryl substituted by one or more R 4-f , 3-7 membered cycloalkyl substituted by one or more R 4-g , substituted by one or more R 4-h 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl substituted by one or more R 4-i , 4-10 membered heterocycloalkenyl substituted by one or more R 4-j , or substituted by one or a plurality of R 4-k substituted 5 to 14-membered heteroaryl; said "5 to 14-membered heteroaryl" and "5 to 14-membered heteroaryl substituted by one or more R 4-k " The heteroatoms in the "5 to 14 membered heteroaryl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the "4-10 membered heterocyclic The heteroatoms in the "4-10 membered heterocycloalkyl" in "alkyl" and "4-10 membered heterocycloalkyl" substituted by one or more R 4-i are selected from N, O and S One or more, the number of heteroatoms is 1, 2 or 3; the "4-10 membered heterocyclenyl" and "4-10 membered heterocyclenyl substituted by one or more R 4-j The heteroatoms in the "4-10 membered heterocycloalkenyl" in "group" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
各R4-a、R4-b、R4-c、R4-d、R4-e和R4-f分别独立地为-OH、氘、卤素、-(CH2)n6N(R5)2、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a-1取代的C1-C6烷基、被一个或多个R4-a-2取代的C1-C6烷基-O-、被一个或多个R4-a-3取代的C1-C6烷基-S-、被一个或多个R4-a-4取代的C2-C6烯基、被一个或多个R4-a-5取代的C2-C6炔基、被一个或多个R4-a-6取代的3-7元环烷基、被一个或多个R4-a-7取代的3-7元环烯基、被一个或多个R4-a-8取代的4-10元杂环烷基、被一个或多个R4-a-9取代的4-10元杂环烯基、被一个或多个R4-a-10取代的C6-C10芳基或被一个或多个R4-a-11取代的5至14元杂芳基；所述“5至14元杂芳基”和“被一个或多个R4-a-11取代的5至14元杂芳基”中的“5至14元杂芳基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烷基”和“被一个或多个R4-a-8取代的4-10元杂环烷基”中的“4-10元杂环烷基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烯基”和“被一个或多个R4-a-9取代的4-10元杂环烯基”中的“4-10元杂环烯基”里的杂原子选自N、 O和S中的一种或多种，杂原子个数为1、2或3个；Each of R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4-f is independently -OH, deuterium, halogen, -(CH 2 ) n6 N(R 5 ) 2 , -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl -S-, C 2 -C 6 alkenyl, C 2 -C 6 Alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heterocycloalkenyl, Aryl, C 1 -C 6 alkyl substituted by one or more R 4-a-1 , C 1 -C 6 alkyl substituted by one or more R 4-a-2 -O-, by one or C 1 -C 6 alkyl-S-substituted by R 4-a-3 , C 2 -C 6 alkenyl substituted by one or more R 4-a-4 , one or more R 4 -a-5 substituted C 2 -C 6 alkynyl, 3-7 membered cycloalkyl substituted by one or more R 4-a-6 , 3-substituted by one or more R 4-a-7 7-membered cycloalkenyl, 4-10-membered heterocycloalkyl substituted by one or more R 4-a-8 , 4-10-membered heterocycloalkenyl substituted by one or more R 4-a-9 , C 6 -C 10 aryl substituted by one or more R 4-a-10 or 5 to 14 membered heteroaryl substituted by one or more R 4-a-11 ; said "5 to 14 membered heteroaryl The heteroatoms in the "5 to 14-membered heteroaryl" in "aryl" and "5 to 14-membered heteroaryl substituted by one or more R 4-a-11 " are selected from N, O and S One or more, the number of heteroatoms is 1, 2 or 3; the "4-10 membered heterocycloalkyl" and "4-10 membered heterocycloalkyl substituted by one or more R 4-a-8 The heteroatoms in the "4-10 membered heterocycloalkyl" in "cycloalkyl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the " The heteroatoms in the "4-10 membered heterocyclenyl" in "4-10 membered heterocyclenyl" and "4-10 membered heterocyclenyl substituted by one or more R 4-a-9 " are selected from from N, One or more of O and S, the number of heteroatoms is 1, 2 or 3;
各R4-g、R4-h、R4-i、R4-j和R4-k分别独立地为-OH、氘、卤素、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、氧代基(＝O)、硫代基(＝S)、-C(＝O)OR7、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-g-1取代的C1-C6烷基、被一个或多个R4-g-2取代的C1-C6烷基-O-、被一个或多个R4-g-3取代的C1-C6烷基-S-、被一个或多个R4-g-4取代的C2-C6烯基、被一个或多个R4-g-5取代的C2-C6炔基、被一个或多个R4-g-6取代的3-7元环烷基、被一个或多个R4-g-7取代的3-7元环烯基、被一个或多个R4-g-8取代的4-10元杂环烷基、被一个或多个R4-g-9取代的4-10元杂环烯基、被一个或多个R4-g-10取代的C6-C10芳基或被一个或多个R4-g-11取代的5至14元杂芳基；所述“5至14元杂芳基”和“被一个或多个R4-g-11取代的5至14元杂芳基”中的“5至14元杂芳基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烷基”和“被一个或多个R4- g-8取代的4-10元杂环烷基”中的“4-10元杂环烷基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烯基”和“被一个或多个R4-g-9取代的4-10元杂环烯基”中的“4-10元杂环烯基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；Each of R 4-g , R 4-h , R 4-i , R 4-j and R 4-k is independently -OH, deuterium, halogen, -(CH 2 ) n6 N(R 5 ) 2 , - CN, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, oxo (=O), thiol (=S), -C(=O)OR 7 , 3-7 membered cycloalkyl, 3 -7-membered cycloalkenyl, 4-10-membered heterocycloalkyl, 4-10-membered heterocycloalkenyl, C 6 -C 10 aryl, 5-14-membered heteroaryl, by one or more R 4-g -1 substituted C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 4-g-2 -O-, C substituted by one or more R 4-g-3 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl substituted by one or more R 4-g-4 , C 2 -C 6 alkyne substituted by one or more R 4-g- 5 Group, 3-7 membered cycloalkyl substituted by one or more R 4-g-6 , 3-7 membered cycloalkenyl substituted by one or more R 4-g-7 , substituted by one or more R 4-10 membered heterocycloalkyl substituted by 4-g-8 , 4-10 membered heterocycloalkenyl substituted by one or more R 4-g-9 , substituted by one or more R 4-g-10 The C 6 -C 10 aryl group or the 5 to 14 membered heteroaryl group substituted by one or more R 4-g-11 ; the "5 to 14 membered heteroaryl group" and "one or more R 4 The heteroatoms in the "5 to 14-membered heteroaryl" in -g-11- substituted 5- to 14-membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1 , 2 or 3; the "4-10 membered heterocycloalkyl" and "4-10 membered heterocycloalkyl substituted by one or more R 4- g-8 " in the "4-10 membered heterocycloalkyl" The heteroatoms in "cycloalkyl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the "4-10 membered heterocycloalkenyl" and "by The heteroatoms in the "4-10-membered heterocycloalkenyl" in one or more R 4-g-9 substituted 4-10-membered heterocycloalkenyls are selected from one or more of N, O and S species, the number of heteroatoms is 1, 2 or 3;
各R4-a-1～R4-a-11和R4-g-1～R4-g-11分别独立地为氘、卤素、-CN、-OH、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-或3-7元环烷基；Each of R 4-a-1 to R 4-a-11 and R 4-g-1 to R 4-g-11 is independently deuterium, halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S- or 3-7 membered cycloalkyl;
R4b为H、氘、-N(R5)2、卤素、-OH、C1-C6烷基、-CN、被一个或多个R4-b-1取代的C1-C6烷基、C1-C6烷基-O-、C2-C6烯基或C2-C6炔基；R 4b is H, deuterium, -N(R 5 ) 2 , halogen, -OH, C 1 -C 6 alkyl, -CN, C 1 -C 6 alkane substituted by one or more R 4-b-1 C 1 -C 6 alkyl-O-, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
各R4-b-1分别独立地为氘、卤素、-CN或-OH；Each R 4-b-1 is independently deuterium, halogen, -CN or -OH;
n1、n2、n3、n4、n5、n6、n7、n8和n9分别独立地为0、1、2、3、4或5；n1, n2, n3, n4, n5, n6, n7, n8 and n9 are independently 0, 1, 2, 3, 4 or 5;
各R5分别独立地为H、-C(＝O)OR7或C1-C6烷基；Each R 5 is independently H, -C(=O)OR 7 or C 1 -C 6 alkyl;
各R6a和R6b分别独立地为H、氘、卤素、-CN、-OH、C1-C6烷基或氘代C1-C6烷基；Each R 6a and R 6b are independently H, deuterium, halogen, -CN, -OH, C 1 -C 6 alkyl or deuterated C 1 -C 6 alkyl;
R7独立地为H、氘、C1-C6烷基、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基或5至14元杂芳基；R 7 is independently H, deuterium, C 1 -C 6 alkyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl , C 6 -C 10 aryl or 5 to 14 membered heteroaryl;
R8独立地为H、氘、-OH或C1-C6烷基。R 8 is independently H, deuterium, -OH or C 1 -C 6 alkyl.
在本发明某些优选实施方案中，所述如式I所示的化合物、其立体异构体或其药学上可接受的盐中的某些基团如下定义，未提及的基团同本发明任一方案所述(简称“在一些实施方式中”)，In some preferred embodiments of the present invention, certain groups in the compound shown in formula I, its stereoisomers or pharmaceutically acceptable salts thereof are defined as follows, and the unmentioned groups are the same as As described in any scheme of the invention (referred to as "in some embodiments"),
在一些实施方式中，所述如式I所示的化合物不为如下任一化合物：






In some embodiments, the compound shown in formula I is not any of the following compounds:






在一些实施方式中，R4a为氘、-CN、C1-C6烷基-S-、-(CH2)n7C(＝O)N(R5)2、-C(＝O)OR7、-C[N(R5)2](＝NR8)、C2-C6烯基、C2-C6炔基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a取代的C1-C6烷基、被一个或多个R4-b取代的C1-C6烷基-O-、被一个或多个R4-c取代的C1-C6烷基-S-、被一个或多个R4-d取代的C2-C6烯基、被一个或多个R4- e取代的C2-C6炔基、被一个或多个R4-f取代的C6-C10芳基、被一个或多个R4-g取代的3-7元环烷基、 被一个或多个R4-h取代的3-7元环烯基、被一个或多个R4-i取代的4-10元杂环烷基、被一个或多个R4-j取代的4-10元杂环烯基或被一个或多个R4-k取代的5至14元杂芳基；In some embodiments, R 4a is deuterium, -CN, C 1 -C 6 alkyl-S-, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , -C(=O)OR 7. -C[N(R 5 ) 2 ](=NR 8 ), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl , 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 4-a , one or more C 1 -C 6 alkyl-O-substituted by R 4-b , C 1 -C 6 alkyl-S- substituted by one or more R 4-c , substituted by one or more R 4-d C 2 -C 6 alkenyl, C 2 -C 6 alkynyl substituted by one or more R 4- e , C 6 -C 10 aryl substituted by one or more R 4-f , one or more A 3-7 membered cycloalkyl group substituted by R 4-g , 3-7 membered cycloalkenyl substituted by one or more R 4-h , 4-10 membered heterocycloalkyl substituted by one or more R 4-i , substituted by one or more R 4-j 4-10 membered heterocycloalkenyl or 5 to 14 membered heteroaryl substituted by one or more R 4-k ;
各R4-a分别独立地为-OH、氘、-(CH2)n6N(R5)2、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a-1取代的C1-C6烷基、被一个或多个R4-a-2取代的C1-C6烷基-O-、被一个或多个R4-a-3取代的C1-C6烷基-S-、被一个或多个R4-a-4取代的C2-C6烯基、被一个或多个R4-a-5取代的C2-C6炔基、被一个或多个R4-a-6取代的3-7元环烷基、被一个或多个R4-a-7取代的3-7元环烯基、被一个或多个R4-a-8取代的4-10元杂环烷基、被一个或多个R4-a-9取代的4-10元杂环烯基、被一个或多个R4-a-10取代的C6-C10芳基或被一个或多个R4-a-11取代的5至14元杂芳基；Each R 4-a is independently -OH, deuterium, -(CH 2 ) n6 N(R 5 ) 2 , -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl , 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 4-a-1 , substituted by one or C 1 -C 6 alkyl-O- substituted by multiple R 4-a-2 , C 1 -C 6 alkyl-S- substituted by one or more R 4-a-3 , one or more C 2 -C 6 alkenyl substituted by R 4-a-4 , C 2 -C 6 alkynyl substituted by one or more R 4-a-5 , one or more R 4-a-6 substituted 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl substituted by one or more R 4-a-7 , 4-10 membered heterocycloalkyl substituted by one or more R 4-a-8 , 4-10 membered heterocycloalkenyl substituted by one or more R 4-a-9 , C 6 -C 10 aryl substituted by one or more R 4-a-10, or substituted by one or more R 4-a-11 substituted 5 to 14 membered heteroaryl;
各R4-b分别独立地为-OH、氘、-(CH2)n6N(R5)2、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a-1取代的C1-C6烷基、被一个或多个R4-a-2取代的C1-C6烷基-O-、被一个或多个R4-a-3取代的C1-C6烷基-S-、被一个或多个R4-a-4取代的C2-C6烯基、被一个或多个R4-a-5取代的C2-C6炔基、被一个或多个R4-a-6取代的3-7元环烷基、被一个或多个R4-a-7取代的3-7元环烯基、被一个或多个R4-a-8取代的4-10元杂环烷基、被一个或多个R4-a-9取代的4-10元杂环烯基、被一个或多个R4-a-10取代的C6-C10芳基或被一个或多个R4-a-11取代的5至14元杂芳基；Each R 4-b is independently -OH, deuterium, -(CH 2 ) n6 N(R 5 ) 2 , -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkene radical, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 4-a-1 , one or more R 4-a-2 Substituted C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S- substituted by one or more R 4-a-3 , substituted by one or more R 4-a-4 C 2 -C 6 alkenyl, C 2 -C 6 alkynyl substituted by one or more R 4-a-5 , 3-7 membered cycloalkyl substituted by one or more R 4-a-6 , 3-7 membered cycloalkenyl substituted by one or more R 4-a-7 , 4-10 membered heterocycloalkyl substituted by one or more R 4-a-8 , one or more R 4 - 4-10 membered heterocycloalkenyl substituted by a-9 , C 6 -C 10 aryl substituted by one or more R 4-a-10 or 5 substituted by one or more R 4-a-11 to 14 membered heteroaryl;
各R4-c、R4-d、R4-e和R4-f分别独立地为-OH、氘、卤素、-(CH2)n6N(R5)2、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a-1取代的C1-C6烷基、被一个或多个R4-a-2取代的C1-C6烷基-O-、被一个或多个R4-a-3取代的C1-C6烷基-S-、被一个或多个R4-a-4取代的C2-C6烯基、被一个或多个R4-a-5取代的C2-C6炔基、被一个或多个R4-a-6取代的3-7元环烷基、被一个或多个R4-a-7取代的3-7元环烯基、被一个或多个R4-a-8取代的4-10元杂环烷基、被一个或多个R4-a-9取代的4-10元杂环烯基、被一个或多个R4-a-10取代的C6-C10芳基或被一个或多个R4-a-11取代的5至14元杂芳基；Each of R 4-c , R 4-d , R 4-e and R 4-f is independently -OH, deuterium, halogen, -(CH 2 ) n6 N(R 5 ) 2 , -CN, C 1 - C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-7 membered cycloalkyl , 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, replaced by one or more R 4 -a-1 substituted C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 4-a-2 -O-, substituted by one or more R 4-a-3 C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl substituted by one or more R 4-a-4 , C 2 -C substituted by one or more R 4-a-5 6 alkynyl, 3-7 membered cycloalkyl substituted by one or more R 4-a-6 , 3-7 membered cycloalkenyl substituted by one or more R 4-a-7 , substituted by one or more 4-10 membered heterocycloalkyl substituted by R 4-a-8 , 4-10 membered heterocycloalkenyl substituted by one or more R 4-a-9 , one or more R 4-a- 10 substituted C 6 -C 10 aryl or 5 to 14 membered heteroaryl substituted by one or more R 4-a-11 ;
各R4-g、R4-h、R4-i、R4-j和R4-k分别独立地为-OH、氘、卤素、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、氧代基(＝O)、硫代基(＝S)、-C(＝O)OR7、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-g-1取代的C1-C6烷基、被一个或多个R4-g-2取代的C1-C6烷基-O-、被一个或多个R4-g-3取代的C1-C6烷基-S-、被一个或多个R4-g-4取代的C2-C6烯基、被一个或多个R4-g-5取代的C2-C6炔基、被一个或多个R4-g-6取代的3-7元环烷基、被一个或多个R4-g-7取代的3-7元环烯基、被一个或多个R4-g-8取代的4-10元杂环烷基、被一个或多个R4-g-9取代的4-10元杂环烯基、被一个或多个R4-g-10取代的C6-C10芳基或被一个或多个R4-g-11取代的5至14元杂芳基。Each of R 4-g , R 4-h , R 4-i , R 4-j and R 4-k is independently -OH, deuterium, halogen, -(CH 2 ) n6 N(R 5 ) 2 , - CN, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, oxo (=O), thiol (=S), -C(=O)OR 7 , 3-7 membered cycloalkyl, 3 -7-membered cycloalkenyl, 4-10-membered heterocycloalkyl, 4-10-membered heterocycloalkenyl, C 6 -C 10 aryl, 5-14-membered heteroaryl, by one or more R 4-g -1 substituted C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 4-g-2 -O-, C substituted by one or more R 4-g-3 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl substituted by one or more R 4-g-4 , C 2 -C 6 alkyne substituted by one or more R 4-g- 5 Group, 3-7 membered cycloalkyl substituted by one or more R 4-g-6 , 3-7 membered cycloalkenyl substituted by one or more R 4-g-7 , substituted by one or more R 4-10 membered heterocycloalkyl substituted by 4-g-8 , 4-10 membered heterocycloalkenyl substituted by one or more R 4-g-9 , substituted by one or more R 4-g-10 C 6 -C 10 aryl or 5- to 14-membered heteroaryl substituted by one or more R 4-g-11 .
在一些实施方式中，R4a为-(CH2)n7C(＝O)N(R5)2、被一个或多个R4-j取代的4-10元杂环烯基、被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基、5至14元杂芳基或被一个或多个R4-a取代的C1-C6烷基；In some embodiments, R 4a is -(CH 2 ) n7 C(=O)N(R 5 ) 2 , a 4-10 membered heterocycloalkenyl substituted by one or more R 4-j , substituted by one or 5 to 14-membered heteroaryl group substituted by multiple R 4-k , C 6 -C 10 aryl group, C 6 -C 10 aryl group, 5 to 14-membered heteroaryl group substituted by one or more R 4-f Or C 1 -C 6 alkyl substituted by one or more R 4-a ;
各R4-a分别独立地为-OH、-CN、-(CH2)n6N(R5)2或C2-C6炔基； Each R 4-a is independently -OH, -CN, -(CH 2 ) n6 N(R 5 ) 2 or C 2 -C 6 alkynyl;
各R4-f分别独立地为-OH、卤素、-(CH2)n6N(R5)2或C2-C6炔基；Each R 4-f is independently -OH, halogen, -(CH 2 ) n6 N(R 5 ) 2 or C 2 -C 6 alkynyl;
各R4-j和R4-k分别独立地为卤素、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6烷基、C1-C6烷基-O-、氧代基(＝O)、4-10元杂环烷基或被一个或多个R4-g-1取代的C1-C6烷基。Each of R 4-j and R 4-k is independently halogen, -(CH 2 ) n6 N(R 5 ) 2 , -CN, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, oxo (=O), 4-10 membered heterocycloalkyl or C substituted by one or more R 4-g-1 1 -C 6 alkyl.
在一些实施方式中，R4a为被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基或5至14元杂芳基；In some embodiments, R 4a is 5 to 14 membered heteroaryl substituted by one or more R 4-k , C 6 -C 10 aryl substituted by one or more R 4-f , C 6 - C 10 aryl or 5 to 14 membered heteroaryl;
各R4-f分别独立地为卤素、-OH或C2-C6炔基；Each R 4-f is independently halogen, -OH or C 2 -C 6 alkynyl;
各R4-k分别独立地为卤素、被一个或多个R4-g-1取代的C1-C6烷基、-(CH2)n6N(R5)2、C1-C6烷基或-CN。Each R 4-k is independently halogen, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , -(CH 2 ) n6 N(R 5 ) 2 , C 1 -C 6 Alkyl or -CN.
在一些实施方式中，环A为4-10元杂环烷基或4-10元杂环烯基，优选4-10元杂环烷基。In some embodiments, ring A is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkenyl, preferably 4-10 membered heterocycloalkyl.
在一些实施方式中，n为0或1，优选0。In some embodiments, n is 0 or 1, preferably 0.
在一些实施方式中，各R1分别独立地为卤素、-CN、-OH、-N(R5)2、C1-C6烷基或被一个或多个R1a取代的C1-C6烷基。In some embodiments, each R 1 is independently halogen, -CN, -OH, -N(R 5 ) 2 , C 1 -C 6 alkyl, or C 1 -C substituted by one or more R 1a 6 alkyl.
在一些实施方式中，各R1a、R1b、R1c和R1d分别独立地为-CN、卤素或-OH。In some embodiments, each of R 1a , R 1b , R 1c , and R 1d is independently —CN, halogen, or —OH.
在一些实施方式中，L为-O-(CR6aR6b)n2-*，*表示与R2连接的一端。In some embodiments, L is -O-(CR 6a R 6b ) n2 - * , and * represents the end connected to R 2 .
在一些实施方式中，R2为4-10元杂环烷基或被一个或多个R2e取代的4-10元杂环烷基，优选被一个或多个R2e取代的4-10元杂环烷基。In some embodiments, R is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl substituted by one or more R 2e , preferably 4-10 membered substituted by one or more R 2e Heterocycloalkyl.
在一些实施方式中，各R2a、R2b、R2c、R2d、R2e、R2f和R2j分别独立地为卤素或C1-C6烷基；优选卤素。In some embodiments, each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2j is independently halogen or C 1 -C 6 alkyl; preferably halogen.
在一些实施方式中，R3为卤素、C6-C10芳基、5至14元杂芳基、被一个或多个R3j取代的C6-C10芳基或被一个或多个R3k取代的5至14元杂芳基；优选卤素或被一个或多个R3j取代的C6-C10芳基。In some embodiments, R 3 is halogen, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 6 -C 10 aryl substituted by one or more R 3j or substituted by one or more R 3k substituted 5- to 14-membered heteroaryl; preferably halogen or C 6 -C 10 aryl substituted by one or more R 3j .
在一些实施方式中，各R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j和R3k分别独立地为卤素、-OH、-N(R5)2、C1-C6烷基、被一个或多个R3-a取代的C1-C6烷基或C2-C6炔基；优选卤素、-OH或C2-C6炔基。In some embodiments, each of R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j and R 3k is independently halogen, -OH, -N (R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl or C 2 -C 6 alkynyl substituted by one or more R 3-a ; preferably halogen, -OH or C 2 - C 6 alkynyl.
在一些实施方式中，各R3-a、R3-b、R3-c、R3-d、R3-e、R3-f、R3-g、R3-h、R3-i、R3-j和R3-k分别独立地为卤素、-CN或-OH。In some embodiments, each of R 3-a , R 3-b , R 3-c , R 3-d , R 3-e , R 3-f , R 3-g , R 3-h , R 3- i , R 3-j and R 3-k are each independently halogen, -CN or -OH.
在一些实施方式中，R4a为C1-C6烷基、-(CH2)n7C(＝O)N(R5)2、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a取代的C1-C6烷基、被一个或多个R4-f取代的C6-C10芳基、被一个或多个R4-j取代的4-10元杂环烯基或被一个或多个R4-k取代的5至14元杂芳基；优选被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基、5至14元杂芳基或被一个或多个R4-a取代的C1-C6烷基。In some embodiments, R 4a is C 1 -C 6 alkyl, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl radical, 5- to 14-membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 4-a , C 6 -C 10 aryl substituted by one or more R 4-f , one or 4-10 membered heterocycloalkenyl substituted by one or more R 4-j or 5 to 14 membered heteroaryl substituted by one or more R 4-k ; preferably 5-membered substituted by one or more R 4-k to 14 membered heteroaryl, C 6 -C 10 aryl substituted by one or more R 4-f , C 6 -C 10 aryl, 5 to 14 membered heteroaryl or substituted by one or more R 4- a substituted C 1 -C 6 alkyl.
在一些实施方式中，R4a为被一个或多个R4-j取代的4-10元杂环烯基、被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基或5至14元杂芳基；优选为被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基或5至14元杂芳基。In some embodiments, R 4a is 4-10 membered heterocycloalkenyl substituted by one or more R 4-j , 5 to 14 membered heteroaryl substituted by one or more R 4-k , substituted by one C 6 -C 10 aryl, C 6 -C 10 aryl or 5 to 14 membered heteroaryl substituted by or multiple R 4- f ; preferably 5 to 14 membered by one or more R 4-k Heteroaryl, C 6 -C 10 aryl substituted by one or more R 4-f , C 6 -C 10 aryl or 5 to 14 membered heteroaryl.
在一些实施方式中，各R4-a、R4-b、R4-c、R4-d、R4-e和R4-f分别独立地为-OH、卤素、-(CH2)n6N(R5)2、-CN或C2-C6炔基；优选OH、卤素或C2-C6炔基。 In some embodiments, each of R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4-f is independently -OH, halogen, -(CH 2 ) n6 N(R 5 ) 2 , —CN or C 2 -C 6 alkynyl; preferably OH, halogen or C 2 -C 6 alkynyl.
在一些实施方式中，各R4-a分别独立地为-OH、-(CH2)n6N(R5)2、-CN或C2-C6炔基；优选为-OH、-(CH2)n6N(R5)2或-CN，进一步优选为-OH。In some embodiments, each R 4-a is independently -OH, -(CH 2 ) n6 N(R 5 ) 2 , -CN or C 2 -C 6 alkynyl; preferably -OH, -(CH 2 ) n6 N(R 5 ) 2 or -CN, more preferably -OH.
在一些实施方式中，各R4-b、R4-c、R4-d、R4-e和R4-f分别独立地为-OH、卤素、-(CH2)n6N(R5)2或C2-C6炔基，优选卤素、-OH或C2-C6炔基。In some embodiments, each of R 4-b , R 4-c , R 4-d , R 4-e and R 4-f is independently -OH, halogen, -(CH 2 ) n6 N(R 5 ) 2 or C 2 -C 6 alkynyl, preferably halogen, —OH or C 2 -C 6 alkynyl.
在一些实施方式中，各R4-g、R4-h、R4-i、R4-j和R4-k分别独立地为卤素、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6烷基、C1-C6烷基-O-、氧代基(＝O)、4-10元杂环烷基或被一个或多个R4- g-1取代的C1-C6烷基；优选卤素、被一个或多个R4-g-1取代的C1-C6烷基、-(CH2)n6N(R5)2、C1-C6烷基或-CN；更优选卤素、被一个或多个R4-g-1取代的C1-C6烷基、-(CH2)n6N(R5)2或C1-C6烷基。In some embodiments, each of R 4-g , R 4-h , R 4-i , R 4-j and R 4-k is independently halogen, -(CH 2 ) n6 N(R 5 ) 2 , -CN, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, oxo (=O), 4- 10-membered heterocycloalkyl or C 1 -C 6 alkyl substituted by one or more R 4- g-1 ; preferably halogen, C 1 -C 6 alkane substituted by one or more R 4-g-1 radical, -(CH 2 ) n6 N(R 5 ) 2 , C 1 -C 6 alkyl or -CN; more preferably halogen, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , -(CH 2 ) n6 N(R 5 ) 2 or C 1 -C 6 alkyl.
在一些实施方式中，各R4-a-1～R4-a-11和R4-g-1～R4-g-11分别独立地为卤素。In some embodiments, each of R 4-a-1 to R 4-a-11 and R 4-g-1 to R 4-g-11 is independently halogen.
在一些实施方式中，R4b为卤素。In some embodiments, R 4b is halogen.
在一些实施方式中，n1、n2、n3、n4、n5、n6、n7、n8和n9分别独立地为0或1。In some embodiments, n1, n2, n3, n4, n5, n6, n7, n8 and n9 are each independently 0 or 1.
在一些实施方式中，n2为1。In some embodiments, n2 is 1.
在一些实施方式中，n1、n3、n4、n5、n6、n7、n8和n9分别独立地为0。In some embodiments, n1, n3, n4, n5, n6, n7, n8 and n9 are each independently 0.
在一些实施方式中，各R6a和R6b分别独立地为H。In some embodiments, each R 6a and R 6b is independently H.
在一些实施方式中，环A为4-10元杂环烷基；In some embodiments, Ring A is a 4-10 membered heterocycloalkyl;
n为0；n is 0;
L为-O-(CR6aR6b)n2-*，*表示与R2连接的一端；L is -O-(CR 6a R 6b ) n2 - * , * represents one end connected to R 2 ;
R2为4-10元杂环烷基或被一个或多个R2e取代的4-10元杂环烷基；R 2 is a 4-10 membered heterocycloalkyl group or a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
各R2e分别独立地为卤素；each R 2e is independently halogen;
R3为卤素或被一个或多个R3j取代的C6-C10芳基；R 3 is halogen or C 6 -C 10 aryl substituted by one or more R 3j ;
各R3j分别独立地为卤素、-OH或C2-C6炔基；Each R 3j is independently halogen, -OH or C 2 -C 6 alkynyl;
R4a为被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基、5至14元杂芳基或被一个或多个R4-a取代的C1-C6烷基；R 4a is a 5- to 14-membered heteroaryl group substituted by one or more R 4-k , a C 6 -C 10 aryl group substituted by one or more R 4-f , a C 6 -C 10 aryl group, 5 to 14-membered heteroaryl or C 1 -C 6 alkyl substituted by one or more R 4-a ;
各R4-a和R4-f分别独立地为OH、卤素或C2-C6炔基；Each R 4-a and R 4-f is independently OH, halogen or C 2 -C 6 alkynyl;
各R4-k分别独立地为卤素、被一个或多个R4-g-1取代的C1-C6烷基、-(CH2)n6N(R5)2或C1-C6烷基；Each R 4-k is independently halogen, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , -(CH 2 ) n6 N(R 5 ) 2 or C 1 -C 6 alkyl;
各R4-g-1分别独立地为卤素；Each R 4-g-1 is independently halogen;
R4b为卤素；R 4b is halogen;
各R5分别独立地为H或C1-C6烷基；Each R 5 is independently H or C 1 -C 6 alkyl;
n2为1；n2 is 1;
n6为0；n6 is 0;
各R6a和R6b分别各自独立地为H。Each R 6a and R 6b are each independently H.
在一些实施方式中，环A为4-10元杂环烷基；In some embodiments, Ring A is a 4-10 membered heterocycloalkyl;
n为0；n is 0;
L为-O-(CR6aR6b)n2-*，*表示与R2连接的一端；L is -O-(CR 6a R 6b ) n2 - * , * represents one end connected to R 2 ;
R2为4-10元杂环烷基或被一个或多个R2e取代的4-10元杂环烷基；R 2 is a 4-10 membered heterocycloalkyl group or a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
各R2e分别独立地为卤素； each R 2e is independently halogen;
R3为卤素或被一个或多个R3j取代的C6-C10芳基；R 3 is halogen or C 6 -C 10 aryl substituted by one or more R 3j ;
各R3j分别独立地为卤素、-OH或C2-C6炔基；Each R 3j is independently halogen, -OH or C 2 -C 6 alkynyl;
R4a为被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基、5至14元杂芳基或被一个或多个R4-a取代的C1-C6烷基；R 4a is a 5- to 14-membered heteroaryl group substituted by one or more R 4-k , a C 6 -C 10 aryl group substituted by one or more R 4-f , a C 6 -C 10 aryl group, 5 to 14-membered heteroaryl or C 1 -C 6 alkyl substituted by one or more R 4-a ;
各R4-a分别独立地为-OH；Each R 4-a is independently -OH;
各R4-f分别独立地为-OH、卤素或C2-C6炔基；Each R 4-f is independently -OH, halogen or C 2 -C 6 alkynyl;
各R4-k分别独立地为卤素、-CN、被一个或多个R4-g-1取代的C1-C6烷基、-(CH2)n6N(R5)2或C1-C6烷基；Each R 4-k is independently halogen, -CN, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , -(CH 2 ) n6 N(R 5 ) 2 or C 1 -C 6 alkyl;
各R4-g-1分别独立地为卤素；Each R 4-g-1 is independently halogen;
R4b为卤素；R 4b is halogen;
各R5分别独立地为H或C1-C6烷基；Each R 5 is independently H or C 1 -C 6 alkyl;
n2为1；n2 is 1;
n6为0；n6 is 0;
各R6a和R6b分别各自独立地为H。Each R 6a and R 6b are each independently H.
在一些实施方式中，环A为4-10元杂环烷基；In some embodiments, Ring A is a 4-10 membered heterocycloalkyl;
n为0；n is 0;
L为-O-(CR6aR6b)n2-*，*表示与R2连接的一端；L is -O-(CR 6a R 6b ) n2 - * , * represents one end connected to R 2 ;
R2为4-10元杂环烷基或被一个或多个R2e取代的4-10元杂环烷基；R 2 is a 4-10 membered heterocycloalkyl group or a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
各R2e分别独立地为卤素或C1-C6烷基；Each R 2e is independently halogen or C 1 -C 6 alkyl;
R3为卤素、C6-C10芳基、5至14元杂芳基、被一个或多个R3j取代的C6-C10芳基或被一个或多个R3k取代的5至14元杂芳基；R 3 is halogen, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 6 -C 10 aryl substituted by one or more R 3j or 5 to 14 substituted by one or more R 3k Metaheteroaryl;
各R3j和R3k分别独立地为卤素、-OH、-N(R5)2、C1-C6烷基、被一个或多个R3-a取代的C1-C6烷基或C2-C6炔基；Each of R 3j and R 3k is independently halogen, -OH, -N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 3-a , or C 2 -C 6 alkynyl;
各R3-a分别独立地为卤素、-CN或-OH；Each R 3-a is independently halogen, -CN or -OH;
R4a为-(CH2)n7C(＝O)N(R5)2、被一个或多个R4-j取代的4-10元杂环烯基、4-10元杂环烯基、被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基、5至14元杂芳基或被一个或多个R4-a取代的C1-C6烷基；R 4a is -(CH 2 ) n7 C(=O)N(R 5 ) 2 , 4-10 membered heterocycloalkenyl substituted by one or more R 4-j , 4-10 membered heterocycloalkenyl, 5 to 14 membered heteroaryl substituted by one or more R 4-k , C 6 -C 10 aryl substituted by one or more R 4-f , C 6 -C 10 aryl, 5 to 14 membered Heteroaryl or C 1 -C 6 alkyl substituted by one or more R 4-a ;
各R4-a分别独立地为-OH、-(CH2)n6N(R5)2或-CN；Each R 4-a is independently -OH, -(CH 2 ) n6 N(R 5 ) 2 or -CN;
各R4-f分别独立地为-OH、卤素或C2-C6炔基；Each R 4-f is independently -OH, halogen or C 2 -C 6 alkynyl;
各R4-k分别独立地为卤素、4-10元杂环烷基、-(CH2)n7C(＝O)N(R5)2、被一个或多个R4-g-1取代的C1-C6烷基、C1-C6烷基-O-、-(CH2)n6N(R5)2、C1-C6烷基或-CN；Each R 4-k is independently halogen, 4-10 membered heterocycloalkyl, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , substituted by one or more R 4-g-1 C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, -(CH 2 ) n6 N(R 5 ) 2 , C 1 -C 6 alkyl or -CN;
各R4-g-1分别独立地为卤素；Each R 4-g-1 is independently halogen;
各R4-j为氧代基(＝O)；each R 4-j is oxo (=O);
R4b为卤素；R 4b is halogen;
各R5分别独立地为H或C1-C6烷基；Each R 5 is independently H or C 1 -C 6 alkyl;
n2为1； n2 is 1;
n6为0；n6 is 0;
n7为0；n7 is 0;
各R6a和R6b分别各自独立地为H。Each R 6a and R 6b are each independently H.
在一些实施方式中，各所述“4-10元杂环烷基”分别独立地为5-8元杂环烷基，例如 (优选)、 In some embodiments, each of the "4-10 membered heterocycloalkyl groups" is independently a 5-8 membered heterocycloalkyl group, for example (preferred ),
在一些实施方式中，各所述“4-10元杂环烷基”分别独立地为其中所述为 In some embodiments, each of the "4-10 membered heterocycloalkyl" is independently which stated for
在一些实施方式中，各所述卤素分别独立地为氟、氯、溴或碘，优选氟或氯。In some embodiments, each of said halogens is independently fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
在一些实施方式中，各所述“C6-C10芳基”分别独立地为苯基或萘基。In some embodiments, each "C 6 -C 10 aryl" is independently phenyl or naphthyl.
在一些实施方式中，各所述“C1-C6烷基”分别独立地为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基或乙基。In some embodiments, each of the "C 1 -C 6 alkyl groups" is independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
在一些实施方式中，各所述“C2-C6炔基”分别独立地为C2-C3炔基，例如乙炔基、丙炔基或炔丙基，优选为乙炔基。In some embodiments, each of the "C 2 -C 6 alkynyl groups" is independently a C 2 -C 3 alkynyl group, such as ethynyl, propynyl or propargyl, preferably ethynyl.
在一些实施方式中，各所述“5至14元杂芳基”分别独立地为“杂原子为N或S，杂原子数为1个或2个的5-10元杂芳基”，例如吡唑基、吡啶基、喹啉基、异喹啉基、喹唑啉基、吲哚基、吲唑基、吡唑并吡啶基、嘧啶基或苯并噻吩基，又例如 In some embodiments, each of the "5- to 14-membered heteroaryl groups" is independently "a 5-10-membered heteroaryl group whose heteroatom is N or S, and the number of heteroatoms is 1 or 2", for example Pyrazolyl, pyridyl, quinolinyl, isoquinolyl, quinazolinyl, indolyl, indazolyl, pyrazolopyridyl, pyrimidinyl or benzothienyl, for example
在一些实施方式中，各所述“4-10元杂环烯基”分别独立地为5-8元杂环烯基，例如 In some embodiments, each of the "4-10 membered heterocycloalkenyl groups" is independently a 5-8 membered heterocycloalkenyl group, for example
在一些实施方式中，各所述“3-7元环烷基”分别独立地为环丙基、环丁基、环戊基或环己基。In some embodiments, each of the "3-7 membered cycloalkyl groups" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
在一些实施方式中，各所述“3-7元环烯基”分别独立地为环丙烯基、环丁烯基、环戊烯基或环己烯基。In some embodiments, each of the "3-7 membered cycloalkenyl groups" is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.
在一些实施方式中，各所述“C2-C6烯基”分别独立地为乙烯基、1-丙烯基、正烯丙基、丁-1-烯 基、丁-2-烯基、戊-1-烯基或戊-1,4-二烯基。In some embodiments, each of the "C 2 -C 6 alkenyl" is independently vinyl, 1-propenyl, n-allyl, but-1-ene but-2-enyl, pent-1-enyl or pent-1,4-dienyl.
在一些实施方式中，环A、R2、R4-g、R4-h、R4-i、R4-j和R4-k中，所述“4-10元杂环烷基”和“被一个或多个R2e取代的4-10元杂环烷基”中的“4-10元杂环烷基”分别独立地为5-8元杂环烷基，例如(优选 In some embodiments, in ring A, R 2 , R 4-g , R 4-h , R 4-i , R 4-j and R 4-k , the "4-10 membered heterocycloalkyl" and "4-10 membered heterocycloalkyl" in "4-10 membered heterocycloalkyl substituted by one or more R 2e " are independently 5-8 membered heterocycloalkyl, for example (preferred
在一些实施方式中，R2a、R2b、R2c、R2d、R2e、R2f、R2j、R3、R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j、R3k、R4-a、R4-b、R4-c、R4-d、R4-e、R4-f、R4-g、R4-h、R4-i、R4-j、R4-k、R4-a-1～R4-a-11、R4- g-1～R4-g-11和R4b中，所述卤素分别独立地为氟、氯、溴或碘。In some embodiments, R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2j , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , R 4-a , R 4-b , R 4-c , R 4-d , R 4-e , R 4-f , R 4-g , R 4 Among -h , R 4-i , R 4-j , R 4-k , R 4-a-1 to R 4-a-11 , R 4 -g-1 to R 4-g-11 and R 4b , The halogens are each independently fluorine, chlorine, bromine or iodine.
在一些实施方式中，R3和R4a中，所述“被一个或多个R3j取代的C6-C10芳基”、“C6-C10芳基”和“被一个或多个R4-f取代的C6-C10芳基”中的“C6-C10芳基”分别独立地为苯基或萘基。In some embodiments, among R 3 and R 4a , the "C 6 -C 10 aryl substituted by one or more R 3j ", "C 6 -C 10 aryl" and "by one or more The "C 6 -C 10 aryl" in "C 6 -C 10 aryl substituted by R 4-f " is independently phenyl or naphthyl.
在一些实施方式中，R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j、R3k、R4a、R4-g、R4-h、R4- i、R4-j、R4-k和R5中，所述“C1-C6烷基”、“被一个或多个R4-a取代的C1-C6烷基”、“C1-C6烷基-O-”和“被一个或多个R4-g-1取代的C1-C6烷基”中的“C1-C6烷基”分别独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。In some embodiments, R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , R 4a , R 4 -g , R 4- h , R 4- i , R 4-j , R 4-k and R 5 , the "C 1 -C 6 alkyl", "C 1 -C 6 substituted by one or more R 4-a "C 1 -C 6 alkyl" in "C 1 -C 6 alkyl-O-" and "C 1 -C 6 alkyl substituted by one or more R 4-g-1 " are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在一些实施方式中，R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j、R3k、R4-a、R4-b、R4-c、R4-d、R4-e和R4-f中，所述“C2-C6炔基”分别独立地为C2-C3炔基，例如乙炔基、丙炔基或炔丙基。In some embodiments, R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , R 4-a , R 4-b , R In 4-c , R 4-d , R 4-e and R 4-f , the "C 2 -C 6 alkynyl" is independently C 2 -C 3 alkynyl, such as ethynyl, propynyl or propargyl.
在一些实施方式中，R4a中，所述“5至14元杂芳基”和“被一个或多个R4-k取代的5至14元杂芳基”中的“5至14元杂芳基”分别独立地为“杂原子为N或S，杂原子数为1个或2个的5-10元杂芳基”，例如吡唑基、吡啶基、喹啉基、异喹啉基、喹唑啉基、吲哚基、吲唑基、吡唑并吡啶基、嘧啶基或苯并噻吩基，又例如 In some embodiments, in R 4a , the "5 to 14 membered heteroaryl" in the "5 to 14 membered heteroaryl" and "5 to 14 membered heteroaryl substituted by one or more R 4-k ""Aryl" is independently "the heteroatom is N or S, and the number of heteroatoms is 1 or 2 5-10 membered heteroaryl", such as pyrazolyl, pyridyl, quinolinyl, isoquinolyl , quinazolinyl, indolyl, indazolyl, pyrazolopyridyl, pyrimidinyl or benzothienyl, and for example
在一些实施方式中，R4a中，“被一个或多个R4-j取代的4-10元杂环烯基”中的“4-10元杂环烯基”分别独立地为5-8元杂环烯基，例如 In some embodiments, in R 4a , "4-10 membered heterocycloalkenyl" in "4-10 membered heterocycloalkenyl substituted by one or more R 4-j " is independently 5-8 membered heterocycloalkenyl, such as
在一些实施方式中，环A为 In some embodiments, Ring A is
在一些实施方式中，n为0。In some embodiments, n is 0.
在一些实施方式中，L为-O-CH2-*，*表示与R2连接的一端。 In some embodiments, L is -O-CH 2 - * , and * represents the end connected to R 2 .
在一些实施方式中，R2为优选 In some embodiments, R is preferred
在一些实施方式中，R4b为F。In some embodiments, R 4b is F.
在一些实施方式中，R3为或Cl。In some embodiments, R 3 is or Cl.
在一些实施方式中，R4a为 优选 更优选 In some embodiments, R 4a is preferred more preferred
在一些实施方式中，所述如式I所示的化合物为如下任一化合物：



In some embodiments, the compound shown in formula I is any one of the following compounds:



在一些实施方式中，所述如式I所示的化合物的药学上可接受的盐为如下任一化合物：的三氟醋酸盐。In some embodiments, the pharmaceutically acceptable salt of the compound shown in formula I is any of the following compounds: of trifluoroacetate.
本发明还提供了一种如下所示化合物(中间体)：




The present invention also provides a compound (intermediate) as shown below:




本发明还提供了如下任一化合物的盐酸盐：


The present invention also provides the hydrochloride salt of any of the following compounds:


本发明还提供了所述如式I所示化合物、其立体异构体或其药学上可接受的盐的制备方法，其可为如下路线：The present invention also provides a preparation method of the compound shown in formula I, its stereoisomer or a pharmaceutically acceptable salt thereof, which can be the following route:
路线一：
Route 1:
其中，P1为氨基保护基，如Boc、PMB、Bn、Cbz、Fmoc等，Wherein, P is an amino protecting group, such as Boc, PMB, Bn, Cbz, Fmoc, etc.,
L、R2、R3和R4a的定义如上所述；L, R 2 , R 3 and R 4a are as defined above;
步骤1：在溶剂中，在碱及催化剂存在下，将如式SM-1所示的化合物进行Suzuki反应，得到如式SM-2所示的化合物即可；Step 1: In a solvent, in the presence of a base and a catalyst, the compound shown in formula SM-1 is subjected to Suzuki reaction to obtain the compound shown in formula SM-2;
步骤2：在溶剂中，在碱及催化剂存在下，将如式SM-2所示的化合物进行Suzuki反应，得到如式SM-3所示的化合物即可；Step 2: In a solvent, in the presence of a base and a catalyst, the compound shown in the formula SM-2 is subjected to Suzuki reaction to obtain the compound shown in the formula SM-3;
步骤3：脱保护反应[R3中取代基R3a、R3b(例如-OH、-NH2、C2-C6炔基)如被保护基保护，可进行脱保护反应得到通式I化合物]；Step 3: deprotection reaction [substituents R 3a and R 3b (such as -OH, -NH 2 , C 2 -C 6 alkynyl) in R 3 are protected by a protecting group, and a deprotection reaction can be performed to obtain a compound of formula I ];
所述步骤3中的脱保护反应满足以下条件的一种或多种：The deprotection reaction in the step 3 meets one or more of the following conditions:
(1)在酸性条件下，进行脱氨基保护基、脱羟基保护基反应；(1) Under acidic conditions, carry out deamination protecting group, dehydroxyl protecting group reaction;
(2)在四丁基氟化铵、四甲基氟化铵或氟化铯存在下，脱TIPS保护；(2) In the presence of tetrabutylammonium fluoride, tetramethylammonium fluoride or cesium fluoride, de-TIPS protection;
路线二：
Route two:
其中，P1为氨基保护基，如Boc、PMB、Bn、Cbz、Fmoc等，Wherein, P is an amino protecting group, such as Boc, PMB, Bn, Cbz, Fmoc, etc.,
L、R2和R4a的定义如上所述；L, R 2 and R 4a are as defined above;
步骤1：在溶剂中，在碱及催化剂存在下，将如式SM-1所示的化合物进行Suzuki反应，得到如式SM-4所示的化合物即可；Step 1: In a solvent, in the presence of a base and a catalyst, the compound shown in formula SM-1 is subjected to a Suzuki reaction to obtain a compound shown in formula SM-4;
步骤2：在酸性条件下，将如式SM-4所示的化合物进行脱氨基保护基反应。Step 2: Under acidic conditions, the compound represented by the formula SM-4 is subjected to a deamination protecting group reaction.
本发明还提供了一种药物组合物，其包含物质A和药用辅料(或药学上可接受的载体)；所述的物质A为上述的如式I所示的化合物、其立体异构体或其药学上可接受的盐。所述的物质A可为治疗有效量的。The present invention also provides a pharmaceutical composition, which comprises substance A and pharmaceutical excipients (or pharmaceutically acceptable carrier); said substance A is the above-mentioned compound shown in formula I, its stereoisomer or a pharmaceutically acceptable salt thereof. Said substance A may be in a therapeutically effective amount.
本发明还提供了一种物质A在制备RAS抑制剂中的应用，所述的物质A为上述的如式I所示的化合物、其立体异构体或其药学上可接受的盐。在所述的应用中，所述的RAS抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为抑制RAS的效果提供快速检测。The present invention also provides an application of substance A in the preparation of RAS inhibitors, wherein said substance A is the above-mentioned compound represented by formula I, its stereoisomer or a pharmaceutically acceptable salt thereof. In the above application, the RAS inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample to provide comparison, or to prepare according to conventional methods in the art A kit is developed to provide rapid detection of the effect of inhibiting RAS.
本发明还提供了一种物质A在制备药物中的应用，所述的药物用于治疗和/或预防RAS介导的疾病；所述的物质A为上述的如式I所示的化合物、其立体异构体或其药学上可接受的盐；所述的物质A为治疗有效量的。The present invention also provides the application of a substance A in the preparation of medicines, and the medicine is used for treating and/or preventing RAS-mediated diseases; the substance A is the above-mentioned compound shown in formula I, its Stereoisomers or pharmaceutically acceptable salts thereof; said substance A is in a therapeutically effective amount.
本发明还提供了一种物质A在制备药物中的应用，所述的药物用于治疗和/或预防癌症；所述的物质A为上述的如式I所示的化合物、其立体异构体或其药学上可接受的盐；所述的物质A为治疗有效量的。The present invention also provides the application of a substance A in the preparation of medicines, and the medicine is used for treating and/or preventing cancer; the substance A is the above-mentioned compound shown in formula I and its stereoisomers or a pharmaceutically acceptable salt thereof; the substance A is in a therapeutically effective amount.
本发明还提供了一种抑制RAS的方法，其包括向患者施用治疗有效量的物质A；所述的物质A为上述的如式I所示的化合物、其立体异构体或其药学上可接受的盐。The present invention also provides a method for inhibiting RAS, which comprises administering a therapeutically effective amount of substance A to a patient; said substance A is the above-mentioned compound represented by formula I, its stereoisomer or its pharmaceutically acceptable Accepted salt.
本发明还提供了一种治疗和/或预防RAS介导的疾病的方法，其包括向患者施用治疗有效量的物质A；所述的物质A为上述的如式I所示的化合物、其立体异构体或其药学上可接受的盐。The present invention also provides a method for treating and/or preventing RAS-mediated diseases, which includes administering a therapeutically effective amount of substance A to a patient; said substance A is the above-mentioned compound represented by formula I, its three-dimensional isomers or pharmaceutically acceptable salts thereof.
本发明还提供了一种治疗和/或预防癌症的方法，其包括向患者施用治疗有效量的物质A；所述的物质A为上述的如式I所示的化合物、其立体异构体或其药学上可接受的盐。The present invention also provides a method for treating and/or preventing cancer, which comprises administering a therapeutically effective amount of substance A to a patient; said substance A is the above-mentioned compound represented by formula I, its stereoisomer or its pharmaceutically acceptable salt.
如上所述的RAS可为KRAS或KRAS突变；例如KRAS G12D、KRAS G12V。The RAS as described above may be KRAS or a KRAS mutation; eg KRAS G12D, KRAS G12V.
如上所述的RAS介导的疾病例如癌症。RAS mediated diseases such as cancer as described above.
如上所述的癌症可选自结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、子宫颈癌、睾丸癌、肾癌、头或颈癌、骨癌、皮肤癌、直肠癌、肝癌、结直肠癌、非小细胞肺癌、小细胞肺癌、食道癌、胃癌、甲状腺癌、膀胱癌、淋巴瘤、白血病和黑色素瘤中的一种或多种。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 Cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophageal cancer, gastric cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有 如下所示的含义。In addition to the foregoing, when used in the description and claims of this application, unless otherwise specified, the following terms have Meaning as shown below.
术语“多个”是指2个、3个、4个或5个。The term "plurality" means 2, 3, 4 or 5.
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸(例如盐酸)、有机酸(例如三氟乙酸、甲酸)。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, the base addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent. A salt. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts. When the compounds of the present invention contain relatively basic functional groups, acid addition can be achieved by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. A salt. The pharmaceutically acceptable acids include inorganic acids (such as hydrochloric acid), organic acids (such as trifluoroacetic acid, formic acid). For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).
本发明中，术语“立体异构体”包括构象异构体和构型异构体，其中构型异构体主要包括顺反异构体和旋光异构体。本发明所述化合物可以以立体异构体的形式存在，并因此涵盖所有可能的立体异构体形式，包括但不限于顺反异构体、对映异构体、非对映异构体、阻转异构体等，本发明所述化合物也可以以前述的立体异构体的任何组合或任何混合物，例如内消旋体、外消旋体、阻转异构体的等量混合物等形式存在；例如单一对映异构体，单一非对映异构体或以上的混合物，或单一阻转异构体或其混合物。当本发明所述的化合物含有烯烃双键时，除非特别说明，否则其包括顺式异构体和反式异构体，以及其任何组合。In the present invention, the term "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. Exist; for example a single enantiomer, a single diastereoisomer or mixtures thereof, or a single atropisomer or a mixture thereof. When the compounds described herein contain olefinic double bonds, unless otherwise specified, they include cis-isomers and trans-isomers, and any combination thereof.
本发明中，“药物组合物”是指包含本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。In the present invention, "pharmaceutical composition" refers to a preparation comprising a compound of the present invention and a vehicle generally accepted in the art for delivering 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.
本发明中，“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如药用辅料)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。In the present invention, "pharmaceutically acceptable" refers to a substance (such as a pharmaceutical excipient) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological effects. React or interact in an undesirable manner with any component contained in the composition.
术语“药用辅料”或“药学上可接受的载体”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009 Sixth Edition)。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。The term "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. Can refer to Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition). 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.
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。The pharmaceutical 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.
当用作药物时，所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐可以以药物组 合物的任何形式给药。这些组合物可根据药学领域熟知的方法制备，可以各种途径施用，视需要局部或系统性治疗和要治疗的区域而定。给予可以是局部(包括表皮和透皮，眼部和粘膜，包括鼻内，阴道和直肠递送)，肺(例如，通过粉末或气溶胶吸入或吹入，包括通过喷雾器；气管内或鼻内)，口服(固体和液体制剂)或胃肠外给予形式。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。外用给药的药物组合物和制剂可包括透皮贴片、油膏剂、乳液、软膏剂、凝胶、滴剂、栓剂、喷剂、液体和粉末。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂：如鼻腔喷雾剂或吸入剂。口服给药可以包括配制为每日一次或每日两次(BID)给药的剂型。胃肠外给药包括静脉内、动脉内、皮下、腹膜内肌肉内或注射或输液；或颅内如鞘内或心室内给药。胃肠外给药可以单次推注剂量形式，或可以是通过连续灌注泵。常规药学载体、水、粉末或油状基底、增稠剂等可能是必须或需要的。包括本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。When used as a medicine, the compound shown in formula I, its stereoisomer or pharmaceutically acceptable salt thereof can be formulated as Any form of administration of the compound. 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. Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, gelcaps, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations. Examples of 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. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants. 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 desirable. Pharmaceutical compositions comprising the present invention may also be in controlled or delayed release dosage forms (eg liposomes or microspheres).
术语“治疗”指治疗性疗法或缓解性措施。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。“治疗”也可以指与不接受治疗的期望存活相比延长生存期。The term "treatment" refers to therapeutic therapy or palliative measures. In relation to a specific condition, treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder. "Treatment" can also refer to prolonging survival as compared to expected survival if not receiving treatment.
术语“预防”是指获得或发生疾病或障碍的风险降低。The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.
术语“治疗有效量”是指在给予患者时足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，但可由本领域技术人员根据需要进行调整。The term "therapeutically 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.
术语“患者”是指根据本发明的实施例，即将或已经接受了该化合物或组合物给药的任何动物，哺乳动物为优，人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。The term "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. The term "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.
在本发明中，术语“取代”或“取代基”是基团中的氢原子被指定的基团所代替。当没有指明取代位置时，取代可以在任何位置，但是只有形成一个稳定的或者是化学意义上可行的化学物才是被允许的。举例说明如下：结构表示环A上的氢原子被p个R4所取代。In the present invention, the term "substituted" or "substituent" is a group in which a hydrogen atom is replaced by the designated group. When no substitution site is indicated, substitutions are at any position, but are permitted only if they result in a stable or chemically viable chemical. Examples are as follows: The structure indicates that the hydrogen atom on ring A is replaced by p R4 .
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被一个或多个R所取代，则所述基团可以任选地至少被一个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with one or more R, said group may optionally be substituted with at least one R, with independent options for each occurrence of R. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
在本发明中，术语“烷基”是指饱和的直链或支链的一价烃基。C1-C6烷基是指具有1-6个碳原子的 烷基，优选为具有1-4个碳原子的烷基，其具体为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。In the present invention, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group. C 1 -C 6 alkyl means having 1-6 carbon atoms An alkyl group, preferably an alkyl group having 1 to 4 carbon atoms, is specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在本发明中，术语“亚苯基”是指从苯环上去掉两个氢原子所得到的基团，即苯基中的一个氢被取代。In the present invention, the term "phenylene" refers to a group obtained by removing two hydrogen atoms from a benzene ring, that is, one hydrogen in the phenyl is replaced.
在本发明中，术语“杂环烷基”是指环烷基中的至少一个碳原子被选自N、O和S的杂原子代替形成的基团。4-10元杂环烷基具体可以为4、5、6、7、8、9或10元杂环烷基。杂环烷基的实例包括但不限于(优选 In the present invention, the term "heterocycloalkyl" refers to a group formed by replacing at least one carbon atom in a cycloalkyl group with a heteroatom selected from N, O and S. The 4-10 membered heterocycloalkyl group can specifically be 4, 5, 6, 7, 8, 9 or 10 membered heterocycloalkyl group. Examples of heterocycloalkyl include, but are not limited to (preferred
本发明中，在本发明中，术语“芳基”是指芳香基团，其中每个环均是芳香性的，例如苯基或萘基。In the present invention, in the present invention, the term "aryl" refers to an aromatic group in which each ring is aromatic, such as phenyl or naphthyl.
在本发明中，术语“杂芳基”是指含有杂原子的芳香基团，优选含有1个、2个或3个独立选自氮、氧和硫的芳族5-6元单环或9-10元双环，当为双环时，其中每个环均具有芳香性，例如吡唑基、吡啶基、喹啉基、异喹啉基、喹唑啉基、吲哚基、吲唑基、吡唑并吡啶基、嘧啶基或苯并噻吩基，又例如 等。In the present invention, the term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably containing 1, 2 or 3 aromatic 5-6-membered monocyclic or 9-membered rings independently selected from nitrogen, oxygen and sulfur -10-membered bicyclic ring, when bicyclic, each ring has aromaticity, such as pyrazolyl, pyridyl, quinolinyl, isoquinolyl, quinazolinyl, indolyl, indazolyl, pyrazolyl, Azolopyridyl, pyrimidinyl or benzothienyl, and for example wait.
本发明中，术语“炔基”是指具有特定碳原子数的一个或多个叁键的直链或支链的烃基(例如C2-C6炔基，又例如C2-C3炔基)。该一个或多个碳碳叁键可以是内部的也可以是末端的，例如叁键在内部的丙炔基或叁键在末端的丙炔基等。In the present invention, the term "alkynyl" refers to a straight-chain or branched chain hydrocarbon group (such as C 2 -C 6 alkynyl, another example C 2 -C 3 alkynyl) having one or more triple bonds with a specific number of carbon atoms ). The one or more carbon-carbon triple bonds may be internal or terminal, such as propynyl with a triple bond internal or propynyl with a triple bond at the end wait.
本发明中，术语“杂环烯基”表示通过杂原子或杂原子团连接的环状烯基。在某一实施例方案中，所述的“杂环烯基”为由2至14个(优选2至6个)碳原子以及1至6个选自N、O、S、S(＝O)和S(＝O)2的杂原子或含杂原子的基团组成的稳定的3至20元(优选3至12元，更优选4至10元，最优选5至8元)含不饱和双键的单环或多环(例如双环、三环或更多环的桥环、并环(稠环)或螺环体系)的非芳香环体系，例如 In the present invention, the term "heterocycloalkenyl" means a cyclic alkenyl linked through a heteroatom or a heteroatom group. In a certain embodiment, the "heterocycloalkenyl" is composed of 2 to 14 (preferably 2 to 6) carbon atoms and 1 to 6 carbon atoms selected from N, O, S, S (=O) A stable 3-20 -membered (preferably 3-12-membered, more preferably 4-10-membered, most preferably 5-8-membered) unsaturated di Bonded monocyclic or polycyclic (e.g. bicyclic, tricyclic or multicyclic bridged rings, double ring (fused ring) or spiro ring systems) non-aromatic ring systems, such as
本发明中，术语“烯基”是指具有至少一个双键的直链或支链的烃链基，仅由碳原子和氢原子组成、具有例如2至12个(优选2至8个，更优选2至6个，最优选2至4个)碳原子，且通过单键与分子的其余部分连接，例如包括但不限于乙烯基、1-丙烯基、正烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基或戊-1,4-二烯基等。In the present invention, the term "alkenyl" refers to a straight or branched hydrocarbon chain group 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 are attached to the rest of the molecule by a single bond, examples including but not limited to vinyl, 1-propenyl, n-allyl, but-1-ene group, but-2-enyl, pent-1-enyl or pent-1,4-dienyl, etc.
本发明中，术语“环烷基”意指饱和的单环或多环(例如双环、三环或更多环的桥环、并环(稠环)或螺环体系)的碳环取代基，且其可经由任何适宜的碳原子通过单键与分子的其余部分连接；如具有3至 15个碳原子的3-15元环烷基，优选具有3至12个碳原子的3-12元环烷基，更优选具有3至7个碳原子的3-7元环烷基，最优选具有3至6个碳原子的3-6元环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基等。In the present invention, the term "cycloalkyl" means a carbocyclic substituent of a saturated monocyclic or polycyclic ring (such as a bicyclic, tricyclic or more ring-bridged ring, a ring (fused ring) or a spiro ring system), and it may be attached to the remainder of the molecule by a single bond via any suitable carbon atom; such as having 3 to 3-15 membered cycloalkyl group with 15 carbon atoms, preferably 3-12 membered cycloalkyl group with 3 to 12 carbon atoms, more preferably 3-7 membered cycloalkyl group with 3 to 7 carbon atoms, most preferably 3-6 membered cycloalkyl having 3 to 6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
本发明中，术语“环烯基”意指具有至少一个双键(如碳碳双键)的部分不饱和的单环或多环(例如双环、三环或更多环的桥环、并环(稠环)或螺环体系)的非芳香性碳环取代基，且其可经由任何适宜的碳原子通过单键与分子的其余部分连接；如具有3至15个碳原子的3-15元环烯基，优选具有3至12个碳原子的3-12元环烯基，更优选具有3至7个碳原子的3-7元环烯基，最优选具有3至6个碳原子的3-6元环烯基。环烯基的实例包括但不限于环丙烯基、环丁烯基、环戊烯基(例如)、环戊二烯基(例如)、环己烯基(例如)、环庚烯基、环己二烯基等。In the present invention, the term "cycloalkenyl" means a partially unsaturated monocyclic or polycyclic (such as a bicyclic, tricyclic or more ring-bridged ring, an acyclic ring) having at least one double bond (such as a carbon-carbon double bond) (fused ring) or spiro ring system) and which may be attached to the rest of the molecule by a single bond via any suitable carbon atom; e.g. 3-15 membered with 3 to 15 carbon atoms Cycloalkenyl, preferably 3-12 membered cycloalkenyl having 3 to 12 carbon atoms, more preferably 3-7 membered cycloalkenyl having 3 to 7 carbon atoms, most preferably 3 to 6 carbon atoms -6 membered cycloalkenyl. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl (e.g. ), cyclopentadienyl (for example ), cyclohexenyl (for example ), cycloheptenyl, cyclohexadienyl, etc.
本发明中，术语“卤素”是指氟、氯、溴或碘，尤其指F或Cl。In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine, especially F or Cl.
本领域技术人员可以理解，根据本领域中使用的惯例，本申请描述基团的结构式中所使用的及是指，相应的基团R通过该位点与化合物中的其它片段、基团进行连接。Those skilled in the art can understand that, according to the practice used in this field, the application describes the structural formula used in the group and means that the corresponding group R is connected to other fragments and groups in the compound through this site.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：该含氮杂环化合物有望治疗和/或预防由KRAS介导的多种疾病，特别是由KRAS G12D和/或KRAS G12V介导的多种疾病。The positive and progressive effect of the present invention is that the nitrogen-containing heterocyclic compound is expected to treat and/or prevent various diseases mediated by KRAS, especially various diseases mediated by KRAS G12D and/or KRAS G12V.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.
本申请中英文缩写如下所示，The Chinese and English abbreviations of this application are as follows,
Boc：叔丁氧羰基；TIPS：三异丙基硅基；MOM：甲氧基甲基(CH3OCH2-)；FA：甲酸；MEOH：甲醇；EtOH：乙醇；DMSO：二甲基亚砜；ACN：乙腈；CDCl3：氘代氯仿。Boc: tert-butoxycarbonyl; TIPS: triisopropylsilyl; MOM: methoxymethyl (CH 3 OCH 2 -); FA: formic acid; MEOH: methanol; EtOH: ethanol; DMSO: dimethyl sulfoxide ; ACN: acetonitrile; CDCl 3 : deuterated chloroform.
中间体1：(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Intermediate 1: (1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl ylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
步骤1：2,6-二氯-3-氟吡啶-4-胺
Step 1: 2,6-Dichloro-3-fluoropyridin-4-amine
将2,6-二氯吡啶-4-胺(6.52g,39.99mmol,1eq)溶于N，N-二甲基甲酰胺(30mL)和乙腈(30mL)中，加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(17g,47.99mmol,1.2eq)，80℃反应半小时。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：0-10％)，得到2,6-二氯-3-氟吡啶-4-胺(4.2g，产率：58.03％)，白色固体。Dissolve 2,6-dichloropyridin-4-amine (6.52g, 39.99mmol, 1eq) in N,N-dimethylformamide (30mL) and acetonitrile (30mL), add 1-chloromethyl-4 -Fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (17g, 47.99mmol, 1.2eq), react at 80°C for half an hour. LCMS monitored the reaction to be complete. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 0-10%) to obtain 2,6-dichloro-3-fluoropyridin-4-amine (4.2g, yield: 58.03%) , white solid.
MS m/z:181.1/183.1[M+H]+ MS m/z:181.1/183.1[M+H] +
步骤2：叔丁基-N-[(叔丁氧基)羰基]-N-(2,6-二氯-3-氟吡啶-4-基)氨基甲酯
Step 2: tert-Butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro-3-fluoropyridin-4-yl)aminomethyl ester
将2,6-二氯-3-氟吡啶-4-胺(4.2g,23.21mmol,1eq)溶于二氯甲烷(40mL)中，加入BOC酸酐(10.29g,47.15mmol,2.03eq)，4-二甲氨基吡啶(457.28mg,3.74mmol,0.16eq)，室温反应16小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：0-20％)，得到叔丁基-N-[(叔丁氧基)羰基]-N-(2,6-二氯-3-氟吡啶-4-基)氨基甲酯(7.0g，产率：79.13％)，白色固体。2,6-Dichloro-3-fluoropyridin-4-amine (4.2g, 23.21mmol, 1eq) was dissolved in dichloromethane (40mL), BOC anhydride (10.29g, 47.15mmol, 2.03eq) was added, 4 -Dimethylaminopyridine (457.28mg, 3.74mmol, 0.16eq), react at room temperature for 16 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 0-20%) to obtain tert-butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro- 3-fluoropyridin-4-yl)aminomethyl ester (7.0 g, yield: 79.13%), white solid.
MS m/z:381.1/383.1[M+H]+ MS m/z:381.1/383.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ8.06-8.01(m,1H),1.42(s,18H). 1 H NMR (400MHz,DMSO-d 6 )δ8.06-8.01(m,1H),1.42(s,18H).
步骤3：叔丁基-4-((叔丁氧羰基)氨基)-2,6-二氯-5-氟尼古丁酯
Step 3: tert-butyl-4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotine ester
将叔丁基-N-[(叔丁氧基)羰基]-N-(2,6-二氯-3-氟吡啶-4-基)氨基甲酯(5.84g,15.32mmol,1eq)溶于四氢呋喃(30mL)中，-78℃滴加二异丙基氨基锂(2M,15.32mL,2eq)，2小时升到室温。反应液加水淬灭，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：0-20％)，得到叔丁基-4-((叔丁氧羰基)氨基)-2,6-二氯-5-氟尼古丁酯(5.0g，产率：85.62％)，棕色固体。tert-Butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro-3-fluoropyridin-4-yl)aminomethyl ester (5.84g, 15.32mmol, 1eq) was dissolved in In tetrahydrofuran (30mL), lithium diisopropylamide (2M, 15.32mL, 2eq) was added dropwise at -78°C and warmed to room temperature for 2 hours. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 0-20%) to obtain tert-butyl-4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5- Flunicotine ester (5.0 g, yield: 85.62%), brown solid.
MS m/z:381.1/383.1[M+H]+ MS m/z:381.1/383.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),1.54(s,9H),1.45(s,9H). 1 H NMR (400MHz,DMSO-d 6 )δ10.06(s,1H),1.54(s,9H),1.45(s,9H).
步骤4：2,6-二氯-3-氟吡啶-4-胺
Step 4: 2,6-Dichloro-3-fluoropyridin-4-amine
将叔丁基-4-((叔丁氧羰基)氨基)-2,6-二氯-5-氟尼古丁酯(13g,34.10mmol,1eq)溶于二氯甲烷(100mL)中，加入三氟乙酸(30mL)，室温反应16小时。LCMS监测反应完全。反应液浓缩，得到2,6-二氯-3-氟吡啶-4-胺(7.67g，粗品)，棕色固体，直接用于下一步。 Dissolve tert-butyl-4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotine ester (13g, 34.10mmol, 1eq) in dichloromethane (100mL) and add trifluoro Acetic acid (30 mL) was reacted at room temperature for 16 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated to give 2,6-dichloro-3-fluoropyridin-4-amine (7.67 g, crude product) as a brown solid, which was directly used in the next step.
MS m/z:225.1[M+H]+ MS m/z:225.1[M+H] +
步骤5：乙基-4-氨基-2,6-二氯-5-氟尼古丁酯
Step 5: Ethyl-4-amino-2,6-dichloro-5-fluoronicotine ester
将2,6-二氯-3-氟吡啶-4-胺(7.67g,34.09mmol,1eq)溶于乙醇(100mL)中，加入浓硫酸(102.35g,1.02mol,30eq)，80℃反应40小时。冷却至室温，向反应液加入饱和碳酸氢钠水溶液，调节PH＝7。乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：20-40％)，得到乙基-4-氨基-2,6-二氯-5-氟尼古丁酯(8.0g，产率：92.76％)，棕色固体。Dissolve 2,6-dichloro-3-fluoropyridin-4-amine (7.67g, 34.09mmol, 1eq) in ethanol (100mL), add concentrated sulfuric acid (102.35g, 1.02mol, 30eq), react at 80°C for 40 Hour. After cooling to room temperature, saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7. Extracted with ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 20-40%) to obtain ethyl-4-amino-2,6-dichloro-5-fluoronicotine ester (8.0 g, yield : 92.76%), brown solid.
MS m/z:253.1/255.1[M+H]+ MS m/z:253.1/255.1[M+H] +
步骤6：乙基-2,6-二氯-5-氟-4-(3-(2,2,2-三氯乙酰基)脲基)尼古丁酯
Step 6: Ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotine ester
将乙基-4-氨基-2,6-二氯-5-氟尼古丁酯(1.13g,4.47mmol,1eq)溶于四氢呋喃(10mL)中，加入三氯乙酰基异氰酸酯(993.57mg,5.27mmol,1.18eq)，室温反应1小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：20-50％)，得到乙基-2,6-二氯-5-氟-4-(3-(2,2,2-三氯乙酰基)脲基)尼古丁酯(1.5g，产率：76.14％)，白色固体。Dissolve ethyl-4-amino-2,6-dichloro-5-fluoronicotine ester (1.13g, 4.47mmol, 1eq) in tetrahydrofuran (10mL), add trichloroacetyl isocyanate (993.57mg, 5.27mmol, 1.18eq), react at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 20-50%) to obtain ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2- Trichloroacetyl)ureido)nicotine ester (1.5 g, yield: 76.14%), white solid.
MS m/z:441.9/443.9[M+H]+ MS m/z:441.9/443.9[M+H] +
步骤7：5,7-二氯-8-氟吡啶并[4,3-d]嘧啶-2,4-二酚
Step 7: 5,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol
将乙基-2,6-二氯-5-氟-4-(3-(2,2,2-三氯乙酰基)脲基)尼古丁酯(3.0g,6.80mmol,1eq)溶于甲醇(40mL)中，加入氨甲醇溶液(7M,2.77mL,2.85eq)，室温反应2小时。LCMS监测反应完全。反应液浓缩，残留物用甲基叔丁基醚打浆，得到5,7-二氯-8-氟吡啶并[4,3-d]嘧啶-2,4-二酚(1.8g，产率：100％)，白色固体。Ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotine ester (3.0 g, 6.80 mmol, 1 eq) was dissolved in methanol ( 40mL), add ammonia methanol solution (7M, 2.77mL, 2.85eq), and react at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was slurried with methyl tert-butyl ether to obtain 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (1.8g, yield: 100%), white solid.
MS m/z:250.1/252.1[M+H]+ MS m/z:250.1/252.1[M+H] +
步骤8：2,4,5,7-四氯-8-氟吡啶并[4,3-d]嘧啶
Step 8: 2,4,5,7-Tetrachloro-8-fluoropyrido[4,3-d]pyrimidine
将5,7-二氯-8-氟吡啶并[4,3-d]嘧啶-2,4-二酚(12g,48.00mmol,1eq)溶于氧氯化磷(100mL),缓慢滴加N,N-二异丙基乙胺(30.71g,237.59mmol,41.38mL,4.95eq)。氮气置换，100℃反应16小时。LCMS监测反应完全，反应液减压浓缩，得到2,4,5,7-四氯-8-氟吡啶并[4,3-d]嘧啶(30g,粗品)，深棕色油状物。粗品直接用于下一步。Dissolve 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (12g, 48.00mmol, 1eq) in phosphorus oxychloride (100mL), slowly add N , N-Diisopropylethylamine (30.71 g, 237.59 mmol, 41.38 mL, 4.95 eq). Replaced with nitrogen, reacted at 100°C for 16 hours. The completion of the reaction was monitored by LCMS, and the reaction solution was concentrated under reduced pressure to obtain 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (30 g, crude product) as a dark brown oil. The crude product was used directly in the next step.
MS m/z:288.2/290.2[M+H]+ MS m/z:288.2/290.2[M+H] +
步骤9：(1R,5S)-叔丁基-3-(2,5,7-三氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 9: (1R,5S)-tert-butyl-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diaze Heterobicyclo[3.2.1]octane-8-carboxylate
将2,4,5,7-四氯-8-氟吡啶并[4,3-d]嘧啶(13.3g,27.81mmol,1eq)溶于二氯甲烷(100mL)，加入N,N-二异丙基乙胺(10.78g,83.44mmol,14.53mL,3eq)。氮气置换，-30℃缓慢加入8-BOC-3,8-二氮杂双环[3.2.1]辛烷(5.90g,27.81mmol,1eq)，反应半小时。LCMS监测反应完全，反应液缓慢加到饱和氯化铵水溶液中淬灭。用二氯甲烷萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：0-16％)，得到(1R,5S)-叔丁基-3-(2,5,7-三氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(8.6g,两步产率：38.74％)，白色固体。Dissolve 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (13.3g, 27.81mmol, 1eq) in dichloromethane (100mL), add N,N-diiso Propylethylamine (10.78g, 83.44mmol, 14.53mL, 3eq). Nitrogen replacement, 8-BOC-3,8-diazabicyclo[3.2.1]octane (5.90g, 27.81mmol, 1eq) was slowly added at -30°C and reacted for half an hour. The completion of the reaction was monitored by LCMS, and the reaction solution was slowly added to saturated aqueous ammonium chloride solution to quench. It was extracted with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 0-16%) to obtain (1R,5S)-tert-butyl-3-(2,5,7-trichloro-8-fluoro Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.6 g, two-step yield: 38.74%) , white solid.
MS m/z:462.1/464.1[M+H]+ MS m/z:462.1/464.1[M+H] +
步骤10：(1R,5S)-叔丁基-3-(5,7-二氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 10: (1R,5S)-tert-butyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazine-7a -yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(2,5,7-三氯-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(8.6g,18.59mmol,1eq)，((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲醇(2.96g,18.59mmol,1eq)溶于二氯甲烷(100mL)中，缓慢加入叔丁醇钠(3.57g,37.17mmol,2eq).氮气氛围下室温反应1小时。LCMS监测反应完全，反应液缓慢倒入饱和氯化铵水溶液中，二氯甲烷萃取。有机相经饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：30-60％)，得到(1R,5S)-叔丁基-3-(5,7-二氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(9g,产率：82.71％)，黄色固体。(1R,5S)-tert-butyl-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabis Cyclo[3.2.1]octane-8-carboxylate (8.6g, 18.59mmol, 1eq), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methanol (2.96 g, 18.59mmol, 1eq) was dissolved in dichloromethane (100mL), and sodium tert-butoxide (3.57g, 37.17mmol, 2eq) was slowly added. The reaction was carried out at room temperature under nitrogen atmosphere for 1 hour. The completion of the reaction was monitored by LCMS, and the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 30-60%) to obtain (1R,5S)-tert-butyl-3-(5,7-dichloro-8-fluoro-2 -(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylate (9 g, yield: 82.71%), yellow solid.
MS m/z:585.1/587.1[M+H]+ MS m/z:585.1/587.1[M+H] +
1H NMR(400MHz,CDCl3)δ5.35(br d,J＝53.2Hz,1H),4.35-4.15(m,4H)3.57-3.20(m,4H),3.08(br s,1H),2.47-1.95(m,5H),1.89-1.59(m,8H),1.53(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ5.35 (br d, J=53.2Hz, 1H), 4.35-4.15 (m, 4H), 3.57-3.20 (m, 4H), 3.08 (br s, 1H), 2.47 -1.95(m,5H),1.89-1.59(m,8H),1.53(s,9H).
19F NMR(376MHz,CDCl3)δ-137.27(s),-172.89(s). 19 F NMR (376MHz, CDCl 3 ) δ-137.27(s), -172.89(s).
步骤11：(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 11: (1R,5S)-tert-Butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl Silyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将叔丁基-(1-(7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,3-二氟哌啶-4-基)氨基甲酯(5.0g,8.54mmol,1eq),((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)乙炔基)三异丙基硅烷(5.03g,9.82mmol,1.15eq)。碳酸钾(3.54g,25.62mmol,3eq)，2-双环己基膦-2,6-二异丙氧基-1,1-联苯(797.02mg,1.71mmol,0.2eq)和甲磺酸(2-二环 己基膦基-2,6-二异丙氧基-1,1-联苯基)(2-氨基-1,1-联苯-2-基)钯(II)(1.43g,1.71mmol,0.2eq)溶于甲苯(50mL)，水(25mL)和乙醇(25mL)的混合溶剂中，置换氮气，80℃反应16小时。LCMS监测反应结束。反应液分液，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，残留物经柱纯化(四氢呋喃/石油醚：0-30％),得到(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(2.5g,产率：25％),黄色固体。The tert-butyl-(1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[ 4,3-d]pyrimidin-4-yl)-3,3-difluoropiperidin-4-yl)aminomethyl ester (5.0g, 8.54mmol, 1eq), ((2-fluoro-6-(methoxy methoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropyl Silane (5.03g, 9.82mmol, 1.15eq). Potassium carbonate (3.54g, 25.62mmol, 3eq), 2-bicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (797.02mg, 1.71mmol, 0.2eq) and methanesulfonic acid (2 -Second ring Hexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (1.43g, 1.71mmol, 0.2 eq) was dissolved in a mixed solvent of toluene (50 mL), water (25 mL) and ethanol (25 mL), replaced with nitrogen, and reacted at 80° C. for 16 hours. LCMS monitored the completion of the reaction. The reaction solution was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to obtain (1R,5S)-tert-butyl- 3-(5-Chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl) -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8 - Diazabicyclo[3.2.1]octane-8-carboxylate (2.5 g, yield: 25%), yellow solid.
MS m/z:935.4/937.4[M+H]+ MS m/z:935.4/937.4[M+H] +
中间体2：(1R,5S)-叔丁基-3-(5-氯-7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Intermediate 2: (1R,5S)-tert-butyl-3-(5-chloro-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3, 8-diazabicyclo[3.2.1]octane-8-carboxylate
步骤1：(1R,5S)-叔丁基-3-(5-氯-7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(5-chloro-7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5,7-二氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1060mg,1.81mmol,1eq)溶于二氧六环(10mL)和水(5mL)中，加入2-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环(697.37mg,1.99mmol,1.1eq),碳酸铯(1.18g,3.62mmol,2eq)，1,1-双(二苯基磷)二茂铁氯化钯(132.48mg,0.181mmol,0.1eq)，氮气保护，80℃反应1小时。LCMS监测反应完全。反应液浓缩，残留物用乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱纯化(四氢 呋喃/石油醚：10-30％)，得到(1R,5S)-叔丁基-3-(5-氯-7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(310mg，产率：22.1％)，棕色固体。(1R,5S)-tert-butyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1060mg, 1.81mmol, 1eq ) was dissolved in dioxane (10mL) and water (5mL), and 2-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5 , 5-tetramethyl-1,3,2-dioxaborolane (697.37mg, 1.99mmol, 1.1eq), cesium carbonate (1.18g, 3.62mmol, 2eq), 1,1-bis(diphenyl Phosphorus) ferrocenepalladium chloride (132.48mg, 0.181mmol, 0.1eq), under nitrogen protection, react at 80°C for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (tetrahydro Furan/petroleum ether: 10-30%) to give (1R,5S)-tert-butyl-3-(5-chloro-7-(7,8-difluoro-3-(methoxymethoxy)naphthalene -1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine -4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (310 mg, yield: 22.1%), brown solid.
MS m/z:773.3[M+H]+ MS m/z:773.3[M+H] +
实施例1：化合物1Example 1: Compound 1
4,4'-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5,7-叉基)二(5,6-二氟萘-2-酚)
4,4'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-5,7-ylidene)bis(5,6-difluoronaphthalene-2 -phenol)
步骤1：(1R,5S)-叔丁基-3-(5,7-二(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(5,7-bis(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5,7-二氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(500mg,0.854mmol,1eq)溶于二氧六环(3mL)和水(1mL)中，加入2-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环(747.6mg,2.14mmol,2.5eq)，碳酸铯(834.76mg,2.56mmol,3eq)，1,1-二(叔丁基磷)二茂铁氯化钯(83.5mg,0.128mol,0.15eq)，氮气保护，100℃反应1小时。LCMS监测反应完全。反应液浓缩，残留物用乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩。粗品经柱纯化(四氢呋喃/石油醚：10-30％)，得到(1R,5S)-叔丁基-3-(5,7-二(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷 -8-甲酸基酯(250mg，产率：30.5％)，棕色固体。(1R,5S)-tert-butyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.854mmol, 1eq ) was dissolved in dioxane (3mL) and water (1mL), and 2-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5 , 5-tetramethyl-1,3,2-dioxaborolane (747.6mg, 2.14mmol, 2.5eq), cesium carbonate (834.76mg, 2.56mmol, 3eq), 1,1-di(tert-butyl Phosphorus) Ferrocenepalladium chloride (83.5mg, 0.128mol, 0.15eq), under nitrogen protection, react at 100°C for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate. The crude product was purified by column (tetrahydrofuran/petroleum ether: 10-30%) to give (1R,5S)-tert-butyl-3-(5,7-bis(7,8-difluoro-3-(methoxymethyl Oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-Formyl ester (250 mg, yield: 30.5%), brown solid.
MS m/z:961.3[M+H]+ MS m/z:961.3[M+H] +
步骤2：化合物1Step 2: Compound 1
4,4'-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5,7-叉基)二(5,6-二氟萘-2-酚)
4,4'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-5,7-ylidene)bis(5,6-difluoronaphthalene-2 -phenol)
将(1R,5S)-叔丁基-3-(5,7-二(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,0.208mmol,1eq)溶于二氯甲烷(2mL)中，加入三氟乙酸(0.6mL)，室温反应1小时。LCMS检测反应完全。反应液浓缩，残留物经HPLC纯化，得到4,4'-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5,7-叉基)二(5,6-二氟萘-2-酚)(31.3mg，产率：18.8％)，白色固体。(1R,5S)-tert-butyl-3-(5,7-bis(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Heterobicyclo[3.2.1]octane-8-carboxylate (200mg, 0.208mmol, 1eq) was dissolved in dichloromethane (2mL), added trifluoroacetic acid (0.6mL), and reacted at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction solution was concentrated, and the residue was purified by HPLC to obtain 4,4'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-5,7-ylidene) Bis(5,6-difluoronaphthalen-2-ol) (31.3 mg, yield: 18.8%), white solid.
HPLC分离条件:HPLC separation conditions:
柱子:Phenomenex C18 75*30mm*3um.Column: Phenomenex C18 75*30mm*3um.
流动相A：water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％：36％-76％；保留时间：9min.Mobile phase A: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%: 36%-76%; retention time: 9min.
MS m/z:773.2[M+H]+ MS m/z:773.2[M+H] +
19F NMR(376MHz,DMSO-d6)δ-143.60(s),-143.96(s),-144.88(s),-144.94(s),-172.01(s),-172.04(s),-172.15(s). 19 F NMR (376MHz,DMSO-d 6 )δ-143.60(s),-143.96(s),-144.88(s),-144.94(s),-172.01(s),-172.04(s),-172.15 (s).
1H NMR(400MHz,DMSO-d6)δ7.79-7.67(m,2H),7.63-7.46(m,2H),7.41-7.30(m,2H),7.28-7.18(m,1H),6.99(br s,1H),5.30(br d,J＝54.4Hz,1H),4.27-4.03(m,2H),3.26-3.18(m,3H),3.17-3.06(m,3H),3.07-2.97(m,3H),2.90-2.80(m,1H),2.21-1.98(m,5H),1.91-1.75(m,3H),1.40(br s,2H). 1 H NMR (400MHz,DMSO-d 6 )δ7.79-7.67(m,2H),7.63-7.46(m,2H),7.41-7.30(m,2H),7.28-7.18(m,1H),6.99 (br s,1H),5.30(br d,J＝54.4Hz,1H),4.27-4.03(m,2H),3.26-3.18(m,3H),3.17-3.06(m,3H),3.07-2.97 (m,3H),2.90-2.80(m,1H),2.21-1.98(m,5H),1.91-1.75(m,3H),1.40(br s,2H).
实施例2：化合物2Example 2: Compound 2
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl )-5-ethynyl-6-fluoronaphthalene-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H -pyrazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(400mg,0.428mmol,1eq)溶于二氧六环(4mL)和水(2mL)中，加入1-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑(177.9mg,0.855mmol,2eq)，1,1-双(二苯基磷)二茂铁氯化钯(62.6mg,0.086mmol,0.2eq)和碳酸铯(417.9mg,1.28mmol,3eq)，氮气保护下，80℃反应2小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化[四氢呋喃(含0.5％氨水)/石油醚：0-35％]，得到(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(240mg，产率：57.2％)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400mg, 0.428mmol, 1eq) was dissolved in dioxane (4mL) and water ( 2mL), add 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (177.9mg, 0.855mmol, 2eq), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (62.6mg, 0.086mmol, 0.2eq) and cesium carbonate (417.9mg, 1.28mmol, 3eq), under nitrogen protection, React at 80°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column [tetrahydrofuran (containing 0.5% ammonia)/petroleum ether: 0-35%] to obtain (1R,5S)-tert-butyl-3-(8-fluoro-7-(7 -Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexa Hydrogen-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-Diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, yield: 57.2%), yellow solid.
MS m/z:981.4[M+H]+ MS m/z:981.4[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐 Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidine- 7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(220mg,0.224mmol,1eq)溶于乙腈(2mL)中，加入盐酸二氧六环溶液(4M,2mL)，室温反应1小时，LCMS监测反应完全。反应液浓缩得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(195.8mg，粗品)，黄色固体，粗品直接用于下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl ) Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy)-5-(1-methyl-1H-pyridine Azol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220mg, 0.224mmol, 1eq) was dissolved in acetonitrile (2mL), and dioxane hydrochloride solution (4M, 2mL) was added, and reacted at room temperature for 1 hour, and the reaction was complete as monitored by LCMS. The reaction solution was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidine -7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (195.8 mg, crude), yellow solid, crude used directly in next step .
MS m/z:837.4[M+H]+ MS m/z:837.4[M+H] +
步骤3：化合物2Step 3: Compound 2
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl )-5-ethynyl-6-fluoronaphthalene-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(195.8mg,0.224mmol,1eq)溶于N,N-二甲基甲酰胺(2mL)中，加入氟化铯(1.70g,11.21mmol,50eq)，室温反应2小时。LCMS监测反应完全。反应液过滤，滤液经HPLC制备，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(5mg，产率：3.3％)，黄色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidine-7- Hydrochloride (195.8mg, 0.224mmol, 1eq) of -6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol was dissolved in N,N-dimethylformaldehyde Add cesium fluoride (1.70 g, 11.21 mmol, 50 eq) to amide (2 mL), and react at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrido[4 ,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (5 mg, yield: 3.3%), yellow solid.
HPLC分离条件: HPLC separation conditions:
柱子:YMC-Triart Prep C18 150*40mm*7umColumn: YMC-Triart Prep C18 150*40mm*7um
流动相A：Water(NH3H2O+NH4HCO3)，流动相B：ACN；梯度B％：29％-69％；保留时间：9min.Mobile phase A: Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; gradient B%: 29%-69%; retention time: 9min.
MS m/z:681.7[M+H]+ MS m/z:681.7[M+H] +
19F NMR(377MHz,DMSO-d6)δ-110.33(s),-145.53(s),-171.98(s),-172.21(s). 19 F NMR (377MHz, DMSO-d 6 )δ-110.33(s),-145.53(s),-171.98(s),-172.21(s).
1H NMR(400MHz,DMSO-d6)δ10.17(br s,1H),8.09-7.70(m,2H),7.63-7.16(m,4H),5.30(br d,J＝53.6Hz,1H),5.01(br d,J＝10.5Hz,1H),4.20-4.10(m,1H),4.07-3.98(m,1H),3.87(s,3H),3.51(br s,1H),3.24-2.92(m,8H),2.88-2.78(m,1H),2.65-2.55(m,1H),2.21-1.96(m,3H),1.93-1.64(m,4H),1.62-1.43(m,2H),0.91(br s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.17(br s,1H),8.09-7.70(m,2H),7.63-7.16(m,4H),5.30(br d,J＝53.6Hz,1H ),5.01(br d,J＝10.5Hz,1H),4.20-4.10(m,1H),4.07-3.98(m,1H),3.87(s,3H),3.51(br s,1H),3.24- 2.92(m,8H),2.88-2.78(m,1H),2.65-2.55(m,1H),2.21-1.96(m,3H),1.93-1.64(m,4H),1.62-1.43(m,2H ),0.91(br s,1H).
实施例3：化合物3Example 3: Compound 3
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5-(1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyne yl-6-fluoronaphthalen-2-ol
步骤1：(1R,5S)-叔丁基-3-(5-(1-(叔-丁氧羰基)-1H-吡唑-4-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(5-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-8-fluoro-7-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H -pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ester
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(400mg,0.428mmol,1eq)溶于二氧六环(4mL)和水(2mL)中，加入叔丁基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吡唑-1-甲酸基酯(251.5mg,0.855mmol,2eq)，1,1-双(二苯基磷)二茂铁氯化钯(62.6mg,0.086mmol,0.2eq)和碳酸铯(417.9mg,1.28mmol,3eq)，氮气保护下，80℃ 反应2小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残留物经柱纯化[四氢呋喃(含0.5％氨水)/石油醚：0-35％]，得到(1R,5S)-叔丁基-3-(5-(1-(叔-丁氧羰基)-1H-吡唑-4-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(130mg，产率：28.5％)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400mg, 0.428mmol, 1eq) was dissolved in dioxane (4mL) and water ( 2mL), add tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate Ester (251.5mg, 0.855mmol, 2eq), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (62.6mg, 0.086mmol, 0.2eq) and cesium carbonate (417.9mg, 1.28mmol, 3eq) , under nitrogen protection, 80℃ React for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column [tetrahydrofuran (containing 0.5% ammonia)/petroleum ether: 0-35 %] to give (1R,5S)-tert-butyl-3-(5-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-8-fluoro-7-(7-fluoro -3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid Base ester (130 mg, yield: 28.5%), yellow solid.
MS m/z:967.5[M+H-100]+ MS m/z:967.5[M+H-100] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(5-(1-(叔-丁氧羰基)-1H-吡唑-4-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(110mg,0.103mmol,1eq)溶于乙腈(1mL)中，加入盐酸二氧六环溶液(4M,1mL)，室温反应1小时。LCMS监测反应完全。反应液浓缩得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(88.6mg，粗品)，黄色固体，粗品直接用于下一步。(1R,5S)-tert-butyl-3-(5-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-8-fluoro-7-(7-fluoro-3- (Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrole Olinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ( 110mg, 0.103mmol, 1eq) was dissolved in acetonitrile (1mL), added dioxane hydrochloride solution (4M, 1mL), and reacted at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl) -6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (88.6 mg, crude product), yellow solid, the crude product was used directly in the next step.
MS m/z:823.4[M+H]+ MS m/z:823.4[M+H] +
步骤3：化合物3Step 3: Compound 3
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5-(1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyne yl-6-fluoronaphthalen-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(88.6mg,0.103mmol,1eq)溶于N,N-二甲基甲酰胺(1mL)中，加入氟化铯(782.1mg,5.15mmol,50eq)，室温反应3小时。LCMS监测反应完全。反应液过滤，滤液经HPLC制备，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(5mg，产率：7.28％)，黄色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1H-pyrazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-6- Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (88.6 mg, 0.103 mmol, 1 eq) was dissolved in N,N-dimethylformamide (1 mL) , add cesium fluoride (782.1mg, 5.15mmol, 50eq), and react at room temperature for 3 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1H-pyrazol-4-yl)pyrido[4,3-d] Pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (5 mg, yield: 7.28%), yellow solid.
HPLC分离条件:HPLC separation conditions:
柱子:YMC-Triart Prep C18 150*40mm*7umColumn: YMC-Triart Prep C18 150*40mm*7um
流动相A：Water(NH3H2O+NH4HCO3)，流动相B：ACN；梯度B％：25％-65％；保留时间：9min.Mobile phase A: Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; gradient B%: 25%-65%; retention time: 9min.
MS m/z:667.6[M+H]+ MS m/z:667.6[M+H] +
19F NMR(377MHz,DMSO-d6)δ-110.30(s),-145.48(s),-171.98(s),-172.22(s). 19 F NMR (377MHz, DMSO-d 6 )δ-110.30(s),-145.48(s),-171.98(s),-172.22(s).
1H NMR(400MHz,DMSO-d6)δ13.15(br s,1H),10.14(br s,1H),8.07-7.88(m,2H),7.56-7.11(m,4H),5.30(br d,J＝54.4Hz,1H),5.00(br d,J＝10.8Hz,1H),4.20-4.10(m,1H),4.08-3.98(m,1H),3.51-3.41(m,1H),3.14-2.80(m,9H),2.10-1.99(m,3H),1.93-1.75(m,5H),1.52-1.42(m,2H),0.88(br s,1H)。 1 H NMR (400MHz,DMSO-d 6 )δ13.15(br s,1H),10.14(br s,1H),8.07-7.88(m,2H),7.56-7.11(m,4H),5.30(br d,J=54.4Hz,1H),5.00(br d,J=10.8Hz,1H),4.20-4.10(m,1H),4.08-3.98(m,1H),3.51-3.41(m,1H), 3.14-2.80 (m, 9H), 2.10-1.99 (m, 3H), 1.93-1.75 (m, 5H), 1.52-1.42 (m, 2H), 0.88 (br s, 1H).
实施例4：化合物4Example 4: Compound 4
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-氟吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5-(5-fluoropyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyne yl-6-fluoronaphthalen-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-氟吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-fluoropyridine-3 -yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(400mg,0.428mmol,1eq)溶于二氧六环(4mL)和水(2mL)中，加入3-氟-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(190.72mg,0.855mmol,2eq)，1,1-双(二苯基磷)二茂铁氯化钯(62.57mg,0.086mmol,0.2eq)和碳酸铯(417.90mg,1.28mmol,3eq)，氮气保护下，80℃反应2小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残留物经柱纯化[四氢呋喃(含0.5％氨水)/石油醚：0-35％]，得到(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-氟吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(260mg，产率：61.0％)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400mg, 0.428mmol, 1eq) was dissolved in dioxane (4mL) and water ( 2mL), add 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (190.72mg, 0.855mmol, 2eq) , 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (62.57mg, 0.086mmol, 0.2eq) and cesium carbonate (417.90mg, 1.28mmol, 3eq), reacted at 80°C for 2 hours under nitrogen protection . LCMS monitored the reaction to be complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column [tetrahydrofuran (containing 0.5% ammonia)/petroleum ether: 0-35 %], to obtain (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl ) Ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy)-5-(5-fluoropyridine- 3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (260mg, yield: 61.0% ), yellow solid.
MS m/z:996.4[M+H]+ MS m/z:996.4[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-氟吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-fluoropyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-氟吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(240mg,0.241mmol,1eq)溶于乙腈(2mL)中，加入盐酸/二氧六环(4M,2mL)，室温反应1小时，LCMS监测反应完全。反应液浓缩得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-氟吡啶-3-基)吡啶并[4,3-d]嘧 啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(214mg，粗品)，黄色固体，粗品直接用于下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl )naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy)-5-(5-fluoropyridin-3-yl )pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240mg, 0.241mmol, 1eq) was dissolved in acetonitrile (2 mL), add hydrochloric acid/dioxane (4M, 2 mL), react at room temperature for 1 hour, and the reaction is complete as monitored by LCMS. The reaction solution was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-fluoropyridin-3-yl)pyrido[4,3-d]pyrim Pyridin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (214 mg, crude), yellow solid, crude used directly in next step .
MS m/z:852.4[M+H]+ MS m/z:852.4[M+H] +
步骤3：化合物4Step 3: Compound 4
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-氟吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5-(5-fluoropyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyne yl-6-fluoronaphthalen-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-氟吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(214mg,0.241mmol,1eq)溶于N,N-二甲基甲酰胺(2mL)中，加入氟化铯(1.83g,12.04mmol,50eq)，室温反应3小时。LCMS监测反应完全。反应液过滤，滤液经HPLC制备，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-氟吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(5mg，产率：2.98％)，黄色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-fluoropyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-6- Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (214 mg, 0.241 mmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), Add cesium fluoride (1.83g, 12.04mmol, 50eq) and react at room temperature for 3 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-fluoropyridin-3-yl)pyrido[4,3-d] Pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (5 mg, yield: 2.98%), yellow solid.
HPLC分离条件:HPLC separation conditions:
柱子:YMC-Triart Prep C18 150*40mm*7umColumn: YMC-Triart Prep C18 150*40mm*7um
流动相A：Water(NH3H2O+NH4HCO3)，流动相B：ACN；梯度B％：35％-75％；保留时间：9min.Mobile phase A: Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; gradient B%: 35%-75%; retention time: 9min.
MS m/z:696.6[M+H]+ MS m/z:696.6[M+H] +
19F NMR(377MHz,DMSO-d6)δ-110.10(s),-110.57(s),-110.76(s),-127.30(s),-140.20(s),-141.27(s),-141.99(s),-172.07(s),-172.15(s). 19 F NMR (377MHz,DMSO-d 6 )δ-110.10(s),-110.57(s),-110.76(s),-127.30(s),-140.20(s),-141.27(s),-141.99 (s), -172.07(s), -172.15(s).
1H NMR(400MHz,DMSO-d6)δ10.18(br s,1H),8.74-8.38(m,2H),8.06-7.72(m,2H),7.52-7.37(m,2H),7.28(br s,1H),5.31(br d,J＝53.6Hz,1H),4.93(br s,1H),4.22-4.03(m,2H),3.24-2.77(m,11H),2.25-1.95(m,3H),1.94-1.69(m,4H),1.47(br s,2H),0.99-0.81(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.18(br s,1H),8.74-8.38(m,2H),8.06-7.72(m,2H),7.52-7.37(m,2H),7.28( br s,1H),5.31(br d,J＝53.6Hz,1H),4.93(br s,1H),4.22-4.03(m,2H),3.24-2.77(m,11H),2.25-1.95(m ,3H),1.94-1.69(m,4H),1.47(br s,2H),0.99-0.81(m,1H).
实施例5：化合物5Embodiment 5: Compound 5
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(3-氟苯基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(3-fluorophenyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluorin-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(3-氟苯基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(3-fluorophenyl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,0.214mmol,1eq)溶于二氧六环(2mL)和水(0.5mL)中，加入3-氟-苯硼酸(59.8mg,0.428mmol,2eq)、碳酸铯(209.0mg,0.641mmol,3eq)和甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1,1-联苯-2-基)钯(II)(31.1mg,0.0428mmol,0.2eq)。氮气保护，80℃反应2小时。LCMS监测反应完全。反应液浓缩，残留物用乙酸乙酯和水萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱纯化(四氢呋喃/石油醚：0-30％)，得到产物(0.13g,产率：61.1％)。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.214mmol, 1eq) was dissolved in dioxane (2mL) and water ( 0.5mL), add 3-fluoro-phenylboronic acid (59.8mg, 0.428mmol, 2eq), cesium carbonate (209.0mg, 0.641mmol, 3eq) and methanesulfonyloxy (diadamantyl-n-butylphosphino )-2-amino-1,1-biphenyl-2-yl)palladium(II) (31.1 mg, 0.0428 mmol, 0.2 eq). Under nitrogen protection, react at 80°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to obtain the product (0.13 g, yield: 61.1%).
MS m/z:995.5[M+H]+ MS m/z:995.5[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(3-氟苯基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐 Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(3-fluorophenyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(3-氟苯基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(100mg,0.100mmol,1eq)溶于乙腈(1mL)中，加入盐酸二氧六环溶液(4M,1.67mL)，室温反应2小时。LCMS检测反应完全。反应液浓缩，得到产物(86mg,粗品)，直接用于下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl ) Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(3-fluorophenyl)pyrido [4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.100 mmol, 1 eq) was dissolved in acetonitrile (1 mL) , add dioxane hydrochloride solution (4M, 1.67mL) and react at room temperature for 2 hours. LCMS detected that the reaction was complete. The reaction solution was concentrated to obtain the product (86 mg, crude product), which was directly used in the next step.
MS m/z:851.5[M+H]+ MS m/z:851.5[M+H] +
步骤3：化合物5Step 3: Compound 5
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(3-氟苯基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(3-fluorophenyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluorin-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(3-氟苯基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(85mg,0.099mmol,1eq)溶于N，N-二甲基甲酰胺(0.5mL)中，加入氟化铯(758.56mg,4.99mmol,50eq)，室温反应2小时。LCMS监测反应完全。将反应液过滤，滤液经HPLC制备得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(3-氟苯基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(20mg,收率：28.8％)，白色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(3-fluorophenyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5 -((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (85mg, 0.099mmol, 1eq) was dissolved in N,N-dimethylformamide (0.5mL) and fluorine was added Cesium chloride (758.56mg, 4.99mmol, 50eq) was reacted at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(3-fluorophenyl)pyrido[4,3-d]pyrimidine-7 -yl)-5-ethynyl-6-fluoronaphthalene-2-ol (20 mg, yield: 28.8%), white solid.
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 80*30mm*5um；Column: Phenomenex C18 80*30mm*5um;
流动相A：water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％：50％-70％；保留时间：10min.Mobile phase A: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%: 50%-70%; retention time: 10min.
MS m/z:695.2[M+H]+ MS m/z:695.2[M+H] +
19F NMR(377MHz,DMSO-d6)δ-110.22(s),-110.72(s),-142.22(s),-143.21(s),-172.21(s). 19 F NMR (377MHz,DMSO-d 6 )δ-110.22(s),-110.72(s),-142.22(s),-143.21(s),-172.21(s).
1H NMR(400MHz,DMSO-d6)δ10.22(br s,1H),7.99(br s,1H),7.59-7.00(m,7H),5.31(br d,J＝54Hz,1H),4.96(br s,1H),4.26-4.01(m,2H),3.95-3.58(m,2H),3.19-2.72(m,8H),2.23-1.98(m,4H),1.94-1.65(m,4H),1.49(br s,2H),0.96(br s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.22(br s,1H),7.99(br s,1H),7.59-7.00(m,7H),5.31(br d,J=54Hz,1H), 4.96(br s,1H),4.26-4.01(m,2H),3.95-3.58(m,2H),3.19-2.72(m,8H),2.23-1.98(m,4H),1.94-1.65(m, 4H), 1.49(br s, 2H), 0.96(br s, 1H).
实施例6：化合物6Embodiment 6: Compound 6
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(萘-1-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(naphthalen-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluorin-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(naphthalen-1-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,0.214mmol,1eq)溶于二氧六环(1mL)和水(1mL)中，加入1-萘硼酸频哪醇酯(108.7mg,0.428mmol,2eq)、碳酸铯(209.0mg,0.641mmol,3eq)和1,1’-二叔丁基膦基二茂铁二氯化钯(27.86mg,0.043mmol,0.2eq)。氮气保护，80℃反应2小时。LCMS监测反应完全。反应液浓缩，残留物用乙酸乙酯和水萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱纯化(四氢呋喃/石油醚：0-30％)，得到产物(90mg,产率：41.0％)。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.214mmol, 1eq) was dissolved in dioxane (1mL) and water ( 1mL), add 1-naphthylboronic acid pinacol ester (108.7mg, 0.428mmol, 2eq), cesium carbonate (209.0mg, 0.641mmol, 3eq) and 1,1'-di-tert-butylphosphinoferrocene Palladium chloride (27.86 mg, 0.043 mmol, 0.2 eq). Under nitrogen protection, react at 80°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to obtain the product (90 mg, yield: 41.0%).
MS m/z:1027.5[M+H]+ MS m/z:1027.5[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(萘-1-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(naphthalen-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(90mg,0.088mmol,1eq)溶于乙腈(1mL)中，加入盐酸二氧六环溶液(4M,1mL)，室温反应2小时。LCMS检测反应完全。反应液浓缩，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(萘-1-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(70mg,粗品)。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl ) Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(naphthalene-1-yl)pyrido [4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (90 mg, 0.088 mmol, 1 eq) was dissolved in acetonitrile (1 mL) In, dioxane hydrochloride solution (4M, 1 mL) was added, and reacted at room temperature for 2 hours. LCMS detected that the reaction was complete. The reaction solution was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(naphthalen-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-6 - Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (70 mg, crude).
MS m/z:883.1[M+H]+ MS m/z:883.1[M+H] +
步骤3：化合物6Step 3: Compound 6
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(萘-1-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(naphthalen-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluorin-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(萘-1-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚(70mg,0.079mmol,1eq)溶于N，N-二甲基甲酰胺(1mL)中，加入氟化铯(760mg,5.00mmol,63.12eq)，室温反应3小时。LCMS监测反应完全。将反应液过滤，滤液经HPLC制备得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(萘-1-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(15mg,收率：26.0％)，白色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(naphthalen-1-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5 -((triisopropylsilyl)ethynyl)naphthalene-2-ol (70mg, 0.079mmol, 1eq) was dissolved in N,N-dimethylformamide (1mL), cesium fluoride (760mg, 5.00mmol, 63.12eq), react at room temperature for 3 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(naphthalen-1-yl)pyrido[4,3-d]pyrimidine-7 -yl)-5-ethynyl-6-fluoronaphthalene-2-ol (15 mg, yield: 26.0%), white solid.
MS m/z:727.0[M+H]+ MS m/z:727.0[M+H] +
HPLC分离条件：HPLC separation conditions:
柱子：YMC-Triart Prep C18 150*40mm*7um；Column: YMC-Triart Prep C18 150*40mm*7um;
流动相A：Water(NH3H2O+NH4HCO3)，流动相B：ACN；梯度B％：43％-83％，保留时间：9min.Mobile phase A: Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; gradient B%: 43%-83%, retention time: 9min.
19F NMR(376MHz,DMSO-d6)δ-110.65(s),-144.13(s),-172.00(s),-172.16(s). 19 F NMR (376MHz, DMSO-d 6 )δ-110.65(s),-144.13(s),-172.00(s),-172.16(s).
1H NMR(400MHz,DMSO-d6)δ8.07-7.90(m,3H),7.64-7.00(m,8H),5.31(br d,J＝54.4Hz,1H),4.27-4.01(m,2H),3.95-3.80(m,1H),3.24-2.91(m,7H),2.90-2.71(m,3H),2.24-2.01(m,4H),1.93-1.73(m,4H),1.44-1.19(m,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.07-7.90(m, 3H), 7.64-7.00(m, 8H), 5.31(br d, J=54.4Hz, 1H), 4.27-4.01(m, 2H),3.95-3.80(m,1H),3.24-2.91(m,7H),2.90-2.71(m,3H),2.24-2.01(m,4H),1.93-1.73(m,4H),1.44- 1.19(m,3H).
实施例7：化合物7Example 7: Compound 7
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吲哚-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H-indol-4-yl)pyrido[4,3-d]pyrimidin-7-yl )-5-ethynyl-6-fluoronaphthalene-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吲哚-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H -indol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(400mg,0.428mmol,1eq)溶于二氧六环(4mL)和水(4mL)中，加入1-甲基-1H-吲哚-4-硼酸嚬哪醇酯(164.9mg,0.641mmol,1.5eq)、碳酸铯(278.6mg,0.855mmol,2eq)和甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1,1-联苯-2-基)钯(II)(62.3mg,0.085mmol,0.2eq)。氮气保护，80℃反应2小时。LCMS监测反应完全。反应液浓缩，残留物用乙酸乙酯萃取。有机相用饱和食盐水洗涤， 无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱纯化(四氢呋喃/石油醚：0-30％)，得到(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吲哚-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(330mg,产率：74.9％)。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400mg, 0.428mmol, 1eq) was dissolved in dioxane (4mL) and water ( 4mL), add 1-methyl-1H-indole-4-boronate (164.9mg, 0.641mmol, 1.5eq), cesium carbonate (278.6mg, 0.855mmol, 2eq) and methanesulfonyloxy (Diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (62.3mg, 0.085mmol, 0.2eq). Under nitrogen protection, react at 80°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate. The organic phase was washed with saturated brine, Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The crude product was purified by column (THF/petroleum ether: 0-30%) to give (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy )-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazin-7a-yl) Methoxy)-5-(1-methyl-1H-indol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] Octane-8-carboxylate (330 mg, yield: 74.9%).
MS m/z:1030.5[M+H]+ MS m/z:1030.5[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吲哚-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H-indol-4-yl)pyrido[4,3-d]pyrimidine- 7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吲哚-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(100mg,0.097mmol,1eq)溶于乙腈(0.5mL)中，加入盐酸二氧六环溶液(4M,0.5mL)，室温反应1小时。LCMS检测反应完全。反应液浓缩，得到粗产物(86mg,粗品)，直接用于下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl ) Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy)-5-(1-methyl-1H-ind Indol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (100mg, 0.097mmol, 1eq) was dissolved in acetonitrile (0.5mL), added dioxane hydrochloride solution (4M, 0.5mL), and reacted at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction solution was concentrated to obtain a crude product (86 mg, crude product), which was directly used in the next step.
MS m/z:886.5[M+H]+ MS m/z:886.5[M+H] +
步骤3：化合物7Step 3: Compound 7
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吲哚-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H-indol-4-yl)pyrido[4,3-d]pyrimidin-7-yl )-5-ethynyl-6-fluoronaphthalene-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基) 甲氧基)-5-(1-甲基-1H-吲哚-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(85mg,0.096mmol,1eq)溶于N，N-二甲基甲酰胺(1.5mL)中，加入氟化铯(728.6mg,4.80mmol,50eq)，室温反应1小时。LCMS监测反应完全。将反应液过滤，滤液经HPLC制备得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-甲基-1H-吲哚-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(20mg,收率：28.6％)，白色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)-5-(1-methyl-1H-indol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropyl Silyl)ethynyl)naphthalene-2-ol hydrochloride (85mg, 0.096mmol, 1eq) was dissolved in N,N-dimethylformamide (1.5mL), cesium fluoride (728.6mg, 4.80 mmol, 50eq), react at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-methyl-1H-indol-4-yl)pyrido[4 ,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (20 mg, yield: 28.6%), white solid.
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 75*30mm*3um；Column: Phenomenex C18 75*30mm*3um;
流动相A：Water(ammonia hydroxide v/v)，流动相B:ACN；梯度B％:37％-77％,保留时间：9min.Mobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 37%-77%, retention time: 9min.
MS m/z:730.3[M+H]+ MS m/z:730.3[M+H] +
19F NMR(377MHz,DMSO-d6)δ-110.53(s),-145.10(s),-172.04(s). 19 F NMR (377MHz,DMSO-d 6 )δ-110.53(s),-145.10(s),-172.04(s).
1H NMR(400MHz,DMSO-d6)δ10.15(br s,1H),8.00(br s,1H),7.69-7.09(m,7H),6.71(br s,1H),5.32(d,J＝55.2Hz,1H),4.96(br s,1H),4.30-4.01(m,2H),3.82(br s,3H),3.75-3.50(m,3H),3.19-2.80(m,8H),2.25-1.99(m,3H),1.96-1.75(m,4H),1.63-1.37(m,2H),1.07-0.84(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.15(br s,1H),8.00(br s,1H),7.69-7.09(m,7H),6.71(br s,1H),5.32(d, J＝55.2Hz,1H),4.96(br s,1H),4.30-4.01(m,2H),3.82(br s,3H),3.75-3.50(m,3H),3.19-2.80(m,8H) ,2.25-1.99(m,3H),1.96-1.75(m,4H),1.63-1.37(m,2H),1.07-0.84(m,1H).
实施例8：化合物8Example 8: Compound 8
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyne yl-6-fluoronaphthalen-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane Alkane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(300.0mg,0.321mmol,1eq)溶于二氧六环(3.0mL)和水(1.0mL)的混合溶剂中,加入1-(四氢-2H-吡喃-2-基)-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吲唑(157.9mg,0.481mmol,1.5eq),碳酸铯(313.4mg,0.962mmol,3eq)，1,1-双(二叔丁基膦)二茂铁氯化钯(41.8mg,0.064mmol,0.2eq)。氮气置换，100℃反应2小时。LCMS监测反应完全，反应液过滤，滤液浓缩，残留物经柱纯化[四氢呋喃/石油醚：0-35％]，得到(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(150mg,产率：32.4％)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300.0mg, 0.321mmol, 1eq) was dissolved in dioxane (3.0mL) and In the mixed solvent of water (1.0mL), add 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-diox Borolane-2-yl)-1H-indazole (157.9mg, 0.481mmol, 1.5eq), cesium carbonate (313.4mg, 0.962mmol, 3eq), 1,1-bis(di-tert-butylphosphine) dioxocene Iron palladium chloride (41.8mg, 0.064mmol, 0.2eq). Replaced with nitrogen, reacted at 100°C for 2 hours. LCMS monitored that the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column [tetrahydrofuran/petroleum ether: 0-35%] to obtain (1R,5S)-tert-butyl-3-(8-fluoro-7-( 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluoro Hexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)pyrido[4 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, yield: 32.4%), yellow solid.
MS m/z:1101.7[M+H]+ MS m/z:1101.7[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,0.182mmol,1eq)溶于乙腈(2.0mL)中，加入盐酸二氧六环溶液(4M,2mL)。室温反应2小时，LCMS监测反应完全，反应液浓缩，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)- 5-(1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚盐酸盐(180mg,粗品)，黄色固体，粗品直接用于下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl ) Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1-(tetrahydro-2H- Pyran-2-yl)-1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate (200mg, 0.182mmol, 1eq) was dissolved in acetonitrile (2.0mL), and dioxane hydrochloride solution (4M, 2mL) was added. After reacting at room temperature for 2 hours, LCMS monitored that the reaction was complete, and the reaction liquid was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8 -Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)- 5-(1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2 -Phenol hydrochloride (180 mg, crude product), yellow solid, the crude product was used directly in the next step.
MS m/z:873.6[M+H]+ MS m/z:873.6[M+H] +
步骤3：化合物8Step 3: Compound 8
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyne yl-6-fluoronaphthalen-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚(200mg,0.167mmol,1eq)溶于N,N-二甲基甲酰胺(3.0mL)中，加入氟化铯(1.27g,8.37mmol,50eq)。室温反应2小时，LCMS监测反应完全，反应液过滤。滤液经HPLC纯化得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(1H-吲唑-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(2.0mg,产率：1.7％)，黄色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-6- Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (200 mg, 0.167 mmol, 1 eq) was dissolved in N,N-dimethylformamide (3.0 mL) and fluorinated Cesium (1.27g, 8.37mmol, 50eq). The reaction was carried out at room temperature for 2 hours, the reaction was complete as monitored by LCMS, and the reaction liquid was filtered. The filtrate was purified by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(1H-indazol-4-yl)pyrido[4,3-d]pyrimidin-7-yl )-5-ethynyl-6-fluoronaphthalene-2-ol (2.0 mg, yield: 1.7%), yellow solid.
HPLC分离条件:HPLC separation conditions:
柱子:Boston Prime C18 150*30mm*5umColumn: Boston Prime C18 150*30mm*5um
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％:40％-60％，保留时间：11min.Mobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 40%-60%, retention time: 11min.
MS m/z:717.3[M+H]+ MS m/z:717.3[M+H] +
19F NMR(377MHz,DMSO-d6)δ-110.39(s),-144.44(s),-171.88(s),-172.00(s),-172.18(s), 19 F NMR (377MHz,DMSO-d 6 )δ-110.39(s),-144.44(s),-171.88(s),-172.00(s),-172.18(s),
1H NMR(400MHz,DMSO-d6)δ13.20(br s,1H),10.18(br s 1H),8.24-7.91(m,2H),7.73-7.28(m,6H),5.32(br d,J＝54.4Hz,1H),4.95(br s,1H),4.20-4.03(m,2H),4.00-3.50(m,6H),3.18-2.75(m,5H),2.21-1.96(m,3H),1.92-1.78(m,4H),1.39(br s,2H),0.94(br s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ13.20(br s,1H),10.18(br s 1H),8.24-7.91(m,2H),7.73-7.28(m,6H),5.32(br d ,J＝54.4Hz,1H),4.95(br s,1H),4.20-4.03(m,2H),4.00-3.50(m,6H),3.18-2.75(m,5H),2.21-1.96(m, 3H),1.92-1.78(m,4H),1.39(br s,2H),0.94(br s,1H).
实施例9：化合物9Example 9: Compound 9
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2- phenol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡唑并[1,5-a]吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrazolo[1, 5-a]pyridin-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(300mg,0.321mmol,1eq)溶于二氧六环(5.0mL),水(1.0mL)和乙醇(2.0mL)的混合溶剂中。加入3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡唑并[1,5-a]吡啶(117.4mg,0.481mmol,1.5eq)，碳酸铯(313.4mg,0.962mmol,3eq)。氮气置换，80℃反应2小时。LCMS监测反应完全，反应液加水淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(四氢呋喃/石油醚：0-35％)，得到(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡唑并[1,5-a]吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(150mg,产率：46.0％)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 0.321mmol, 1eq) was dissolved in dioxane (5.0mL), water (1.0mL) and ethanol (2.0mL) in a mixed solvent. Add 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (117.4mg, 0.481mmol, 1.5eq), cesium carbonate (313.4mg, 0.962mmol, 3eq). Replaced with nitrogen, reacted at 80°C for 2 hours. The completion of the reaction was monitored by LCMS. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-35%) to obtain (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-( Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrroline Azin-7a-yl)methoxy)-5-(pyrazolo[1,5-a]pyridin-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylate (150 mg, yield: 46.0%), yellow solid.
MS m/z:1017.6[M+H]+ MS m/z:1017.6[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡唑并[1,5-a]吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐 Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrazolo[1,5-a]pyridin-3-yl)pyrido[4,3-d] Pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡唑并[1,5-a]吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(150mg,0.147mmol,1eq)溶于乙腈(2.0mL)中，加入盐酸二氧六环溶液(4M,2mL)。室温反应1小时。LCMS监测反应完全，反应液浓缩，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡唑并[1,5-a]吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(150mg，粗品)，黄色固体，粗品直接用于下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl )naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrazolo[1,5- a]pyridin-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (150mg, 0.147 mmol, 1eq) was dissolved in acetonitrile (2.0mL), and dioxane hydrochloride solution (4M, 2mL) was added. React at room temperature for 1 hour. LCMS monitored that the reaction was complete, and the reaction solution was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrazolo[1,5-a]pyridin-3-yl)pyrido [4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (150 mg, crude), yellow solid , the crude product was used directly in the next step.
MS m/z:873.6[M+H]+ MS m/z:873.6[M+H] +
步骤3：化合物9Step 3: Compound 9
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2- phenol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡唑并[1,5-a]吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(150mg,0.172mmol,1eq)溶于N,N-二甲基甲酰胺(2mL)中，加入氟化铯(2.61g,17.2mmol,100eq)，氮气氛围下室温反应2小时。LCMS监测反应完全，反应液过滤，滤液经HPLC分离，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(20mg,产率：16.2％)，黄色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrazolo[1,5-a]pyridin-3-yl)pyrido[4,3-d]pyrimidine- 7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (150mg, 0.172mmol, 1eq) dissolved in N,N-dimethyl To formamide (2 mL), cesium fluoride (2.61 g, 17.2 mmol, 100 eq) was added, and reacted at room temperature for 2 hours under nitrogen atmosphere. LCMS monitored that the reaction was complete, the reaction solution was filtered, and the filtrate was separated by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5 -Chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-7- yl)-5-ethynyl-6-fluoronaphthalen-2-ol (20 mg, yield: 16.2%), yellow solid.
HPLC分离条件:HPLC separation conditions:
柱子:Boston Prime C18 150*30mm*5umColumn: Boston Prime C18 150*30mm*5um
流动相A：water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％:31％-51％，保留时间：13min Mobile phase A: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%: 31%-51%, retention time: 13min
MS m/z:717.2[M+H]+ MS m/z:717.2[M+H] +
19F NMR(376MHz,DMSO-d6)δ110.28(s),-145.79(s),-171.98(s),-172.21(s). 19 F NMR (376MHz, DMSO-d 6 ) δ110.28(s), -145.79(s), -171.98(s), -172.21(s).
1H NMR(400MHz,DMSO-d6)δ10.17(br s,1H),8.79(d,J＝7.0Hz,1H),8.10(br s,1H),8.06-7.92(m,1H),7.75(br s,1H),7.58-7.38(m,2H),7.38-7.23(m,2H),7.01(t,J＝7.4Hz,1H),5.31(br d,J＝53.2Hz 1H),5.08-4.84(m,1H),4.29-4.01(m,2H),3.50-3.36(m,2H),3.19-2.75(m,8H),2.54-2.52(m,1H),2.25-2.00(m,3H),1.92-1.63(m,4H),1.56-1.40(m,2H),0.94-0.81(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.17(br s,1H),8.79(d,J=7.0Hz,1H),8.10(br s,1H),8.06-7.92(m,1H), 7.75(br s,1H),7.58-7.38(m,2H),7.38-7.23(m,2H),7.01(t,J=7.4Hz,1H),5.31(br d,J=53.2Hz 1H), 5.08-4.84(m,1H),4.29-4.01(m,2H),3.50-3.36(m,2H),3.19-2.75(m,8H),2.54-2.52(m,1H),2.25-2.00(m ,3H),1.92-1.63(m,4H),1.56-1.40(m,2H),0.94-0.81(m,1H).
实施例10：化合物10Example 10: Compound 10
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluorin-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-3-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(400mg,0.428mmol,1eq)溶于二氧六环(4mL)和水(2mL)的混合溶液中，加入吡啶-3-基硼酸(105.12mg,0.855mmol,2eq)，1,1-双(二苯基磷)二茂铁氯化钯(62.6mg,0.086mmol,0.2eq)和碳酸铯(417.9mg,1.28mmol,3eq)，氮气保护下，80℃反应2小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残留物经柱纯化[四氢呋喃(含0.5％氨水)/石油醚：0-35％]，得到(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲 氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(210mg，产率：50.2％)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400mg, 0.428mmol, 1eq) was dissolved in dioxane (4mL) and water ( 2mL), add pyridin-3-ylboronic acid (105.12mg, 0.855mmol, 2eq), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (62.6mg, 0.086mmol, 0.2eq ) and cesium carbonate (417.9mg, 1.28mmol, 3eq), reacted at 80°C for 2 hours under nitrogen protection. LCMS monitored the reaction to be complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column [tetrahydrofuran (containing 0.5% ammonia)/petroleum ether: 0-35 %] to obtain (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl Oxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazine-7a- Base)methoxy)-5-(pyridin-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 - Formyl ester (210 mg, yield: 50.2%), yellow solid.
MS m/z:978.5[M+H]+ MS m/z:978.5[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(210mg,0.215mmol,1eq)溶于乙腈(4mL)中，加入盐酸二氧六环溶液(4M,4mL)，室温反应1小时，LCMS监测反应完全。反应液浓缩得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(186.9mg，粗品)，黄色固体，粗品直接用于下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl ) Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy)-5-(pyridin-3-yl)pyrido [4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (210 mg, 0.215 mmol, 1 eq) was dissolved in acetonitrile (4 mL) In, dioxane hydrochloride solution (4M, 4mL) was added and reacted at room temperature for 1 hour, and the reaction was completed by LCMS monitoring. The reaction solution was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-6- Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (186.9 mg, crude), yellow solid, the crude was used directly in the next step.
MS m/z:834.6[M+H]+ MS m/z:834.6[M+H] +
步骤3：化合物10Step 3: Compound 10
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluorin-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基) 甲氧基)-5-(吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(186.9mg,0.215mmol,1eq)溶于N,N-二甲基甲酰胺(2mL)中，加入氟化铯(4.89g,32.20mmol,150eq)，室温反应2小时。LCMS监测反应完全。反应液过滤，滤液经HPLC制备，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(25mg，产率：19.0％)，白色固体4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)-5-(pyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene -2-Phenol hydrochloride (186.9mg, 0.215mmol, 1eq) was dissolved in N,N-dimethylformamide (2mL), cesium fluoride (4.89g, 32.20mmol, 150eq) was added, and reaction at room temperature 2 Hour. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-3-yl)pyrido[4,3-d]pyrimidine-7 -yl)-5-ethynyl-6-fluoronaphthalene-2-ol (25 mg, yield: 19.0%), white solid
HPLC分离条件:HPLC separation conditions:
柱子:Phenomenex C18 75*30mm*3umColumn: Phenomenex C18 75*30mm*3um
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％:28％-68％，保留时间：9minMobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 28%-68%, retention time: 9min
MS m/z:678.3[M+H]+ MS m/z:678.3[M+H] +
19F NMR(377MHz,DMSO-d6)δ-110.18(s),-110.44(s),-110.64(s),-142.30(s),-143.13(s),-143.40(s),-172.27(s). 19 F NMR (377MHz,DMSO-d 6 )δ-110.18(s),-110.44(s),-110.64(s),-142.30(s),-143.13(s),-143.40(s),-172.27 (s).
1H NMR(400MHz,DMSO-d6)δ10.18(br s,1H),8.66(br d,J＝3.7Hz,2H),8.11-7.69(m,2H),7.59-7.16(m,4H),5.30(br d,J＝53.6Hz,1H),4.92(br s,1H),4.24-4.01(m,2H),3.96-3.56(m,1H),3.49-3.34(m,2H),3.18-2.93(m,5H),2.92-2.70(m,2H),2.24-1.97(m,3H),1.96-1.58(m,5H),1.44(br s,2H),0.90(br s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.18(br s,1H),8.66(br d,J=3.7Hz,2H),8.11-7.69(m,2H),7.59-7.16(m,4H ),5.30(br d,J＝53.6Hz,1H),4.92(br s,1H),4.24-4.01(m,2H),3.96-3.56(m,1H),3.49-3.34(m,2H), 3.18-2.93(m,5H),2.92-2.70(m,2H),2.24-1.97(m,3H),1.96-1.58(m,5H),1.44(br s,2H),0.90(br s,1H ).
实施例11：化合物11Example 11: Compound 11
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(嘧啶-5-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrimidin-5-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluorin-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(嘧啶-5-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrimidin-5-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(300mg,0.321mmol,1eq)溶于二氧六环(3mL)和水(1.5mL)中，加入嘧啶-5-基硼酸(79.4mg,0.641mmol,2eq)，1,1-双(二苯基磷)二茂铁氯化钯(46.9mg,0.641mmol,0.2eq)和碳酸铯(313.4mg,0.962mmol,3eq)，氮气保护下，80℃反应2小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化[四氢呋喃(含0.5％氨水)/石油醚：0-35％]，得到(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(嘧啶-5-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(180mg，产率：57.3％)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 0.321mmol, 1eq) was dissolved in dioxane (3mL) and water ( 1.5mL), add pyrimidin-5-ylboronic acid (79.4mg, 0.641mmol, 2eq), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (46.9mg, 0.641mmol, 0.2eq) and Cesium carbonate (313.4mg, 0.962mmol, 3eq) was reacted at 80°C for 2 hours under nitrogen protection. LCMS monitored the reaction to be complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column [tetrahydrofuran (containing 0.5% ammonia)/petroleum ether: 0-35%] to obtain (1R,5S)-tert-butyl-3-(8-fluoro-7-(7 -Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexa Hydrogen-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrimidin-5-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabis Cyclo[3.2.1]octane-8-carboxylate (180 mg, yield: 57.3%), yellow solid.
MS m/z:979.5[M+H]+ MS m/z:979.5[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(嘧啶-5-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrimidin-5-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(嘧啶-5-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,0.204mmol,1eq)溶于乙腈(2mL)中，加入盐酸二氧六环溶液(4M,2mL)，室温反应1小时，LCMS监测反应完全。反应液浓缩得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(嘧啶-5-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(178.0mg，粗品)，黄色固体，粗品直接用于 下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl ) Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrimidin-5-yl)pyrido [4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.204mmol, 1eq) was dissolved in acetonitrile (2mL) In, dioxane hydrochloride solution (4M, 2mL) was added, reacted at room temperature for 1 hour, and the reaction was complete by LCMS monitoring. The reaction solution was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrimidin-5-yl)pyrido[4,3-d]pyrimidin-7-yl)-6- Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (178.0 mg, crude product), yellow solid, the crude product was directly used in Next step.
MS m/z:835.6[M+H]+ MS m/z:835.6[M+H] +
步骤3：化合物11Step 3: Compound 11
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(嘧啶-5-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrimidin-5-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluorin-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(嘧啶-5-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(178.0mg,0.204mmol,1eq)溶于N,N-二甲基甲酰胺(2mL)中，加入氟化铯(4.65g,30.64mmol,150eq)，室温反应2小时。LCMS监测反应完全。反应液过滤，滤液经HPLC制备，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(嘧啶-5-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(25mg，产率：18.0％)，黄色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrimidin-5-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5 -((Triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (178.0 mg, 0.204 mmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL) and fluorine was added Cesium chloride (4.65g, 30.64mmol, 150eq) was reacted at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrimidin-5-yl)pyrido[4,3-d]pyrimidine-7 -yl)-5-ethynyl-6-fluoronaphthalen-2-ol (25 mg, yield: 18.0%), yellow solid.
HPLC分离条件:HPLC separation conditions:
柱子:YMC-Triart Prep C18 150*40mm*7umColumn: YMC-Triart Prep C18 150*40mm*7um
流动相A：Water(NH3H2O+NH4HCO3)，流动相B：ACN；梯度B％：29％-69％，保留时间9minMobile phase A: Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; Gradient B%: 29%-69%, retention time 9min
MS m/z:679.3[M+H]+ MS m/z:679.3[M+H] +
19F NMR(376MHz,DMSO-d6)δ-110.08(s),-110.58(s),-141.13(s),-141.68(s),-172.09(s),-172.15(s). 19 F NMR (376MHz, DMSO-d 6 )δ-110.08(s),-110.58(s),-141.13(s),-141.68(s),-172.09(s),-172.15(s).
1H NMR(400MHz,DMSO-d6)δ10.26(br s,1H),9.30(br s,1H),8.93(br s,2H),8.00(br s,1H),7.63-7.36(m,2H),7.29(br s,1H),5.31(br d,J＝54.0Hz,1H),4.92(br s,1H),4.30-4.01(m,2H),3.96-3.57(m,1H),3.45-3.34(m,3H),3.25-2.95(m,5H),2.90-2.70(m,2H),2.24-2.00(m,3H),1.95-1.74(m,4H),1.46(br s,2H),1.02-0.73(m,1H) 1 H NMR (400MHz,DMSO-d 6 )δ10.26(br s,1H),9.30(br s,1H),8.93(br s,2H),8.00(br s,1H),7.63-7.36(m ,2H),7.29(br s,1H),5.31(br d,J=54.0Hz,1H),4.92(br s,1H),4.30-4.01(m,2H),3.96-3.57(m,1H) ,3.45-3.34(m,3H),3.25-2.95(m,5H),2.90-2.70(m,2H),2.24-2.00(m,3H),1.95-1.74(m,4H),1.46(br s ,2H),1.02-0.73(m,1H)
实施例12：化合物12Example 12: Compound 12
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲氧基吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methoxypyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5 -Ethynyl-6-fluoronaphthalen-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲氧基吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methoxypyridine -3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(400mg,0.428mmol,1eq)溶于二氧六环(4mL)和水(2mL)的混合溶液中，加入3-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(201.0mg,0.856mmol,2eq)，1,1-双(二叔丁基膦)二茂铁氯化钯(55.7mg,0.086mmol,0.2eq)和碳酸铯(417.9mg,1.282mmol,3eq)，氮气保护下，80℃反应2小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化[四氢呋喃(含0.5％氨水)/石油醚：0-35％]，得到(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲氧基吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(340mg，产率：78.9％)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400mg, 0.428mmol, 1eq) was dissolved in dioxane (4mL) and water ( 2mL) of the mixed solution, add 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (201.0mg, 0.856mmol, 2eq), 1,1-bis(di-tert-butylphosphino)ferrocenepalladium chloride (55.7mg, 0.086mmol, 0.2eq) and cesium carbonate (417.9mg, 1.282mmol, 3eq), under nitrogen protection , react at 80°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column [tetrahydrofuran (containing 0.5% ammonia)/petroleum ether: 0-35%] to obtain (1R,5S)-tert-butyl-3-(8-fluoro-7-(7 -Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexa Hydrogen-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methoxypyridin-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8 - Diazabicyclo[3.2.1]octane-8-carboxylate (340 mg, yield: 78.9%), yellow solid.
MS m/z:1008.5[M+H]+ MS m/z:1008.5[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲氧基吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐 Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methoxypyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl )-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲氧基吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(320mg,0.317mmol,1eq)溶于乙腈(2mL)中，加入盐酸二氧六环溶液(4M,2mL)，室温反应1小时，LCMS监测反应完全。反应液浓缩得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲氧基吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(274.0mg，粗品)，黄色固体，粗品直接用于下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl )Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methoxypyridine-3 -yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (320mg, 0.317mmol, 1eq) In acetonitrile (2 mL), dioxane hydrochloride solution (4M, 2 mL) was added, reacted at room temperature for 1 hour, and the reaction was complete as monitored by LCMS. The reaction solution was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methoxypyridin-3-yl)pyrido[4,3-d]pyrimidine-7- yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (274.0 mg, crude product), yellow solid, the crude product was used directly in the next step.
MS m/z:864.3[M+H]+ MS m/z:864.3[M+H] +
步骤3：化合物12Step 3: Compound 12
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲氧基吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methoxypyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5 -Ethynyl-6-fluoronaphthalen-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲氧基吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(274.0mg,0.317mmol,1eq)溶于N,N-二甲基甲酰胺(3mL)中，加入氟化铯(7.23g,47.56mmol,150eq)，室温反应2小时。LCMS监测反应完全。反应液过滤，滤液经HPLC制备，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲氧基吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(35.0mg,产率：15.6％)，白色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methoxypyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)- The hydrochloride salt of 6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (274.0mg, 0.317mmol, 1eq) was dissolved in N,N-dimethylformamide (3mL ), add cesium fluoride (7.23g, 47.56mmol, 150eq), and react at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methoxypyridin-3-yl)pyrido[4,3- d] Pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (35.0 mg, yield: 15.6%), white solid.
HPLC分离条件:HPLC separation conditions:
柱子:Boston Prime C18 150*30mm*5um Column: Boston Prime C18 150*30mm*5um
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％:40％-60％，保留时间：13minMobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 40%-60%, retention time: 13min
MS m/z:708.3[M+H]+ MS m/z:708.3[M+H] +
19F NMR(377MHz,DMSO-d6)δ-110.18(s),-141.97(s),-142.64(s),-172.22(s). 19 F NMR (377MHz, DMSO-d 6 )δ-110.18(s),-141.97(s),-142.64(s),-172.22(s).
1H NMR(400MHz,DMSO-d6)δ10.13(br s,1H),8.46-8.08(m,2H),8.04-7.93(m,1H),7.63-7.11(m,4H),5.30(br d,J＝54.0Hz,1H),5.15-4.75(br s,1H),4.23-4.04(m,2H),3.85(s,3H),3.54-3.31(m,4H),3.24-2.97(m,5H),2.96-2.73(m,2H),2.27-1.99(m,3H),1.97-1.62(m,4H),1.48(br s,2H),0.87(br s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.13(br s,1H),8.46-8.08(m,2H),8.04-7.93(m,1H),7.63-7.11(m,4H),5.30( br d,J＝54.0Hz,1H),5.15-4.75(br s,1H),4.23-4.04(m,2H),3.85(s,3H),3.54-3.31(m,4H),3.24-2.97( m,5H),2.96-2.73(m,2H),2.27-1.99(m,3H),1.97-1.62(m,4H),1.48(br s,2H),0.87(br s,1H).
实施例13：化合物13Example 13: Compound 13
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5- Ethynyl-6-fluoronaphthalen-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methylpyridine- 3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(300mg,0.321mmol,1eq)溶于二氧六环(3mL)和水(1.5mL)中，加入3-甲基-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶(140.5mg,0.641mmol,2eq)、碳酸铯(209.0mg,0.641mmol,3eq)和[1,1-双(二叔丁基膦)二茂铁]二氯化钯(II)(41.8mg,0.064mmol,0.2eq)，氮气保护，80℃反应2小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残留物粗品经柱纯化(四氢呋喃/石油醚：0-30％)，得到(1R,5S)-叔 丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(240mg,产率：75.4％)，棕黄色油状物。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 0.321mmol, 1eq) was dissolved in dioxane (3mL) and water ( 1.5mL), add 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (140.5mg, 0.641mmol, 2eq), cesium carbonate (209.0mg, 0.641mmol, 3eq) and [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (41.8mg, 0.064mmol, 0.2eq), Under nitrogen protection, react at 80°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude residue was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to obtain ( 1R,5S)-tert Butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)- 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methylpyridin-3-yl)pyrido[4,3 -d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (240 mg, yield: 75.4%), brown oil.
MS m/z:992.5[M+H]+ MS m/z:992.5[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl) -6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(120mg，0.121mmol,1eq)溶于乙腈(1mL)中，加入盐酸二氧六环溶液(4M,0.5mL)，室温反应2小时。LCMS监测反应完全。反应液浓缩，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(102.5mg,粗品)，棕黄色油状物，粗品直接用于下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl ) Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methylpyridine-3- Base) pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120mg, 0.121mmol, 1eq) was dissolved in To acetonitrile (1 mL), dioxane hydrochloride solution (4M, 0.5 mL) was added and reacted at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methylpyridin-3-yl)pyrido[4,3-d]pyrimidine-7- Hydrochloride salt of -6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (102.5 mg, crude product), brown-yellow oil, the crude product was directly used in the next step.
MS m/z:848.6[M+H]+ MS m/z:848.6[M+H] +
步骤3：化合物13Step 3: Compound 13
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5- Ethynyl-6-fluoronaphthalen-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基) 甲氧基)-5-(5-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(100mg,0.101mmol,1eq)溶于N,N-二甲基甲酰胺(1mL)中，加入氟化铯(1.53g,10.08mmol,100eq)，室温反应2小时。LCMS监测反应完全。反应液过滤，滤液经HPLC制备得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-甲基吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(10mg,收率：14.3％)，白色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)-5-(5-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl) Ethynyl)naphthalene-2-ol hydrochloride (100mg, 0.101mmol, 1eq) was dissolved in N,N-dimethylformamide (1mL), cesium fluoride (1.53g, 10.08mmol, 100eq) was added, React at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-( ((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-methylpyridin-3-yl)pyrido[4,3-d] Pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (10 mg, yield: 14.3%), white solid.
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 75*30mm*3um；Column: Phenomenex C18 75*30mm*3um;
流动相A：water(ammonia hydroxide v/v)，流动相B：ACN，梯度B％:39％-79％，保留时间：9minMobile phase A: water (ammonia hydroxide v/v), mobile phase B: ACN, gradient B%: 39%-79%, retention time: 9min
MS m/z:692.5[M+H]+ MS m/z:692.5[M+H] +
19F NMR(376MHz,DMSO-d6)δ-110.18(s),-110.67(s),-142.31(s),-143.12(s),-172.00(s),-172.24(s). 19 F NMR (376MHz, DMSO-d 6 )δ-110.18(s),-110.67(s),-142.31(s),-143.12(s),-172.00(s),-172.24(s).
1H NMR(400MHz,DMSO-d6)δ10.20(br s,1H),8.66-8.10(m,2H),8.00(br s,1H),7.76(br s,1H),7.56-7.37(m,2H),7.29(br s,1H),5.31(br d,J＝53.2Hz,1H),4.94(br s,1H),4.25-4.00(m,2H),3.97-3.43(m,2H),3.21-2.97(m,5H),2.96-2.55(m,3H),2.36(s,3H),2.20-1.98(m,3H),1.98-1.62(m,5H),1.57-1.33(m,2H),1.03-0.83(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.20(br s,1H),8.66-8.10(m,2H),8.00(br s,1H),7.76(br s,1H),7.56-7.37( m,2H),7.29(br s,1H),5.31(br d,J＝53.2Hz,1H),4.94(br s,1H),4.25-4.00(m,2H),3.97-3.43(m,2H ),3.21-2.97(m,5H),2.96-2.55(m,3H),2.36(s,3H),2.20-1.98(m,3H),1.98-1.62(m,5H),1.57-1.33(m ,2H),1.03-0.83(m,1H).
实施例14：化合物14Example 14: Compound 14
5-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)尼古丁腈甲酸盐
5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene -1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine -5-yl) nicotine nitrile formate
步骤1：(1R,5S)-叔丁基-3-(5-(5-氰基吡啶-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(5-(5-cyanopyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy )-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(300mg,0.321mmol,1eq)溶于二氧六环(3mL)中，加入5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)尼古丁腈(147.6mg,0.641mmol,2eq)、碳酸铯(313.4mg,0.962mmol,3eq)和甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1,1-联苯-2-基)钯(II)(46.7mg,0.064mmol,0.2eq)，氮气保护，80℃反应2小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。残留物经柱纯化(四氢呋喃/石油醚：0-30％)，得到(1R,5S)-叔丁基-3-(5-(5-氰基吡啶-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(240mg,产率：74.6％)，浅黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 0.321mmol, 1eq) was dissolved in dioxane (3mL), added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotine nitrile (147.6mg, 0.641mmol, 2eq), cesium carbonate (313.4mg, 0.962 mmol, 3eq) and methanesulfonyloxy (diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl) palladium (II) (46.7mg, 0.064mmol, 0.2 eq), under nitrogen protection, reacted at 80° C. for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column (THF/petroleum ether: 0-30%) to give (1R,5S)-tert-butyl-3-(5-(5-cyanopyridin-3-yl)-8-fluoro-7 -(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane Alkane-8-carboxylate (240 mg, yield: 74.6%), pale yellow solid.
MS m/z:1003.5[M+H]+ MS m/z:1003.5[M+H] +
步骤2：5-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-7-(7-氟-3-羟基-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)尼古丁腈的盐酸盐Step 2: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3- Hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-5-yl)nicotinenitrile hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(5-(5-氰基吡啶-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,0.199mmol,1eq)溶于乙腈(2mL)中，加入盐酸二氧六环溶液(4M,2.00mL)，室温反应1小时。LCMS监测反应完全。反应液浓缩，得到5-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-7-(7-氟-3-羟基-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)尼古丁腈的盐酸盐(200mg,粗品)，黄色固 体，粗品直接用于下一步。(1R,5S)-tert-butyl-3-(5-(5-cyanopyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)- 8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazin-7a-yl)methoxy Base) pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.199mmol, 1eq) was dissolved in To acetonitrile (2 mL), dioxane hydrochloride solution (4M, 2.00 mL) was added and reacted at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated to obtain 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(7-fluoro- 3-Hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazine-7a- yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)nicotinenitrile hydrochloride (200mg, crude product), yellow solid The crude product was directly used in the next step.
MS m/z:859.3[M+H]+ MS m/z:859.3[M+H] +
步骤3：化合物14Step 3: Compound 14
5-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)尼古丁腈甲酸盐
5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene -1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine -5-yl) nicotine nitrile formate
将5-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-7-(7-氟-3-羟基-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)尼古丁腈的盐酸盐(200mg,0.233mmol,1eq)溶于N,N-二甲基甲酰胺(2mL)中，加入氟化铯(3.54g,23.28mmol,100eq)，室温反应12小时。LCMS监测反应完全。反应液过滤，滤液经HPLC制备得到5-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)尼古丁腈甲酸盐(30mg,产率：18.3％)，淡黄色固体。5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(7-fluoro-3-hydroxyl- 8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazin-7a-yl)methoxy yl)pyrido[4,3-d]pyrimidin-5-yl)nicotine nitrile hydrochloride (200mg, 0.233mmol, 1eq) was dissolved in N,N-dimethylformamide (2mL), added fluorinated Cesium (3.54g, 23.28mmol, 100eq), react at room temperature for 12 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl -7-Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyridine And[4,3-d]pyrimidin-5-yl)nicotine nitrile formate (30 mg, yield: 18.3%), pale yellow solid.
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 75*30mm*3um；Column: Phenomenex C18 75*30mm*3um;
流动相A：Water(FA)，流动相B：ACN；梯度B％：1％-41％，保留时间：9minMobile phase A: Water (FA), mobile phase B: ACN; Gradient B%: 1%-41%, retention time: 9min
MS m/z:702.9[M+H]+ MS m/z:702.9[M+H] +
19F NMR(376MHz,DMSO-d6)δ-109.95(s),-110.11(s),-110.32(s),-110.53(s),-140.72(s),-141.50(s),-172.88(s),-172.15(s). 19 F NMR (376MHz,DMSO-d 6 )δ-109.95(s),-110.11(s),-110.32(s),-110.53(s),-140.72(s),-141.50(s),-172.88 (s), -172.15(s).
1H NMR(400MHz,DMSO-d6)δ9.24-8.79(m,2H),8.58-8.31(m,1H),8.23(s,1H),7.99(br s,1H),7.55-7.35(m,2H),7.28(br s,1H),5.31(br d,J＝54.0Hz,1H),4.95(br s,1H),4.28-4.00(m,2H),3.81-3.44(m,4H),3.22-2.97(m,5H),2.91-2.76(m,2H),2.22-1.97(m,3H),1.95-1.64(m,4H),1.50(br s,2H),0.95(br s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ9.24-8.79(m,2H),8.58-8.31(m,1H),8.23(s,1H),7.99(br s,1H),7.55-7.35( m,2H),7.28(br s,1H),5.31(br d,J＝54.0Hz,1H),4.95(br s,1H),4.28-4.00(m,2H),3.81-3.44(m,4H ),3.22-2.97(m,5H),2.91-2.76(m,2H),2.22-1.97(m,3H),1.95-1.64(m,4H),1.50(br s,2H),0.95(br s ,1H).
实施例15：化合物15Example 15: Compound 15
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-(5-(二甲氨基)吡啶-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(5-(dimethylamino)pyridin-3-yl) -8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol
步骤1：(1R,5S)-叔丁基-3-(5-(5-(二甲氨基)吡啶-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(5-(5-(dimethylamino)pyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxy Methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazine-7a -yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(0.3g,0.321mmol,1eq)溶于二氧六环(5mL)和水(1mL)中，加入N,N-二甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-3-胺(159.1mg,0.641mmol,2eq)、碳酸铯(313.4mg,0.962mmol,3eq)和[1,1-双(二叔丁基膦)二茂铁]二氯化钯(II)(41.8mg,0.064mmol,0.2eq)。氮气保护，80℃反应2小时。LCMS监测反应完全。反应液浓缩，残留物用乙酸乙酯和水萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱纯化(四氢呋喃/石油醚：0-30％)，得到产物(0.23g,产率：70.2％)。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.3g, 0.321mmol, 1eq) was dissolved in dioxane (5mL) and water (1mL), add N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine- ( 41.8 mg, 0.064 mmol, 0.2 eq). Under nitrogen protection, react at 80°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to obtain the product (0.23 g, yield: 70.2%).
MS m/z:1021.6[M+H]+ MS m/z:1021.6[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-(5-(二甲氨基)吡啶-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐 Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(5-(dimethylamino)pyridine-3 -yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-7 -yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(5-(5-(二甲氨基)吡啶-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(0.2g,0.196mmol,1eq)溶于乙腈(2mL)中，加入盐酸二氧六环溶液(4M,1mL)，室温反应1小时。LCMS检测反应完全。反应液浓缩，得到产物(171.8mg,粗品)，直接用于下一步。(1R,5S)-tert-butyl-3-(5-(5-(dimethylamino)pyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy Base)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.2g, 0.196mmol, 1eq) was dissolved in acetonitrile (2mL), added dioxane hydrochloride solution (4M, 1mL), and reacted at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction solution was concentrated to obtain the product (171.8 mg, crude product), which was directly used in the next step.
MS m/z:877.6[M+H]+ MS m/z:877.6[M+H] +
步骤3：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-(5-(二甲氨基)吡啶-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Step 3: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-(5-(dimethylamino)pyridine-3 -yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-7 -yl)-5-ethynyl-6-fluoronaphthalene-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-(5-(二甲氨基)吡啶-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(0.2g,0.228mmol,1eq)溶于N，N-二甲基甲酰胺(3mL)中，加入氟化铯(3.46g,22.80mmol,100eq)，室温反应过夜。LCMS监测反应完全。将反应液过滤，滤液经HPLC制备得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-(5-(二甲氨基)吡啶-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(20mg,收率：12.2％)，白色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(5-(dimethylamino)pyridin-3-yl )-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl )-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (0.2g, 0.228mmol, 1eq) dissolved in N,N-dimethylformamide (3mL), cesium fluoride (3.46g, 22.80mmol, 100eq) was added, and reacted overnight at room temperature. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(5-( Dimethylamino)pyridin-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4, 3-d] pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (20 mg, yield: 12.2%), white solid.
MS m/z:721.5[M+H]+ MS m/z:721.5[M+H] +
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 80*30mm*5um流速：35mL/minColumn: Phenomenex C18 80*30mm*5um Flow rate: 35mL/min
流动相A：[Water(0.1％氨水v/v)-ACN]流动相B：ACN；梯度：40％-60％(v/v),10min Mobile phase A: [Water (0.1% ammonia v/v)-ACN] mobile phase B: ACN; Gradient: 40%-60% (v/v), 10min
19F NMR(377MHz,DMSO-d6)δ-110.23,-110.74,-142.49,-172.03,-172.24. 19 F NMR (377MHz, DMSO-d 6 ) δ-110.23, -110.74, -142.49, -172.03, -172.24.
1H NMR(400MHz,DMSO-d6)δ10.18(br s,1H),8.42-7.70(m,3H),7.64-6.72(m,4H),5.40-5.21(m,1H),4.95(br s,1H),4.23-4.01(m,2H),3.99-3.55(m,1H),3.51-3.36(m,2H),3.26-3.00(m,5H),2.95(s,6H),2.89-2.71(m,2H),2.60-2.50(m,1H),2.28-1.95(m,4H),1.94-1.63(m,3H),1.46(br s,2H),0.91(br s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.18(br s,1H),8.42-7.70(m,3H),7.64-6.72(m,4H),5.40-5.21(m,1H),4.95( br s,1H),4.23-4.01(m,2H),3.99-3.55(m,1H),3.51-3.36(m,2H),3.26-3.00(m,5H),2.95(s,6H),2.89 -2.71(m,2H),2.60-2.50(m,1H),2.28-1.95(m,4H),1.94-1.63(m,3H),1.46(br s,2H),0.91(br s,1H) .
实施例16：化合物16Example 16: Compound 16
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-(5-氯吡啶-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(5-chloropyridin-3-yl)-8-fluoro -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyne yl-6-fluoronaphthalen-2-ol
步骤1：(1R,5S)-叔丁基-3-(5-(5-氯吡啶-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(5-(5-chloropyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy) -8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazin-7a-yl)methyl Oxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(400mg,0.428mmol,1eq)溶于二氧六环(4mL)和水(2mL)的混合溶液中，加入(5-氯吡啶-3-基)硼酸(134.56mg,0.855mmol,2eq)，1,1-双(二苯基磷)二茂铁氯化钯(62.57mg,0.086mmol,0.2eq)和碳酸铯(417.90mg,1.28mmol,3eq)，氮气保护下，80℃反应2小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残留物经柱纯化[四氢呋喃(含0.5％氨水)/石油醚：0-35％]，得到(1R,5S)-叔丁基-3-(5-(5-氯吡啶-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(300mg，产率：69.3％)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400mg, 0.428mmol, 1eq) was dissolved in dioxane (4mL) and water ( 2mL) of the mixed solution, add (5-chloropyridin-3-yl)boronic acid (134.56mg, 0.855mmol, 2eq), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (62.57mg, 0.086mmol, 0.2eq) and cesium carbonate (417.90mg, 1.28mmol, 3eq), reacted at 80°C for 2 hours under nitrogen protection. LCMS monitored the reaction to be complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column [tetrahydrofuran (containing 0.5% ammonia)/petroleum ether: 0-35 %] to give (1R,5S)-tert-butyl-3-(5-(5-chloropyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy )-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, yield: 69.3% ), yellow solid.
MS m/z:1012.4[M+H]+ MS m/z:1012.4[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-(5-氯吡啶-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(5-chloropyridin-3-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(5-(5-氯吡啶-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(300mg,0.296mmol,1eq)溶于乙腈(6mL)中，加入盐酸二氧六环溶液(4M,6mL)，室温反应1小时，LCMS监测反应完全。反应液浓缩得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-(5-氯吡啶-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(268.1mg，粗品)，黄色固体，粗品直接用于下一步。(1R,5S)-tert-butyl-3-(5-(5-chloropyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8 -((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazin-7a-yl)methoxy )pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 0.296mmol, 1eq) was dissolved in acetonitrile (6mL), add dioxane hydrochloride solution (4M, 6mL), react at room temperature for 1 hour, and the reaction is complete by LCMS monitoring. The reaction solution was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(5-chloropyridin-3-yl) -8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl) -6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (268.1 mg, crude product), yellow solid, the crude product was directly used in the next step.
MS m/z:868.6[M+H]+ MS m/z:868.6[M+H] +
步骤3：化合物16Step 3: Compound 16
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-(5-氯吡啶-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(5-chloropyridin-3-yl)-8-fluoro -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyne yl-6-fluoronaphthalen-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-(5-氯吡啶-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(268.1mg,0.296mmol,1eq,盐酸盐)溶于N,N-二甲基甲酰胺(3mL)中，加入氟化铯(6.75g,44.44mmol,150eq)，室温反应2小时。LCMS监测反应完全。反应液过滤，滤液经HPLC制备，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-(5-氯吡啶-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡 咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(30mg,产率：15.1％)，白色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(5-chloropyridin-3-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6- Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (268.1mg, 0.296mmol, 1eq, hydrochloride) dissolved in N,N-dimethylformamide (3mL), cesium fluoride (6.75g, 44.44mmol, 150eq) was added and reacted at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-(5-chloro Pyridin-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyridine Poroxolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (30mg, yield: 15.1%) , white solid.
HPLC分离条件:HPLC separation conditions:
柱子:Phenomenex C18 75*30mm*3umColumn: Phenomenex C18 75*30mm*3um
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％：38％-78％，保留时间：9minMobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 38%-78%, retention time: 9min
MS m/z:712.3[M+H]+ MS m/z:712.3[M+H] +
19F NMR(376MHz,DMSO-d6)δ-110.12(s),-110.36(s),-110.62(s),-141.09(s),-172.26(s). 19 F NMR (376MHz, DMSO-d 6 )δ-110.12(s),-110.36(s),-110.62(s),-141.09(s),-172.26(s).
1H NMR(400MHz,DMSO-d6)δ10.23(br s,1H),8.75(br s,2H),8.00(br s,2H),7.60-7.15(m,3H),5.31(br d,J＝54.0Hz,1H),4.94(br s,1H),4.25-4.02(m,2H),4.00-3.63(m,1H),3.57-3.37(m,2H),3.20-2.98(m,5H),2.92-2.69(m,3H),2.25-1.97(m,3H),1.91-1.73(m,4H),1.47(br s,2H),0.91(br s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.23(br s,1H),8.75(br s,2H),8.00(br s,2H),7.60-7.15(m,3H),5.31(br d ,J＝54.0Hz,1H),4.94(br s,1H),4.25-4.02(m,2H),4.00-3.63(m,1H),3.57-3.37(m,2H),3.20-2.98(m, 5H),2.92-2.69(m,3H),2.25-1.97(m,3H),1.91-1.73(m,4H),1.47(br s,2H),0.91(br s,1H).
实施例17：化合物17Example 17: Compound 17
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-吗啉代吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-morpholinopyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5 -Ethynyl-6-fluoronaphthalen-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2S,7aR)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-吗啉代吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2S,7aR)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-morpholinopyridine -3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(500mg,0.534mmol,1eq)溶于二氧六环(3mL)和水(3mL)中，加入4-(5-(4,4,5,5-四 甲基-1,3,2-二噁硼戊环-2-基)吡啶-3-基)吗啉(310.1mg,1.07mmol,2eq)、碳酸铯(522.4mg,1.60mmol,3eq)和1,1’-二叔丁基膦基二茂铁二氯化钯(69.7mg,0.107mmol,0.2eq)，氮气保护，80℃反应5小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。残留物经柱纯化(四氢呋喃/石油醚：0-38％)，得到(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2S,7aR)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-吗啉代吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(360mg,产率：63.4％)。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.534mmol, 1eq) was dissolved in dioxane (3mL) and water ( 3mL), add 4-(5-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)morpholine (310.1mg, 1.07mmol, 2eq), cesium carbonate (522.4mg, 1.60mmol, 3eq) and 1 , 1'-di-tert-butylphosphinoferrocenepalladium dichloride (69.7mg, 0.107mmol, 0.2eq), under nitrogen protection, react at 80°C for 5 hours. LCMS monitored the reaction to be complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column (THF/petroleum ether: 0-38%) to give (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy Base)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2S,7aR)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl )methoxy)-5-(5-morpholinopyridin-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] Octane-8-carboxylate (360 mg, yield: 63.4%).
MS m/z:1063.5[M+H]+ MS m/z:1063.5[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2S,7aR)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-吗啉代吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2S,7aR) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-morpholinopyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl )-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2S,7aR)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-吗啉代吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,0.188mmol,1eq)溶于乙腈(2mL)中，加入盐酸二氧六环溶液(4M,2.00mL)，室温反应半小时。LCMS检测反应完全。反应液浓缩，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2S,7aR)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-吗啉代吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(200mg,粗品)，黄色油状物，粗品直接用于下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl )Naphthalene-1-yl)-2-(((2S,7aR)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-morpholinopyridine-3 -yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.188mmol, 1eq) To acetonitrile (2 mL), add dioxane hydrochloride solution (4M, 2.00 mL) and react at room temperature for half an hour. LCMS detected that the reaction was complete. The reaction solution was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2S, 7aR)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-morpholinopyridin-3-yl)pyrido[4,3-d]pyrimidine-7 -yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (200 mg, crude product), yellow oil, the crude product was used directly in the next step.
MS m/z:919.7[M+H]+ MS m/z:919.7[M+H] +
步骤3：化合物17Step 3: Compound 17
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-吗啉代吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-morpholinopyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5 -Ethynyl-6-fluoronaphthalen-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2S,7aR)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-吗啉代吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(200mg,0.218mmol,1eq)溶于N,N-二甲基甲酰胺(2mL)中，加入氟化铯(4.96g,32.64mmol,150eq)，室温反应1小时。LCMS监测反应完全。反应液过滤，滤液经HPLC制备得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-吗啉代吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(30mg,收率：18.1％)，白色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2S,7aR)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-morpholinopyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl)- The hydrochloride salt of 6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (200mg, 0.218mmol, 1eq) was dissolved in N,N-dimethylformamide (2mL) In, cesium fluoride (4.96g, 32.64mmol, 150eq) was added and reacted at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-( ((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-morpholinopyridin-3-yl)pyrido[4,3-d ]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (30 mg, yield: 18.1%), white solid.
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 75*30mm*3umColumn: Phenomenex C18 75*30mm*3um
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％：34％-74％，保留时间：9minMobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 34%-74%, retention time: 9min
MS m/z:763.2[M+H]+ MS m/z:763.2[M+H] +
19F NMR(377MHz,DMSO-d6)δ-110.23(s),-110.70(s),-142.19(s),-172.08(s),-172.25(s). 19 F NMR (377MHz, DMSO-d 6 )δ-110.23(s),-110.70(s),-142.19(s),-172.08(s),-172.25(s).
1H NMR(400MHz,DMSO-d6)δ10.18(br s,1H),8.56-8.13(m,2H),7.99(br s,1H),7.57-6.91(m,4H),5.31(br d,J＝53.6Hz,1H),4.94(br s,1H),4.24-3.98(m,2H),3.98-3.54(m,6H),3.42(br s,1H),3.23-3.02(m,9H),2.89-2.73(m,2H),2.21-2.00(m,3H),1.93-1.62(m,5H),1.46(br s,2H),0.91(br s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.18(br s,1H),8.56-8.13(m,2H),7.99(br s,1H),7.57-6.91(m,4H),5.31(br d,J＝53.6Hz,1H),4.94(br s,1H),4.24-3.98(m,2H),3.98-3.54(m,6H),3.42(br s,1H),3.23-3.02(m, 9H),2.89-2.73(m,2H),2.21-2.00(m,3H),1.93-1.62(m,5H),1.46(br s,2H),0.91(br s,1H).
实施例18：化合物18Example 18: Compound 18
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-(三氟甲基)吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-(trifluoromethyl)pyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl )-5-ethynyl-6-fluoronaphthalene-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-(三氟甲基)吡啶-3-基)吡啶并[4,3-d]嘧啶- 4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-(trifluoromethyl Base) pyridin-3-yl) pyrido[4,3-d]pyrimidine- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(400mg,0.428mmol,1eq)溶于二氧六环(2.5mL),水(0.5mL)和乙醇(1mL)中，加入3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-5-(三氟甲基)吡啶(350.2mg,1.28mmol,3eq),四三苯基膦钯(98.8mg,0.086mmol,0.2eq),碳酸铯(417.9mg,1.28mmol,3eq)，氮气保护下80℃反应3小时。LCMS监测反应完全，反应液用水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱层析纯化(四氢呋喃/石油醚：0-20％)，得到(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-(三氟甲基)吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(340mg,粗产品)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400mg, 0.428mmol, 1eq) was dissolved in dioxane (2.5mL), water (0.5mL) and ethanol (1mL), add 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl Base) pyridine (350.2mg, 1.28mmol, 3eq), tetrakistriphenylphosphine palladium (98.8mg, 0.086mmol, 0.2eq), cesium carbonate (417.9mg, 1.28mmol, 3eq), react at 80°C for 3 hours under nitrogen protection . The completion of the reaction was monitored by LCMS, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column chromatography (tetrahydrofuran/petroleum ether: 0-20%) to obtain (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3 -(Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H- Pyrrolinazin-7a-yl)methoxy)-5-(5-(trifluoromethyl)pyridin-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylate (340 mg, crude product), yellow solid.
MS m/z:1046.5[M+H]+ MS m/z:1046.5[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-(三氟甲基)吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-(trifluoromethyl)pyridin-3-yl)pyrido[4,3-d]pyrimidine- 7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-(三氟甲基)吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(330mg,0.315mmol,1eq)溶于乙腈(3mL)，加入盐酸二氧六环溶液(4M,3mL)，室温反应1小时。LCMS监测反应完全，反应液浓缩，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-(三氟甲基)吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(280mg,粗产 品)，黄色固体，粗品直接投入下一步反应。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl ) Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy)-5-(5-(trifluoromethyl) Pyridin-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (330mg, 0.315mmol, 1eq) was dissolved in acetonitrile (3mL), added dioxane hydrochloride solution (4M, 3mL), and reacted at room temperature for 1 hour. LCMS monitored that the reaction was complete, and the reaction solution was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-(trifluoromethyl)pyridin-3-yl)pyrido[4 ,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (280mg, crude product), a yellow solid, and the crude product was directly put into the next reaction.
MS m/z:902.3[M+H]+ MS m/z:902.3[M+H] +
步骤3：化合物18Step 3: Compound 18
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-(三氟甲基)吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-(trifluoromethyl)pyridin-3-yl)pyrido[4,3-d]pyrimidin-7-yl )-5-ethynyl-6-fluoronaphthalene-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-(三氟甲基)吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(280mg,0.310mmol,1eq)溶于N,N-二甲基甲酰胺(5mL)，加入氟化铯(7.07g,46.56mmol,150eq)，室温反应2小时。LCMS监测反应完全，反应液过滤，滤液经HPLC纯化，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-(三氟甲基)吡啶-3-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(45.07mg，产率：19.3％)，白色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-(trifluoromethyl)pyridin-3-yl)pyrido[4,3-d]pyrimidine-7- Hydrochloride (280mg, 0.310mmol, 1eq) of -6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol was dissolved in N,N-dimethylformamide (5mL), cesium fluoride (7.07g, 46.56mmol, 150eq) was added and reacted at room temperature for 2 hours. LCMS monitored that the reaction was complete, the reaction solution was filtered, and the filtrate was purified by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8 -Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-(trifluoromethyl)pyridin-3-yl ) pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (45.07 mg, yield: 19.3%), white solid.
HPLC分离条件:HPLC separation conditions:
柱子:Phenomenex C18 75*30mm*3um；Column: Phenomenex C18 75*30mm*3um;
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％:40％-80％，保留时间：9minMobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 40%-80%, retention time: 9min
MS m/z:746.3[M+H]+ MS m/z:746.3[M+H] +
19F NMR(376MHz,DMSO-d6)δ-60.59(s),-110.63(s),-140.83(s),-172.11(s). 19 F NMR (376MHz, DMSO-d 6 )δ-60.59(s),-110.63(s),-140.83(s),-172.11(s).
1H NMR(400MHz,DMSO-d6)δ10.24(br s,1H),9.10(s,2H),8.28(s,1H),8.00(s,1H),7.60-7.40(m,2H),7.29(s,1H),5.31(br d,J＝54.4Hz,1H),4.91(s,1H),4.29-4.04(m,2H),4.00-3.63(m,1H),3.30-2.60(m,9H),2.23-2.00(m,3H),1.94-1.68(m,5H),1.46(s,2H),1.16-0.81(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.24(br s,1H),9.10(s,2H),8.28(s,1H),8.00(s,1H),7.60-7.40(m,2H) ,7.29(s,1H),5.31(br d,J=54.4Hz,1H),4.91(s,1H),4.29-4.04(m,2H),4.00-3.63(m,1H),3.30-2.60( m,9H),2.23-2.00(m,3H),1.94-1.68(m,5H),1.46(s,2H),1.16-0.81(m,1H).
实施例19：化合物19Example 19: Compound 19
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(异喹啉-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚的三氟醋酸盐 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(isoquinolin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl Trifluoroacetate of -6-fluoronaphthalen-2-ol
的三氟醋酸盐 trifluoroacetate
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(异喹啉-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(isoquinoline-4- Base) pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(600mg,0.641mmol,1eq),4-异喹啉硼酸嚬哪醇酯(490.8mg,1.92mmol,3eq),1,1-二(叔丁基磷)二茂铁氯化钯(83.6mg,0.128mmol,0.2eq),碳酸铯(626.9mg,1.92mmol,3eq)溶于二氧六环(5mL)和水(2.5mL)，氮气保护下80℃反应过夜。LCMS监测反应完全，反应液用水稀释，乙酸乙酯萃取，有机相用无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱层析纯化(四氢呋喃/石油醚：0-20％)，得到(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(异喹啉-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(400mg,粗产品)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600mg, 0.641mmol, 1eq), 4-isoquinoline boronic acid indol ester ( 490.8mg, 1.92mmol, 3eq), 1,1-di(tert-butylphosphino)ferrocene palladium chloride (83.6mg, 0.128mmol, 0.2eq), cesium carbonate (626.9mg, 1.92mmol, 3eq) dissolved in Dioxane (5 mL) and water (2.5 mL) were reacted overnight at 80° C. under nitrogen protection. The completion of the reaction was monitored by LCMS, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column chromatography (tetrahydrofuran/petroleum ether: 0-20%) to obtain (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3 -(Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H- Pyrrolinazin-7a-yl)methoxy)-5-(isoquinolin-4-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[ 3.2.1] Octane-8-carboxylate (400 mg, crude product), yellow solid.
MS m/z:1028.5[M+H]+ MS m/z:1028.5[M+H] +
步骤2：(1R,5S)-叔丁基-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(异喹啉-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 2: (1R,5S)-tert-Butyl-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2 -(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(isoquinolin-4-yl)pyrido[4,3-d] Pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(异喹啉-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,0.195mmol,1eq)溶于N,N-二甲基甲酰胺(2mL)，加入氟化铯(147.7mg,0.973mmol,5eq)，室温反应1小时。LCMS监测反应完全，反应液用水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩得到(1R,5S)-叔丁基-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(异喹啉-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(160mg，粗产品)，棕色油状物。该粗产品直接投入下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl )Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(isoquinolin-4-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.195mmol, 1eq) was dissolved in N, N-dimethylformamide (2mL) was added cesium fluoride (147.7mg, 0.973mmol, 5eq) and reacted at room temperature for 1 hour. The completion of the reaction was monitored by LCMS, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate gave (1R,5S)-tert-butyl-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(isoquinolin-4-yl)pyrido[4,3- d] Pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, crude product), brown oil. This crude product is directly sent to the next step.
MS m/z:872.3[M+H]+ MS m/z:872.3[M+H] +
步骤3：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(异喹啉-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚的三氟醋酸盐Step 3: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(isoquinolin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5 -Trifluoroacetate of ethynyl-6-fluoronaphthalen-2-ol
的三氟醋酸盐 trifluoroacetate
将(1R,5S)-叔丁基-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(异喹啉-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(160mg,0.184mmol,1eq)溶于二氯甲烷(5mL)，加入三氟乙酸(2.5mL)，室温反应1小时。LCMS监测反应完全，反应液浓缩，残留物经HPLC纯化，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(异喹啉-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚的三氟醋酸盐(50mg，产率：31.4％)，红色固体。(1R,5S)-tert-butyl-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-8-fluoro-2-( ((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(isoquinolin-4-yl)pyrido[4,3-d]pyrimidine- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160mg, 0.184mmol, 1eq) was dissolved in dichloromethane (5mL), added trifluoroacetic acid (2.5 mL), react at room temperature for 1 hour. LCMS monitored that the reaction was complete, the reaction solution was concentrated, and the residue was purified by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(isoquinolin-4-yl)pyrido[4 ,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol trifluoroacetate (50 mg, yield: 31.4%), red solid.
MS m/z:728.4[M+H]+ MS m/z:728.4[M+H] +
HPLC分离条件:HPLC separation conditions:
柱子：YMC-Actus Triart C18 150*30mm*5um；流速：30mL/min Column: YMC-Actus Triart C18 150*30mm*5um; flow rate: 30mL/min
流动相A:Water(0.1％三氟乙酸，v/v)流动相B:ACN梯度B％:0％-38％(v/v),保留时间：9minMobile phase A: Water (0.1% trifluoroacetic acid, v/v) mobile phase B: ACN gradient B%: 0%-38% (v/v), retention time: 9min
19F NMR(376MHz,DMSO-d6)δ-74.00(s),-119.52(s),-134.08(s),-172.83(s),-173.00(s). 19 F NMR (376MHz, DMSO-d 6 )δ-74.00(s),-119.52(s),-134.08(s),-172.83(s),-173.00(s).
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.71(br s,1H),8.52(br s,1H),8.42(d,J＝32Hz,1H),8.09(br s,1H),8.00(br s,1H),7.93-7.86(m,1H),7.78-7.65(m,2H),7.59-7.46(m,1H),5.66(br d,J＝52.4Hz,1H),5.39-5.22(m,1H),5.05(br s,2H),4.85(br s,2H),4.10-3.76(m,5H),3.49-3.26(m,3H),2.81-2.56(m,3H),2.47-2.39(m,1H),2.37-2.09(m,3H),1.88-1.57(m,4H). 1 H NMR (400MHz, DMSO-d 6 )δ9.67(s,1H),8.71(br s,1H),8.52(br s,1H),8.42(d,J=32Hz,1H),8.09(br s,1H),8.00(br s,1H),7.93-7.86(m,1H),7.78-7.65(m,2H),7.59-7.46(m,1H),5.66(br d,J＝52.4Hz, 1H),5.39-5.22(m,1H),5.05(br s,2H),4.85(br s,2H),4.10-3.76(m,5H),3.49-3.26(m,3H),2.81-2.56( m,3H),2.47-2.39(m,1H),2.37-2.09(m,3H),1.88-1.57(m,4H).
实施例20：化合物20Example 20: Compound 20
5-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)尼克酰胺
5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene -1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine -5-yl) nicotinamide
步骤1：(1R,5S)-叔丁基-3-(5-(5-氨基羰基吡啶-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(5-(5-aminocarbonylpyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy )-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-(5-氰基吡啶-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,0.199mmol,1eq)溶于二甲亚枫(2mL)中，加入碳酸钾(165.3mg,1.20mmol,6eq)和过氧化氢水溶液(470mg,4.15mmol,20.8eq,30％含量)。室温反应3小时。LCMS监测反应完全。反应液用饱和亚硫酸钠水溶液淬灭，二氯甲烷萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。得到产物(200mg,粗品)，直接用于下一步。 (1R,5S)-tert-butyl-3-(5-(5-cyanopyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)- 8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazin-7a-yl)methoxy Base) pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.199mmol, 1eq) was dissolved in To dimethyl sulfoxide (2 mL), potassium carbonate (165.3 mg, 1.20 mmol, 6 eq) and aqueous hydrogen peroxide (470 mg, 4.15 mmol, 20.8 eq, 30% content) were added. React at room temperature for 3 hours. LCMS monitored the reaction to be complete. The reaction solution was quenched with saturated aqueous sodium sulfite and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product (200 mg, crude) was obtained and used directly in the next step.
MS m/z:1021.5[M+H]+ MS m/z:1021.5[M+H] +
步骤2：5-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-7-(7-氟-3-羟基-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)尼克酰胺的盐酸盐Step 2: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3- Hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-5-yl)nicotinamide hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(5-(5-氨基羰基吡啶-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,0.196mmol,1eq)溶于乙腈(2mL)中，加入盐酸二氧六环溶液(4M,2mL)，室温反应2小时。LCMS检测反应完全。反应液浓缩，得到产物(150mg,粗品)，直接用于下一步。(1R,5S)-tert-butyl-3-(5-(5-aminocarbonylpyridin-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)- 8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazin-7a-yl)methoxy Base) pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.196mmol, 1eq) was dissolved in To acetonitrile (2 mL), dioxane hydrochloride solution (4M, 2 mL) was added and reacted at room temperature for 2 hours. LCMS detected that the reaction was complete. The reaction solution was concentrated to obtain the product (150 mg, crude product), which was directly used in the next step.
MS m/z:877.1[M+H]+ MS m/z:877.1[M+H] +
步骤3：5-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)尼克酰胺
Step 3: 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3 -Hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3- d] pyrimidin-5-yl) nicotinamide
将5-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-7-(7-氟-3-羟基-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)尼克酰胺的盐酸盐(150mg,0.171mmol,1eq)溶于N，N-二甲基甲酰胺(2mL)中，加入氟化铯(2.60g,17.10mmol,100eq)，室温反应6小时。LCMS检测反应完全。将反应液过滤，滤液经HPLC制备得到5-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯 啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)尼克酰胺(40mg,收率：32.4％)，白色固体。5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(7-fluoro-3-hydroxyl- 8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazin-7a-yl)methoxy yl)pyrido[4,3-d]pyrimidin-5-yl)nicotinamide hydrochloride (150mg, 0.171mmol, 1eq) was dissolved in N,N-dimethylformamide (2mL), added fluoride Cesium (2.60g, 17.10mmol, 100eq), react at room temperature for 6 hours. LCMS detected that the reaction was complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 5-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-acetylene Base-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrole Phyrazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)nickelamide (40 mg, yield: 32.4%), white solid.
HPLC分离条件：HPLC separation conditions:
柱子:Phenomenex C18 80*30mm*5um；流速：35mL/minColumn: Phenomenex C18 80*30mm*5um; flow rate: 35mL/min
流动相A:Water(0.05％氨水，v/v)流动相B:ACN；梯度：38％-58％(v/v),保留时间：10min.Mobile phase A: Water (0.05% ammonia water, v/v) Mobile phase B: ACN; gradient: 38%-58% (v/v), retention time: 10min.
MS m/z:721.4[M+H]+ MS m/z:721.4[M+H] +
19F NMR(376MHz,DMSO-d6)δ-110.45(s),-141.72(s),-172.19(s). 19 F NMR (376MHz, DMSO-d 6 )δ-110.45(s),-141.72(s),-172.19(s).
1H NMR(400MHz,DMSO-d6)δ10.27(br s,1H),9.17(br s,2H),8.30(br s,2H),8.00(br d,J＝5.5Hz,1H),7.73(br s,1H),7.55-7.38(m,2H),7.29(br s,1H),5.34(d,J＝54.8Hz,1H),4.35-4.05(m,2H),3.85(br s,1H),3.29(br s,2H),3.18(br s,6H),2.90(br s,2H),2.24-2.03(m,3H),1.96-1.79(m,5H),1.73(br s,2H),1.24(s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.27(br s,1H),9.17(br s,2H),8.30(br s,2H),8.00(br d,J=5.5Hz,1H), 7.73(br s,1H),7.55-7.38(m,2H),7.29(br s,1H),5.34(d,J=54.8Hz,1H),4.35-4.05(m,2H),3.85(br s ,1H),3.29(br s,2H),3.18(br s,6H),2.90(br s,2H),2.24-2.03(m,3H),1.96-1.79(m,5H),1.73(br s ,2H),1.24(s,1H).
实施例21：化合物21Example 21: Compound 21
4-(5-(6-氨基吡啶-3-基)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(5-(6-aminopyridin-3-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyne yl-6-fluoronaphthalen-2-ol
步骤1：(1R,5S)-叔丁基-3-(5-(6-((叔-丁氧基羰基)氨基)吡啶-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯
Step 1: (1R,5S)-tert-Butyl-3-(5-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-8-fluoro-7-(7-fluoro- 3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H -pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(500mg,0.534mmol,1eq)，叔丁基-(5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)吡啶-2-基)氨基甲酯(342.2mg,1.07mmol,2eq)，碳酸铯(522.4mg,1.60mmol,3eq)溶于二氧六环(8mL)和水 (4mL)中，加入1,1-二(叔丁基磷)二茂铁氯化钯(69.7mg,0.107mmol,0.2eq)，氮气置换3次，80℃反应12小时。LCMS监测反应完全。反应液用乙酸乙酯和水萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱纯化(四氢呋喃/石油醚：0-50％)，得到产物(400mg,产率：68.5％)(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.534mmol, 1eq), tert-butyl-(5-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)aminomethyl ester (342.2mg, 1.07mmol, 2eq), cesium carbonate (522.4mg, 1.60mmol, 3eq) dissolved in dioxane (8mL) and water (4 mL), add 1,1-bis(tert-butylphosphino)ferrocenepalladium chloride (69.7mg, 0.107mmol, 0.2eq), replace with nitrogen three times, and react at 80°C for 12 hours. LCMS monitored the reaction to be complete. The reaction solution was extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (tetrahydrofuran/petroleum ether: 0-50%) to obtain the product (400mg, yield: 68.5%)
MS m/z:1093.6[M+H]+ MS m/z:1093.6[M+H] +
步骤2：4-(5-(6-氨基吡啶-3-基)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(5-(6-aminopyridin-3-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)- 6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(5-(6-((叔-丁氧基羰基)氨基)吡啶-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(400mg,0.36mmol,1eq)溶于乙腈(8mL)，加入盐酸二氧六环溶液(4M,7mL)，室温反应1小时。LCMS监测反应完全。反应液浓缩得到产物(粗品300mg)，直接用于下一步反应。(1R,5S)-tert-butyl-3-(5-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-8-fluoro-7-(7-fluoro-3- (Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrole Olinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ( 400mg, 0.36mmol, 1eq) was dissolved in acetonitrile (8mL), added dioxane hydrochloride solution (4M, 7mL), and reacted at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated to obtain the product (crude product 300 mg), which was directly used in the next reaction.
MS m/z:849.6[M+H]+ MS m/z:849.6[M+H] +
步骤3：化合物21Step 3: Compound 21
4-(5-(6-氨基吡啶-3-基)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(5-(6-aminopyridin-3-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyne yl-6-fluoronaphthalen-2-ol
将4-(5-(6-氨基吡啶-3-基)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(150mg,0.177mmol,1eq),溶于N,N-二甲基甲酰胺(2mL)，加入氟化铯(4.03g,26.50mmol, 150eq).室温反应2小时。LCMS监测反应完全。反应液过滤，滤液经HPLC制备得到产物(10mg,收率：8.2％)，白色固体。4-(5-(6-aminopyridin-3-yl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6- Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (150mg, 0.177mmol, 1eq), dissolved in N,N-dimethylformamide (2mL), Add cesium fluoride (4.03g, 26.50mmol, 150eq). React at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain the product (10 mg, yield: 8.2%) as a white solid.
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 75*30mm*3umColumn: Phenomenex C18 75*30mm*3um
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN，梯度B％:31％-71％，保留时间：9minMobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN, gradient B%: 31%-71%, retention time: 9min
MS m/z:693.4[M+H]+ MS m/z:693.4[M+H] +
19F NMR(377MHz,DMSO-d6)δ-110.33(s),-145.86(s),-172.00(s),-172.21(s). 19 F NMR (377MHz, DMSO-d 6 )δ-110.33(s),-145.86(s),-172.00(s),-172.21(s).
1H NMR(400MHz,DMSO-d6)δ10.17(br s,1H),8.06-7.91(m,1H),7.55-7.12(m,4H),6.56-6.28(m,3H),5.30(br d,J＝54.0Hz,1H),4.96(br d,J＝11.0Hz,1H),4.20-4.11(m,1H),4.05(br d,J＝9.9Hz,1H),3.64-3.43(m,4H),3.22-3.00(m,5H),2.99-2.80(m,3H),2.26-1.96(m,3H),1.94-1.75(m,4H),1.48(br d,J＝8.6Hz,2H),0.97-0.80(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.17(br s,1H),8.06-7.91(m,1H),7.55-7.12(m,4H),6.56-6.28(m,3H),5.30( br d,J=54.0Hz,1H),4.96(br d,J=11.0Hz,1H),4.20-4.11(m,1H),4.05(br d,J=9.9Hz,1H),3.64-3.43( m,4H),3.22-3.00(m,5H),2.99-2.80(m,3H),2.26-1.96(m,3H),1.94-1.75(m,4H),1.48(br d,J＝8.6Hz ,2H),0.97-0.80(m,1H).
实施例22：化合物22Example 22: Compound 22
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluorin-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-4-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(300mg,0.321mmol,1eq)溶于二氧六环(2mL)和水(1mL)中，加入吡啶-4-基硼 酸(78.8mg,0.641mmol,2eq)、1,1-双(二叔丁基膦)二茂铁氯化钯(41.8mg,0.064mmol,0.2eq)和碳酸铯(313.4mg,0.962mmol,3eq)，氮气保护下，100℃反应2小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化[四氢呋喃/石油醚：0-50％]，得到产物(170mg，产率：54.2％)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 0.321mmol, 1eq) was dissolved in dioxane (2mL) and water ( 1 mL), add pyridin-4-ylboron acid (78.8mg, 0.641mmol, 2eq), 1,1-bis(di-tert-butylphosphino)ferrocenepalladium chloride (41.8mg, 0.064mmol, 0.2eq) and cesium carbonate (313.4mg, 0.962mmol, 3eq ), reacted at 100° C. for 2 hours under the protection of nitrogen. LCMS monitored the reaction to be complete. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by column [tetrahydrofuran/petroleum ether: 0-50%] to obtain the product (170 mg, yield: 54.2%) as a yellow solid.
MS m/z:978.6[M+H]+ MS m/z:978.6[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(170mg,0.174mmol,1eq)溶于二氧六环(2mL)中，加入盐酸二氧六环溶液(4M,1mL)，室温反应2小时，LCMS监测反应完全。反应液浓缩得到粗产品(145mg)，黄色固体，粗品直接用于下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl ) Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-4-yl)pyrido [4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (170mg, 0.174mmol, 1eq) dissolved in dioxane (2 mL), add dioxane hydrochloride solution (4M, 1 mL), react at room temperature for 2 hours, and the reaction is complete as monitored by LCMS. The reaction solution was concentrated to obtain the crude product (145 mg) as a yellow solid, which was used directly in the next step.
MS m/z:834.4[M+H]+ MS m/z:834.4[M+H] +
步骤3：化合物22Step 3: Compound 22
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-4-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluorin-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(145mg,0.174mmol,1eq)溶于N,N-二甲基甲酰胺(2mL)中，加入氟化铯(2.42g,15.90mmol, 91.51eq)，室温反应过夜。LCMS监测反应完全。反应液过滤，滤液经HPLC制备，得到产品(50mg，产率：42.5％)，白色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5 -((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (145mg, 0.174mmol, 1eq) was dissolved in N,N-dimethylformamide (2mL) and fluorinated Cesium (2.42g, 15.90mmol, 91.51eq), react overnight at room temperature. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain the product (50 mg, yield: 42.5%) as a white solid.
HPLC分离条件:HPLC separation conditions:
柱子:Phenomenex C18 80*30mm*5umColumn: Phenomenex C18 80*30mm*5um
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％:50％-70％，保留时间：15minMobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 50%-70%, retention time: 15min
MS m/z:678.2[M+H]+ MS m/z:678.2[M+H] +
19F NMR(377MHz,DMSO-d6)δ-110.13(s),-110.39(s),-110.62(s),-141.18(s),-142.00(s),-172.09(s),-172.21(s). 19 F NMR (377MHz,DMSO-d 6 )δ-110.13(s),-110.39(s),-110.62(s),-141.18(s),-142.00(s),-172.09(s),-172.21 (s).
1H NMR(400MHz,DMSO-d6)δ10.19(br s,1H),8.67(br d,J＝5.0Hz,2H),8.00(br s,1H),7.83-7.17(m,5H),5.31(br d,J＝54Hz,1H),4.94(br s,1H),4.25-4.04(m,2H),3.96-3.35(m,4H),3.20-2.95(m,5H),2.91-2.77(m,2H),2.22-1.98(m,3H),1.94-1.60(m,4H),1.45(br s,2H),0.96(br s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.19(br s,1H),8.67(br d,J=5.0Hz,2H),8.00(br s,1H),7.83-7.17(m,5H) ,5.31(br d,J=54Hz,1H),4.94(br s,1H),4.25-4.04(m,2H),3.96-3.35(m,4H),3.20-2.95(m,5H),2.91- 2.77(m,2H),2.22-1.98(m,3H),1.94-1.60(m,4H),1.45(br s,2H),0.96(br s,1H).
实施例23：化合物23Example 23: Compound 23
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-2-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluorin-2-ol
步骤1：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-2-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-2-yl) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1- 基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(300mg,0.320mmol,1eq)溶于二氧六环(5.0mL)，加入2-(三丁基甲锡烷基)吡啶(177.1mg,0.481mmol,1.5eq)，四三苯基膦钯(74.1mg,0.0641mmol,0.2eq)。氮气置换，100℃反应4小时。LCMS监测反应完全，反应液减压浓缩，残留物经柱纯化(四氢呋喃/石油醚：0-35％)，得到(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-2-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,产率：63.7％)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1- Base)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3 , 8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 0.320mmol, 1eq) was dissolved in dioxane (5.0mL) and 2-(tributylstannyl) was added Pyridine (177.1 mg, 0.481 mmol, 1.5 eq), tetrakistriphenylphosphine palladium (74.1 mg, 0.0641 mmol, 0.2 eq). Replaced with nitrogen, reacted at 100°C for 4 hours. LCMS monitored that the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-35%) to obtain (1R,5S)-tert-butyl-3-(8-fluoro-7-(7 -Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexa Hydrogen-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabis Cyclo[3.2.1]octane-8-carboxylate (200 mg, yield: 63.7%), yellow solid.
MS m/z:978.4[M+H]+ MS m/z:978.4[M+H] +
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-2-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡唑并[1,5-a]吡啶-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,0.204mol,1eq)溶于乙腈(2.0mL)，加入盐酸二氧六环溶液(4M,2mL)。室温反应1小时。LCMS监测反应完全，反应液减压浓缩，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-2-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(180mg，粗品)，黄色固体。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl )naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyrazolo[1,5- a]pyridin-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.204 mol, 1eq) was dissolved in acetonitrile (2.0mL), and dioxane hydrochloride solution (4M, 2mL) was added. React at room temperature for 1 hour. LCMS monitored that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-2-yl)pyrido[4,3-d]pyrimidine -7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (180 mg, crude), yellow solid.
MS m/z:834.4[M+H]+ MS m/z:834.4[M+H] +
步骤3：化合物23Step 3: Compound 23
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-2-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluorin-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-2-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(180mg,0.215mmol,1eq)溶于N,N-二甲基甲酰胺(3.0mL)，加入氟化铯(1.64g,10.79mmol,50eq)，氮气氛围下室温反应2小时。LCMS监测反应完全，反应液过滤，滤液经HPLC分离，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-2-基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(30mg,产率：20.5％)，黄色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5 -((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (180mg, 0.215mmol, 1eq) was dissolved in N,N-dimethylformamide (3.0mL) and added with fluoride Cesium (1.64g, 10.79mmol, 50eq) was reacted at room temperature under nitrogen atmosphere for 2 hours. LCMS monitored that the reaction was complete, the reaction solution was filtered, and the filtrate was separated by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8 -Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-2-yl)pyrido[4,3- d] Pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (30 mg, yield: 20.5%), yellow solid.
HPLC分离条件:HPLC separation conditions:
柱子:Phenomenex C18 75*30mm*3umColumn: Phenomenex C18 75*30mm*3um
流动相A：water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％：34％-74％，保留时间：9minMobile phase A: water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%: 34%-74%, retention time: 9min
MS m/z:678.3[M+H]+ MS m/z:678.3[M+H] +
19F NMR(376MHz,DMSO-d6)δ110.25(s),-142.43(s),-171.98(s),-172.19(s). 19 F NMR (376MHz, DMSO-d 6 ) δ110.25(s), -142.43(s), -171.98(s), -172.19(s).
1H NMR(400MHz,DMSO-d6)δ10.19(br s,1H),8.58(d,J＝4.5Hz,1H),8.08-7.89(m,3H),7.58-7.39(m,3H),7.38-7.15(m,1H),5.30(br d,J＝53.6Hz,1H),4.96(br s,1H),4.23-3.98(m,2H),3.82-3.60(m,1H),3.53-3.36(m,2H),3.16-2.91(m,5H),2.89-2.73(m,2H),2.21-1.98(m,3H),1.93-1.73(m,3H),1.71-1.31(m,4H),0.98(br s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ10.19(br s,1H),8.58(d,J=4.5Hz,1H),8.08-7.89(m,3H),7.58-7.39(m,3H) ,7.38-7.15(m,1H),5.30(br d,J=53.6Hz,1H),4.96(br s,1H),4.23-3.98(m,2H),3.82-3.60(m,1H),3.53 -3.36(m,2H),3.16-2.91(m,5H),2.89-2.73(m,2H),2.21-1.98(m,3H),1.93-1.73(m,3H),1.71-1.31(m, 4H), 0.98(br s, 1H).
实施例24：化合物24Example 24: Compound 24
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(羟甲基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(hydroxymethyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphthalene-2-ol
步骤1：甲基4-((1R,5S)-8-(叔-丁氧羰基)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-7-(7-氟-3-(甲氧 基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-甲酸基酯
Step 1: Methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro- 7-(7-fluoro-3-(methoxy methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazine- 7a-yl)methoxy)pyrido[4,3-d]pyrimidine-5-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(500mg,0.454mmol,1eq)溶于甲醇(10mL)中,加三乙胺(137.90mg,1.36mmol,3eq)和1,1-双(二苯基磷)二茂铁氯化钯(66.5mg,0.0909mmol,0.2eq)。氮气置换，反应在一氧化碳(50Psi)氛围下80℃反应过夜。LCMS监测反应完全，反应液过滤，滤液浓缩，残留物经柱纯化(四氢呋喃/石油醚：0-30％)得到甲基4-((1R,5S)-8-(叔-丁氧羰基)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-甲酸基酯(300mg,产率：68.9％)，黄色固体。(1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.454 mmol, 1 eq) was dissolved in methanol (10 mL), and triethylamine was added (137.90mg, 1.36mmol, 3eq) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (66.5mg, 0.0909mmol, 0.2eq). Nitrogen replacement, the reaction was carried out overnight at 80° C. under a carbon monoxide (50 Psi) atmosphere. LCMS monitored that the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to obtain methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)- 3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triiso Propylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4 ,3-d]pyrimidine-5-carboxylate (300 mg, yield: 68.9%), yellow solid.
MS m/z:959.4[M+H]+ MS m/z:959.4[M+H] +
步骤2：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(羟甲基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 2: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(hydroxymethyl)pyrido [4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将甲基4-((1R,5S)-8-(叔-丁氧羰基)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-甲酸基酯(200mg,0.209mmol,1eq)溶于四氢呋喃(5.0mL)中，氮气置换。-70℃缓慢滴加二异丁基氢化铝(1M,1.04mL,5eq)，滴加完毕后缓慢升至室温，室温反应过夜。LCMS监测反应完全，反应液用十水硫酸钠淬灭。无水硫酸钠干燥，过滤，滤液浓缩，残留物经柱纯化(四氢呋 喃/石油醚：0-30％)，得到(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(羟甲基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(70mg，产率：36.1％)，黄色固体。Methyl 4-((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-7- (7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-5-carboxylate (200mg, 0.209mmol, 1eq) was dissolved in tetrahydrofuran (5.0mL) , nitrogen replacement. Diisobutylaluminum hydride (1M, 1.04mL, 5eq) was slowly added dropwise at -70°C. After the dropwise addition was completed, it was slowly raised to room temperature and reacted at room temperature overnight. The completion of the reaction was monitored by LCMS, and the reaction solution was quenched with sodium sulfate decahydrate. Dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by column (THF Fran/petroleum ether: 0-30%) to obtain (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-( (Triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)- 5-(Hydroxymethyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (70 mg, yield : 36.1%), yellow solid.
MS m/z:931.7[M+H]+ MS m/z:931.7[M+H] +
步骤3：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(羟甲基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 3: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS) -2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(hydroxymethyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5 -((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(羟甲基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(60mg,0.0644mmol,1eq)溶于乙腈(3.0mL)中，加入盐酸二氧六环溶液(4M,1.6mL)，室温反应1小时。LCMS监测反应完全，反应液浓缩得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(羟甲基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(55mg,粗品)，黄色固体。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl )naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(hydroxymethyl)pyrido[4 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.0644 mmol, 1 eq) was dissolved in acetonitrile (3.0 mL) , add dioxane hydrochloride solution (4M, 1.6mL) and react at room temperature for 1 hour. LCMS monitored that the reaction was complete, and the reaction solution was concentrated to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-( ((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(hydroxymethyl)pyrido[4,3-d]pyrimidin-7-yl) -6-Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (55 mg, crude product), yellow solid.
MS m/z:787.4[M+H]+ MS m/z:787.4[M+H] +
步骤4：化合物24Step 4: Compound 24
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(羟甲基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(hydroxymethyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphthalene-2-ol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(羟甲基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(55mg,0.0668mmol,1eq),溶于N,N-二甲基甲酰胺(3.0mL)中，加入(507.3mg,3.34mmol,50eq),室 温反应1小时。LCMS监测反应完全。反应液过滤，滤液经HPLC分离得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(羟甲基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚(6.6mg，产率：15.7％),黄色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(hydroxymethyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-( (Triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (55mg, 0.0668mmol, 1eq), dissolved in N,N-dimethylformamide (3.0mL), added (507.3 mg, 3.34mmol, 50eq), room Warm reaction for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was separated by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-( ((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(hydroxymethyl)pyrido[4,3-d]pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalene-2-ol (6.6 mg, yield: 15.7%), yellow solid.
HPLC分离条件:HPLC separation conditions:
柱子:YMC-Triart Prep C18 150*40mm*7umColumn: YMC-Triart Prep C18 150*40mm*7um
流动相A：Water(NH3H2O+NH4HCO3)，流动相B：ACN；梯度B％：24％-64％，保留时间：9minMobile phase A: Water (NH3H2O+NH4HCO3), mobile phase B: ACN; Gradient B%: 24%-64%, retention time: 9min
MS m/z:631.4[M+H]+ MS m/z:631.4[M+H] +
19F NMR(377MHz,DMSO-d6)δ-110.61(s),-110.70(s),-143.93(s),-172.06(s),-172.16(s). 19 F NMR (377MHz, DMSO-d 6 )δ-110.61(s),-110.70(s),-143.93(s),-172.06(s),-172.16(s).
1H NMR(400MHz,DMSO-d6)δ7.98(dd,J＝6.0,9.2Hz,1H),7.47(t,J＝9.0Hz,1H),7.40(d,J＝2.4Hz,1H),7.26(br s,1H),5.28(br d,J＝54.0Hz,1H),4.78-4.28(m,3H),4.19-3.95(m,2H),3.87-3.56(m,8H),3.15-2.95(m,3H),2.87-2.78(m,1H),2.17-1.93(m,4H),1.90-1.50(m,6H). 1 H NMR (400MHz, DMSO-d 6 )δ7.98(dd, J=6.0,9.2Hz,1H),7.47(t,J=9.0Hz,1H),7.40(d,J=2.4Hz,1H) ,7.26(br s,1H),5.28(br d,J=54.0Hz,1H),4.78-4.28(m,3H),4.19-3.95(m,2H),3.87-3.56(m,8H),3.15 -2.95(m,3H),2.87-2.78(m,1H),2.17-1.93(m,4H),1.90-1.50(m,6H).
实施例25：化合物25Example 25: Compound 25
4-(5-(氨基甲基)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
4-(5-(aminomethyl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(( (2R,7aS)-2-Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoro Naphthalene-2-ol
步骤1：(1R,5S)-叔丁基-3-(5-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(5-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-Diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(0.2g,0.216mmol,1eq)溶于N,N-二甲基甲酰胺(5mL)中，加入氟化铯(984.07 mg,6.48mmol,30eq)，室温反应1小时。LCMS监测反应完全。反应过滤浓缩得到(1R,5S)-叔丁基-3-(5-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(0.2g,粗品)，棕色油状。(1R,5S)-tert-butyl-3-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethyl Silyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3- d] pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.2g, 0.216mmol, 1eq) dissolved in N,N-dimethylformaldehyde Amide (5mL), add cesium fluoride (984.07 mg, 6.48mmol, 30eq), react at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction was filtered and concentrated to obtain (1R,5S)-tert-butyl-3-(5-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl) -8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) -3,8-Diazabicyclo[3.2.1]octane-8-carboxylate (0.2 g, crude), brown oil.
MS m/z:770.4[M+H]+ MS m/z:770.4[M+H] +
步骤2：(1R,5S)-叔丁基-3-(5-(氨基甲基)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 2: (1R,5S)-tert-butyl-3-(5-(aminomethyl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1- Base)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4- base)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(0.2g,0.260mmol,1eq)和雷尼镍(22.26mg,0.260mmol,1eq)溶于二氧六环(5mL)中，反应液于氢气(45psi)氛围下60℃反应过夜。LCMS监测反应完全。反应液过滤浓缩，残留物经柱层析纯化(甲醇/二氯甲烷：0-10％)，得到(1R,5S)-叔丁基-3-(5-(氨基甲基)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(0.08g,产率：39.6％)，黄色固体。(1R,5S)-tert-butyl-3-(5-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3, 8-diazabicyclo[3.2.1]octane-8-carboxylate (0.2g, 0.260mmol, 1eq) and Raney nickel (22.26mg, 0.260mmol, 1eq) were dissolved in dioxane (5mL ), the reaction solution was reacted overnight at 60° C. under a hydrogen (45 psi) atmosphere. LCMS monitored the reaction to be complete. The reaction solution was concentrated by filtration, and the residue was purified by column chromatography (methanol/dichloromethane: 0-10%) to obtain (1R,5S)-tert-butyl-3-(5-(aminomethyl)-7-( 8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrroline Azin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.08 g, yield: 39.6%), yellow solid.
MS m/z:778.5[M+H]+ MS m/z:778.5[M+H] +
步骤3：化合物25Step 3: Compound 25
4-(5-(氨基甲基)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
4-(5-(aminomethyl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(( (2R,7aS)-2-Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoro Naphthalene-2-ol
将(1R,5S)-叔丁基-3-(5-(氨基甲基)-7-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2- 氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(0.08g,0.103mmol,1eq)溶于二氯甲烷(3mL)中，加入三氟乙酸(1mL)，氮气置换后，室温反应1小时。LCMS监测反应完全。反应液浓缩，残留物经HPLC纯化，得到4-(5-(氨基甲基)-4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚(20mg，产率：30.7％)，白色固体。(1R,5S)-tert-butyl-3-(5-(aminomethyl)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl) -8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-Carboxylate (0.08g, 0.103mmol, 1eq) was dissolved in dichloromethane (3mL), added trifluoroacetic acid (1mL), replaced with nitrogen, and reacted at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by HPLC to obtain 4-(5-(aminomethyl)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3- Base)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-7- (1)-5-ethyl-6-fluoronaphthalen-2-ol (20 mg, yield: 30.7%), white solid.
HPLC分离条件:HPLC separation conditions:
柱子:Phenomenex C18 80*30mm*5umColumn: Phenomenex C18 80*30mm*5um
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％：45％-65％，保留时间：10minMobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 45%-65%, retention time: 10min
MS m/z:634.4[M+H]+ MS m/z:634.4[M+H] +
19F NMR(376MHz,DMSO-d6)δ-119.59(s),-143.17(s),-144.39(s),-172.17(s). 19 F NMR (376MHz, DMSO-d 6 )δ-119.59(s),-143.17(s),-144.39(s),-172.17(s).
1H NMR(400MHz,DMSO-d6)δ7.76(dd,J＝6.1,9.0Hz,1H),7.37-7.31(m,2H),7.12(br s,1H),5.28(br d,J＝54.0Hz,1H),4.61-4.23(m,3H),4.22-3.97(m,4H),3.94-3.67(m,4H),3.09(br d,J＝7.7Hz,3H),3.05-2.97(m,2H),2.90-2.76(m,2H),2.12(br s,1H),2.05-1.95(m,3H),1.87-1.73(m,4H),1.53(br s,3H),0.69(br t,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.76 (dd, J=6.1, 9.0Hz, 1H), 7.37-7.31 (m, 2H), 7.12 (br s, 1H), 5.28 (br d, J ＝54.0Hz,1H),4.61-4.23(m,3H),4.22-3.97(m,4H),3.94-3.67(m,4H),3.09(br d,J＝7.7Hz,3H),3.05-2.97 (m,2H),2.90-2.76(m,2H),2.12(br s,1H),2.05-1.95(m,3H),1.87-1.73(m,4H),1.53(br s,3H),0.69 (br t,J=7.1Hz,3H).
实施例26：化合物26Example 26: Compound 26
4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-甲酰胺
4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-5- Formamide
步骤1：(1R,5S)-叔丁基-3-(5-氨基羰基-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(5-aminocarbonyl-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-Diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(10.0mg,0.0108mmol,1eq)溶于二甲基亚砜(0.5mL)中，加入过氧化氢(12.0mg,0.106mmol,0.0102mL,30％含量,9.80eq)和碳酸钾(10.0mg,0.0724mmol,6.70eq)，室温反应3小时。LCMS监测反应完全。加入饱和亚硫酸钠水溶液淬灭反应，加水稀释，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经TLC板分离(石油醚:四氢呋喃＝1:1)得到产物(8mg,产率：94.0％),无色油状物。(1R,5S)-tert-butyl-3-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethyl Silyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3- d] pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10.0mg, 0.0108mmol, 1eq) was dissolved in dimethyl sulfoxide (0.5mL ), add hydrogen peroxide (12.0mg, 0.106mmol, 0.0102mL, 30% content, 9.80eq) and potassium carbonate (10.0mg, 0.0724mmol, 6.70eq), and react at room temperature for 3 hours. LCMS monitored the reaction to be complete. The reaction was quenched by adding saturated aqueous sodium sulfite solution, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was separated by TLC plate (petroleum ether: tetrahydrofuran = 1:1) to obtain the product (8 mg, yield: 94.0%) as a colorless oil.
MS m/z:788.4[M+H]+ MS m/z:788.4[M+H] +
步骤2：化合物26Step 2: Compound 26
4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-甲酰胺
4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Base)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-5- Formamide
将(1R,5S)-叔丁基-3-(5-氨基羰基-7-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(10.0mg,0.0127mmol,1eq)溶于乙腈(1mL)中加入盐酸乙酸乙酯溶液(4M,0.5mL)，室温反应8小时。LCMS监测反应完全。将反应液浓缩，残余物经HPLC纯化得到4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-甲酰胺(3mg,产率：33.8％)，白色固体。(1R,5S)-tert-butyl-3-(5-aminocarbonyl-7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3, 8-diazabicyclo[3.2.1]octane-8-carboxylate (10.0mg, 0.0127mmol, 1eq) was dissolved in acetonitrile (1mL) and hydrochloric acid ethyl acetate solution (4M, 0.5mL) was added at room temperature React for 8 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by HPLC to obtain 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl- 7-Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidine-5-carboxamide (3 mg, yield: 33.8%), white solid.
MS m/z:644.3[M+H]+ MS m/z:644.3[M+H] +
HPLC分离条件:HPLC separation conditions:
柱子:Boston Prime C18 150*30mm*5um； Column: Boston Prime C18 150*30mm*5um;
流动相A：Water(NH3H2O+NH4HCO3)，流动相B：ACN；梯度B％:34％-64％保留时间：10minMobile phase A: Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; Gradient B%: 34%-64% Retention time: 10min
19F NMR(376MHz,DMSO-d6)δ-110.38(s),-138.24(s),-172.10(s),-172.16(s). 19 F NMR (376MHz, DMSO-d 6 )δ-110.38(s),-138.24(s),-172.10(s),-172.16(s).
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),7.99(dd,J＝6.0,9.0Hz,1H),7.83(s,1H),7.61(br s,1H),7.48(t,J＝8.9Hz,1H),7.41(d,J＝2.5Hz,1H),7.27(br s,1H),5.29(br d,J＝52.8Hz,1H),4.19-3.95(m,2H),3.74(br s,1H),3.56-3.43(m,1H),3.29-2.97(m,9H),2.90-2.77(m,1H),2.09-1.96(m,3H),1.91-1.73(m,4H),1.57(br s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ10.18(s,1H),7.99(dd,J=6.0,9.0Hz,1H),7.83(s,1H),7.61(br s,1H),7.48 (t,J=8.9Hz,1H),7.41(d,J=2.5Hz,1H),7.27(br s,1H),5.29(br d,J=52.8Hz,1H),4.19-3.95(m, 2H),3.74(br s,1H),3.56-3.43(m,1H),3.29-2.97(m,9H),2.90-2.77(m,1H),2.09-1.96(m,3H),1.91-1.73 (m,4H),1.57(br s,3H).
实施例27：化合物27Example 27: Compound 27
3-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)-1,2,4-噁二唑-5(4H)-酮
3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene -1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine -5-yl)-1,2,4-oxadiazol-5(4H)-one
步骤1：(1R,5S)-叔丁基-3-(5-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯
Step 1: (1R,5S)-tert-butyl-3-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl ylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氯-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.0g,1.07mmol,1eq)溶于N,N-二甲基甲酰胺(20mL)中，加入氰化锌(627.6mg,5.34mmol,5eq)、1,1-双(二苯基膦基)二茂铁(237.0mg,0.428mmol,0.4eq)和三(二亚苄基丙酮)钯(391.5mg,0.428mmol,0.4eq)，氮气保护下，110℃反应1小时。LCMS监测反应完全。反应液加水淬灭，过滤。滤液用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化[四氢呋喃/石油醚：0-30％]，得到产物(780mg，产率：78.7％)，黄色固体。 (1R,5S)-tert-butyl-3-(5-chloro-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilane Base) ethynyl) naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0g, 1.07mmol, 1eq) dissolved in N,N-dimethylformamide (20mL), add zinc cyanide (627.6mg, 5.34mmol, 5eq), 1,1-bis(diphenylphosphino)ferrocene (237.0mg, 0.428mmol, 0.4eq) and tris(diphenylene Proxylacetonate) palladium (391.5mg, 0.428mmol, 0.4eq), under the protection of nitrogen, react at 110°C for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was quenched with water and filtered. The filtrate was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by column [tetrahydrofuran/petroleum ether: 0-30%] to obtain the product (780 mg, yield: 78.7%) as a yellow solid.
MS m/z:926.5[M+H]+ MS m/z:926.5[M+H] +
步骤2：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-((Z)-N'-羟基氨基甲亚胺酰基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯
Step 2: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-((Z)-N' -Hydroxyaminocarbaimidoyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5-氰基-8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(0.20g,0.216mmol,1eq)溶于乙醇(10mL)中，缓慢滴加盐酸羟胺(30mg,0.432mmol,2eq)和碳酸氢钠(54.4mg,0.648mmol,3eq)的水溶液(1mL)，室温条件反应2小时。LCMS监测反应完全。反应液用水和乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经HPLC制备，得到粗产品(200mg)，黄色固体。(1R,5S)-tert-butyl-3-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethyl Silyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3- d] pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.20g, 0.216mmol, 1eq) was dissolved in ethanol (10mL), slowly drop Add hydroxylamine hydrochloride (30mg, 0.432mmol, 2eq) and aqueous solution (1mL) of sodium bicarbonate (54.4mg, 0.648mmol, 3eq), and react at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was extracted with water and ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated and the residue was prepared by HPLC to give the crude product (200 mg) as a yellow solid.
MS m/z:959.5[M+H]+ MS m/z:959.5[M+H] +
步骤3：(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(5-氧亚基-4,5-二氢-1,2,4-噁二唑-3-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 3: (1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) Ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(5-oxoylidene- 4,5-dihydro-1,2,4-oxadiazol-3-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(-N'-羟基氨基甲亚胺酰基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(200mg,0.209mmol,1eq)溶于乙腈(1.5mL)中，缓慢滴加1.8-二氮杂二环[5.4.0]十一烷-7-烯(119.0mg,0.782mmol,3.75eq)和1,1-羰基二咪唑(33.81mg,0.209mmol,1eq),氮气保护下，0℃反应1小时。LCMS监测反应完全。反应液加入饱和氯化铵水溶液(10 mL)淬灭，过滤，乙腈萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经HPLC制备，得到产品(100mg，产率：64.9％)，黄色固体。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl ) Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(-N'-hydroxylaminomethylidene Aminoyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.209mmol, 1eq) In acetonitrile (1.5mL), 1.8-diazabicyclo[5.4.0]undec-7-ene (119.0mg, 0.782mmol, 3.75eq) and 1,1-carbonyldiimidazole (33.81 mg, 0.209mmol, 1eq), under nitrogen protection, react at 0°C for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was added saturated aqueous ammonium chloride (10 mL), filtered, extracted with acetonitrile, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was prepared by HPLC to obtain the product (100 mg, yield: 64.9%) as a yellow solid.
MS m/z:985.6[M+H]+ MS m/z:985.6[M+H] +
HPLC分离条件:HPLC separation conditions:
柱子:Boston Uni C18 40*150*5um；Column: Boston Uni C18 40*150*5um;
流动相A：Water(FA)，流动相：ACN；梯度B％：46％-76％，保留时间：10minMobile phase A: Water (FA), mobile phase: ACN; Gradient B%: 46%-76%, retention time: 10min
步骤4：3-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-7-(7-氟-3-羟基-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)-1,2,4-噁二唑-5(4H)-酮的盐酸盐Step 4: 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3- Hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)pyrido[4,3-d]pyrimidin-5-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(8-氟-7-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(吡啶-4-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(30mg,0.030mmol,1eq)溶于二氧六环(4mL)中，加入盐酸二氧六环溶液(4M,1mL)，室温反应过夜。LCMS监测反应完全。反应液浓缩得到产品(30mg，粗品)，黄色油状物，粗品直接用于下一步。(1R,5S)-tert-butyl-3-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl ) Naphthalene-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(pyridin-4-yl)pyrido [4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30mg, 0.030mmol, 1eq) dissolved in dioxane (4mL), add dioxane hydrochloride solution (4M, 1mL) and react overnight at room temperature. LCMS monitored the reaction to be complete. The reaction solution was concentrated to obtain the product (30 mg, crude product) as a yellow oil, and the crude product was directly used in the next step.
MS m/z:841.5[M+H]+ MS m/z:841.5[M+H] +
步骤5：化合物27Step 5: Compound 27
3-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)-1,2,4-噁二唑-5(4H)-酮
3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene -1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine -5-yl)-1,2,4-oxadiazol-5(4H)-one
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基) 甲氧基)-5-(吡啶-4-基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(30mg,0.036mmol,1eq)溶于N,N-二甲基甲酰胺(4mL)中，加入氟化铯(0.5g,3.29mmol,92.28eq)，室温反应1小时。LCMS监测反应完全。反应液过滤，滤液经HPLC制备，得到产品(20mg，产率：81.9％)，类白色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)-5-(pyridin-4-yl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene -2-Phenol hydrochloride (30mg, 0.036mmol, 1eq) was dissolved in N,N-dimethylformamide (4mL), cesium fluoride (0.5g, 3.29mmol, 92.28eq) was added, and the reaction was carried out at room temperature for 1 Hour. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain the product (20 mg, yield: 81.9%) as an off-white solid.
HPLC分离条件:HPLC separation conditions:
柱子:Phenomenex C18 75*30mm*3umColumn: Phenomenex C18 75*30mm*3um
流动相A：Water(FA)，流动相B：ACN；梯度B％:0％-40％；保留时间：9minMobile phase A: Water (FA), mobile phase B: ACN; gradient B%: 0%-40%; retention time: 9min
MS m/z:685.2[M+H]+ MS m/z:685.2[M+H] +
19F NMR(377MHz,DMSO-d6)δ-110.62(s),-141.11(s),-141.31(s),-141.48(s),-172.19(s). 19 F NMR (377MHz, DMSO-d 6 )δ-110.62(s),-141.11(s),-141.31(s),-141.48(s),-172.19(s).
1H NMR(400MHz,DMSO-d6)δ10.25(br s,1H),8.15(s,1H),8.00(dd,J＝6.0,9.0Hz,1H),7.49(t,J＝8.9Hz,1H),7.41(d,J＝2.3Hz,1H),7.27(br s,1H),5.30(br d,J＝53.6Hz,1H),4.21-4.03(m,2H),4.01-3.82(m,2H),3.77(s,1H),3.25-3.03(m,8H),2.90-2.81(m,1H),2.19-1.66(m,10H). 1 H NMR (400MHz,DMSO-d 6 )δ10.25(br s,1H),8.15(s,1H),8.00(dd,J=6.0,9.0Hz,1H),7.49(t,J=8.9Hz ,1H),7.41(d,J=2.3Hz,1H),7.27(br s,1H),5.30(br d,J=53.6Hz,1H),4.21-4.03(m,2H),4.01-3.82( m,2H),3.77(s,1H),3.25-3.03(m,8H),2.90-2.81(m,1H),2.19-1.66(m,10H).
实施例28：化合物28Example 28: Compound 28
4,4'-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5,7-二基)二(5-乙炔基-6-氟萘-2-酚)
4,4'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5,7-diyl)bis(5-ethynyl-6 -fluoronaphthalene-2-ol)
步骤1：叔丁基-(1R,5S)-3-(7-氯-8-氟-5-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯
Step 1: tert-butyl-(1R,5S)-3-(7-chloro-8-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl Silyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidazin-7a(5H)-yl)methoxy)pyrido[ 4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
在100mL反应瓶中，将叔丁基-3-(5,7-二氯-8-氟-2-((2R，7aS)-2-氟四氢-1H-吡咯啉-7a(5H)-基)甲 氧基)吡啶[4,3-d]嘧啶-4-基)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸酯(2g,3.42mmol,1eq)溶于甲苯(25mL)中，加入((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3-二氧戊环-2-基)萘-1-基)乙炔基)三异丙基硅烷(3.5g,6.84mmol,2eq)，四三苯基膦钯(791mg,0.684mmol,0.2eq)，再加入氢氧化钠(410mg,10.26mmol,3eq)溶于水(5mL)中的水溶液，置换氮气，自然升到100℃反应4小时。LCMS监测反应完成。反应液加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/二氯甲烷：0-100％)，得到叔丁基-(1R,5S)-3-(7-氯-8-氟-5-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(340mg,产率：10.63％)，黄色固体。In a 100mL reaction flask, tert-butyl-3-(5,7-dichloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)- Base) A Oxy)pyridin[4,3-d]pyrimidin-4-yl)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (2g, 3.42mmol, 1eq) dissolved in toluene (25mL), add ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl )naphthalene-1-yl)ethynyl)triisopropylsilane (3.5g, 6.84mmol, 2eq), tetrakistriphenylphosphine palladium (791mg, 0.684mmol, 0.2eq), then add sodium hydroxide (410mg, 10.26 mmol, 3eq) was dissolved in water (5mL) in an aqueous solution, nitrogen was replaced, and the reaction was naturally raised to 100°C for 4 hours. LCMS monitored the completion of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column (ethyl acetate/dichloromethane: 0-100%) to obtain tert-butyl-(1R,5S)-3-(7-chloro-8-fluoro-5-( 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolidinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] Octane-8-carboxylate (340 mg, yield: 10.63%), yellow solid.
MS m/z:935.3[M+H]+ MS m/z:935.3[M+H] +
步骤2：叔丁基-(1R,5S)-3-(8-氟-5,7-二(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯
Step 2: tert-butyl-(1R,5S)-3-(8-fluoro-5,7-bis(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethyl Silyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
将叔丁基-(1R,5S)-3-(7-氯-8-氟-5-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(600mg,0.642mmol,1eq)溶于甲苯(10mL)和水(2mL)中，加入((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)乙炔基)三异丙基硅烷(987mg,1.927mmol,3eq)，四三苯基磷钯(148mg,0.128mmol,0.2eq)，氢氧化钠(103mg,2.568mmol,4eq)，100℃搅拌反应4小时，LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物制备板纯化(甲醇/二氯甲烷：9％)，得到叔丁基-(1R,5S)-3-(8-氟-5,7-二(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(350mg,产率：42.4％)，淡黄色固体。Tert-butyl-(1R,5S)-3-(7-chloro-8-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl Base) ethynyl) naphthalene-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidazin-7a(5H)-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600 mg, 0.642 mmol, 1 eq) was dissolved in toluene (10 mL) and water ( 2mL), add ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)naphthalene-1-yl)ethynyl)triisopropylsilane (987mg, 1.927mmol, 3eq), tetrakistriphenylphosphopalladium (148mg, 0.128mmol, 0.2eq), sodium hydroxide (103mg, 2.568mmol , 4eq), the reaction was stirred at 100°C for 4 hours, and the reaction was completed by LCMS monitoring. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by preparative plates (methanol/dichloromethane: 9%) to give tert-butyl-(1R,5S)-3-(8-fluoro-5,7-bis(7-fluoro-3 -(Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Carboxylate (350 mg, yield: 42.4%), pale yellow solid.
MS m/z:1285.5[M+H]+ MS m/z:1285.5[M+H] +
步骤3：4,4'-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5,7-二基)二(6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚)的盐酸盐 Step 3: 4,4'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5,7-diyl)bis(6-fluoro -5-((triisopropylsilyl)ethynyl)naphthalene-2-ol) hydrochloride
的盐酸盐 hydrochloride
将叔丁基-(1R,5S)-3-(8-氟-5,7-二(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(300mg,0.233mmol,1eq)溶于乙腈(5mL)中，加入盐酸/1,4-二氧六环(4M,5ml)，室温反应2小时。LCMS监测反应完全。反应液浓缩，得到4,4'-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5,7-二基)二(6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚)的盐酸盐(200mg,产率：78.3％)，黄色固体。tert-butyl-(1R,5S)-3-(8-fluoro-5,7-bis(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl )ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 0.233mmol, 1eq) was dissolved in acetonitrile (5mL) and hydrochloric acid was added /1,4-dioxane (4M, 5ml), react at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated to obtain 4,4'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(( (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5,7-diyl)bis(6 -Fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol) hydrochloride (200 mg, yield: 78.3%), yellow solid.
MS m/z:1097.5[M+H]+ MS m/z:1097.5[M+H] +
步骤4：化合物28Step 4: Compound 28
4,4'-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5,7-二基)二(5-乙炔基-6-氟萘-2-酚)
4,4'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5,7-diyl)bis(5-ethynyl-6 -fluoronaphthalene-2-ol)
将4,4'-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5,7-二基)二(6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚)的盐酸盐(180mg,0.164mmol,1eq)溶于N,N-二甲基甲酰胺(3mL)中，加入盐酸氟化铯(622mg,4.1mmol,25eq)，室温反应16小时。LCMS监测反应完全。制备色谱纯化，得到4,4'-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5,7-二基)二(5-乙炔基-6-氟萘-2-酚)(30mg,产率：23.3％)，黄色固体。4,4'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5,7-diyl)bis(6-fluoro-5 -((triisopropylsilyl)ethynyl)naphthalene-2-ol) hydrochloride (180mg, 0.164mmol, 1eq) was dissolved in N,N-dimethylformamide (3mL), added hydrochloric acid Cesium fluoride (622mg, 4.1mmol, 25eq), react at room temperature for 16 hours. LCMS monitored the reaction to be complete. Purification by preparative chromatography afforded 4,4'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-5,7-diyl)bis(5 -ethynyl-6-fluoronaphthalene-2-ol) (30 mg, yield: 23.3%), yellow solid.
HPLC分离条件:HPLC separation conditions:
柱子:Phenomenex C18 80*40mm*3um； Column: Phenomenex C18 80*40mm*3um;
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％:25％-65％；保留时间：9minMobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%: 25%-65%; retention time: 9min
MS m/z:785[M+H]+ MS m/z:785[M+H] +
19F NMR(377MHz,DMSO-d6)δ-172.10(s),-141.79(s),-110.90(s),-110.47(s). 19 F NMR (377MHz, DMSO-d 6 )δ-172.10(s),-141.79(s),-110.90(s),-110.47(s).
1H NMR(400MHz,DMSO-d6)δ7.93(dt,J＝10.0,5.8Hz,1H),7.45-7.33(m,5H),7.10(s,1H),5.32(d,J＝54.2Hz,1H),4.53(s,2H),4.28-4.06(m,3H),3.91-3.82(m,2H),3.62(d,J＝6.1Hz,1H),3.15-3.06(m,4H),2.91-2.86(m,2H),2.56(s,1H),2.21-2.04(m,3H),1.94-1.77(m,4H),1.42(s,3H). 1 H NMR (400MHz, DMSO-d6) δ7.93 (dt, J = 10.0, 5.8Hz, 1H), 7.45-7.33 (m, 5H), 7.10 (s, 1H), 5.32 (d, J = 54.2Hz ,1H),4.53(s,2H),4.28-4.06(m,3H),3.91-3.82(m,2H),3.62(d,J=6.1Hz,1H),3.15-3.06(m,4H), 2.91-2.86(m,2H),2.56(s,1H),2.21-2.04(m,3H),1.94-1.77(m,4H),1.42(s,3H).
实施例29:化合物29Embodiment 29: Compound 29
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolidinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)-5-ethynyl-6-fluoronaphthalene -2-phenol
步骤1：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐Step 1: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)-6-fluoro-5- ((Triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
的盐酸盐 hydrochloride
将叔丁基-(1R,5S)-3-(7-氯-8-氟-5-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(900mg,0.96mmol,1eq)(参考实施例28步骤1的产物制备)溶于乙腈(5mL)中，加入盐酸/1,4-二氧六环(4M,5ml)，室温反应2小时。LCMS监测反应完全。反应液浓缩，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(1g,产率：100％)，淡黄色固体。 Tert-butyl-(1R,5S)-3-(7-chloro-8-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl Base) ethynyl) naphthalene-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidazin-7a(5H)-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (900mg, 0.96mmol, 1eq) (the product of step 1 of reference example 28 Preparation) was dissolved in acetonitrile (5 mL), added hydrochloric acid/1,4-dioxane (4M, 5 ml), and reacted at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated to give 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)-6-fluoro- Hydrochloride salt of 5-((triisopropylsilyl)ethynyl)naphthalene-2-ol (1 g, yield: 100%), pale yellow solid.
MS m/z:791[M+H]+ MS m/z:791[M+H] +
步骤2：化合物29Step 2: Compound 29
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)-5-乙炔基-6-氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolidinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)-5-ethynyl-6-fluoronaphthalene -2-phenol
将4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)-6-氟-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚的盐酸盐(240mg,0.278mmol,1eq)溶于N,N-二甲基甲酰胺(2mL)中，加入氟化铯(1.05g,6.95mmol,25eq)，室温反应16小时。LCMS监测反应完全。制备色谱纯化，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)-5-乙炔基-6-氟萘-2-酚(25mg,产率：14.2％)，黄色固体。4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)-6-fluoro-5-( Triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (240mg, 0.278mmol, 1eq) was dissolved in N,N-dimethylformamide (2mL), cesium fluoride (1.05 g, 6.95mmol, 25eq), react at room temperature for 16 hours. LCMS monitored the reaction to be complete. Purification by preparative chromatography afforded 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)-5-ethynyl -6-fluoronaphthalen-2-ol (25 mg, yield: 14.2%), yellow solid.
HPLC分离条件:HPLC separation conditions:
柱子:Phenomenex C18 80*40mm*3um；Column: Phenomenex C18 80*40mm*3um;
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN，梯度B％：25％-65％；保留时间：9min.Mobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN, gradient B%: 25%-65%; retention time: 9min.
MS m/z:635[M+H]+ MS m/z:635[M+H] +
19F NMR(377MHz,DMSO-d6)δ-172.14(s),-139.46(s),-109.96(s). 19 F NMR (377MHz, DMSO-d 6 )δ-172.14(s),-139.46(s),-109.96(s).
1H NMR(400MHz,DMSO-d6)δ8.00(dd,J＝9.2,5.9Hz,1H),7.50(t,J＝9.0Hz,1H),7.38(d,J＝2.6Hz,1H),7.01(s,1H),5.36-5.21(m,1H),4.39(s,1H),4.22-4.03(m,2H),3.76(d,J＝12.0Hz,1H),3.45(br,3H),3.15-3.06(m,2H),3.02(d,J＝2.6Hz,1H),2.90-2.81(m,2H),2.15-2.00(m,3H),1.90-1.75(m,4H),1.37(s,3H). 1 H NMR (400MHz, DMSO-d6) δ8.00 (dd, J=9.2,5.9Hz, 1H), 7.50(t, J=9.0Hz, 1H), 7.38(d, J=2.6Hz, 1H), 7.01(s,1H),5.36-5.21(m,1H),4.39(s,1H),4.22-4.03(m,2H),3.76(d,J＝12.0Hz,1H),3.45(br,3H) ,3.15-3.06(m,2H),3.02(d,J＝2.6Hz,1H),2.90-2.81(m,2H),2.15-2.00(m,3H),1.90-1.75(m,4H),1.37 (s,3H).
实施例30：化合物30Example 30: Compound 30
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)-5,6-二氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)-5,6-difluoronaphthalen-2-ol
步骤1：(1R,5S)-叔丁基-3-(7-氯-5-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(7-chloro-5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5,7-二氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1060mg,1.81mmol,1eq)溶于二氧六环(10mL)和水(5mL)中，加入2-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环(697.4mg,1.99mmol,1.1eq),碳酸铯(1.18g,3.62mmol,2eq)，1,1-双(二苯基磷)二茂铁氯化钯(132.5mg,0.181mmol,0.1eq)，氮气保护，80℃反应1小时。LCMS监测反应完全。反应液浓缩，残留物用乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱纯化(四氢呋喃/石油醚：10-30％)，得到(1R,5S)-叔丁基-3-(7-氯-5-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯的混合物(310mg，产率：22.2％)，棕色固体。(1R,5S)-tert-butyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1060mg, 1.81mmol, 1eq ) was dissolved in dioxane (10mL) and water (5mL), and 2-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5 , 5-tetramethyl-1,3,2-dioxaborolane (697.4mg, 1.99mmol, 1.1eq), cesium carbonate (1.18g, 3.62mmol, 2eq), 1,1-bis(diphenyl Phosphorus) ferrocenepalladium chloride (132.5mg, 0.181mmol, 0.1eq), under nitrogen protection, react at 80°C for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (tetrahydrofuran/petroleum ether: 10-30%) to give (1R,5S)-tert-butyl-3-(7-chloro-5-(7,8-difluoro-3-(methoxy Methoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4, Mixture of 3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylates (310 mg, yield: 22.2%), brown solid.
MS m/z:773.3[M+H]+ MS m/z:773.3[M+H] +
步骤2：化合物30Step 2: Compound 30
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)-5,6-二氟萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)-5,6-difluoronaphthalen-2-ol
将(1R,5S)-叔丁基-3-(7-氯-5-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(300mg,0.388mmol,1eq)溶于二氯甲烷(10mL)中，加入三氟乙酸(3mL)，室温反应1小时。LCMS检测反应完全。反应液浓缩，残留物经HPLC纯化，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)-5,6-二氟萘-2-酚(42mg，产率：8.4％)，白色固体。(1R,5S)-tert-butyl-3-(7-chloro-5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2 -(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylate (300mg, 0.388mmol, 1eq) was dissolved in dichloromethane (10mL), added trifluoroacetic acid (3mL), and reacted at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction solution was concentrated, and the residue was purified by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8 -Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)-5 , 6-difluoronaphthalen-2-ol (42 mg, yield: 8.4%), white solid.
HPLC分离条件:HPLC separation conditions:
柱子:Waters Xbridge BEH C18 100*30mm*10um；Column: Waters Xbridge BEH C18 100*30mm*10um;
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％：24％-64％；保留时间：10minMobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN; gradient B%: 24%-64%; retention time: 10min
MS m/z:629.2[M+H]+ MS m/z:629.2[M+H] +
19F NMR(377MHz,DMSO-d6)δ-139.88(s),-139.91(s),-143.76(s),-172.07(s),-172.17(s). 19 F NMR (377MHz, DMSO-d 6 )δ-139.88(s),-139.91(s),-143.76(s),-172.07(s),-172.17(s).
1H NMR(400MHz,DMSO-d6)δ10.21(br s,1H),7.77(dd,J＝4.9,8.8Hz,1H),7.68-7.57(m,1H),7.38(s,1H),7.01(br s,1H),5.30(br d,J＝53.6Hz,1H),4.22-4.04(m,2H),3.44-3.33(m,5H),3.15-2.95(m,5H),2.88-2.79(m,1H),2.22-1.94(m,4H),1.91-1.70(m,3H),1.36(m,3H). 1 H NMR (400MHz,DMSO-d 6 )δ10.21(br s,1H),7.77(dd,J=4.9,8.8Hz,1H),7.68-7.57(m,1H),7.38(s,1H) ,7.01(br s,1H),5.30(br d,J=53.6Hz,1H),4.22-4.04(m,2H),3.44-3.33(m,5H),3.15-2.95(m,5H),2.88 -2.79(m,1H),2.22-1.94(m,4H),1.91-1.70(m,3H),1.36(m,3H).
实施例31：化合物31Example 31: Compound 31
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-amino-7-fluorobenzo[b] Thiophene-3-carbonitrile
步骤1：(1R,5S)-叔丁基-3-(5-(2-((叔-丁氧羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-7-氯-8-氟-2- (((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(5-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl )-7-chloro-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Heterobicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5,7-二氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(500mg,0.854mmol,1eq)溶于二氧六环(5mL)中，加入叔丁基-(3-氰基-4-(5,5-二甲基-1,3,2-二噁硼己环-2-基)-7-氟苯并[b]噻吩-2-基)氨基甲酯(517.9mg,1.28mmol,1.5eq)、碳酸铯(834.8mg,2.56mmol,3eq)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(125.0mg,0.171mmol,0.2eq)，氮气保护，80℃反应2小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残留物经柱纯化(四氢呋喃/石油醚：0-30％)，得到(1R,5S)-叔丁基-3-(5-(2-((叔-丁氧羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,产率：27.9％)。黄色固体。(1R,5S)-tert-butyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.854mmol, 1eq ) was dissolved in dioxane (5 mL), and tert-butyl-(3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl) was added -7-fluorobenzo[b]thiophen-2-yl)aminomethyl ester (517.9mg, 1.28mmol, 1.5eq), cesium carbonate (834.8mg, 2.56mmol, 3eq) and [1,1'-bis(di Phenylphosphino)ferrocene]palladium dichloride (125.0mg, 0.171mmol, 0.2eq), under nitrogen protection, react at 80°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to obtain (1R ,5S)-tert-butyl-3-(5-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-7-chloro -8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) -3,8-Diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, yield: 27.9%). yellow solid.
MS m/z:841.4[M+H]+ MS m/z:841.4[M+H] +
步骤2：化合物31Step 2: Compound 31
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-amino-7-fluorobenzo[b] Thiophene-3-carbonitrile
将(1R,5S)-叔丁基-3-(5-(2-((叔-丁氧羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(300mg,0.356mmol,1eq)溶于乙腈(2mL)中，加入盐酸二氧六环溶液(4M,2.00mL)，室温反应6小时。LCMS监测反应完全。反应液浓缩，残留物经HPLC纯化，得到4-(4-((1R,5S)-3,8-二 氮杂二环[3.2.1]辛烷-3-基)-5-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-2-氨基-7-氟苯并[b]噻吩-3-甲腈(70mg,产率：15.3％)。白色固体。(1R,5S)-tert-butyl-3-(5-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)- 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine-4 -yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300mg, 0.356mmol, 1eq) was dissolved in acetonitrile (2mL), and dioxane hydrochloride solution was added ( 4M, 2.00mL), react at room temperature for 6 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by HPLC to obtain 4-(4-((1R,5S)-3,8-di Azabicyclo[3.2.1]octane-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl )methoxy)pyrido[4,3-d]pyrimidin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (70 mg, yield: 15.3%). white solid.
HPLC分离条件：HPLC separation conditions:
柱子：Waters Xbridge BEH C18 100*30mm*10um；Column: Waters Xbridge BEH C18 100*30mm*10um;
流动相A：Water(NH3H2O+NH4HCO3)，流动相B：ACN；梯度B％:23％-63％，保留时间：11minMobile phase A: Water (NH 3 H 2 O+NH 4 HCO 3 ), mobile phase B: ACN; gradient B%: 23%-63%, retention time: 11min
MS m/z:663.2[M+Na]+ MS m/z:663.2[M+Na] +
19F NMR(377MHz,DMSO-d6)δ-115.16(s),-139.91(s),-172.07(s),-172.16(s). 19 F NMR (377MHz, DMSO-d 6 )δ-115.16(s),-139.91(s),-172.07(s),-172.16(s).
1H NMR(400MHz,DMSO-d6)δ8.20(br s,2H),7.40-6.73(m,2H),5.30(br d,J＝54.0Hz,1H),4.81(br s,1H),4.23-4.00(m,2H),3.33-2.80(m,9H),2.21-1.95(m,4H),1.93-1.71(m,4H),1.41(br s,2H),1.09-0.59(m,1H). 1 H NMR (400MHz,DMSO-d 6 )δ8.20(br s,2H),7.40-6.73(m,2H),5.30(br d,J=54.0Hz,1H),4.81(br s,1H) ,4.23-4.00(m,2H),3.33-2.80(m,9H),2.21-1.95(m,4H),1.93-1.71(m,4H),1.41(br s,2H),1.09-0.59(m ,1H).
实施例32：化合物32Example 32: Compound 32
4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-5-(7,8-二氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶
4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-5-(7,8-difluoronaphthalen-1-yl) -8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine
步骤1：(1R,5S)-叔丁基-3-(7-氯-5-(7,8-二氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(7-chloro-5-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] Octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5,7-二氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,0.342mmol,1eq)溶于二氧六环(2mL)和水(1mL)的混合溶液中，加入2-(7,8-二氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环(89.2mg,0.307mmol,0.9eq)，1,1-双(二苯基磷)二茂铁氯化钯(50mg,0.0683mmol,0.2eq)和碳酸铯(333.9mg,1.02mmol,3eq)，氮气保护下，80℃反应2小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残留物经HPLC制备，得到(1R,5S)- 叔丁基-3-(7-氯-5-(7,8-二氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(25mg，收率：10.4％)，白色固体。(1R,5S)-tert-butyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.342mmol, 1eq ) was dissolved in a mixed solution of dioxane (2mL) and water (1mL), and 2-(7,8-difluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1 , 3,2-Dioxaborolane (89.2mg, 0.307mmol, 0.9eq), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (50mg, 0.0683mmol, 0.2eq) and cesium carbonate (333.9mg, 1.02mmol, 3eq), reacted at 80°C for 2 hours under nitrogen protection. LCMS monitored the reaction to be complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was prepared by HPLC to obtain (1R,5S)- tert-butyl-3-(7-chloro-5-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrole Olinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate ( 25 mg, yield: 10.4%), white solid.
HPLC分离条件:HPLC separation conditions:
柱子:AgNO3_silica 150*25mm*15umColumn: AgNO3_silica 150*25mm*15um
流动相A：Heptane，流动相B：EtOH(0.1％NH3H2O)；梯度B％：0％-90％；保留时间：9minMobile phase A: Heptane, Mobile phase B: EtOH (0.1% NH3H2O); Gradient B%: 0%-90%; Retention time: 9min
MS m/z:713.3[M+H]+ MS m/z:713.3[M+H] +
19F NMR(377MHz,DMSO-d6)δ-138.50(s),-139.83(s),-172.09(s),-172.16(s). 19 F NMR (377MHz, DMSO-d 6 )δ-138.50(s),-139.83(s),-172.09(s),-172.16(s).
1H NMR(400MHz,DMSO-d6)δ8.18(br d,J＝7.9Hz,1H),8.02(br s,1H),7.87-7.25(m,3H),5.29(br d,J＝54.8Hz,1H),4.29-4.01(m,2H),3.98-3.44(m,3H),3.20-2.96(m,3H),2.92-2.78(m,1H),2.26-1.72(m,8H),1.68-0.97(m,14H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.18 (br d, J = 7.9Hz, 1H), 8.02 (br s, 1H), 7.87-7.25 (m, 3H), 5.29 (br d, J = 54.8Hz,1H),4.29-4.01(m,2H),3.98-3.44(m,3H),3.20-2.96(m,3H),2.92-2.78(m,1H),2.26-1.72(m,8H) ,1.68-0.97(m,14H).
步骤2：化合物32Step 2: Compound 32
4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-5-(7,8-二氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶
4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-5-(7,8-difluoronaphthalen-1-yl) -8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine
将(1R,5S)-叔丁基-3-(7-氯-5-(7,8-二氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(25mg,0.0351mmol,1eq)溶于二氯甲烷(0.9mL)中，加入三氟乙酸(0.3mL)，室温反应1小时，LCMS监测反应完全。反应液浓缩，残留物经HPLC制备，得到4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-5-(7,8-二氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶(7mg，收率：23.9％)，白色固体。(1R,5S)-tert-butyl-3-(7-chloro-5-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-Carboxyl ester (25mg, 0.0351mmol, 1eq) was dissolved in dichloromethane (0.9mL), added trifluoroacetic acid (0.3mL), reacted at room temperature for 1 hour, and the reaction was complete by LCMS monitoring. The reaction solution was concentrated, and the residue was prepared by HPLC to obtain 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-5-(7 , 8-difluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4 ,3-d]pyrimidine (7 mg, yield: 23.9%), white solid.
HPLC分离条件:HPLC separation conditions:
柱子:Phenomenex C18 75*30mm*3umColumn: Phenomenex C18 75*30mm*3um
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％：47％-87％，保留时间：9minMobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 47%-87%, retention time: 9min
MS m/z:613.2[M+H]+ MS m/z:613.2[M+H] +
19F NMR(377MHz,DMSO-d6)δ-138.44(s),-138.47(s),-140.05(s),-172.07(s),-172.17(s). 19 F NMR (377MHz, DMSO-d 6 )δ-138.44(s),-138.47(s),-140.05(s),-172.07(s),-172.17(s).
1H NMR(400MHz,DMSO-d6)δ8.12(br d,J＝64.8Hz,2H),7.90-7.22(m,3H),5.29(br d,J＝54.0Hz,1H),4.32-3.88(m,3H),3.19-2.77(m,8H),2.23-1.74(m,8H),1.48-1.04(m,4H). 1 H NMR (400MHz, DMSO-d 6 )δ8.12 (br d, J=64.8Hz, 2H), 7.90-7.22 (m, 3H), 5.29 (br d, J=54.0Hz, 1H), 4.32- 3.88(m,3H),3.19-2.77(m,8H),2.23-1.74(m,8H),1.48-1.04(m,4H).
实施例33：化合物33 Example 33: Compound 33
4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)萘-2-酚
4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)naphthalene-2-ol
步骤1：(1R,5S)-叔丁基-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(3-(甲氧基甲氧基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)-5-(3-(methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[ 3.2.1] Octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5,7-二氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(600.0mg,1.02mmol,1eq)溶于甲苯(1mL)和水(0.2mL)中，加入2-(3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环(322.0mg,1.02mmol,1eq)，氢氧化钠(172.5mg,3.07mmol,3eq)，四三苯基膦钯(236.9mg,0.205mmol,0.2eq)，氮气保护，100℃反应1小时。LCMS监测反应完全。反应液浓缩，残留物用水和乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩。残留物经SFC拆分，得到产物(200mg，产率：26.5％)，白色固体。(1R,5S)-tert-butyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600.0mg, 1.02mmol, 1eq) was dissolved in toluene (1mL) and water (0.2mL), and 2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1 , 3,2-dioxaborolane (322.0mg, 1.02mmol, 1eq), sodium hydroxide (172.5mg, 3.07mmol, 3eq), tetrakistriphenylphosphine palladium (236.9mg, 0.205mmol, 0.2eq), Under nitrogen protection, react at 100°C for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was extracted with water and ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate. The residue was resolved by SFC to obtain the product (200 mg, yield: 26.5%) as a white solid.
MS m/z:737.3[M+H]+ MS m/z:737.3[M+H] +
SFC手性分离条件:SFC chiral separation conditions:
柱子：DAICEL CHIRALCEL OD(250mm*30mm,10um)Column: DAICEL CHIRALCEL OD (250mm*30mm, 10um)
流动相A：0.1％NH3H2O，流动相B：MEOH；梯度B％:35％-35％Mobile Phase A: 0.1% NH 3 H 2 O, Mobile Phase B: MEOH; Gradient B%: 35%-35%
步骤2：4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)萘-2-酚和4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-5-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Step 2: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-((( 2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)naphthalene-2-ol and 4-(4 -((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-chloro-8-fluoro-2-(((2R,7aS)-2- Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol
将(1R,5S)-叔丁基-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(3-(甲氧基甲氧基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(190mg,0.274mmol,1eq)溶于乙腈(3mL)中，加入盐酸二氧六环溶液(4M,1.5mL)，室温反应1小时。LCMS检测反应完全。反应液浓缩，残留物经HPLC分离纯化，得到4-(4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-5-基)萘-2-酚(10mg，产率：6.2％)，白色固体。(1R,5S)-tert-butyl-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy Base)-5-(3-(methoxymethoxy)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] Octane-8-carboxylate (190mg, 0.274mmol, 1eq) was dissolved in acetonitrile (3mL), added dioxane hydrochloride solution (4M, 1.5mL), and reacted at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction solution was concentrated, and the residue was separated and purified by HPLC to obtain 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro- 8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-5-yl)naphthalene -2-phenol (10 mg, yield: 6.2%), white solid.
MS m/z:593.2[M+H]+ MS m/z:593.2[M+H] +
HPLC分离条件:HPLC separation conditions:
柱子:Kromasil Eternity XT 150*30mm*10um；流速：60mL/minColumn: Kromasil Eternity XT 150*30mm*10um; flow rate: 60mL/min
流动相A:Water(0.05％氨水，v/v)流动相B:ACN；梯度B％：14％-54％(v/v),保留时间：9minMobile phase A: Water (0.05% ammonia water, v/v) Mobile phase B: ACN; Gradient B%: 14%-54% (v/v), retention time: 9min
1H NMR(400MHz,DMSO-d6)δ9.67(br s,1H),8.09-7.88(m,1H),7.81(br d,J＝7.9Hz,1H),7.46(br t,J＝7.5Hz,1H),7.31(br s,2H),7.00(br s,1H),5.31(br d,J＝55.6Hz,1H),4.18(br s,3H),3.43-3.17(m,6H),2.90-2.80(m,2H),2.17-1.98(m,4H),1.96-1.62(m,5H),1.37(br s,3H). 1 H NMR (400MHz, DMSO-d 6 )δ9.67(br s, 1H), 8.09-7.88(m, 1H), 7.81(br d, J=7.9Hz, 1H), 7.46(br t, J= 7.5Hz,1H),7.31(br s,2H),7.00(br s,1H),5.31(br d,J＝55.6Hz,1H),4.18(br s,3H),3.43-3.17(m,6H ),2.90-2.80(m,2H),2.17-1.98(m,4H),1.96-1.62(m,5H),1.37(br s,3H).
实施例34：化合物34Example 34: Compound 34
4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-5-(8-乙炔基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶
4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-5-(8-ethynylnaphthalen-1-yl)-8 -Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine
步骤1：(1R,5S)-叔丁基-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(8-((三异丙基甲硅烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯
Step 1: (1R,5S)-tert-butyl-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl) Methoxy)-5-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylate
将(1R,5S)-叔丁基-3-(5,7-二氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(200mg,0.342mmol,1eq)溶于甲苯(3mL)和水(0.6mL)的混合溶液中，加入三异丙基((8-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)萘-1-基)乙炔基)硅烷(222.6mg,0.512mmol,1.5eq)、四三苯基膦钯(79.0mg,0.068mmol,0.2eq)和氢氧化钠(41.0mg,1.02mmol,3eq)，氮气保护下，100℃反应3小时。LCMS监测反应完全。反应液加水淬灭，乙酸乙酯萃取，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残留物经TLC板分离[四氢呋喃(含0.5％氨水)：石油醚＝3:1]，得到(1R,5S)-叔丁基-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(8-((三异丙基甲硅烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(110mg，产率：37.6％)，棕色固体。(1R,5S)-tert-butyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.342mmol, 1eq ) was dissolved in a mixed solution of toluene (3mL) and water (0.6mL), adding triisopropyl ((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborol Cyclo-2-yl)naphthalen-1-yl)ethynyl)silane (222.6mg, 0.512mmol, 1.5eq), tetrakistriphenylphosphine palladium (79.0mg, 0.068mmol, 0.2eq) and sodium hydroxide (41.0mg , 1.02mmol, 3eq), under the protection of nitrogen, react at 100°C for 3 hours. LCMS monitored the reaction to be complete. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by a TLC plate [tetrahydrofuran (containing 0.5% ammonia): petroleum ether = 3: 1], to give (1R,5S)-tert-butyl-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl )Methoxy)-5-(8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylate (110 mg, yield: 37.6%), brown solid.
MS m/z:857.5[M+H]+ MS m/z:857.5[M+H] +
步骤2：4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(8-((三异丙基甲硅烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶的盐酸盐Step 2: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-chloro-8-fluoro-2-(((2R,7aS )-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)pyrido[ 4,3-d] pyrimidine hydrochloride
的盐酸盐 hydrochloride
将(1R,5S)-叔丁基-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(8-((三异丙基甲硅烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(80mg,93.29umol,1eq)溶于乙腈(2mL)中，加入盐酸二氧六环溶液(4M,2mL)，室温反应2小时，LCMS监测反应完全。反应液浓缩得到4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(8-((三异丙基甲硅烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶的盐酸盐(74.1mg，100％)，棕色固体。(1R,5S)-tert-butyl-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy Base)-5-(8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Bicyclo[3.2.1]octane-8-carboxylate (80mg, 93.29umol, 1eq) was dissolved in acetonitrile (2mL), added dioxane hydrochloride solution (4M, 2mL), reacted at room temperature for 2 hours, LCMS Monitor for completeness of reaction. The reaction solution was concentrated to obtain 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)pyrido [4,3-d]pyrimidine hydrochloride (74.1 mg, 100%), brown solid.
MS m/z:757.2[M+H]+ MS m/z:757.2[M+H] +
步骤3：4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-5-(8-乙炔基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶
Step 3: 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-chloro-5-(8-ethynylnaphthalen-1-yl )-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine
将4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5-(8-((三异丙基甲硅烷基)乙炔基)萘-1-基)吡啶并[4,3-d]嘧啶的盐酸盐(74.1mg,0.093mmol,1eq)溶于N,N-二甲基甲酰胺(1mL)中，加入氟化铯(2.13g,13.99mmol,150eq)，室温反应2小时。LCMS监测反应完全。反应液过滤，滤液经HPLC制备，得到4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-5-(8-乙炔基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶(20mg，产率：35.7％)，白色固体4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-8-fluoro-2-(((2R,7aS)- 2-Fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5-(8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)pyrido[4, 3-d] Dissolve pyrimidine hydrochloride (74.1mg, 0.093mmol, 1eq) in N,N-dimethylformamide (1mL), add cesium fluoride (2.13g, 13.99mmol, 150eq), and react at room temperature 2 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-5-(8- Ethynylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3- d] pyrimidine (20 mg, yield: 35.7%), white solid
HPLC分离条件:HPLC separation conditions:
柱子:Phenomenex C18 75*30mm*3um；流速：30mL/minColumn: Phenomenex C18 75*30mm*3um; flow rate: 30mL/min
流动相A:Water(0.05％氨水,v/v)流动相B:ACN；梯度B％：34％-74％(v/v),保留时间：11minMobile phase A: Water (0.05% ammonia water, v/v) Mobile phase B: ACN; Gradient B%: 34%-74% (v/v), retention time: 11min
MS m/z:601.4[M+H]+ MS m/z:601.4[M+H] +
19F NMR(376MHz,DMSO-d6)δ-139.86(s),-172.09(s),-172.20(s). 19 F NMR (376MHz,DMSO-d 6 )δ-139.86(s),-172.09(s),-172.20(s).
1H NMR(400MHz,DMSO-d6)δ8.15(d,J＝8.3Hz,2H),7.80(br d,J＝6.5Hz,1H),7.68-7.56(m,2H),7.40(br s,1H),5.30(br d,J＝54.4Hz,1H),4.25-4.01(m,3H),3.80(br d,J＝10.3Hz,1H),3.22-2.94(m,5H),2.91-2.72(m,2H),2.23-1.95(m,4H),1.93-1.53(m,5H),1.33(br s,3H),1.03(br s,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.15(d, J=8.3Hz, 2H), 7.80(br d, J=6.5Hz, 1H), 7.68-7.56(m, 2H), 7.40(br s,1H),5.30(br d,J=54.4Hz,1H),4.25-4.01(m,3H),3.80(br d,J=10.3Hz,1H),3.22-2.94(m,5H),2.91 -2.72(m,2H),2.23-1.95(m,4H),1.93-1.53(m,5H),1.33(br s,3H),1.03(br s,1H).
实施例35：化合物35Example 35: Compound 35
4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-5-(8-氯萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶
4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-5-(8-chloronaphthalen-1-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine
步骤1：(1R,5S)-叔丁基-3-(7-氯-5-(8-氯萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯
Step 1: (1R,5S)-tert-butyl-3-(7-chloro-5-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Hexahydro-1H-pyrrolidinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate
将(1R,5S)-叔丁基-3-(5,7-二氯-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(500mg,0.854mmol,1eq)溶于甲苯(10mL)和水(2mL)中，加入2-(8-氯萘-1-基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环(369.7mg,1.28mmol,1.5eq)，氢氧化钠(102.5mg,2.56mmol,3eq)，四三苯基膦钯(197.4mg,0.171mmol,0.2eq)，氮气保护，100℃反应过夜。LCMS监测反应完全。反应液浓缩，残留物用水和乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩。粗品经柱纯化(乙酸乙酯/石油醚：0-35％)，得到产物(200mg，粗产品)，黄色固体。(1R,5S)-tert-butyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.854mmol, 1eq ) was dissolved in toluene (10mL) and water (2mL), and 2-(8-chloronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolol was added Cyclo(369.7mg, 1.28mmol, 1.5eq), sodium hydroxide (102.5mg, 2.56mmol, 3eq), tetrakistriphenylphosphine palladium (197.4mg, 0.171mmol, 0.2eq), under nitrogen protection, react overnight at 100°C. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was extracted with water and ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate. The crude product was purified by column (ethyl acetate/petroleum ether: 0-35%) to give the product (200 mg, crude product) as a yellow solid.
MS m/z:711.3[M+H]+ MS m/z:711.3[M+H] +
步骤2：化合物35Step 2: Compound 35
4-((1R,5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-7-氯-5-(8-氯萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶
4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-chloro-5-(8-chloronaphthalen-1-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine
将(1R,5S)-叔丁基-3-(7-氯-5-(8-氯萘-1-基)-8-氟-2-(((2R,7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(190mg,0.267mmol,1eq)溶于乙腈(2mL)中，加入盐酸二氧六环溶液(4M,0.6mL)，室温反应1小时。LCMS检测反应完全。反应液浓缩，残留物经HPLC纯化，SFC拆分，得到产物(15mg，产率：9.19％,)，白色固体。(1R,5S)-tert-butyl-3-(7-chloro-5-(8-chloronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro -1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Carboxylate (190mg, 0.267mmol, 1eq) was dissolved in acetonitrile (2mL), added with dioxane hydrochloride solution (4M, 0.6mL), and reacted at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction solution was concentrated, and the residue was purified by HPLC and resolved by SFC to obtain the product (15 mg, yield: 9.19%) as a white solid.
HPLC分离条件:HPLC separation conditions:
柱子:Kromasil Eternity XT 150*30mm*10umColumn: Kromasil Eternity XT 150*30mm*10um
流动相A：Water(ammonia hydroxide v/v)，流动相B：ACN；梯度B％：40％-80％，保留时间：9minMobile phase A: Water (ammonia hydroxide v/v), mobile phase B: ACN; Gradient B%: 40%-80%, retention time: 9min
SFC手性分离条件: SFC chiral separation conditions:
柱子：DAICEL CHIRALCEL OJ(250mm*30mm,10um)Column: DAICEL CHIRALCEL OJ (250mm*30mm, 10um)
流动相A：0.1％NH3H2O，流动相B：ETOH；梯度B％：35％-35％Mobile Phase A: 0.1% NH 3 H 2 O, Mobile Phase B: ETOH; Gradient B %: 35%-35%
MS m/z:611.4[M+H]+ MS m/z:611.4[M+H] +
19F NMR(376MHz,DMSO-d6)δ-140.16(s),-172.08(s),-172.19(s). 19 F NMR (376MHz, DMSO-d 6 )δ-140.16(s),-172.08(s),-172.19(s).
1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝8.0Hz,1H),8.13(d,J＝7.8Hz,1H),7.73(br d,J＝7.5Hz,1H),7.68-7.56(m,2H),7.49(br s,1H),5.30(br d,J＝54.0Hz,1H),4.23-4.12(m,1H),4.11-4.01(m,1H),3.85-3.69(m,1H),3.50-3.35(m,3H),3.18-3.06(m,3H),3.03(s,1H),2.91(br s,1H),2.88-2.78(m,1H),2.23-1.95(m,4H),1.93-1.71(m,4H),1.42-1.26(m,2H),1.22-1.09(m,1H). 1 H NMR (400MHz, DMSO-d6) δ8.21(d, J=8.0Hz, 1H), 8.13(d, J=7.8Hz, 1H), 7.73(br d, J=7.5Hz, 1H), 7.68 -7.56(m,2H),7.49(br s,1H),5.30(br d,J＝54.0Hz,1H),4.23-4.12(m,1H),4.11-4.01(m,1H),3.85-3.69 (m,1H),3.50-3.35(m,3H),3.18-3.06(m,3H),3.03(s,1H),2.91(br s,1H),2.88-2.78(m,1H),2.23- 1.95(m,4H),1.93-1.71(m,4H),1.42-1.26(m,2H),1.22-1.09(m,1H).
测试实施例1：对Ba/F3KRAS-G12D、Ba/F3KRAS-G12V稳转细胞株和含KRAS G12D突变的AGS肿瘤细胞株的增殖抑制活性：Test Example 1: Proliferation inhibitory activity on Ba/F3KRAS-G12D, Ba/F3KRAS-G12V stably transfected cell lines and AGS tumor cell lines containing KRAS G12D mutation:
本测试实施例1用于测定本发明化合物在体外对小鼠原B细胞Ba/F3稳定表达KRAS G12D/V突变蛋白的Ba/F3KRAS-G12D和Ba/F3KRAS-G12V细胞，及表达KRAS G12D突变蛋白的胃癌AGS细胞的增殖抑制活性。This test example 1 is used to determine the Ba/F3KRAS-G12D and Ba/F3KRAS-G12V cells that the compound of the present invention stably expresses the KRAS G12D/V mutant protein in the original B cell Ba/F3 of the mouse in vitro, and expresses the KRAS G12D mutant protein Proliferation inhibitory activity of gastric cancer AGS cells.
细胞来源：Ba/F3KRAS-G12D和Ba/F3KRAS-G12V购自康源博创生物科技(北京)有限公司，货号分别为KC-1259和KC-1261；AGS购自上海拜力生物科技有限公司。Cell source: Ba/F3KRAS-G12D and Ba/F3KRAS-G12V were purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd., product numbers KC-1259 and KC-1261, respectively; AGS was purchased from Shanghai Baili Biotechnology Co., Ltd.
取处于对数生长期的细胞接种在96孔板中(Ba/F3KRAS-G12D，Ba/F3KRAS-G12V，AGS细胞分别为8000,8000,4000个/孔,90μl/孔)，37℃、5％CO2培养1天后加入梯度稀释的待测化合物。具体如下：取事先溶解在DMSO中的化合物储存液(10mM)，倍比(4倍)稀释为10个梯度浓度，并用培养基在另一96孔板中稀释到目的浓度的10倍，然后在接种细胞的96孔板中加入化合物溶液10μl/孔，即到达目的浓度(10000,2500,625,156,39,10,2.5,0.6,0.15,0.04nM)。每个浓度设3个复孔，并设空白对照。放入37℃、5％CO2中继续培养72h后，每孔加入50μl2.0试剂(荧光素酶ATP生物发光检测试剂，购自Promega,货号G9243)，震荡2min，室温孵育8min后，检测荧光发光强度(收光时间为100ms)。计算各浓度化合物对细胞增殖的抑制率。Cells in the logarithmic growth phase were seeded in 96-well plates (Ba/F3KRAS-G12D, Ba/F3KRAS-G12V, AGS cells were 8000, 8000, 4000 cells/well, 90 μl/well), 37°C, 5% After CO 2 incubation for 1 day, serially diluted test compounds were added. The details are as follows: take the stock solution (10mM) of the compound dissolved in DMSO in advance, dilute it to 10 gradient concentrations by doubling ratio (4 times), and dilute it to 10 times of the target concentration in another 96-well plate with medium, and then in Add 10 μl/well of the compound solution to the 96-well plate inoculated with cells to reach the target concentration (10000, 2500, 625, 156, 39, 10, 2.5, 0.6, 0.15, 0.04 nM). Three replicate wells were set up for each concentration, and a blank control was set up. Place in 37°C, 5% CO 2 and continue to culture for 72h, add 50μl per well 2.0 reagent (luciferase ATP bioluminescence detection reagent, purchased from Promega, product number G9243), shaking for 2 minutes, and after incubating at room temperature for 8 minutes, detect the fluorescence intensity (light collection time is 100ms). The inhibitory rate of each concentration compound on cell proliferation was calculated.
细胞增殖抑制率(％)＝[(发光强度72小时含细胞培养基对照组-发光强度72小时化合物组)/(发光强度72小时含细胞培养基对照组–发光强度72小时无细胞培养基对照组)]×100％。Cell proliferation inhibition rate (%)=[(luminous intensity 72 hours containing cell medium control group -luminous intensity 72 hours compound group )/(luminous intensity 72 hours containing cell medium control group -luminous intensity 72 hours no cell medium control group )] × 100%.
使用GraphPad Prism 8.3软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC50值，结果见下表。



GraphPad Prism 8.3 software was used to analyze the data, and the nonlinear S-curve regression was used to fit the data to obtain a dose-effect curve, and the IC 50 value was calculated accordingly. The results are shown in the table below.



A≤1μM；1μM＜B≤5μM；5μM＜C≤10μM。A≤1μM; 1μM<B≤5μM; 5μM<C≤10μM.
测试结果表明本发明化合物(尤其是化合物4、化合物6、化合物10、化合物13、化合物18、化合物21、化合物22、化合物24、化合物29)对含KRAS G12D/V突变的Ba/F3KRAS-G12D、Ba/F3KRAS-G12V和AGS细胞具有良好的增殖抑制活性。The test results show that the compounds of the present invention (especially compound 4, compound 6, compound 10, compound 13, compound 18, compound 21, compound 22, compound 24, compound 29) are effective against Ba/F3KRAS-G12D containing KRAS G12D/V mutation, Ba/F3KRAS-G12V and AGS cells have good proliferation inhibitory activity.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。 Although the specific implementations of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes or changes can be made to these implementations without departing from the principle and essence of the present invention. Revise. Accordingly, the protection scope of the present invention is defined by the appended claims.

Claims (18)

  1. 如式I所示的化合物、其立体异构体或其药学上可接受的盐：
    The compound shown in formula I, its stereoisomer or pharmaceutically acceptable salt thereof:
    其中，环A为3-7元环烷基、3-7元环烯基、4-10元杂环烷基或4-10元杂环烯基；所述4-10元杂环烷基和4-10元杂环烯基里的杂原子个数为1或2个，其中所述杂原子选自N、O和S中的一种或两种；Wherein, Ring A is 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkenyl; said 4-10 membered heterocycloalkyl and The number of heteroatoms in the 4-10 membered heterocycloalkenyl is 1 or 2, wherein the heteroatoms are selected from one or both of N, O and S;
    n为0、1、2、3、4、5、6、7、8、9或10；n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
    各R1分别独立地为氘、卤素、-CN、-OH、-N(R5)2、硝基、C1-C6烷基、被一个或多个R1a取代的C1-C6烷基、C1-C6烷基-O-、被一个或多个R1b取代的C1-C6烷基-O-、C2-C6烯基、被一个或多个R1c取代的C2-C6烯基、C2-C6炔基、被一个或多个R1d取代的C2-C6炔基、-C(＝O)H、-CO2R5、-C(＝O)N(R5)2、5至14元杂芳基或氧代基(＝O)；所述的5至14元杂芳基中杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；Each R 1 is independently deuterium, halogen, -CN, -OH, -N(R 5 ) 2 , nitro, C 1 -C 6 alkyl, C 1 -C 6 substituted by one or more R 1a Alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-O- substituted by one or more R 1b , C 2 -C 6 alkenyl, substituted by one or more R 1c C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkynyl substituted by one or more R 1d , -C(=O)H, -CO 2 R 5 , -C (=O)N(R 5 ) 2 , 5 to 14-membered heteroaryl or oxo group (=O); the heteroatom in the 5 to 14-membered heteroaryl is selected from one of N, O and S One or more kinds, the number of heteroatoms is 1, 2 or 3;
    各R1a、R1b、R1c和R1d分别独立地为氘、-CN、卤素或-OH；Each of R 1a , R 1b , R 1c and R 1d is independently deuterium, -CN, halogen or -OH;
    L为-(CR6aR6b)n1-*、-O-(CR6aR6b)n2-*、-S-(CR6aR6b)n3-*或-N(R5)(CR6aR6b)n4-*；*表示与R2连接的一端；L is -(CR 6a R 6b ) n1 -*, -O-(CR 6a R 6b ) n2 -*, -S-(CR 6a R 6b ) n3 -* or -N(R 5 )(CR 6a R 6b ) n4- *; * indicates one end connected with R2 ;
    R2为H、-COOH、-N(R5)2、C1-C6烷基、C1-C6烷基-O-、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、-NHC(＝NH)NH2，-C(O)N(R5)2、-CH(CH2OR5)[(CH2)n5OR5]、-N(R5)C(＝O)-(C6-C10芳基)、-C(＝O)O-(C1-C6烷基)、被一个或多个R2a取代的C1-C6烷基、被一个或多个R2b取代的C1-C6烷基-O-、被一个或多个R2c取代的3-7元环烷基、被一个或多个R2d取代的3-7元环烯基、被一个或多个R2e取代的4-10元杂环烷基、被一个或多个R2f取代的-C(＝O)O-(C1-C6烷基)、被一个或多个R2g取代的C6-C10芳基、被一个或多个R2h取代的5至14元杂芳基、-N(R5)C(＝O)-(被一个或多个R2i取代的C6-C10芳基)或被一个或多个R2j取代的4-10元杂环烯基；所述“4-10元杂环烷基”和“被一个或多个R2e取代的4-10元的杂环烷基”中的“4-10元杂环烷基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烯基”和“被一个或多个R2j取代的4-10元杂环烯基”中的“4-10元杂环烯基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“5至14元杂芳基”和“被一个或多个R2h取代的5至14元杂芳基”中的“5至14元杂芳基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；R 2 is H, -COOH, -N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl , 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, -NHC(=NH)NH 2 , -C(O)N (R 5 ) 2 , -CH(CH 2 OR 5 )[(CH 2 ) n5 OR 5 ], -N(R 5 )C(=O)-(C 6 -C 10 aryl), -C(= O)O-(C 1 -C 6 alkyl), C 1 -C 6 alkyl substituted by one or more R 2a , C 1 -C 6 alkyl substituted by one or more R 2b -O- , 3-7 membered cycloalkyl substituted by one or more R 2c , 3-7 membered cycloalkenyl substituted by one or more R 2d , 4-10 membered heterocycle substituted by one or more R 2e Alkyl, -C(=O)O-(C 1 -C 6 alkyl) substituted by one or more R 2f , C 6 -C 10 aryl substituted by one or more R 2g , by one or A 5- to 14-membered heteroaryl group substituted by multiple R 2h , -N(R 5 )C(=O)-(C 6 -C 10 aryl substituted by one or more R 2i ) or by one or more A 4-10 membered heterocycloalkenyl group substituted by R 2j ; "4 in the "4-10 membered heterocycloalkyl group" and "4-10 membered heterocycloalkyl group substituted by one or more R 2e " The heteroatoms in -10-membered heterocycloalkyl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the "4-10-membered heterocycloalkenyl The heteroatoms in the "4-10-membered heterocyclenyl" in "and "4-10-membered heterocyclenyl substituted by one or more R 2j " are selected from one or more of N, O and S The number of heteroatoms is 1, 2 or 3; the "5 to 14 membered heteroaryl group" and "5 to 14 membered heteroaryl group substituted by one or more R 2h " The heteroatoms in "membered heteroaryl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
    各R2a、R2b、R2c、R2d、R2e、R2f和R2j分别独立地为卤素、-OH、氘、-CN、-C(＝O)H、C1-C6烷基、被一个或多个R2-a取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷基-O-、被一个或多个R2- b取代的C1-C6烷基-O-、苯基-Q-、FO2S-亚苯基-Q-、苯基-C(＝O)NH-、-N(R5)2、(Cl-C6烷基)-O-(C1-C6烷基)-、(Cl-C6烷基)-C(＝O)-、氧代基(＝O)、(被一个或多个卤素取代的Cl-C6烷基)-C(＝O)-、-SO2F、(Cl-C6烷基)-SO2-、(Cl-C6烷基)-O-(Cl-C6烷基)-O-、-CH2OC(＝O)N(R5)2、(Cl-C6烷基)-O-C(＝O)-NHCH2-、-CH2NHC(＝O)N(R5)2、(Cl-C6烷基)-C(＝O)NHCH2-、(吡唑基)-CH2-、(Cl-C6烷基)-SO2-NHCH2-、(4-10元杂环烷基)-C(＝O)-OCH2-、(R5)2N-C(＝O)-O-、(Cl-C6烷基)-O-(Cl-C6烷基)-NH-C(＝O)-O-、苯基-(Cl-C6烷基)-NH-C(＝O)-O-、(4-10元杂环烷基)-C(＝O)-O-或(4-10元杂环烷基)-CH2-；所述“苯基-C(＝O)NH-”和“苯基-(Cl-C6烷基)-NH-C(＝O)-O-”里的“苯基”任选被-C(＝O)H、卤素、CN或OH取代；所述“(4-10元杂环烷基)-C(＝O)-OCH2-”、“(4-10元杂环烷基)-C(＝O)-O-”和“(4-10元杂环烷基)-CH2-”里的“4-10元杂环烷基”任选被0、1或2个氧代基(＝O)取代；所述“(4-10元杂环烷基)-C(＝O)-OCH2-”、“(4-10元杂环烷基)-C(＝O)-O-”和“(4-10元杂环烷基)-CH2-”里的“4-10元杂环烷基”中的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；Each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2j is independently halogen, -OH, deuterium, -CN, -C(=O)H, C 1 -C 6 alkyl , C 1 -C 6 alkyl, C 2 -C 6 alkenyl , C 2 -C 6 alkynyl, C 1 -C 6 alkyl-O- substituted by one or more R 2-a , by one or Multiple R 2- b substituted C 1 -C 6 alkyl-O-, phenyl-Q-, FO 2 S-phenylene-Q-, phenyl-C(=O)NH-, -N(R 5 ) 2 , (C 1 -C 6 alkyl)-O-(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)-C(=O)-, oxo (=O), (by C l -C 6 alkyl)-C(=O)-, -SO 2 F, (C l -C 6 alkyl) -SO 2 -, (C l -C 6 alkyl) substituted by one or more halogens )-O-(C 1 -C 6 alkyl)-O-, -CH 2 OC(=O)N(R 5 ) 2 , (C 1 -C 6 alkyl)-OC(=O)-NHCH 2 -, -CH 2 NHC(=O)N(R 5 ) 2 , (C l -C 6 alkyl)-C(=O)NHCH 2 -, (pyrazolyl)-CH 2 -, (C l - C 6 alkyl)-SO 2 -NHCH 2 -, (4-10 membered heterocycloalkyl)-C(=O)-OCH 2 -, (R 5 ) 2 NC(=O)-O-, (C l -C 6 alkyl)-O-(C l -C 6 alkyl)-NH-C(=O)-O-, phenyl-(C l -C 6 alkyl)-NH-C(=O )-O-, (4-10 membered heterocycloalkyl)-C(=O)-O- or (4-10 membered heterocycloalkyl)-CH 2 -; said "phenyl-C(=O )NH-" and "phenyl-(C 1 -C 6 alkyl)-NH-C(=O)-O-" in "phenyl" is optionally replaced by -C(=O)H, halogen, CN or OH substitution; the "(4-10 membered heterocycloalkyl)-C(=O)-OCH 2 -", "(4-10 membered heterocycloalkyl)-C(=O)-O-" and "4-10-membered heterocycloalkyl" in "(4-10-membered heterocycloalkyl)-CH 2 -" is optionally substituted by 0, 1 or 2 oxo groups (=O); the " (4-10 membered heterocycloalkyl)-C(=O)-OCH 2 -”, “(4-10 membered heterocycloalkyl)-C(=O)-O-” and “(4-10 membered The heteroatoms in the "4-10 membered heterocycloalkyl" in "heterocycloalkyl)-CH 2 -" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
    各Q分别独立地为连接单键或-O-；Each Q is independently a connecting single bond or -O-;
    各R2-a和R2-b分别独立地为氘、-CN、卤素或-OH；Each R 2-a and R 2-b are independently deuterium, -CN, halogen or -OH;
    各R2g、R2h和R2i分别独立地为卤素、-OH、-C(＝O)H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷基-O-、被一个或多个卤素或OH取代的C1-C6烷基或-N(R5)2；Each of R 2g , R 2h and R 2i is independently halogen, -OH, -C(=O)H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl substituted by one or more halogens or OH, or -N(R 5 ) 2 ;
    R3为卤素、-OH、氘、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、硝基、-(CH2)n6N(R5)2、-NHC(＝NH)NH2、-(CH2)n7C(＝O)N(R5)2、-(CH2)n8C(＝O)R5、-N(R5)C(＝O)-(C6-C10芳基)、-(CH2)n9C(＝O)O-(C1-C6烷基)、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R3a取代的C1-C6烷基、被一个或多个R3b取代的C1-C6烷基-O-、被一个或多个R3c取代的C1-C6烷基-S-、被一个或多个R3d取代的C2-C6烯基、被一个或多个R3e取代的C2-C6炔基、被一个或多个R3f取代的3-7元环烷基、被一个或多个R3g取代的3-7元环烯基、被一个或多个R3h取代的4-10元杂环烷基、被一个或多个R3i取代的4-10元杂环烯基、被一个或多个R3j取代的C6-C10芳基或被一个或多个R3k取代的5至14元杂芳基；所述“5至14元杂芳基”和“被一个或多个R3k取代的5至14元杂芳基”中的“5至14元杂芳基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烷基”和“被一个或多个R3h取代的4-10元杂环烷基”中的“4-10元杂环烷基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烯基”和“被一个或多个R3i取代的4-10元杂环烯基”中的“4-10元杂环烯基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；R 3 is halogen, -OH, deuterium, -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl , C 2 -C 6 alkynyl, nitro, -(CH 2 ) n6 N(R 5 ) 2 , -NHC(=NH)NH 2 , -(CH 2 ) n7 C(=O)N(R 5 ) 2 , -(CH 2 ) n8 C(=O)R 5 , -N(R 5 )C(=O)-(C 6 -C 10 aryl), -(CH 2 ) n9 C(=O)O -(C 1 -C 6 alkyl), 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6 -C 10 Aryl, 5- to 14-membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 3a , C 1 -C 6 alkyl substituted by one or more R 3b -O-, one C 1 -C 6 alkyl-S- substituted by one or more R 3c , C 2 -C 6 alkenyl substituted by one or more R 3d , C 2 -C 6 alkyne substituted by one or more R 3e group, 3-7 membered cycloalkyl substituted by one or more R 3f , 3-7 membered cycloalkenyl substituted by one or more R 3g , 4-10 membered heterogeneous substituted by one or more R 3h Cycloalkyl, 4-10 membered heterocycloalkenyl substituted by one or more R 3i , C 6 -C 10 aryl substituted by one or more R 3j or 5 to 10 substituted by one or more R 3k 14-membered heteroaryl; the heteroaryl in the "5- to 14-membered heteroaryl" in the "5- to 14-membered heteroaryl" and "5 to 14-membered heteroaryl substituted by one or more R3k " Atoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the "4-10 membered heterocycloalkyl" and "substituted by one or more R 3h The heteroatoms in the "4-10 membered heterocycloalkyl" in "4-10 membered heterocycloalkyl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the hetero in the "4-10-membered heterocyclenyl" in the "4-10-membered heterocyclenyl" and "4-10-membered heterocyclenyl substituted by one or more R3i " Atoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
    各R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j和R3k分别独立地为氘、卤素、-OH、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、-N(R5)2、-(CH2)-C(＝O)N(R5)2、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R3-a取代的C1-C6烷基、被一个或多个R3-b取代的C1-C6烷基-O-、被一个或多个R3-c取代的C1-C6烷基-S-、被一个或多个R3-d取代的C2-C6烯基、被一个或多个R3-e取代的C2-C6炔基、被一个或多个R3-f取代的3-7元环烷基、被一个或多个R3-g取代的4-10元杂环烷基、被一个或多个R3-h取代的5至14元杂芳基、被一个或多个R3-i取代的3-7元环烯基、被一个或多个R3-j取代的4-10元杂环烯基或被一个或多个R3-k取代的C6-C10芳基；所述“4-10元杂环烷基”和“被一个或多个R3-g取 代的4-10元杂环烷基”中的“4-10元杂环烷基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烯基”和“被一个或多个R3-j取代的4-10元杂环烯基”中的“4-10元杂环烯基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“5至14元杂芳基”和“被一个或多个R3-h取代的5至14元杂芳基”中的“5至14元杂芳基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；Each of R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j and R 3k is independently deuterium, halogen, -OH, -CN, C 1 - C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -N(R 5 ) 2 , -(CH 2 )-C(=O)N(R 5 ) 2 , 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycle Alkenyl, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 3-a , C substituted by one or more R 3-b 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S- substituted by one or more R 3-c , C 2 -C 6 alkenyl substituted by one or more R 3-d , C 2 -C 6 alkynyl substituted by one or more R 3-e , 3-7 membered cycloalkyl substituted by one or more R 3-f , substituted by one or more R 3-g 4-10 membered heterocycloalkyl, 5 to 14 membered heteroaryl substituted by one or more R 3-h , 3-7 membered cycloalkenyl substituted by one or more R 3-i , substituted by one or A 4-10 membered heterocycloalkenyl group substituted by multiple R 3-j or a C 6 -C 10 aryl group substituted by one or more R 3-k ; said "4-10 membered heterocycloalkyl" and " is taken by one or more R 3-g The heteroatoms in the "4-10-membered heterocycloalkyl" in "substituted 4-10-membered heterocycloalkyl" are selected from one or more of N, O and S, and the number of heteroatoms is 1 or 2 or 3; the "4-10-membered heterocyclenyl" in the "4-10-membered heterocyclenyl" and "4-10-membered heterocyclenyl substituted by one or more R3 -j " The heteroatoms in the group are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; The heteroatoms in the "5-14-membered heteroaryl" in 3-h substituted 5-14-membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
    各R3-a、R3-b、R3-c、R3-d、R3-e、R3-f、R3-g、R3-h、R3-i、R3-j和R3-k分别独立地为氘、卤素、-CN、-OH、C1-C6烷基、C1-C6烷基-O-或3-7元环烷基；Each of R 3-a , R 3-b , R 3-c , R 3-d , R 3-e , R 3-f , R 3-g , R 3-h , R 3-i , R 3-j and R 3-k are independently deuterium, halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O- or 3-7 membered cycloalkyl;
    R4a为氘、-OH、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、-(CH2)n7C(＝O)N(R5)2、-C(＝O)OR7、-C[N(R5)2](＝NR8)、C2-C6烯基、C2-C6炔基、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a取代的C1-C6烷基、被一个或多个R4-b取代的C1-C6烷基-O-、被一个或多个R4-c取代的C1-C6烷基-S-、被一个或多个R4-d取代的C2-C6烯基、被一个或多个R4-e取代的C2-C6炔基、被一个或多个R4-f取代的C6-C10芳基、被一个或多个R4-g取代的3-7元环烷基、被一个或多个R4-h取代的3-7元环烯基、被一个或多个R4-i取代的4-10元杂环烷基、被一个或多个R4-j取代的4-10元杂环烯基或被一个或多个R4-k取代的5至14元杂芳基；所述“5至14元杂芳基”和“被一个或多个R4-k取代的5至14元杂芳基”中的“5至14元杂芳基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烷基”和“被一个或多个R4-i取代的4-10元杂环烷基”中的“4-10元杂环烷基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烯基”和“被一个或多个R4-j取代的4-10元杂环烯基”中的“4-10元杂环烯基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；R 4a is deuterium, -OH, -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl -S-, -(CH 2 ) n7 C(= O)N(R 5 ) 2 , -C(=O)OR 7 , -C[N(R 5 ) 2 ](=NR 8 ), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 4-a , C 1 -C 6 alkyl-O- substituted by one or more R 4-b , one or more R 4-c Substituted C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl substituted by one or more R 4-d , C 2 -C 6 alkynyl substituted by one or more R 4-e , C 6 -C 10 aryl substituted by one or more R 4-f , 3-7 membered cycloalkyl substituted by one or more R 4-g , substituted by one or more R 4-h 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl substituted by one or more R 4-i , 4-10 membered heterocycloalkenyl substituted by one or more R 4-j , or substituted by one or a plurality of R 4-k substituted 5 to 14-membered heteroaryl; said "5 to 14-membered heteroaryl" and "5 to 14-membered heteroaryl substituted by one or more R 4-k " The heteroatoms in the "5 to 14 membered heteroaryl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the "4-10 membered heterocyclic The heteroatoms in the "4-10 membered heterocycloalkyl" in "alkyl" and "4-10 membered heterocycloalkyl" substituted by one or more R 4-i are selected from N, O and S One or more, the number of heteroatoms is 1, 2 or 3; the "4-10 membered heterocyclenyl" and "4-10 membered heterocyclenyl substituted by one or more R 4-j The heteroatoms in the "4-10 membered heterocycloalkenyl" in "group" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
    各R4-a、R4-b、R4-c、R4-d、R4-e和R4-f分别独立地为-OH、氘、卤素、-(CH2)n6N(R5)2、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a-1取代的C1-C6烷基、被一个或多个R4-a-2取代的C1-C6烷基-O-、被一个或多个R4-a-3取代的C1-C6烷基-S-、被一个或多个R4-a-4取代的C2-C6烯基、被一个或多个R4-a-5取代的C2-C6炔基、被一个或多个R4-a-6取代的3-7元环烷基、被一个或多个R4-a-7取代的3-7元环烯基、被一个或多个R4-a-8取代的4-10元杂环烷基、被一个或多个R4-a-9取代的4-10元杂环烯基、被一个或多个R4-a-10取代的C6-C10芳基或被一个或多个R4-a-11取代的5至14元杂芳基；所述“5至14元杂芳基”和“被一个或多个R4-a-11取代的5至14元杂芳基”中的“5至14元杂芳基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烷基”和“被一个或多个R4-a-8取代的4-10元杂环烷基”中的“4-10元杂环烷基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烯基”和“被一个或多个R4-a-9取代的4-10元杂环烯基”中的“4-10元杂环烯基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；Each of R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4-f is independently -OH, deuterium, halogen, -(CH 2 ) n6 N(R 5 ) 2 , -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl -S-, C 2 -C 6 alkenyl, C 2 -C 6 Alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heterocycloalkenyl, Aryl, C 1 -C 6 alkyl substituted by one or more R 4-a-1 , C 1 -C 6 alkyl substituted by one or more R 4-a-2 -O-, by one or C 1 -C 6 alkyl-S-substituted by R 4-a-3 , C 2 -C 6 alkenyl substituted by one or more R 4-a-4 , one or more R 4 -a-5 substituted C 2 -C 6 alkynyl, 3-7 membered cycloalkyl substituted by one or more R 4-a-6 , 3-substituted by one or more R 4-a-7 7-membered cycloalkenyl, 4-10-membered heterocycloalkyl substituted by one or more R 4-a-8 , 4-10-membered heterocycloalkenyl substituted by one or more R 4-a-9 , C 6 -C 10 aryl substituted by one or more R 4-a-10 or 5 to 14 membered heteroaryl substituted by one or more R 4-a-11 ; said "5 to 14 membered heteroaryl The heteroatoms in the "5 to 14-membered heteroaryl" in "aryl" and "5 to 14-membered heteroaryl substituted by one or more R 4-a-11 " are selected from N, O and S One or more, the number of heteroatoms is 1, 2 or 3; the "4-10 membered heterocycloalkyl" and "4-10 membered heterocycloalkyl substituted by one or more R 4-a-8 The heteroatoms in the "4-10 membered heterocycloalkyl" in "cycloalkyl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; the " The heteroatoms in the "4-10 membered heterocyclenyl" in "4-10 membered heterocyclenyl" and "4-10 membered heterocyclenyl substituted by one or more R 4-a-9 " are selected from From one or more of N, O and S, the number of heteroatoms is 1, 2 or 3;
    各R4-g、R4-h、R4-i、R4-j和R4-k分别独立地为-OH、氘、卤素、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、氧代基(＝O)、硫代基(＝S)、-C(＝O)OR7、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14 元杂芳基、被一个或多个R4-g-1取代的C1-C6烷基、被一个或多个R4-g-2取代的C1-C6烷基-O-、被一个或多个R4-g-3取代的C1-C6烷基-S-、被一个或多个R4-g-4取代的C2-C6烯基、被一个或多个R4-g-5取代的C2-C6炔基、被一个或多个R4-g-6取代的3-7元环烷基、被一个或多个R4-g-7取代的3-7元环烯基、被一个或多个R4-g-8取代的4-10元杂环烷基、被一个或多个R4-g-9取代的4-10元杂环烯基、被一个或多个R4-g-10取代的C6-C10芳基或被一个或多个R4-g-11取代的5至14元杂芳基；所述“5至14元杂芳基”和“被一个或多个R4-g-11取代的5至14元杂芳基”中的“5至14元杂芳基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烷基”和“被一个或多个R4- g-8取代的4-10元杂环烷基”中的“4-10元杂环烷基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；所述“4-10元杂环烯基”和“被一个或多个R4-g-9取代的4-10元杂环烯基”中的“4-10元杂环烯基”里的杂原子选自N、O和S中的一种或多种，杂原子个数为1、2或3个；Each of R 4-g , R 4-h , R 4-i , R 4-j and R 4-k is independently -OH, deuterium, halogen, -(CH 2 ) n6 N(R 5 ) 2 , - CN, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, oxo (=O), thiol (=S), -C(=O)OR 7 , 3-7 membered cycloalkyl, 3 -7-membered cycloalkenyl, 4-10-membered heterocycloalkyl, 4-10-membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 Member heteroaryl, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , C 1 -C 6 alkyl substituted by one or more R 4-g-2 -O-, C 1 -C 6 alkyl-S- substituted by one or more R 4-g-3 , C 2 -C 6 alkenyl substituted by one or more R 4-g-4 , one or more C 2 -C 6 alkynyl substituted by R 4-g-5 , 3-7 membered cycloalkyl substituted by one or more R 4-g-6 , substituted by one or more R 4-g-7 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl substituted by one or more R 4-g-8 , 4-10 membered heterocycloalkene substituted by one or more R 4-g-9 group, a C 6 -C 10 aryl group substituted by one or more R 4-g-10 or a 5 to 14 membered heteroaryl group substituted by one or more R 4-g-11 ; the "5 to 14 The heteroatoms in the "5 to 14-membered heteroaryl" in "heteroaryl" and "5 to 14-membered heteroaryl substituted by one or more R 4-g-11 " are selected from N, O and S One or more of them, the number of heteroatoms is 1, 2 or 3; the "4-10 membered heterocycloalkyl" and "4-10 substituted by one or more R 4- g-8 The heteroatoms in the "4-10 membered heterocycloalkyl" in "membered heterocycloalkyl" are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; The hetero in the "4-10 membered heterocycloalkenyl" in the "4-10 membered heterocycloalkenyl" and "4-10 membered heterocycloalkenyl substituted by one or more R 4-g-9 " Atoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
    各R4-a-1～R4-a-11和R4-g-1～R4-g-11分别独立地为氘、卤素、-CN、-OH、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-或3-7元环烷基；Each of R 4-a-1 to R 4-a-11 and R 4-g-1 to R 4-g-11 is independently deuterium, halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S- or 3-7 membered cycloalkyl;
    R4b为H、氘、-N(R5)2、卤素、-OH、C1-C6烷基、-CN、被一个或多个R4-b-1取代的C1-C6烷基、C1-C6烷基-O-、C2-C6烯基或C2-C6炔基；R 4b is H, deuterium, -N(R 5 ) 2 , halogen, -OH, C 1 -C 6 alkyl, -CN, C 1 -C 6 alkane substituted by one or more R 4-b-1 C 1 -C 6 alkyl-O-, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
    各R4-b-1分别独立地为氘、卤素、-CN或-OH；Each R 4-b-1 is independently deuterium, halogen, -CN or -OH;
    n1、n2、n3、n4、n5、n6、n7、n8和n9分别独立地为0、1、2、3、4或5；n1, n2, n3, n4, n5, n6, n7, n8 and n9 are independently 0, 1, 2, 3, 4 or 5;
    各R5分别独立地为H、-C(＝O)OR7或C1-C6烷基；Each R 5 is independently H, -C(=O)OR 7 or C 1 -C 6 alkyl;
    各R6a和R6b分别独立地为H、氘、卤素、-CN、-OH、C1-C6烷基或氘代C1-C6烷基；Each R 6a and R 6b are independently H, deuterium, halogen, -CN, -OH, C 1 -C 6 alkyl or deuterated C 1 -C 6 alkyl;
    R7独立地为H、氘、C1-C6烷基、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基或5至14元杂芳基；R 7 is independently H, deuterium, C 1 -C 6 alkyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl , C 6 -C 10 aryl or 5 to 14 membered heteroaryl;
    R8独立地为H、氘、-OH或C1-C6烷基。R 8 is independently H, deuterium, -OH or C 1 -C 6 alkyl.
  2. 如权利要求1所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述如式I所示的化合物不为如下任一化合物：






    The compound shown in formula I, its stereoisomer or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the compound shown in formula I is not any of the following compounds:






  3. 如权利要求1所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，The compound shown in formula I, its stereoisomer or its pharmaceutically acceptable salt as claimed in claim 1, is characterized in that,
    R4a为氘、-CN、C1-C6烷基-S-、-(CH2)n7C(＝O)N(R5)2、-C(＝O)OR7、-C[N(R5)2](＝NR8)、C2-C6烯基、C2-C6炔基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a取代的C1-C6烷基、被一个或多个R4-b取代的C1-C6烷基-O-、被一个或多个R4-c取代的C1-C6烷基-S-、被一个或多个R4-d取代的C2-C6烯基、被一个或多个R4-e取代的C2-C6炔基、被一个或多个R4-f取代的C6-C10芳基、被一个或多个R4-g取代的3-7元环烷基、被一个或多个R4-h取代的3-7元环烯基、被一个或多个R4-i取代的4-10元杂环烷基、被一个或多个R4-j取代的4-10元杂环烯基或被一个或多个R4-k取代的5至14元杂芳基；R 4a is deuterium, -CN, C 1 -C 6 alkyl-S-, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , -C(=O)OR 7 , -C[N (R 5 ) 2 ](=NR 8 ), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered hetero Cycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 4-a , substituted by one or more R 4-b C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S- substituted by one or more R 4-c , C 2 -C 6 alkene substituted by one or more R 4-d C 2 -C 6 alkynyl substituted by one or more R 4-e , C 6 -C 10 aryl substituted by one or more R 4-f , substituted by one or more R 4-g 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl substituted by one or more R 4-h , 4-10 membered heterocycloalkyl substituted by one or more R 4-i , one Or a 4-10 membered heterocyclenyl group substituted by multiple R 4-j or a 5 to 14 membered heteroaryl group substituted by one or more R 4-k ;
    各R4-a分别独立地为-OH、氘、-(CH2)n6N(R5)2、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a-1取代的C1-C6烷基、被一个或多个R4-a-2取代的C1-C6烷基-O-、被一个或多个R4-a-3取代的C1-C6烷基-S-、被一个或多个R4-a-4取代的C2-C6烯基、被一个或多个R4-a-5取代的C2-C6炔基、被一个或多个R4-a-6取代的3-7元环烷基、被一个或多个R4-a-7取代的3-7元环烯基、被一个或多个R4-a-8取代的4-10元杂环烷基、被一个或多个R4-a-9取代的4-10元杂环烯基、被一个或多个R4-a-10取代的C6-C10芳基或被一个或多个R4-a-11取代的5至14元杂芳基；Each R 4-a is independently -OH, deuterium, -(CH 2 ) n6 N(R 5 ) 2 , -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl , 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 4-a-1 , substituted by one or C 1 -C 6 alkyl-O- substituted by multiple R 4-a-2 , C 1 -C 6 alkyl-S- substituted by one or more R 4-a-3 , one or more C 2 -C 6 alkenyl substituted by R 4-a-4 , C 2 -C 6 alkynyl substituted by one or more R 4-a-5 , one or more R 4-a-6 substituted 3-7 membered cycloalkyl, 3-7 membered cycloalkenyl substituted by one or more R 4-a-7 , 4-10 membered heterocycloalkyl substituted by one or more R 4-a-8 , 4-10 membered heterocycloalkenyl substituted by one or more R 4-a-9 , C 6 -C 10 aryl substituted by one or more R 4-a-10, or substituted by one or more R 4-a-11 substituted 5 to 14 membered heteroaryl;
    各R4-b分别独立地为-OH、氘、-(CH2)n6N(R5)2、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a-1取代的C1-C6烷基、被一个或多个R4-a-2取代的C1-C6烷基-O-、被一个或多个R4-a-3取代的C1-C6烷基-S-、被一个或多个R4-a-4取代的C2-C6烯基、被一个或多个R4-a-5取代的C2-C6炔基、被一个或多个R4-a-6取代的3-7元环烷基、被一个或多个R4-a-7取代的3-7元环烯基、被一 个或多个R4-a-8取代的4-10元杂环烷基、被一个或多个R4-a-9取代的4-10元杂环烯基、被一个或多个R4-a-10取代的C6-C10芳基或被一个或多个R4-a-11取代的5至14元杂芳基；Each R 4-b is independently -OH, deuterium, -(CH 2 ) n6 N(R 5 ) 2 , -CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkene radical, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 4-a-1 , one or more R 4-a-2 Substituted C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S- substituted by one or more R 4-a-3 , substituted by one or more R 4-a-4 C 2 -C 6 alkenyl, C 2 -C 6 alkynyl substituted by one or more R 4-a-5 , 3-7 membered cycloalkyl substituted by one or more R 4-a-6 , 3-7 membered cycloalkenyl substituted by one or more R 4-a-7 , by one 4-10 membered heterocycloalkyl substituted by one or more R 4-a-8 , 4-10 membered heterocycloalkenyl substituted by one or more R 4-a-9 , one or more R 4 -a-10 substituted C 6 -C 10 aryl or 5 to 14 membered heteroaryl substituted by one or more R 4-a-11 ;
    各R4-c、R4-d、R4-e和R4-f分别独立地为-OH、氘、卤素、-(CH2)n6N(R5)2、-CN、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a-1取代的C1-C6烷基、被一个或多个R4-a-2取代的C1-C6烷基-O-、被一个或多个R4-a-3取代的C1-C6烷基-S-、被一个或多个R4-a-4取代的C2-C6烯基、被一个或多个R4-a-5取代的C2-C6炔基、被一个或多个R4-a-6取代的3-7元环烷基、被一个或多个R4-a-7取代的3-7元环烯基、被一个或多个R4-a-8取代的4-10元杂环烷基、被一个或多个R4-a-9取代的4-10元杂环烯基、被一个或多个R4-a-10取代的C6-C10芳基或被一个或多个R4-a-11取代的5至14元杂芳基；Each of R 4-c , R 4-d , R 4-e and R 4-f is independently -OH, deuterium, halogen, -(CH 2 ) n6 N(R 5 ) 2 , -CN, C 1 - C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3-7 membered cycloalkyl , 3-7 membered cycloalkenyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, replaced by one or more R 4 -a-1 substituted C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 4-a-2 -O-, substituted by one or more R 4-a-3 C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl substituted by one or more R 4-a-4 , C 2 -C substituted by one or more R 4-a-5 6 alkynyl, 3-7 membered cycloalkyl substituted by one or more R 4-a-6 , 3-7 membered cycloalkenyl substituted by one or more R 4-a-7 , substituted by one or more 4-10 membered heterocycloalkyl substituted by R 4-a-8 , 4-10 membered heterocycloalkenyl substituted by one or more R 4-a-9 , one or more R 4-a- 10 substituted C 6 -C 10 aryl or 5 to 14 membered heteroaryl substituted by one or more R 4-a-11 ;
    各R4-g、R4-h、R4-i、R4-j和R4-k分别独立地为-OH、氘、卤素、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6烷基、C1-C6烷基-O-、C1-C6烷基-S-、C2-C6烯基、C2-C6炔基、氧代基(＝O)、硫代基(＝S)、-C(＝O)OR7、3-7元环烷基、3-7元环烯基、4-10元杂环烷基、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-g-1取代的C1-C6烷基、被一个或多个R4-g-2取代的C1-C6烷基-O-、被一个或多个R4-g-3取代的C1-C6烷基-S-、被一个或多个R4-g-4取代的C2-C6烯基、被一个或多个R4-g-5取代的C2-C6炔基、被一个或多个R4-g-6取代的3-7元环烷基、被一个或多个R4-g-7取代的3-7元环烯基、被一个或多个R4-g-8取代的4-10元杂环烷基、被一个或多个R4-g-9取代的4-10元杂环烯基、被一个或多个R4-g-10取代的C6-C10芳基或被一个或多个R4-g-11取代的5至14元杂芳基；Each of R 4-g , R 4-h , R 4-i , R 4-j and R 4-k is independently -OH, deuterium, halogen, -(CH 2 ) n6 N(R 5 ) 2 , - CN, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, C 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, oxo (=O), thiol (=S), -C(=O)OR 7 , 3-7 membered cycloalkyl, 3 -7-membered cycloalkenyl, 4-10-membered heterocycloalkyl, 4-10-membered heterocycloalkenyl, C 6 -C 10 aryl, 5-14-membered heteroaryl, by one or more R 4-g -1 substituted C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 4-g-2 -O-, C substituted by one or more R 4-g-3 1 -C 6 alkyl-S-, C 2 -C 6 alkenyl substituted by one or more R 4-g-4 , C 2 -C 6 alkyne substituted by one or more R 4-g- 5 Group, 3-7 membered cycloalkyl substituted by one or more R 4-g-6 , 3-7 membered cycloalkenyl substituted by one or more R 4-g-7 , substituted by one or more R 4-10 membered heterocycloalkyl substituted by 4-g-8 , 4-10 membered heterocycloalkenyl substituted by one or more R 4-g-9 , substituted by one or more R 4-g-10 C 6 -C 10 aryl or 5 to 14 membered heteroaryl substituted by one or more R 4-g-11 ;
    优选地，R4a为-(CH2)n7C(＝O)N(R5)2、被一个或多个R4-j取代的4-10元杂环烯基、被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基、5至14元杂芳基或被一个或多个R4-a取代的C1-C6烷基；Preferably, R 4a is -(CH 2 ) n7 C(=O)N(R 5 ) 2 , a 4-10 membered heterocycloalkenyl substituted by one or more R 4-j , one or more R 5 to 14-membered heteroaryl substituted by 4-k , C 6 -C 10 aryl substituted by one or more R 4-f , C 6 -C 10 aryl, 5 to 14-membered heteroaryl or by one or C 1 -C 6 alkyl substituted by multiple R 4-a ;
    各R4-a分别独立地为-OH、-CN、-(CH2)n6N(R5)2或C2-C6炔基；Each R 4-a is independently -OH, -CN, -(CH 2 ) n6 N(R 5 ) 2 or C 2 -C 6 alkynyl;
    各R4-f分别独立地为-OH、卤素、-(CH2)n6N(R5)2或C2-C6炔基；Each R 4-f is independently -OH, halogen, -(CH 2 ) n6 N(R 5 ) 2 or C 2 -C 6 alkynyl;
    各R4-j和R4-k分别独立地为卤素、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6烷基、C1-C6烷基-O-、氧代基(＝O)、4-10元杂环烷基或被一个或多个R4-g-1取代的C1-C6烷基；Each of R 4-j and R 4-k is independently halogen, -(CH 2 ) n6 N(R 5 ) 2 , -CN, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, oxo (=O), 4-10 membered heterocycloalkyl or C substituted by one or more R 4-g-1 1 -C 6 alkyl;
    更优选地，R4a为被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基或5至14元杂芳基；More preferably, R 4a is 5 to 14 membered heteroaryl substituted by one or more R 4-k , C 6 -C 10 aryl substituted by one or more R 4-f , C 6 -C 10 Aryl or 5 to 14 membered heteroaryl;
    各R4-f分别独立地为卤素、-OH或C2-C6炔基；Each R 4-f is independently halogen, -OH or C 2 -C 6 alkynyl;
    各R4-k分别独立地为卤素、被一个或多个R4-g-1取代的C1-C6烷基、-(CH2)n6N(R5)2、C1-C6烷基或-CN。Each R 4-k is independently halogen, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , -(CH 2 ) n6 N(R 5 ) 2 , C 1 -C 6 Alkyl or -CN.
  4. 如权利要求1所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐满足以下条件中的一个或多个：The compound shown in formula I, its stereoisomer or pharmaceutically acceptable salt thereof as claimed in claim 1, characterized in that, the compound shown in formula I, its stereoisomer or Its pharmaceutically acceptable salt meets one or more of the following conditions:
    (1)环A为4-10元杂环烷基或4-10元杂环烯基；(1) Ring A is 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkenyl;
    (2)n为0或1；(2) n is 0 or 1;
    (3)各R1分别独立地为卤素、-CN、-OH、-N(R5)2、C1-C6烷基或被一个或多个R1a取代的C1-C6烷基； (3) Each R 1 is independently halogen, -CN, -OH, -N(R 5 ) 2 , C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more R 1a ;
    (4)各R1a、R1b、R1c和R1d分别独立地为-CN、卤素或-OH；(4) each of R 1a , R 1b , R 1c and R 1d is independently -CN, halogen or -OH;
    (5)L为-O-(CR6aR6b)n2-*，*表示与R2连接的一端；(5) L is -O-(CR 6a R 6b ) n2 -*, * indicates the end connected to R 2 ;
    (6)R2为4-10元杂环烷基或被一个或多个R2e取代的4-10元杂环烷基；(6) R 2 is a 4-10 membered heterocycloalkyl group or a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
    (7)各R2a、R2b、R2c、R2d、R2e、R2f和R2j分别独立地为卤素或C1-C6烷基；(7) each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2j is independently halogen or C 1 -C 6 alkyl;
    (8)R3为卤素、C6-C10芳基、5至14元杂芳基、被一个或多个R3j取代的C6-C10芳基或被一个或多个R3k取代的5至14元杂芳基；(8) R 3 is halogen, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 6 -C 10 aryl substituted by one or more R 3j or substituted by one or more R 3k 5 to 14 membered heteroaryl;
    (9)各R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j和R3k分别独立地为卤素、-OH、-N(R5)2、C1-C6烷基、被一个或多个R3-a取代的C1-C6烷基或C2-C6炔基；(9) Each of R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j and R 3k is independently halogen, -OH, -N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl or C 2 -C 6 alkynyl substituted by one or more R 3-a ;
    (10)各R3-a、R3-b、R3-c、R3-d、R3-e、R3-f、R3-g、R3-h、R3-i、R3-j和R3-k分别独立地为卤素、-CN或-OH；(10) Each of R 3-a , R 3-b , R 3-c , R 3-d , R 3-e , R 3-f , R 3-g , R 3-h , R 3-i , R 3-j and R 3-k are independently halogen, -CN or -OH;
    (11)R4a为C1-C6烷基、-(CH2)n7C(＝O)N(R5)2、4-10元杂环烯基、C6-C10芳基、5至14元杂芳基、被一个或多个R4-a取代的C1-C6烷基、被一个或多个R4-f取代的C6-C10芳基、被一个或多个R4-j取代的4-10元杂环烯基或被一个或多个R4-k取代的5至14元杂芳基；(11) R 4a is C 1 -C 6 alkyl, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , 4-10 membered heterocycloalkenyl, C 6 -C 10 aryl, 5 to 14-membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R 4-a , C 6 -C 10 aryl substituted by one or more R 4-f , one or more A 4-10 membered heterocyclenyl group substituted by R 4-j or a 5 to 14 membered heteroaryl group substituted by one or more R 4-k ;
    优选地，R4a为被一个或多个R4-j取代的4-10元杂环烯基、被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基或5至14元杂芳基；Preferably, R 4a is 4-10 membered heterocycloalkenyl substituted by one or more R 4-j , 5 to 14 membered heteroaryl substituted by one or more R 4-k , substituted by one or more R 4-f substituted C 6 -C 10 aryl, C 6 -C 10 aryl or 5 to 14 membered heteroaryl;
    更优选地，R4a为被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基或5至14元杂芳基；More preferably, R 4a is 5 to 14 membered heteroaryl substituted by one or more R 4-k , C 6 -C 10 aryl substituted by one or more R 4-f , C 6 -C 10 Aryl or 5 to 14 membered heteroaryl;
    (12)各R4-a、R4-b、R4-c、R4-d、R4-e和R4-f分别独立地为-OH、卤素、-(CH2)n6N(R5)2、-CN或C2-C6炔基；(12) Each of R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4-f is independently -OH, halogen, -(CH 2 ) n6 N( R 5 ) 2 , -CN or C 2 -C 6 alkynyl;
    优选地，各R4-a可分别独立地为-OH、-(CH2)n6N(R5)2、-CN或C2-C6炔基；各R4-b、R4-c、R4-d、R4-e和R4-f可分别独立地为-OH、卤素、-(CH2)n6N(R5)2或C2-C6炔基；Preferably, each R 4-a can be independently -OH, -(CH 2 ) n6 N(R 5 ) 2 , -CN or C 2 -C 6 alkynyl; each R 4-b , R 4-c , R 4-d , R 4-e and R 4-f can be independently -OH, halogen, -(CH 2 ) n6 N(R 5 ) 2 or C 2 -C 6 alkynyl;
    更优选地，各R4-a可分别独立地为-OH、-(CH2)n6N(R5)2或-CN，进一步优选为-OH；各R4-b、R4- c、R4-d、R4-e和R4-f可分别独立地为卤素、-OH或C2-C6炔基；More preferably, each R 4-a can be independently -OH, -(CH 2 ) n6 N(R 5 ) 2 or -CN, more preferably -OH; each R 4-b , R 4- c , R 4-d , R 4-e and R 4-f can be independently halogen, -OH or C 2 -C 6 alkynyl;
    (13)各R4-g、R4-h、R4-i、R4-j和R4-k分别独立地为卤素、-(CH2)n6N(R5)2、-CN、-(CH2)n7C(＝O)N(R5)2、C1-C6烷基、C1-C6烷基-O-、氧代基(＝O)、4-10元杂环烷基或被一个或多个R4-g-1取代的C1-C6烷基；(13) Each of R 4-g , R 4-h , R 4-i , R 4-j and R 4-k is independently halogen, -(CH 2 ) n6 N(R 5 ) 2 , -CN, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, oxo (=O), 4-10 membered hetero Cycloalkyl or C 1 -C 6 alkyl substituted by one or more R 4-g-1 ;
    (14)各R4-a-1～R4-a-11和R4-g-1～R4-g-11分别独立地为卤素；(14) Each of R 4-a-1 to R 4-a-11 and R 4-g-1 to R 4-g-11 is independently halogen;
    (15)R4b为卤素；(15) R 4b is halogen;
    (16)n1、n2、n3、n4、n5、n6、n7、n8和n9分别独立地为0或1；(16) n1, n2, n3, n4, n5, n6, n7, n8 and n9 are independently 0 or 1;
    (17)各R6a和R6b分别独立地为H。(17) Each of R 6a and R 6b is independently H.
  5. 如权利要求1所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐满足以下条件中的一个或多个：The compound shown in formula I, its stereoisomer or pharmaceutically acceptable salt thereof as claimed in claim 1, characterized in that, the compound shown in formula I, its stereoisomer or Its pharmaceutically acceptable salt meets one or more of the following conditions:
    (1)环A为4-10元杂环烷基；(1) Ring A is a 4-10 membered heterocycloalkyl group;
    (2)n为0；(2) n is 0;
    (3)R2为被一个或多个R2e取代的4-10元杂环烷基；(3) R 2 is a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
    (4)各R2a、R2b、R2c、R2d、R2e、R2f和R2j分别独立地为卤素；(4) each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2j is independently halogen;
    (5)R3为卤素或被一个或多个R3j取代的C6-C10芳基； (5) R 3 is halogen or C 6 -C 10 aryl substituted by one or more R 3j ;
    (6)各R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j和R3k分别独立地为卤素、-OH或C2-C6炔基；(6) Each of R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j and R 3k is independently halogen, -OH or C 2 -C 6 Alkynyl;
    (7)R4a为被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基、5至14元杂芳基或被一个或多个R4-a取代的C1-C6烷基；(7) R 4a is a 5- to 14-membered heteroaryl group substituted by one or more R 4-k , a C 6 -C 10 aryl group substituted by one or more R 4-f , a C 6 -C 10 aryl group radical, 5 to 14 membered heteroaryl or C 1 -C 6 alkyl substituted by one or more R 4-a ;
    (8)各R4-a、R4-b、R4-c、R4-d、R4-e和R4-f分别独立地为OH、卤素或C2-C6炔基；(8) Each of R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4-f is independently OH, halogen or C 2 -C 6 alkynyl;
    (9)各R4-g、R4-h、R4-i、R4-j和R4-k分别独立地为卤素、被一个或多个R4-g-1取代的C1-C6烷基、-(CH2)n6N(R5)2、C1-C6烷基或-CN；优选卤素、被一个或多个R4-g-1取代的C1-C6烷基、-(CH2)n6N(R5)2或C1-C6烷基；(9) Each of R 4-g , R 4-h , R 4-i , R 4-j and R 4-k is independently halogen, C 1 - substituted by one or more R 4-g-1 C 6 alkyl, -(CH 2 ) n6 N(R 5 ) 2 , C 1 -C 6 alkyl or -CN; preferably halogen, C 1 -C 6 substituted by one or more R 4-g-1 Alkyl, -(CH 2 ) n6 N(R 5 ) 2 or C 1 -C 6 alkyl;
    (10)n2为1；(10) n2 is 1;
    (11)n1、n3、n4、n5、n6、n7、n8和n9分别独立地为0。(11) n1, n3, n4, n5, n6, n7, n8 and n9 are each independently 0.
  6. 如权利要求1所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述的如式I所示的化合物满足如下任一方案：The compound shown in formula I, its stereoisomer or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the compound shown in formula I satisfies any of the following schemes:
    方案一：环A为4-10元杂环烷基；Scheme 1: Ring A is a 4-10 membered heterocycloalkyl group;
    n为0；n is 0;
    L为-O-(CR6aR6b)n2-*，*表示与R2连接的一端；L is -O-(CR 6a R 6b ) n2 -*, * represents one end connected with R 2 ;
    R2为4-10元杂环烷基或被一个或多个R2e取代的4-10元杂环烷基；R 2 is a 4-10 membered heterocycloalkyl group or a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
    各R2e分别独立地为卤素；each R 2e is independently halogen;
    R3为卤素或被一个或多个R3j取代的C6-C10芳基；R 3 is halogen or C 6 -C 10 aryl substituted by one or more R 3j ;
    各R3j分别独立地为卤素、-OH或C2-C6炔基；Each R 3j is independently halogen, -OH or C 2 -C 6 alkynyl;
    R4a为被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基、5至14元杂芳基或被一个或多个R4-a取代的C1-C6烷基；R 4a is a 5- to 14-membered heteroaryl group substituted by one or more R 4-k , a C 6 -C 10 aryl group substituted by one or more R 4-f , a C 6 -C 10 aryl group, 5 to 14-membered heteroaryl or C 1 -C 6 alkyl substituted by one or more R 4-a ;
    各R4-a和R4-f分别独立地为OH、卤素或C2-C6炔基；Each R 4-a and R 4-f is independently OH, halogen or C 2 -C 6 alkynyl;
    各R4-k分别独立地为卤素、被一个或多个R4-g-1取代的C1-C6烷基、-(CH2)n6N(R5)2或C1-C6烷基；Each R 4-k is independently halogen, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , -(CH 2 ) n6 N(R 5 ) 2 or C 1 -C 6 alkyl;
    各R4-g-1分别独立地为卤素；Each R 4-g-1 is independently halogen;
    R4b为卤素；R 4b is halogen;
    各R5分别独立地为H或C1-C6烷基；Each R 5 is independently H or C 1 -C 6 alkyl;
    n2为1；n2 is 1;
    n6为0；n6 is 0;
    各R6a和R6b分别各自独立地为Heach R 6a and R 6b are each independently H
    方案二：环A为4-10元杂环烷基；Scheme 2: Ring A is a 4-10 membered heterocycloalkyl group;
    n为0；n is 0;
    L为-O-(CR6aR6b)n2-*，*表示与R2连接的一端；L is -O-(CR 6a R 6b ) n2 -*, * represents one end connected with R 2 ;
    R2为4-10元杂环烷基或被一个或多个R2e取代的4-10元杂环烷基；R 2 is a 4-10 membered heterocycloalkyl group or a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
    各R2e分别独立地为卤素；each R 2e is independently halogen;
    R3为卤素或被一个或多个R3j取代的C6-C10芳基；R 3 is halogen or C 6 -C 10 aryl substituted by one or more R 3j ;
    各R3j分别独立地为卤素、-OH或C2-C6炔基； Each R 3j is independently halogen, -OH or C 2 -C 6 alkynyl;
    R4a为被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基、5至14元杂芳基或被一个或多个R4-a取代的C1-C6烷基；R 4a is a 5- to 14-membered heteroaryl group substituted by one or more R 4-k , a C 6 -C 10 aryl group substituted by one or more R 4-f , a C 6 -C 10 aryl group, 5 to 14-membered heteroaryl or C 1 -C 6 alkyl substituted by one or more R 4-a ;
    各R4-a分别独立地为-OH；Each R 4-a is independently -OH;
    各R4-f分别独立地为-OH、卤素或C2-C6炔基；Each R 4-f is independently -OH, halogen or C 2 -C 6 alkynyl;
    各R4-k分别独立地为卤素、-CN、被一个或多个R4-g-1取代的C1-C6烷基、-(CH2)n6N(R5)2或C1-C6烷基；Each R 4-k is independently halogen, -CN, C 1 -C 6 alkyl substituted by one or more R 4-g-1 , -(CH 2 ) n6 N(R 5 ) 2 or C 1 -C 6 alkyl;
    各R4-g-1分别独立地为卤素；Each R 4-g-1 is independently halogen;
    R4b为卤素；R 4b is halogen;
    各R5分别独立地为H或C1-C6烷基；Each R 5 is independently H or C 1 -C 6 alkyl;
    n2为1；n2 is 1;
    n6为0；n6 is 0;
    各R6a和R6b分别各自独立地为H；each R 6a and R 6b are each independently H;
    方案三：环A为4-10元杂环烷基；Scheme 3: Ring A is a 4-10 membered heterocycloalkyl group;
    n为0；n is 0;
    L为-O-(CR6aR6b)n2-*，*表示与R2连接的一端；L is -O-(CR 6a R 6b ) n2 -*, * represents one end connected with R 2 ;
    R2为4-10元杂环烷基或被一个或多个R2e取代的4-10元杂环烷基；R 2 is a 4-10 membered heterocycloalkyl group or a 4-10 membered heterocycloalkyl group substituted by one or more R 2e ;
    各R2e分别独立地为卤素或C1-C6烷基；Each R 2e is independently halogen or C 1 -C 6 alkyl;
    R3为卤素、C6-C10芳基、5至14元杂芳基、被一个或多个R3j取代的C6-C10芳基或被一个或多个R3k取代的5至14元杂芳基；R 3 is halogen, C 6 -C 10 aryl, 5 to 14 membered heteroaryl, C 6 -C 10 aryl substituted by one or more R 3j or 5 to 14 substituted by one or more R 3k Metaheteroaryl;
    各R3j和R3k分别独立地为卤素、-OH、-N(R5)2、C1-C6烷基、被一个或多个R3-a取代的C1-C6烷基或C2-C6炔基；Each of R 3j and R 3k is independently halogen, -OH, -N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by one or more R 3-a , or C 2 -C 6 alkynyl;
    各R3-a分别独立地为卤素、-CN或-OH；Each R 3-a is independently halogen, -CN or -OH;
    R4a为-(CH2)n7C(＝O)N(R5)2、被一个或多个R4-j取代的4-10元杂环烯基、4-10元杂环烯基、被一个或多个R4-k取代的5至14元杂芳基、被一个或多个R4-f取代的C6-C10芳基、C6-C10芳基、5至14元杂芳基或被一个或多个R4-a取代的C1-C6烷基；R 4a is -(CH 2 ) n7 C(=O)N(R 5 ) 2 , 4-10 membered heterocycloalkenyl substituted by one or more R 4-j , 4-10 membered heterocycloalkenyl, 5 to 14 membered heteroaryl substituted by one or more R 4-k , C 6 -C 10 aryl substituted by one or more R 4-f , C 6 -C 10 aryl, 5 to 14 membered Heteroaryl or C 1 -C 6 alkyl substituted by one or more R 4-a ;
    各R4-a分别独立地为-OH、-(CH2)n6N(R5)2或-CN；Each R 4-a is independently -OH, -(CH 2 ) n6 N(R 5 ) 2 or -CN;
    各R4-f分别独立地为-OH、卤素或C2-C6炔基；Each R 4-f is independently -OH, halogen or C 2 -C 6 alkynyl;
    各R4-k分别独立地为卤素、4-10元杂环烷基、-(CH2)n7C(＝O)N(R5)2、被一个或多个R4-g-1取代的C1-C6烷基、C1-C6烷基-O-、-(CH2)n6N(R5)2、C1-C6烷基或-CN；Each R 4-k is independently halogen, 4-10 membered heterocycloalkyl, -(CH 2 ) n7 C(=O)N(R 5 ) 2 , substituted by one or more R 4-g-1 C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, -(CH 2 ) n6 N(R 5 ) 2 , C 1 -C 6 alkyl or -CN;
    各R4-g-1分别独立地为卤素；Each R 4-g-1 is independently halogen;
    各R4-j为氧代基(＝O)；each R 4-j is oxo (=O);
    R4b为卤素；R 4b is halogen;
    各R5分别独立地为H或C1-C6烷基；Each R 5 is independently H or C 1 -C 6 alkyl;
    n2为1；n2 is 1;
    n6为0；n6 is 0;
    n7为0； n7 is 0;
    各R6a和R6b分别各自独立地为H。Each R 6a and R 6b are each independently H.
  7. 如权利要求1-6中任一项所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐满足以下条件中的一个或多个：The compound shown in formula I as described in any one of claims 1-6, its stereoisomer or pharmaceutically acceptable salt thereof, is characterized in that, the compound shown in formula I, Its stereoisomer or pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:
    (1)各所述“4-10元杂环烷基”分别独立地为5-8元杂环烷基，例如 (1) Each of the "4-10 membered heterocycloalkyl groups" is independently a 5-8 membered heterocycloalkyl group, for example
    (2)各所述卤素分别独立地为氟、氯、溴或碘；(2) each of said halogens is independently fluorine, chlorine, bromine or iodine;
    (3)各所述“C6-C10芳基”分别独立地为苯基或萘基；(3) Each of the "C 6 -C 10 aryl" is independently phenyl or naphthyl;
    (4)各所述“C1-C6烷基”分别独立地为C1-C4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；(4) Each of the "C 1 -C 6 alkyl groups" is independently a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    (5)各所述“C2-C6炔基”分别独立地为C2-C3炔基，例如乙炔基、丙炔基或炔丙基；(5) Each of the "C 2 -C 6 alkynyl groups" is independently a C 2 -C 3 alkynyl group, such as ethynyl, propynyl or propargyl;
    (6)各所述“5至14元杂芳基”分别独立地为“杂原子为N或S，杂原子数为1个或2个的5-10元杂芳基”，例如吡唑基、吡啶基、喹啉基、异喹啉基、喹唑啉基、吲哚基、吲唑基、吡唑并吡啶基、嘧啶基或苯并噻吩基；(6) Each of the "5- to 14-membered heteroaryl groups" is independently "a 5-10-membered heteroaryl group whose heteroatom is N or S, and the number of heteroatoms is 1 or 2", such as pyrazolyl , pyridyl, quinolinyl, isoquinolyl, quinazolinyl, indolyl, indazolyl, pyrazolopyridyl, pyrimidinyl or benzothienyl;
    (7)各所述“4-10元杂环烯基”分别独立地为5-8元杂环烯基，例如 (7) Each of the "4-10 membered heterocyclenyl groups" is independently a 5-8 membered heterocyclenyl group, for example
    (8)各所述“3-7元环烷基”分别独立地为环丙基、环丁基、环戊基或环己基；(8) Each of the "3-7 membered cycloalkyl groups" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
    (9)各所述“3-7元环烯基”分别独立地为环丙烯基、环丁烯基、环戊烯基或环己烯基；(9) Each of the "3-7 membered cycloalkenyl groups" is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl;
    (10)各所述“C2-C6烯基”分别独立地为乙烯基、1-丙烯基、正烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基或戊-1,4-二烯基。(10) Each of the "C 2 -C 6 alkenyl" is independently vinyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1- alkenyl or pent-1,4-dienyl.
  8. 如权利要求1-6中任一项所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐满足以下条件中的一个或多个：The compound shown in formula I as described in any one of claims 1-6, its stereoisomer or pharmaceutically acceptable salt thereof, is characterized in that, the compound shown in formula I, Its stereoisomer or pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:
    (1)环A、R2、R4-g、R4-h、R4-i、R4-j和R4-k中，所述“4-10元杂环烷基”和“被一个或多个R2e取代的4-10元杂环烷基”中的“4-10元杂环烷基”分别独立地为5-8元杂环烷基，例如 (1) In ring A, R 2 , R 4-g , R 4-h , R 4-i , R 4-j and R 4-k , the "4-10 membered heterocycloalkyl" and "are The "4-10-membered heterocycloalkyl group" in the 4-10-membered heterocycloalkyl group substituted by one or more R 2e is independently a 5-8-membered heterocycloalkyl group, for example
    (2)R2a、R2b、R2c、R2d、R2e、R2f、R2j、R3、R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j、 R3k、R4-a、R4-b、R4-c、R4-d、R4-e、R4-f、R4-g、R4-h、R4-i、R4-j、R4-k、R4-a-1～R4-a-11、R4-g-1～R4-g-11和R4b中，所述“卤素”分别独立地为氟、氯、溴或碘；(2) R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2j , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , R 4-a , R 4-b , R 4-c , R 4-d , R 4-e , R 4-f , R 4-g , R 4-h , R 4-i , R 4 In -j , R 4-k , R 4-a-1 to R 4-a-11 , R 4-g-1 to R 4-g-11 and R 4b , the "halogen" is independently fluorine , chlorine, bromine or iodine;
    (3)R3和R4a中，所述“被一个或多个R3j取代的C6-C10芳基”、“C6-C10芳基”和“被一个或多个R4-f取代的C6-C10芳基”中的“C6-C10芳基”分别独立地为苯基或萘基；(3) Among R 3 and R 4a , the "C 6 -C 10 aryl substituted by one or more R 3j ", "C 6 -C 10 aryl" and "one or more R 4- The "C 6 -C 10 aryl" in f substituted C 6 -C 10 aryl" are independently phenyl or naphthyl;
    (4)R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j、R3k、R4a、R4-g、R4-h、R4-i、R4-j、R4-k和R5中，所述“C1-C6烷基”、“被一个或多个R4-a取代的C1-C6烷基”、“C1-C6烷基-O-”和“被一个或多个R4-g-1取代的C1-C6烷基”中的“C1-C6烷基”分别独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；(4) R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , R 4a , R 4 -g , R 4-h , R Among 4-i , R 4-j , R 4-k and R 5 , the "C 1 -C 6 alkyl", "C 1 -C 6 alkyl substituted by one or more R 4-a ""C 1 -C 6 alkyl" in "C 1 -C 6 alkyl-O-" and " C 1 -C 6 alkyl substituted by one or more R 4-g-1 " are independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    (5)R3a、R3b、R3c、R3d、R3e、R3f、R3g、R3h、R3i、R3j、R3k、R4-a、R4-b、R4-c、R4-d、R4-e和R4- f中，所述“C2-C6炔基”分别独立地为C2-C3炔基，例如乙炔基、丙炔基或炔丙基；(5) R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , R 4-a , R 4-b , R 4-c , R 4-d , R 4-e and R 4- f , the "C 2 -C 6 alkynyl" is independently C 2 -C 3 alkynyl, such as ethynyl, propynyl or propargyl base;
    (6)R4a中，所述“5至14元杂芳基”和“被一个或多个R4-k取代的5至14元杂芳基”中的“5至14元杂芳基”分别独立地为“杂原子为N或S，杂原子数为1个或2个的5-10元杂芳基”，例如吡唑基、吡啶基、喹啉基、异喹啉基、喹唑啉基、吲哚基、吲唑基、吡唑并吡啶基、嘧啶基或苯并噻吩基；(6) In R 4a , the "5 to 14-membered heteroaryl" in the "5 to 14-membered heteroaryl" and "5 to 14-membered heteroaryl substituted by one or more R 4-k " Each independently is "the heteroatom is N or S, and the number of heteroatoms is 1 or 2 5-10 membered heteroaryl", such as pyrazolyl, pyridyl, quinolinyl, isoquinolyl, quinazolyl Linyl, indolyl, indazolyl, pyrazolopyridyl, pyrimidinyl or benzothienyl;
    (7)R4a中，“被一个或多个R4-j取代的4-10元杂环烯基”中的“4-10元杂环烯基”分别独立地为5-8元杂环烯基，例如 (7) In R 4a , the "4-10 membered heterocycloalkenyl" in "4-10 membered heterocycloalkenyl substituted by one or more R 4-j " are independently 5-8 membered heterocycles Alkenyl, eg
  9. 如权利要求7所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐满足以下条件中的一个或多个：The compound shown in formula I, its stereoisomer or pharmaceutically acceptable salt thereof as claimed in claim 7, characterized in that, the compound shown in formula I, its stereoisomer or Its pharmaceutically acceptable salt meets one or more of the following conditions:
    (1)各所述“4-10元杂环烷基”分别独立地为其中所述为 (1) Each of the "4-10 membered heterocycloalkyl groups" is independently which stated for
    (2)各所述卤素分别独立地为氟或氯；(2) each of said halogens is independently fluorine or chlorine;
    (3)各所述“C1-C6烷基”分别独立地为甲基或乙基；(3) Each of the "C 1 -C 6 alkyl" is independently methyl or ethyl;
    (4)各所述“C2-C6炔基”分别独立地为乙炔基；(4) Each of the "C 2 -C 6 alkynyl groups" is independently an ethynyl group;
    (5)各所述“5至14元杂芳基”分别独立地为 (5) Each of the "5- to 14-membered heteroaryl groups" is independently
  10. 如权利要求1所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐满足以下条件中的一个或多个：The compound shown in formula I, its stereoisomer or pharmaceutically acceptable salt thereof as claimed in claim 1, characterized in that, the compound shown in formula I, its stereoisomer or Its pharmaceutically acceptable salt meets one or more of the following conditions:
    (1)环A为 (1) Ring A is
    (2)n为0；(2) n is 0;
    (3)L为-O-CH2-*，*表示与R2连接的一端；(3) L is -O-CH 2 -*, * represents one end connected with R 2 ;
    (4)R2为 (4) R 2 is
    (5)R4b为F；(5) R 4b is F;
    (6)R3为或Cl；(6) R 3 is or Cl;
    (7)R4a为 (7) R 4a is
  11. 如权利要求1或10所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐满足以下条件中的一个或多个：The compound shown in formula I, its stereoisomer or pharmaceutically acceptable salt thereof as claimed in claim 1 or 10, characterized in that, the compound shown in formula I, its stereoisomer The body or a pharmaceutically acceptable salt thereof meets one or more of the following conditions:
    (1)R2为 (1) R2 is
    (2)R4a为 优选 (2) R 4a is preferred
  12. 如权利要求1所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐，其特征在于，如式I所示的化合物为如下任一化合物：



    The compound shown in formula I as claimed in claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, is characterized in that, the compound shown in formula I is any one of the following compounds:



    或者，所述如式I所示的化合物的药学上可接受的盐为如下任一化合物：
    的三氟醋酸盐。    Alternatively, the pharmaceutically acceptable salt of the compound shown in formula I is any of the following compounds:
    of trifluoroacetate.
  13. 一种如下所示化合物：




    A compound shown below:




    或者，如下任一化合物的盐酸盐：

    Alternatively, the hydrochloride salt of any of the following compounds:

  14. 如权利要求1-12中任一项所述的如式I所示化合物、其立体异构体或其药学上可接受的盐的制备方法，其为如下路线：The preparation method of the compound shown in formula I as described in any one of claims 1-12, its stereoisomer or its pharmaceutically acceptable salt, it is following route:
    路线一：
    Route 1:
    其中，P1为氨基保护基，例如Boc、PMB、Bn、Cbz、Fmoc，Wherein, P is an amino protecting group, such as Boc, PMB, Bn, Cbz, Fmoc,
    L、R2、R3和R4a的定义如权利要求1-12中任一项所述；The definitions of L, R 2 , R 3 and R 4a are as described in any one of claims 1-12;
    步骤1：在溶剂中，在碱及催化剂存在下，将如式SM-1所示的化合物进行Suzuki反应，得到如式SM-2所示的化合物即可；Step 1: In a solvent, in the presence of a base and a catalyst, the compound shown in formula SM-1 is subjected to Suzuki reaction to obtain the compound shown in formula SM-2;
    步骤2：在溶剂中，在碱及催化剂存在下，将如式SM-2所示的化合物进行Suzuki反应，得到如式SM-3所示的化合物即可；Step 2: In a solvent, in the presence of a base and a catalyst, the compound shown in the formula SM-2 is subjected to Suzuki reaction to obtain the compound shown in the formula SM-3;
    步骤3：脱保护反应[R3中取代基R3a、R3b(例如-OH、-NH2、C2-C6炔基)如被保护基保护，可进行脱保护反应得到通式I化合物]；Step 3: deprotection reaction [substituents R 3a and R 3b (such as -OH, -NH 2 , C 2 -C 6 alkynyl) in R 3 are protected by a protecting group, and a deprotection reaction can be performed to obtain a compound of formula I ];
    所述步骤3中的脱保护反应满足以下条件的一种或多种：The deprotection reaction in the step 3 meets one or more of the following conditions:
    (1)在酸性条件下，进行脱氨基保护基、脱羟基保护基反应；(1) Under acidic conditions, carry out deamination protecting group, dehydroxyl protecting group reaction;
    (2)在四丁基氟化铵、四甲基氟化铵或氟化铯存在下，脱TIPS保护；(2) In the presence of tetrabutylammonium fluoride, tetramethylammonium fluoride or cesium fluoride, de-TIPS protection;
    路线二：
    Route two:
    其中，P1为氨基保护基，例如Boc、PMB、Bn、Cbz或Fmoc，Wherein, P 1 is an amino protecting group, such as Boc, PMB, Bn, Cbz or Fmoc,
    L、R2和R4a的定义如权利要求1-12中任一项所述；L, R 2 and R 4a are as defined in any one of claims 1-12;
    步骤1：在溶剂中，在碱及催化剂存在下，将如式SM-1所示的化合物进行Suzuki反应，得到如式SM-4所示的化合物即可；Step 1: In a solvent, in the presence of a base and a catalyst, the compound shown in formula SM-1 is subjected to a Suzuki reaction to obtain a compound shown in formula SM-4;
    步骤2：在酸性条件下，将如式SM-4所示的化合物进行脱氨基保护基反应。Step 2: Under acidic conditions, the compound represented by the formula SM-4 is subjected to a deamination protecting group reaction.
  15. 一种药物组合物，其包含物质A和药用辅料；其特征在于，所述的物质A为如权利要求1-12 中任一项所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐。A pharmaceutical composition comprising substance A and pharmaceutical excipients; characterized in that, said substance A is as claimed in claims 1-12 Any one of the compounds shown in formula I, its stereoisomers or pharmaceutically acceptable salts thereof.
  16. 一种物质A在制备RAS抑制剂中的应用，其特征在于，所述的物质A为如权利要求1-12中任一项所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐；A kind of application of substance A in the preparation of RAS inhibitor, it is characterized in that, described substance A is the compound shown in formula I as described in any one of claim 1-12, its stereoisomer or its pharmaceutically acceptable salt;
    所述的RAS为KRAS或KRAS突变；例如KRAS G12D、KRAS G12V。The RAS is KRAS or KRAS mutation; for example KRAS G12D, KRAS G12V.
  17. 一种物质A在制备药物中的应用，其特征在于，A kind of application of substance A in the preparation of medicine, characterized in that,
    所述的物质A为如权利要求1-12中任一项所述的如式I所示的化合物、其立体异构体或其药学上可接受的盐；所述的物质A可为治疗有效量的；所述的药物可为用于治疗和/或预防RAS介导的疾病的药物；或，所述的药物可为用于治疗和/或预防癌症的药物。Described material A is the compound shown in formula I as described in any one in claim 1-12, its stereoisomer or its pharmaceutically acceptable salt; Described material A can be therapeutically effective The amount; the drug can be used to treat and/or prevent RAS-mediated diseases; or, the drug can be used to treat and/or prevent cancer.
  18. 如权利要求17所述的应用，其特征在于，所述的应用满足以下条件中的一个或多个：The application according to claim 17, wherein the application satisfies one or more of the following conditions:
    (1)所述的RAS为KRAS或KRAS突变；例如KRAS G12D、KRAS G12V；(1) The RAS is KRAS or KRAS mutation; for example, KRAS G12D, KRAS G12V;
    (2)所述的RAS介导的疾病为癌症；(2) The disease mediated by RAS is cancer;
    (3)所述的癌症选自结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、子宫颈癌、睾丸癌、肾癌、头或颈癌、骨癌、皮肤癌、直肠癌、肝癌、结直肠癌、非小细胞肺癌、小细胞肺癌、食道癌、胃癌、甲状腺癌、膀胱癌、淋巴瘤、白血病和黑色素瘤中的一种或多种。 (3) The cancer is 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, One or more of rectal cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophagus cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.
PCT/CN2023/072929 2022-01-28 2023-01-18 Nitrogen-containing heterocyclic compound, and preparation method therefor and use thereof WO2023143312A1 (en)

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