WO2024061333A1 - Kras mutant protein inhibitor, preparation method therefor, and use thereof - Google Patents

Kras mutant protein inhibitor, preparation method therefor, and use thereof Download PDF

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WO2024061333A1
WO2024061333A1 PCT/CN2023/120527 CN2023120527W WO2024061333A1 WO 2024061333 A1 WO2024061333 A1 WO 2024061333A1 CN 2023120527 W CN2023120527 W CN 2023120527W WO 2024061333 A1 WO2024061333 A1 WO 2024061333A1
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alkyl
group
compound
membered
alkylene
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PCT/CN2023/120527
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French (fr)
Chinese (zh)
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尹磊
刘小晶
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甘李药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a compound capable of inhibiting KRas. Specifically, the present invention relates to a compound capable of inhibiting the activity of KRas mutant protein, a pharmaceutical composition comprising the compound, and a preparation method and use thereof.
  • KRas is one of the commonly mutated genes in the RAS gene family, accounting for approximately 86% of the total RAS gene mutations (for example, see Salgia et al., (2021) Cell Reports Medicine 2, 100186, January 19.).
  • KRas protein is encoded by Kirsten rat sarcoma virus oncogene homolog (KRas), which belongs to the small GTPase (smallGTPase) containing 188 amino acids and belongs to the RAS superprotein family. KRas protein maintains normal biological functions by cycling between "inactivated” and “activated” states in response to extracellular signals (for example, see Alamgeer et al., (2013) Current Opin Pharmcol. 13: 394-401 ).
  • KRas mutations are present in approximately 40%-50% of colorectal cancer patients, 30% of non-small cell lung cancer patients, and 80%-90% of pancreatic cancer patients worldwide. Positive (see, e.g., Hofmann et al., (2022) Cancer Discovery; 12:924-937). According to statistics from Frost & Sullivan, the number of major KRas mutation-positive cancers worldwide has increased from 1.8 million in 2016 to 2.009 million in 2020, and is expected to increase to 2.276 million in 2025. Faced with this huge therapeutic need, there are no clinically effective solutions and therefore there is a huge unmet medical need for therapeutic intervention in cancer patients with RAS mutations.
  • Mirati Therapeutics and Yifang Biotechnology Co., Ltd. have successively disclosed KRas G12D inhibitor patents, namely WO2021041671 and WO2022042630.
  • KRas G12D inhibitor patents namely WO2021041671 and WO2022042630.
  • the molecular structures of the representative compound MRTX1133 of the patent WO2021041671 and the representative compound PC-1 of WO2022042630 are respectively As shown in the following structural formula:
  • KRas mutation is one of the important factors leading to colorectal cancer, lung cancer and pancreatic cancer, especially in pancreatic cancer, the incidence rate is as high as 36%, and there is no therapeutic drug targeting this target. Therefore, there is huge potential for this targeted drug. Due to market demand, it is of great significance to develop this target drug. There is an urgent need to develop new KRas mutant protein inhibitors to provide patients with more medication options.
  • One object of the present invention is to provide a new compound that inhibits the activity of KRas mutant protein.
  • the compounds provided by the invention can selectively inhibit the activity of KRas mutant protein and can be used to treat cell proliferation disorders to a certain extent.
  • the present invention adopts the following technical solutions:
  • One aspect of the invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein ,
  • R 1 is CR 1a or N;
  • R 1a is selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxyalkylene, -COO alkyl, carboxyl, amino, -CONH 2 , -NHCO alkyl, alkyl , alkylene cyano, alkenyl and alkynyl; preferably, R 1a is selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, -COO C 1-6 alkyl, carboxyl, amino, -CONH 2. -NHCOC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkylenecyano, C 2-6 alkenyl and C 2-6 alkynyl;
  • R 2 is a 3-12 membered saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring containing at least 1 N atom, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring optionally substituted by one, two or more R 2a ; preferably, R 2 is a 3-12 membered saturated or partially saturated monocyclic ring, bridged ring, fused ring or containing 1, 2 or 3 ring N Spiro ring, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spiro ring is optionally substituted by one or more R 2a ; preferably, R 2 is a saturated or spiro ring containing 1 or 2 ring N Partially saturated 3-10-membered monocyclic ring, 6-12-membered bridged ring, 4-10-membered fused ring or 5-12-membered s
  • R 3 is selected from alkyl, alkylenehydroxy, -L-heterocyclyl, -L-aryl, -L-arylene-L-heterocyclyl, -L-heteroarylene-L-heterocycle base, -L-heteroaryl, -L-heterocyclylene-L-OCO-N(R 5 ) 2 , -L-heterocyclylene-L-NR 5 -CO-N(R 5 ) 2 , -L-heterocyclylene-L-NR 5 -CO-R 5 , -L-cycloalkyl, -L-cycloalkylene-LN(R 5 ) 2 , -L-cycloalkylene-L- Heterocyclyl and -L-cycloalkylene-LN(R 5 ) 2 , wherein the heterocyclyl, heteroarylene, heteroaryl, and heterocyclylene each independently contain 1, 2, 3 Or 4 heteroatoms each
  • Cy 2 is an aryl group fused to Cy 1 , a saturated or partially unsaturated cycloalkyl group, a heteroaryl group containing 1, 2 or 3 heteroatoms each independently selected from N, O and S, containing 1, A saturated heterocycloalkyl group with 2 or 3 heteroatoms each independently selected from N, O and S, or a partially unsaturated heterocycloalkyl group containing 1, 2 or 3 heteroatoms each independently selected from N, O and S.
  • Cycloalkyl, the aryl, saturated or partially unsaturated cycloalkyl, heteroaryl, heterocycloalkyl can optionally be 1, 2, 3 or more selected from halogen, alkyl, Hydroxy, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl , heterocyclyl, and heteroaryl substituents, optionally, the alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl groups are substituted by 1, 2 One, three or more selected from halogen, alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylene Substituted
  • q 0, 1, or 2;
  • Each occurrence of R a is independently selected from hydrogen, halogen, alkyl, alkynyl, hydroxy, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkylenehydroxy, aryl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, and heteroaryl, optionally, the Alkyl, alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylenehydroxy, aryl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, and
  • the heteroaryl group is 1, 2, 3 or more selected from F, Cl, Br, I, C 1-6 alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl Base, -CO-C 1-6 alkyl, C 1-6 alkoxy
  • R b When connected to R b When it is a double bond, R b is independently O, S or C(R 5 ) 2 each time it appears; when it is connected to R b When it is a single bond, each occurrence of R b is independently selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, cyano, amino, aminoalkyl, alkyleneamino, cycloalkyl, heterocyclyl , -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkylenehydroxy, aryl, alkynyl, alkenyl, and heteroaryl, preferably, each occurrence of R b is independently Selected from hydrogen, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, cyano, amino, amino C 1-6 alkyl, C 1-6 alkylene amino , C 3-10 cycloalkyl, C 3-10 heterocyclyl, -CONH 2
  • R c is selected from H, C 1-6 alkyl, -CN, - ⁇ -R ca , -CONH 2 and -OCONH 2 ; when R 2 contains 2 ring N atoms, and when R c is C 1-6 When R 1 is N, R 4 is When R 2 contains 2 ring N atoms, when R c is H, R 1 is CR 1a , and R 1a is When CN, R 4 is R 3 is
  • each R ca is independently selected from hydrogen, amino, hydroxyl, halogen, cyano, -CONH 2 , -NHC(O)C 1-6 alkyl, -CO-C 1-6 Alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylene amino, C 1-6 alkylene NHC 1-6 alkyl, C 1-6 alkylene hydroxyl, C 2-6 alkynyl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, and heteroaryl, optionally, the C 1-6 alkyl, C 1 -6 alkylene, C 2-6 alkynyl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are 1, 2, 3 or more selected from halogen, Alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-
  • R d is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, hydroxy, mercapto, hydroxyalkylene, carboxyl, oxo, alkoxy, amino, -CONH 2 , - NHC(O)alkyl, alkyl, C 1-6 alkylenecyano, -CO-alkyl, alkylamino, alkyleneamino, alkyleneNHalkyl, aryl, cycloalkyl, hetero Cyclic group, heteroaryl group, alkenyl group and alkynyl group, optionally, the alkyl group, alkylene group, alkynyl group, alkenyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are replaced by 1, 2, 3 or more selected from halogen, alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO
  • R 4 is selected from aryl and heteroaryl substituted by 0, 1, 2, 3, 4, 5, or more R 4a , and the heteroaryl contains 1, 2, 3 or 4 each independently selected from Heteroatoms of N, O and S; preferably, R 4 is selected from 6-12-membered aryl and 5-12-membered heteroaryl substituted by 0, 1, 2, 3, 4, 5, or more R 4a base, the 5-12 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S; preferably, R 4 is selected from 0, 1, 2, 3, 4 , 5, or more R 4a substituted phenyl, naphthyl, 5-6 membered heteroaryl, 7-8 membered heteroaryl, 9-10 membered heteroaryl, and benzo 5-6 membered heteroaryl base, the 5-6-membered heteroaryl, 7-8-membered heteroaryl, 9-10-membered heteroaryl, and benzo 5-6-membered heteroaryl include 1, 2, 3 or 4 independently selected heteroatom
  • C 1-6 alkyl-CO-NR 4c - halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylene amino , 3-10 membered cycloalkyl, 3-10 membered cycloalkylene C 1-6 alkyl, 3-10 membered heterocycloalkyl and 3-10 membered heterocycloalkylene C 1-6 alkyl, any Optionally, the C 2-6 alkynyl, C 2-6 alkenyl, C 2-6 alkynylene, C 2-6 alkenylene, C 1-6 alkylene, C 1-6 alkoxy , C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 3-10 heterocycloalkyl and C 3-10 heterocycloalkylene One or more selected from halogen, alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOCOC
  • Each occurrence of R 4c is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxyalkylene, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, amino, - CONH 2 , -NHCOC 1-6 alkyl, alkyl, C 1-6 alkylenecyano, alkenyl and alkynyl;
  • Another aspect of the invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, in,
  • R 1 is CR 1a or N;
  • R 1a is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester group, carboxyl, -CONH 2 , amino, -NHCOC 1-6 alkyl, Alkyl, C 1-4 alkylcyano, alkenyl and alkynyl;
  • R 2 is a 3-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring containing at least 1 N, wherein the saturated or partially saturated monocyclic, bridged or spirocyclic ring is optionally substituted by one or more R 2a ; each time R 2a appears, each R 2a is independently selected from halogen, cyano, hydroxyl, thiol, hydroxymethyl, ester, carboxyl, carbonyl, amino, -CONH 2 -NHCOC 1-6 alkyl, alkyl, C 1-4 alkylcyano, alkenyl and alkynyl; preferably, R 2 is a 3-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring containing 1 ring N, wherein the saturated or partially saturated monocyclic, bridged or spirocyclic ring is optionally substituted by one or more R 2a ; preferably, R R2a is a saturated or partially saturated 3, 5, 6, 7,
  • Each L is independently selected from C 1-6 alkylene, C 1-6 hydroxyalkyl and heteroaryl;
  • Cy 2 is fused with Cy 1 , and Cy 2 is an aryl group or a 5-7-membered heteroaryl group containing 1 or 2 heteroatoms, a 5-7-membered saturated heterocycloalkyl group, or a 5-7-membered unsaturated heterocycloalkyl group; and when Cy 2 is an aryl group or a pyridyl group, it has the structural formula
  • Each occurrence of Ra is independently selected from hydrogen, halo, alkyl, alkynyl, hydroxy, cyano, -CONH2 , -NHCOC1-6alkyl , -CO-alkyl, C1-4alkoxy , C1-4alkylamino , C1-4alkylhydroxy, aryl, C2-4alkynyl , C2-6alkenyl , cycloalkyl, heterocyclyl, heteroaryl;
  • Rc is selected from -CN, - ⁇ - Rca , At each occurrence of Rca , each
  • R d is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, oxo, oxyalkyl, amino, -CONH 2 , -NHC(O)C 1-6 alkyl, alkyl, C 1-4 alkylcyano, alkenyl and alkynyl;
  • R 4 is selected from phenyl, naphthyl, 5-6 membered heteroaryl, benzo 5-6 membered heterocyclyl, benzo 5-6 membered cycloalkenyl and benzo 5-6 membered heteroaryl substituted by 1, 2, or 3 R 4a or 1, 2 or 3 R 4b ; each R 4a is independently selected from halo, -OH, -SH, -NH 2 , -CN, -CO-alkyl, -CON(R 4c ) 2 , C 1-4 alkyl, halo C 1-4 alkyl, halo C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl and 4-7 membered heterocycloalkyl C 1-4 alkyl; each R 4b is independently selected from halo, -OH, -SH, -NH 2 , -NO 2 , -
  • each R 4a is independently selected from H, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, halogen, -OH, -SH, -CN, -COR 5 , -CON(R 5 ) 2 , -OCON(R 5 ) 2 and - ⁇ -R ca ;
  • each R ca is independently selected from hydrogen, halogen, -CN, -COO-alkyl, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, C 1-4 Alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylhydroxy, aryl, C 2-4 alkynyl, C 2-6 alkenyl, cycloalkyl, heterocycle base and heteroaryl;
  • R 6 is independently selected from H and C 1-4 alkyl
  • the compound of formula I is not:
  • R 4 is selected from
  • R 2 is selected from
  • R 3 is selected from C 1-6 alkyl
  • n 0, 1, 2 or 3; each time R 3b appears, it is independently selected from covalent bond, -COC 1-6 alkylene, C 1-6 alkylene, C 1-6 deuterated Alkyl, cycloalkylene, C 1-6 haloalkylene, heterocyclylene, arylene and heteroarylene; and
  • each R 3c is independently selected from hydrogen, deuterium atom, halo, C 1-6 alkyl, -CONH 2 , -NHCOC 1-6 alkyl, C 1-6 alkyl-NHCOC 1-6 alkyl, hydroxyl, amino, hydroxyalkylene, cyano, alkylamino, haloalkyl, C 1-6 alkoxy.
  • R 3 is selected from
  • the compound is selected from Preferably, the pharmaceutically acceptable salt of the compound is an acid salt of the compound, preferably the pharmaceutically acceptable salt of the compound is an organic acid salt of the compound, preferably the pharmaceutically acceptable salt of the compound is a formate salt of the compound, preferably the formate salt contains 0.1-3 moles of formate ions per mole of the compound, preferably the formate salt contains 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2 or 3 moles of formate ions per mole of the compound.
  • Another aspect of the present invention provides a pharmaceutical composition, which is characterized in that it contains a therapeutically effective amount of any of the compounds described above, its pharmaceutically acceptable salts, stereoisomers, tautomers, and solvents. compounds, metabolites, prodrugs, polymorphs or deuterated compounds, and pharmaceutically acceptable excipients.
  • the invention also provides a compound as described above or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, or The application of a pharmaceutical composition as described above in the preparation of a medicament for inhibiting the activity of KRas mutant protein, preferably, the application of a pharmaceutical composition for inhibiting the activity of KRas G12D.
  • the KRas mutant protein-related cancer is selected from:
  • Non-small cell lung cancer colon adenocarcinoma, multiple myeloma, colon cancer, and pancreatic cancer
  • bronchial cancer Alveolar carcinoma, sarcoma, lymphoma, bronchial adenoma, enchondromatous hamartoma, mesothelioma
  • esophageal squamous cell carcinoma esophageal leiomyosarcoma
  • esophageal adenocarcinoma esophageal lymphoma
  • gastric cancer gastric lymphoma, gastric leiomyosarcoma
  • Pancreatic ductal adenocarcinoma insulinoma, gastrinoma, carcinoid tumor, glucagonoma, vasoactive intestinal peptide tumor, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, small intestinal leiomyoma, small intestinal hemangiom
  • the novel KRas inhibitor provided by the present invention has better activity and stability than the clinical drugs in the prior art, and has better medicinal prospects.
  • metabolites of the compounds of formula I ie compounds produced in vivo following administration of the drug.
  • Some examples of metabolites according to the present invention include: (i) when the compound of formula I contains a methyl group, its hydroxymethyl derivative (-CH3->-CH2OH); (ii) when the compound of formula I contains an alkoxy group, Its hydroxyl derivative (-OR->-OH); (iii) When the compound of formula I contains a tertiary amino group, its secondary amino derivative Biological (-NR1R2->-NHR1 or -NHR2); (iv) When the compound of formula I contains a secondary amino group, its primary amino derivative (-NHR1->-NH2); (v) When the compound of formula I contains a phenyl moiety, Its phenol derivative (-Ph->-PhOH); and (vi) when the compound of formula I contains an amide group, its carboxylic acid derivative (-CONH2->COOH).
  • solvate refers to a form of a compound of the present invention that forms a solid or liquid complex by coordination with a solvent molecule. Examples of such forms are hydrates, alcoholates, etc.
  • prodrug refers to any agent that is converted in the body to the parent drug.
  • Prodrugs are often useful because, in some cases, they are easier to administer than the parent drug. For example, they are bioavailable through oral administration, whereas the parent drug is not. Prodrugs may also improve solubility in pharmaceutical compositions relative to the parent drug. Prodrugs can be converted to the parent drug via enzymatic methods as well as metabolic hydrolysis pathways.
  • pharmaceutically acceptable salts refers to salts that retain the biological potency of the free acids and bases of a particular compound without adverse biological effects.
  • pharmaceutically acceptable salts include, but are not limited to: salts formed by compound (I) and any of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, hexane Acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid , methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulf
  • KRas mutant proteins herein include but are not limited to KRAS G12D, KRAS G12C, KRAS G12S, KRAS G12V, KRAS G12A and KRAS G13D.
  • KRas G12C refers to the mutated form of the mammalian KRas protein in which glycine at position 12 is mutated to cysteine.
  • KRas G12D refers to the mutated form of glycine at position 12 of the KRas protein to aspartic acid.
  • the mutations of KRAS G12D, KRAS G12C, KRAS G12S, KRAS G12V, KRAS G12A and KRAS G13D are similar to the above, the difference lies in the specific amino acid residue after mutation or the position of the specific mutation.
  • KRas G12D -related disease or disorder refers to a disease or disorder associated with, induced by, or harboring a KRas G12D mutation, a non-limiting example of which is a related cancer caused by a KRas G12D mutation.
  • an "effective dose" of a compound is an amount sufficient to negatively regulate or inhibit KRas mutein activity, and such dose may be administered alone or may be administered according to an effective regimen.
  • a "therapeutically effective dose” of a compound is an amount that negatively modulates or inhibits the activity of KRas mutant protein and is sufficient to ameliorate or alleviate symptoms or eliminate or reverse the progression of a disorder, which may be administered in a single dose or according to an effective regimen Apply.
  • the amount of a compound of the present application that constitutes a "therapeutically effective dose” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, and can be routinely determined by one of skill in the art. based on your own knowledge and the content of this disclosure.
  • the concentration and route of administration to patients may vary depending on the cancer being treated.
  • the compounds or pharmaceutical compositions thereof, pharmaceutically acceptable salts thereof may be co-administered with other anti-tumor compounds, or with Used in combination with other treatments (such as radiotherapy or surgical intervention) as a preoperative or postoperative adjuvant.
  • treatment refers to the administration of a compound or composition described herein to prevent, ameliorate or eliminate a disease or a condition associated with said disease, and includes: 1) preventing the occurrence of a disease or disease state in a mammal , especially when such mammals are prone to suffer from the disease state, but have not been accurately judged to have suffered from the disease state; 2) alleviate the disease or make the disease state subside; 3) inhibit the disease or curb its development.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
  • pharmaceutically acceptable refers to those compounds, materials, compositions or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without undue Toxicity, allergic reactions, irritation or other problems or complications.
  • salts refers to salts that retain the desired biological activity of the compound and exhibit minimal or no undesirable toxicological effects, such as with organic bases or acids, inorganic bases or acids, with basic or acidic amino acids
  • the salt formed can be metal salt, quaternary ammonium salt, sulfate, hydrochloride, formate, trifluoroacetate, phosphate, fumarate, maleate, tartrate, citrate, Benzoates, etc.
  • optical isomer is caused by the presence of one or more symmetry axes and/or centers in a molecule, resulting in the rotation of polarized light beams.
  • optical isomer more precisely includes enantiomers and diastereomers in pure form or in the form of a mixture; and two compounds that are isomers may have significantly different pharmaceutical activities.
  • This application also includes compounds in which one or more atoms of the compound are replaced by isotopes, and the isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, iodine, etc., preferably deuterium ( 2H ) substitution, wherein deuterium Substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.
  • substituted means that any one or more H atoms on a specific atom are replaced by a substituent, as long as the atomic valence rules are followed and the substituted compound is stable.
  • the term “optionally” or “optionally” means that the described situation may or may not occur, for example, the methyl group is "optionally” substituted by a halogen, and the methyl group can be unsubstituted (CH 3 ), mono Substituted (such as CH 2 F), polysubstituted (such as CHF 2 ) or completely substituted (CF 3 ).
  • CH 3 unsubstituted
  • mono Substituted such as CH 2 F
  • polysubstituted such as CHF 2
  • CF 3 completely substituted
  • no substitution or substitution pattern is introduced that is sterically impossible or cannot be synthesized.
  • C 1-6 means that the group may have an integer number of carbon atoms from 1 to 6, and similarly “C 2-6” means that the group may have an integer number of carbon atoms from 2 to 6.
  • variable e.g, R1
  • R1 variable in the composition or structure of a compound
  • its definition in each instance is independent. For example, if a group is substituted with 2 R 1's , there is an independent option for each R 1 .
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • cyano refers to the -CN group; "hydroxy” refers to the -OH group; “hydroxymethyl” refers to -CH 2 OH Group; “mercapto” refers to the -SH group; “amine” refers to the -NH 2 group.
  • Amide refers to a group containing -CONH-
  • esteer refers to a group containing -COOR, where R is an alkyl group.
  • Carbonyl refers to a group containing -CO-
  • carboxyl refers to a group containing -COOH
  • Alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one carbon-carbon triple bond, such as ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (HC ⁇ C-CH 2 -), propargyl alcohol (-C ⁇ C-CH 2 OH), etc.
  • alkenyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one carbon-carbon double bond.
  • alkyl refers to a hydrocarbon group of the general formula C n CH 2n +1, which alkyl group may be straight or branched. (Such as methyl, ethyl, isopropyl, n-butyl, isobutyl, 2-methylbutyl, etc.). Similarly, the alkyl portion of alkoxy, alkylamino, alkylthio has the same definition.
  • alkoxy refers to -O-alkyl
  • alkylthio refers to -S-alkyl.
  • alkylamino refers to -NH-alkyl.
  • dialkylamino or “dialkylamino” refers to -N(alkyl) 2 .
  • alkylene refers to an alkyl group containing two H atoms on a carbon atom. Such as methylene (-CH 2 -).
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, paracyclic or spirocyclic ring. It is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, etc.
  • partially saturated means containing some double bonds. Such as cyclopentenyl, cyclohexenyl, cycloimine, etc.
  • heterocycloalkyl or “heterocyclyl” refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged, paracyclic or spirocyclic ring.
  • the heterocycle is generally a 3 to 12 membered ring containing 1 to 4 heteroatoms independently selected from N, O, or S, where the ring N atom can be oxidized to NO, and the ring S atom can be Oxidized to SO or SO 2 , the remaining ring atoms are carbon.
  • 3-membered heterocycloalkyl examples include, but are not limited to, ethylene oxide, propylene oxide, ethylene sulfide, and aziridinyl
  • 4-membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxanyl, Butylcyclyl, thibutylcyclyl, etc.
  • Examples of 5-membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolidinyl, pyrrolidonyl, imidazolidinyl, oxazolidinyl, oxazole Alkanonyl, isothiazolidinyl, etc.
  • Examples of 6-membered heterocycloalkyl include but are not limited to piperidyl, tetrahydropyranyl, morpholinyl, piperazinyl, 1,4-dioxanyl, 1,4-thioxanyl, thiomorpholinyl, 1,3-dithianyl, piperidinonyl, etc.
  • Examples of 7-membered heterocycloalkyl include but are not limited to azepanyl, Oxyazepanyl, oxygen or thiepanyl, etc.
  • Examples of pendant rings include, but are not limited to, azabicyclopentanyl, azabicyclohexyl, azabicyclooctyl, decahydroquinolyl, etc.
  • Examples of bridged rings include, but are not limited to, quinuclidinyl, hexahydro- 1H-pyrrolo[2,1-c][1,4]oxazinyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, etc.
  • spiro rings include but are not limited to aza Spiroheptyl, oxazaspirononyl, oxazaspirooctyl, etc.
  • the heterocyclic group is optionally substituted at one or more positions on the ring carbon or ring nitrogen by one or more R8 , wherein R8 is as defined for Formula I or Formula II.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, tetralin, and the like.
  • Aryl also refers to a bicyclic or tricyclic ring system, wherein one or both of the corresponding rings of the aryl ring system may be saturated or partially saturated, and wherein if the ring system includes two saturated rings, then the saturated ring Can be fused or spirocyclic.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, S, the remaining ring atoms are C, and has at least one aromatic ring.
  • the heteroaryl group has a 4- to 8-membered ring, especially a 5- to 8-membered ring, or a plurality of fused rings containing 6 to 14, especially 6 to 10, ring atoms.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, triazinyl , quinolyl, isoquinolyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzimidazolyl , benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, etc.
  • Heteroaryl also refers to a bicyclic ring system having from 1 to 3 heteroatoms selected from the group consisting of O, S and N in each ring, in addition to carbon atoms, in which one ring may be saturated or partially saturated.
  • Compounds of the present application may be asymmetric (having one or more stereoisomers), and unless otherwise stated, all stereoisomers include enantiomers and diastereomers. Its isomers can be separated by chiral resolution.
  • the compounds of the present application may have one or more atropisomers, and unless otherwise specified, the atropisomers refer to optically active isomers produced due to the obstruction of free rotation between single bonds.
  • the isomers can be separated by means of chiral resolution.
  • the present invention includes any possible solvates and polymorphs.
  • the type of solvent used to form the solvate is not particularly limited as long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone and other similar solvents can be used.
  • the present invention includes any possible tautomers and their pharmaceutically acceptable salts, as well as their mixtures.
  • Compounds of the invention can be prepared from commercially available reagents (commercially available reagents can be used without further purification) using the synthetic methods and preparation schemes described herein.
  • the compounds of the invention may also be prepared using other reagents and conventional methods well known to those skilled in the art.
  • Each product or intermediate obtained by the reaction in the synthetic route can be obtained by conventional separation techniques, including but not limited to filtration, distillation, recrystallization, preparative TLC, column chromatography separation, etc.
  • the starting materials can be synthesized by themselves or purchased from commercial institutions (for example, but not limited to Bidex, Anergy, Inochem, and Exploration Platform, etc.). These raw materials can be characterized using conventional means, such as physical constants and spectral data.
  • DCM dichloromethane
  • DMSO dimethyl sulfoxide
  • DMF N, N-dimethylformamide
  • THF tetrahydrofuran
  • DCE 1,2-dichloroethane
  • ACN acetonitrile
  • PE petroleum ether
  • EtOAc ethyl acetate
  • Tol represents toluene
  • NMP represents N-methylpyrrolidone
  • i-PrOH represents isopropyl alcohol
  • MeOH represents methanol
  • MeONa represents sodium methoxide
  • EtOH represents ethanol
  • Boc represents tert-butoxycarbonyl
  • Boc 2 O Di-tert-butyl dicarbonate
  • TEA is triethylamine
  • DIEA N, N-diisopropylethylamine
  • Bn represents benzyl
  • TFA trifluoroacetic acid
  • TFAA is trifluoroacetic anhydride
  • NCS is butyl
  • Step A refers to the preparation method in patent WO2021041671.
  • Compound I-1 is reacted with trichloroacetyl isocyanate, and then the intermediate is cyclized in a methanol solution of ammonia to obtain compound I-2.
  • step B compound I-2 and phosphorus oxychloride are combined with an organic base (such as DIEA) to prepare dichloropyrimidine compound I-3.
  • step C the nitrogen-containing heterocyclic ring R 2 selectively substitutes the dichloropyrimidine compound I-3 under the action of a base and DMF to obtain the compound I-4.
  • the nitrogen-containing heterocyclic ring R 2 can also be combined with the dichloropyrimidine compound I-4 through the boron-containing ester R 2 and the dichloropyrimidine compound I-3.
  • the pyrimidine is subjected to Suzuki coupling reaction to obtain compound I-4.
  • step D a nucleophile with the formula HYR 3 is used to replace the chlorine of the compound I-4 in the presence of a base such as cesium carbonate and 1,4-dioxane as a solvent to introduce the substituent -YR 3 to obtain the compound I-5.
  • step E the thiomethyl group is replaced with chlorine using trimethylsilyl chloride to obtain compound I-6.
  • step F the compound containing R 4 is obtained by Suzuki coupling of boronic acid ester or boronic acid with pyrimidine chloride, and then the target compound can be obtained through deprotection in step G.
  • the target compound is generally purified by reverse-phase preparative HPLC and Obtained by concentration and lyophilization.
  • X and X' are each selected from a halogen group, and the electronegativity of X is greater than that of X', for example, when X is Cl, X' is Br; or, when X is F, X' is Cl or Br.
  • step A the initial raw material II-1 is reacted with an acyl chloride containing an R 5 group (preferably an electron-withdrawing group such as a cyano group or an ester group) to obtain amide II-2.
  • step B the ring is closed under the action of a strong base such as sodium hydride to obtain compound II-3.
  • phosphorus oxychloride is used to selectively carry out hydroxyl chlorination to obtain compound II-4.
  • step D the nitrogen-containing heterocycle R 2 is selectively nucleophilically substituted with chloropyridine compound II-4 under the action of a base and DMF to obtain compound II-5.
  • step E compound II-5 is subjected to a Mitsnobu reaction in DEAD or DIAD, triphenylphosphine, and fatty alcohol HOR 3 to obtain ether II-6.
  • step F a compound containing R 4 is obtained by Suzuki coupling of boric acid ester or boric acid with pyrimidine chloride, and then the target compound II-7 is obtained by deprotection in step G.
  • the target compound is generally purified by reverse phase preparative HPLC and obtained by concentration and lyophilization.
  • X and X' are each selected from halo groups, and the electronegativity of Except -YR 3 is not hydrogen, all substituents are prepared as defined for the compound of formula I according to Scheme III.
  • step A methyl orotate is brominated under the action of bromine to obtain compound III-2.
  • step B phosphorus oxychloride and DIEA are used to chlorine the hydroxyl group to obtain dichloropyrimidine compound III-3.
  • nitrogen-containing heterocycle R 2 undergoes selective nucleophilic substitution of dichloropyrimidine compound III-3 under the action of a base and DMF to obtain compound III-4.
  • step D amine ester exchange occurs between allylamine containing R 4 group and methyl ester compound III-4 under the action of LiHMDS to obtain amide compound III-5.
  • step E the substituent -YR is introduced by replacing the chlorine of the chloropyrimidine compound III-5 using a nucleophile of formula HYR 3 in the presence of a base such as cesium carbonate and 1,4-dioxane as a solvent. 3
  • step E compound III-6.
  • step F compound III-6 undergoes Heck reaction under the action of a palladium catalyst and an organic base (such as triethylamine) for ring closure to obtain an intermediate with an exocyclic double bond. This intermediate is deprotected in step G.
  • the target compound III-7 can be obtained, which is generally purified by reverse-phase preparative HPLC and obtained by concentration and lyophilization.
  • X and X' are each selected from halo groups, and the electronegativity of Except -YR3 is not hydrogen, all substituents are prepared as defined for the compound of formula I according to Scheme IV.
  • step A ethyl chloroacetoacetate and S-methylisothiourea sulfate undergo ring closure to obtain pyrimidine compound IV-2.
  • step B NBS is used as the brominating agent to substitute bromine on the pyrimidine ring to obtain intermediate IV-3.
  • step C compound IV-4 is synthesized from intermediate IV-3 in one pot under the combined action of PyBOP, base (DIEA) and nitrogen-containing heterocyclic ring R2 .
  • step D the substitution reaction between propenylamine containing R 4 group and chloride IV-4 is carried out under heating with a base such as K 2 CO 3 and acetonitrile to obtain compound IV-5.
  • a palladium catalyst is used to perform Heck reaction ring closure to obtain exocyclic double bond compound IV-6.
  • step F the thioether compound IV-6 is oxidized with m-CPBA to obtain sulfoxide, which is then combined with a nucleophile of the formula HYR 3 in a base such as cesium carbonate and 1,4-dioxane as a solvent.
  • the sulfoxide group of the sulfoxide pyrimidine compound is replaced to introduce the substituent -YR 3 to obtain an intermediate compound.
  • the intermediate compound can be deprotected in step G to obtain the target compound IV-7.
  • the target compound is generally passed through reversed-phase Purified by preparative HPLC and obtained by concentration and lyophilization.
  • step A diethyl oxaloacetate sodium salt and S-methylisothiourea sulfate are ring-closed under strong alkaline conditions such as sodium hydroxide to obtain pyrimidine carboxylic acid compound V-2.
  • step B NBS is used as the brominating agent to substitute bromine on the pyrimidine ring to obtain brominated intermediate V-3.
  • step C carboxylic acid V-3 and allylamine are subjected to amide condensation to obtain the compound Compound V-4.
  • step D intermediate V-4 is used to synthesize compound V-5 in one pot under the combined action of PyBOP, base (DIEA) and nitrogen-containing heterocyclic ring R2 .
  • step E a palladium catalyst is used to perform ring closure through Heck reaction to obtain compound V-6 with a double bond in the ring.
  • step F Chan-Lam coupling is performed between boronic acid containing R 4 group and lactam V-6 under the catalysis of copper salt to obtain compound V-7 containing R 4 .
  • step G the thioether compound V-7 is oxidized with m-CPBA to obtain sulfoxide, which is then combined with a nucleophile of the formula HYR 3 in a base such as cesium carbonate and 1,4-dioxane as a solvent.
  • the sulfoxide group of the sulfoxide pyrimidine compound is replaced to introduce the substituent -YR 3 to obtain an intermediate compound.
  • the intermediate compound can be deprotected in step H to obtain the target compound V-8.
  • the target compound is generally passed through reversed-phase Purified by preparative HPLC and obtained by concentration and lyophilization.
  • Step A the hydroxyl group is chlorinated by phosphorus oxychloride and then reacted with nitrogen-containing heterocycle R 2 to obtain compound VI-2.
  • step B chloropyridine compound VI-2 undergoes Suzuki coupling with methylboronic acid under the catalysis of palladium reagent to introduce methyl to obtain compound VI-3.
  • step C boric acid ester or boric acid and chloropyridine VI-3 are Suzuki coupled again under the catalysis of palladium reagent to obtain compound VI-4 containing R 4.
  • step D the methyl group is oxidized by selenium dioxide to obtain aldehyde VI-5.
  • step E dimethyl (1-diazo-2-oxopropyl)phosphonate reagent (Ohira-Bestman reagent) and aldehyde VI-5 are used to generate alkyne VI-6 under the action of potassium carbonate and methanol.
  • step F sulfoxide is obtained by oxidation of thioether compound VI-6 with m-CPBA, and then with a nucleophilic reagent of formula HYR 3 , in the presence of a base such as LiHMDS and THF as a solvent, the sulfoxide group of the sulfoxide pyrimidine compound is replaced to introduce the substituent -YR 3 to obtain an intermediate compound, and the intermediate is deprotected in step G to obtain the target compound VI-7, which is generally purified by reverse phase preparative HPLC and obtained by concentration and lyophilization.
  • a base such as LiHMDS and THF
  • step A intermediate aldehyde VI-5 is reacted with hydroxylamine hydrochloride and a base such as potassium carbonate to obtain intermediate oxime VII-1.
  • step B the oxime is dehydrated in the presence of acetic anhydride to form cyano groups.
  • step C the thioether compound VII-2 is used to obtain sulfoxide under the oxidation of m-CPBA, and then the nucleophile of formula HYR 3 is used to replace the sulfoxide pyrimidine compound with a base such as LiHMDS and THF as a solvent.
  • the sulfoxide group is used to introduce the substituent -YR 3 to obtain an intermediate compound.
  • the intermediate compound can be deprotected in step D to obtain the target compound VII-3.
  • the target compound is generally purified by reverse-phase preparative HPLC and concentrated and frozen. You can do it.
  • step E at low temperature, use a base such as LiHMDS in anhydrous THF to abstract the H of the terminal alkyne and then mix it with an electrophile containing an R (except H) group (such as deuterated water, halogenated hydrocarbon, Aldehydes, ketones, etc.) react to generate substituted alkynyl compounds VII-4. Then the final target compound VII-5 can be obtained by similar operations to steps C and D.
  • step A trifluoroethyl trifluoromethanesulfonate is used to react with raw material VI-1 under the action of DMF and alkali to generate phenol ether VIII-1.
  • step B use the Rca-substituted acetylene reagent The coupling reaction with chloropyridine VIII-1 was catalyzed by a palladium reagent to obtain a pyridopyrimidine derivative VIII-2 containing an alkynyl group.
  • step C the nitrogen-containing heterocycle R 2 is used to perform a nucleophilic substitution reaction with VIII-2 under the action of a base to introduce the compound VIII-3 containing the R 2 group.
  • step D a Suzuki coupling or Stille coupling reaction using a boronic acid ester or boric acid containing an R 4 group, or an organic tin reagent and chloropyridine VI-3 under the catalysis of a palladium reagent is used to obtain a compound VIII containing R 4 -4.
  • step E the thioether compound VIII-4 is oxidized with m-CPBA to obtain sulfoxide, and then the nucleophile of formula HYR 3 is used to replace the sulfoxide pyrimidine compound with a base such as LiHMDS and THF as a solvent.
  • the sulfoxide group is used to introduce the substituent -YR 3 to obtain an intermediate compound.
  • the intermediate compound can be deprotected in step F to obtain the target compound VIII-5.
  • the target compound is generally purified by reverse-phase preparative HPLC and concentrated and frozen. You can do it.
  • Step AN-allyl-8-chloronaphthalene-1-amine Combine 1-bromo-8-chloronaphthalene (500mg, 2.07mmol), allylamine hydrochloride (293mg, 3.11mmol), cesium carbonate (1.35g, 4.15mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (240mg, 0.42mmol) and tris(dibenzylideneacetone)dipalladium (190mg, 0.21mmol)
  • the 1,4-dioxane (8 mL) solution was stirred at 110°C overnight under nitrogen protection. The reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step B 5-Bromo-2,6-dihydroxypyrimidine-4-carboxylic acid methyl ester: To a solution of methyl orotate (10g, 58.82mmol) in methanol (120.0mL), bromine (3mL, 58.82mmol) was added dropwise ). The mixture was stirred at 65°C overnight. Filter under reduced pressure and wash the filter cake with methanol to obtain a white solid (10.67g, 43.02 mmol, 73% yield), LCMS: m/z 249.2 (M+H).
  • Step C 5-Bromo-2,6-dichloropyrimidine-4-carboxylic acid methyl ester: Heat 5-bromo-2,6-dihydroxypyrimidine-4-carboxylic acid methyl ester (5.00g, 20.08mmol) at 100°C , a mixture of phosphorus oxychloride (50 mL) and N,N-dimethylformamide (0.9 ml) overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give crude product.
  • Step D (1R, 5S)-3-(5-bromo-2-chloro-6-(methylformate)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: To a solution of 5-bromo-2,6-dichloropyrimidine-4-carboxylic acid methyl ester (500 mg, 1.76 mmol,) in dichloromethane (5.0 mL) was added triethylamine (213 mg, 2.11 mmol) and 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (336 mg, 1.59 mmol).
  • Step E (1R,5S)-3-(6-(allyl(8-chloronaphthalen-1-yl)carbamoyl)-5-bromo-2-chloropyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: under nitrogen protection, -20°C, to (1R,5S)-3-(5-bromo-2-chloro-6-(carboxylic acid) Methyl)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (211 mg, 0.45 mmol) and N-allyl-8-chloronaphthalene- LiHMDS (917 ⁇ L, 0.92 mmol) was added to a solution of 1-amine (100 mg, 0.45 mmol) in toluene (8.0 mL), and the mixture was stirred
  • Step F (1R,5S)-3-(6-(allyl(8-chloronaphth-1-yl)carbamoyl)-5-bromo-2-((tetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: to (1R,5S)-3-( 6-(allyl(8-chloronaphth-1-yl)carbamoyl)-5-bromo-2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane -To a solution of 8-tert-butylcarboxylate (110 mg, 0.17 mmol) in 2-methyltetrahydrofuran (2.0 mL), N,N-diisopropylethylamine (219 mg,
  • Step G (1R,5S)-3-(7-(8-chloronaphth-1-yl)-5-enyl)-8-oxo-2-((tetrahydro-1H-pyrrolazine-7a( 5H)-yl)methoxy)-5,6,7,8-tetrahydropyridone[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane Alkane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(6-(allyl(8-chloronaphth-1-yl)carbamoyl)-5-bromo-2-(tetrahydro -1H-Pyrrozine-7a(5H)-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
  • Step A 6-Chloro-4-(2-cyanoacetamide)-5-fluoronicotinic acid ethyl ester: To 4-amino-6-chloro-5-fluoronicotinic acid ethyl ester (2.0 g, 9.1 mmol) in DMF (25 mL), add sodium hydride (734 mg, 18.2 mmol), and stir at room temperature for 1 h. 2-cyanoacetyl chloride (3.0 g, 29.4 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 3 h.
  • Step B 7-Chloro-8-fluoro-2,4-dioxane-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbonitrile: To 6-chloro-4- To a solution of (2-cyanoacetamide)-5-fluoronicotinic acid ethyl ester (1.8g, 6.3mmol) in MeOH (25mL), sodium methoxide (670.0mg, 12.6mmol) was added, and the mixture was stirred at 80°C under nitrogen protection. 3h. The solid was removed by filtration and concentrated to give the product (500 mg, 2 mmol, 69% yield). LCMS: m/z 240.0(M+H).
  • Step C 4,7-Dichloro-8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridine-3-nitrile: 7-Chloro-8-fluoro-2,4- Dioxetane-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbonitrile (500 mg, 2.0 mmol) was stirred at 90°C for 1.5 h in a solution of phosphorus oxychloride (5 mL). The residue was added dropwise to ice water and the pH value was adjusted to 7-8 with saturated NaHCO 3 . The aqueous layer was extracted with EtOAc, the organic layer was filtered and concentrated in vacuo to give the product (460 mg, 1.8 mmol, 89% yield) LCMS: m/z 258.0 (M+H).
  • Step D (1R,5S)-(7-chloro-3-cyano-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo [3.2. 1]
  • Octane-8-carboxylic acid tert-butyl ester 4,7-dichloro-8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carbonitrile (460 mg, DIEA (804.0 mg, 6.2 mmol) was added to a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (530.0 mg, 2.5 mmol) in DMF (10 mL) (1.8 mmol).
  • Step E (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1 , 6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-(7-chloro-3-cyano) Tert-butyl-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.9 mmol ), N-methyl-L-prolinol (147.0 mg, 1.4 mmol), and triphenylphosphine (473.0 mg, 1.8 mmol) in tetrahydrofuran (10 mL) were added dropwise to DIAD (545.0 mg
  • Step F (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether))-8-(triisopropylsilyl)acetylene yl)naphth-1-yl)2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diaza Heterobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((S)-1) -Methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300.0mg
  • Step G (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)-naphthalen-1-yl)-8-fluoro- 2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane Alkane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(( Triisopropylsilyl)ethynyl)naphth-1-yl)2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl )-tert-butyl 3,8-di
  • a solution of the ester 140.0 mg, 0.19
  • reaction formula is:
  • Step BN-allyl-3-(methoxymethoxy)naphthalene-1-amine Combine 1-bromo-3-(methoxymethoxy)naphthalene (30 mg, 0.113mmol), allylamine (16 mg , 0.169mmol), Xantphos (13mg, 0.023mmol), Pd 2 (dba) 3 (10mg, 0.011mmol) and cesium carbonate (73mg, 0.226mmol) in 1,4-dioxane (1.00mL) in nitrogen Stir at 110°C for 1 hour under atmosphere. Mix the reaction The mixture was diluted with water and extracted with ethyl acetate.
  • Step C Using (1R,5S)-3-(5-bromo-2-chloro-6-(methylformate)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-tert-butylcarboxylate is used as raw material, and N-allyl-3-(methoxymethoxy)naphthalene-1-amine is used instead of N-allyl-8-chloronaphthyl-1-amine, and ( 2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol instead of (hexahydro-1H-pyrrolin-7a-yl)methanol, as in the example Step 1 EH Synthesis Example 3, LCMS: m/z 571.3 (M+H).
  • reaction formula is:
  • Step A 6-(Chloromethyl)-2-(methylthio)pyrimidin-4-ol: To chloroacetoacetate ethyl ester (10g, 60.6mmol), 2-methyl-2-mercaptourea sulfate (16.8 g, 60.6 mmol) in water (100 ml) was added sodium carbonate (9.6 g, 90.9 mmol), and the reaction mixture was stirred at 25°C for 6 hours. Use 5 M HCl to adjust the pH to acidity, filter, and dry the filter cake in a vacuum drying oven to obtain the product (7.8 g, 68% yield), which is used in the next step. LCMS: m/z 191.1(M+H).
  • NBS N-bromosuccinimide
  • Step C (1R,5S)-3-(5-bromo-6-(chloromethyl)-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo [3.2.1 ]
  • Octane-8-carboxylic acid tert-butyl ester To 5-bromo-6-(chloromethyl)-2-(methylthio)pyrimidin-4-ol (2g, 7.43mmol) in acetonitrile (15ml) at 0°C ) solution, add 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (3.9g, 7.43mmol) and DIEA (2.9g, 22.3mmol) in sequence, stir under nitrogen protection for 5 minutes and then add 3, 8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.7g, 8.18mmol), and then continue stirring for 1 hour.
  • Step D (1R,5S)-3-(6-((allyl(3-(methoxymethoxy)naphth-1-yl)amino)methyl)-5-bromo-2-( Methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(5-bromo-6- (Chloromethyl)-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (63 mg, 0.26 mmol), N - Allyl-3-(methoxymethoxy)naphthalene-1-amine (86 mg, 0.19 mmol), potassium iodide (3 mg, 0.02 mmol), potassium carbonate (77 mg, 0.56 mmol) in acetonitrile
  • Step E (1R,5S)-3-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5-alkenyl-2-(methylthio)-5,6,7 , 8-Tetrahydropyridono[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S )-3-(6-((allyl(3-(methoxymethoxy)naphthalen-1-yl)amino)methyl)-5-bromo-2-(methylthio)pyrimidine-4 -tert-butyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.30mmol), triphenylphosphine (16mg, 0.06mmol), palladium acetate (7mg, 0.03 mmol), a solution of cesium
  • Step F (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3- (Methoxymethoxy)naphth-1-yl)-5-enyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: to (1R,5S)-3-(7-(3-(methoxymethoxy)naphthalene) at -40°C -1-yl)-5-alkenyl-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8- Add m-chloroperoxybenzoic acid (29 mg, 0.170 m
  • Step G 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl))-2-(((2R,7aS)-2-fluorotetraz Hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylene-5,8-dihydropyridone[3,4-d]pyrimidin-7(6H)-yl)naphthalene -2-Phenol: to (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7- (3-(methoxymethoxy)naphth-1-yl)-5-enyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)- To a solution of tert-butyl 3,8-diazabicy
  • Example 4 was obtained as a salt containing a formic acid (3.55 mg, 7% yield), LCMS: m/z 557.2(M+H).
  • Step A (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-(7-chloro-3-cyano-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3 .2.1] tert-butyl octane-8-carboxylate (400 mg, 0.9 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (222.0 mg, 1.4 mmol),
  • Step B (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(triisopropylsilyl)acetylene yl)naphth-1-yl)2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4- (1R, 5S)-3-(7-chloro-3-cyano-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300.0mg, 0.5mmol), ((2-fluor
  • Step C (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)-naphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxy Methyl ether)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)
  • Step D 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1 -yl)-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-1,6-naphthyridine-3- Nitrile: (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)-naphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-di A solution of azabicyclo
  • Step A Ethyl 2-(methylthio)-4-(3-(2,2,2-trichloroacetyl)urea)pyrimidine-5-carboxylate: add 4-amino-2 in an ice-water bath Trichloroacetyl isocyanate (530 mg) was added to a solution of (methylthio)pyrimidine-5-carboxylic acid ethyl ester (500 mg, 2.35 mmol) in THF (4 ml), and the mixture was stirred at room temperature for 1 hour.
  • Step B 7-(Methylthio)pyrimido[4,5-d]pyrimidine-2,4-diol: 2-(methylthio)-4-(3-(2,2 , Add a methanol solution of ammonia (7M, 8ml) to 2-trichloroacetyl)urea)pyrimidine-5-carboxylic acid ethyl ester, and stir at 25°C for 2 hours. Filter and wash with methanol (500ml ⁇ 3) to obtain crude product (480mg) for the next step.
  • LCMS m/z 210.0(M+H).
  • Step C 2,4-Dichloro-7-(methylthio)pyrimido[4,5-d]pyrimidine: To 7-(methylthio)pyrimido[4,5-d]pyrimidine at 0°C DIEA (888 mg, 6.85 mmol) was slowly added dropwise to a solution of 2,4-diol (480 mg, 2.28 mmol) in POCl 3 (4 ml), and the reaction solution was heated to 100°C and stirred for 2 hours. The reaction solution was concentrated and used directly in the next step. LCMS: m/z 247.0(M+H).
  • Step D (1R,5S)-3-(2-chloro-7-(methylthio)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1]
  • Octane-8-carboxylic acid tert-butyl ester 2,4-dichloro-7-(methylthio)pyrimido[4,5-d]pyrimidine was diluted with DCM (5ml) and added to 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (480 mg, 2.26 mmol) and DIEA (10 ml) were slowly added and stirred at 25°C for 2 hours.
  • Step E (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(methylthio) (1R,5S)-3 -(2-Chloro-7-(methylthio)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert.
  • Step G (1R,5S)-3-(7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3, 8-Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(7-chloro-2-((2R,7aS)-2-fluorotetra Hydrogen-1H-pyridinyl-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-tert-butylcar
  • Step I 4-(5-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro -1H-Pyrrozine-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: (1R ,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethylether)naphthalene-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3 , A solution of tert-butyl 8-diazabicyclo[3.2.1]octane-8-car
  • Step A tert-Butyl 4-(7-chloro-3-cyano-8-fluoro-2-hydroxy-1,6-naphthyl-4-yl)piperazine-1-carboxylate: Add DIEA (804.0 mg, 6.2 mmol) to a solution of 4,7-dichloro-8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carbonitrile (460 mg, 1.8 mmol) and tert-butyl piperazine-1-carboxylate (530.0 mg, 2.5 mmol) in DMF (10 mL), and stir at 80°C for 2 h.
  • DIEA 804.0 mg, 6.2 mmol
  • Step B (S)-4-(7-chloro-3-cyano-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthalene-4 -tert-butyl)piperazine-1-carboxylate: 4-(7-chloro-3-cyano-8-fluoro-2-hydroxy-1,6-naphthyl-4-yl)piperazine-1-carboxylic acid A solution of tert-butyl ester (380 mg, 0.7 mmol), N-methyl-L-prolinol (125.0 mg, 1.4 mmol), triphenylphosphine (473.0 mg, 1.8 mmol) in tetrahydrofuran (10 mL) at 0°C DIAD (545.0 mg, 2.7 mmol) was added dropwise and stirred at room temperature for 2 h.
  • tert-butyl ester 400 mg, 0.7 mmol
  • Step C (S)-4-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl) Naphthyl-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphth-4-yl)piperazine-1-carboxylic acid tert-butyl ester: (S )-4-(7-chloro-3-cyano-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphth-4-yl)piperazine -1-tert-butylcarboxylate (300.0mg, 0.6mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3 , 2-Dioxaborane-2-yl)naphthalen-1-
  • Step D (S)-4-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalene-1-yl)-8-fluoro-2-( (1-methylpyrrolidin-2-yl)methoxy)-1,6-naphth-4-yl)piperazine-1-carboxylic acid tert-butyl ester: (S)-4-(3-cyano- 8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-methyl Pyrrolidin-2-yl)methoxy)-1,6-naphth-4-yl)piperazine-1-carboxylic acid tert-butyl ester (200.0 mg, 0.25 mmol), cesium fluoride (131.0 mg, 0.9 mmol) in Solution in D
  • Step E (S)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-1,6-naphthalen-3-carbonitrile: A solution of (S)-tert-butyl 4-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthalen-4-yl)piperazine-1-carboxylate (100.0 mg, 0.14 mmol) in dichloromethane (3 mL) was added dropwise to a solution of hydrochloric acid in 1,4-dioxane.
  • Step A 6-Hydroxy-2-(methylthio)pyrimidine-4-carboxylic acid: To diethyl oxaloacetate sodium salt (2g, 9.4mmol) and 2-methyl-2-urea mercaptosulfate (1.3g, To a solution of 9.4 mmol) in H 2 O (20.0 mL) was added NaOH (750 mg, 18.8 mmol). The mixture was stirred at room temperature for 12 hours. Use 4M HCl to adjust the pH of the reaction solution to about 1.0, precipitate a white solid, filter it with suction, and wash the filter cake with H 2 O to obtain a white solid (500 mg, 2.69 mmol, 29% yield), LCMS: m/z 187.2 (M+H ).
  • Step B 5-Bromo-6-hydroxy-2-(methylthio)pyrimidine-4-carboxylic acid: To 6-hydroxy-2-(methylthio)pyrimidine-4-carboxylic acid (800 mg, 4.30 mmol) in tetrahydrofuran ( 10 mL) solution was added N-bromosuccinimide (1.14 g, 6.45 mmol). The mixture was stirred at 40°C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain crude product. Ethyl acetate was pulped and filtered to obtain a yellow solid (1.00g, 3.79mmol, 88% yield), LCMS: m/z 264.9 (M+H).
  • Step CN-allyl-5-bromo-6-hydroxy-2-(methylthio)pyrimidine-4-carboxamide to 5-bromo-6-hydroxy-2-(methylthio)pyrimidine-4-carboxylic acid
  • HATU (2.37 g, 6.25 mmol
  • Allylamine (587mg, 6.25mmol) and N,N-diisopropylethylamine (1.61g, 12.50mmol). The mixture was stirred at room temperature for 3 hours.
  • Step D tert-Butyl (1R,5S)-3-(6-(allylcarbamoyl)-5-bromo-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of N-allyl-5-bromo-6-hydroxy-2-(methylthio)pyrimidine-4-carboxamide (200 mg, 0.65 mmol) in acetonitrile (10.0 mL) was added 1H-benzotriazole-1-oxytris(1-pyrrolidinyl)phosphine hexafluorophosphate (PyBop) (512 mg, 0.98 mmol).
  • PyBop 1H-benzotriazole-1-oxytris(1-pyrrolidinyl)phosphine hexafluorophosphate
  • Step E 3-(5-Methyl-2-(methylthio)-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(6-(allylcarbamoyl)-5-bromo-2-(methylthio) (1g, 2.00mmol), N,N-diisopropylethylamine (648mg) , 5.02mmol) and a solution of trans-bis[o-(di-o-tolylphosphine)benzyl]dipalladium(II)diacetate (188mg, 0.20mmol) in N,N-dimethylaniline (4.00mL) under nitrogen Stir at 150°C for 3 hours under atmosphere.
  • Step F 3-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5-methyl-2-(methylthio)-8-oxo-7,8-dihydro Pyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: convert 3-(5-methyl-2 -(Methylthio)-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-tert-butylcarboxylate (260mg, 0.622mmol), (3-(methoxymethoxy)naphthalen-1-yl)boronic acid (226mg, 1.244mmol), pyridine (492mg, 6.22mmol) and copper acetate ( A solution of 169 mg, 0.93
  • Step G 3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-3-(methoxymethoxy )naphth-1-yl)5-methyl-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2 .1]
  • Octane-8-carboxylic acid tert-butyl ester at -40°C to 3-(7-(3-(methoxymethoxy)naphthyl-1-yl)-5-methyl-2-( Methylthio)-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 -To a solution of tert-butyl formate (140 mg,
  • Example 8 As a salt containing two formic acids (50 mg, 0.088 mmol, 48% yield), LCMS: m/z 571.3 (M+H).
  • Step A 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol:
  • This intermediate can be prepared from 4-amine according to the method in patent WO2022042630 Preparation of base-2,6-dichloropyridine.
  • Step B (1R,5S)-3-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4 - A solution of alcohol (5.0g, 17.8mmol) in acetonitrile (50mL) was added with phosphorus oxychloride (4.0g, 26.7mmol) and DIEA (4.6g, 35.6mmol) and stirred at 80°C for 2h.
  • Step C (1R,5S)-3-(7-chloro-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: A solution of (1R,5S)-3-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (5.0 g, 17.8 mmol), methylboronic acid (2.6 g, 44.5 mmol), Pd(dppf) Cl2 (1.3 g, 1.8 mmol), potassium phosphate (11.3 g, 53.4 mmol) in toluene (80 mL) and water (8 mL) was stirred at
  • Step D (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Tert-butyl carboxylate: (1R,5S)-3-(7-chloro-8-fluoro-5-methyl-2- (Methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.0g, 4.4mmol ), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-di
  • Step E (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-5-formyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Tert-butyl carboxylate: (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether))-8-((triisopropylsilyl)ethynyl) )naphth-1-yl)-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane To a solution of tert-butyl alkan
  • Step F (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether))-8-((triisopropylsilyl)acetylene yl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Tert-butyl carboxylate: (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether))-8-((triisopropylsilyl)ethynyl) )naphth-1-yl)-5-formyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane To a solution of alkane
  • Step G (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether))-8-((triisopropylsilyl)acetylene (yl)naphth-1-yl)-2-(methylsulfoxide)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-tert-butylcarboxylate: (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(triiso Propylsilyl)ethynyl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ] A solution of tert-buty
  • Step H (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)acetylene) base)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine ring-7a (5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethylether)-8-((triisopropylsilyl)ethynyl) Naphthyl-1-yl)-2-(methylsulfoxide)pyrido[4,3-
  • Step I (1R,5S)-3-(5-ethynyl-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3 A solution of tert-butyl-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H
  • Step J 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyridine ring)-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluoronaphthalen-2-phenol: (1R,5S)-3-(5-ethynyl-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalene-1-yl) -8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4 To a solution of -3
  • Example 9 was obtained as a salt containing a formic acid (6.72 mg, 0.01 mmol, 10% yield).
  • LCMS m/z 625.2(M+H).
  • Example 10 Use N-methyl-D-prolinol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol according to Example 9 step HJ
  • the synthesis was carried out to obtain Example 10 as a salt containing a formic acid (10.4 mg, 0.01 mmol, 10% yield).
  • LCMS m/z 581.2(M+H).
  • Example 11 Use N-methyl-L-prolinol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol according to Example 9 step HJ
  • the synthesis of Example 11 was carried out as a salt containing a formic acid (4.75 mg, 7% yield).
  • Step A (1R,5S)-8-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester: Use 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester instead of 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester.
  • Bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was synthesized according to step B of Example 9, LCMS: m/z 474.1 (M+H).
  • Step A (1R,5S)-8-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-5-formyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3- Tert-butyl formate: (1R,5S)-8-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3 , 8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester was used as raw material, and was synthesized according to steps C-E of Example 9, LCMS: m/z 818.4 (M+H).
  • Step B (1R,5S)-8-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-5-((E)-(hydroxyimine)methyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diaza Bicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester: to (1R,5S)-8-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-( (Triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-formyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8- To a solution of diazabicyclo[3.2.1]oc
  • Step C (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(tri Isopropylsilyl)ethynyl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1]
  • Octane-3-carboxylic acid tert-butyl ester Add acetic anhydride (4 mg, 0.037 mmol) and potassium carbonate (7 mg, 0.048 mmol) to the reaction solution in the previous step and heat to 55°C and stir for 1 hour. The reaction mixture was diluted with ethyl acetate and water was added, extracted with ethyl acetate, dried over Na2SO4 , and concentrated to give a crude product. It was used in the next step without further purification.
  • Step D (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether))-8-(triisopropylsilyl)acetylene (yl)naphth-1-yl)-2-(methylsulfoxide)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 3-tert-butylcarboxylate: (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(triisopropyl Silyl)ethynyl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] To a dichloromethane solution (2 ml) of octan
  • reaction solution was quenched with saturated sodium thiosulfate aqueous solution, extracted with dichloromethane (50 ml) and sodium carbonate aqueous solution, dried over Na 2 SO 4 , filtered and concentrated to obtain a crude product which was used in the next step without purification.
  • Step E (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(triisopropylsilyl)acetylene yl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)pyrido[4,3-d] Pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester: to (1R,5S)-8-(5-cyano-8-fluoro-7 -(7-Fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylsulfoxide)pyrido[4 ,
  • Step F (1R,5S)-8-(5-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalene-1-yl)-8-fluoro-2 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester: to (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methane) Oxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(
  • Step G 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy Naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine-5-nitrile: to (1R,5S)-8-(5-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalene-1-yl) -8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4- To a solution of tert
  • Step A 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine: 5,7-dichloro-8-fluoro-2- Thiopyrido[4,3-d]pyrimidin-4(3H)-one (2.0g, 7.5mmol) was dissolved in phosphorus oxychloride, DIEA (2.9g, 22.6mmol) was added under ice bath and stirred at 100°C overnight. Concentrate in vacuo to give crude product (9.0 g) LCMS: m/z 265.9 (M+H).
  • Step B 2,5,7-Trichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: Combine 2,4,5,7 -To a solution of tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (5.0g, 17.8mmol) in toluene (50mL), trifluoroethanol (4.0g, 26.7mmol) and sodium tert-butoxide (4.6 g, 35.6 mmol) and stirred at 0°C for 2 h.
  • Step C 5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-( 2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: to 2,5,7-trichloro-8-fluoro-4-(2,2,2-trifluoroethoxy
  • pyrido[4,3-d]pyrimidine 1.3g, 3.72mmol
  • 2-methyltetrahydrofuran 10.0mL
  • N,N-diisopropylethylamine 961mg, 7.45mmol
  • Hexahydro-1H-pyrrolizin-7a-yl)methanol (1.18 g, 7.45 mmol).
  • Step D 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: 5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine.
  • Step E (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: To 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: To a solution of (5H)-yl)methoxy)-5-(propyn
  • Step F 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2- (((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine-4 -tert-butyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: (1R,5S)-3-(7-chloro-8-fluoro-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8 -Diazabicyclo[3.
  • Step G 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diaza Heterobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(triisopropyl Silyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propanyl) Al
  • Step H 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H -Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -Phenol: 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethylether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-di To a solution of azabic
  • Step A 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-( 2,2,2-Trifluoroethoxy)pyrido[4,3-d]pyrimidin-5-yl)propynyl)carbamic acid tert-butyl ester: 5,7-dichloro-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido [4,3-d]pyrimidine (200 mg, 0.42 mmol), N-(tert-butoxycarbonyl) propargylamine (263 mg, 1.7 mmol), triethylamine (128 mg, 1.27 mmol) and bis(triphenylphosphine)di
  • Step B (1R,5S)-3-(5-(3-(tert-butylcarbamate)propynyl)-7-chloro-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-tert-butylcarboxylate: to 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy tert-butyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-5-yl)propynyl)carbamate (110 mg, 0.20 mmol) Add 3,8-diazabic
  • Step C 3-(5-(3-(tert-butylcarbamate)propynyl)-8-fluoro-7-chloro-(7-fluoro-3-(methoxymethyl ether)-8-( (Triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(5 -(3-(tert-butylcarbamate)propynyl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)
  • Step D 3-(5-(3-(tert-butylcarbamate)propynyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethylether)naphthalene-1-yl )-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4 -base)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: 3-(5-(3-(tert-butylcarbamate)propynyl)-8 -Fluoro-7-chloro-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,
  • Step E 4-(5-(3-Aminopropyne)-4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphthalene-2-phenol: 3-(5-(3-(tert-butylcarbamate)propynyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethylether)naphthalene -1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3
  • Example 22 is a salt containing a formic acid (1.6 mg, 0.0026 mmol, 10% yield).
  • Example 24 was a salt containing two formic acids (14 mg, 0.023 mmol).
  • Step A (1R,5S)-3-(7-(2-((tert-butyl formate)amino)-7-fluorobenzothiazol-4-yl)-8-fluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Compound (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS) )-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diaza Heterobicyclo[3.
  • Step B 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-7-fluorobenzo Thiazole-2-amine: 1R,5S)-3-(7-(2-((tert-butyl formate)amino)-7-fluorobenzothiazol-4-yl)-8-fluoro-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine-4- To a solution of tert-butyl)-3,8-d
  • Step A 5,7-Dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a DMF solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (5.0g, 17.9mmol) was added N,N-diiso Propylethylamine (6.9g, 53.6mmol) and trifluoroethyl triflate (6.2g, 26.9mmol). The mixture was stirred at room temperature for 5 hours.
  • Step B 5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-7-chloro-8-fluoro-2-(methylthio)-4-(2,2, 2-Trifluoroethoxy)pyrido[4,3-d]pyrimidine: 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-tri Fluoroethoxy)pyrido[4,3-d]pyrimidine (1.2g, 3.32mmol), tert-butyldimethyl(2-propynyloxy)silane (1.7g, 9.97mmol), triethyl A mixture of amine (1.0 g, 9.97 mmol) and bis(triphenylphosphine)bis(acetate)palladium(II) (249 mg, 0.33 mmol) in 1,4-dioxane (7 mL) was degassed and purged with nitrogen.
  • Step C (1R,5S)-tert-butyl 3-(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To 5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-7-chloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (700 mg, 1.41 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (450 mg, 2.21 mmol) and potassium carbonate (390 mg, 2.83 mmol) were added to a solution of N,N-d
  • Step D (1R,5S)-3-(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-8-fluoro-7-(7-fluoro-3-( Methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl) -3,8-diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(5-(3-((tert-butyldimethylsilyl)) Oxy)propynyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]Octyl-8-carboxy
  • Step E 3-(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether) -8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) Methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: to (1R,5S)-3 -(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-( (Triisopropyls
  • Aqueous sodium thiosulfate solution was added to quench, the residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution, and the aqueous layer was extracted with dichloromethane and the organic phase was washed with saturated NaCl, dried over Na 2 SO 4 and concentrated. , the crude product is obtained, which is directly used in the next step.
  • Step F 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(3-hydroxypropynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester: 3-(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-8-fluoro -7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2 -Fluorine
  • Step G 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(3-hydroxypropyne)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyne
  • Base-6-fluoronaphthalene-2-phenol To 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthyl-1-yl)-8-fluoro-2-( ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(3-hydroxypropynyl)pyrido[4,3-d]pyrimidine To a solution of
  • Example 26 was obtained as a salt containing a formic acid (6.0 mg, 0.009 mmol).
  • LCMS m/z 655.2(M+H).
  • Step A (1R,5S)-3-(7-(8-cyanonaphth-1-yl)-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(7-chloro-8-fluoro-5- Methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester ( 500mg, 0.907mmol), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-naphthalenenitrile (380mg, 1.361mmol), Methane [n-Butylbis(1-a
  • Step B (1R,5S)-3-(7-(8-carbamoylnaphthalen-1-yl)-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3 -d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(7-(8-cyanonaphthalene- 1-yl)-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] A concentrated sulfuric acid solution of octyl-8-carboxylic acid tert-butyl ester (20 mg, 0.035 mmol) was heated to 95°C and stirred for 2 hours.
  • Step C (1R,5S)-3-(7-(8-carbamoylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: To (1R,5S)-3-(7-( To a solution of tert-butyl (2-(4-(2-aminoformylnaphthyl)naphthyl)-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.034 mmol
  • reaction solution was quenched with saturated aqueous sodium thiosulfate solution, extracted with dichloromethane (50 ml) and aqueous sodium carbonate solution, dried over Na 2 SO 4 , and concentrated by rotary evaporation to obtain a crude product that was used in the next step without purification.
  • Step D 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyridinyl-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-1-naphthylcarboxamide: (1R,5S)-3-(7-(8-carbamoylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine ring -7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- A solution of tert-butyl formate (10 mg
  • Step A 7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d ]pyrimidine: to 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine ( 2.0g, 5.5mmol) 1,4-dioxane (20mL) solution was added with bis(triphenylphosphine)palladium acetate (374.5mg, 0.5mmol), triethylamine (1.6g, 16.5mmol) and propyne (1M) (8.2 mL, 8.2 mmol) was stirred at 105°C for 1 h under nitrogen atmosphere.
  • Step B tert-Butyl 3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate: To a solution of 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.0 g, 5.5 mmol) in DMF (8 mL) were added potassium carbonate (2.2 g, 16.5 mmol) and 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (1.6 g, 8.2 mmol) and stirred at room temperature for 1 h.
  • Step C 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2- (Methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl Esters: 3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-di Azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (2.0g, 4.4mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5 ,5-tetramethyl-1,3,2-di
  • Step D 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyridazine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine- 4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester: to 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl) Ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidine- To a solution
  • Step E 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrimidin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diaza Heterobicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(triisopropyl Silyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridazin-7a(5H)-yl)methoxy)-5-( Propargyl)
  • Step F 4-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrazine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene -2-Phenol: To 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethylether)naphth-1-yl)8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrimidin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6 - To a solution of diazabicyclo
  • Example 38 was obtained as a salt containing a formic acid (7.32 mg, 0.01 mmol).
  • LCMS m/z 625.2(M+H).
  • Step H 7-Chloro-5-(cyclopropaneethynyl)-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine: 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.0 g, 5.5 mmol) in 1,4-dioxane (20 mL) was added bis(triphenylphosphine)palladium acetate (374.5 mg, 0.5 mmol), triethylamine (1.6 g, 16.5 mmol) and cyclopropyl Acetylene (561.0 mg, 8.2 mmol) was stirred at 105°C for 1 h under nitrogen atmosphere.
  • Example 40 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine-7 -yl)-5-ethynyl-6-fluoronaphthalene-2-phenol
  • Step A (1R,5S)-8-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl) -3,8-Diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester: 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4- (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (120mg, 0.355mmol), tert.
  • Step A (1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl) -3,8-Diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester: 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4- (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (120mg, 0.355mmol), (1R,5S)-3,8-diazabicyclo[3.2.1]octane A solution of alkane-8-carboxylic acid tert-butyl ester (113 mg, 0.533 mmol) and potassium carbonate (98 mg, 0.71 mmol) in N,N-dimethylformamide was stirred at room temperature for 2 hours.
  • Step B 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)-5-(propanol) Alkynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphth-2-phenol: (1R,5S)- 3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo [3.2.1] Octyl-8-carboxylic acid tert-butyl ester (2.0g, 4.2mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetrahydrofuran) Methyl-1,3,2-dioxabo
  • Example 43 is a salt containing a formic acid (4.76 mg, 0.007 mmol), LCMS: m/z 613.3 (M+H).
  • Step A 6-Chloro-4-((4-methoxybenzyl)amino)-2-methylnicotinic acid ethyl ester: To 4,6-dichloro-2-methylnicotinic acid ethyl ester (10.0g , 42.7mmol) in DMSO (50mL) solution, PMBNH 2 (10.5g, 76.9mmol) and DIEA (16.5g, 128.2mmol) were added, and stirred at 50°C for 12h.
  • Step D.7-Chloro-2-mercapto-5-methylpyridone[4,3-d]pyrimidin-4-ol A solution of 4-amino-6-chloro-2-methylnicotinic acid (4.0 g, 21.6 mmol) in dichlorothionyl (120 mL) was stirred at 50°C for 6 h. Concentrated. The residue was added to a solution of ammonium thiocyanate (4.9 g, 64.8 mmol) in acetone (120 mL) at 0°C. Stirred at room temperature for 1 h. The mixture was filtered through filter paper and the filtrate was concentrated to give a crude product (3.7 g), LCMS: m/z 228.0 (M+H).
  • Step E 7-Chloro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol: 7-chloro-2-mercapto-5-methylpyridone[ 4,3-d]pyrimidin-4-ol (3.7 g, 16.3 mmol), sodium hydroxide (1.3 g, 32.6 mmol) in MeOH (100 mL) and water (25 mL). Methyl iodide (4.6g, 32.6mmol) was added at 0°C and stirred at room temperature for 1 h. The residue was added to water (100 ml), and the pH was adjusted to 5-6 with 4M hydrochloric acid.
  • Step F (1R,5S)-3-(7-chloro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diaza Heterobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: 7-chloro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (3.2 g, 13.3 mmol) in acetonitrile (50 mL) was added with phosphorus oxychloride (3.1 g, 20.0 mmol) and DIEA (3.4 g, 26.6 mmol), stirred at 80°C for 2 h, and concentrated to obtain a crude product.
  • phosphorus oxychloride 3.1 g, 20.0 mmol
  • DIEA 3.4 g, 26.6 mmol
  • Example 46 was carried out according to steps F and H of Example 20 as a salt containing a formic acid.
  • LCMS m/z 581.2(M+H).
  • Example 47 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid.
  • Example 50 With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and triisopropyl ((8 -(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-1-yl)ethynyl)silane as raw material, according to the steps F-H of Example 20
  • the synthesis of Example 50 was carried out as a salt containing a formic acid.
  • Example 51 was prepared as a salt containing a formic acid by referring to the method of Synthetic Example 39.
  • Example 52 7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine
  • LCMS m/z 569.2(M+H).
  • Example 55 was prepared as a salt containing a formic acid by referring to the method of Synthetic Example 39.
  • Example 60 With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 3-chloro-5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-4-(trifluoromethyl)aniline was used as raw material, according to steps F and H of Example 20 The synthesis of Example 60 was carried out as a salt containing a formic acid.
  • Example 61 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid.
  • Example 62 contains a formic acid. of salt.
  • Example 63 was carried out according to steps F and H of Example 20. It is a salt containing 0.5 formic acid.
  • Example 65 is carried out according to steps F and H of Example 20 It is a salt containing a formic acid.
  • LCMS m/z 598.2(M+H).
  • Step A (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxy ether)naphthyl-1-yl)-8-fluoro-2-(methylthio) )-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: ( 1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester (200 mg, 0.42 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1 -y
  • TLC monitors the complete reaction of the raw materials. After diluting with EtOAc, add water and mix, and extract the aqueous layer with EtOAc. Wash the organic phase with saturated NaCl and dry it over Na 2 SO 4. Filter the combined organic phase, dry it, load it onto silica gel and pass it through column chromatography. Purification, eluting with 10-50% ethyl acetate/petroleum ether, gave the product (130 mg, 0.19 mmol, 47% yield) LCMS: m/z 676.3 (M+H).
  • Step B 3-(7-(8-ethyl-7-fluoro-3-(methoxy ether)naphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4- Fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[ 3.2.1]
  • Octane-8-carboxylic acid tert-butyl ester to (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthalene-1-yl )-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]
  • Step C 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2S,4R)- 4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- Fluoronaphthyl-2-phenol: To 3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(((2S, 4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- To a solution of diazabicyclo[3.2.1]octane-8-carboxylic
  • Example 71 is a salt containing two formic acids.
  • Example 73 With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 7-(4,4, Using 5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-indole-5-amine as raw material, the synthesis of Example 73 was carried out according to steps F and H of Example 20. It is a salt containing a formic acid. LCMS: m/z 585.3(M+H).
  • Example 76 contains A salt of formic acid.
  • Example 77 can be prepared as a salt containing a formic acid.
  • Example 78 is a salt containing a formic acid.
  • Example 80 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid.
  • Example 83 contains 0.5 Formic acid salt.
  • Example 86 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing 0.5 formic acid.
  • Example 90 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid.
  • Example 91 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid.
  • Example 92 can be prepared as a salt containing one formic acid using corresponding raw materials and reagents.
  • Example 93 can be prepared as a salt containing a formic acid.
  • Example 96 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid.
  • Example 97 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid.
  • Example 100 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing 0.5 formic acid.
  • Example 106 was synthesized by referring to the preparation method of Steps B and C of Example 69 to prepare a salt containing a formic acid.
  • Example 108 was synthesized into a salt containing 0.5 formic acid by referring to the preparation method of Steps B and C of Example 69.
  • Example 110 was synthesized by referring to the preparation method of steps B and C of Example 69.
  • Example 111 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid.
  • Example 112 can be prepared as a salt containing a formic acid.
  • LCMS m/z 571.3(M+H).
  • Example 113 can be prepared as a salt containing a formic acid.
  • LCMS m/z 599.3(M+H).
  • Example 114 can be prepared as a salt containing a formic acid.
  • LCMS m/z 625.3(M+H).
  • Example 117 can be prepared as a salt containing 0.5 formic acid.
  • LCMS m/z 611.3(M+H).
  • Example 138 was prepared according to the synthetic method of synthetic steps B to F of Example 38 as a salt containing 0.1 formic acid.
  • Example 147 was prepared as a salt containing 0.2 formic acid by referring to the synthesis method of synthesis steps B to F of Example 38.
  • Example 148 was prepared according to the synthetic method of synthetic steps B to F of Example 38 as a salt containing 0.2 formic acid.
  • Example 149 was prepared according to the synthetic method of synthetic steps B to F of Example 38 as a salt containing 0.5 formic acid.
  • Example 152 was prepared by referring to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid.
  • Example 154 was prepared as a salt containing 0.3 formic acid by referring to the synthesis method of synthesis steps B to F of Example 38.
  • Example 155 was prepared as a salt containing 0.1 formic acid by referring to the synthetic method of synthetic steps B to F of Example 38.
  • Example 156 was prepared as a salt containing a formic acid by referring to the synthesis method of synthesis steps B to F of Example 38.
  • Example 159 was prepared by referring to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing two formic acids.
  • Example 160 was prepared as a salt containing 0.5 formic acid by referring to the synthetic method of synthetic steps B to F of Example 38.
  • Example 166 7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents were used as raw materials, and a salt containing 0.5 formic acid was prepared in Example 166 by referring to the synthesis method of synthesis steps B to F of Example 38.
  • Example 177 was prepared as a salt containing 0.5 formic acid by referring to the synthesis method of synthesis steps B to F of Example 38.
  • Example 182 was prepared by referring to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid.
  • Example 186 a salt containing one formic acid, was prepared by referring to the synthetic method of synthetic steps B to F of Example 38.
  • Example 190 was prepared as a salt containing 0.3 formic acid by referring to the synthetic method of synthetic steps B to F of Example 38.
  • Example 196 7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents were used as raw materials, and the salt containing two formic acids was prepared in Example 196 by referring to the synthesis method of synthesis steps B to F of Example 38.
  • Example 198 was prepared by referring to the synthesis method of synthesis steps B to F of Example 38.
  • Example 199 was prepared by referring to the synthesis method of synthesis steps B to F of Example 38.
  • Example 200 was prepared by referring to the synthesis method of synthesis steps B to F of Example 38.
  • Examples 201-310 in the table below can be prepared by referring to the synthesis method and corresponding reagents of steps B to F in Example 38.
  • KRas protein is a GTPase that can convert the protein from the GTP state (activated state) to the GDP state (inactivated state).
  • the protein in the GDP state is used, and the addition of guanine nucleotide exchange factor and GTP causes GDP to become GTP, thereby activating the protein.
  • the RAF protein added at the same time can be connected to the protein in the active state.
  • the Alpha detection beads added later are connected to the RAF protein and the active protein respectively, thereby detecting the molecular activity of the laboratory compound.
  • the final concentrations of the compounds from high to low are 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, 0.15nM, 0.04nM, 0nM.
  • the group with a compound concentration of 0 nM was the blank group, and the final DMSO content was 0.5%.
  • the compound working solution can be prepared according to the method of standard PC-1.
  • the group with a compound concentration of 0 nM was the blank group, and the final DMSO content was 0.5%.
  • the inhibition rate of each compound at each concentration point was calculated according to the following formula, and the IC 50 value was obtained by curve fitting using the software Graphpad Prism 8.0. (You need to deduct the value of the blank hole first, the eleventh hole)
  • the effect of the compound invented in this experiment on the inhibition of human pancreatic cancer ASPC-1 cell proliferation was evaluated through in vitro cell testing using the CELL TITER-GLO (CTG) luminescence method.
  • CTG luminescence method can detect the number of viable cells by quantitatively measuring ATP. .
  • the final concentrations of compounds used for ASPC-1 cells were 10000nM, 1666.67nM, 277.78nM, 46.30nM, 7.72nM, 1.29nM, 0.21nM, 0.036nM, 0.0060nM and 0nM from high to low.
  • the compound concentration group was 0nM.
  • the final DMSO content was 0.5%.
  • the cell plates were placed in a cell culture incubator and cultured for 120 h.
  • the compound solution was prepared in the same manner as the above standard PC-1.

Abstract

Provided are a compound of formula I having KRas inhibitory activity, a pharmaceutical composition comprising the compound, a preparation method therefor, and use thereof. The compound has remarkable selectivity, inhibitory activity, and better medicinal prospects.

Description

一种KRAS突变蛋白抑制剂、及其制备方法和应用A KRAS mutant protein inhibitor, preparation method and application thereof 技术领域Technical field
本发明属于医药领域，具体涉及一种具有抑制KRas的化合物。具体地，本发明涉及抑制KRas突变蛋白活性的化合物、包括所述化合物的药物组合物及其制备方法和用途。The present invention belongs to the field of medicine, and specifically relates to a compound capable of inhibiting KRas. Specifically, the present invention relates to a compound capable of inhibiting the activity of KRas mutant protein, a pharmaceutical composition comprising the compound, and a preparation method and use thereof.
背景技术Background technique
RAS是第一个被发现的人类肿瘤基因。RAS基因家族目前已知的成员包括KRas、NRAS和HRAS。KRas是RAS基因家族常见的突变基因之一，大约占RAS基因突变总数的86％(例如，参见Salgia等人，(2021)Cell Reports Medicine 2,100186,January 19.)。KRas蛋白由Kirsten大鼠肉瘤病毒癌基因同源物(KRas)编码，属于含有188个氨基酸的小GTP酶(smallGTPase)，属于RAS超蛋白家族。KRas蛋白通过响应细胞外信号，在“失活”和“激活”两种状态之间循环转换，保持正常的生物功能(例如，参见Alamgeer等人，(2013)Current Opin Pharmcol.13：394-401)。RAS was the first human tumor gene discovered. Currently known members of the RAS gene family include KRas, NRAS and HRAS. KRas is one of the commonly mutated genes in the RAS gene family, accounting for approximately 86% of the total RAS gene mutations (for example, see Salgia et al., (2021) Cell Reports Medicine 2, 100186, January 19.). KRas protein is encoded by Kirsten rat sarcoma virus oncogene homolog (KRas), which belongs to the small GTPase (smallGTPase) containing 188 amino acids and belongs to the RAS superprotein family. KRas protein maintains normal biological functions by cycling between "inactivated" and "activated" states in response to extracellular signals (for example, see Alamgeer et al., (2013) Current Opin Pharmcol. 13: 394-401 ).
作为人类癌症谱系中肿瘤发展最常见的驱动因素之一，全球约有40％-50％的结直肠癌患者，30％的非小细胞肺癌患者及80％-90％的胰腺癌患者存在KRas突变阳性(例如，参见Hofmann等人，(2022)Cancer Discovery；12：924-937)。据弗若斯特沙利文的数据统计，全球主要KRas突变阳性癌症的发病人数从2016年的180万人增长至2020年的200.9万人，并预计于2025年增长至227.6万人。面对这一巨大的治疗需求，临床上尚未有有效的解决方案，因此，对于具有RAS突变的癌症患者的治疗干预，存在着巨大的未满足的医疗需求。As one of the most common drivers of tumor development in the human cancer spectrum, KRas mutations are present in approximately 40%-50% of colorectal cancer patients, 30% of non-small cell lung cancer patients, and 80%-90% of pancreatic cancer patients worldwide. Positive (see, e.g., Hofmann et al., (2022) Cancer Discovery; 12:924-937). According to statistics from Frost & Sullivan, the number of major KRas mutation-positive cancers worldwide has increased from 1.8 million in 2016 to 2.009 million in 2020, and is expected to increase to 2.276 million in 2025. Faced with this huge therapeutic need, there are no clinically effective solutions and therefore there is a huge unmet medical need for therapeutic intervention in cancer patients with RAS mutations.
目前，Mirati Therapeutics公司和益方生物科技股份有限公司相继公开了KRasG12D抑制剂专利，分别是WO2021041671和WO2022042630，其中，专利WO2021041671的代表性化合物MRTX1133和WO2022042630的代表性化合物PC-1的分子结构分别如下述结构式所示：
At present, Mirati Therapeutics and Yifang Biotechnology Co., Ltd. have successively disclosed KRas G12D inhibitor patents, namely WO2021041671 and WO2022042630. Among them, the molecular structures of the representative compound MRTX1133 of the patent WO2021041671 and the representative compound PC-1 of WO2022042630 are respectively As shown in the following structural formula:
虽然这两家公司公开了其研究专利，但是目前MRTX1133和PC-1均处于临床试验阶段，药物活性和临床治疗效果仍存在不确定性。KRas突变是导致结直肠癌、肺癌和胰腺癌的重要因素之一，尤其是在胰腺癌中发生比例高达36％，且尚无针对该靶点的治疗药物，因此，该靶向药物存在巨大的市场需求，研发此靶点药物具有非常重要意义，急需要开发新的KRas突变蛋白抑制剂，为患者提供更多的用药选择。Although the two companies have disclosed their research patents, both MRTX1133 and PC-1 are currently in the clinical trial stage, and there is still uncertainty about drug activity and clinical therapeutic effects. KRas mutation is one of the important factors leading to colorectal cancer, lung cancer and pancreatic cancer, especially in pancreatic cancer, the incidence rate is as high as 36%, and there is no therapeutic drug targeting this target. Therefore, there is huge potential for this targeted drug. Due to market demand, it is of great significance to develop this target drug. There is an urgent need to develop new KRas mutant protein inhibitors to provide patients with more medication options.
发明内容Contents of the invention
本发明的一个目的在于提供一种新的抑制KRas突变蛋白活性的化合物。 本发明提供的化合物，能够选择性的抑制KRas突变蛋白活性，在一定程度上可以用于治疗细胞增殖障碍性疾病。为了达到此效果，本发明采用了以下技术方案：One object of the present invention is to provide a new compound that inhibits the activity of KRas mutant protein. The compounds provided by the invention can selectively inhibit the activity of KRas mutant protein and can be used to treat cell proliferation disorders to a certain extent. In order to achieve this effect, the present invention adopts the following technical solutions:
本发明一方面提供一种式Ⅰ化合物，或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，其中，
One aspect of the invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein ,
其中，R1为CR1a或N；R1a选自氢、卤素、氰基、羟基、巯基、羟基亚烷基、-COO烷基、羧基、氨基、-CONH2、-NHCO烷基、烷基、亚烷基氰基、烯基和炔基；优选地，R1a选自氢、卤素、氰基、羟基、巯基、羟甲基、-COO C1-6烷基、羧基、氨基、-CONH2、-NHCOC1-6烷基、C1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基；Wherein, R 1 is CR 1a or N; R 1a is selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxyalkylene, -COO alkyl, carboxyl, amino, -CONH 2 , -NHCO alkyl, alkyl , alkylene cyano, alkenyl and alkynyl; preferably, R 1a is selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, -COO C 1-6 alkyl, carboxyl, amino, -CONH 2. -NHCOC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkylenecyano, C 2-6 alkenyl and C 2-6 alkynyl;
R2为至少含1个N原子的3-12元饱和或部分饱和的单环、桥环、稠环或螺环，其中所述饱和或部分饱和的单环、桥环、稠环或螺环任选地被一个、两个或更多个R2a取代；优选地，R2为含1、2或3个环N的3-12元饱和或部分饱和的单环、桥环、稠环或螺环，其中所述饱和或部分饱和的单环、桥环、稠环或螺环任选地被一个或多个R2a取代；优选地，R2为含1或2个环N的饱和或部分饱和的3-10元单环、6-12元桥环、4-10元稠环或5-12元螺环，其中所述饱和或部分饱和的单环、桥环、稠环或螺环任选地被一个或多个R2a取代；优选地，R2为含1或2个环N，并且含0、1、2或3个独立选自O和S的环杂原子的饱和或部分饱和的3、5、6、7、或8元单环、6、7、8、9、或10元桥环、4、5、6、7、8、9、或10元稠环、或5、6、7、8、9、10、11或12元螺环，其中所述饱和或部分饱和的单环、桥环、稠环或螺环任选地被一个或多个R2a取代；每次R2a出现时各自独立地选自卤素、氰基、羟基、巯基、羟基亚烷基、羧基、氨基、-CONH2、-NHCO烷基、烷基、亚烷基氰基、亚烷基炔基、亚烷基COO烷基、-NHCOC1-6烷基、烯基、氧代基(＝O)、环烷基、杂环基和炔基，任选地，所述亚烷基、烷基、炔基、烯基、环烷基、和杂环基被一个、两个或更多个选自卤素、氰基、氨基、羟基、羟亚烷基、巯基、-C(O)O-烷基、-OC(O)-烷基、羧基、氧代基、(＝CH2)、-CONH2、-NHC(O)C1-6烷基、C1-6烷基-NHCOC1-6亚烷基、烷基、烷基氨基、C1-6卤代烷基、C1-6烷氧基、亚芳基C1-6烷基、芳基C1-6亚烷基、(C1-6烷氧基)C1-6亚烷基-、(C1-6烷基)C(＝O)-、(C1-6卤代烷基)C(＝O)-、-CH2NHCOC1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基的取代基所取代；优选地，每次R2a出现时各自独立地选自F、Cl、Br、I、氰基、羟基、巯基、羟基C1-6亚烷基、羧基、氨基、-CONH2、-NHCOC1-6烷基、C1-6烷基、C1-6亚烷基氰基、C1-6亚烷基炔基、C1-6亚烷基COO C1-6烷基、-NHCOC1-6烷基、C2-6烯基、氧代基(＝O)和C2-6炔基，任选地，所述C1-6亚烷基、C1-6烷基、C2-6炔基、和C2-6烯基被一个、两个或更多个选自卤素、氰基、氨基、羟基、羟亚烷基、巯基、-C(O)O-烷基、-OC(O)-烷基、 羧基、氧代基、(＝CH2)、-CONH2、-NHC(O)C1-6烷基、C1-6烷基-NHCOC1-6亚烷基、C1-6烷基、C1-6烷基氨基、C1-6卤代烷基、C1-6烷氧基、亚芳基C1-6烷基、芳基C1-6亚烷基、(C1-6烷氧基)C1-6亚烷基-、(C1-6烷基)C(＝O)-、(C1-6卤代烷基)C(＝O)-、-CH2NHCOC1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基的取代基所取代；R 2 is a 3-12 membered saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring containing at least 1 N atom, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring optionally substituted by one, two or more R 2a ; preferably, R 2 is a 3-12 membered saturated or partially saturated monocyclic ring, bridged ring, fused ring or containing 1, 2 or 3 ring N Spiro ring, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spiro ring is optionally substituted by one or more R 2a ; preferably, R 2 is a saturated or spiro ring containing 1 or 2 ring N Partially saturated 3-10-membered monocyclic ring, 6-12-membered bridged ring, 4-10-membered fused ring or 5-12-membered spirocyclic ring, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring Optionally substituted by one or more R 2a ; preferably, R 2 is a saturated or partial ring containing 1 or 2 ring N's and containing 0, 1, 2 or 3 ring heteroatoms independently selected from O and S Saturated 3, 5, 6, 7, or 8-membered monocyclic ring, 6, 7, 8, 9, or 10-membered bridged ring, 4, 5, 6, 7, 8, 9, or 10-membered fused ring, or 5 , 6, 7, 8, 9, 10, 11 or 12 membered spirocyclic rings, wherein the saturated or partially saturated monocyclic, bridged, fused or spirocyclic rings are optionally substituted by one or more R 2a ; each Each R 2a occurrence is independently selected from halogen, cyano, hydroxy, mercapto, hydroxyalkylene, carboxyl, amino, -CONH 2 , -NHCO alkyl, alkyl, alkylenecyano, alkylene alkyne base, alkylene COO alkyl, -NHCOC 1-6 alkyl, alkenyl, oxo (=O), cycloalkyl, heterocyclyl and alkynyl, optionally, the alkylene, alkyl The base, alkynyl, alkenyl, cycloalkyl, and heterocyclyl groups are one, two or more selected from halogen, cyano, amino, hydroxyl, hydroxyalkylene, mercapto, -C(O)O- Alkyl, -OC(O)-alkyl, carboxyl, oxo, (=CH 2 ), -CONH 2 , -NHC(O)C 1-6 alkyl, C 1-6 alkyl -NHCOC 1- 6 alkylene, alkyl, alkylamino, C 1-6 haloalkyl, C 1-6 alkoxy, arylene C 1-6 alkyl, aryl C 1-6 alkylene, (C 1 -6 alkoxy)C 1-6 alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH 2 NHCOC 1 -6 alkyl, C 1-6 alkylene cyano, C 2-6 alkenyl and C 2-6 alkynyl substituents; preferably, each occurrence of R 2a is independently selected from F, Cl, Br, I, cyano group, hydroxyl group, mercapto group, hydroxyl C 1-6 alkylene group, carboxyl group, amino group, -CONH 2 , -NHCOC 1-6 alkyl group, C 1-6 alkyl group, C 1-6 alkylene group Alkyl cyano group, C 1-6 alkylene alkynyl group, C 1-6 alkylene COO C 1-6 alkyl group, -NHCOC 1-6 alkyl group, C 2-6 alkenyl group, oxo group (= O) and C 2-6 alkynyl, optionally, the C 1-6 alkylene, C 1-6 alkyl, C 2-6 alkynyl, and C 2-6 alkenyl are replaced by one or two or more selected from halogen, cyano, amino, hydroxyl, hydroxyalkylene, mercapto, -C(O)O-alkyl, -OC(O)-alkyl, Carboxyl group, oxo group, (=CH 2 ), -CONH 2 , -NHC(O)C 1-6 alkyl, C 1-6 alkyl -NHCOC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 alkoxy, arylene C 1-6 alkyl, aryl C 1-6 alkylene, (C 1-6 alkoxy Base) C 1-6 alkylene-, (C 1-6 alkyl) C (= O)-, (C 1-6 haloalkyl) C (= O)-, -CH 2 NHCOC 1-6 alkyl , substituted by substituents of C 1-6 alkylene cyano group, C 2-6 alkenyl group and C 2-6 alkynyl group;
Y为CRxRy、O、S、S＝O、S(＝O)2或NRx，Rx和Ry每次出现时分别独立地选自氢、烷基、环烷基、杂环基、亚烷基氨基烷基、芳基和亚烷基芳基；优选地，Rx和Ry每次出现时分别独立地选自氢、和C1-6烷基；Y is CR x R y , O, S, S=O, S(=O) 2 or NR x , R x and R y are independently selected from hydrogen, alkyl, cycloalkyl, heterocycle each time they appear. group, alkyleneaminoalkyl, aryl and alkylenearyl; preferably, R x and R y are independently selected from hydrogen, and C 1-6 alkyl each time they appear;
R3选自烷基、亚烷基羟基、-L-杂环基、-L-芳基、-L-亚芳基-L-杂环基、-L-亚杂芳基-L-杂环基、-L-杂芳基、-L-亚杂环基-L-OCO-N(R5)2、-L-亚杂环基-L-NR5-CO-N(R5)2、-L-亚杂环基-L-NR5-CO-R5、-L-环烷基、-L-亚环烷基-L-N(R5)2、-L-亚环烷基-L-杂环基和-L-亚环烷基-L-N(R5)2，其中，所述杂环基、亚杂芳基、杂芳基、和亚杂环基各自独立地含有1、2、3或4个各自独立选自N、O和S的杂原子，所述烷基、烷基羟基、杂环基、芳基、亚芳基、亚杂芳基、杂芳基、亚杂环基、环烷基和亚环烷基可任选被一个、两个或更多个选自卤素、氰基、氨基、羟基、羟烷基、巯基、-C(O)O-烷基、-OC(O)-烷基、羧基、氧代基、(＝CH2)、-CONH2、-NHC(O)C1-6烷基、C1-6烷基-NHCOC1-6亚烷基、烷基、烷基氨基、C1-6卤代烷基、C1-6烷氧基、C1-6烷基取代的吡唑基、亚芳基C1-6烷基、芳基C1-6亚烷基、(C1-6烷氧基)C1-6亚烷基-、(C1-6烷基)C(＝O)-、(C1-6卤代烷基)C(＝O)-、-CH2NHCOC1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基的取代基所取代；优选地，R3选自C1-6烷基、C1-6烷基羟基、-L-(3-12元杂环基)、-L-(6-10元亚芳基)、-L-(6-10元亚芳基)-L-(3-12元杂环基)、-L-(5-12元亚杂芳基)-L-(3-12元杂环基)、-L-(5-12元杂芳基)、-L-(3-12元亚杂环基)-L-OCO-N(R5)2、-L-(3-12元亚杂环基)-L-NR5-CO-N(R5)2、-L-(3-12元亚杂环基)-L-NR5-CO-R5、-L-(3-10元环烷基)、-L-(3-10元亚环烷基)-L-N(R5)2、-L-(3-10元亚环烷基)-L-(3-12元杂环基)和-L-(3-10元亚环烷基)-L-N(R5)2，其中，所述3-12元杂环基、3-12元亚杂环基、5-12元亚杂芳基和5-12元杂芳基，各自独立地含有1、2、或3个各自独立选自N、O和S的杂原子，所述C1-6烷基、C1-6亚烷基羟基、3-12元杂环基、6-10元芳基、6-10元亚芳基、5-12元亚杂芳基、5-12元杂芳基、3-12元亚杂环基、3-10元环烷基和3-10元亚环烷基可任选被一个、两个或更多个选自F、Cl、Br、I、氰基、氨基、羟基、C1-6羟烷基、巯基、-C(O)O-C1-6烷基、-OC(O)-C1-6烷基、羧基、氧代基、(＝CH2)、-CONH2、-NHC(O)C1-6烷基、C1-6烷基-NHCOC1-6亚烷基、C1-6烷基、C1-6烷基氨基、C1-6卤代烷基、C1-6烷氧基、C1-6烷基取代的吡唑基、亚芳基C1-6烷基、芳基C1-6亚烷基、(C1-6烷氧基)C1-6亚烷基-、(C1-6烷基)C(＝O)-、(C1-6卤代烷基)C(＝O)-、-CH2NHCOC1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基的取代基所取代；R 3 is selected from alkyl, alkylenehydroxy, -L-heterocyclyl, -L-aryl, -L-arylene-L-heterocyclyl, -L-heteroarylene-L-heterocycle base, -L-heteroaryl, -L-heterocyclylene-L-OCO-N(R 5 ) 2 , -L-heterocyclylene-L-NR 5 -CO-N(R 5 ) 2 , -L-heterocyclylene-L-NR 5 -CO-R 5 , -L-cycloalkyl, -L-cycloalkylene-LN(R 5 ) 2 , -L-cycloalkylene-L- Heterocyclyl and -L-cycloalkylene-LN(R 5 ) 2 , wherein the heterocyclyl, heteroarylene, heteroaryl, and heterocyclylene each independently contain 1, 2, 3 Or 4 heteroatoms each independently selected from N, O and S, the alkyl group, alkylhydroxy group, heterocyclylene group, aryl group, arylene group, heteroarylene group, heteroaryl group, heterocyclylene group, Cycloalkyl and cycloalkylene groups may be optionally substituted by one, two or more selected from halogen, cyano, amino, hydroxyl, hydroxyalkyl, mercapto, -C(O)O-alkyl, -OC( O)-alkyl, carboxyl, oxo, (=CH 2 ), -CONH 2 , -NHC(O)C 1-6 alkyl, C 1-6 alkyl -NHCOC 1-6 alkylene, alkyl group, alkylamino, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkyl substituted pyrazolyl, arylene C 1-6 alkyl, aryl C 1-6 alkyl Alkyl, (C 1-6 alkoxy) C 1-6 alkylene-, (C 1-6 alkyl) C (=O)-, (C 1-6 haloalkyl) C (=O)- , -CH 2 NHCOC 1-6 alkyl, C 1-6 alkylene cyano, C 2-6 alkenyl and C 2-6 alkynyl substituents substituted; preferably, R 3 is selected from C 1- 6 alkyl group, C 1-6 alkyl hydroxyl group, -L-(3-12 membered heterocyclyl group), -L-(6-10 membered arylene group), -L-(6-10 membered arylene group) -L-(3-12 membered heterocyclyl), -L-(5-12 membered heteroarylene) -L-(3-12 membered heterocyclyl), -L-(5-12 membered heteroarylene) ), -L-(3-12 membered heterocyclylene)-L-OCO-N(R 5 ) 2 , -L-(3-12 membered heterocyclylene)-L-NR 5 -CO-N( R 5 ) 2 , -L-(3-12 membered heterocyclylene)-L-NR 5 -CO-R 5 , -L-(3-10 membered cycloalkyl), -L-(3-10 membered Cycloalkylene)-LN(R 5 ) 2 , -L-(3-10-membered cycloalkylene)-L-(3-12-membered heterocyclylene) and -L-(3-10-membered cycloalkylene) base)-LN(R 5 ) 2 , wherein the 3-12-membered heterocyclyl group, 3-12-membered heterocyclylene group, 5-12-membered heteroarylene group and 5-12-membered heteroarylene group are each independently contains 1, 2, or 3 heteroatoms each independently selected from N, O and S, the C 1-6 alkyl group, C 1-6 alkylene hydroxyl group, 3-12 membered heterocyclyl group, 6- 10-membered aryl, 6-10-membered arylene, 5-12-membered heteroarylene, 5-12-membered heteroarylene, 3-12-membered heterocyclylene, 3-10-membered cycloalkyl and 3-10 The one-membered cycloalkylene group may be optionally replaced by one, two or more members selected from F, Cl, Br, I, cyano, amino, hydroxyl, C 1-6 hydroxyalkyl, mercapto, -C(O)OC 1-6 alkyl, -OC(O)-C 1-6 alkyl, carboxyl, oxo group, (=CH 2 ), -CONH 2 , -NHC(O)C 1-6 alkyl, C 1- 6 alkyl-NHCOC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkyl substituted Pyrazolyl , arylene C 1-6 alkyl, aryl C 1-6 alkylene, (C 1-6 alkoxy) C 1-6 alkylene-, (C 1-6 alkyl) C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH 2 NHCOC 1-6 alkyl, C 1-6 alkylenecyano, C 2-6 alkenyl and C Substituted by 2-6 alkynyl substituents;
L每次出现时各自独立地选自共价键、C1-6亚烷基、C1-6羟亚烷基、-C(O)C1-6亚烷基、-C(O)O-、-OC(O)-、C1-6氘代亚烷基、C1-6卤代亚烷基、亚环烷基、亚杂环基、亚芳基和亚杂芳基，任选地，所述C1-6亚烷基、C1-6羟亚 烷基、C1-6氘代亚烷基、C1-6卤代亚烷基、亚环烷基、亚杂环基、亚芳基和亚杂芳基被一个、两个或更多个选自F、Cl、Br、I、氰基、氨基、羟基、C1-6羟烷基、巯基、-C(O)O-C1-6烷基、-OC(O)-C1-6烷基、羧基、氧代基、(＝CH2)、-CONH2、-NHC(O)C1-6烷基、C1-6烷基-NHCOC1-6亚烷基、C1-6烷基、C1-6烷基氨基、C1-6卤代烷基、C1-6烷氧基、亚芳基C1-6烷基、芳基C1-6亚烷基、(C1-6烷氧基)C1-6亚烷基-、(C1-6烷基)C(＝O)-、(C1-6卤代烷基)C(＝O)-、-CH2NHCOC1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基的取代基所取代；Each occurrence of L is independently selected from covalent bond, C 1-6 alkylene, C 1-6 hydroxyalkylene, -C(O)C 1-6 alkylene, -C(O)O -, -OC(O)-, C 1-6 deuterated alkylene, C 1-6 haloalkylene, cycloalkylene, heterocyclylene, arylene and heteroarylene, optional Ground, the C 1-6 alkylene group, C 1-6 hydroxyl group Alkyl, C 1-6 deuterated alkylene, C 1-6 haloalkylene, cycloalkylene, heterocyclylene, arylene and heteroarylene are substituted by one, two or more Selected from F, Cl, Br, I, cyano, amino, hydroxyl, C 1-6 hydroxyalkyl, mercapto, -C(O)OC 1-6 alkyl, -OC(O)-C 1-6 alkyl group, carboxyl, oxo group, (=CH 2 ), -CONH 2 , -NHC(O)C 1-6 alkyl, C 1-6 alkyl -NHCOC 1-6 alkylene, C 1-6 alkyl group, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 alkoxy, arylene C 1-6 alkyl, aryl C 1-6 alkylene, (C 1-6 Alkoxy)C 1-6 alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH 2 NHCOC 1-6 Substituted by alkyl, C 1-6 alkylene cyano, C 2-6 alkenyl and C 2-6 alkynyl substituents;
R5每次出现独立地选自氢、卤素、氰基、氨基、羟基、羟基亚烷基、巯基、-C(O)O-烷基、-OC(O)-烷基、羧基、氧代基、(＝CH2)、-CONH2、-NHC(O)C1-6烷基、C1-6烷基-NHCOC1-6烷基、烷基、烷基氨基、C1-6卤代烷基、C1-6烷氧基、C1-6烷基取代的吡唑基、亚芳基C1-6烷基、芳基C1-6亚烷基、(C1-6烷氧基)C1-6亚烷基-、(C1-6烷基)C(＝O)-、(C1-6卤代烷基)C(＝O)-、-CH2NHCO C1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基；Each occurrence of R 5 is independently selected from hydrogen, halogen, cyano, amino, hydroxyl, hydroxyalkylene, mercapto, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, oxo Base, (=CH 2 ), -CONH 2 , -NHC(O)C 1-6 alkyl, C 1-6 alkyl -NHCOC 1-6 alkyl, alkyl, alkylamino, C 1-6 haloalkyl base, C 1-6 alkoxy group, C 1-6 alkyl substituted pyrazolyl group, arylene C 1-6 alkyl group, aryl C 1-6 alkylene group, (C 1-6 alkoxy group )C 1-6 alkylene-, (C 1-6 alkyl)C (=O)-, (C 1-6 haloalkyl) C (=O)-, -CH 2 NHCO C 1-6 alkyl , C 1-6 alkylene cyano group, C 2-6 alkenyl group and C 2-6 alkynyl group;
Cy2为与Cy1稠合连接的芳基、饱和或部分不饱和的环烷基、含有1、2或3个各自独立选自N、O和S的杂原子的杂芳基、含有1、2或3个各自独立选自N、O和S的杂原子的饱和的杂环烷基、或含有1、2或3个各自独立选自N、O和S的杂原子的部分不饱和的杂环烷基，所述芳基、饱和或部分不饱和的环烷基、杂芳基、杂环烷基可任选地被1个、2个、3个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、烷氧基、烷基氨基、亚烷基羟基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基的取代基所取代，任选地，所述烷基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基被1个、2个、3个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、烷氧基、烷基氨基、亚烷基羟基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基的取代基所取代；Cy2为与Cy1稠合连接的6-10元芳基、饱和或部分不饱和的3-10元环烷基、含有1、2或3个各自独立选自N、O和S的杂原子的5-10元杂芳基、含有1、2或3个各自独立选自N、O和S的杂原子的5-10元饱和杂环烷基、或含有1、2或3个各自独立选自N、O和S的杂原子的5-10元部分不饱和杂环烷基，所述芳基、饱和或部分不饱和的环烷基、杂芳基、杂环烷基可任选地被1个、2个、3个或多个选自F、Cl、Br、I、C1-6烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、C6-10芳基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、和C5-10杂芳基的取代基所取代，任选地，所述C1-6烷基、C6-10芳基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、和C5-10杂芳基被1个、2个、3个或多个选自F、Cl、Br、I、C1-6烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、C6-10芳基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、和C5-10杂芳基的取代基所取代；优选地，Cy2选 自其中表示与R4的连接位点，表示Cy2与Cy1稠合位置；Cy 2 is an aryl group fused to Cy 1 , a saturated or partially unsaturated cycloalkyl group, a heteroaryl group containing 1, 2 or 3 heteroatoms each independently selected from N, O and S, containing 1, A saturated heterocycloalkyl group with 2 or 3 heteroatoms each independently selected from N, O and S, or a partially unsaturated heterocycloalkyl group containing 1, 2 or 3 heteroatoms each independently selected from N, O and S. Cycloalkyl, the aryl, saturated or partially unsaturated cycloalkyl, heteroaryl, heterocycloalkyl can optionally be 1, 2, 3 or more selected from halogen, alkyl, Hydroxy, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl , heterocyclyl, and heteroaryl substituents, optionally, the alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl groups are substituted by 1, 2 One, three or more selected from halogen, alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylene Substituted with hydroxyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents; Cy 2 is a 6-10-membered aryl group fused to Cy 1 , saturated or partially un Saturated 3-10 membered cycloalkyl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms each independently selected from N, O and S, 5-10 membered heteroaryl containing 1, 2 or 3 each independently selected from N , a 5-10 membered saturated heterocycloalkyl group with heteroatoms of O and S, or a 5-10 membered partially unsaturated heterocycloalkyl group containing 1, 2 or 3 heteroatoms each independently selected from N, O and S , the aryl group, saturated or partially unsaturated cycloalkyl group, heteroaryl group, heterocycloalkyl group can optionally be 1, 2, 3 or more selected from F, Cl, Br, I, C 1-6 alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl Amino, C 1-6 alkylenehydroxy, C 6-10 aryl, C 2-6 alkynyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl , and C 5-10 heteroaryl substituents, optionally, the C 1-6 alkyl, C 6-10 aryl, C 2-6 alkynyl, C 2-6 alkenyl, C 3-10 Cycloalkyl, C 3-10 heterocyclyl, and C 5-10 heteroaryl are substituted by 1, 2, 3 or more selected from F, Cl, Br, I, C 1-6 alkyl, hydroxyl , cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylene Substitution of hydroxyl, C 6-10 aryl, C 2-6 alkynyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, and C 5-10 heteroaryl Substituted with radicals; preferably, Cy 2 is selected since in Indicates the connection site with R 4 , Indicates the fused position of Cy 2 and Cy 1 ;
q为0，1，或2；q is 0, 1, or 2;
Ra每次出现时各自独立地选自氢、卤素、烷基、炔基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、芳基、C2-6烯基、环烷基、杂环基、和杂芳基，任选地，所述烷基、炔基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、芳基、C2-6烯基、环烷基、杂环基、和杂芳基被被1个、2个、3个或多个选自F、Cl、Br、I、C1-6烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、C6-10芳基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、和C5-10杂芳基的取代基所取代；当R2含有2个环N原子时，Cy2为且Ra为H时，R4是R3是当Cy2是且Ra为H时，R4是R3是 Each occurrence of R a is independently selected from hydrogen, halogen, alkyl, alkynyl, hydroxy, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkylenehydroxy, aryl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, and heteroaryl, optionally, the Alkyl, alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylenehydroxy, aryl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, and The heteroaryl group is 1, 2, 3 or more selected from F, Cl, Br, I, C 1-6 alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl Base, -CO-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylene hydroxy, C 6-10 aryl, C 2-6 alkynyl , C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, and C 5-10 heteroaryl substituents; when R 2 contains 2 ring N atoms, Cy 2 for And when R a is H, R 4 is R 3 is When Cy 2 is And when R a is H, R 4 is R 3 is
当与Rb连接的为双键时，Rb每次出现时各自独立地为O、S或者C(R5)2；当与Rb连接的为单键时，Rb每次出现时各自独立地选自氢、卤素、烷基、烷氧基、羟基、氰基、氨基、氨基烷基、亚烷基氨基、环烷基、杂环基、-CONH2、-NHCOC1-6烷基、-CO-烷基、亚烷基羟基、芳基、炔基、烯基、和杂芳基，优选地，Rb每次出现时各自独立地选自氢、F、Cl、Br、I，C1-6烷基、C1-6烷氧基、羟基、氰基、氨基、氨基C1-6烷基、C1-6亚烷基氨基、C3-10环烷基、C3-10杂环基、-CONH2、-NHCOC1-6烷基、-CO-C1-6烷基、C1-6亚烷基羟基、C6-10芳基、C2-6炔基、C2-6烯基、和C5-10杂芳基；When connected to R b When it is a double bond, R b is independently O, S or C(R 5 ) 2 each time it appears; when it is connected to R b When it is a single bond, each occurrence of R b is independently selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, cyano, amino, aminoalkyl, alkyleneamino, cycloalkyl, heterocyclyl , -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkylenehydroxy, aryl, alkynyl, alkenyl, and heteroaryl, preferably, each occurrence of R b is independently Selected from hydrogen, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, cyano, amino, amino C 1-6 alkyl, C 1-6 alkylene amino , C 3-10 cycloalkyl, C 3-10 heterocyclyl, -CONH 2 , -NHCOC 1-6 alkyl, -CO-C 1-6 alkyl, C 1-6 alkylene hydroxyl, C 6 -10 aryl, C 2-6 alkynyl, C 2-6 alkenyl, and C 5-10 heteroaryl;
Rc选自H、C1-6烷基、-CN、-≡-Rca、-CONH2和-OCONH2；当R2含有2个环N原子时，且当Rc为C1-6烷基或H时，R1为N时，R4为 当R2含有2个环N原子时，当Rc为H时，R1为CR1a，R1a为 CN时，R4为R3为 R c is selected from H, C 1-6 alkyl, -CN, -≡-R ca , -CONH 2 and -OCONH 2 ; when R 2 contains 2 ring N atoms, and when R c is C 1-6 When R 1 is N, R 4 is When R 2 contains 2 ring N atoms, when R c is H, R 1 is CR 1a , and R 1a is When CN, R 4 is R 3 is
Rca每次出现时，每个Rca各自独立地选自氢、氨基、羟基、卤素、氰基、-CONH2、-NHC(O)C1-6烷基、-CO-C1-6烷基、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基氨基、C1-6亚烷基NHC1-6烷基、C1-6亚烷基羟基、C2-6炔基、C2-6烯基、环烷基、杂环基、和杂芳基，任选地，所述C1-6烷基、C1-6亚烷基、C2-6炔基、C2-6烯基、环烷基、杂环基、芳基和杂芳基被1个、2个、3个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、烷氧基、烷基氨基、亚烷基羟基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基的取代基所取代；优选地，Rca每次出现时，每个Rca各自独立地选自氢、氨基、羟基、F、Cl、Br、I、氰基、-CONH2、-NHC(O)C1-6烷基、-CO-C1-6烷基、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基氨基、C1-6亚烷基NHC1-6烷基、C1-6亚烷基羟基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、C6-10芳基和C5-10杂芳基，任选地，所述C1-6烷基、C1-6亚烷基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、C6-10芳基和C5-10杂芳基被1个、2个、3个或多个选自F、Cl、Br、I、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、烷氧基、烷基氨基、亚烷基羟基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基的取代基所取代；优选地，Rca每次出现时，每个Rca各自独立地选自氢、-CH3、-C(CH3)3、-C(CH3)2OH、-CH(CH3)OH、-C2H5、-C3H7、-C4H9、-CH2OH、-C2H4OH、-C3H6OH、-CH2NH2、-CH2NHCH3、和环丙基；Each occurrence of R ca , each R ca is independently selected from hydrogen, amino, hydroxyl, halogen, cyano, -CONH 2 , -NHC(O)C 1-6 alkyl, -CO-C 1-6 Alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylene amino, C 1-6 alkylene NHC 1-6 alkyl, C 1-6 alkylene hydroxyl, C 2-6 alkynyl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, and heteroaryl, optionally, the C 1-6 alkyl, C 1 -6 alkylene, C 2-6 alkynyl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are 1, 2, 3 or more selected from halogen, Alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, Substituted with cycloalkyl, heterocyclyl, and heteroaryl substituents; preferably, each time R ca occurs, each R ca is independently selected from hydrogen, amino, hydroxyl, F, Cl, Br, I , cyano group, -CONH 2 , -NHC(O)C 1-6 alkyl, -CO-C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl amino group, C 1-6 alkylene amino group, C 1-6 alkylene NHC 1-6 alkyl group, C 1-6 alkylene hydroxyl group, C 2-6 alkynyl group, C 2-6 alkenyl group, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl and C 5-10 heteroaryl, optionally, the C 1-6 alkyl, C 1-6 alkylene , C 2-6 alkynyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl and C 5-10 heteroaryl are replaced by 1, 2 One, three or more selected from F, Cl, Br, I, alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkyl substituted with substituents of amino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl; preferably, each time R ca appears, each R ca is Independently selected from hydrogen, -CH 3 , -C(CH 3 ) 3 , -C(CH 3 ) 2 OH, -CH(CH 3 )OH, -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -CH 2 OH, -C 2 H 4 OH, -C 3 H 6 OH, -CH 2 NH 2 , -CH 2 NHCH 3 , and cyclopropyl;
当R2为R4为 且当Rca 为氢时，Rd为氟时，Y为O时，R3不为 When R 2 is R 4 is And when R ca When it is hydrogen, when R d is fluorine, when Y is O, when R 3 is not
Rd每次出现时各自独立地选自氢、氟、氯、溴、碘、氰基、羟基、巯基、羟基亚烷基、羧基、氧代基、烷氧基、氨基、-CONH2、-NHC(O)烷基、烷基、C1-6亚烷基氰基、-CO-烷基、烷基氨基、亚烷基氨基、亚烷基NH烷基、芳基、环烷基、杂环基、杂芳基、烯基和炔基，任选地，所述烷基、亚烷基、炔基、烯基、环烷基、杂环基、芳基和杂芳基被1个、2个、3个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、烷氧基、烷基氨基、亚烷基羟基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基的取代基所取代；优选地，Rd每次出现时各自独立地选自氢、氟、氯、溴、碘、氰基、羟基、巯基、羟基C1-6亚烷基、羧基、氧代基、C1-6烷氧基、氨基、-CONH2、-NHC(O)C1-6烷基、C1-6烷基、C1-6亚烷基氰基、-CO-C1-6烷基、C1-6烷基氨基、C1-6亚烷基氨基、C1-6亚烷基NH烷基、C6-10芳基、C3-10环烷基、C3-10杂环基、C5-10杂芳基、C2-6烯基和C2-6炔基，任选地，所述C1-6烷基、C1-6亚烷基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、C6-10芳基和C5-10杂芳基被1个、2个、3个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、C6-10芳基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、和C5-10杂芳基的取代基所取代；Each occurrence of R d is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, hydroxy, mercapto, hydroxyalkylene, carboxyl, oxo, alkoxy, amino, -CONH 2 , - NHC(O)alkyl, alkyl, C 1-6 alkylenecyano, -CO-alkyl, alkylamino, alkyleneamino, alkyleneNHalkyl, aryl, cycloalkyl, hetero Cyclic group, heteroaryl group, alkenyl group and alkynyl group, optionally, the alkyl group, alkylene group, alkynyl group, alkenyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are replaced by 1, 2, 3 or more selected from halogen, alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylene hydroxyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents; preferably, each occurrence of R d is independently selected from hydrogen, fluorine, chlorine, Bromine, iodine, cyano, hydroxyl, mercapto, hydroxy C 1-6 alkylene, carboxyl, oxo, C 1-6 alkoxy, amino, -CONH 2 , -NHC(O)C 1-6 alkane group, C 1-6 alkyl, C 1-6 alkylene cyano, -CO-C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkylene amino, C 1-6 Alkylene NH alkyl, C 6-10 aryl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 5-10 heteroaryl, C 2-6 alkenyl and C 2-6 alkyne base, optionally, the C 1-6 alkyl group, C 1-6 alkylene group, C 2-6 alkynyl group, C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 3-10 hetero group The ring group, C 6-10 aryl group and C 5-10 heteroaryl group are 1, 2, 3 or more selected from halogen, alkyl, hydroxyl, cyano group, amino, -CONH 2 , -NHCOC 1 -6 alkyl, -CO-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylene hydroxy, C 6-10 aryl, C 2- Substituted with substituents of 6 alkynyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, and C 5-10 heteroaryl;
R4选自被0、1、2、3、4、5、或更多个R4a取代的芳基和杂芳基，所述杂芳基包含1、2、3或4个各自独立选自N、O和S的杂原子；优选地，R4选自被0、1、2、3、4、5、或更多个R4a取代的6-12元芳基和5-12元杂芳基，所述5-12元杂芳基包含1、2、3或4个各自独立选自N、O和S的杂原子；优选地，R4选自被0、1、2、3、4、5、或更多个R4a取代的苯基、萘基、5-6元杂芳基、7-8元杂芳基、9-10元杂芳基、和苯并5-6元杂芳基，所述5-6元杂芳基、7-8元杂芳基、9-10元杂芳基、和苯并5-6元杂芳基包含1、2、3或4个各自独立选自N、O和S的杂原子；R4a每次出现时各自独立地选自卤素、炔基、烯基、亚炔基烷基、亚烯基烷基、亚烷基氰基、烷氧基、-OH、-SH、-NH2、-NH-R4c、-CN、-CO-烷基、-CON(R4c)2、烷基-CO-NR4c-、烷基、卤代烷基、卤代烷氧基、烷基氨基、亚烷基氨基、环烷基、亚环烷基烷基、芳基、杂芳基、杂环烷基和亚杂环烷基烷基，任选地，所述炔基、烯基、亚炔基、亚烯基、亚烷基、烷氧基、烷基、环烷基、芳基、杂芳基、杂环烷基和亚杂 环烷基被一个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、烷氧基、烷基氨基、亚烷基羟基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基的取代基所取代；优选地，R4a每次出现独立地选自C1-6烷基、F、Cl、Br、I、C2-6炔基、C2-6烯基、C2-6亚炔基C1-6烷基、C2-6亚烯基C1-6烷基、C1-6亚烷基氰基、C1-6烷氧基、-OH、-SH、-NH2、-NH-R4c、-CN、-CO 1-6烷基、-CON(R4c)2、C1-6烷基-CO-NR4c-、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基氨基、3-10元环烷基、3-10元亚环烷基C1-6烷基、3-10元杂环烷基和3-10元亚杂环烷基C1-6烷基，任选地，所述C2-6炔基、C2-6烯基、C2-6亚炔基、C2-6亚烯基、C1-6亚烷基、C1-6烷氧基、C1-6烷基、C3-10环烷基、C6-10芳基、C5-10杂芳基、C3-10杂环烷基和C3-10亚杂环烷基被一个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、C6-10芳基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、和C5-10杂芳基的取代基所取代；R 4 is selected from aryl and heteroaryl substituted by 0, 1, 2, 3, 4, 5, or more R 4a , and the heteroaryl contains 1, 2, 3 or 4 each independently selected from Heteroatoms of N, O and S; preferably, R 4 is selected from 6-12-membered aryl and 5-12-membered heteroaryl substituted by 0, 1, 2, 3, 4, 5, or more R 4a base, the 5-12 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S; preferably, R 4 is selected from 0, 1, 2, 3, 4 , 5, or more R 4a substituted phenyl, naphthyl, 5-6 membered heteroaryl, 7-8 membered heteroaryl, 9-10 membered heteroaryl, and benzo 5-6 membered heteroaryl base, the 5-6-membered heteroaryl, 7-8-membered heteroaryl, 9-10-membered heteroaryl, and benzo 5-6-membered heteroaryl include 1, 2, 3 or 4 independently selected heteroatoms from N, O, and S; each occurrence of R 4a is independently selected from halogen, alkynyl, alkenyl, alkynylenealkyl, alkenylenealkyl, alkylenecyano, alkoxy , -OH, -SH, -NH 2 , -NH-R 4c , -CN, -CO-alkyl, -CON(R 4c ) 2 , alkyl-CO-NR 4c -, alkyl, haloalkyl, haloalkyl Oxy, alkylamino, alkyleneamino, cycloalkyl, cycloalkylenealkyl, aryl, heteroaryl, heterocycloalkyl and heterocycloalkylenealkyl, optionally, the alkyne base, alkenyl, alkynylene, alkenylene, alkylene, alkoxy, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl and heteroylene The cycloalkyl group is one or more selected from halogen, alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylene Substituted with hydroxyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents; preferably, each occurrence of R 4a is independently selected from C 1-6 alkyl, F , Cl, Br, I, C 2-6 alkynyl, C 2-6 alkenyl, C 2-6 alkynylene C 1-6 alkyl, C 2-6 alkenylene C 1-6 alkyl, C 1-6 alkylenecyano, C 1-6 alkoxy, -OH, -SH, -NH 2 , -NH-R 4c , -CN, -CO 1-6 alkyl, -CON(R 4c ) 2. C 1-6 alkyl-CO-NR 4c -, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylene amino , 3-10 membered cycloalkyl, 3-10 membered cycloalkylene C 1-6 alkyl, 3-10 membered heterocycloalkyl and 3-10 membered heterocycloalkylene C 1-6 alkyl, any Optionally, the C 2-6 alkynyl, C 2-6 alkenyl, C 2-6 alkynylene, C 2-6 alkenylene, C 1-6 alkylene, C 1-6 alkoxy , C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 3-10 heterocycloalkyl and C 3-10 heterocycloalkylene One or more selected from halogen, alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-C 1-6 alkyl, C 1-6 alkoxy, C 1 -6 alkylamino, C 1-6 alkylene hydroxyl, C 6-10 aryl, C 2-6 alkynyl, C 2-6 alkenyl, C 3-10 cycloalkyl , C 3-10 heterocycle substituted with C 5-10 heteroaryl substituents;
R4c每次出现各自独立地选自氢、卤素、氰基、羟基、巯基、羟基亚烷基、-C(O)O-烷基、-OC(O)-烷基、羧基、氨基、-CONH2、-NHCOC1-6烷基、烷基、C1-6亚烷基氰基、烯基和炔基；Each occurrence of R 4c is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxyalkylene, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, amino, - CONH 2 , -NHCOC 1-6 alkyl, alkyl, C 1-6 alkylenecyano, alkenyl and alkynyl;
式Ⅰ化合物不为：

Compounds of formula I are not:

本发明另一方面提供一种式Ⅰ化合物，或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，其中，
Another aspect of the invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, in,
其中，R1为CR1a或N；R1a独立地选自氢、卤素、氰基、羟基、巯基、羟甲基、酯基、羧基、-CONH2、氨基、-NHCOC1-6烷基、烷基、C1-4烷基氰基、烯基和炔基；Wherein, R 1 is CR 1a or N; R 1a is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester group, carboxyl, -CONH 2 , amino, -NHCOC 1-6 alkyl, Alkyl, C 1-4 alkylcyano, alkenyl and alkynyl;
R2为至少含1个N的3-12元饱和或部分饱和的单环、桥环或螺环，其中所述饱和或部分饱和的单环、桥环或螺环任选地被一个或多个R2a取代；每次R2a出现时，每个R2a分别独立地选自卤素、氰基、羟基、巯基、羟甲基、酯基、羧基、羰基、氨基、-CONH2-NHCOC1-6烷基、烷基、C1-4烷基氰基、烯基和炔基；优选地，R2为含1个环N的3-12元饱和或部分饱和的单环、桥环或螺环，其中所述饱和或部分饱和的单环、桥环或螺环任选地被一个或多个R2a取代；优选地，R2为含1个环N，并且含0、1、2或3个独立选自O和S的环杂原子的饱和或部分饱和的3、5、6、7、或8元单环、6、7、8、9、或10元桥环、4、5、6、7、8、9、或10元稠环、或5、6、7、8、9、10、11或12元螺环，其中所述饱和或部分饱和的单环、桥环、稠环或螺环任选地被一个或多个R2a取代；每次R2a出现时，每个R2a分别独立地选自卤素、氰基、羟基、巯基、羟甲基、-COO烷基、羧基、氧代基、-NH2、-CONH2、-NHC(O)C1-6烷基、烷基、C1-4烷基氰基、烯基和炔基；R 2 is a 3-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring containing at least 1 N, wherein the saturated or partially saturated monocyclic, bridged or spirocyclic ring is optionally substituted by one or more R 2a ; each time R 2a appears, each R 2a is independently selected from halogen, cyano, hydroxyl, thiol, hydroxymethyl, ester, carboxyl, carbonyl, amino, -CONH 2 -NHCOC 1-6 alkyl, alkyl, C 1-4 alkylcyano, alkenyl and alkynyl; preferably, R 2 is a 3-12 membered saturated or partially saturated monocyclic, bridged or spirocyclic ring containing 1 ring N, wherein the saturated or partially saturated monocyclic, bridged or spirocyclic ring is optionally substituted by one or more R 2a ; preferably, R R2a is a saturated or partially saturated 3, 5, 6, 7, or 8-membered monocyclic ring, a 6, 7, 8, 9, or 10-membered bridged ring, a 4, 5, 6, 7, 8, 9, or 10-membered fused ring, or a 5, 6, 7, 8, 9, 10, 11, or 12-membered spirocyclic ring containing 1 ring N and 0, 1, 2, or 3 ring heteroatoms independently selected from O and S, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring, or spirocyclic ring is optionally substituted with one or more R2a; each R2a is independently selected from halogen, cyano, hydroxyl, thiol, hydroxymethyl, -COOalkyl, carboxyl, oxo, -NH2 , -CONH2 , -NHC(O) C1-6alkyl , alkyl, C1-4alkylcyano , alkenyl, and alkynyl at each occurrence;
Y为-CRxRy-、-O-、-S-、-S＝O-、-S(＝O)2-或-NRx-，Rx和Ry分别独立地选自氢、烷基、环烷基、杂环基、烷基氨基烷基、芳基和烷基芳基；Y is -CR x R y -, -O-, -S-, -S=O-, -S(=O) 2 - or -NR x -, R x and R y are independently selected from hydrogen, alkane base, cycloalkyl, heterocyclyl, alkylaminoalkyl, aryl and alkylaryl;
R3为各自独立地选自氢、烷基、羟基烷基、二羟基烷基、烷基胺基烷基、二烷基胺基烷基、环烷基、杂环基、-L-N(R5)2、-L-NHC(＝NH)NH2、-L-C(O)N(R5)2、-L-NR5C(O)-芳基、-L-C1-6卤代烷基、-L-OR5、-L-杂环基、-L- 芳基、-L-杂芳基、-L-环烷基、氮杂饱和或部分饱和的单环或并环、和氧杂饱和或部分饱和的单环或稠环，其中所述杂芳基、芳基、饱和或部分饱和的单环或稠环部分以及-L-杂环基的所述杂环基部分和-L-环烷基的所述环烷基部分可任选被一个或多个R5取代；R 3 is each independently selected from hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, heterocyclyl, -LN (R 5 ) 2 , -L-NHC(=NH)NH 2 , -LC(O)N(R 5 ) 2 , -L-NR 5 C(O)-aryl, -LC 1-6 haloalkyl, -L- OR 5 , -L-heterocyclyl, -L- Aryl, -L-heteroaryl, -L-cycloalkyl, aza-saturated or partially saturated monocyclic or fused rings, and oxa-saturated or partially saturated monocyclic or condensed rings, wherein said heteroaryl , an aryl group, a saturated or partially saturated monocyclic or fused ring moiety and the heterocyclyl moiety of -L-heterocyclyl and the cycloalkyl moiety of -L-cycloalkyl may optionally be replaced by one or more R 5 substitution;
每个L独立地选自C1-6亚烷基、C1-6羟烷基和杂芳基；Each L is independently selected from C 1-6 alkylene, C 1-6 hydroxyalkyl and heteroaryl;
R5每次出现时，每个R5独立地选自氢、卤素、氰基、羟基、巯基、羟甲基、酯基、羧基、羰基、-NH2、-CONH2、-NHC(O)C1-6烷基、烷基、C1-4卤代烷基、C1-4烷氧基、C1-4烷基取代的吡唑基、芳基C1-4烷基、(C1-4烷氧基)C1-4烷基-、(C1-4烷基)C(＝O)-、(C1-4卤代烷基)C(＝O)-、-CH2NHCO C1-6烷基、C1-4烷基氰基、C2-6烯基和C2-6炔基；Each time R 5 occurs, each R 5 is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, carbonyl, -NH 2 , -CONH 2 , -NHC(O) C 1-6 alkyl, alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkyl substituted pyrazolyl, aryl C 1-4 alkyl, (C 1- 4Alkoxy )C 1-4 alkyl-, (C 1-4 alkyl)C(=O)-, (C 1-4 haloalkyl)C(=O)-, -CH 2 NHCO C 1- 6 alkyl, C 1-4 alkyl cyano, C 2-6 alkenyl and C 2-6 alkynyl;
Cy2与Cy1稠合连接，且Cy2为芳基或含有1或2个杂原子的5-7元杂芳基、5-7元饱和杂环烷基或5-7元不饱和杂环烷基；且当Cy2为芳基或吡啶基时，具有结构式Ra每次出现时，每个Ra独立地选自氢、卤基、烷基、炔基、羟基、氰基、-CONH2、-NHCOC1-6烷基、-CO-烷基、C1-4烷氧基、C1-4烷基氨基、C1-4烷基羟基、芳基、C2-4炔基、C2-6烯基、环烷基、杂环基、杂芳基；Rc选自-CN、-≡-Rca、Rca每次出现时，每个Rca独立地选自氢、卤素、氰基、-COO-烷基、-NHC(O)C1-6烷基、-CO-烷基、C1-4烷基、C1-4烷氧基、C1-4烷基氨基、C1-4烷基羟基、芳基、C2-4炔基、C2-6烯基、环烷基、杂环基和杂芳基；Cy 2 is fused with Cy 1 , and Cy 2 is an aryl group or a 5-7-membered heteroaryl group containing 1 or 2 heteroatoms, a 5-7-membered saturated heterocycloalkyl group, or a 5-7-membered unsaturated heterocycloalkyl group; and when Cy 2 is an aryl group or a pyridyl group, it has the structural formula Each occurrence of Ra is independently selected from hydrogen, halo, alkyl, alkynyl, hydroxy, cyano, -CONH2 , -NHCOC1-6alkyl , -CO-alkyl, C1-4alkoxy , C1-4alkylamino , C1-4alkylhydroxy, aryl, C2-4alkynyl , C2-6alkenyl , cycloalkyl, heterocyclyl, heteroaryl; Rc is selected from -CN, -≡- Rca , At each occurrence of Rca , each Rca is independently selected from hydrogen, halogen, cyano, -COO-alkyl, -NHC(O) C1-6alkyl , -CO-alkyl, C1-4alkyl , C1-4alkoxy, C1-4alkylamino , C1-4alkylhydroxy , aryl, C2-4alkynyl , C2-6alkenyl , cycloalkyl , heterocyclyl, and heteroaryl;
每次Rd出现时各自独立地选自氢、卤素、氰基、羟基、巯基、羟甲基、酯基、羧基、氧代、氧烷基、氨基、-CONH2、-NHC(O)C1-6烷基、烷基、C1-4烷基氰基、烯基和炔基；Each occurrence of R d is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, oxo, oxyalkyl, amino, -CONH 2 , -NHC(O)C 1-6 alkyl, alkyl, C 1-4 alkylcyano, alkenyl and alkynyl;
R4选自被1、2、或3个R4a或1、2或3个R4b取代的苯基、萘基、5-6元杂芳基、苯并5-6元杂环基、苯并5-6元环烯基和苯并5-6元杂芳基；每个R4a独立地选自卤基、-OH、-SH、-NH2、-CN、-CO-烷基、-CON(R4c)2、C1-4烷基、卤代C1-4烷基、卤代C1-4烷氧基、C1-4烷基氨基、二C1-4烷基氨基、3-7元环烷基、4-7元杂环烷基和4-7元杂环烷基C1-4烷基；每个R4b分别各自独立地选自卤基、-OH、-SH、-NH2、-NO2、-CN、-CO-烷基、-CON(R4c)2、三唑基、C1-6烷基、C2-6烯基、C2-4炔基、C1-6烷氧基、C1-6的烷硫基、C1-6的烷基氨基、C1-6的烷基氰基、二C1-6烷基氨基、氨基C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6的烷基氨基、卤代C1-6烷硫基、二(卤代C1-6烷基)氨基；R4c每次出现时，每个R4c各自独立地选自氢、卤素、氰基、羟基、巯基、羟甲基、酯基、羧基、氨基、-CONH2、-NHCOC1-6烷基、烷基、C1-4烷基氰基、烯基和炔基，或者由两个连接到同一个C原子的R4c形成＝O； R 4 is selected from phenyl, naphthyl, 5-6 membered heteroaryl, benzo 5-6 membered heterocyclyl, benzo 5-6 membered cycloalkenyl and benzo 5-6 membered heteroaryl substituted by 1, 2, or 3 R 4a or 1, 2 or 3 R 4b ; each R 4a is independently selected from halo, -OH, -SH, -NH 2 , -CN, -CO-alkyl, -CON(R 4c ) 2 , C 1-4 alkyl, halo C 1-4 alkyl, halo C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl and 4-7 membered heterocycloalkyl C 1-4 alkyl; each R 4b is independently selected from halo, -OH, -SH, -NH 2 , -NO 2 , -CN, -CO-alkyl, -CON(R 4c ) 2 , triazolyl, C 1-4 R 4c is independently selected from hydrogen, halogen , cyano , hydroxyl , thiol , hydroxymethyl, ester, carboxyl, amino, -CONH 2 , -NHCOC 1-6 alkyl, alkyl, C 1-4 alkylcyano , alkenyl and alkynyl , or is formed by two R 4c attached to the same C atom to form = 0 ;
当R4为时，m为0至6的整数，每次R4a出现时，每个R4a独立地选自H、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、卤素、-OH、-SH、-CN、-COR5、-CON(R5)2、-OCON(R5)2和-≡-Rca；When R4 is , m is an integer from 0 to 6, and each time R 4a occurs, each R 4a is independently selected from H, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, halogen, -OH, -SH, -CN, -COR 5 , -CON(R 5 ) 2 , -OCON(R 5 ) 2 and -≡-R ca ;
每次Rca出现时，每个Rca独立地选自氢、卤素、-CN、-COO-烷基、-CONH2、-NHCOC1-6烷基、-CO-烷基、C1-4烷基、C1-4烷氧基、C1-4烷基氨基、C1-4烷基羟基、芳基、C2-4炔基、C2-6烯基、环烷基、杂环基和杂芳基；Each time R ca occurs, each R ca is independently selected from hydrogen, halogen, -CN, -COO-alkyl, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, C 1-4 Alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylhydroxy, aryl, C 2-4 alkynyl, C 2-6 alkenyl, cycloalkyl, heterocycle base and heteroaryl;
每次R6出现时，R6独立地选自H和C1-4烷基；Each time R 6 occurs, R 6 is independently selected from H and C 1-4 alkyl;
优选地，式Ⅰ化合物不为：

Preferably, the compound of formula I is not:

在其中一个技术方案中，R4选自


In one of the technical solutions, R 4 is selected from


在其中一个技术方案中，R2选自 In one of the technical solutions, R 2 is selected from
在其中一个技术方案中，其中，R3选自C1-6烷基、 In one of the technical solutions, R 3 is selected from C 1-6 alkyl,
其中，n＝0、1、2或3；每次R3b出现时独立地选自共价键、-COC1-6亚烷基、C1-6亚烷基、C1-6氘代亚烷基、亚环烷基、C1-6卤代亚烷基、亚杂环基、亚芳基和亚杂芳基；和Where n=0, 1, 2 or 3; each time R 3b appears, it is independently selected from covalent bond, -COC 1-6 alkylene, C 1-6 alkylene, C 1-6 deuterated Alkyl, cycloalkylene, C 1-6 haloalkylene, heterocyclylene, arylene and heteroarylene; and
每次R3c出现时，每个R3c独立地选自氢、氘原子、卤基、C1-6烷基、-CONH2、-NHCOC1-6烷基、C1-6烷基-NHCOC1-6烷基、羟基、氨基、羟基亚烷基、氰基、烷基氨基、卤代烷基、C1-6烷氧基。Each time R 3c occurs, each R 3c is independently selected from hydrogen, deuterium atom, halo, C 1-6 alkyl, -CONH 2 , -NHCOC 1-6 alkyl, C 1-6 alkyl-NHCOC 1-6 alkyl, hydroxyl, amino, hydroxyalkylene, cyano, alkylamino, haloalkyl, C 1-6 alkoxy.
在其中一个技术方案中，R3选自


In one of the technical solutions, R 3 is selected from


在其中一个技术方案中，所述化合物选自选自 优选地，所述化合物的药学上可接受的盐为所述化合物的酸式盐，优选所述化合物的药学上可接受的盐为所述化合物的有机酸式盐，优选所述化合物的药学上可接受的盐为所述化合物的甲酸盐，优选每摩尔所述化合物的甲酸盐含0.1-3摩尔的甲酸离子，优选每摩尔所述化合物的甲酸盐含0.1、0.2、0.3、0.4、0.5、1、2或3摩尔甲酸离子。In one of the technical solutions, the compound is selected from Preferably, the pharmaceutically acceptable salt of the compound is an acid salt of the compound, preferably the pharmaceutically acceptable salt of the compound is an organic acid salt of the compound, preferably the pharmaceutically acceptable salt of the compound is a formate salt of the compound, preferably the formate salt contains 0.1-3 moles of formate ions per mole of the compound, preferably the formate salt contains 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2 or 3 moles of formate ions per mole of the compound.
本发明另一方面提供一种药物组合物，其特征在于，包含治疗有效量的如上文所述的任一化合物、其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，以及药学上可接受的赋形剂。Another aspect of the present invention provides a pharmaceutical composition, which is characterized in that it contains a therapeutically effective amount of any of the compounds described above, its pharmaceutically acceptable salts, stereoisomers, tautomers, and solvents. compounds, metabolites, prodrugs, polymorphs or deuterated compounds, and pharmaceutically acceptable excipients.
本发明还提供了如上文所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，或者如上文所述的药物组合物在制备用于抑制KRas突变蛋白活性的药物中的应用，优选，在制备用于抑制KRas G12D活性的药物中的应用。The invention also provides a compound as described above or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, or The application of a pharmaceutical composition as described above in the preparation of a medicament for inhibiting the activity of KRas mutant protein, preferably, the application of a pharmaceutical composition for inhibiting the activity of KRas G12D.
在其中一个方案中，所述KRas突变蛋白相关癌症选自：In one of the scenarios, the KRas mutant protein-related cancer is selected from:
非小细胞肺癌、结肠腺癌、多发性骨髓瘤、结肠癌和胰腺癌；支气管癌、 肺泡癌、肉瘤、淋巴瘤、支气管腺瘤、软骨瘤错构瘤、间皮瘤；食管鳞状细胞癌、食管平滑肌肉瘤、食管腺癌、食管淋巴瘤、胃癌、胃淋巴瘤、胃平滑肌肉瘤、胰腺导管腺癌、胰岛素瘤、胃泌素瘤、类癌瘤、胰高血糖素瘤、血管活性肠肽瘤、小肠腺癌、小肠淋巴瘤、小肠类癌瘤、小肠平滑肌瘤、小肠血管瘤、小肠卡波西肉瘤、小肠脂肪瘤、小肠纤维瘤、小肠神经纤维瘤、大肠腺癌、大肠管状腺瘤、大肠错构瘤、大肠绒毛状腺瘤、大肠平滑肌瘤；心脏肉瘤、心脏血管肉瘤、心脏纤维肉瘤、心脏脂肪肉瘤、心脏横纹肌肉瘤、心脏粘液瘤、心脏纤维瘤、心脏横纹肌瘤、心脏脂肪瘤和心脏畸胎瘤；肝细胞瘤或肝细胞癌、胆管癌、肝母细胞瘤、肝脏血管肉瘤、肝细胞腺瘤、肝脏血管瘤；胆囊癌、胆管癌、壶腹癌；威尔姆氏瘤、肾母细胞瘤、淋巴瘤、白血病、鳞状细胞癌、移行细胞癌、肾腺癌、前列腺腺癌、肉瘤、睾丸精原细胞瘤、睾丸畸胎瘤、睾丸畸胎癌、睾丸肉瘤、睾丸胚胎性癌、睾丸绒毛膜癌、睾丸间质细胞癌、睾丸纤维腺瘤、睾丸纤维瘤、睾丸腺瘤样瘤、睾丸脂肪瘤；骨肉瘤、纤维肉瘤、软骨肉瘤、尤文氏肉瘤、恶性纤维性组织细胞瘤、网织细胞肉瘤、良性软骨瘤、恶性巨细胞肿瘤脊索瘤、软骨母细胞瘤、骨软骨瘤、骨软骨外生骨疣、软骨黏液样纤维瘤、骨样骨瘤和巨细胞肿瘤；骨瘤、黄色瘤、血管瘤、肉芽肿、畸形性骨炎、脑膜瘤、胶质瘤、脑膜肉瘤、脑星形细胞瘤、髓母细胞瘤、室管膜瘤、神经胶质瘤、生殖细胞瘤、松果体瘤、神经鞘瘤、少突胶质细胞瘤、多形性胶质母细胞瘤、视网膜母细胞瘤、神经胶质瘤、先天性肿瘤、脑膜瘤、脊髓神经纤维瘤、肉瘤；子宫内膜癌、浆液性囊腺癌、粘液性囊腺癌、粒层细胞-鞘细胞瘤、恶性畸胎瘤、外阴腺癌、外阴鳞状细胞癌、外阴上皮内癌、外阴纤维肉瘤、外阴黑色素瘤、阴道鳞状细胞癌、阴道透明细胞癌、阴道葡萄状肉瘤、胚胎性横纹肌肉瘤、输卵管癌；急性骨髓性白血病、慢性骨髓性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病、骨髓增殖性疾病、多发性骨髓瘤、骨髓增生异常综合征、霍奇金病、非霍奇金淋巴瘤、恶性淋巴瘤；皮肤恶性黑色素瘤、皮肤卡波西肉瘤、皮肤基底细胞癌、皮肤鳞状细胞癌、皮肤发育不良痣、皮肤脂肪瘤、皮肤血管瘤、皮肤纤维瘤、皮肤瘢痕疙瘩、牛皮癣；肾上腺成神经细胞瘤中的一种或多种。Non-small cell lung cancer, colon adenocarcinoma, multiple myeloma, colon cancer, and pancreatic cancer; bronchial cancer, Alveolar carcinoma, sarcoma, lymphoma, bronchial adenoma, enchondromatous hamartoma, mesothelioma; esophageal squamous cell carcinoma, esophageal leiomyosarcoma, esophageal adenocarcinoma, esophageal lymphoma, gastric cancer, gastric lymphoma, gastric leiomyosarcoma, Pancreatic ductal adenocarcinoma, insulinoma, gastrinoma, carcinoid tumor, glucagonoma, vasoactive intestinal peptide tumor, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, small intestinal leiomyoma, small intestinal hemangioma , Kaposi's sarcoma of the small intestine, lipoma of the small intestine, fibroma of the small intestine, neurofibroma of the small intestine, adenocarcinoma of the large intestine, tubular adenoma of the large intestine, hamartoma of the large intestine, villous adenoma of the large intestine, leiomyoma of the large intestine; cardiac sarcoma, cardiovascular disease Sarcoma, cardiac fibrosarcoma, cardiac liposarcoma, cardiac rhabdomyosarcoma, cardiac myxoma, cardiac fibroma, cardiac rhabdomyomas, cardiac lipoma and cardiac teratoma; hepatoma or hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma , hepatic angiosarcoma, hepatocellular adenoma, hepatic hemangioma; gallbladder cancer, cholangiocarcinoma, ampullary cancer; Wilms' tumor, nephroblastoma, lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, renal Adenocarcinoma, prostate adenocarcinoma, sarcoma, testicular seminoma, testicular teratoma, testicular teratocarcinoma, testicular sarcoma, testicular embryonal carcinoma, testicular choriocarcinoma, testicular Leydig cell carcinoma, testicular fibroadenoma, testis Fibroma, testicular adenomatoid tumor, testicular lipoma; osteosarcoma, fibrosarcoma, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma, reticulocyte sarcoma, benign chondroma, malignant giant cell tumor, chordoma, chondroma blastoma, osteochondroma, osteochondral exostosis, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; osteoma, xanthoma, hemangioma, granuloma, osteitis deformans, meningioma, Glioma, meningosarcoma, cerebral astrocytoma, medulloblastoma, ependymoma, glioma, germ cell tumor, pineal tumor, schwannoma, oligodendroglioma, polymorphic glioblastoma, retinoblastoma, glioma, congenital tumors, meningiomas, spinal neurofibromas, sarcomas; endometrial cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa Cells - sheath cell tumor, malignant teratoma, vulvar adenocarcinoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal squamous cell carcinoma, vaginal clear cell carcinoma, vaginal botryoid sarcoma, Embryonal rhabdomyosarcoma, fallopian tube cancer; acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's Disease, non-Hodgkin's lymphoma, malignant lymphoma; cutaneous malignant melanoma, cutaneous Kaposi's sarcoma, cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, cutaneous dysplastic nevus, cutaneous lipoma, cutaneous hemangioma, cutaneous fibrosis tumor, skin keloid, psoriasis; one or more of adrenal neuroblastoma.
本发明提供的新型的KRas抑制剂与现有技术中临床中的药物相比具有更佳的活性和稳定性，具有较好的药用前景。The novel KRas inhibitor provided by the present invention has better activity and stability than the clinical drugs in the prior art, and has better medicinal prospects.
具体实施例Specific embodiments
定义以及详细说明Definition and detailed description
除非另有说明，本发明中使用的所有技术和科学术语所具有的含义应该按照本领域普通的含义去理解，当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, all technical and scientific terms used in the present invention shall have the meanings common in the art, and when a trade name appears herein, it is intended to refer to its corresponding trade product or its active ingredient.
在本发明的范围内还包括式I化合物的代谢产物，也就是在药物给药后体内生成的化合物。根据本发明的代谢产物的某些实例包括：(i)当式I化合物含有甲基，其羟甲基衍生物(-CH3-＞-CH2OH)；(ii)当式I化合物含有烷氧基，其羟基衍生物(-OR-＞-OH)；(iii)当式I化合物含有叔氨基，其仲氨基衍 生物(-NR1R2-＞-NHR1或-NHR2)；(iv)当式I化合物含有仲氨基，其伯氨基衍生物(-NHR1-＞-NH2)；(v)当式I化合物含有苯基部分，其苯酚衍生物(-Ph-＞-PhOH)；和(vi)当式I化合物含有酰胺基，其羧酸衍生物(-CONH2-＞COOH)。Also included within the scope of the present invention are metabolites of the compounds of formula I, ie compounds produced in vivo following administration of the drug. Some examples of metabolites according to the present invention include: (i) when the compound of formula I contains a methyl group, its hydroxymethyl derivative (-CH3->-CH2OH); (ii) when the compound of formula I contains an alkoxy group, Its hydroxyl derivative (-OR->-OH); (iii) When the compound of formula I contains a tertiary amino group, its secondary amino derivative Biological (-NR1R2->-NHR1 or -NHR2); (iv) When the compound of formula I contains a secondary amino group, its primary amino derivative (-NHR1->-NH2); (v) When the compound of formula I contains a phenyl moiety, Its phenol derivative (-Ph->-PhOH); and (vi) when the compound of formula I contains an amide group, its carboxylic acid derivative (-CONH2->COOH).
术语“溶剂化物”是指通过与溶剂分子配位形成固态或液态的配合物的本专利发明的化合物的形式。此类形式的实例为水合物、醇合物等。The term "solvate" refers to a form of a compound of the present invention that forms a solid or liquid complex by coordination with a solvent molecule. Examples of such forms are hydrates, alcoholates, etc.
术语“前药”是指在体内转化成母体药物的任何药剂。前药常常是有用的，因为，在某些情况下，他们比母体药物更易于给药。例如，通过口服给药，它们是可生物利用的，而母体药物却不是。前药相对于母体药物还可改善药物组合物中的溶解度。前药可经由酶的方法以及代谢水解的途径被转化为母体药物。The term "prodrug" refers to any agent that is converted in the body to the parent drug. Prodrugs are often useful because, in some cases, they are easier to administer than the parent drug. For example, they are bioavailable through oral administration, whereas the parent drug is not. Prodrugs may also improve solubility in pharmaceutical compositions relative to the parent drug. Prodrugs can be converted to the parent drug via enzymatic methods as well as metabolic hydrolysis pathways.
术语“药学上可接受的盐”指保留了特定化合物的游离酸和碱的生物学效力而没有生物学不良作用的盐。药学上可接受的盐的例子包括但不限于：化合物(I)与任意如下酸所形成的盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、和硬脂酸；优选为富马酸盐。The term "pharmaceutically acceptable salts" refers to salts that retain the biological potency of the free acids and bases of a particular compound without adverse biological effects. Examples of pharmaceutically acceptable salts include, but are not limited to: salts formed by compound (I) and any of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, hexane Acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid , methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethyl Acetic acid, tert-butyl acetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, and stearic acid; preferably fumarate.
本文中“KRas突变蛋白”包括且不限于KRAS G12D、KRAS G12C、KRAS G12S、KRAS G12V、KRAS G12A和KRAS G13D。“KRas mutant proteins” herein include but are not limited to KRAS G12D, KRAS G12C, KRAS G12S, KRAS G12V, KRAS G12A and KRAS G13D.
本文中，“KRasG12C”是指哺乳动物KRas蛋白的突变形式，其12位的甘氨酸突变成半胱氨酸，同样,“KRasG12D”是KRas蛋白的12位的甘氨酸突变成天冬氨酸。KRAS G12D、KRAS G12C、KRAS G12S、KRAS G12V、KRAS G12A和KRAS G13D的突变与上述类似，区别在于突变后的具体氨基酸残基或具体突变的位置。In this article, "KRas G12C " refers to the mutated form of the mammalian KRas protein in which glycine at position 12 is mutated to cysteine. Similarly, "KRas G12D " refers to the mutated form of glycine at position 12 of the KRas protein to aspartic acid. The mutations of KRAS G12D, KRAS G12C, KRAS G12S, KRAS G12V, KRAS G12A and KRAS G13D are similar to the above, the difference lies in the specific amino acid residue after mutation or the position of the specific mutation.
本文中，“KRasG12D相关疾病或病症”是指与KRasG12D突变相关或由其诱导或具有所述突变的疾病或病症，其非限制性实例是KRasG12D突变引起的相关癌症。As used herein, "KRas G12D -related disease or disorder" refers to a disease or disorder associated with, induced by, or harboring a KRas G12D mutation, a non-limiting example of which is a related cancer caused by a KRas G12D mutation.
本文中，化合物的“有效剂量”是足以负调节或抑制KRas突变蛋白活性的量，这样的剂量可以单独施用或可根据有效的方案施用。As used herein, an "effective dose" of a compound is an amount sufficient to negatively regulate or inhibit KRas mutein activity, and such dose may be administered alone or may be administered according to an effective regimen.
本文中，化合物的“治疗有效剂量”是能负调节或抑制KRas突变蛋白活性的量，这样的量足以改善或能够减轻症状或消除或逆转病症的进展，其可以单剂量施用或根据有效的方案施用。构成“治疗有效剂量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，可例行性地由本领域技术人员根据其自身的知识及本公开内容而定。As used herein, a "therapeutically effective dose" of a compound is an amount that negatively modulates or inhibits the activity of KRas mutant protein and is sufficient to ameliorate or alleviate symptoms or eliminate or reverse the progression of a disorder, which may be administered in a single dose or according to an effective regimen Apply. The amount of a compound of the present application that constitutes a "therapeutically effective dose" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, and can be routinely determined by one of skill in the art. based on your own knowledge and the content of this disclosure.
对患者的施用浓度和途径可根据待治疗的癌症而发生变化。化合物或其药物组合物、其药学上可接受的盐可与其他抗肿瘤化合物共同施用，或与其 他治疗方法(如放疗或外科手术干预)联用，作为术前或术后得到佐药。The concentration and route of administration to patients may vary depending on the cancer being treated. The compounds or pharmaceutical compositions thereof, pharmaceutically acceptable salts thereof, may be co-administered with other anti-tumor compounds, or with Used in combination with other treatments (such as radiotherapy or surgical intervention) as a preoperative or postoperative adjuvant.
本文中，“治疗”是指本申请所述化合物或组合物进行给药以预防、改善或消除疾病或与所述疾病相关的病症，且包括：1)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被准断为已经患有该疾病状态；2)缓解疾病或使疾病状态消退；3)抑制疾病或遏制其发展。As used herein, "treatment" refers to the administration of a compound or composition described herein to prevent, ameliorate or eliminate a disease or a condition associated with said disease, and includes: 1) preventing the occurrence of a disease or disease state in a mammal , especially when such mammals are prone to suffer from the disease state, but have not been accurately judged to have suffered from the disease state; 2) alleviate the disease or make the disease state subside; 3) inhibit the disease or curb its development.
本文中，“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。As used herein, "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
本文中，“药学上可接受的”是针对那些化合物、材料、组合物或剂型而言，它们在可靠的医学判断的范围内，适用于与人类和动物的组织接触使用，而没有过多的毒性、过敏性反应、刺激性或其他问题或并发症等。As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without undue Toxicity, allergic reactions, irritation or other problems or complications.
术语“药学上可接受的盐”指保留化合物的期望生物活性并且表现出最小的或没有不期望的毒理作用的盐，如与有机碱或酸、无机碱或酸、与碱性或酸性氨基酸形成的盐，可以是金属盐、季铵盐、硫酸盐、盐酸盐、甲酸盐、三氟乙酸盐、磷酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐等。The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the compound and exhibit minimal or no undesirable toxicological effects, such as with organic bases or acids, inorganic bases or acids, with basic or acidic amino acids The salt formed can be metal salt, quaternary ammonium salt, sulfate, hydrochloride, formate, trifluoroacetate, phosphate, fumarate, maleate, tartrate, citrate, Benzoates, etc.
术语“旋光异构体”是因分子中一个或多个对称轴和/或中心的存在而产生，导致偏振光束的旋转。术语“旋光异构体”更确切地包括纯形式或混合物形式的对映异构体和非对映异构体；而互为异构体的两种化合物可能存在差异显著的药学活性。The term "optical isomer" is caused by the presence of one or more symmetry axes and/or centers in a molecule, resulting in the rotation of polarized light beams. The term "optical isomer" more precisely includes enantiomers and diastereomers in pure form or in the form of a mixture; and two compounds that are isomers may have significantly different pharmaceutical activities.
本文中，“包括”或“包含”应理解为开发的、非排他性的意义，即“包括不限于”。As used herein, "includes" or "includes" shall be understood in a developmental, non-exclusive sense, i.e., "including without limitation."
本申请还包括化合物的一个或多个原子被同位素置换得到的化合物，其同位素包括氢、碳、氮、氧、磷、硫、氟、氯、碘等，优选氘(2H)取代，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。This application also includes compounds in which one or more atoms of the compound are replaced by isotopes, and the isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, iodine, etc., preferably deuterium ( 2H ) substitution, wherein deuterium Substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.
术语“被取代”是指特定原子上的任意一个或多个H原子被取代基取代，只要符合原子价态规则并且取代后的化合物是稳定的。The term "substituted" means that any one or more H atoms on a specific atom are replaced by a substituent, as long as the atomic valence rules are followed and the substituted compound is stable.
术语“任选”或“任选地”是指所描述的情况可以发生或不发生，例如，甲基“任选”被卤素取代，指甲基可以是未被取代的(CH3)、单取代的(如CH2F)、多取代的(如CHF2)或完全被取代的(CF3)。对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在或不能合成的取代或取代模式。The term "optionally" or "optionally" means that the described situation may or may not occur, for example, the methyl group is "optionally" substituted by a halogen, and the methyl group can be unsubstituted (CH 3 ), mono Substituted (such as CH 2 F), polysubstituted (such as CHF 2 ) or completely substituted (CF 3 ). For any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible or cannot be synthesized.
“C1-6”是指该基团可以具有1至6的整数个碳原子，同样“C2-6”是指该基团可以具有2至6的整数个碳原子。"C 1-6 " means that the group may have an integer number of carbon atoms from 1 to 6, and similarly "C 2-6 " means that the group may have an integer number of carbon atoms from 2 to 6.
当任何变量(例如R1)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。例如，如果一个基团被2个R1取代，则每个R1都有独立的选项。When any variable (eg, R1 ) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. For example, if a group is substituted with 2 R 1's , there is an independent option for each R 1 .
术语“卤素”或“卤基”是指氟、氯、溴和碘。The term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.
术语“氰基”指-CN基团；“羟基”指-OH基团；“羟甲基”指-CH2OH 基团；“巯基”指-SH基团；“胺基”指-NH2基团。The term "cyano" refers to the -CN group; "hydroxy" refers to the -OH group; "hydroxymethyl" refers to -CH 2 OH Group; "mercapto" refers to the -SH group; "amine" refers to the -NH 2 group.
“酰胺基”指含有-CONH-的基团，“酰基”是指含有R-C(＝O)-的基团，“酯基”是指含有-COOR的基团，其中R是烷基。"Amide" refers to a group containing -CONH-, "acyl" refers to a group containing R-C(=O)-, and "ester" refers to a group containing -COOR, where R is an alkyl group.
当“---”或指向环基内部而非具体位置时，表示取代基在环基上的取代位置不固定；当“---”或指向某基团的具体位置时，表示取代基取代并连接到该固定的取代位置。When "---" or When pointing to the inside of the ring group instead of a specific position, it means that the substitution position of the substituent on the ring group is not fixed; when “---” or When pointed to a specific position on a group, it indicates that the substituent is substituted and attached to that fixed substitution position.
“羰基”指含有-CO-的基团，“羧基”是指含有-COOH的基团。"Carbonyl" refers to a group containing -CO-, and "carboxyl" refers to a group containing -COOH.
“炔基”指由碳原子和氢原子组成的直链或支链的具有至少一个碳碳三键的不饱和脂肪族烃基。如乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH3)、2-丙炔基(HC≡C-CH2-)、丙炔醇基(-C≡C-CH2OH)等。"Alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one carbon-carbon triple bond, such as ethynyl (-C≡CH), 1-propynyl (-C≡C-CH 3 ), 2-propynyl (HC≡C-CH 2 -), propargyl alcohol (-C≡C-CH 2 OH), etc.
“烯基”指由碳原子和氢原子组成的直链或支链的具有至少一个碳碳双键的不饱和脂肪族烃基。烯基的非限制性实例包括但不限于乙烯基(-CH＝CH2)、1-丙烯基(CH3-CH＝CH-)、异丁烯基、1,3-丁二烯基等。"Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl (-CH= CH2 ), 1-propenyl ( CH3 -CH=CH-), isobutenyl, 1,3-butadienyl, and the like.
术语“烷基”是指通式为CnCH2n+1的烃基，该烷基可以是直链或支链的。(如甲基，乙基、异丙基、正丁基、异丁基、2-甲基丁基等)。类似地，烷氧基、烷基胺基、烷硫基的烷基部分具有相同定义。The term "alkyl" refers to a hydrocarbon group of the general formula C n CH 2n +1, which alkyl group may be straight or branched. (Such as methyl, ethyl, isopropyl, n-butyl, isobutyl, 2-methylbutyl, etc.). Similarly, the alkyl portion of alkoxy, alkylamino, alkylthio has the same definition.
术语“烷氧基”是指-O-烷基。The term "alkoxy" refers to -O-alkyl.
术语“烷硫基”是指-S-烷基。The term "alkylthio" refers to -S-alkyl.
术语“烷基胺基”、“氨基烷基”、或“胺基烷基”是指-NH-烷基。The term "alkylamino," "aminoalkyl," or "aminoalkyl" refers to -NH-alkyl.
术语“二烷基胺基”或“二烷基氨基”是指-N(烷基)2。The term "dialkylamino" or "dialkylamino" refers to -N(alkyl) 2 .
术语“亚烷基”是指碳原子上含有两个H原子的烷基。如亚甲基(-CH2-)。The term "alkylene" refers to an alkyl group containing two H atoms on a carbon atom. Such as methylene (-CH 2 -).
术语“环烷基”指完全饱和的并且可以以呈单环、桥环、并环或螺环存在的碳环。其不仅限制为环丙基、环丁基、环戊基、环己基、双环[2.2.1]庚基、双环[2.2.2]辛基、金刚烷基等。The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, paracyclic or spirocyclic ring. It is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, etc.
术语“部分饱和”是指含有部分双键。如环戊烯基、环己烯基、环亚胺基等。The term "partially saturated" means containing some double bonds. Such as cyclopentenyl, cyclohexenyl, cycloimine, etc.
术语“杂环烷基”或“杂环基”是指完全饱和的并且可以以单环、桥环、并环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至4个独立地选自N、O或S的杂原子的3至12元环，其中环N原子可以被氧化成N-O，并且环S原子可被氧化成SO或SO2，其余环原子是碳。3元杂环烷基的实例包括但不限于环氧乙烷基、环氧丙烷基、环硫乙烷、氮杂环丙烷基，4元杂环烷基的实例包括但不限于吖丁啶基、噁丁环基、噻丁环基等，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、四氢吡咯烷基、吡咯烷酮基、咪唑烷基、噁唑烷基、噁唑烷酮基、异噻唑烷基等，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、吗啉基、哌嗪基、1,4-二氧六环基、1,4-噻噁烷基、硫代吗啉基、1,3-二噻烷基、哌啶烷酮基等，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧氮杂环庚烷基、氧或硫杂环庚烷基等。并环的实例包括但不限于氮杂双环戊烷基、氮杂双环己基、氮杂双环辛烷基、十氢喹啉基等等，桥环实例包括但不限于奎宁环基、六氢-1H-吡咯并[2,1-c][1,4]噁嗪基、二氢-1H,3H,5H-噁唑并[3,4-c]噁唑基等，螺环实例包括但不限于氮杂 螺庚烷基、氧杂氮杂螺壬烷基、氧杂氮杂螺辛烷基等。杂环基团任选地在一个或多个位置的环碳或环氮上被一个或多个R8取代，其中R8如针对式I或式Ⅱ所定义。The term "heterocycloalkyl" or "heterocyclyl" refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged, paracyclic or spirocyclic ring. Unless otherwise indicated, the heterocycle is generally a 3 to 12 membered ring containing 1 to 4 heteroatoms independently selected from N, O, or S, where the ring N atom can be oxidized to NO, and the ring S atom can be Oxidized to SO or SO 2 , the remaining ring atoms are carbon. Examples of 3-membered heterocycloalkyl include, but are not limited to, ethylene oxide, propylene oxide, ethylene sulfide, and aziridinyl, and examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxanyl, Butylcyclyl, thibutylcyclyl, etc. Examples of 5-membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolidinyl, pyrrolidonyl, imidazolidinyl, oxazolidinyl, oxazole Alkanonyl, isothiazolidinyl, etc. Examples of 6-membered heterocycloalkyl include but are not limited to piperidyl, tetrahydropyranyl, morpholinyl, piperazinyl, 1,4-dioxanyl, 1,4-thioxanyl, thiomorpholinyl, 1,3-dithianyl, piperidinonyl, etc. Examples of 7-membered heterocycloalkyl include but are not limited to azepanyl, Oxyazepanyl, oxygen or thiepanyl, etc. Examples of pendant rings include, but are not limited to, azabicyclopentanyl, azabicyclohexyl, azabicyclooctyl, decahydroquinolyl, etc. Examples of bridged rings include, but are not limited to, quinuclidinyl, hexahydro- 1H-pyrrolo[2,1-c][1,4]oxazinyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, etc. Examples of spiro rings include but are not limited to aza Spiroheptyl, oxazaspirononyl, oxazaspirooctyl, etc. The heterocyclic group is optionally substituted at one or more positions on the ring carbon or ring nitrogen by one or more R8 , wherein R8 is as defined for Formula I or Formula II.
术语“芳基”是指具有共扼的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、蒽基、芴基和1,2,3,4-四氢化萘等。芳基还指双环或三环体系，其中所述芳基环系相应的一个或两个环可以是饱和或部分饱和的，并且其中如果所述环系包括两个饱和环，则所述饱和环可以是稠合或螺环的。The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, tetralin, and the like. Aryl also refers to a bicyclic or tricyclic ring system, wherein one or both of the corresponding rings of the aryl ring system may be saturated or partially saturated, and wherein if the ring system includes two saturated rings, then the saturated ring Can be fused or spirocyclic.
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选地，杂芳基具有4至8元环，尤其是5至8元环，或包含6至14个，尤其是6至10个环原子的多个稠合环。杂芳基的实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、三唑基、四唑基、三嗪基、喹啉基、异喹啉基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基、苯并噁唑基、苯并噻唑基、苯并三唑基、苯并咪唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基等。“杂芳基”还指除碳原子外，每个环还具有1至3个选自由O、S和N组成的杂原子的双环体系，其中一个环可以是饱和的或部分饱和的。The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, S, the remaining ring atoms are C, and has at least one aromatic ring. Preferably, the heteroaryl group has a 4- to 8-membered ring, especially a 5- to 8-membered ring, or a plurality of fused rings containing 6 to 14, especially 6 to 10, ring atoms. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, triazinyl , quinolyl, isoquinolyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzimidazolyl , benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, etc. "Heteroaryl" also refers to a bicyclic ring system having from 1 to 3 heteroatoms selected from the group consisting of O, S and N in each ring, in addition to carbon atoms, in which one ring may be saturated or partially saturated.
本申请化合物可以是不对称(具有一个或多个立体异构体)的，除非另有说明，所有立体异构体都包括对映异构体和非对映异构体。其异构体可以通过手性拆分的手段分离得到。Compounds of the present application may be asymmetric (having one or more stereoisomers), and unless otherwise stated, all stereoisomers include enantiomers and diastereomers. Its isomers can be separated by chiral resolution.
本申请化合物可以具有一个或多个阻转异构体，除非另有说明，所述阻转异构体是指由于单键之间的自由旋转受阻而产生的光学活性异构体。其异构体可以通过手性拆分的手段分离得到。The compounds of the present application may have one or more atropisomers, and unless otherwise specified, the atropisomers refer to optically active isomers produced due to the obstruction of free rotation between single bonds. The isomers can be separated by means of chiral resolution.
当式I所示化合物及其药学上可接受的盐以溶剂化物或多晶型的形式存在时，本发明包括任何可能的溶剂化物和多晶型形式。形成溶剂化物的溶剂类型没有特别的限定，只要该溶剂是药理学上可以接受的。例如，水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。When the compound represented by Formula I and its pharmaceutically acceptable salts exist in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent used to form the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone and other similar solvents can be used.
当式I所示化合物存在互变异构体时，除非特别声明，本发明包括任何可能的互变异构体和其药学上可接受的盐，及它们的混合物。When tautomers exist for the compound represented by formula I, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, as well as their mixtures.
本领域技术人员将认识到，使用合适的、已知或普遍接受的细胞和/或动物模型进行的体内和体外试验都可以预测测试化合物治疗或预防给定病症的能力。在患者中进行的人体临床试验，包括首次人体试验、剂量范围试验和功效试验，可根据临床和医学领域中熟知的方法来完成。Those skilled in the art will recognize that both in vivo and in vitro testing using appropriate, known or generally accepted cell and/or animal models can predict the ability of a test compound to treat or prevent a given condition. Human clinical trials in patients, including first-in-human trials, dose range trials, and efficacy trials, can be completed according to methods well known in the clinical and medical fields.
以下通过实施例对本发明作进一步的说明。需要注意的是，这些实施例不构成对本发明保护范围的限制。The present invention will be further described below through examples. It should be noted that these examples do not limit the scope of the present invention.
一、实验试剂表

1. Experimental reagent list

二、实验仪器及耗材

2. Experimental instruments and consumables

本发明的化合物可使用本文所述的合成方法和制备方案通过商业可得的试剂(市售的试剂无需进一步纯化即可使用)来制备。也可以使用本领域技术人员众所周知的其他试剂和常规方法来制备本发明的化合物。Compounds of the invention can be prepared from commercially available reagents (commercially available reagents can be used without further purification) using the synthetic methods and preparation schemes described herein. The compounds of the invention may also be prepared using other reagents and conventional methods well known to those skilled in the art.
三、制备方案3. Preparation plan
合成路线中反应所得的每一个产物或中间体可以通过传统分离技术来得到，这种传统技术包括但不限于过滤、蒸馏、重结晶、制备TLC、柱色谱分离等。起始原料可以通过自己合成或从商业机构(例如，不限于毕得、安耐吉、伊诺凯和探索平台等)购买获得。这些原料可以使用常规手段进行表征，比如物理常数和光谱数据等。Each product or intermediate obtained by the reaction in the synthetic route can be obtained by conventional separation techniques, including but not limited to filtration, distillation, recrystallization, preparative TLC, column chromatography separation, etc. The starting materials can be synthesized by themselves or purchased from commercial institutions (for example, but not limited to Bidex, Anergy, Inochem, and Exploration Platform, etc.). These raw materials can be characterized using conventional means, such as physical constants and spectral data.
本申请采用下述缩略词：This application uses the following abbreviations:
DCM代表二氯甲烷；DMSO代表二甲基亚砜；DMF代表N，N-二甲基甲酰胺；THF代表四氢呋喃；DCE是1,2-二氯乙烷；ACN是乙腈；PE代表石油醚；EtOAc代表乙酸乙酯；Tol代表甲苯；NMP代表N-甲基吡咯烷酮；i-PrOH代表异丙醇；MeOH是甲醇；MeONa是甲醇钠；EtOH代表乙醇；Boc代表叔丁氧羰基；Boc2O是二叔丁基二碳酸酯；TEA是三乙胺；DIEA是N，N-二异丙基乙胺；Bn代表苄基；TFA为三氟乙酸；TFAA为三氟乙酸酐；NCS为氯代丁二酰亚胺；NBS为溴代丁二酰亚胺；NaH代表氢化钠；AcOH为乙酸；MsCl是甲磺酰氯；Ph3P是三苯基膦；DPPF是1，1’-双(二苯基膦基)二茂铁；HATU是2-(7-氧化苯并三氮唑)-N,N,N,N'-四甲基脲六氟磷酸盐；n-BuLi是正丁基锂；t-BuOK是叔丁醇钾；t-BuONa是叔丁醇钾；LiHMDS是双三甲基硅基胺基锂；DEAD是偶氮二甲酸二乙酯；DIAD是偶氮二甲酸二异丙酯；Pd(OAc)2是乙酸钯；Pd(PPh3P)2Cl2是双(三苯基膦)氯化钯；SEMCl代表(2-(氯甲氧基)乙基)三甲基硅烷；MOMBr是溴甲基甲醚；RuPhos-Pd-G3是甲磺酸(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)；Pd2(dba)3是三(亚苄基丙酮)二钯；BINAP是1，1’-联萘-2，2’ 双二苯膦；X-Phos是2-二环己基膦-2’,4’,6’-三异丙基联苯；PyBOP是1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐；m-CPBA是间氯过氧苯甲酸等。DCM represents dichloromethane; DMSO represents dimethyl sulfoxide; DMF represents N, N-dimethylformamide; THF represents tetrahydrofuran; DCE represents 1,2-dichloroethane; ACN represents acetonitrile; PE represents petroleum ether; EtOAc represents ethyl acetate; Tol represents toluene; NMP represents N-methylpyrrolidone; i-PrOH represents isopropyl alcohol; MeOH represents methanol; MeONa represents sodium methoxide; EtOH represents ethanol; Boc represents tert-butoxycarbonyl; Boc 2 O is Di-tert-butyl dicarbonate; TEA is triethylamine; DIEA is N, N-diisopropylethylamine; Bn represents benzyl; TFA is trifluoroacetic acid; TFAA is trifluoroacetic anhydride; NCS is butyl chloride Diimide; NBS is bromosuccinimide; NaH represents sodium hydride; AcOH is acetic acid; MsCl is methanesulfonyl chloride; Ph 3 P is triphenylphosphine; DPPF is 1,1'-bis(diphenyl Phosphinoyl)ferrocene; HATU is 2-(7-benzotriazole oxide)-N,N,N,N'-tetramethylurea hexafluorophosphate; n-BuLi is n-butyllithium; t -BuOK is potassium tert-butoxide; t-BuONa is potassium tert-butoxide; LiHMDS is lithium bistrimethylsilylamide; DEAD is diethyl azodicarboxylate; DIAD is diisopropyl azodicarboxylate; Pd(OAc) 2 is palladium acetate; Pd(PPh 3 P) 2 Cl 2 is bis(triphenylphosphine)palladium chloride; SEMCl represents (2-(chloromethoxy)ethyl)trimethylsilane; MOMBr is bromomethyl methyl ether; RuPhos-Pd-G3 is methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino -1,1'-biphenyl-2-yl)palladium(II); Pd 2 (dba) 3 is tris(benzylideneacetone)dipalladium; BINAP is 1,1'-binaphthyl-2,2' Bisdiphenylphosphine; Fluorophosphate; m-CPBA is meta-chloroperoxybenzoic acid, etc.
针对式I中的一些实施例，可根据一般方案I制备。For some embodiments in Formula I, they can be prepared according to General Scheme I.
1、方案I
1. Plan I
其中，X选自F、Cl、Br等卤基，除了-Y-R3不是氢之外，所有取代基均如针对式I所定义化合物根据方案I制备。步骤A参考专利WO2021041671中的制备方法，将化合物I-1与三氯乙酰异氰酸酯反应，后将中间体在氨的甲醇溶液中环合得到化合物I-2。在步骤B中，化合物I-2与三氯氧磷在有机碱(如DIEA)的共同作用下制备二氯嘧啶化合物I-3。在步骤C中，含氮杂环R2在碱和DMF的作用下，对二氯嘧啶化合物I-3进行选择性地取代得到化合物I-4，也可以通过含硼酯的R2与二氯嘧啶发送Suzuki偶联反应得到化合物I-4。在步骤D中，利用具有式H-Y-R3的亲核试剂，在例如碳酸铯的碱和1,4-二氧六环为溶剂下，取代化合物I-4的氯来引入取代基-Y-R3得到化合物I-5。在步骤E中，利用三甲基氯硅烷将硫甲基置换成氯得到化合物I-6。在F步骤中，利用硼酸酯或硼酸与嘧啶氯的Suzuki偶联得到含有R4的化合物，然后经过步骤G的脱保护就可以得到目标化合物，该目标化合物一般通过反相的制备HPLC纯化并通过浓缩和冻干得到。 Wherein , Step A refers to the preparation method in patent WO2021041671. Compound I-1 is reacted with trichloroacetyl isocyanate, and then the intermediate is cyclized in a methanol solution of ammonia to obtain compound I-2. In step B, compound I-2 and phosphorus oxychloride are combined with an organic base (such as DIEA) to prepare dichloropyrimidine compound I-3. In step C, the nitrogen-containing heterocyclic ring R 2 selectively substitutes the dichloropyrimidine compound I-3 under the action of a base and DMF to obtain the compound I-4. The nitrogen-containing heterocyclic ring R 2 can also be combined with the dichloropyrimidine compound I-4 through the boron-containing ester R 2 and the dichloropyrimidine compound I-3. The pyrimidine is subjected to Suzuki coupling reaction to obtain compound I-4. In step D, a nucleophile with the formula HYR 3 is used to replace the chlorine of the compound I-4 in the presence of a base such as cesium carbonate and 1,4-dioxane as a solvent to introduce the substituent -YR 3 to obtain the compound I-5. In step E, the thiomethyl group is replaced with chlorine using trimethylsilyl chloride to obtain compound I-6. In step F, the compound containing R 4 is obtained by Suzuki coupling of boronic acid ester or boronic acid with pyrimidine chloride, and then the target compound can be obtained through deprotection in step G. The target compound is generally purified by reverse-phase preparative HPLC and Obtained by concentration and lyophilization.
2、方案Ⅱ2. Plan II
对于式I中的一些实施例，可通过一般方案Ⅱ来制备。
For some embodiments of formula I, they can be prepared by general scheme II.
其中，X和X’各自分别选自卤基，且X的电负性大于X’，例如，当X为Cl时，X’为Br；或者，X为F时，X’为Cl或Br。在步骤A中，利用初始原料Ⅱ-1与含有R5基团(优选氰基、酯基等吸电子基团)的酰氯反应得到酰胺Ⅱ-2。在步骤B中，在诸如氢化钠类型的强碱作用下进行关环得到化合物Ⅱ-3。在步骤C中，利用三氯氧磷选择性地进行羟基氯代获得化合物Ⅱ-4。在步骤D中，含氮杂环R2在碱和DMF的作用下，对氯吡啶化合物Ⅱ-4进行选择性亲核取代得到化合物Ⅱ-5。在步骤E中，利用化合物Ⅱ-5在DEAD或DIAD、三苯基磷，脂肪醇H-O-R3进行Mitsnobu反应得到醚Ⅱ-6。在步骤F中，利用硼酸酯或硼酸与嘧啶氯的Suzuki偶联得到含有R4的化合物，然后经过步骤G的脱保护就可以得到目标化合物Ⅱ-7，该目标化合物一般通过反相的制备HPLC纯化并通过浓缩和冻干得到。Wherein, X and X' are each selected from a halogen group, and the electronegativity of X is greater than that of X', for example, when X is Cl, X' is Br; or, when X is F, X' is Cl or Br. In step A, the initial raw material II-1 is reacted with an acyl chloride containing an R 5 group (preferably an electron-withdrawing group such as a cyano group or an ester group) to obtain amide II-2. In step B, the ring is closed under the action of a strong base such as sodium hydride to obtain compound II-3. In step C, phosphorus oxychloride is used to selectively carry out hydroxyl chlorination to obtain compound II-4. In step D, the nitrogen-containing heterocycle R 2 is selectively nucleophilically substituted with chloropyridine compound II-4 under the action of a base and DMF to obtain compound II-5. In step E, compound II-5 is subjected to a Mitsnobu reaction in DEAD or DIAD, triphenylphosphine, and fatty alcohol HOR 3 to obtain ether II-6. In step F, a compound containing R 4 is obtained by Suzuki coupling of boric acid ester or boric acid with pyrimidine chloride, and then the target compound II-7 is obtained by deprotection in step G. The target compound is generally purified by reverse phase preparative HPLC and obtained by concentration and lyophilization.
3、方案Ⅲ3. Plan III
对于式I中的一些实施例，也可通过一般方案Ⅲ来制备。
For some embodiments in formula I, they can also be prepared by general scheme III.
其中，X和X’各自分别选自卤基，且X的电负性大于X’，例如，当X为Cl时，X’为Br；或者，X为F时，X’为Cl或Br。除了-Y-R3不是氢之外，所有取代基均如针对式Ⅰ所定义化合物根据方案Ⅲ制备。在步骤A中，乳清酸甲酯在溴素的作用下进行溴代得到化合物Ⅲ-2。在步骤B中，利用三氯氧磷和DIEA进行羟基的氯代，得到二氯嘧啶化合物Ⅲ-3。在步骤C中，含氮杂环R2在碱和DMF的作用下，对二氯嘧啶化合物Ⅲ-3进行选择性亲核取代得到化合物Ⅲ-4。在步骤D中，含有R4基团的丙烯基胺与甲酯化合物Ⅲ-4在LiHMDS的作用下发生胺酯交换得到酰胺化合物Ⅲ-5。在步骤E中，利用具有式H-Y-R3的亲核试剂，在诸如碳酸铯的碱和1,4-二氧六环为溶剂下，取代氯代嘧啶化合物Ⅲ-5的氯来引入取代基-Y-R3得到化合物Ⅲ-6。在步骤F中，化合物Ⅲ-6在钯催化剂和有机碱(如三乙胺)的作用下进行Heck反应进行关环，得到环外双键的中间体，该中间体在步骤G的脱保护就可以得到目标化合物Ⅲ-7，该目标化合物一般通过反相的制备HPLC纯化并通过浓缩和冻干得到。Wherein, X and X' are each selected from halo groups, and the electronegativity of Except -YR 3 is not hydrogen, all substituents are prepared as defined for the compound of formula I according to Scheme III. In step A, methyl orotate is brominated under the action of bromine to obtain compound III-2. In step B, phosphorus oxychloride and DIEA are used to chlorine the hydroxyl group to obtain dichloropyrimidine compound III-3. In step C, nitrogen-containing heterocycle R 2 undergoes selective nucleophilic substitution of dichloropyrimidine compound III-3 under the action of a base and DMF to obtain compound III-4. In step D, amine ester exchange occurs between allylamine containing R 4 group and methyl ester compound III-4 under the action of LiHMDS to obtain amide compound III-5. In step E, the substituent -YR is introduced by replacing the chlorine of the chloropyrimidine compound III-5 using a nucleophile of formula HYR 3 in the presence of a base such as cesium carbonate and 1,4-dioxane as a solvent. 3 Obtain compound III-6. In step F, compound III-6 undergoes Heck reaction under the action of a palladium catalyst and an organic base (such as triethylamine) for ring closure to obtain an intermediate with an exocyclic double bond. This intermediate is deprotected in step G. The target compound III-7 can be obtained, which is generally purified by reverse-phase preparative HPLC and obtained by concentration and lyophilization.
4、方案Ⅳ4. Plan IV
对于式I中的一些实施例，可通过一般方案Ⅳ来制备。
For some embodiments of formula I, they can be prepared by general scheme IV.
其中，X和X’各自分别选自卤基，且X的电负性大于X’，例如，当X为Cl时，X’为Br；或者，X为F时，X’为Cl或Br。除了-Y-R3不是氢之外，所有取代基均如针对式Ⅰ所定义化合物根据方案Ⅳ制备。在步骤A中，氯代乙酰乙酸乙酯与S-甲基异硫脲硫酸盐进行关环得到嘧啶化合物Ⅳ-2。在步骤B中，利用NBS为溴化剂进行嘧啶环上的溴取代得到中间体Ⅳ-3。在步骤C中，中间体Ⅳ-3在PyBOP、碱(DIEA)和含氮杂环R2的共同作用下，一锅法合成化合物Ⅳ-4。在步骤D中，含有R4基团的丙烯基胺与氯代物Ⅳ-4在诸如K2CO3的碱和乙腈加热下进行取代反应得到化合物Ⅳ-5。在步骤E中，利用钯催化剂进行Heck反应关环得到环外双键化合物Ⅳ-6。在步骤F中，利用硫醚化合物Ⅳ-6在m-CPBA的氧化下得到亚砜，再与式H-Y-R3的亲核试剂，在诸如碳酸铯的碱和1,4-二氧六环为溶剂下，取代亚砜嘧啶化合物的亚砜基团来引入取代基-Y-R3得到中间体化合物，该中间体在步骤G的脱保护就可以得到目标化合物Ⅳ-7，该目标化合物一般通过反相的制备HPLC纯化并通过浓缩和冻干得到。Wherein, X and X' are each selected from halo groups, and the electronegativity of Except -YR3 is not hydrogen, all substituents are prepared as defined for the compound of formula I according to Scheme IV. In step A, ethyl chloroacetoacetate and S-methylisothiourea sulfate undergo ring closure to obtain pyrimidine compound IV-2. In step B, NBS is used as the brominating agent to substitute bromine on the pyrimidine ring to obtain intermediate IV-3. In step C, compound IV-4 is synthesized from intermediate IV-3 in one pot under the combined action of PyBOP, base (DIEA) and nitrogen-containing heterocyclic ring R2 . In step D, the substitution reaction between propenylamine containing R 4 group and chloride IV-4 is carried out under heating with a base such as K 2 CO 3 and acetonitrile to obtain compound IV-5. In step E, a palladium catalyst is used to perform Heck reaction ring closure to obtain exocyclic double bond compound IV-6. In step F, the thioether compound IV-6 is oxidized with m-CPBA to obtain sulfoxide, which is then combined with a nucleophile of the formula HYR 3 in a base such as cesium carbonate and 1,4-dioxane as a solvent. Under this method, the sulfoxide group of the sulfoxide pyrimidine compound is replaced to introduce the substituent -YR 3 to obtain an intermediate compound. The intermediate compound can be deprotected in step G to obtain the target compound IV-7. The target compound is generally passed through reversed-phase Purified by preparative HPLC and obtained by concentration and lyophilization.
5、方案Ⅴ5. Plan V
对于式I中的一些实施例，可通过一般方案V来制备。
For some embodiments in Formula I, they can be prepared by General Scheme V.
其中，X选自F、Cl、Br等卤基，除了-Y-R3不是氢之外，所有取代基均如针对式Ⅰ所定义化合物根据方案Ⅴ制备。在步骤A中，草酰乙酸二乙酯钠盐与S-甲基异硫脲硫酸盐在诸如氢氧化钠强碱性条件下进行关环得到嘧啶羧酸化合物Ⅴ-2。在步骤B中，利用NBS为溴化剂进行嘧啶环上的溴取代得到溴代中间体Ⅴ-3。在步骤C中，通过羧酸Ⅴ-3与烯丙基胺进行酰胺缩合得到化 合物Ⅴ-4。在步骤D中，中间体Ⅴ-4在PyBOP、碱(DIEA)和含氮杂环R2的共同作用下，一锅法合成化合物Ⅴ-5。在步骤E中，利用钯催化剂进行Heck反应关环得到环内双键化合物Ⅴ-6。在步骤F中，利用含R4基团的硼酸与内酰胺Ⅴ-6在铜盐的催化下发生Chan-Lam偶联得到含有R4的化合物Ⅴ-7。在步骤G中，利用硫醚化合物Ⅴ-7在m-CPBA的氧化下得到亚砜，再与式H-Y-R3的亲核试剂，在诸如碳酸铯的碱和1,4-二氧六环为溶剂下，取代亚砜嘧啶化合物的亚砜基团来引入取代基-Y-R3得到中间体化合物，该中间体在步骤H的脱保护就可以得到目标化合物Ⅴ-8，该目标化合物一般通过反相的制备HPLC纯化并通过浓缩和冻干得到。 Wherein , In step A, diethyl oxaloacetate sodium salt and S-methylisothiourea sulfate are ring-closed under strong alkaline conditions such as sodium hydroxide to obtain pyrimidine carboxylic acid compound V-2. In step B, NBS is used as the brominating agent to substitute bromine on the pyrimidine ring to obtain brominated intermediate V-3. In step C, carboxylic acid V-3 and allylamine are subjected to amide condensation to obtain the compound Compound V-4. In step D, intermediate V-4 is used to synthesize compound V-5 in one pot under the combined action of PyBOP, base (DIEA) and nitrogen-containing heterocyclic ring R2 . In step E, a palladium catalyst is used to perform ring closure through Heck reaction to obtain compound V-6 with a double bond in the ring. In step F, Chan-Lam coupling is performed between boronic acid containing R 4 group and lactam V-6 under the catalysis of copper salt to obtain compound V-7 containing R 4 . In step G, the thioether compound V-7 is oxidized with m-CPBA to obtain sulfoxide, which is then combined with a nucleophile of the formula HYR 3 in a base such as cesium carbonate and 1,4-dioxane as a solvent. Under this method, the sulfoxide group of the sulfoxide pyrimidine compound is replaced to introduce the substituent -YR 3 to obtain an intermediate compound. The intermediate compound can be deprotected in step H to obtain the target compound V-8. The target compound is generally passed through reversed-phase Purified by preparative HPLC and obtained by concentration and lyophilization.
6、方案Ⅵ6. Plan VI
对于式I中的一些实施例，可通过一般方案Ⅵ来制备。
For some embodiments of formula I, they can be prepared by general scheme VI.
其中除了-Y-R3不是氢之外，所有取代基均如针对式I所定义化合物根据方案Ⅵ制备。中间体Ⅵ-1可以参照专利WO2022042630中的方法以4-胺基-2,6-二氯吡啶制备。在步骤A中，利用三氯氧磷进行羟基的氯代后再与含氮杂环R2反应得到化合物Ⅵ-2。在步骤B中，氯吡啶化合物Ⅵ-2在钯试剂的催化下与甲基硼酸发生Suzuki偶联引入甲基制得化合物Ⅵ-3。在步骤C中，利用硼酸酯或硼酸与氯吡啶Ⅵ-3在钯试剂的催化下再发生Suzuki偶联得到含有R4的化合物Ⅵ-4。在步骤D中，利用二氧化硒对甲基进行氧化得到醛Ⅵ-5。在步骤E中，使用(1-重氮基-2-氧代丙基)膦酸二甲酯试剂(Ohira-Bestman试剂)与醛Ⅵ-5在碳酸钾和甲醇的作用下生成炔Ⅵ-6。在步骤F中，利用硫醚化合物Ⅵ-6在m-CPBA的氧化下得到亚砜，再与式H-Y-R3的亲核试剂，在诸如LiHMDS的碱和THF为溶剂下，取代亚砜嘧啶化合物的亚砜基团来引入取代基-Y-R3得到中间体化合物，该中间体在步骤G的脱保护就可以得到目标化合物Ⅵ-7，该目标化合物一般通过反相的制备HPLC纯化并通过浓缩和冻干得到。Wherein, except that -YR 3 is not hydrogen, all substituents are prepared according to Scheme VI as defined for compounds of Formula I. Intermediate VI-1 can be prepared with 4-amino-2,6-dichloropyridine by referring to the method in patent WO2022042630. In step A, the hydroxyl group is chlorinated by phosphorus oxychloride and then reacted with nitrogen-containing heterocycle R 2 to obtain compound VI-2. In step B, chloropyridine compound VI-2 undergoes Suzuki coupling with methylboronic acid under the catalysis of palladium reagent to introduce methyl to obtain compound VI-3. In step C, boric acid ester or boric acid and chloropyridine VI-3 are Suzuki coupled again under the catalysis of palladium reagent to obtain compound VI-4 containing R 4. In step D, the methyl group is oxidized by selenium dioxide to obtain aldehyde VI-5. In step E, dimethyl (1-diazo-2-oxopropyl)phosphonate reagent (Ohira-Bestman reagent) and aldehyde VI-5 are used to generate alkyne VI-6 under the action of potassium carbonate and methanol. In step F, sulfoxide is obtained by oxidation of thioether compound VI-6 with m-CPBA, and then with a nucleophilic reagent of formula HYR 3 , in the presence of a base such as LiHMDS and THF as a solvent, the sulfoxide group of the sulfoxide pyrimidine compound is replaced to introduce the substituent -YR 3 to obtain an intermediate compound, and the intermediate is deprotected in step G to obtain the target compound VI-7, which is generally purified by reverse phase preparative HPLC and obtained by concentration and lyophilization.
7、方案Ⅶ7. Plan VII
如上文针对方案Ⅵ所描述的中间体Ⅵ-5、Ⅵ-6，可按照一般方案Ⅶ制备式I化合物的一些实施例。
Some embodiments of the compounds of Formula I can be prepared according to the general Scheme VII, as described above for Scheme VI as intermediates VI-5, VI-6.
其中除了-Y-R3不是氢之外，所有取代基均如针对式I所定义化合物由中间体Ⅵ-5和Ⅵ-6按照方案Ⅶ制备。在步骤A中，中间体醛Ⅵ-5在盐酸羟胺和诸如碳酸钾的碱作用下得到中间体肟Ⅶ-1。在步骤B中，肟在醋酸酐的作用下脱水形成氰基。在步骤C中，利用硫醚化合物Ⅶ-2在m-CPBA的氧化下得到亚砜，再与式H-Y-R3的亲核试剂，在诸如LiHMDS的碱和THF为溶剂下，取代亚砜嘧啶化合物的亚砜基团来引入取代基-Y-R3得到中间体化合物，该中间体在步骤D的脱保护就可以得到目标化合物Ⅶ-3，该目标化合物一般通过反相的制备HPLC纯化并通过浓缩和冻干得到。在步骤E中，低温下，利用诸如LiHMDS的碱在无水THF中，夺取端炔的H后与含R(除去H之外的)基团的亲电试剂(例如氘水、卤代烃、醛、酮等)反应生成取代的炔基化合物Ⅶ-4。然后类似步骤C、D的操作就可以得到最后的目标化合物Ⅶ-5。In which all substituents are as defined for formula I except -YR 3 is not hydrogen. The compound is prepared from intermediates VI-5 and VI-6 according to Scheme VII. In step A, intermediate aldehyde VI-5 is reacted with hydroxylamine hydrochloride and a base such as potassium carbonate to obtain intermediate oxime VII-1. In step B, the oxime is dehydrated in the presence of acetic anhydride to form cyano groups. In step C, the thioether compound VII-2 is used to obtain sulfoxide under the oxidation of m-CPBA, and then the nucleophile of formula HYR 3 is used to replace the sulfoxide pyrimidine compound with a base such as LiHMDS and THF as a solvent. The sulfoxide group is used to introduce the substituent -YR 3 to obtain an intermediate compound. The intermediate compound can be deprotected in step D to obtain the target compound VII-3. The target compound is generally purified by reverse-phase preparative HPLC and concentrated and frozen. You can do it. In step E, at low temperature, use a base such as LiHMDS in anhydrous THF to abstract the H of the terminal alkyne and then mix it with an electrophile containing an R (except H) group (such as deuterated water, halogenated hydrocarbon, Aldehydes, ketones, etc.) react to generate substituted alkynyl compounds VII-4. Then the final target compound VII-5 can be obtained by similar operations to steps C and D.
8、方案VIII:8. Plan VIII:
对于式I中的一些实施例，可通过一般方案VIII来制备。
For some embodiments of formula I, they can be prepared by general scheme VIII.
其中除了-Y-R3不是氢之外，所有取代基均如针对式I所定义化合物根据方案ⅥII制备。在步骤A中，使用三氟甲磺酸三氟乙酯与原料VI-1在DMF和碱的作用下反应生成酚醚VIII-1。在步骤B中，利用Rca取代的乙炔试剂 在钯试剂的催化下与氯吡啶VIII-1发生偶联反应得到含有炔基的吡啶并嘧啶衍生物VIII-2。在步骤C中，使用含氮杂环R2在碱的作用下与VIII-2进行亲核取代反应引入含R2基团的化合物VIII-3。在步骤D中，利用含R4基团的硼酸酯或硼酸，或有机锡试剂与氯吡啶Ⅵ-3在钯试剂的催化下发生Suzuki偶联或Stille偶联反应得到含有R4的化合物ⅥII-4。在步骤E中，利用硫醚化合物ⅥII-4在m-CPBA的氧化下得到亚砜，再与式H-Y-R3的亲核试剂，在诸如LiHMDS的碱和THF为溶剂下，取代亚砜嘧啶化合物的亚砜基团来引入取代基-Y-R3得到中间体化合物，该中间体在步骤F的脱保护就可以得到目标化合物ⅥII-5，该目标化合物一般通过反相的制备HPLC纯化并通过浓缩和冻干得到。Wherein except -YR 3 is not hydrogen, all substituents are prepared as defined for the compound of formula I according to Scheme VIII. In step A, trifluoroethyl trifluoromethanesulfonate is used to react with raw material VI-1 under the action of DMF and alkali to generate phenol ether VIII-1. In step B, use the Rca-substituted acetylene reagent The coupling reaction with chloropyridine VIII-1 was catalyzed by a palladium reagent to obtain a pyridopyrimidine derivative VIII-2 containing an alkynyl group. In step C, the nitrogen-containing heterocycle R 2 is used to perform a nucleophilic substitution reaction with VIII-2 under the action of a base to introduce the compound VIII-3 containing the R 2 group. In step D, a Suzuki coupling or Stille coupling reaction using a boronic acid ester or boric acid containing an R 4 group, or an organic tin reagent and chloropyridine VI-3 under the catalysis of a palladium reagent is used to obtain a compound VIII containing R 4 -4. In step E, the thioether compound VIII-4 is oxidized with m-CPBA to obtain sulfoxide, and then the nucleophile of formula HYR 3 is used to replace the sulfoxide pyrimidine compound with a base such as LiHMDS and THF as a solvent. The sulfoxide group is used to introduce the substituent -YR 3 to obtain an intermediate compound. The intermediate compound can be deprotected in step F to obtain the target compound VIII-5. The target compound is generally purified by reverse-phase preparative HPLC and concentrated and frozen. You can do it.
实施例1制备4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-氯萘-1-基)-5-烯基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6，7-二氢吡啶酮[3,4-d]嘧啶-8(5H)-酮
Example 1 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-chloronaphthalen-1-yl)-5-enyl-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6,7-dihydropyridone[3,4-d]pyrimidin-8(5H)-one
步骤A.N-烯丙基-8-氯萘-1-胺：将1-溴-8-氯萘(500mg，2.07mmol)、烯丙胺盐酸盐(293mg，3.11mmol)、碳酸铯(1.35g，4.15mmol)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(240mg，0.42mmol)和三(二亚苄基丙酮)二钯(190mg，0.21mmol)的1,4-二氧六环(8mL)溶液在氮气保护下于110℃搅拌过夜。将反应混合物用水稀释并用乙酸乙酯萃取。合并的有机层用盐水洗涤，干燥，过滤并减压浓缩，得到粗产物。通过柱色谱纯化残余物(SiO2，石油醚:乙酸乙酯＝10:1至5:1)，得到为油状的产物(180.0mg，0.83mmol，40％收率)，LCMS:m/z 218.2(M+H)。Step AN-allyl-8-chloronaphthalene-1-amine: Combine 1-bromo-8-chloronaphthalene (500mg, 2.07mmol), allylamine hydrochloride (293mg, 3.11mmol), cesium carbonate (1.35g, 4.15mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (240mg, 0.42mmol) and tris(dibenzylideneacetone)dipalladium (190mg, 0.21mmol) The 1,4-dioxane (8 mL) solution was stirred at 110°C overnight under nitrogen protection. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain an oily product (180.0 mg, 0.83 mmol, 40% yield), LCMS: m/z 218.2 (M+H).
步骤B.5-溴-2，6-二羟基嘧啶-4-甲酸甲酯：向乳清酸甲酯(10g，58.82mmol)的甲醇(120.0mL)溶液中滴加溴素(3mL，58.82mmol)。将混合物在65℃下搅拌过夜。减压抽滤，甲醇洗涤滤饼，得到白色固体(10.67g，43.02 mmol，73％收率)，LCMS:m/z 249.2(M+H)。Step B. 5-Bromo-2,6-dihydroxypyrimidine-4-carboxylic acid methyl ester: To a solution of methyl orotate (10g, 58.82mmol) in methanol (120.0mL), bromine (3mL, 58.82mmol) was added dropwise ). The mixture was stirred at 65°C overnight. Filter under reduced pressure and wash the filter cake with methanol to obtain a white solid (10.67g, 43.02 mmol, 73% yield), LCMS: m/z 249.2 (M+H).
步骤C.5-溴-2，6-二氯嘧啶-4-甲酸甲酯：在100℃下加热5-溴-2，6-二羟基嘧啶-4-甲酸甲酯(5.00g，20.08mmol)、三氯氧磷(50mL)和N,N-二甲基甲酰胺(0.9ml)的混合物过夜。将反应混合物冷却至室温并真空浓缩。使残余物在水(30mL)与乙酸乙酯(30mL)之间分配。合并的有机层用盐水洗涤，干燥，过滤并减压浓缩，得到粗产物。通过柱色谱纯化残余物(SiO2，石油醚:乙酸乙酯＝100:1至100:5)，得到白色固体(4.0g，14.08mmol，70％收率)，LCMS:m/z 285.2(M+H)。Step C. 5-Bromo-2,6-dichloropyrimidine-4-carboxylic acid methyl ester: Heat 5-bromo-2,6-dihydroxypyrimidine-4-carboxylic acid methyl ester (5.00g, 20.08mmol) at 100°C , a mixture of phosphorus oxychloride (50 mL) and N,N-dimethylformamide (0.9 ml) overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether: ethyl acetate = 100:1 to 100:5) to obtain a white solid (4.0 g, 14.08 mmol, 70% yield), LCMS: m/z 285.2 (M +H).
步骤D.(1R,5S)-3-(5-溴-2-氯-6-(甲酸甲酯)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：向5-溴-2，6-二氯嘧啶-4-甲酸甲酯(500mg，1.76mmol，)的二氯甲烷(5.0mL)溶液中添加三乙胺(213mg，2.11mmol)和3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(336mg，1.59mmol)。0℃下搅拌1小时。减压浓缩反应混合物，得到粗产物。通过柱色谱纯化残余物(SiO2，石油醚:乙酸乙酯＝10:0至5:1)，得到白色固体(664.0mg，1.43mmol，82％收率)，LCMS:m/z 463.2(M+H)。Step D. (1R, 5S)-3-(5-bromo-2-chloro-6-(methylformate)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: To a solution of 5-bromo-2,6-dichloropyrimidine-4-carboxylic acid methyl ester (500 mg, 1.76 mmol,) in dichloromethane (5.0 mL) was added triethylamine (213 mg, 2.11 mmol) and 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (336 mg, 1.59 mmol). The mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether:ethyl acetate=10:0 to 5:1) to give a white solid (664.0 mg, 1.43 mmol, 82% yield), LCMS: m/z 463.2 (M+H).
步骤E.(1R,5S)-3-(6-(烯丙基(8-氯萘-1-基)氨甲酰基)-5-溴-2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：氮气保护下，-20℃，向(1R,5S)-3-(5-溴-2-氯-6-(甲酸甲酯)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(211mg，0.45mmol)和N-烯丙基-8-氯萘-1-胺(100mg，0.45mmol)的甲苯(8.0mL)溶液中添加LiHMDS(917μL，0.92mmol)，室温下搅拌2小时。将反应混合物用水稀释并用乙酸乙酯萃取。合并的有机层用盐水洗涤，干燥，过滤并减压浓缩，得到粗产物。通过制备型TLC纯化(SiO2，石油醚:乙酸乙酯＝4:1)，得到黄色油状物(110.0mg，38％收率)，LCMS:m/z646.2(M+H)。Step E. (1R,5S)-3-(6-(allyl(8-chloronaphthalen-1-yl)carbamoyl)-5-bromo-2-chloropyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: under nitrogen protection, -20℃, to (1R,5S)-3-(5-bromo-2-chloro-6-(carboxylic acid) Methyl)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (211 mg, 0.45 mmol) and N-allyl-8-chloronaphthalene- LiHMDS (917 μL, 0.92 mmol) was added to a solution of 1-amine (100 mg, 0.45 mmol) in toluene (8.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give crude product. Purified by preparative TLC (SiO 2 , petroleum ether: ethyl acetate = 4:1), a yellow oil (110.0 mg, 38% yield) was obtained, LCMS: m/z 646.2 (M+H).
步骤F.(1R,5S)-3-(6-(烯丙基(8-氯萘-1-基)氨甲酰基)-5-溴-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：向(1R,5S)-3-(6-(烯丙基(8-氯萘-1-基)氨甲酰基)-5-溴-2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(110mg，0.17mmol)的2-甲基四氢呋喃(2.0mL)溶液中添加N,N-二异丙基乙胺(219mg，1.70mmol)和(六氢-1H-吡咯啉-7a-基)甲醇(240mg，1.70mmol)。将混合物在90℃搅拌48小时。减压浓缩反应混合物得到粗产物。通过制备型TLC纯化(SiO2，石油醚:乙酸乙酯＝0:1)，得到黄色固体(90mg，0.12mmol，71％收率)，LCMS:m/z 751.2(M+H)。Step F. (1R,5S)-3-(6-(allyl(8-chloronaphth-1-yl)carbamoyl)-5-bromo-2-((tetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: to (1R,5S)-3-( 6-(allyl(8-chloronaphth-1-yl)carbamoyl)-5-bromo-2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane -To a solution of 8-tert-butylcarboxylate (110 mg, 0.17 mmol) in 2-methyltetrahydrofuran (2.0 mL), N,N-diisopropylethylamine (219 mg, 1.70 mmol) and (hexahydro-1H-pyrrole) were added Phin-7a-yl)methanol (240 mg, 1.70 mmol). The mixture was stirred at 90°C for 48 hours. The reaction mixture was concentrated under reduced pressure to obtain crude product. Purification by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=0:1) gave a yellow solid (90 mg, 0.12 mmol, 71% yield), LCMS: m/z 751.2 (M+H).
步骤G.(1R,5S)-3-(7-(8-氯萘-1-基)-5-烯基)-8-氧代-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5，6，7，8-四氢吡啶酮[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：将(1R,5S)-3-(6-(烯丙基(8-氯萘-1-基)氨甲酰基)-5-溴-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(60mg，0.08mmol)、三乙胺(20mg，0.2mmol)、醋酸钯(4mg，0.016mmol)、三苯基膦(4mg，0.016mmol)和四丁基溴化铵(64mg，0.2mmol)的二甲基甲酰胺(2.00mL)溶液在氮气保护 下于90℃搅拌12小时。将反应混合物用水稀释并用乙酸乙酯萃取。合并的有机层用盐水洗涤，干燥，过滤并减压浓缩，得到粗产物。通过制备型TLC纯化(SiO2，二氯甲烷:甲醇＝10:1)，得到黄色油状物(30.0mg，0.045mmol，56％收率),LCMS:m/z 671.2(M+H)。Step G. (1R,5S)-3-(7-(8-chloronaphth-1-yl)-5-enyl)-8-oxo-2-((tetrahydro-1H-pyrrolazine-7a( 5H)-yl)methoxy)-5,6,7,8-tetrahydropyridone[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane Alkane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(6-(allyl(8-chloronaphth-1-yl)carbamoyl)-5-bromo-2-(tetrahydro -1H-Pyrrozine-7a(5H)-yl)methoxy)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (60 mg, 0.08 mmol), triethylamine (20 mg, 0.2 mmol), palladium acetate (4 mg, 0.016 mmol), triphenylphosphine (4 mg, 0.016 mmol) and tetrabutylammonium bromide (64 mg, 0.2 mmol) in dimethylmethane Amide (2.00mL) solution was protected with nitrogen Stir at 90°C for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give crude product. Purification by preparative TLC (SiO 2 , dichloromethane:methanol=10:1) gave yellow oil (30.0 mg, 0.045 mmol, 56% yield), LCMS: m/z 671.2 (M+H).
步骤H.4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-氯萘-1-基)-5-烯基-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-6，7-二氢吡啶酮[3,4-d]嘧啶-8(5H)-酮：向(1R,5S)-3-(7-(8-氯萘-1-基)-5-烯基)-8-氧代-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5，6，7，8-四氢吡啶酮[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(40mg，0.059mmol)的二氯甲烷(2mL)溶液中添加三氟乙酸(0.5mL)并将反应物在室温搅拌1h。将反应物真空浓缩,用乙酸乙酯与饱和碳酸氢钠水溶液萃取，收集有机相并浓缩得到粗品。将粗品通过制备型HPLC纯化，得到实施例1(2mg，0.0035mmol，5.9％收率)。LCMS:m/z 571.3(M+H)。1HNMR(600MHz,DMSO-d6)δ8.12(d,J＝8.4Hz,1H),8.08(d,J＝8.1Hz,1H),7.71(t,J＝7.8Hz,1H),7.66(dd,J＝7.5,1.2Hz,1H),7.63(dd,J＝7.3,1.3Hz,1H),7.55(t,J＝7.9Hz,1H),5.53(s,1H),5.07(s,1H),4.72(d,J＝13.7Hz,1H),4.48(d,J＝13.7Hz,1H),4.13–3.97(m,3H),3.52(d,J＝13.0Hz,2H),3.18–3.09(m,3H),3.08–2.95(m,3H),2.69–2.62(m,1H),1.95–1.89(m,2H),1.89–1.81(m,2H),1.80–1.70(m,3H),1.69–1.57(m,5H)。Step H.4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-chloronaphth-1-yl)-5-enyl- 2-((Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6,7-dihydropyridone[3,4-d]pyrimidin-8(5H)-one: to ( 1R,5S)-3-(7-(8-chloronaphth-1-yl)-5-enyl)-8-oxo-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl) )methoxy)-5,6,7,8-tetrahydropyridone[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- To a solution of tert-butyl formate (40 mg, 0.059 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL) and the reaction was stirred at room temperature for 1 h. The reaction was concentrated in vacuo, extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic phase was collected and concentrated to obtain crude product. The crude product was purified by preparative HPLC to give Example 1 (2 mg, 0.0035 mmol, 5.9% yield). LCMS: m/z 571.3(M+H). 1 HNMR (600MHz, DMSO-d 6 ) δ8.12(d,J＝8.4Hz,1H),8.08(d,J＝8.1Hz,1H),7.71(t,J＝7.8Hz,1H),7.66( dd,J＝7.5,1.2Hz,1H),7.63(dd,J＝7.3,1.3Hz,1H),7.55(t,J＝7.9Hz,1H),5.53(s,1H),5.07(s,1H ),4.72(d,J＝13.7Hz,1H),4.48(d,J＝13.7Hz,1H),4.13–3.97(m,3H),3.52(d,J＝13.0Hz,2H),3.18–3.09 (m,3H),3.08–2.95(m,3H),2.69–2.62(m,1H),1.95–1.89(m,2H),1.89–1.81(m,2H),1.80–1.70(m,3H) ,1.69–1.57(m,5H).
实施例2制备4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S)-1-甲基吡咯烷)-2-基)甲氧基)-1，6-萘啶-3-腈

Example 2 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene- 1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin)-2-yl)methoxy)-1,6-naphthyridin-3-carbonitrile

步骤A.6-氯-4-(2-氰基乙酰胺)-5-氟烟酸乙酯：在0℃下，向4-胺基-6-氯-5-氟烟酸乙酯(2.0g，9.1mmol)的DMF(25mL)溶液中加入氢化钠(734mg，18.2mmol),室温搅拌1h。0℃下逐滴添加2-氰基乙酰氯(3.0g，29.4mmol)。将混合物在室温搅拌3h。使残余物在EtOAc与水之间分配,并用EtOAc(2x)，萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-50％EtOAc/石油醚洗脱,得到产物(1.8g,6.2mmol,69％收率)LCMS:m/z 286.0(M+H)。Step A. 6-Chloro-4-(2-cyanoacetamide)-5-fluoronicotinic acid ethyl ester: To 4-amino-6-chloro-5-fluoronicotinic acid ethyl ester (2.0 g, 9.1 mmol) in DMF (25 mL), add sodium hydride (734 mg, 18.2 mmol), and stir at room temperature for 1 h. 2-cyanoacetyl chloride (3.0 g, 29.4 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 3 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc (2x) and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried , loaded onto silica gel and passed through Purification by flash column chromatography, eluting with 0-50% EtOAc/petroleum ether, gave the product (1.8 g, 6.2 mmol, 69% yield) LCMS: m/z 286.0 (M+H).
步骤B.7-氯-8-氟-2，4-二氧杂环-1，2，3，4，-四氢-1，6-萘啶-3-腈：向6-氯-4-(2-氰基乙酰胺)-5-氟烟酸乙酯(1.8g，6.3mmol)的MeOH(25mL)溶液中加入甲醇钠(670.0mg，12.6mmol),氮气保护下将混合物在80℃搅拌3h。通过过滤除去固体，浓缩，得到产物(500mg,2mmol,69％收率)。LCMS:m/z 240.0(M+H)。Step B. 7-Chloro-8-fluoro-2,4-dioxane-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbonitrile: To 6-chloro-4- To a solution of (2-cyanoacetamide)-5-fluoronicotinic acid ethyl ester (1.8g, 6.3mmol) in MeOH (25mL), sodium methoxide (670.0mg, 12.6mmol) was added, and the mixture was stirred at 80°C under nitrogen protection. 3h. The solid was removed by filtration and concentrated to give the product (500 mg, 2 mmol, 69% yield). LCMS: m/z 240.0(M+H).
步骤C.4，7-二氯-8-氟-2-氧代-1，2-二氢-1，6-萘啶-3-腈：将7-氯-8-氟-2，4-二氧杂环-1，2，3，4，-四氢-1，6-萘啶-3-腈(500mg，2.0mmol)在三氯氧磷(5mL)的溶液中90℃搅拌1.5h。将残余物滴加于冰水中并用饱和NaHCO3调PH值为7-8。用EtOAc萃取水层，将有机层过滤并真空浓缩，得到产物(460mg,1.8mmol,89％收率)LCMS:m/z 258.0(M+H)。Step C. 4,7-Dichloro-8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridine-3-nitrile: 7-Chloro-8-fluoro-2,4- Dioxetane-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carbonitrile (500 mg, 2.0 mmol) was stirred at 90°C for 1.5 h in a solution of phosphorus oxychloride (5 mL). The residue was added dropwise to ice water and the pH value was adjusted to 7-8 with saturated NaHCO 3 . The aqueous layer was extracted with EtOAc, the organic layer was filtered and concentrated in vacuo to give the product (460 mg, 1.8 mmol, 89% yield) LCMS: m/z 258.0 (M+H).
步骤D.(1R，5S)-(7-氯-3-氰基-8-氟-2-羟基-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：向4，7-二氯-8-氟-2-氧代-1，2-二氢-1，6-萘啶-3-腈(460mg，1.8mmol)、3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(530.0mg，2.5mmol)的DMF(10mL)溶液中加入DIEA(804.0mg，6.2mmol),80℃搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-5％MeOH/DCM洗脱,得到产物(400mg,0.9mmol,52％收率)LCMS:m/z 434.1(M+H)。 Step D. (1R,5S)-(7-chloro-3-cyano-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo [3.2. 1] Octane-8-carboxylic acid tert-butyl ester: 4,7-dichloro-8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carbonitrile (460 mg, DIEA (804.0 mg, 6.2 mmol) was added to a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (530.0 mg, 2.5 mmol) in DMF (10 mL) (1.8 mmol). , stir at 80℃ for 2h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluting with 0-5% MeOH/DCM, the product (400 mg, 0.9 mmol, 52% yield) was obtained. LCMS: m/z 434.1 (M+H).
步骤E.(1R，5S)-3-(7-氯-3-氰基-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R，5S)-(7-氯-3-氰基-8-氟-2-羟基-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(400mg，0.9mmol)、N-甲基-L-脯氨醇(147.0mg，1.4mmol)、三苯基膦(473.0mg，1.8mmol)在四氢呋喃(10mL)中的溶液在0℃逐滴加入DIAD(545.0mg，2.7mmol),室温搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(300mg,0.6mmol,63％收率)LCMS:m/z531.2(M+H)。Step E. (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1 , 6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-(7-chloro-3-cyano) Tert-butyl-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.9 mmol ), N-methyl-L-prolinol (147.0 mg, 1.4 mmol), and triphenylphosphine (473.0 mg, 1.8 mmol) in tetrahydrofuran (10 mL) were added dropwise to DIAD (545.0 mg, 2.7mmol), stirred at room temperature for 2h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluted with 0-10% MeOH/DCM to obtain the product (300 mg, 0.6 mmol, 63% yield) LCMS: m/z531.2 (M+H).
步骤F.(1R，5S)-3-(3-氰基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅烷基)乙炔基)萘-1-基)2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R，5S)-3-(7-氯-3-氰基-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(300.0mg，0.6mmol)、((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(369.0mg，0.7mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(44.0mg，0.06mmol)、磷酸钾(381.0mg，1.8mmol)在四氢呋喃(10mL)和水(1mL)中的溶液。氮气环境下65℃搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(220mg,0.25mmol,42％收率)LCMS:m/z 881.5(M+H)。Step F. (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether))-8-(triisopropylsilyl)acetylene yl)naphth-1-yl)2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diaza Heterobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((S)-1) -Methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300.0mg, 0.6mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxabor Borane-2-yl) naphth-1-yl) ethynyl) triisopropylsilane (369.0 mg, 0.7 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino - A solution of 1,1'-biphenyl-2-yl)palladium (44.0 mg, 0.06 mmol), potassium phosphate (381.0 mg, 1.8 mmol) in tetrahydrofuran (10 mL) and water (1 mL). Stir at 65°C for 2 hours under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluting with 0-10% MeOH/DCM, the product (220 mg, 0.25 mmol, 42% yield) was obtained. LCMS: m/z 881.5 (M+H).
步骤G.(1R，5S)-3-(3-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲醚)-萘-1-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R，5S)-3-(3-氰基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅烷基)乙炔基)萘-1-基)2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(220.0mg，0.25mmol)、氟化铯(151.0mg，1.0mmol)在DMF(10mL)中的溶液，氮气环境下室温搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(140mg,0.19mmol,77％收率)LCMS:m/z 725.3(M+H)。Step G. (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)-naphthalen-1-yl)-8-fluoro- 2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane Alkane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(( Triisopropylsilyl)ethynyl)naphth-1-yl)2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl )-tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220.0 mg, 0.25 mmol), cesium fluoride (151.0 mg, 1.0 mmol) in DMF (10 mL) The solution was stirred at room temperature under nitrogen atmosphere for 1 hour. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluting with 0-10% MeOH/DCM, the product (140 mg, 0.19 mmol, 77% yield) was obtained. LCMS: m/z 725.3 (M+H).
步骤H.4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S)-1-甲基吡咯烷)-2-基)甲氧基)-1，6-萘啶-3-腈：将(1R，5S)-3-(3-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲醚)-萘-1-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(140.0mg，0.19mmol)在二氯甲烷(3mL)中的溶液逐滴加入盐酸的1,4-dioxane溶液。室温搅拌1h。浓缩，将残余物倒入 饱和NaHCO3、DCM和MeOH的混合物中。用DCM和MeOH萃取水层，合并的有机层用盐水洗涤，经Na2SO4干燥，过滤并真空浓缩。通过制备型HPLC(5-95％ACN/水/0.1％FA，经20min)纯化。将产品加入碳酸氢钠、DCM和MeOH中萃取，有机相干燥浓缩，加入纯化水，冻干，得到实施例2(17.0mg,0.03mmol,15％收率)。LCMS:m/z 581.2(M+H)。1H NMR(600MHz,DMSO-d6)δ10.30(s,1H),9.03(s,1H),7.98(dd,J＝9.2,5.8Hz,1H),7.47(t,J＝9.0Hz,1H),7.40(d,J＝2.6Hz,1H),7.22(t,J＝2.2Hz,1H),4.48(td,J＝10.8,5.0Hz,1H),4.38(ddd,J＝10.9,8.8,5.5Hz,1H),3.99(d,J＝3.4Hz,1H),3.84–3.78(m,2H),3.72–3.66(m,2H),3.05–2.99(m,2H),2.99–2.93(m,3H),2.67–2.61(m,1H),2.40(s,3H),2.23–2.19(m,1H),2.18(d,J＝9.4Hz,1H),1.99–1.93(m,1H),1.71–1.64(m,2H)。Step H.4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1 -yl)-8-fluoro-2-(((S)-1-methylpyrrolidin)-2-yl)methoxy)-1,6-naphthyridine-3-carbonitrile: (1R,5S) -3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)-naphthalen-1-yl)-8-fluoro-2-(((S)- 1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl A solution of the ester (140.0 mg, 0.19 mmol) in dichloromethane (3 mL) was added dropwise to a solution of hydrochloric acid in 1,4-dioxane. Stir at room temperature for 1 hour. Concentrate and pour the residue into in a mixture of saturated NaHCO 3 , DCM and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and concentrated in vacuo. Purified by preparative HPLC (5-95% ACN/water/0.1% FA over 20 min). The product was added to sodium bicarbonate, DCM and MeOH for extraction, the organic phase was dried and concentrated, purified water was added, and lyophilized to obtain Example 2 (17.0 mg, 0.03 mmol, 15% yield). LCMS: m/z 581.2(M+H). 1 H NMR (600MHz, DMSO-d 6 ) δ10.30 (s, 1H), 9.03 (s, 1H), 7.98 (dd, J = 9.2, 5.8Hz, 1H), 7.47 (t, J = 9.0Hz, 1H),7.40(d,J＝2.6Hz,1H),7.22(t,J＝2.2Hz,1H),4.48(td,J＝10.8,5.0Hz,1H),4.38(ddd,J＝10.9,8.8 ,5.5Hz,1H),3.99(d,J＝3.4Hz,1H),3.84–3.78(m,2H),3.72–3.66(m,2H),3.05–2.99(m,2H),2.99–2.93( m,3H),2.67–2.61(m,1H),2.40(s,3H),2.23–2.19(m,1H),2.18(d,J＝9.4Hz,1H),1.99–1.93(m,1H) ,1.71–1.64(m,2H).
实施例3制备4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)-5-烯基-6，7-二氢吡啶酮[3,4-d]嘧啶-8(5H)-酮
Example 3 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H -Pyrrozine-7a(5H)-yl)methoxy)-7-(3-hydroxynaphth-1-yl)-5-enyl-6,7-dihydropyridone[3,4-d]pyrimidine -8(5H)-ketone
反应式为：
The reaction formula is:
步骤A.1-溴-3-(甲氧基甲氧基)萘：氮气保护下，向1-溴-3-羟基萘(500mg，2.24mmol)和DIEA(868mg，6.27mmol)的二氯甲烷(8mL)溶液中添加溴甲基甲醚(0.27mL，3.36mmol)。将混合物在0℃下搅拌0.5小时。将反应混合物用水稀释并用二氯甲烷萃取。合并的有机层用盐水洗涤，干燥，过滤并减压浓缩，得到粗产物。将混合物通过柱色谱直接纯化，用(PE/EtOAc＝1:10)洗脱，得到产物(160mg，0.60mmol，27％收率)。Step A. 1-Bromo-3-(methoxymethoxy)naphthalene: Under nitrogen protection, add 1-bromo-3-hydroxynaphthalene (500mg, 2.24mmol) and DIEA (868mg, 6.27mmol) in dichloromethane (8 mL) solution was added bromomethyl ether (0.27 mL, 3.36 mmol). The mixture was stirred at 0°C for 0.5 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give crude product. The mixture was directly purified by column chromatography, eluting with (PE/EtOAc=1:10), to give the product (160 mg, 0.60 mmol, 27% yield).
步骤B.N-烯丙基-3-(甲氧基甲氧基)萘-1-胺：将1-溴-3-(甲氧基甲氧基)萘(30mg，0.113mmol)、烯丙胺(16mg，0.169mmol)、Xantphos(13mg，0.023mmol)、Pd2(dba)3(10mg，0.011mmol)和碳酸铯(73mg，0.226mmol)的1,4-二氧六环(1.00mL)溶液在氮气气氛下于110℃搅拌1小时。将反应混 合物用水稀释并用乙酸乙酯萃取。合并的有机层用盐水洗涤，干燥，过滤并减压浓缩，得到粗产物。通过制备型TLC纯化残余物(SiO2，石油醚:乙酸乙酯＝10:1)，得到黄色油状物(20.0mg，0.0819mmol，73％收率),LCMS:m/z 244.2(M+H)。Step BN-allyl-3-(methoxymethoxy)naphthalene-1-amine: Combine 1-bromo-3-(methoxymethoxy)naphthalene (30 mg, 0.113mmol), allylamine (16 mg , 0.169mmol), Xantphos (13mg, 0.023mmol), Pd 2 (dba) 3 (10mg, 0.011mmol) and cesium carbonate (73mg, 0.226mmol) in 1,4-dioxane (1.00mL) in nitrogen Stir at 110°C for 1 hour under atmosphere. Mix the reaction The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give crude product. The residue was purified by preparative TLC (SiO 2 , petroleum ether: ethyl acetate = 10:1) to obtain a yellow oil (20.0 mg, 0.0819 mmol, 73% yield), LCMS: m/z 244.2 (M+H ).
步骤C.以(1R,5S)-3-(5-溴-2-氯-6-(甲酸甲酯)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯为原料，用N-烯丙基-3-(甲氧基甲氧基)萘-1-胺代替N-烯丙基-8-氯萘-1-胺，用(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇代替(六氢-1H-吡咯啉-7a-基)甲醇，按到实施例1的步骤E-H合成实施例3，LCMS:m/z 571.3(M+H)。1HNMR(600MHz,DMSO-d6)δ7.83(d,J＝8.3Hz,1H),7.57(d,J＝8.4Hz,1H),7.49–7.43(m,1H),7.31–7.27(m,2H),7.21(d,J＝2.3Hz,1H),7.13(t,J＝2.1Hz,1H),5.53(s,1H),5.35–5.22(m,1H),5.06(s,1H),4.67(d,J＝13.3Hz,1H),4.33(d,J＝13.3Hz,1H),4.06(d,J＝10.2Hz,2H),3.95(d,J＝10.3Hz,1H),3.48–3.40(m,4H),3.12–3.07(m,3H),2.86–2.80(m,2H),2.13–2.10(m,2H),2.07–2.04(m,1H),2.02–1.96(m,1H),1.88–1.83(m,1H),1.81–1.73(m,2H),1.64–1.50(m,3H)。Step C. Using (1R,5S)-3-(5-bromo-2-chloro-6-(methylformate)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-tert-butylcarboxylate is used as raw material, and N-allyl-3-(methoxymethoxy)naphthalene-1-amine is used instead of N-allyl-8-chloronaphthyl-1-amine, and ( 2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol instead of (hexahydro-1H-pyrrolin-7a-yl)methanol, as in the example Step 1 EH Synthesis Example 3, LCMS: m/z 571.3 (M+H). 1 HNMR(600MHz, DMSO-d 6 )δ7.83(d,J＝8.3Hz,1H),7.57(d,J＝8.4Hz,1H),7.49–7.43(m,1H),7.31–7.27(m ,2H),7.21(d,J＝2.3Hz,1H),7.13(t,J＝2.1Hz,1H),5.53(s,1H),5.35–5.22(m,1H),5.06(s,1H) ,4.67(d,J＝13.3Hz,1H),4.33(d,J＝13.3Hz,1H),4.06(d,J＝10.2Hz,2H),3.95(d,J＝10.3Hz,1H),3.48 –3.40(m,4H),3.12–3.07(m,3H),2.86–2.80(m,2H),2.13–2.10(m,2H),2.07–2.04(m,1H),2.02–1.96(m, 1H),1.88–1.83(m,1H),1.81–1.73(m,2H),1.64–1.50(m,3H).
实施例4制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基))-2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-亚甲基-5，8-二氢吡啶酮[3,4-d]嘧啶-7(6H)-基)萘-2-酚
Example 4 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl))-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methylene-5,8-dihydropyridone[3,4-d]pyrimidin-7(6H)-yl) Naphth-2-phenol
反应式为：
The reaction formula is:
步骤A.6-(氯甲基)-2-(甲硫基)嘧啶-4-醇：向氯乙酰乙酸乙酯(10g，60.6mmol)，2-甲基-2-疏基硫酸脲(16.8g，60.6mmol)的水(100ml)溶液中加入碳酸钠(9.6g，90.9mmol)，将反应混合物在25℃搅拌6小时。用5M的HCl调节PH至酸性，过滤，真空干燥箱将滤饼烘干，得到产品(7.8g，68％收率)即用于下一步。LCMS:m/z 191.1(M+H)。Step A. 6-(Chloromethyl)-2-(methylthio)pyrimidin-4-ol: To chloroacetoacetate ethyl ester (10g, 60.6mmol), 2-methyl-2-mercaptourea sulfate (16.8 g, 60.6 mmol) in water (100 ml) was added sodium carbonate (9.6 g, 90.9 mmol), and the reaction mixture was stirred at 25°C for 6 hours. Use 5 M HCl to adjust the pH to acidity, filter, and dry the filter cake in a vacuum drying oven to obtain the product (7.8 g, 68% yield), which is used in the next step. LCMS: m/z 191.1(M+H).
步骤B.5-溴-6-(氯甲基)-2-(甲硫基)嘧啶-4-醇：向6-(氯甲基)-2- (甲硫基)嘧啶-4-醇(3.68g，19.26mmol)的乙腈(40ml)溶液加入N-溴代丁二酰亚胺(NBS)(3.4g，19.26mmol)，加热至80℃搅拌3小时。将反应混合物过滤，并用石油醚/乙酸乙酯＝40/1淋洗，滤饼即为产品(3.8g，74％收率)，LCMS:m/z 268.9(M+H)。Step B. 5-Bromo-6-(chloromethyl)-2-(methylthio)pyrimidin-4-ol: To 6-(chloromethyl)-2- A solution of (methylthio)pyrimidin-4-ol (3.68g, 19.26mmol) in acetonitrile (40ml) was added with N-bromosuccinimide (NBS) (3.4g, 19.26mmol), heated to 80°C and stirred for 3 Hour. The reaction mixture was filtered and rinsed with petroleum ether/ethyl acetate = 40/1. The filter cake was the product (3.8g, 74% yield), LCMS: m/z 268.9 (M+H).
步骤C.(1R,5S)-3-(5-溴-6-(氯甲基)-2-(甲硫基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：0℃下，向5-溴-6-(氯甲基)-2-(甲硫基)嘧啶-4-醇(2g，7.43mmol)的乙腈(15ml)溶液中依次加入1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(3.9g，7.43mmol)，DIEA(2.9g，22.3mmol)，氮气保护下搅拌5min后加入3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(1.7g，8.18mmol)，后继续搅拌1小时。将反应混合物用乙酸乙酯稀释加水，乙酸乙酯萃取，经Na2SO4干燥，过滤、浓缩得到粗产物。然后通过柱色谱(SiO2，石油醚/乙酸乙酯＝15/1)纯化得到黄色油状物(1.1g，32％收率)，LCMS:m/z 463.1(M+H)。Step C. (1R,5S)-3-(5-bromo-6-(chloromethyl)-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo [3.2.1 ] Octane-8-carboxylic acid tert-butyl ester: To 5-bromo-6-(chloromethyl)-2-(methylthio)pyrimidin-4-ol (2g, 7.43mmol) in acetonitrile (15ml) at 0°C ) solution, add 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (3.9g, 7.43mmol) and DIEA (2.9g, 22.3mmol) in sequence, stir under nitrogen protection for 5 minutes and then add 3, 8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.7g, 8.18mmol), and then continue stirring for 1 hour. The reaction mixture was diluted with ethyl acetate, water was added, extracted with ethyl acetate, dried over Na 2 SO 4 , filtered, and concentrated to obtain a crude product. Then it was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate = 15/1) to obtain a yellow oil (1.1 g, 32% yield), LCMS: m/z 463.1 (M+H).
步骤D.(1R,5S)-3-(6-((烯丙基(3-(甲氧基甲氧基)萘-1-基)胺基)甲基)-5-溴-2-(甲硫基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：将(1R,5S)-3-(5-溴-6-(氯甲基)-2-(甲硫基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(63mg，0.26mmol)，N-烯丙基-3-(甲氧基甲氧基)萘-1-胺(86mg，0.19mmol)，碘化钾(3mg，0.02mmol)，碳酸钾(77mg，0.56mmol)的乙腈(1ml)溶液在氮气环境下加热至80℃搅拌16小时。将反应混合物用乙酸乙酯稀释并用水和乙酸乙酯萃取，经Na2SO4干燥，过滤、浓缩得到粗产物。然后通过柱色谱(SiO2，石油醚/乙酸乙酯＝5/1)纯化得到黄色油状物(40mg，32％收率)，LCMS:m/z 670.2(M+H)。Step D. (1R,5S)-3-(6-((allyl(3-(methoxymethoxy)naphth-1-yl)amino)methyl)-5-bromo-2-( Methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(5-bromo-6- (Chloromethyl)-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (63 mg, 0.26 mmol), N - Allyl-3-(methoxymethoxy)naphthalene-1-amine (86 mg, 0.19 mmol), potassium iodide (3 mg, 0.02 mmol), potassium carbonate (77 mg, 0.56 mmol) in acetonitrile (1 ml) Heat to 80°C under nitrogen atmosphere and stir for 16 hours. The reaction mixture was diluted with ethyl acetate and extracted with water and ethyl acetate, dried over Na2SO4 , filtered and concentrated to give the crude product. Then it was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate = 5/1) to obtain a yellow oil (40 mg, 32% yield), LCMS: m/z 670.2 (M+H).
步骤E.(1R,5S)-3-(7-(3-(甲氧基甲氧基)萘-1-基)-5-烯基-2-(甲硫基)-5，6，7，8-四氢吡啶酮并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：将(1R,5S)-3-(6-((烯丙基(3-(甲氧基甲氧基)萘-1-基)胺基)甲基)-5-溴-2-(甲硫基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(200mg，0.30mmol)，三苯基膦(16mg，0.06mmol)，醋酸钯(7mg，0.03mmol)，碳酸铯(244mg，0.75mmol)的甲苯(5ml)溶液在氮气环境中加热至110℃搅拌3小时。将反应混合物用乙酸乙酯稀释并用水和乙酸乙酯萃取，经Na2SO4干燥，过滤、浓缩得到粗产物。然后通过柱色谱(SiO2，石油醚/乙酸乙酯＝3/1)纯化得到黄色固体(135mg，77％收率)，LCMS:m/z 590.3(M+H)。Step E. (1R,5S)-3-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5-alkenyl-2-(methylthio)-5,6,7 , 8-Tetrahydropyridono[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S )-3-(6-((allyl(3-(methoxymethoxy)naphthalen-1-yl)amino)methyl)-5-bromo-2-(methylthio)pyrimidine-4 -tert-butyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200mg, 0.30mmol), triphenylphosphine (16mg, 0.06mmol), palladium acetate (7mg, 0.03 mmol), a solution of cesium carbonate (244 mg, 0.75 mmol) in toluene (5 ml) was heated to 110°C in a nitrogen atmosphere and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate and extracted with water and ethyl acetate, dried over Na2SO4 , filtered and concentrated to give the crude product. Then it was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate = 3/1) to obtain a yellow solid (135 mg, 77% yield), LCMS: m/z 590.3 (M+H).
步骤F.(1R,5S)-3-(2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)-5-烯基-5，6，7，8-四氢吡啶酮并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：在-40℃下，向(1R,5S)-3-(7-(3-(甲氧基甲氧基)萘-1-基)-5-烯基-2-(甲硫基)-5，6，7，8-四氢吡啶酮并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(100mg，0.170mmol)的二氯甲烷溶液(2ml)中加入间氯过氧苯甲酸(29mg，0.170mmol)，并搅拌2小时。饱和硫代硫酸钠水溶液淬灭反应液，并用二氯甲烷(50ml)和碳酸钠水溶液萃取，经Na2SO4干燥，通过 旋转蒸发浓缩，得到粗品不做纯化即用于下一步。将此粗品(130mg，0.21mmol)，(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇(68mg，0.42mmol)，DIEA(83mg，0.63mmol)的异丙醇(0.7ml)溶液加热至90℃搅拌10小时。将反应混合物用乙酸乙酯稀释并用水和乙酸乙酯萃取，经Na2SO4干燥，过滤、浓缩得到粗产物。然后通过柱色谱(SiO2，石油醚/乙酸乙酯＝3/1)纯化得到黄色固体(60mg，40％收率)，LCMS:m/z 701.4(M+H)。Step F. (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3- (Methoxymethoxy)naphth-1-yl)-5-enyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: to (1R,5S)-3-(7-(3-(methoxymethoxy)naphthalene) at -40°C -1-yl)-5-alkenyl-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8- Add m-chloroperoxybenzoic acid (29 mg, 0.170 mmol) to a dichloromethane solution (2 ml) of diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.170 mmol), and stir for 2 Hour. The reaction solution was quenched with saturated aqueous sodium thiosulfate solution, extracted with dichloromethane (50 ml) and aqueous sodium carbonate solution, dried over Na 2 SO 4 , and filtered through Concentrated by rotary evaporation, the crude product was obtained and used in the next step without purification. This crude product (130 mg, 0.21 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol (68 mg, 0.42 mmol), DIEA ( A solution of 83 mg, 0.63 mmol) in isopropyl alcohol (0.7 ml) was heated to 90°C and stirred for 10 hours. The reaction mixture was diluted with ethyl acetate and extracted with water and ethyl acetate, dried over Na2SO4 , filtered and concentrated to give the crude product. It was then purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate = 3/1) to obtain a yellow solid (60 mg, 40% yield), LCMS: m/z 701.4 (M+H).
步骤G.4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基))-2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-亚甲基-5，8-二氢吡啶酮[3,4-d]嘧啶-7(6H)-基)萘-2-酚：向(1R,5S)-3-(2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-(甲氧基甲氧基)萘-1-基)-5-烯基-5，6，7，8-四氢吡啶酮并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(60mg，0.08mmol)的二氯甲烷(2mL)溶液中逐滴加入盐酸的1,4-dioxane溶液。室温搅拌1h。浓缩，将残余物倒入饱和NaHCO3、DCM和MeOH的混合物中。用DCM和MeOH萃取水层，合并的有机层用盐水洗涤，经Na2SO4干燥，过滤并真空浓缩。通过制备型HPLC(5-95％ACN/水/0.1％FA，经20min)纯化、冻干，得到实施例4为含一个甲酸的盐(3.55mg,7％收率)，LCMS:m/z 557.2(M+H)。1HNMR(600MHz,DMSO-d6)δ9.68(s,1H),8.27(s,1H),7.91(d,J＝8.4Hz,1H),7.64(d,J＝8.2Hz,1H),7.37(t,J＝7.4Hz,1H),7.27(t,J＝7.6Hz,1H),6.81(d,J＝2.2Hz,1H),6.60(d,J＝2.2Hz,1H),5.27(d,J＝54.3Hz,1H),5.11(s,1H),4.92(s,1H),4.19(s,2H),4.04(s,2H),4.00(d,J＝10.2Hz,1H),3.89(d,J＝10.2Hz,1H),3.48(s,3H),3.12–3.04(m,4H),3.01(s,1H),2.82(q,J＝8.3Hz,1H),2.11–2.06(m,1H),2.03(d,J＝3.1Hz,1H),2.01–1.94(m,1H),1.84(d,J＝10.0Hz,1H),1.76(d,J＝11.7Hz,2H),1.59-1.53(m，4H)。Step G. 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl))-2-(((2R,7aS)-2-fluorotetraz Hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-methylene-5,8-dihydropyridone[3,4-d]pyrimidin-7(6H)-yl)naphthalene -2-Phenol: to (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7- (3-(methoxymethoxy)naphth-1-yl)-5-enyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)- To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.08 mmol) in dichloromethane (2 mL) was added a solution of hydrochloric acid in 1,4-dioxane dropwise. Stir at room temperature for 1 hour. Concentrate and pour the residue into a mixture of saturated NaHCO3 , DCM and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and concentrated in vacuo. Purified by preparative HPLC (5-95% ACN/water/0.1% FA, over 20 min) and lyophilized, Example 4 was obtained as a salt containing a formic acid (3.55 mg, 7% yield), LCMS: m/z 557.2(M+H). 1 HNMR (600MHz, DMSO-d 6 ) δ9.68 (s, 1H), 8.27 (s, 1H), 7.91 (d, J = 8.4Hz, 1H), 7.64 (d, J = 8.2Hz, 1H), 7.37(t,J＝7.4Hz,1H),7.27(t,J＝7.6Hz,1H),6.81(d,J＝2.2Hz,1H),6.60(d,J＝2.2Hz,1H),5.27( d,J＝54.3Hz,1H),5.11(s,1H),4.92(s,1H),4.19(s,2H),4.04(s,2H),4.00(d,J＝10.2Hz,1H), 3.89(d,J＝10.2Hz,1H),3.48(s,3H),3.12–3.04(m,4H),3.01(s,1H),2.82(q,J＝8.3Hz,1H),2.11–2.06 (m,1H),2.03(d,J＝3.1Hz,1H),2.01–1.94(m,1H),1.84(d,J＝10.0Hz,1H),1.76(d,J＝11.7Hz,2H) ,1.59-1.53(m,4H).
实施例5制备4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2S,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-1，6-萘啶-3-腈

Example 5 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene- 1-yl)-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-1,6-naphthyridine-3 -Nitrile

步骤A.(1R，5S)-3-(7-氯-3-氰基-8-氟-2-(((2R，7aS)-2-氟四氢-1H-吡呤环7a(5H)-基)甲氧基)-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R，5S)-(7-氯-3-氰基-8-氟-2-羟基-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(400mg，0.9mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(222.0mg，1.4mmol)、三苯基膦(473.0mg，1.8mmol)在四氢呋喃(10mL)中的溶液在0℃逐滴加入DIAD(545.0mg，2.7mmol),室温搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(300mg,0.5mmol,58％收率)LCMS:m/z 575.4(M+H)。Step A. (1R,5S)-3-(7-chloro-3-cyano-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Resuspend (1R,5S)-(7-chloro-3-cyano-8-fluoro-2-hydroxy-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3 .2.1] tert-butyl octane-8-carboxylate (400 mg, 0.9 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (222.0 mg, 1.4 mmol), triphenylphosphine (473.0 mg, 1.8 mmol) in tetrahydrofuran (10 mL) was added DIAD (545.0 mg, 2.7 mmol) dropwise at 0°C and stirred at room temperature for 2 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na 2 SO 4 , the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography, eluting with 0-10% MeOH/DCM to give the product (300 mg, 0.5 mmol, 58% yield) LCMS: m/z 575.4 (M+H).
步骤B.(1R，5S)-3-(3-氰基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅烷基)乙炔基)萘-1-基)2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R，5S)-3-(7-氯-3-氰基-8-氟-2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(300.0mg，0.5mmol)、((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(369.0mg，0.7mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(44.0mg，0.06mmol)、磷酸钾(381.0mg，1.8mmol)在四氢呋喃(10mL)和水(1mL)中的溶液。氮气环境下65℃搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(220mg,0.23mmol,47％收率)LCMS:m/z 925.5(M+H)。Step B. (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(triisopropylsilyl)acetylene yl)naphth-1-yl)2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4- (1R, 5S)-3-(7-chloro-3-cyano-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300.0mg, 0.5mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (369.0mg, 0.7mmol), methanesulfonic acid [n-Butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (44.0 mg, 0.06 mmol), potassium phosphate (381.0 mg, 1.8 mmol) in A solution in tetrahydrofuran (10 mL) and water (1 mL). Stir at 65°C for 2 hours under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluting with 0-10% MeOH/DCM, the product (220 mg, 0.23 mmol, 47% yield) was obtained. LCMS: m/z 925.5 (M+H).
步骤C.(1R，5S)-3-(3-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲醚)-萘-1-基)-8-氟-2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R，5S)-3-(3-氰基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅烷基)乙炔基)萘-1-基)2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧 基)-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(220.0mg，0.23mmol)、氟化铯(139.0mg，0.9mmol)在DMF(10mL)中的溶液。氮气环境下室温搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(140mg,0.18mmol,79％收率)LCMS:m/z 769.3(M+H)。Step C. (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)-naphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxy Methyl ether)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H) -Methoxy tert-butyl)-1,6-naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (220.0 mg, 0.23 mmol), cesium fluoride ( 139.0 mg, 0.9 mmol) in DMF (10 mL). Stir at room temperature for 1 hour under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluting with 0-10% MeOH/DCM, the product (140 mg, 0.18 mmol, 79% yield) was obtained. LCMS: m/z 769.3 (M+H).
步骤D.4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2S,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-1，6-萘啶-3-腈：将(1R，5S)-3-(3-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲醚)-萘-1-基)-8-氟-2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-1，6-萘啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(140.0mg，0.18mmol)在二氯甲烷(3mL)中的溶液逐滴加入盐酸的1,4-dioxane溶液。室温搅拌1h。浓缩，将残余物倒入饱和NaHCO3、DCM和MeOH的混合物中。用DCM和MeOH萃取水层，合并的有机层用盐水洗涤，经Na2SO4干燥，过滤并真空浓缩。通过快速柱色谱纯化残余物，用制备型HPLC(5-95％ACN/水/0.1％FA，经20min)纯化。将产品加入碳酸氢钠、DCM和MeOH中萃取，有机相干燥浓缩，加入纯化水，冻干，得到实施例5(6.97mg,0.01mmol,6％收率)。LCMS:m/z 625.2(M+H)。1H NMR(600MHz,DMSO-d6)δ9.15(s,1H),8.45(s,1H),7.97(dd,J＝9.2,5.9Hz,1H),7.46(t,J＝9.0Hz,1H),7.40(d,J＝2.5Hz,1H),7.21(d,J＝2.5Hz,1H),5.36–5.24(m,1H),4.22(dd,J＝10.4,7.9Hz,1H),4.16(dd,J＝10.4,5.5Hz,1H),3.95–3.89(m,3H),3.71–3.65(m,2H),3.57–3.51(m,2H),3.21–3.14(m,1H),3.13–3.08(m,1H),3.07–3.00(m,1H),2.83(q,J＝7.9,7.5Hz,1H),2.16–2.08(m,2H),2.07–1.95(m,3H),1.86–1.73(m,5H)。Step D. 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1 -yl)-8-fluoro-2-(((2S,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-1,6-naphthyridine-3- Nitrile: (1R,5S)-3-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)-naphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,6-naphthyridin-4-yl)-3,8-di A solution of azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (140.0 mg, 0.18 mmol) in dichloromethane (3 mL) was added dropwise to a solution of hydrochloric acid in 1,4-dioxane. Stir at room temperature for 1 hour. Concentrate and pour the residue into a mixture of saturated NaHCO3 , DCM and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography and preparative HPLC (5-95% ACN/water/0.1% FA over 20 min). The product was added to sodium bicarbonate, DCM and MeOH for extraction, the organic phase was dried and concentrated, purified water was added, and lyophilized to obtain Example 5 (6.97 mg, 0.01 mmol, 6% yield). LCMS: m/z 625.2(M+H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.15 (s, 1H), 8.45 (s, 1H), 7.97 (dd, J = 9.2, 5.9Hz, 1H), 7.46 (t, J = 9.0Hz, 1H),7.40(d,J＝2.5Hz,1H),7.21(d,J＝2.5Hz,1H),5.36–5.24(m,1H),4.22(dd,J＝10.4,7.9Hz,1H), 4.16(dd,J＝10.4,5.5Hz,1H),3.95–3.89(m,3H),3.71–3.65(m,2H),3.57–3.51(m,2H),3.21–3.14(m,1H), 3.13–3.08(m,1H),3.07–3.00(m,1H),2.83(q,J＝7.9,7.5Hz,1H),2.16–2.08(m,2H),2.07–1.95(m,3H), 1.86–1.73(m,5H).
实施例6制备4-(5-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)嘧啶并[4,5-d]嘧啶-2-基)-5-乙炔基-6-氟萘-2-酚
Example 6 Preparation of 4-(5-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((2R,7aS)-2-fluorotetrazine) Hydrogen-1H-pyrrozin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-2-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol
反应式如下：
The reaction formula is as follows:
步骤A.2-(甲硫基)-4-(3-(2，2，2-三氯乙酰基)脲)嘧啶-5-羧酸乙酯：向冰水浴下的4-胺基-2-(甲硫基)嘧啶-5-羧酸乙酯(500mg，2.35mmol)的THF(4ml)溶液中加入三氯乙酰基异氰酸酯(530mg)，室温搅拌1小时。将反应混合物用二氯甲烷(20ml×2)稀释并用水(100ml×2)萃取，经Na2SO4干燥，通过旋转蒸发浓缩，得到白色固体(550mg，粗品)不经纯化即用于下一步。LCMS:m/z 401.0(M+H)。Step A. Ethyl 2-(methylthio)-4-(3-(2,2,2-trichloroacetyl)urea)pyrimidine-5-carboxylate: add 4-amino-2 in an ice-water bath Trichloroacetyl isocyanate (530 mg) was added to a solution of (methylthio)pyrimidine-5-carboxylic acid ethyl ester (500 mg, 2.35 mmol) in THF (4 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (20 ml × 2) and extracted with water (100 ml × 2), dried over Na 2 SO 4 and concentrated by rotary evaporation to obtain a white solid (550 mg, crude product) which was used in the next step without purification. . LCMS: m/z 401.0(M+H).
步骤B.7-(甲硫基)嘧啶并[4,5-d]嘧啶-2，4-二醇：在0℃下向2-(甲硫基)-4-(3-(2，2，2-三氯乙酰基)脲)嘧啶-5-羧酸乙酯中加入氨的甲醇溶液(7M，8ml)，在25℃下搅拌2小时。过滤并用甲醇(500ml×3)洗涤，得到粗品(480mg)用于下一步。LCMS:m/z 210.0(M+H)。Step B. 7-(Methylthio)pyrimido[4,5-d]pyrimidine-2,4-diol: 2-(methylthio)-4-(3-(2,2 , Add a methanol solution of ammonia (7M, 8ml) to 2-trichloroacetyl)urea)pyrimidine-5-carboxylic acid ethyl ester, and stir at 25°C for 2 hours. Filter and wash with methanol (500ml×3) to obtain crude product (480mg) for the next step. LCMS: m/z 210.0(M+H).
步骤C.2，4-二氯-7-(甲硫基)嘧啶并[4,5-d]嘧啶：在0℃下向7-(甲硫基)嘧啶并[4,5-d]嘧啶-2，4-二醇(480mg，2.28mmol)的POCl3(4ml)溶液中缓慢滴加DIEA(888mg，6.85mmol)，并将反应液加热至100℃搅拌2小时。反应液浓缩后直接用于下一步。LCMS:m/z 247.0(M+H)。Step C. 2,4-Dichloro-7-(methylthio)pyrimido[4,5-d]pyrimidine: To 7-(methylthio)pyrimido[4,5-d]pyrimidine at 0°C DIEA (888 mg, 6.85 mmol) was slowly added dropwise to a solution of 2,4-diol (480 mg, 2.28 mmol) in POCl 3 (4 ml), and the reaction solution was heated to 100°C and stirred for 2 hours. The reaction solution was concentrated and used directly in the next step. LCMS: m/z 247.0(M+H).
步骤D.(1R,5S)-3-(2-氯-7-(甲硫基)嘧啶并[4,5-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将2，4-二氯-7-(甲硫基)嘧啶并[4,5-d]嘧啶用DCM(5ml)稀释，在0℃下向其中缓慢加入3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(480mg，2.26mmol)和DIEA(10ml)，并在25℃下搅拌2小时。将反应混合物用DCM稀释并加水，用二氯甲烷萃取，经Na2SO4干燥，通过旋转蒸发浓缩，得到粗产物。然后通过柱色谱(SiO2，石油醚/乙酸乙酯＝1/1)纯化得到黄色固体产物(620mg，62％收率)。LCMS:m/z 423.1(M+H)。Step D. (1R,5S)-3-(2-chloro-7-(methylthio)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] Octane-8-carboxylic acid tert-butyl ester: 2,4-dichloro-7-(methylthio)pyrimido[4,5-d]pyrimidine was diluted with DCM (5ml) and added to 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (480 mg, 2.26 mmol) and DIEA (10 ml) were slowly added and stirred at 25°C for 2 hours. The reaction mixture was diluted with DCM and water added, extracted with dichloromethane, dried over Na2SO4 , and concentrated by rotary evaporation to give the crude product. Then it was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate = 1/1) to obtain a yellow solid product (620 mg, 62% yield). LCMS: m/z 423.1(M+H).
步骤E.(1R,5S)-3-(2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(甲硫基)嘧啶并[4,5-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R,5S)-3-(2-氯-7-(甲硫基)嘧啶并[4,5-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(100mg，0.24mmol)，(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(75mg，0.47mmol)，DIEA(92mg， 0.71mmol)加入1,4-二氧六环(1ml)的溶液中，反应混合物加热至90℃搅拌过夜。将反应物用乙酸乙酯(20ml)稀释并加水，乙酸乙酯萃取，经Na2SO4干燥，浓缩得到粗产物。然后通过柱色谱(SiO2，二氯甲烷/甲醇＝10/1)纯化得到黄色固体(70mg，54％收率)。LCMS:m/z 546.3(M+H)。Step E. (1R,5S)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(methylthio) (1R,5S)-3 -(2-Chloro-7-(methylthio)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert. Butyl ester (100 mg, 0.24 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-yl]methanol (75 mg, 0.47 mmol), DIEA ( 92mg, 0.71 mmol) was added to the solution of 1,4-dioxane (1 ml), and the reaction mixture was heated to 90°C and stirred overnight. The reaction was diluted with ethyl acetate (20 ml) and water was added, extracted with ethyl acetate, dried over Na 2 SO 4 and concentrated to give the crude product. It was then purified by column chromatography (SiO 2 , dichloromethane/methanol = 10/1) to obtain a yellow solid (70 mg, 54% yield). LCMS: m/z 546.3(M+H).
步骤F.(1R,5S)-3-(7-氯-2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)嘧啶并[4,5-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：在0℃下向(1R,5S)-3-(2-(((2R，7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-7-(甲硫基)嘧啶并[4,5-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(300mg，0.55mmol)的THF/DCM＝1/1(5ml)的溶液中氮气保护下滴加磺酰氯(742mg，5.50mmol)，反应液在25℃搅拌1小时。反应混合物用饱和NaHCO3水溶液(8ml)淬灭，用DCM(50ml)萃取，经Na2SO4干燥，浓缩得到粗产物。然后通过柱色谱(SiO2，二氯甲烷/甲醇＝10/1)纯化得到黄色固体(216mg，74％收率)。LCMS:m/z534.2(M+H)。Step F. (1R,5S)-3-(7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrimido [4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: to (1R,5S)-3 at 0°C -(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridinyl-7a(5H)-yl)methoxy)-7-(methylthio)pyrimido[4,5- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300 mg, 0.55 mmol) in THF/DCM = 1/1 (5 ml) Sulfonyl chloride (742 mg, 5.50 mmol) was added dropwise to the solution under nitrogen protection, and the reaction solution was stirred at 25°C for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO 3 (8 ml), extracted with DCM (50 ml), dried over Na 2 SO 4 and concentrated to give the crude product. It was then purified by column chromatography (SiO 2 , dichloromethane/methanol = 10/1) to obtain a yellow solid (216 mg, 74% yield). LCMS: m/z534.2(M+H).
步骤G.(1R,5S)-3-(7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)嘧啶并[4,5-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R,5S)-3-(7-氯-2-(((2R，7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)嘧啶并[4,5-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(130mg，0.24mmol，1当量)，((2-氟-6-(甲氧基甲醚)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(236mg,0.27mmol)，甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(18mg，0.02mmol)，磷酸钾(155mg，0.73mmol)，在THF/H2O＝4/1的溶液中氮气保护加热至60℃搅拌3小时。反应混合物用乙酸乙酯稀释并加水，乙酸乙酯萃取，有机相用饱和NaCl洗涤，经Na2SO4干燥，浓缩得到粗产物。然后通过柱色谱(SiO2，二氯甲烷/甲醇＝8/1)纯化得到黄色固体(70mg，33％收率)。LCMS:m/z 884.5(M+H)。Step G. (1R,5S)-3-(7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3, 8-Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(7-chloro-2-((2R,7aS)-2-fluorotetra Hydrogen-1H-pyridinyl-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-tert-butylcarboxylate (130mg, 0.24mmol, 1 equivalent), ((2-fluoro-6-(methoxymethyl ether)-8-(4,4,5,5-tetramethyl-1) ,3,2-Dioxaborane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (236mg, 0.27mmol), methanesulfonic acid [n-butyldi(1-adamantane) Phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (18 mg, 0.02 mmol), potassium phosphate (155 mg, 0.73 mmol), solution in THF/H 2 O = 4/1 Heat to 60°C under medium nitrogen atmosphere and stir for 3 hours. The reaction mixture was diluted with ethyl acetate and water was added, extracted with ethyl acetate, the organic phase was washed with saturated NaCl, dried over Na2SO4 , and concentrated to obtain the crude product . It was then purified by column chromatography (SiO 2 , dichloromethane/methanol = 8/1) to obtain a yellow solid (70 mg, 33% yield). LCMS: m/z 884.5(M+H).
步骤H.(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)-2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)嘧啶并[4,5-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R,5S)-3-(7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)嘧啶并[4,5-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(70mg，0.08mmol)、氟化铯(24mg，0.16mmol)在DMF(2mL)的溶液中。氮气环境下25℃搅拌1小时。反应混合物用乙酸乙酯稀释并加水，乙酸乙酯萃取，有机相用饱和NaCl洗涤，经Na2SO4干燥，浓缩得到粗产物。然后通过柱色谱(SiO2，二氯甲烷/甲醇＝8/1)纯化得到产物(50mg,89％收率)LCMS:m/z 728.3(M+H)。Step H. (1R,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethylether)naphthalen-1-yl)-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ] Octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl) Ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrimido[4,5-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70 mg, 0.08 mmol), cesium fluoride (24 mg, 0.16 mmol) in DMF ( 2mL) solution. Stir at 25°C for 1 hour under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and water was added, extracted with ethyl acetate, the organic phase was washed with saturated NaCl, dried over Na2SO4 , and concentrated to obtain the crude product . The product was then purified by column chromatography (SiO 2 , dichloromethane/methanol = 8/1) to obtain the product (50 mg, 89% yield) LCMS: m/z 728.3 (M+H).
步骤I.4-(5-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)嘧啶并[4,5-d]嘧啶-2-基)-5-乙炔基-6-氟萘-2-酚：将(1R,5S)-3-(7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基) -2-(((2R，7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)嘧啶并[4,5-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(50mg，0.07mmol)在二氯甲烷(2mL)中的溶液逐滴加入盐酸的1,4-dioxane溶液。室温搅拌1h。浓缩，将残余物倒入饱和NaHCO3、DCM和MeOH的混合物中。用DCM和MeOH萃取水层，合并的有机层用盐水洗涤，经Na2SO4干燥，过滤并真空浓缩。通过制备型HPLC(5-95％ACN/水/0.1％FA，经20min)纯化。将产品加入碳酸氢钠和DCM:MeOH(10:1)中萃取，有机相干燥浓缩，加入纯化水，冻干，得到实施例6(2.21mg，6％收率)。LCMS:m/z 584.3(M+H)。1H NMR(600MHz,DMSO-d6)δ9.34(s,1H),8.21(s,2H),7.97(dd,J＝9.2,5.8Hz,1H),7.46(t,J＝9.0Hz,1H),7.37(d,J＝2.5Hz,1H),7.28(d,J＝2.5Hz,1H),5.33(s,1H),5.25–5.23(m,1H),4.11(d,J＝10.4Hz,1H),4.03(d,J＝10.4Hz,1H),4.01(s,1H),3.64(s,3H),3.12–3.07(m,3H),3.03(s,1H),2.87–2.81(m,2H),2.63–2.60(m,1H),2.41–2.38(m,1H),2.13–2.10(m,1H),2.06(d,J＝3.2Hz,1H),2.00(dd,J＝11.8,6.5Hz,2H),1.87–1.84(m,1H),1.81–1.76(m,2H),1.70(s,3H)。Step I. 4-(5-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(((2R,7aS)-2-fluorotetrahydro -1H-Pyrrozine-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-2-yl)-5-ethynyl-6-fluoronaphthalen-2-ol: (1R ,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethylether)naphthalene-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrimido[4,5-d]pyrimidin-4-yl)-3 , A solution of tert-butyl 8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.07 mmol) in dichloromethane (2 mL) was added dropwise to a solution of 1,4-dioxane hydrochloric acid. Stir at room temperature for 1 hour. Concentrate and pour the residue into a mixture of saturated NaHCO3 , DCM and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and concentrated in vacuo. Purified by preparative HPLC (5-95% ACN/water/0.1% FA over 20 min). The product was added to sodium bicarbonate and DCM:MeOH (10:1) for extraction, the organic phase was dried and concentrated, purified water was added, and lyophilized to obtain Example 6 (2.21 mg, 6% yield). LCMS: m/z 584.3(M+H). 1 H NMR (600MHz, DMSO-d 6 ) δ9.34 (s, 1H), 8.21 (s, 2H), 7.97 (dd, J = 9.2, 5.8Hz, 1H), 7.46 (t, J = 9.0Hz, 1H),7.37(d,J＝2.5Hz,1H),7.28(d,J＝2.5Hz,1H),5.33(s,1H),5.25–5.23(m,1H),4.11(d,J＝10.4 Hz,1H),4.03(d,J＝10.4Hz,1H),4.01(s,1H),3.64(s,3H),3.12–3.07(m,3H),3.03(s,1H),2.87–2.81 (m,2H),2.63–2.60(m,1H),2.41–2.38(m,1H),2.13–2.10(m,1H),2.06(d,J＝3.2Hz,1H),2.00(dd,J ＝11.8,6.5Hz,2H),1.87–1.84(m,1H),1.81–1.76(m,2H),1.70(s,3H).
实施例7制备(S)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-((1-甲基吡咯烷-2-基)甲氧基)-4-(哌嗪-1-基)-1，6-萘-3-腈
Example 7 Preparation of (S)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methyl Oxy)-4-(piperazin-1-yl)-1,6-naphthalene-3-nitrile
步骤A.4-(7-氯-3-氰基-8-氟-2-羟基-1，6-萘-4-基)哌嗪-1-甲酸叔丁酯：将4，7-二氯-8-氟-2-氧代-1，2-二氢-1，6-萘啶-3-腈(460mg，1.8mmol)、哌嗪-1-甲酸叔丁酯(530.0mg，2.5mmol)在DMF(10mL)中的溶液加入DIEA(804.0mg，6.2mmol),80℃搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-5％MeOH/DCM洗脱,得到产物(380mg,0.7mmol,50％收率)LCMS:m/z 408.1(M+H)。 Step A. tert-Butyl 4-(7-chloro-3-cyano-8-fluoro-2-hydroxy-1,6-naphthyl-4-yl)piperazine-1-carboxylate: Add DIEA (804.0 mg, 6.2 mmol) to a solution of 4,7-dichloro-8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carbonitrile (460 mg, 1.8 mmol) and tert-butyl piperazine-1-carboxylate (530.0 mg, 2.5 mmol) in DMF (10 mL), and stir at 80°C for 2 h. The residue was partitioned between EtOAc and water and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2S04 , the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-5% MeOH/DCM to give the product (380 mg, 0.7 mmol, 50% yield) LCMS: m/z 408.1 (M+H).
步骤B.(S)-4-(7-氯-3-氰基-8-氟-2-((1-甲基吡咯烷-2-基)甲氧基)-1，6-萘-4-基)哌嗪-1-甲酸叔丁酯：将4-(7-氯-3-氰基-8-氟-2-羟基-1，6-萘-4-基)哌嗪-1-甲酸叔丁酯(380mg，0.7mmol)、N-甲基-L-脯氨醇(125.0mg，1.4mmol)、三苯基膦(473.0mg，1.8mmol)在四氢呋喃(10mL)中的溶液在0℃逐滴加入DIAD(545.0mg，2.7mmol),室温搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(300mg,0.6mmol,63％收率)LCMS:m/z 505.2(M+H)。Step B. (S)-4-(7-chloro-3-cyano-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthalene-4 -tert-butyl)piperazine-1-carboxylate: 4-(7-chloro-3-cyano-8-fluoro-2-hydroxy-1,6-naphthyl-4-yl)piperazine-1-carboxylic acid A solution of tert-butyl ester (380 mg, 0.7 mmol), N-methyl-L-prolinol (125.0 mg, 1.4 mmol), triphenylphosphine (473.0 mg, 1.8 mmol) in tetrahydrofuran (10 mL) at 0°C DIAD (545.0 mg, 2.7 mmol) was added dropwise and stirred at room temperature for 2 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluted with 0-10% MeOH/DCM to obtain the product (300 mg, 0.6 mmol, 63% yield) LCMS: m/z 505.2 (M+H).
步骤C.(S)-4-(3-氰基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-((1-甲基吡咯烷-2-基)甲氧基)-1，6-萘-4-基)哌嗪-1-甲酸叔丁酯：将(S)-4-(7-氯-3-氰基-8-氟-2-((1-甲基吡咯烷-2-基)甲氧基)-1，6-萘-4-基)哌嗪-1-甲酸叔丁酯(300.0mg，0.6mmol)、((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(369.0mg，0.7mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(44.0mg，0.06mmol)、磷酸钾(381.0mg，1.8mmol)在四氢呋喃(10mL)和水(1mL)中的溶液。氮气环境下65℃搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(200mg,0.22mmol,42％收率)LCMS:m/z 855.4(M+H)。Step C. (S)-4-(3-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl) Naphthyl-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphth-4-yl)piperazine-1-carboxylic acid tert-butyl ester: (S )-4-(7-chloro-3-cyano-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphth-4-yl)piperazine -1-tert-butylcarboxylate (300.0mg, 0.6mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3 , 2-Dioxaborane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (369.0mg, 0.7mmol), methanesulfonic acid [n-butyldi(1-adamantyl) )phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (44.0 mg, 0.06 mmol), potassium phosphate (381.0 mg, 1.8 mmol) in tetrahydrofuran (10 mL) and water (1 mL) solution. Stir at 65°C for 2 hours under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluted with 0-10% MeOH/DCM to obtain the product (200 mg, 0.22 mmol, 42% yield) LCMS: m/z 855.4 (M+H).
步骤D.(S)-4-(3-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)-8-氟-2-((1-甲基吡咯烷-2-基)甲氧基)-1，6-萘-4-基)哌嗪-1-甲酸叔丁酯：将(S)-4-(3-氰基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-((1-甲基吡咯烷-2-基)甲氧基)-1，6-萘-4-基)哌嗪-1-甲酸叔丁酯(200.0mg，0.25mmol)、氟化铯(131.0mg，0.9mmol)在DMF(10mL)中的溶液。氮气环境下室温搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(100mg,0.14mmol,68％收率)LCMS:m/z 699.3(M+H)。Step D. (S)-4-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalene-1-yl)-8-fluoro-2-( (1-methylpyrrolidin-2-yl)methoxy)-1,6-naphth-4-yl)piperazine-1-carboxylic acid tert-butyl ester: (S)-4-(3-cyano- 8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-methyl Pyrrolidin-2-yl)methoxy)-1,6-naphth-4-yl)piperazine-1-carboxylic acid tert-butyl ester (200.0 mg, 0.25 mmol), cesium fluoride (131.0 mg, 0.9 mmol) in Solution in DMF (10 mL). Stir at room temperature for 1 hour under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluted with 0-10% MeOH/DCM to obtain the product (100 mg, 0.14 mmol, 68% yield) LCMS: m/z 699.3 (M+H).
步骤E.(S)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-((1-甲基吡咯烷-2-基)甲氧基)-4-(哌嗪-1-基)-1，6-萘-3-腈：将(S)-4-(3-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)-8-氟-2-((1-甲基吡咯烷-2-基)甲氧基)-1，6-萘-4-基)哌嗪-1-甲酸叔丁酯(100.0mg，0.14mmol)在二氯甲烷(3mL)中的溶液逐滴加入盐酸的1,4-dioxane溶液。室温搅拌1h。浓缩，将残余物倒入饱和NaHCO3、DCM和MeOH的混合物中。用DCM和MeOH萃取水层，合并的有机层用盐水洗涤，经Na2SO4干燥，过滤并真空浓缩。通过制备型HPLC(5-95％ACN/水/0.1％FA，经20min)纯化。将产品加入碳酸氢钠、DCM和MeOH中萃取，有机相干燥浓缩，加入纯化水，冻干，得到实 施例7(36.4mg,0.06mmol,46％收率)。LCMS:m/z 555.2(M+H)。1H NMR(600MHz,DMSO-d6)δ10.30(s,1H),9.03(s,1H),7.98(dd,J＝9.2,5.8Hz,1H),7.47(t,J＝9.0Hz,1H),7.40(d,J＝2.6Hz,1H),7.22(t,J＝2.2Hz,1H),4.48(td,J＝10.8,5.0Hz,1H),4.38(ddd,J＝10.9,8.8,5.5Hz,1H),3.99(d,J＝3.4Hz,1H),3.84–3.78(m,2H),3.72–3.66(m,2H),3.05–2.99(m,2H),2.99–2.93(m,3H),2.67–2.61(m,1H),2.40(s,3H),2.23–2.19(m,1H),2.18(d,J＝9.4Hz,1H),1.99–1.93(m,1H),1.71–1.64(m,2H)。Step E. (S)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-1,6-naphthalen-3-carbonitrile: A solution of (S)-tert-butyl 4-(3-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-1,6-naphthalen-4-yl)piperazine-1-carboxylate (100.0 mg, 0.14 mmol) in dichloromethane (3 mL) was added dropwise to a solution of hydrochloric acid in 1,4-dioxane. Stir at room temperature for 1 h. Concentrate and pour the residue into a mixture of saturated NaHCO 3 , DCM and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and concentrated in vacuo. Purification was performed by preparative HPLC (5-95% ACN/water/0.1% FA over 20 min). The product was extracted with sodium bicarbonate, DCM and MeOH, the organic phase was dried and concentrated, purified water was added, and lyophilized to obtain the actual product. Example 7 (36.4 mg, 0.06 mmol, 46% yield). LCMS: m/z 555.2 (M+H). 1 H NMR (600 MHz, DMSO-d 6 ) δ 10.30 (s, 1H), 9.03 (s, 1H), 7.98 (dd, J = 9.2, 5.8 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 7.22 (t, J = 2.2 Hz, 1H), 4.48 (td, J = 10.8, 5.0 Hz, 1H), 4.38 (ddd, J = 10.9, 8.8, 5.5 Hz, 1H), 3.99 (d, J =3.4Hz, 1H), 3.84–3.78(m, 2H), 3.72–3.66(m, 2H), 3.05–2.99(m, 2H), 2.99–2.93(m, 3H), 2.67–2.61(m, 1H), 2.40(s, 3H), 2.23–2.19(m, 1H), 2.18(d, J=9.4Hz, 1H), 1.99–1.93(m, 1H), 1.71–1.64(m, 2H).
实施例8制备4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)-5-甲基吡啶[3,4-d]嘧啶-8(7H)-酮
Example 8 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H -Pyrrozine-7a(5H)-yl)methoxy)-7-(3-hydroxynaphth-1-yl)-5-methylpyridin[3,4-d]pyrimidin-8(7H)-one
反应式如下：
The reaction formula is as follows:
步骤A.6-羟基-2-(甲硫基)嘧啶-4-甲酸：向草酰乙酸二乙酯钠盐(2g，9.4mmol)和2-甲基-2-巯基硫酸脲(1.3g，9.4mmol)在H2O(20.0mL)中的溶液中添加NaOH(750mg，18.8mmol)。将混合物在室温下搅拌12小时。用4M HCl调节反应液pH至1.0左右，析出白色固体，抽滤，H2O洗涤滤饼，得到白色固体(500mg,2.69mmol，29％收率)，LCMS:m/z 187.2(M+H)。Step A. 6-Hydroxy-2-(methylthio)pyrimidine-4-carboxylic acid: To diethyl oxaloacetate sodium salt (2g, 9.4mmol) and 2-methyl-2-urea mercaptosulfate (1.3g, To a solution of 9.4 mmol) in H 2 O (20.0 mL) was added NaOH (750 mg, 18.8 mmol). The mixture was stirred at room temperature for 12 hours. Use 4M HCl to adjust the pH of the reaction solution to about 1.0, precipitate a white solid, filter it with suction, and wash the filter cake with H 2 O to obtain a white solid (500 mg, 2.69 mmol, 29% yield), LCMS: m/z 187.2 (M+H ).
步骤B.5-溴-6-羟基-2-(甲硫基)嘧啶-4-甲酸：向6-羟基-2-(甲硫基)嘧啶-4-甲酸(800mg，4.30mmol)的四氢呋喃(10mL)溶液中添加N-溴代丁二酰亚胺(1.14g，6.45mmol)。将混合物在40℃搅拌4小时。减压浓缩反应混合物，得到粗产物。乙酸乙酯打浆，抽滤，得到黄色固体(1.00g，3.79mmol，88％收率)，LCMS:m/z 264.9(M+H)。Step B. 5-Bromo-6-hydroxy-2-(methylthio)pyrimidine-4-carboxylic acid: To 6-hydroxy-2-(methylthio)pyrimidine-4-carboxylic acid (800 mg, 4.30 mmol) in tetrahydrofuran ( 10 mL) solution was added N-bromosuccinimide (1.14 g, 6.45 mmol). The mixture was stirred at 40°C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain crude product. Ethyl acetate was pulped and filtered to obtain a yellow solid (1.00g, 3.79mmol, 88% yield), LCMS: m/z 264.9 (M+H).
步骤C.N-烯丙基-5-溴-6-羟基-2-(甲硫基)嘧啶-4-甲酰胺：向5-溴-6-羟基-2-(甲硫基)嘧啶-4-甲酸(1.1g，4.17mmol)的二甲基甲酰胺(10.0mL)溶液中添加HATU(2.37g，6.25mmol)。将混合物在室温下搅拌0.5小时。随后向反应液中添加烯丙胺(587mg，6.25mmol)和N,N-二异丙基乙胺(1.61g， 12.50mmol)。将混合物在室温下搅拌3小时。用稀盐酸调节反应液pH至6左右，并用乙酸乙酯萃取。合并的有机层用盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩，得到粗产物。通过柱色谱纯化残余物(SiO2，石油醚:乙酸乙酯＝1:1至0:1)，得到为白色固体(650.0mg，2.13mmol，51％收率)，LCMS:m/z463.2(M+H)。Step CN-allyl-5-bromo-6-hydroxy-2-(methylthio)pyrimidine-4-carboxamide: to 5-bromo-6-hydroxy-2-(methylthio)pyrimidine-4-carboxylic acid To a solution of (1.1 g, 4.17 mmol) in dimethylformamide (10.0 mL) was added HATU (2.37 g, 6.25 mmol). The mixture was stirred at room temperature for 0.5 hours. Allylamine (587mg, 6.25mmol) and N,N-diisopropylethylamine (1.61g, 12.50mmol). The mixture was stirred at room temperature for 3 hours. Adjust the pH of the reaction solution to about 6 with dilute hydrochloric acid, and extract with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether: ethyl acetate = 1:1 to 0:1) to obtain a white solid (650.0 mg, 2.13 mmol, 51% yield), LCMS: m/z 463.2 (M+H).
步骤D.(1R,5S)-3-(6-(烯丙基氨甲酰基)-5-溴-2-(甲硫基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：向N-烯丙基-5-溴-6-羟基-2-(甲硫基)嘧啶-4-甲酰胺(200mg，0.65mmol)的乙腈(10.0mL)溶液中添加1H-苯并三唑-1-氧基三(1-吡咯烷基)膦六氟磷酸盐(PyBop)(512mg，0.98mmol)。将混合物在室温下搅拌5分钟。随后向反应液中添加3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(208mg，0.98mmol)和DIEA(256mg，1.97mmol)。将混合物在室温下搅拌1小时。将反应混合物用水稀释并用乙酸乙酯萃取。合并的有机层用盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩，得到粗产物。通过柱色谱纯化残余物(SiO2，二氯甲烷:甲醇＝20:1)，得到白色固体(250.0mg，0.50mmol，77％收率)，LCMS:m/z 498.2(M+H)。Step D. tert-Butyl (1R,5S)-3-(6-(allylcarbamoyl)-5-bromo-2-(methylthio)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a solution of N-allyl-5-bromo-6-hydroxy-2-(methylthio)pyrimidine-4-carboxamide (200 mg, 0.65 mmol) in acetonitrile (10.0 mL) was added 1H-benzotriazole-1-oxytris(1-pyrrolidinyl)phosphine hexafluorophosphate (PyBop) (512 mg, 0.98 mmol). The mixture was stirred at room temperature for 5 minutes. Subsequently, tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (208 mg, 0.98 mmol) and DIEA (256 mg, 1.97 mmol) were added to the reaction solution. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (SiO 2 , dichloromethane:methanol=20:1) to give a white solid (250.0 mg, 0.50 mmol, 77% yield), LCMS: m/z 498.2 (M+H).
步骤E.3-(5-甲基-2-(甲硫基)-8-氧代-7，8-二氢吡啶酮并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：将(1R,5S)-3-(6-(烯丙基氨甲酰基)-5-溴-2-(甲硫基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(1g，2.00mmol)、N,N-二异丙基乙胺(648mg，5.02mmol)和反式-双[邻(二邻甲苯基膦)苄基]二乙酸二钯(Ⅱ)(188mg，0.20mmol)的N,N-二甲基苯胺(4.00mL)溶液在氮气气氛下于150℃搅拌3小时。将反应混合物用水稀释并用二氯甲烷萃取。合并的有机层用盐水洗涤，干燥，过滤并减压浓缩，得到粗产物。通过制备型TLC纯化(SiO2，二氯甲烷:甲醇＝10:1)，得到黄色固体(200.0mg，0.478mmol，24％收率),LCMS:m/z 418.2(M+H)。Step E. 3-(5-Methyl-2-(methylthio)-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(6-(allylcarbamoyl)-5-bromo-2-(methylthio) (1g, 2.00mmol), N,N-diisopropylethylamine (648mg) , 5.02mmol) and a solution of trans-bis[o-(di-o-tolylphosphine)benzyl]dipalladium(II)diacetate (188mg, 0.20mmol) in N,N-dimethylaniline (4.00mL) under nitrogen Stir at 150°C for 3 hours under atmosphere. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give crude product. Purification by preparative TLC (SiO 2 , dichloromethane:methanol=10:1) gave a yellow solid (200.0 mg, 0.478 mmol, 24% yield), LCMS: m/z 418.2 (M+H).
步骤F.3-(7-(3-(甲氧基甲氧基)萘-1-基)-5-甲基-2-(甲硫基)-8-氧代-7，8-二氢吡啶酮并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：将3-(5-甲基-2-(甲硫基)-8-氧代-7，8-二氢吡啶酮并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(260mg，0.622mmol)、(3-(甲氧基甲氧基)萘-1-基)硼酸(226mg，1.244mmol)、吡啶(492mg，6.22mmol)和醋酸铜(169mg，0.93mmol)的二氯甲烷(4.00mL)溶液在氧气气氛下于室温搅拌12小时。将反应混合物用水稀释并用二氯甲烷萃取。合并的有机层用盐水洗涤，干燥，过滤并减压浓缩，得到粗产物。通过制备型TLC纯化(SiO2，二氯甲烷:甲醇＝10:1)，得到黄色固体(170.0mg，281mmol，45％收率)，LCMS:m/z 604.2(M+H)。Step F. 3-(7-(3-(methoxymethoxy)naphthalen-1-yl)-5-methyl-2-(methylthio)-8-oxo-7,8-dihydro Pyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: convert 3-(5-methyl-2 -(Methylthio)-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-tert-butylcarboxylate (260mg, 0.622mmol), (3-(methoxymethoxy)naphthalen-1-yl)boronic acid (226mg, 1.244mmol), pyridine (492mg, 6.22mmol) and copper acetate ( A solution of 169 mg, 0.93 mmol) in dichloromethane (4.00 mL) was stirred at room temperature under an oxygen atmosphere for 12 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to give crude product. Purification by preparative TLC (SiO 2 , dichloromethane:methanol=10:1) gave a yellow solid (170.0 mg, 281 mmol, 45% yield), LCMS: m/z 604.2 (M+H).
步骤G.3-(2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-3-(甲氧基甲氧基)萘-1-基)5-甲基-8-氧代-7，8-二氢吡啶酮并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：在-40℃下向3-(7-(3-(甲氧基甲氧基)萘-1-基)-5-甲基-2-(甲硫基)-8-氧代-7，8-二氢吡啶酮并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(140mg，0.232mmol)的二氯甲烷(2.0ml)溶液中添加3-氯过氧苯甲酸(44mg，0.255 mmol)。将溶液搅拌1小时。将反应物真空浓缩,用乙酸乙酯与饱和碳酸氢钠水溶液萃取，收集有机相并浓缩得到中间体粗品。向中间体在1,4-二氧六环(2.0mL)中的溶液中添加((2R,8S)-2-氟-1,2,3,4,5,6,7-六氢吡咯嗪-7-基)甲醇(74mg，0.467mmol)和N,N-二异丙基乙胺(90mg，0.695mmol)。将混合物在90℃下搅拌3小时。将反应混合物用水稀释并用乙酸乙酯萃取。合并的有机层用盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩，得到粗产物。通过柱色谱纯化(SiO2，二氯甲烷:甲醇＝10:1)，得到白色固体(130.0mg，0.18mmol，78％收率)，LCMS:m/z 358.2(M/2+H)。Step G. 3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-3-(methoxymethoxy )naphth-1-yl)5-methyl-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2 .1] Octane-8-carboxylic acid tert-butyl ester: at -40°C to 3-(7-(3-(methoxymethoxy)naphthyl-1-yl)-5-methyl-2-( Methylthio)-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8 -To a solution of tert-butyl formate (140 mg, 0.232 mmol) in dichloromethane (2.0 ml), 3-chloroperoxybenzoic acid (44 mg, 0.255 mmol). The solution was stirred for 1 hour. The reaction was concentrated in vacuo, extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic phase was collected and concentrated to obtain a crude intermediate. To a solution of the intermediate in 1,4-dioxane (2.0 mL) was added ((2R,8S)-2-fluoro-1,2,3,4,5,6,7-hexahydropyrrozine -7-yl)methanol (74 mg, 0.467 mmol) and N,N-diisopropylethylamine (90 mg, 0.695 mmol). The mixture was stirred at 90°C for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. Purification by column chromatography (SiO 2 , dichloromethane:methanol=10:1) gave a white solid (130.0 mg, 0.18 mmol, 78% yield), LCMS: m/z 358.2 (M/2+H).
步骤H.4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-(3-羟基萘-1-基)-5-甲基吡啶[3,4-d]嘧啶-8(7H)-酮：向3-(2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-7-3-(甲氧基甲氧基)萘-1-基)5-甲基-8-氧代-7，8-二氢吡啶酮并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(130mg，0.182mmol)的乙腈(5.0mL)溶液中添加盐酸的二氧六环溶液(4M,1.0mL)并将反应物在室温搅拌1小时。将反应物真空浓缩,用乙酸乙酯与饱和碳酸氢钠水溶液萃取，收集有机相并浓缩得到粗品。将粗品通过反相制备型HPLC纯化，得到实施例8为含两个甲酸的盐(50mg，0.088mmol，48％收率)，LCMS:m/z 571.3(M+H)。1H NMR(600MHz,DMSO-d6)δ8.26(s,2H),7.83(d,J＝8.3Hz,1H),7.47(ddd,J＝8.1,6.2,1.6Hz,1H),7.29(q,J＝6.7,5.1Hz,3H),7.13(t,J＝2.1Hz,1H),7.04(s,1H),5.34–5.20(m,1H),4.20–4.02(m,2H),4.10(dd,J＝10.3,3.7Hz,2H),4.00(dd,J＝10.3,2.3Hz,2H),3.63–3.53(m,2H),3.14–3.07(m,2H),3.04(s,1H),2.87–2.81(m,1H),2.18–2.10(m,4H),2.08–2.05(m,1H),2.03–1.97(m,1H),1.88–1.83(m,1H),1.81–1.73(m,2H),1.70–1.43(m,4H)。Step H.4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrozine-7a(5H)-yl)methoxy)-7-(3-hydroxynaphth-1-yl)-5-methylpyridin[3,4-d]pyrimidin-8(7H)-one: to 3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-3-(methoxymethoxy)naphthalene- 1-yl)5-methyl-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] To a solution of tert-butyl octane-8-carboxylate (130 mg, 0.182 mmol) in acetonitrile (5.0 mL) was added hydrochloric acid in dioxane (4 M, 1.0 mL) and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo, extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic phase was collected and concentrated to obtain crude product. The crude product was purified by reverse phase preparative HPLC to obtain Example 8 as a salt containing two formic acids (50 mg, 0.088 mmol, 48% yield), LCMS: m/z 571.3 (M+H). 1 H NMR (600MHz, DMSO-d 6 ) δ8.26 (s, 2H), 7.83 (d, J = 8.3 Hz, 1H), 7.47 (ddd, J = 8.1, 6.2, 1.6 Hz, 1H), 7.29 ( q,J＝6.7,5.1Hz,3H),7.13(t,J＝2.1Hz,1H),7.04(s,1H),5.34–5.20(m,1H),4.20–4.02(m,2H),4.10 (dd,J＝10.3,3.7Hz,2H),4.00(dd,J＝10.3,2.3Hz,2H),3.63–3.53(m,2H),3.14–3.07(m,2H),3.04(s,1H ),2.87–2.81(m,1H),2.18–2.10(m,4H),2.08–2.05(m,1H),2.03–1.97(m,1H),1.88–1.83(m,1H),1.81–1.73 (m,2H),1.70–1.43(m,4H).
实施例9制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 9 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- Fluoronaphth-2-phenol
反应式如下：
The reaction formula is as follows:
步骤A.5,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇：此中间体可以参照专利WO2022042630中的方法以4-胺基-2,6-二氯吡啶制备。Step A. 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol: This intermediate can be prepared from 4-amine according to the method in patent WO2022042630 Preparation of base-2,6-dichloropyridine.
步骤B.(1R,5S)-3-(5，7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：将5,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇(5.0g，17.8mmol)在乙腈(50mL)中的溶液加入三氯氧磷(4.0g，26.7mmol)和DIEA(4.6g，35.6mmol)在80℃搅拌2h。在0℃下向反应液中加入DIEA(4.6g，35.6mmol)和3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(5.6g，26.7mmol)。室温搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-20％乙酸乙酯/石油醚洗脱,得到产物(5.0g,10.5mmol,59％收率)LCMS:m/z 474.1(M+H)。Step B. (1R,5S)-3-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine-4 - A solution of alcohol (5.0g, 17.8mmol) in acetonitrile (50mL) was added with phosphorus oxychloride (4.0g, 26.7mmol) and DIEA (4.6g, 35.6mmol) and stirred at 80°C for 2h. DIEA (4.6g, 35.6mmol) and 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (5.6g, 26.7mmol) were added to the reaction solution at 0°C. Stir at room temperature for 1 hour. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluting with 0-20% ethyl acetate/petroleum ether, the product (5.0g, 10.5mmol, 59% yield) was obtained. LCMS: m/z 474.1 (M+H).
步骤C.(1R,5S)-3-(7-氯-8-氟-5-甲基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R,5S)-3-(5，7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(5.0g，17.8mmol)、甲基硼酸(2.6g，44.5mmol)、Pd(dppf)Cl2(1.3g，1.8mmol)、磷酸钾(11.3g，53.4mmol)在甲苯(80mL)和水(8mL)中的溶液。氮气环境下105℃搅拌12h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％乙酸乙酯/石油醚洗脱,得到产物(2.0g,4.4mmol,25％收率)LCMS:m/z 454.1(M+H)。Step C. (1R,5S)-3-(7-chloro-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: A solution of (1R,5S)-3-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (5.0 g, 17.8 mmol), methylboronic acid (2.6 g, 44.5 mmol), Pd(dppf) Cl2 (1.3 g, 1.8 mmol), potassium phosphate (11.3 g, 53.4 mmol) in toluene (80 mL) and water (8 mL) was stirred at 105°C under nitrogen for 12 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl , dried over Na2S04 , the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% ethyl acetate in petroleum ether to give the product (2.0 g, 4.4 mmol, 25% yield) LCMS: m/z 454.1 (M+H).
步骤D.(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-5-甲基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R,5S)-3-(7-氯-8-氟-5-甲基-2- (甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(2.0g，4.4mmol)、((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(2.9g，5.7mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(320.0mg，0.44mmol)、磷酸钾(2.8g，13.2mmol)在四氢呋喃(10mL)和水(1mL)中的溶液。氮气环境下65℃搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(2.2g,2.7mmol,63％收率)。Step D. (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Tert-butyl carboxylate: (1R,5S)-3-(7-chloro-8-fluoro-5-methyl-2- (Methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.0g, 4.4mmol ), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl )Naphthalen-1-yl)ethynyl)triisopropylsilane (2.9g, 5.7mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'- A solution of biphenyl-2-yl)palladium (320.0 mg, 0.44 mmol), potassium phosphate (2.8 g, 13.2 mmol) in tetrahydrofuran (10 mL) and water (1 mL). Stir at 65°C for 2 hours under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluting with 0-10% MeOH/DCM, the product (2.2g, 2.7mmol, 63% yield) was obtained.
步骤E.(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-5-甲酰基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-5-甲基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(2.2g，2.7mmol)在1,4-dioxane(15mL)中的溶液加入二氧化硒(594.0mg，5.4mmol)。氮气环境下105℃搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-30％乙酸乙酯/石油醚洗脱,得到产物(2.2g,2.4mmol,91％收率)。Step E. (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-5-formyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Tert-butyl carboxylate: (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether))-8-((triisopropylsilyl)ethynyl) )naphth-1-yl)-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane To a solution of tert-butyl alkane-8-carboxylate (2.2 g, 2.7 mmol) in 1,4-dioxane (15 mL) was added selenium dioxide (594.0 mg, 5.4 mmol). Stir at 105°C for 1 hour under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluting with 0-30% ethyl acetate/petroleum ether, the product (2.2g, 2.4mmol, 91% yield) was obtained.
步骤F.(1R,5S)-3-(5-乙炔基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R,5S)-3-(8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-5-甲酰基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(2.2g，2.7mmol)在MeOH(15mL)中的溶液加入碳酸铯(1.7g，5.4mmol)、(1-重氮基-2-氧代丙基)膦酸二甲酯(1.0g，5.4mmol)室温搅拌1h。使残余物在二氯甲烷与水之间分配,并用二氯甲烷萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，干燥装载到硅胶上并通过快速柱色谱纯化，用0-30％乙酸乙酯/石油醚洗脱，得到产物(1.3g,1.5mmol,59％收率)。Step F. (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether))-8-((triisopropylsilyl)acetylene yl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Tert-butyl carboxylate: (1R,5S)-3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether))-8-((triisopropylsilyl)ethynyl) )naphth-1-yl)-5-formyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane To a solution of alkane-8-carboxylic acid tert-butyl ester (2.2g, 2.7mmol) in MeOH (15mL) was added cesium carbonate (1.7g, 5.4mmol), (1-diazo-2-oxopropyl)phosphine Acid dimethyl ester (1.0g, 5.4mmol) was stirred at room temperature for 1 h. The residue was partitioned between dichloromethane and water, and the aqueous layer was extracted with dichloromethane and the organic phase was washed with saturated NaCl, dried over Na2SO4 , dried onto silica gel and purified by flash column chromatography with 0 - Elution with 30% ethyl acetate/petroleum ether gave the product (1.3 g, 1.5 mmol, 59% yield).
步骤G.(1R,5S)-3-(5-乙炔基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(甲基亚砜基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R,5S)-3-(5-乙炔基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.3g，1.5mmol)在DCM(10mL)中的溶液加入间氯过氧苯甲酸(387.0mg，2.2mmol)室温搅拌1h。加入硫代硫酸钠水溶液淬灭，使残余物在二氯甲烷与碳酸氢钠水溶液之间分配,并用二氯甲烷萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，浓缩，得到粗品可直接用于下一步。LCMS:m/z 830.4(M+H)。Step G. (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether))-8-((triisopropylsilyl)acetylene (yl)naphth-1-yl)-2-(methylsulfoxide)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-tert-butylcarboxylate: (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(triiso Propylsilyl)ethynyl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ] A solution of tert-butyl octane-8-carboxylate (1.3g, 1.5mmol) in DCM (10mL) was added with m-chloroperoxybenzoic acid (387.0mg, 2.2mmol) and stirred at room temperature for 1 h. Aqueous sodium thiosulfate solution was added to quench, the residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution, and the aqueous layer was extracted with dichloromethane and the organic phase was washed with saturated NaCl, dried over Na2SO4 , and concentrated , The crude product can be used directly in the next step. LCMS: m/z 830.4(M+H).
步骤H.(1R,5S)-3-(5-乙炔基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a (5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R,5S)-3-(5-乙炔基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(甲基亚砜基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.5g，1.5mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基-甲醇(131.0mg，0.9mmol)在THF(10mL)中的溶液。氮气环境下0℃逐滴加入LiHMDS(3.0ml,3.0mmol)搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(800.0mg,0.86mmol,57％收率)，LCMS:m/z 925.5(M+H)。Step H. (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)acetylene) base)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine ring-7a (5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3-(methoxymethylether)-8-((triisopropylsilyl)ethynyl) Naphthyl-1-yl)-2-(methylsulfoxide)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Tert-butyl carboxylate (1.5g, 1.5mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-yl-methanol (131.0mg, 0.9 mmol) in THF (10 mL). LiHMDS (3.0 ml, 3.0 mmol) was added dropwise at 0°C under nitrogen atmosphere and stirred for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluted with 0-10% MeOH/DCM to obtain the product (800.0 mg, 0.86 mmol, 57% yield), LCMS: m/z 925.5 (M+H).
步骤I.(1R,5S)-3-(5-乙炔基-7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯：将(1R,5S)-3-(5-乙炔基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(800.0mg，0.86mmol)、氟化铯(498.0mg，3.3mmol)在DMF(10mL)中的溶液。氮气环境下室温搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(540mg,0.70mmol,82％收率)LCMS:m/z 769.3(M+H)。Step I. (1R,5S)-3-(5-ethynyl-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(5-ethynyl-8-fluoro-7-(7-fluoro-3 A solution of tert-butyl-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800.0 mg, 0.86 mmol) and cesium fluoride (498.0 mg, 3.3 mmol) in DMF (10 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The residue was partitioned between EtOAc and water and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2S04 , the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% MeOH/DCM to give the product (540 mg, 0.70 mmol, 82% yield) LCMS: m/z 769.3 (M+H).
步骤J.4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡呤环)-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚：将(1R,5S)-3-(5-乙炔基-7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(80.0mg，0.10mmol)在二氯甲烷(3mL)中的溶液逐滴加入三氟乙酸(0.5ml)。室温搅拌20min。浓缩，将残余物倒入饱和NaHCO3、DCM和MeOH的混合物中。用DCM和MeOH萃取水层，合并的有机层用盐水洗涤，经Na2SO4干燥，过滤并真空浓缩。然后通过制备型HPLC(5-95％ACN/水/0.1％FA，经20min)纯化。冻干，得到实施例9为含一个甲酸的盐(6.72mg,0.01mmol,10％收率)。LCMS:m/z 625.2(M+H)。1HNMR(600MHz,Methanol-d4)δ8.52(s,1H),7.89(dd,J＝9.1,5.6Hz,1H),7.41–7.33(m,2H),7.24(t,J＝2.5Hz,1H),5.45–5.34(m,1H),4.63–4.58(m,3H),4.44(dd,J＝11.0,5.5Hz,1H),4.38(dd,J＝10.9,5.5Hz,1H),3.84–3.74(m,3H),3.46–3.38(m,2H),3.23–3.11(m,2H),2.45(d,J＝15.9Hz,1H),2.42–2.29(m,2H),2.26–2.18(m,1H),2.16–2.08(m,2H),2.03–1.96(m,2H),1.91–1.82(m,2H),1.71–1.60(m,1H),1.37–1.26(m,1H)。Step J. 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyridine ring)-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluoronaphthalen-2-phenol: (1R,5S)-3-(5-ethynyl-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalene-1-yl) -8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4 To a solution of -3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (80.0 mg, 0.10 mmol) in dichloromethane (3 mL), trifluoroacetic acid was added dropwise (0.5ml). Stir at room temperature for 20 minutes. Concentrate and pour the residue into a mixture of saturated NaHCO3 , DCM and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and concentrated in vacuo. It was then purified by preparative HPLC (5-95% ACN/water/0.1% FA over 20 min). After freeze-drying, Example 9 was obtained as a salt containing a formic acid (6.72 mg, 0.01 mmol, 10% yield). LCMS: m/z 625.2(M+H). 1 HNMR (600MHz, Methanol-d 4 ) δ8.52 (s, 1H), 7.89 (dd, J = 9.1, 5.6Hz, 1H), 7.41–7.33 (m, 2H), 7.24 (t, J = 2.5Hz ,1H),5.45–5.34(m,1H),4.63–4.58(m,3H),4.44(dd,J＝11.0,5.5Hz,1H),4.38(dd,J＝10.9,5.5Hz,1H), 3.84–3.74(m,3H),3.46–3.38(m,2H),3.23–3.11(m,2H),2.45(d,J＝15.9Hz,1H),2.42–2.29(m,2H),2.26– 2.18(m,1H),2.16–2.08(m,2H),2.03–1.96(m,2H),1.91–1.82(m,2H),1.71–1.60(m,1H),1.37–1.26(m,1H ).
实施例10制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基 -8-氟-2-(((R)-1-甲基吡咯烷-2-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 10 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl -8-Fluoro-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Fluoronaphen-2-phenol
用N-甲基-D-脯氨醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，根据实施例9步骤H-J进行合成得到实施例10为含一个甲酸的盐(10.4mg,0.01mmol,10％收率)。LCMS:m/z 581.2(M+H)。1H NMR(400MHz,DMSO-d6)δ8.20(s,1H),7.99(dd,J＝9.2,5.9Hz,1H),7.48(t,J＝9.0Hz,1H),7.40(d,J＝2.6Hz,1H),7.22(d,J＝2.5Hz,1H),4.75(s,1H),4.40(dd,J＝10.7,4.9Hz,1H),4.20(dd,J＝10.8,6.3Hz,1H),3.80(s,1H),3.56–3.44(m,5H),2.96(dt,J＝8.9,4.3Hz,2H),2.60(dd,J＝8.5,5.3Hz,1H),2.38(d,J＝5.5Hz,1H),2.36(s,3H),2.19(q,J＝8.6Hz,1H),1.99–1.89(m,1H),1.74–1.51(m,6H)。Use N-methyl-D-prolinol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol according to Example 9 step HJ The synthesis was carried out to obtain Example 10 as a salt containing a formic acid (10.4 mg, 0.01 mmol, 10% yield). LCMS: m/z 581.2(M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.20 (s, 1H), 7.99 (dd, J = 9.2, 5.9Hz, 1H), 7.48 (t, J = 9.0Hz, 1H), 7.40 (d, J＝2.6Hz,1H),7.22(d,J＝2.5Hz,1H),4.75(s,1H),4.40(dd,J＝10.7,4.9Hz,1H),4.20(dd,J＝10.8,6.3 Hz,1H),3.80(s,1H),3.56–3.44(m,5H),2.96(dt,J＝8.9,4.3Hz,2H),2.60(dd,J＝8.5,5.3Hz,1H),2.38 (d,J＝5.5Hz,1H),2.36(s,3H),2.19(q,J＝8.6Hz,1H),1.99–1.89(m,1H),1.74–1.51(m,6H).
实施例11制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 11 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((( S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol
用N-甲基-L-脯氨醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，根据实施例9步骤H-J进行合成实施例11为含一个甲酸的盐(4.75mg,7％收率)。LCMS:m/z 581.2(M+H)。1H NMR(400MHz,DMSO-d6)δ8.26(s,1H),7.99(dd,J＝9.3,5.9Hz,1H),7.47(t,J＝9.0Hz,1H),7.42–7.39(m,1H),7.23(d,J＝2.6Hz,1H),4.75(s,1H),4.40(dd,J＝11.2,4.7Hz,1H),4.20(dd,J＝10.8,6.2Hz,1H),3.38–3.24(m,2H),3.80(s,1H),2.95(dt,J＝8.9,4.3Hz,2H),2.59(t,J＝7.0Hz,1H),2.38(d,J＝4.0Hz,1H),2.36(s,3H),2.28–2.14(m,2H),2.00–1.88(m,2H),1.74–1.51(m,7H)。Use N-methyl-L-prolinol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol according to Example 9 step HJ The synthesis of Example 11 was carried out as a salt containing a formic acid (4.75 mg, 7% yield). LCMS: m/z 581.2(M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.26 (s, 1H), 7.99 (dd, J = 9.3, 5.9Hz, 1H), 7.47 (t, J = 9.0Hz, 1H), 7.42–7.39 ( m,1H),7.23(d,J＝2.6Hz,1H),4.75(s,1H),4.40(dd,J＝11.2,4.7Hz,1H),4.20(dd,J＝10.8,6.2Hz,1H ),3.38–3.24(m,2H),3.80(s,1H),2.95(dt,J＝8.9,4.3Hz,2H),2.59(t,J＝7.0Hz,1H),2.38(d,J＝ 4.0Hz,1H),2.36(s,3H),2.28–2.14(m,2H),2.00–1.88(m,2H),1.74–1.51(m,7H).
实施例12制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 12 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-(tetra Hydrogen-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-phenol
用(六氢-1H-吡咯嗪-7a-基)甲醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，根据实施例9步骤H-J进行合成(3.3mg,0.01mmol,10％收率)。LCMS:m/z 606.3(M+H)。1H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.07(dd,J＝9.2,5.6Hz,1H),6.57–6.50(m,2H),6.42(d,J＝2.6Hz,1H),4.08–4.01(m,4H),3.82–3.77(m,2H),2.88–2.77(m,4H),2.73–2.63(m,2H),2.42(dd,J＝11.8,6.1Hz,2H),1.49(dt,J＝11.4,5.2Hz,2H),1.43–1.21(m,7H),1.11(dd,J＝11.5,5.3Hz,1H),1.03–0.95(m,2H)。Use (hexahydro-1H-pyrrolizin-7a-yl)methanol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol, according to the implementation Example 9 step HJ was synthesized (3.3 mg, 0.01 mmol, 10% yield). LCMS: m/z 606.3(M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.72 (s, 1H), 7.07 (dd, J = 9.2, 5.6 Hz, 1H), 6.57–6.50 (m, 2H), 6.42 (d, J = 2.6 Hz,1H),4.08–4.01(m,4H),3.82–3.77(m,2H),2.88–2.77(m,4H),2.73–2.63(m,2H),2.42(dd,J＝11.8,6.1 Hz,2H),1.49(dt,J＝11.4,5.2Hz,2H),1.43–1.21(m,7H),1.11(dd,J＝11.5,5.3Hz,1H),1.03–0.95(m,2H) .
实施例13制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-8-基)-5-乙炔基-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 13 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-5-ethynyl-8-fluoro-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- Fluoronaphth-2-phenol
步骤A.(1R,5S)-8-(5，7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯：用3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯代替3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯按到实施例9的步骤B合成，LCMS:m/z 474.1(M+H)。Step A. (1R,5S)-8-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester: Use 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester instead of 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester. Bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was synthesized according to step B of Example 9, LCMS: m/z 474.1 (M+H).
以(1R,5S)-8-(5，7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯为原料，按到实施例9的步骤C-J合成实施例13为含一个甲酸的盐(4.75mg,7％收率)。LCMS:m/z 625.2(M+H)。1H NMR(400MHz,Methanol-d4)δ8.54(s,1H),7.88(dd,J＝9.2,5.7Hz,1H),7.39–7.36(m,1H),7.33(d,J＝9.0Hz,1H),7.26(d,J＝2.6Hz,1H),5.46–5.28(m,1H),4.95(d,J＝20.1Hz,2H),4.44–4.38(m,1H),4.34(d,J＝10.9Hz,1H),3.69–3.56(m,2H),3.52–3.44(m,1H),3.20–3.02(m,3H),2.84(d,J＝13.5Hz,2H),2.31(dd,J＝24.2,14.7Hz,5H),2.24–1.91(m,7H)。 (1R,5S)-8-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diaza Heterobicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester was used as the raw material, and the step CJ of Example 9 was followed to synthesize Example 13 into a salt containing a formic acid (4.75 mg, 7% yield). LCMS: m/z 625.2(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.54 (s, 1H), 7.88 (dd, J = 9.2, 5.7Hz, 1H), 7.39–7.36 (m, 1H), 7.33 (d, J = 9.0 Hz,1H),7.26(d,J＝2.6Hz,1H),5.46–5.28(m,1H),4.95(d,J＝20.1Hz,2H),4.44–4.38(m,1H),4.34(d ,J＝10.9Hz,1H),3.69–3.56(m,2H),3.52–3.44(m,1H),3.20–3.02(m,3H),2.84(d,J＝13.5Hz,2H),2.31( dd,J＝24.2,14.7Hz,5H),2.24–1.91(m,7H).
实施例14制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-8-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5-腈
Example 14 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-7-(8-ethynyl-7-fluoro-3- Hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3 -d]pyrimidine-5-nitrile
反应式如下：
The reaction formula is as follows:
步骤A.(1R,5S)-8-(8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-5-甲酰基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯：以(1R,5S)-8-(5，7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯为原料，按照实施例9的步骤C-E合成，LCMS:m/z 818.4(M+H)。Step A. (1R,5S)-8-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-5-formyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3- Tert-butyl formate: (1R,5S)-8-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3 , 8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester was used as raw material, and was synthesized according to steps C-E of Example 9, LCMS: m/z 818.4 (M+H).
步骤B.(1R,5S)-8-(8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-5-((E)-(羟基亚胺)甲基)-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯：向(1R,5S)-8-(8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-5-甲酰基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯(20mg，0.024mmol)的二甲基亚砜(0.5ml)溶液中加入三乙胺(5mg，0.049mmol)，盐酸羟胺(2mg，0.032mmol)加热至110℃搅拌1小时。反应液不做后处理即用与下一步。Step B. (1R,5S)-8-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-5-((E)-(hydroxyimine)methyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diaza Bicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester: to (1R,5S)-8-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-( (Triisopropylsilyl)ethynyl)naphthalen-1-yl)-5-formyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8- To a solution of diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (20mg, 0.024mmol) in dimethyl sulfoxide (0.5ml) was added triethylamine (5mg, 0.049mmol), hydroxylamine hydrochloride ( 2 mg, 0.032 mmol), heated to 110°C and stirred for 1 hour. The reaction solution was used in the next step without post-treatment.
步骤C.(1R,5S)-8-(5-氰基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三 异丙基硅基)乙炔基)萘-1-基)-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯：往上一步反应液中加入乙酸酐(4mg，0.037mmol)，碳酸钾(7mg，0.048mmol)并加热至55℃搅拌1小时。将反应混合物用乙酸乙酯稀释并加水，用乙酸乙酯萃取，经Na2SO4干燥，浓缩得到粗品。不做进一步纯化及即用于下一步。Step C. (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(tri Isopropylsilyl)ethynyl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2. 1] Octane-3-carboxylic acid tert-butyl ester: Add acetic anhydride (4 mg, 0.037 mmol) and potassium carbonate (7 mg, 0.048 mmol) to the reaction solution in the previous step and heat to 55°C and stir for 1 hour. The reaction mixture was diluted with ethyl acetate and water was added, extracted with ethyl acetate, dried over Na2SO4 , and concentrated to give a crude product. It was used in the next step without further purification.
步骤D.(1R,5S)-8-(5-氰基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(甲基亚砜基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯：向(1R,5S)-8-(5-氰基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯(20mg，0.024mmol)的二氯甲烷溶液(2ml)中加入间氯过氧苯甲酸(5mg，0.032mmol)在25℃中搅拌2小时。饱和硫代硫酸钠水溶液淬灭反应液，并用二氯甲烷(50ml)和碳酸钠水溶液萃取，经Na2SO4干燥，过滤后浓缩，得到粗品不做纯化即用于下一步。Step D. (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether))-8-(triisopropylsilyl)acetylene (yl)naphth-1-yl)-2-(methylsulfoxide)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 3-tert-butylcarboxylate: (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(triisopropyl Silyl)ethynyl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] To a dichloromethane solution (2 ml) of octane-3-carboxylic acid tert-butyl ester (20 mg, 0.024 mmol) was added m-chloroperoxybenzoic acid (5 mg, 0.032 mmol), and the mixture was stirred at 25°C for 2 hours. The reaction solution was quenched with saturated sodium thiosulfate aqueous solution, extracted with dichloromethane (50 ml) and sodium carbonate aqueous solution, dried over Na 2 SO 4 , filtered and concentrated to obtain a crude product which was used in the next step without purification.
步骤E.(1R,5S)-8-(5-氰基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯：往(1R,5S)-8-(5-氰基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(甲基亚砜基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯(20mg，0.024mmol)，(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇(76mg，0.48mmol)的THF溶液(1ml)中在氮气环境下0℃缓慢加入双三甲基硅基胺基锂(0.072mL，0.072mmol)并在0℃下搅拌1小时。将反应混合物用乙酸乙酯稀释并加水，用乙酸乙酯萃取，经Na2SO4干燥，过滤后浓缩，得到粗产物。然后通过柱色谱(SiO2，石油醚/乙酸乙酯＝1/2)纯化得到黄色固体(174mg，50％收率)。LCMS:m/z 926.5(M+H)。Step E. (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(triisopropylsilyl)acetylene yl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)pyrido[4,3-d] Pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester: to (1R,5S)-8-(5-cyano-8-fluoro-7 -(7-Fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylsulfoxide)pyrido[4 ,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (20mg, 0.024mmol), (2R,8S)-2-fluoro -To a THF solution (1 ml) of 1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol (76 mg, 0.48 mmol), slowly add bistrimethylsilylamine at 0°C in a nitrogen atmosphere. Lithium (0.072 mL, 0.072 mmol) and stirred at 0°C for 1 hour. The reaction mixture was diluted with ethyl acetate and water was added, extracted with ethyl acetate, dried over Na2SO4 , filtered and concentrated to give crude product . Then it was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate = 1/2) to obtain a yellow solid (174 mg, 50% yield). LCMS: m/z 926.5(M+H).
步骤F.(1R,5S)-8-(5-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯：往(1R,5S)-8-(5-氰基-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯(174mg，0.188mmol)的DMF(2ml)溶液中加入氟化铯(57mg，0.376mmol)，在25℃下搅拌1小时。将反应混合物用乙酸乙酯稀释并加水，用乙酸乙酯萃取，经Na2SO4干燥，过滤后浓缩，得到粗产物。然后通过柱色谱(SiO2，石油醚/乙酸乙酯＝1/2)纯化得到黄色固体(83mg，57％收率)。LCMS:m/z 770.3(M+H)。Step F. (1R,5S)-8-(5-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalene-1-yl)-8-fluoro-2 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester: to (1R,5S)-8-(5-cyano-8-fluoro-7-(7-fluoro-3-(methane) Oxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a( 5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (174 mg, Cesium fluoride (57 mg, 0.376 mmol) was added to a solution of DMF (2 ml) containing 0.188 mmol), and the mixture was stirred at 25° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and water was added, extracted with ethyl acetate, dried over Na2SO4 , filtered and concentrated to give crude product . It was then purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate = 1/2) to obtain a yellow solid (83 mg, 57% yield). LCMS: m/z 770.3(M+H).
步骤G.4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-8-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5-腈：往(1R,5S)-8-(5-氰基-7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯(80mg，0.10mmol)的二氯甲烷(2mL)溶液中逐滴加入三 氟乙酸。室温搅拌20min。浓缩，将残余物倒入饱和NaHCO3、DCM和MeOH的混合物中。用DCM和MeOH萃取水层，合并的有机层用盐水洗涤，经Na2SO4干燥，过滤并真空浓缩。通过制备型HPLC(5-95％ACN/水/0.1％FA，经20min)纯化。冻干，得到实施例14为含一个甲酸的盐(4.75mg,7％收率)。LCMS:m/z 626.2(M+H)。1H NMR(600MHz,DMSO-d6)δ10.28(s,1H),8.16(s,1H),8.03(dd,J＝9.2,5.8Hz,1H),7.51(t,J＝9.0Hz,1H),7.46(d,J＝2.6Hz,1H),7.29(t,J＝2.4Hz,1H),5.34(s,1H),5.25(s,1H),4.68(d,J＝4.7Hz,2H),4.18(t,J＝10.3Hz,1H),4.08(dd,J＝10.4,7.8Hz,1H),4.00(d,J＝2.4Hz,1H),3.19(d,J＝11.5Hz,2H),3.09(d,J＝6.9Hz,2H),3.04(d,J＝2.6Hz,1H),2.84(q,J＝8.5,7.6Hz,1H),2.76–2.69(m,2H),2.17(s,1H),2.13(d,J＝3.2Hz,1H),2.09–1.98(m,4H),1.89–1.84(m,1H),1.79(dq,J＝14.9,8.8,7.9Hz,3H)。Step G. 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-7-(8-ethynyl-7-fluoro-3-hydroxy Naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidine-5-nitrile: to (1R,5S)-8-(5-cyano-7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalene-1-yl) -8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4- To a solution of tert-butyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (80 mg, 0.10 mmol) in dichloromethane (2 mL), three Fluoroacetic acid. Stir at room temperature for 20 minutes. Concentrate and pour the residue into a mixture of saturated NaHCO3 , DCM and MeOH. The aqueous layer was extracted with DCM and MeOH, and the combined organic layers were washed with brine, dried over Na2SO4 , filtered and concentrated in vacuo. Purified by preparative HPLC (5-95% ACN/water/0.1% FA over 20 min). After freeze-drying, Example 14 was obtained as a salt containing a formic acid (4.75 mg, 7% yield). LCMS: m/z 626.2(M+H). 1 H NMR (600MHz, DMSO-d 6 ) δ10.28 (s, 1H), 8.16 (s, 1H), 8.03 (dd, J = 9.2, 5.8Hz, 1H), 7.51 (t, J = 9.0Hz, 1H),7.46(d,J＝2.6Hz,1H),7.29(t,J＝2.4Hz,1H),5.34(s,1H),5.25(s,1H),4.68(d,J＝4.7Hz, 2H),4.18(t,J＝10.3Hz,1H),4.08(dd,J＝10.4,7.8Hz,1H),4.00(d,J＝2.4Hz,1H),3.19(d,J＝11.5Hz, 2H),3.09(d,J＝6.9Hz,2H),3.04(d,J＝2.6Hz,1H),2.84(q,J＝8.5,7.6Hz,1H),2.76–2.69(m,2H), 2.17(s,1H),2.13(d,J＝3.2Hz,1H),2.09–1.98(m,4H),1.89–1.84(m,1H),1.79(dq,J＝14.9,8.8,7.9Hz, 3H).
实施例15制备4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-5-腈
Example 15 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene- 1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)pyrido[4,3-d] Pyrimidine-5-nitrile
以(1R,5S)-3-(5，7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯为原料，按到实施例14的步骤A-G进行合成得到实施例15为含两个甲酸的盐。LCMS:m/z 626.2(M+H)。1H NMR(600MHz,DMSO-d6)δ8.36(s,2H),8.01(dd,J＝9.2,5.8Hz,1H),7.50(t,J＝9.0Hz,1H),7.45(d,J＝2.6Hz,1H),7.26(t,J＝2.5Hz,1H),5.35–5.23(m,1H),4.18(t,J＝10.8Hz,1H),4.07(dd,J＝10.3,5.6Hz,1H),3.99(s,1H),3.56–3.46(m,2H),3.12–3.06(m,4H),3.03(s,1H),2.84(dd,J＝9.7,6.3Hz,2H),2.13(d,J＝3.9Hz,1H),2.07(d,J＝3.7Hz,1H),2.03–1.97(m,2H),1.88–1.83(m,1H),1.82–1.74(m,3H),1.62–1.55(m,3H)。(1R,5S)-3-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diaza Heterobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester was used as the raw material, and was synthesized according to step AG of Example 14 to obtain Example 15, which is a salt containing two formic acids. LCMS: m/z 626.2(M+H). 1 H NMR (600MHz, DMSO-d 6 ) δ8.36 (s, 2H), 8.01 (dd, J = 9.2, 5.8Hz, 1H), 7.50 (t, J = 9.0Hz, 1H), 7.45 (d, J＝2.6Hz,1H),7.26(t,J＝2.5Hz,1H),5.35–5.23(m,1H),4.18(t,J＝10.8Hz,1H),4.07(dd,J＝10.3,5.6 Hz,1H),3.99(s,1H),3.56–3.46(m,2H),3.12–3.06(m,4H),3.03(s,1H),2.84(dd,J＝9.7,6.3Hz,2H) ,2.13(d,J＝3.9Hz,1H),2.07(d,J＝3.7Hz,1H),2.03–1.97(m,2H),1.88–1.83(m,1H),1.82–1.74(m,3H ),1.62–1.55(m,3H).
实施例16制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-((1-(哌啶-1-基)丙-2-基)醇)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 16 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((1 -(piperidin-1-yl)prop-2-yl)ol)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-phenol
用1-(哌啶-1-基)丙-2-酚代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，根据实施例9步骤H-J进行合成，得到实施例16为含两个甲酸的盐。 LCMS:m/z 609.3(M+H)。1H NMR(600MHz,DMSO-d6)δ8.30(s,2H),7.99(dd,J＝9.2,5.8Hz,1H),7.48(t,J＝9.0Hz,1H),7.41(d,J＝2.6Hz,1H),7.23(d,J＝12.5Hz,1H),5.45–5.37(m,1H),4.76(s,1H),3.79(d,J＝16.8Hz,2H),3.50(s,1H),3.37(dd,J＝10.9,5.2Hz,1H),3.29(dd,J＝10.8,5.7Hz,1H),2.63–2.57(m,1H),2.47–2.34(m,6H),1.60–1.53(m,2H),1.44–1.36(m,4H),1.36–1.28(m,6H),1.26–1.21(m,2H)。Use 1-(piperidin-1-yl)propan-2-phenol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol according to The synthesis was carried out in step HJ of Example 9, and Example 16 was obtained as a salt containing two formic acids. LCMS: m/z 609.3(M+H). 1 H NMR (600MHz, DMSO-d 6 ) δ8.30 (s, 2H), 7.99 (dd, J = 9.2, 5.8Hz, 1H), 7.48 (t, J = 9.0Hz, 1H), 7.41 (d, J＝2.6Hz,1H),7.23(d,J＝12.5Hz,1H),5.45–5.37(m,1H),4.76(s,1H),3.79(d,J＝16.8Hz,2H),3.50( s,1H),3.37(dd,J＝10.9,5.2Hz,1H),3.29(dd,J＝10.8,5.7Hz,1H),2.63–2.57(m,1H),2.47–2.34(m,6H) ,1.60–1.53(m,2H),1.44–1.36(m,4H),1.36–1.28(m,6H),1.26–1.21(m,2H).
实施例17制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-(((2S，4S)-4-氟-1-甲基吡咯烷-2-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基--6-氟萘-2-酚
Example 17 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((( 2S, 4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl--6-fluoronaphthalene -2-phenol
用((2S，4S)-4-氟-1-甲基吡咯烷-2-基)甲醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，根据实施例9步骤H-J进行合成，得到实施例17为含三个甲酸的盐。LCMS:m/z 599.2(M+H)。1H NMR(400MHz,DMSO-d6)δ8.40(s,3H),7.98(dd,J＝9.2,5.9Hz,1H),7.47(t,J＝9.0Hz,1H),7.40(d,J＝2.6Hz,1H),7.23(d,J＝2.6Hz,1H),5.24–5.06(m,1H),4.76(s,1H),4.47(dd,J＝10.9,5.1Hz,1H),4.29–4.24(m,1H),3.80(s,1H),3.42–3.26(m,3H),3.22–3.10(m,3H),2.70–2.62(m,2H),2.47–2.30(m,6H),1.90–1.74(m,2H),1.59–1.49(m,2H)。Use ((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methanol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrole Azin-7-ylmethanol was synthesized according to step HJ of Example 9 to obtain a salt containing three formic acids in Example 17. LCMS: m/z 599.2(M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.40 (s, 3H), 7.98 (dd, J = 9.2, 5.9Hz, 1H), 7.47 (t, J = 9.0Hz, 1H), 7.40 (d, J＝2.6Hz,1H),7.23(d,J＝2.6Hz,1H),5.24–5.06(m,1H),4.76(s,1H),4.47(dd,J＝10.9,5.1Hz,1H), 4.29–4.24(m,1H),3.80(s,1H),3.42–3.26(m,3H),3.22–3.10(m,3H),2.70–2.62(m,2H),2.47–2.30(m,6H ),1.90–1.74(m,2H),1.59–1.49(m,2H).
实施例18制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-((1-(吗啉甲基)环丙基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基--6-氟萘-2-酚
Example 18 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((1 -(morpholinylmethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl--6-fluoronaphthalen-2-phenol
用(1-(吗啉甲基)环丙基)甲醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，根据实施例9步骤H-J进行合成，得到实施例18为含一个甲酸的盐。LCMS:m/z 637.3(M+H)。1H NMR(400MHz,Methanol-d4)δ8.53(s,1H),7.89(dd,J＝9.1,5.7Hz,1H),7.39–7.31(m,2H),7.24(d,J＝2.6Hz,1H),4.65–4.55(m,1H),4.46(s,1H),4.40–4.27(m,1H),4.07–3.95(m,1H),3.92–3.76(d,J＝19.8Hz,3H),3.73–3.63(m,4H),3.55–3.48(m,1H),3.35(s,2H),2.59–2.50(m,3H),2.50–2.34(m,3H),1.98(s,1H),1.92–1.82(s,2H),1.69(s,1H),0.74(t,J＝5.5Hz,2H),0.55(t,J＝5.6Hz,2H)。 Use (1-(morpholinylmethyl)cyclopropyl)methanol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol, according to the implementation The synthesis was carried out in step HJ of Example 9 to obtain a salt containing a formic acid in Example 18. LCMS: m/z 637.3(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.53 (s, 1H), 7.89 (dd, J = 9.1, 5.7Hz, 1H), 7.39–7.31 (m, 2H), 7.24 (d, J = 2.6 Hz,1H),4.65–4.55(m,1H),4.46(s,1H),4.40–4.27(m,1H),4.07–3.95(m,1H),3.92–3.76(d,J＝19.8Hz, 3H),3.73–3.63(m,4H),3.55–3.48(m,1H),3.35(s,2H),2.59–2.50(m,3H),2.50–2.34(m,3H),1.98(s, 1H),1.92–1.82(s,2H),1.69(s,1H),0.74(t,J＝5.5Hz,2H),0.55(t,J＝5.6Hz,2H).
实施例19制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基--6-氟萘-2-酚
Example 19 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((( 2S, 4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl--6-fluoronaphthalene -2-phenol
用((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，根据实施例9步骤H-J进行合成，得到实施例19为含一个甲酸的盐。LCMS:m/z 599.2(M+H)。1H NMR(600MHz,DMSO-d6)δ8.22(s,1H),8.00(dd,J＝9.2,5.9Hz,1H),7.49(t,J＝9.0Hz,1H),7.41(d,J＝2.5Hz,1H),7.23(s,1H),5.26–5.13(m,1H),4.78(s,1H),4.44(dt,J＝9.8,4.5Hz,1H),4.32(dt,J＝10.0,4.3Hz,1H),3.82(s,2H),3.60–3.48(m,5H),2.94(dq,J＝10.7,5.4Hz,2H),2.45(dd,J＝11.5,3.0Hz,1H),2.41(s,3H),2.19–2.09(m,2H),1.99–1.86(m,2H),1.64–1.52(m,2H)。Use ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrole Azin-7-ylmethanol was synthesized according to step HJ of Example 9 to obtain a salt containing a formic acid in Example 19. LCMS: m/z 599.2(M+H). 1 H NMR (600MHz, DMSO-d 6 ) δ8.22 (s, 1H), 8.00 (dd, J = 9.2, 5.9Hz, 1H), 7.49 (t, J = 9.0Hz, 1H), 7.41 (d, J＝2.5Hz,1H),7.23(s,1H),5.26–5.13(m,1H),4.78(s,1H),4.44(dt,J＝9.8,4.5Hz,1H),4.32(dt,J ＝10.0,4.3Hz,1H),3.82(s,2H),3.60–3.48(m,5H),2.94(dq,J＝10.7,5.4Hz,2H),2.45(dd,J＝11.5,3.0Hz, 1H),2.41(s,3H),2.19–2.09(m,2H),1.99–1.86(m,2H),1.64–1.52(m,2H).
实施例20制备4-(4-(3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 20 Preparation of 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-phenol
反应式如下：
The reaction formula is as follows:
步骤A：2，4，5，7-四氯-8-氟吡啶并[4,3-d]嘧啶：将5，7-二氯-8-氟-2- 巯基吡啶并[4,3-d]嘧啶-4(3H)-酮(2.0g，7.5mmol)溶于三氯氧磷，冰浴下加入DIEA(2.9g，22.6mmol)后100℃搅拌过夜。真空浓缩，得到粗品(9.0g)LCMS:m/z 265.9(M+H)。Step A: 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine: 5,7-dichloro-8-fluoro-2- Thiopyrido[4,3-d]pyrimidin-4(3H)-one (2.0g, 7.5mmol) was dissolved in phosphorus oxychloride, DIEA (2.9g, 22.6mmol) was added under ice bath and stirred at 100°C overnight. Concentrate in vacuo to give crude product (9.0 g) LCMS: m/z 265.9 (M+H).
步骤B：2，5，7-三氯-8-氟-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶：将2，4，5，7-四氯-8-氟吡啶并[4,3-d]嘧啶(5.0g，17.8mmol)在甲苯(50mL)中的溶液加入三氟乙醇(4.0g，26.7mmol)和叔丁醇钠(4.6g，35.6mmol)在0℃搅拌2h。TLC监测反应完全，使用EtOAc与饱和氯化铵水溶液萃取,有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-20％乙酸乙酯/石油醚洗脱,得到产物(800mg,2.29mmol,30％收率)LCMS:m/z 350.1(M+H)。Step B: 2,5,7-Trichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: Combine 2,4,5,7 -To a solution of tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (5.0g, 17.8mmol) in toluene (50mL), trifluoroethanol (4.0g, 26.7mmol) and sodium tert-butoxide (4.6 g, 35.6 mmol) and stirred at 0°C for 2 h. TLC monitored the reaction to be complete, extracted with EtOAc and saturated aqueous ammonium chloride solution, washed the organic phase with saturated NaCl, dried over Na 2 SO 4 , filtered the combined organic phases, dried, loaded onto silica gel and purified by column chromatography, using 0 Elution with -20% ethyl acetate/petroleum ether gave the product (800 mg, 2.29 mmol, 30% yield) LCMS: m/z 350.1 (M+H).
步骤C：5，7-二氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶：向2，5，7-三氯-8-氟-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶(1.3g，3.72mmol)的2-甲基四氢呋喃(10.0mL)溶液中添加N,N-二异丙基乙胺(961mg，7.45mmol)和(六氢-1H-吡咯嗪-7a-基)甲醇(1.18g，7.45mmol)。将混合物在0℃搅拌1小时。减压浓缩反应混合物，得到残余物。通过柱色谱纯化，用30-60％乙酸乙酯/石油醚洗脱,得到产物(760mg,1.61mmol,43％收率)LCMS:m/z 473.1(M+H)。Step C: 5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-( 2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: to 2,5,7-trichloro-8-fluoro-4-(2,2,2-trifluoroethoxy To a solution of pyrido[4,3-d]pyrimidine (1.3g, 3.72mmol) in 2-methyltetrahydrofuran (10.0mL), N,N-diisopropylethylamine (961mg, 7.45mmol) and ( Hexahydro-1H-pyrrolizin-7a-yl)methanol (1.18 g, 7.45 mmol). The mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. Purification by column chromatography, eluting with 30-60% ethyl acetate/petroleum ether, gave the product (760 mg, 1.61 mmol, 43% yield) LCMS: m/z 473.1 (M+H).
步骤D：7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶：将5，7-二氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶(260mg，0.55mmol)、丙炔(123mg，2.2mmol)、三乙胺(167mg，1.65mmol)和二(三苯基膦)二(乙酸)钯(II)(41mg，0.55mmol)在1,4-二氧六环(5mL)中的混合物脱气并用氮气吹扫3次。将混合物在氮气气氛下在100℃搅拌2小时。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层，将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用40-70％乙酸乙酯/石油醚洗脱,得到产物(180mg,0.38mmol,69％收率),LCMS:m/z 477.1(M+H)。Step D: 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: 5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine. A mixture of (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (260 mg, 0.55 mmol), propyne (123 mg, 2.2 mmol), triethylamine (167 mg, 1.65 mmol) and bis(triphenylphosphine)bis(acetic acid)palladium(II) (41 mg, 0.55 mmol) in 1,4-dioxane (5 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na 2 SO 4 , the combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography, eluting with 40-70% ethyl acetate/petroleum ether to give the product (180 mg, 0.38 mmol, 69% yield), LCMS: m/z 477.1 (M+H).
步骤E：(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：向7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶(180mg，0.38mmol)的N,N-二甲基甲酰胺(4.0mL)溶液中添加3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(120mg，0.57mmol)和碳酸钾(104mg，0.76mmol)。将混合物在0℃下搅拌1小时。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层，将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-30％MeOH/DCM洗脱,得到产物(130mg,0.22mmol,60％收率),LCMS:m/z 589.1(M+H)。 Step E: (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: To 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: To a solution of (5H)-yl)methoxy)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (180 mg, 0.38 mmol) in N,N-dimethylformamide (4.0 mL) was added tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.57 mmol) and potassium carbonate (104 mg, 0.76 mmol). The mixture was stirred at 0°C for 1 hour. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na 2 SO 4 , the combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography, eluting with 0-30% MeOH/DCM to give the product (130 mg, 0.22 mmol, 60% yield), LCMS: m/z 589.1 (M+H).
步骤F：3-(8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：将(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(120mg，0.20mmol)、((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(126mg，0.24mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(15mg，0.02mmol)、磷酸钾(130mg，0.61mmol)在四氢呋喃(5mL)和水(1mL)中的溶液。氮气环境下65℃搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层，将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(100mg,0.11mmol,52％收率)，LCMS:m/z 470.8(M/2+H)。Step F: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2- (((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine-4 -tert-butyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: (1R,5S)-3-(7-chloro-8-fluoro-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (120 mg, 0.20 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (126mg, 0.24mmol), methanesulfonic acid [ n-Butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (15 mg, 0.02 mmol), potassium phosphate (130 mg, 0.61 mmol) in tetrahydrofuran (5 mL ) and a solution in water (1 mL). Stir at 65°C for 2 hours under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography , eluted with 0-10% MeOH/DCM to obtain the product (100 mg, 0.11 mmol, 52% yield), LCMS: m/z 470.8 (M/2+H).
步骤G：3-(7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：将3-(8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(100mg，0.11mmol)和氟化铯(65mg，0.43mmol)溶于DMF(5mL)，氮气环境下室温搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层，将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(70mg,0.09mmol,84％收率)，LCMS:m/z 783.3(M+H)。Step G: 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diaza Heterobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(triisopropyl Silyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propanyl) Alkynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.11 mmol) and fluorination Cesium (65 mg, 0.43 mmol) was dissolved in DMF (5 mL) and stirred at room temperature under nitrogen atmosphere for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography , eluted with 0-10% MeOH/DCM to obtain the product (70 mg, 0.09 mmol, 84% yield), LCMS: m/z 783.3 (M+H).
步骤H:4-(4-(3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚：将3-(7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(70mg,0.09mmol)的二氯甲烷(3mL)溶液中逐滴加入三氟乙酸(0.5ml)。室温搅拌40min。浓缩，将残余物倒入饱和NaHCO3(20mL)和DCM:MeOH(10:1)(15mL)的混合物中。用DCM:MeOH(10:1)(2×15mL)萃取水层，合并的有机层用盐水(15mL)洗涤，经Na2SO4干燥，过滤并真空浓缩。然后通过制备型HPLC(5-95％ACN/水/0.1％FA，经20min)纯化。冻干，得到实施例20为含0.5个甲酸的盐(18.0mg,0.028mmol,31％收率)。LCMS:m/z639.3(M+H)。1H NMR(400MHz,Methanol-d4)δ8.50(s,0.5H),7.89(dd,J＝9.2,5.7Hz,1H),7.37(d,J＝2.3Hz,1H),7.34(d,J＝9.0Hz,1H),7.24–7.21(m,1H),5.54–5.35(m,1H),4.47–(m,3H),3.86(d,J＝11.8Hz,2H),3.59–3.45(m,3H),3.28–3.17(m,1H),2.55–2.32(m,2H),2.31–2.24(m,1H),2.22(s,3H),2.19–2.11(m,2H),2.09–1.98(m,2H),1.91(br.s,3H),1.38–1.30(m,4H)。 Step H: 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H -Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -Phenol: 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethylether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-di To a solution of azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (70 mg, 0.09 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 ml) dropwise. Stir at room temperature for 40 minutes. Concentrate and pour the residue into a mixture of saturated NaHCO3 (20 mL) and DCM:MeOH (10:1) (15 mL). The aqueous layer was extracted with DCM:MeOH (10:1) (2 x 15 mL) and the combined organic layers were washed with brine (15 mL), dried over Na2SO4 , filtered and concentrated in vacuo . It was then purified by preparative HPLC (5-95% ACN/water/0.1% FA over 20 min). After freeze-drying, Example 20 was obtained as a salt containing 0.5 formic acid (18.0 mg, 0.028 mmol, 31% yield). LCMS:m/z639.3(M+H). 1H NMR (400MHz, Methanol-d4) δ8.50 (s, 0.5H), 7.89 (dd, J = 9.2, 5.7Hz, 1H), 7.37 (d, J = 2.3Hz, 1H), 7.34 (d, J ＝9.0Hz,1H),7.24–7.21(m,1H),5.54–5.35(m,1H),4.47–(m,3H),3.86(d,J＝11.8Hz,2H),3.59–3.45(m ,3H),3.28–3.17(m,1H),2.55–2.32(m,2H),2.31–2.24(m,1H),2.22(s,3H),2.19–2.11(m,2H),2.09–1.98 (m,2H),1.91(br.s,3H),1.38–1.30(m,4H).
实施例21制备4-(5-(3-胺基丙炔)-4-(3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 21 Preparation of 4-(5-(3-aminopropyne)-4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- Fluoronaphth-2-phenol
反应式如下：
The reaction formula is as follows:
步骤A.3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶-5-基)丙炔基)胺基甲酸叔丁酯：将5，7-二氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶(200mg，0.42mmol)、N-(叔丁氧羰基)炔丙胺(263mg，1.7mmol)、三乙胺(128mg，1.27mmol)和二(三苯基膦)二(乙酸)钯(II)(31mg，0.042mmol)在1,4-二氧六环(4mL)中的混合物脱气并用氮气吹扫3次。将混合物在氮气气氛下在100℃搅拌2小时。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层，将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用40-70％乙酸乙酯/石油醚洗脱,得到产物(150mg,0.25mmol,60％收率),LCMS:m/z 592.1(M+H)。Step A. 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-( 2,2,2-Trifluoroethoxy)pyrido[4,3-d]pyrimidin-5-yl)propynyl)carbamic acid tert-butyl ester: 5,7-dichloro-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido [4,3-d]pyrimidine (200 mg, 0.42 mmol), N-(tert-butoxycarbonyl) propargylamine (263 mg, 1.7 mmol), triethylamine (128 mg, 1.27 mmol) and bis(triphenylphosphine)di A mixture of palladium(II)(acetate) (31 mg, 0.042 mmol) in 1,4-dioxane (4 mL) was degassed and purged 3 times with nitrogen. The mixture was stirred at 100°C for 2 hours under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography , eluted with 40-70% ethyl acetate/petroleum ether to obtain the product (150 mg, 0.25 mmol, 60% yield), LCMS: m/z 592.1 (M+H).
步骤B.(1R，5S)-3-(5-(3-(胺基甲酸叔丁酯)丙炔基)-7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯：向3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶-5-基)丙炔基)胺基甲酸叔丁酯(110mg，0.20mmol)的N,N-二甲基甲酰胺(4.0mL)溶液中添加3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(64mg，0.30mmol)和碳酸钾(56mg，0.41mmol)。将混合物在0℃下搅拌2小时。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层，将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶 上并通过柱色谱纯化，用0-30％MeOH/DCM洗脱,得到产物(80mg,0.11mmol,57％收率),LCMS:m/z 704.1(M+H)。Step B. (1R,5S)-3-(5-(3-(tert-butylcarbamate)propynyl)-7-chloro-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane -8-tert-butylcarboxylate: to 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy tert-butyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-5-yl)propynyl)carbamate (110 mg, 0.20 mmol) Add 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (64 mg, 0.30 mmol) and potassium carbonate (56 mg) to a solution of N,N-dimethylformamide (4.0 mL). ,0.41mmol). The mixture was stirred at 0°C for 2 hours. Partition the residue between EtOAc and water, and extract the aqueous layer with EtOAc, wash the organic phase with saturated NaCl, dry over Na2SO4 , filter the combined organic phases , dry and load onto silica gel and purified by column chromatography, eluting with 0-30% MeOH/DCM, to give the product (80 mg, 0.11 mmol, 57% yield), LCMS: m/z 704.1 (M+H).
步骤C.3-(5-(3-(胺基甲酸叔丁酯)丙炔基)-8-氟-7-氯-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：将(1R，5S)-3-(5-(3-(胺基甲酸叔丁酯)丙炔基)-7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯(70mg，0.09mmol)、((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(76mg，0.15mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(7mg，0.009mmol)、磷酸钾(63mg，0.29mmol)的四氢呋喃(2.5mL)和水(0.5mL)溶液于氮气环境下65℃搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层，将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(60mg,0.057mmol,58％收率),LCMS:m/z 527.8(M/2+H)。Step C. 3-(5-(3-(tert-butylcarbamate)propynyl)-8-fluoro-7-chloro-(7-fluoro-3-(methoxymethyl ether)-8-( (Triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(5 -(3-(tert-butylcarbamate)propynyl)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H) -(yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylic acid tert-butyl ester (70 mg, 0.09mmol) , ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) Naphthyl-1-yl)ethynyl)triisopropylsilane (76 mg, 0.15 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl A solution of -2-yl)palladium (7 mg, 0.009 mmol) and potassium phosphate (63 mg, 0.29 mmol) in tetrahydrofuran (2.5 mL) and water (0.5 mL) was stirred at 65°C for 2 h under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography , eluted with 0-10% MeOH/DCM to obtain the product (60 mg, 0.057 mmol, 58% yield), LCMS: m/z 527.8 (M/2+H).
步骤D.3-(5-(3-(胺基甲酸叔丁酯)丙炔基)-7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：将3-(5-(3-(胺基甲酸叔丁酯)丙炔基)-8-氟-7-氯-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(60mg，0.057mmol)和氟化铯(43mg，0.28mmol)溶于DMF(4mL)，氮气环境下室温搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层，将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(30mg,0.033mmol,59％收率)LCMS:m/z 449.8(M/2+H)。Step D. 3-(5-(3-(tert-butylcarbamate)propynyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethylether)naphthalene-1-yl )-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4 -base)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: 3-(5-(3-(tert-butylcarbamate)propynyl)-8 -Fluoro-7-chloro-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[ 3.2.1] Octane-8-carboxylic acid tert-butyl ester (60 mg, 0.057 mmol) and cesium fluoride (43 mg, 0.28 mmol) were dissolved in DMF (4 mL), and stirred at room temperature under nitrogen atmosphere for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography , eluted with 0-10% MeOH/DCM to obtain the product (30 mg, 0.033 mmol, 59% yield) LCMS: m/z 449.8 (M/2+H).
步骤E.4-(5-(3-胺基丙炔)-4-(3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚：将3-(5-(3-(胺基甲酸叔丁酯)丙炔基)-7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(20mg,0.022mmol)在二氯甲烷(3mL)中的溶液逐滴加入三氟乙酸(0.5ml)。室温搅拌40min。浓缩，将残余物倒入饱和NaHCO3(20mL)和DCM:MeOH(10:1)(15mL)的混合物中。用DCM:MeOH(10:1)(2×15mL)萃取水层，合并的有机层用盐水(15mL)洗涤，经Na2SO4干燥，过滤并真空浓缩。然后通过制备型HPLC(5-95％ACN/水/0.1％FA，经20min)纯化。冻干，得到实施例21为含一个甲酸的盐(2.0mg,0.003mmol,14％收率)。LCMS:m/z 654.3(M+H)。 Step E. 4-(5-(3-Aminopropyne)-4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphthalene-2-phenol: 3-(5-(3-(tert-butylcarbamate)propynyl)-7-(8-ethynyl-7-fluoro-3-(methoxymethylether)naphthalene -1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (20 mg, 0.022 mmol) in dichloromethane (3 mL) was added dropwise Fluoroacetic acid (0.5ml). Stir at room temperature for 40 minutes. Concentrate and pour the residue into a mixture of saturated NaHCO3 (20 mL) and DCM:MeOH (10:1) (15 mL). The aqueous layer was extracted with DCM:MeOH (10:1) (2 x 15 mL) and the combined organic layers were washed with brine (15 mL), dried over Na2SO4 , filtered and concentrated in vacuo . It was then purified by preparative HPLC (5-95% ACN/water/0.1% FA over 20 min). After freeze-drying, Example 21 was obtained as a salt containing a formic acid (2.0 mg, 0.003 mmol, 14% yield). LCMS: m/z 654.3(M+H).
实施例22制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基萘-2-酚
Example 22 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl Naphth-2-phenol
用((6-(甲氧基甲醚)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷代替((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷，根据实施例20步骤F-H进行合成实施例22为含一个甲酸的盐(1.6mg,0.0026mmol,10％收率)。Use ((6-(methoxymethyl ether)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl )ethynyl)triisopropylsilane instead of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxo) Heteraborane-2-yl) naphth-1-yl) ethynyl) triisopropylsilane was synthesized according to steps F-H of Example 20. Example 22 is a salt containing a formic acid (1.6 mg, 0.0026 mmol, 10% yield).
LCMS:m/z 621.2(M+H)。LCMS: m/z 621.2 (M+H).
1H NMR(400MHz,Methanol-d4)δ8.51(s,1H),7.84(dd,J＝8.4,1.3Hz,1H),7.54(dd,J＝7.2,1.3Hz,1H),7.42(dd,J＝8.3,7.1Hz,1H),7.35(d,J＝2.6Hz,1H),7.18(t,J＝2.0Hz,1H),5.52–5.34(m,1H),4.45(q,J＝11.7,11.1Hz,3H),4.04–3.78(m,4H),3.56–3.44(m,3H),3.23(q,J＝7.3Hz,2H),3.01(d,J＝4.5Hz,1H),2.45–2.34(m,2H),2.30–2.22(m,1H),2.21(s,3H),2.19–2.10(m,2H),2.08–1.95(m,2H),1.95–1.82(m,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.51 (s, 1H), 7.84 (dd, J = 8.4, 1.3 Hz, 1H), 7.54 ( dd, J = 7.2, 1.3 Hz, 1H), 7.42 ( dd,J＝8.3,7.1Hz,1H),7.35(d,J＝2.6Hz,1H),7.18(t,J＝2.0Hz,1H),5.52–5.34(m,1H),4.45(q,J ＝11.7,11.1Hz,3H),4.04–3.78(m,4H),3.56–3.44(m,3H),3.23(q,J＝7.3Hz,2H),3.01(d,J＝4.5Hz,1H) ,2.45–2.34(m,2H),2.30–2.22(m,1H),2.21(s,3H),2.19–2.10(m,2H),2.08–1.95(m,2H),1.95–1.82(m, 3H).
实施例23制备4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙炔基-7-氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶
Example 23 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethynyl-7-fluoronaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine
用((2-氟-8-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)萘-1-基)乙炔基)三异丙基硅烷代替((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷，根据实施例20步骤F-H进行合成实施例23为含一个甲酸的盐(18mg,0.029mmol)。LCMS:m/z 621.2(M+H)。1H NMR(400MHz,Methanol-d4)δ8.52(s,1H),8.17–8.12(m,2H),7.71–7.64(m,2H),7.47(t,J＝9.0Hz,1H),5.50–5.33(m,1H),4.49–4.38(m,3H),4.04–3.78(m,4H),3.60–3.43(m,3H),3.42(dd,J＝4.2,1.0Hz,1H),3.23–3.14(m,1H),2.56–2.33(m,2H),2.32–2.23(m,2H),2.22(s,3H),2.19–2.08(m,2H),2.06–1.96(m,1H),1.92–1.64(m,4H)。Use ((2-fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphth-1-yl)ethynyl) tri Isopropylsilane instead of ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)naphth-1-yl)ethynyl)triisopropylsilane was synthesized according to step FH of Example 20. Example 23 was a salt containing a formic acid (18 mg, 0.029 mmol). LCMS: m/z 621.2(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.52 (s, 1H), 8.17–8.12 (m, 2H), 7.71–7.64 (m, 2H), 7.47 (t, J = 9.0Hz, 1H), 5.50–5.33(m,1H),4.49–4.38(m,3H),4.04–3.78(m,4H),3.60–3.43(m,3H),3.42(dd,J＝4.2,1.0Hz,1H), 3.23–3.14(m,1H),2.56–2.33(m,2H),2.32–2.23(m,2H),2.22(s,3H),2.19–2.08(m,2H),2.06–1.96(m,1H ),1.92–1.64(m,4H).
实施例24制备4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-7-(7，8-二氟萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶
Example 24 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(7,8-difluoronaphthalene-1-yl)-8 -Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3- d]pyrimidine
用2-(7,8-二氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷代替((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷，根据实施例20步骤F和H进行合成实施例24为含两个甲酸的盐(14mg,0.023mmol)。LCMS:m/z 617.2(M+H)。Replace ((2-fluoro-6-(methyl Oxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triiso Propylsilane was synthesized according to steps F and H of Example 20. Example 24 was a salt containing two formic acids (14 mg, 0.023 mmol). LCMS: m/z 617.2(M+H).
1H NMR(400MHz,DMSO-d6)δ8.30(s,2H),8.23–8.19(m,1H),8.02(ddd,J＝9.2,5.1,1.6Hz,1H),7.78–7.69(m,3H),5.36–5.19(m,1H),4.14(d,J＝10.3Hz,2H),4.04(d,J＝10.3Hz,2H),3.55(br.s,2H),3.13–3.04(m,3H),3.02–2.98(m,1H),2.87–2.77(m,1H),2.17(s,3H),2.13(d,J＝5.1Hz,1H),2.09–1.95(m,3H),1.88–1.71(m,4H),1.64–1.55(m,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.30 (s, 2H), 8.23–8.19 (m, 1H), 8.02 (ddd, J = 9.2, 5.1, 1.6Hz, 1H), 7.78–7.69 (m ,3H),5.36–5.19(m,1H),4.14(d,J＝10.3Hz,2H),4.04(d,J＝10.3Hz,2H),3.55(br.s,2H),3.13–3.04( m,3H),3.02–2.98(m,1H),2.87–2.77(m,1H),2.17(s,3H),2.13(d,J＝5.1Hz,1H),2.09–1.95(m,3H) ,1.88–1.71(m,4H),1.64–1.55(m,3H).
实施例25制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-7-氟苯并噻唑-2-胺
Example 25 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-7-fluorobenzene Thiazol-2-amine
反应式如下：
The reaction formula is as follows:
步骤A.(1R,5S)-3-(7-(2-((甲酸叔丁酯)胺基)-7-氟苯并噻唑-4-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：将化合物(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(100mg，0.17mmol)、(2-((叔丁氧羰基)氨基)-7-氟苯并[D]噻唑-4-基)硼酸(424mg，1.36mmol)、四三苯基膦钯(20mg，0.017mmol)、碳酸钠(54mg，0.51mmol)在1,4-二氧六环(5mL)和水(1mL)中的溶液。氮气环境下90℃搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层，将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(140mg,0.17mmol,99％收率)，LCMS:m/z 411.2(M/2+H)。 Step A. (1R,5S)-3-(7-(2-((tert-butyl formate)amino)-7-fluorobenzothiazol-4-yl)-8-fluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)- 3,8-Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: Compound (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS) )-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diaza Heterobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (100 mg, 0.17 mmol), (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[D]thiazol-4-yl) Boric acid (424 mg, 1.36 mmol), palladium tetraphenylphosphine (20 mg, 0.017 mmol), sodium carbonate (54 mg, 0.51 mmol) in 1,4-dioxane (5 mL) and water (1 mL). Stir at 90°C for 2 hours under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography , eluted with 0-10% MeOH/DCM to obtain the product (140 mg, 0.17 mmol, 99% yield), LCMS: m/z 411.2 (M/2+H).
步骤B.4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-7-氟苯并噻唑-2-胺：将1R,5S)-3-(7-(2-((甲酸叔丁酯)胺基)-7-氟苯并噻唑-4-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(50mg,0.061mmol)在二氯甲烷(3mL)中的溶液逐滴加入三氟乙酸(0.5ml)。室温搅拌3h。真空浓缩，将残余物倒入饱和NaHCO3(20mL)和DCM:MeOH(10:1)(15mL)的混合物中。用DCM:MeOH(10:1)(2×15mL)萃取水层，合并的有机层用盐水(15mL)洗涤，经Na2SO4干燥，过滤并真空浓缩。然后通过制备型HPLC(5-95％ACN/水/0.1％FA，经20min)纯化。冻干，得到实施例25为含两个甲酸的盐(15mg,0.024mmol)。LCMS:m/z 621.2(M+H)。Step B. 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-7-fluorobenzo Thiazole-2-amine: 1R,5S)-3-(7-(2-((tert-butyl formate)amino)-7-fluorobenzothiazol-4-yl)-8-fluoro-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine-4- To a solution of tert-butyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.061 mmol) in dichloromethane (3 mL), trifluoroacetic acid (0.5 ml) was added dropwise ). Stir at room temperature for 3h. Concentrate in vacuo and pour the residue into a mixture of saturated NaHCO3 (20 mL) and DCM:MeOH (10:1) (15 mL). The aqueous layer was extracted with DCM:MeOH (10:1) (2 x 15 mL) and the combined organic layers were washed with brine (15 mL), dried over Na2SO4 , filtered and concentrated in vacuo . It was then purified by preparative HPLC (5-95% ACN/water/0.1% FA over 20 min). After freeze-drying, Example 25 was obtained as a salt containing two formic acids (15 mg, 0.024 mmol). LCMS: m/z 621.2(M+H).
1H NMR(400MHz,DMSO-d6)δ8.29(s,2H),7.96(s,2H),7.46(dd,J＝8.5,5.8Hz,1H),7.07(t,J＝8.8Hz,1H),5.37–5.18(m,1H),4.13(d,J＝10.4Hz,2H),4.04(d,J＝10.4Hz,2H),3.50(br,s,2H),3.12–3.04(m,3H),3.03–2.98(m,1H),2.86–2.78(m,1H),2.18(s,3H),2.12(d,J＝3.7Hz,1H),2.06–1.94(m,3H),1.87–1.71(m,4H),1.59–1.53(s,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.29 (s, 2H), 7.96 (s, 2H), 7.46 (dd, J = 8.5, 5.8Hz, 1H), 7.07 (t, J = 8.8Hz, 1H),5.37–5.18(m,1H),4.13(d,J＝10.4Hz,2H),4.04(d,J＝10.4Hz,2H),3.50(br,s,2H),3.12–3.04(m ,3H),3.03–2.98(m,1H),2.86–2.78(m,1H),2.18(s,3H),2.12(d,J＝3.7Hz,1H),2.06–1.94(m,3H), 1.87–1.71(m,4H),1.59–1.53(s,3H).
实施例26制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(3-羟基丙炔)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 26 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(3-hydroxypropyne)pyrido[4,3-d]pyrimidin-7-yl)-5- Ethynyl-6-fluoronaphthalene-2-phenol
反应式如下：
The reaction formula is as follows:
步骤A.5，7-二氯-8-氟-2-(甲硫基)-4-(2，2，2-三氟乙氧基)吡啶并并[4,3-d]嘧啶：向5,7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇(5.0g，17.9mmol)的DMF溶液中添加N,N-二异丙基乙胺(6.9g，53.6mmol)和三氟甲磺酸三氟乙酯(6.2g，26.9mmol)。将混合物在室温搅拌5小时。使残余物在EtOAc与饱和氯化铵水溶液之间分配,并用EtOAc萃取水层，有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-20％乙酸乙酯/石油醚洗脱,得到产物(2g,5.54mmol,31％收率)LCMS:m/z 362.1(M+H)。Step A. 5,7-Dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a DMF solution of 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (5.0g, 17.9mmol) was added N,N-diiso Propylethylamine (6.9g, 53.6mmol) and trifluoroethyl triflate (6.2g, 26.9mmol). The mixture was stirred at room temperature for 5 hours. The residue was partitioned between EtOAc and saturated aqueous ammonium chloride, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried, loaded onto silica gel and passed through Purification by column chromatography, eluting with 0-20% ethyl acetate/petroleum ether, gave the product (2g, 5.54mmol, 31% yield) LCMS: m/z 362.1 (M+H).
步骤B.5-(3-((叔丁基二甲基甲硅烷基)氧)丙炔基)-7-氯-8-氟-2-(甲硫基)-4-(2，2，2-三氟乙氧基)吡啶并并[4,3-d]嘧啶：将5，7-二氯-8-氟-2-(甲硫基)-4-(2，2，2-三氟乙氧基)吡啶并并[4,3-d]嘧啶(1.2g，3.32mmol)、叔丁基二甲基(2-丙炔基氧基)硅烷(1.7g，9.97mmol)、三乙胺(1.0g，9.97mmol)和二(三苯基膦)二(乙酸)钯(II)(249mg，0.33mmol)在1,4-二氧六环(7mL)中的混合物脱气并用氮气吹扫3次。将混合物在氮气气氛下在90℃搅拌2小时。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层,将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-15％乙酸乙酯/石油醚洗脱,得到产物(700mg,1.41mmol,43％收率),LCMS:m/z 496.2(M+H)。Step B. 5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-7-chloro-8-fluoro-2-(methylthio)-4-(2,2, 2-Trifluoroethoxy)pyrido[4,3-d]pyrimidine: 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-tri Fluoroethoxy)pyrido[4,3-d]pyrimidine (1.2g, 3.32mmol), tert-butyldimethyl(2-propynyloxy)silane (1.7g, 9.97mmol), triethyl A mixture of amine (1.0 g, 9.97 mmol) and bis(triphenylphosphine)bis(acetate)palladium(II) (249 mg, 0.33 mmol) in 1,4-dioxane (7 mL) was degassed and purged with nitrogen. Scan 3 times. The mixture was stirred at 90°C for 2 hours under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography , eluting with 0-15% ethyl acetate/petroleum ether, the product (700 mg, 1.41 mmol, 43% yield) was obtained, LCMS: m/z 496.2 (M+H).
步骤C.(1R,5S)-3-(5-(3-((叔丁基二甲基甲硅烷基)氧)丙炔基)-7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯：向5-(3-((叔丁基二甲基甲硅烷基)氧)丙炔基)-7-氯-8-氟-2-(甲硫基)-4-(2，2，2-三氟乙氧基)吡啶并并[4,3-d]嘧啶(700mg，1.41 mmol)的N,N-二甲基甲酰胺(9.0mL)溶液中添加3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(450mg，2.21mmol)和碳酸钾(390mg，2.83mmol)。将混合物在0℃下搅拌1小时。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层,将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-20％乙酸乙酯/石油醚洗脱,得到产物(560mg,0.92mmol,65％收率)。Step C. (1R,5S)-tert-butyl 3-(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To 5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-7-chloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (700 mg, 1.41 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (450 mg, 2.21 mmol) and potassium carbonate (390 mg, 2.83 mmol) were added to a solution of N,N-dimethylformamide (9.0 mL). The mixture was stirred at 0 ° C for 1 hour. The residue was distributed between EtOAc and water, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na 2 SO 4 , the combined organic phase was filtered, dried, loaded onto silica gel and purified by column chromatography, eluted with 0-20% ethyl acetate/petroleum ether to give the product (560 mg, 0.92 mmol, 65% yield).
步骤D.(1R,5S)-3-(5-(3-((叔丁基二甲基甲硅烷基)氧)丙炔基)-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯：将(1R,5S)-3-(5-(3-((叔丁基二甲基甲硅烷基)氧)丙炔基)-7-氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯(320mg，0.53mmol)、((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(540mg，1.05mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(38mg，0.053mmol)、磷酸钾(335mg，1.58mmol)在四氢呋喃(10mL)和水(2mL)中的溶液。氮气环境下65℃搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层,将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用20-60％乙酸乙酯/石油醚洗脱,得到产物(200mg,0.21mmol,40％收率)。Step D. (1R,5S)-3-(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-8-fluoro-7-(7-fluoro-3-( Methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl) -3,8-diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(5-(3-((tert-butyldimethylsilyl)) Oxy)propynyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1 ]Octyl-8-carboxylic acid tert-butyl ester (320mg, 0.53mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1, 3,2-Dioxaboran-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (540mg, 1.05mmol), methanesulfonic acid [n-butyldi(1-adamantyl) A solution of phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (38 mg, 0.053 mmol), potassium phosphate (335 mg, 1.58 mmol) in tetrahydrofuran (10 mL) and water (2 mL). Stir at 65°C for 2 hours under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography , eluting with 20-60% ethyl acetate/petroleum ether, the product (200 mg, 0.21 mmol, 40% yield) was obtained.
步骤E.3-(5-(3-((叔丁基二甲基甲硅烷基)氧)丙炔基)-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯：向(1R,5S)-3-(5-(3-((叔丁基二甲基甲硅烷基)氧)丙炔基)-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯(200.0mg，0.21mmol)的DCM(10mL)溶液中加入间氯过氧苯甲酸(43.0mg，0.25mmol)0℃搅拌1h。加入硫代硫酸钠水溶液淬灭，使残余物在二氯甲烷与碳酸氢钠水溶液之间分配,并用二氯甲烷,萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，浓缩，得到粗品，直接用于下一步。将粗品(200.0mg，0.21mmol)、(六氢-1H-吡咯啉-7a-基)甲醇(50.0mg，0.32mmol)在THF(5mL)中的溶液。氮气环境下0℃逐滴加入LiHMDS(0.63ml,0.63mmol)搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc(2x)萃取水层,将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(100.0mg,0.09mmol,45％收率)LCMS:m/z 535.5(M/2+H)Step E. 3-(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether) -8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) Methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: to (1R,5S)-3 -(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-( (Triisopropylsilyl)ethynyl)naphth-1-yl)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[ 3.2.1] To a solution of octyl-8-carboxylic acid tert-butyl ester (200.0 mg, 0.21 mmol) in DCM (10 mL), m-chloroperoxybenzoic acid (43.0 mg, 0.25 mmol) was added and stirred at 0°C for 1 hour. Aqueous sodium thiosulfate solution was added to quench, the residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution, and the aqueous layer was extracted with dichloromethane and the organic phase was washed with saturated NaCl, dried over Na 2 SO 4 and concentrated. , the crude product is obtained, which is directly used in the next step. A solution of crude product (200.0 mg, 0.21 mmol), (hexahydro-1H-pyrrolin-7a-yl)methanol (50.0 mg, 0.32 mmol) in THF (5 mL) was added. LiHMDS (0.63 ml, 0.63 mmol) was added dropwise at 0°C under nitrogen atmosphere and stirred for 1 h. Partition the residue between EtOAc and water and extract the aqueous layer with EtOAc (2x), wash the organic phase with saturated NaCl, dry over Na2SO4 , filter the combined organic phases, dry, load onto silica gel and pass Purification by column chromatography, eluting with 0-10% MeOH/DCM, gave the product (100.0 mg, 0.09 mmol, 45% yield) LCMS: m/z 535.5 (M/2+H)
步骤F.3-(7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(3-羟基丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯：将3-(5-(3-((叔丁基二甲基甲硅烷基)氧)丙炔基)-8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H- 吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯(100mg，0.09mmol)和氟化铯(70mg，0.46mmol)溶于DMF(5mL)，氮气环境下室温搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水相，将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(55mg,0.069mmol,76％收率)LCMS:m/z 799.3(M+H)。Step F. 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(3-hydroxypropynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester: 3-(5-(3-((tert-butyldimethylsilyl)oxy)propynyl)-8-fluoro -7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2 -Fluorine-1H- Pyrrozine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl Ester (100 mg, 0.09 mmol) and cesium fluoride (70 mg, 0.46 mmol) were dissolved in DMF (5 mL), and stirred at room temperature under nitrogen atmosphere for 1 h. The residue was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried , loaded onto silica gel and purified by column chromatography , eluting with 0-10% MeOH/DCM, the product (55 mg, 0.069 mmol, 76% yield) was obtained. LCMS: m/z 799.3 (M+H).
步骤G.4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(3-羟基丙炔)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚：向3-(7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(3-羟基丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯(25mg,0.03mmol)的二氯甲烷(3mL)溶液中逐滴加入三氟乙酸(0.5ml)。室温搅拌40min。浓缩，将残余物倒入饱和NaHCO3(20mL)和DCM:MeOH(10:1)(15mL)的混合物中。用DCM:MeOH(10:1)(2×15mL)萃取水层，合并的有机层用盐水(15mL)洗涤，经Na2SO4干燥，过滤并真空浓缩。然后通过制备型HPLC(5-95％ACN/水/0.1％FA，经20min)纯化。冻干，得到实施例26为含一个甲酸的盐(6.0mg,0.009mmol)。LCMS:m/z 655.2(M+H)。1H NMR(400MHz,DMSO-d6)δ10.20(br.s,1H),8.18(s,1H),8.00(dd,J＝9.2,5.9Hz,1H),7.48(t,J＝9.0Hz,1H),7.41(d,J＝2.6Hz,1H),7.21(t,J＝2.2Hz,1H),5.53(br.s,1H),5.37–5.20(m,1H),4.40(s,2H),4.15(dd,J＝10.4,4.6Hz,1H),4.04(dd,J＝10.3,2.6Hz,1H),3.83(s,1H),3.72(br.s,3H),3.17–3.05(m,3H),3.05–2.97(m,2H),2.87–2.80(m,1H),2.13(d,J＝3.6Hz,1H),2.05(d,J＝3.9Hz,1H),2.03–1.96(m,1H),1.89–1.72(m,4H),1.71–1.58(m,3H),1.56–1.41(m,1H)。Step G. 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(3-hydroxypropyne)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyne Base-6-fluoronaphthalene-2-phenol: To 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthyl-1-yl)-8-fluoro-2-( ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(3-hydroxypropynyl)pyrido[4,3-d]pyrimidine To a solution of -4-yl)-3,8-diazabicyclo[3.2.1]octan-8-carboxylic acid tert-butyl ester (25 mg, 0.03 mmol) in dichloromethane (3 mL), trifluoroacetic acid (0.5 ml). Stir at room temperature for 40 minutes. Concentrate and pour the residue into a mixture of saturated NaHCO3 (20 mL) and DCM:MeOH (10:1) (15 mL). The aqueous layer was extracted with DCM:MeOH (10:1) (2 x 15 mL) and the combined organic layers were washed with brine (15 mL), dried over Na2SO4 , filtered and concentrated in vacuo . It was then purified by preparative HPLC (5-95% ACN/water/0.1% FA over 20 min). After lyophilization, Example 26 was obtained as a salt containing a formic acid (6.0 mg, 0.009 mmol). LCMS: m/z 655.2(M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.20 (br.s, 1H), 8.18 (s, 1H), 8.00 (dd, J = 9.2, 5.9Hz, 1H), 7.48 (t, J = 9.0 Hz,1H),7.41(d,J＝2.6Hz,1H),7.21(t,J＝2.2Hz,1H),5.53(br.s,1H),5.37–5.20(m,1H),4.40(s ,2H),4.15(dd,J＝10.4,4.6Hz,1H),4.04(dd,J＝10.3,2.6Hz,1H),3.83(s,1H),3.72(br.s,3H),3.17– 3.05(m,3H),3.05–2.97(m,2H),2.87–2.80(m,1H),2.13(d,J＝3.6Hz,1H),2.05(d,J＝3.9Hz,1H),2.03 –1.96(m,1H),1.89–1.72(m,4H),1.71–1.58(m,3H),1.56–1.41(m,1H).
实施例27制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-8-基)-5-乙炔基-8-氟-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 27 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-5-ethynyl-8-fluoro-2-((tetrazabicyclo[3.2.1]oct-8-yl) Hydrogen-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-phenol
以(1R,5S)-8-(5，7-二氯-8-氟-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯为原料，用(六氢-1H-吡咯啉-7a-基)甲醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，按到实施例9步骤H-J进行合成，得到含两个甲酸的盐(4.72mg，0.007mmol)。LCMS:m/z 607.6(M+H)。1H NMR(600MHz,DMSO-d6)δ8.28(s,2H),7.99(dd,J＝9.2,5.9Hz,1H),7.48(t,J＝8.9Hz,1H),7.41(d,J＝2.5Hz,1H),7.25(d,J＝2.5Hz,1H),4.88(s,1H),4.76–4.69(m,2H),4.10–4.04(m,2H),3.87(d,J＝6.4Hz,1H),2.98–2.93(m,2H),2.67–2.60(m,2H),2.60–2.54(m,2H),2.06–1.98(m,3H), 1.93–1.87(m,3H),1.86–1.73(m,5H),1.62–1.56(m,3H)。(1R,5S)-8-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diaza Heterobicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester was used as raw material, and (hexahydro-1H-pyrrolin-7a-yl)methanol was used instead of (2R,8S)-2-fluoro-1,2,3 , 5,6,7-hexahydropyrrozin-7-ylmethanol was synthesized according to step HJ of Example 9 to obtain a salt containing two formic acids (4.72 mg, 0.007 mmol). LCMS: m/z 607.6(M+H). 1 H NMR (600MHz, DMSO-d 6 ) δ8.28 (s, 2H), 7.99 (dd, J = 9.2, 5.9Hz, 1H), 7.48 (t, J = 8.9Hz, 1H), 7.41 (d, J＝2.5Hz,1H),7.25(d,J＝2.5Hz,1H),4.88(s,1H),4.76–4.69(m,2H),4.10–4.04(m,2H),3.87(d,J ＝6.4Hz,1H),2.98–2.93(m,2H),2.67–2.60(m,2H),2.60–2.54(m,2H),2.06–1.98(m,3H), 1.93–1.87(m,3H),1.86–1.73(m,5H),1.62–1.56(m,3H).
实施例28制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-((1-(哌啶-1-甲基)环丙基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基--6-氟萘-2-酚
Example 28 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((1 -(Piperidine-1-methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl--6-fluoronaphthalen-2-phenol
用(1-(哌啶-1-甲基)环丙基)甲醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，按到实施例9步骤H-J进行合成，得到实施例28为含0.5个甲酸的盐(1.51mg，0.002mmol)。LCMS:m/z 635.6(M+H)。1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.14(s,0.5H),8.01(dd,J＝9.2,5.9Hz,1H),7.50(t,J＝9.0Hz,1H),7.43(d,J＝2.5Hz,1H),7.22(d,J＝2.5Hz,1H),4.99–4.75(m,2H),4.63–4.43(m,2H),4.42–4.25(m,3H),4.23–3.75(m,7H),2.82–2.62(m,2H),1.90–1.32(m,10H),0.82–0.69(m,2H),0.66–0.49(m,2H)。Use (1-(piperidin-1-methyl)cyclopropyl)methanol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol , proceed to step HJ of Example 9 for synthesis, and obtain Example 28 as a salt containing 0.5 formic acid (1.51 mg, 0.002 mmol). LCMS: m/z 635.6(M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.26 (s, 1H), 8.14 (s, 0.5H), 8.01 (dd, J = 9.2, 5.9Hz, 1H), 7.50 (t, J = 9.0Hz ,1H),7.43(d,J＝2.5Hz,1H),7.22(d,J＝2.5Hz,1H),4.99–4.75(m,2H),4.63–4.43(m,2H),4.42–4.25( m,3H),4.23–3.75(m,7H),2.82–2.62(m,2H),1.90–1.32(m,10H),0.82–0.69(m,2H),0.66–0.49(m,2H).
实施例29制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((S)-1-(4,4-二氟哌啶-1-基)丙-2-基)醇)-5-乙炔基-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基--6-氟萘-2-酚
Example 29 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((S)-1-(4,4 -Difluoropiperidin-1-yl)prop-2-yl)ol)-5-ethynyl-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl--6 -Fluoronaphen-2-phenol
用(S)-1-(4,4-二氟哌啶-1-基)丙-2-醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，按到实施例9步骤H-J进行合成，得到实施例29为含一个甲酸的盐(16.72mg，0.024mmol)。LCMS:m/z 645.6(M+H)。1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.00(dd,J＝9.2,5.9Hz,1H),7.49(t,J＝9.0Hz,1H),7.41(d,J＝2.5Hz,1H),7.23(dd,J＝8.9,2.5Hz,1H),5.47–5.38(m,1H),4.78(s,1H),3.83(br.s,1H),3.76(s,1H),3.62–3.45(m,3H),2.75–2.53(m,8H),1.92–1.77(m,5H),1.63–1.53(m,3H),1.32(dd,J＝6.3,4.4Hz,3H)。Use (S)-1-(4,4-difluoropiperidin-1-yl)propan-2-ol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexane Hydropyrrozin-7-ylmethanol was synthesized according to step HJ of Example 9, and Example 29 was obtained as a salt containing a formic acid (16.72 mg, 0.024 mmol). LCMS: m/z 645.6(M+H). 1 H NMR (400MHz, DMSO-d6) δ8.23(s,1H),8.00(dd,J＝9.2,5.9Hz,1H),7.49(t,J＝9.0Hz,1H),7.41(d,J ＝2.5Hz,1H),7.23(dd,J＝8.9,2.5Hz,1H),5.47–5.38(m,1H),4.78(s,1H),3.83(br.s,1H),3.76(s, 1H),3.62–3.45(m,3H),2.75–2.53(m,8H),1.92–1.77(m,5H),1.63–1.53(m,3H),1.32(dd,J＝6.3,4.4Hz, 3H).
实施例30制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-(((S)-1-(吡咯烷-1-基)丙-2-基)醇)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基--6-氟萘-2-酚
Example 30 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((( S)-1-(pyrrolidin-1-yl)prop-2-yl)ol)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl--6-fluoronaphthalene-2- phenol
用((S)-1-(吡咯烷-1-基)丙-2-醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，按到实施例9步骤H-J进行合成，得到实施例30为含一个甲酸的盐(9.09mg，0.014mmol)。LCMS:m/z 595.6(M+H)。1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),8.00(dd,J＝9.2,5.9Hz,1H),7.49(t,J＝9.0Hz,1H),7.41(d,J＝2.6Hz,1H),7.23(d,J＝2.4Hz,1H),5.41–5.33(m,1H),4.78(s,1H),3.82(d,J＝7.9Hz,1H),3.57(br.s,4H),2.76(dd,J＝12.5,6.9Hz,1H),2.69–2.52(m,7H),1.69–1.43(m,8H),1.33(t,J＝6.0Hz,3H)。Use ((S)-1-(pyrrolidin-1-yl)propan-2-ol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozine-7 -Methanol was synthesized according to step HJ of Example 9, and Example 30 was obtained as a salt containing a formic acid (9.09 mg, 0.014 mmol). LCMS: m/z 595.6 (M+H). 1 H NMR (400MHz, DMSO-d 6 )δ8.19(s,1H),8.00(dd,J＝9.2,5.9Hz,1H),7.49(t,J＝9.0Hz,1H),7.41(d,J＝2.6Hz,1H ),7.23(d,J＝2.4Hz,1H),5.41–5.33(m,1H),4.78(s,1H),3.82(d,J＝7.9Hz,1H),3.57(br.s,4H) ,2.76(dd,J＝12.5,6.9Hz,1H),2.69–2.52(m,7H),1.69–1.43(m,8H),1.33(t,J＝6.0Hz,3H).
实施例31制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-(((S)-1-((R)-3-氟吡咯烷-1-基)丙-2-基)醇)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基--6-氟萘-2-酚
Example 31 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((( S)-1-((R)-3-fluoropyrrolidin-1-yl)prop-2-yl)ol)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-- 6-fluoronaphthalene-2-phenol
用(S)-1-((R)-3-氟吡咯烷-1-基)丙-2-醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，按到实施例9步骤H-J进行合成，得到实施例31为含一个甲酸的盐(3.1mg，0.005mmol)。LCMS:m/z 613.6(M+H)。1H NMR(400MHz,Methanol-d4)δ8.53(s,1H),7.89(dd,J＝9.2,5.7Hz,1H),7.41–7.31(m,2H),7.24(t,J＝3.2Hz,1H),5.60(s,1H),5.26–5.08(m,2H),4.62(s,1H),4.31(s,1H),4.10–3.80(m,4H),3.17–3.12(m,1H),3.06–2.94(m,2H),2.92–2.75(m,2H),2.73–2.61(m,2H),2.26–2.08(m,2H),1.96–1.68(m,4H),1.45(dd,J＝6.2,4.1Hz,3H)。Use (S)-1-((R)-3-fluoropyrrolidin-1-yl)propan-2-ol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7- Hexahydropyrrozin-7-ylmethanol was synthesized according to step HJ of Example 9 to obtain Example 31 as a salt containing a formic acid (3.1 mg, 0.005 mmol). LCMS: m/z 613.6(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.53 (s, 1H), 7.89 (dd, J = 9.2, 5.7Hz, 1H), 7.41–7.31 (m, 2H), 7.24 (t, J = 3.2 Hz,1H),5.60(s,1H),5.26–5.08(m,2H),4.62(s,1H),4.31(s,1H),4.10–3.80(m,4H),3.17–3.12(m, 1H),3.06–2.94(m,2H),2.92–2.75(m,2H),2.73–2.61(m,2H),2.26–2.08(m,2H),1.96–1.68(m,4H),1.45( dd,J＝6.2,4.1Hz,3H).
实施例32制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-((1-((4-甲基哌嗪-1-基)甲基)环丙基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基--6-氟萘-2-酚
Example 32 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((1-((4-methylpiperazin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
用1-((4-甲基哌嗪-1-基)甲基)环丙基)甲醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，按到实施例9步骤H-J进行合成，得到实施例32为含 一个甲酸的盐(5.15mg，0.007mmol)。LCMS:m/z 650.6(M+H)。1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),7.99(t,J＝7.5Hz,1H),7.48(t,J＝9.0Hz,1H),7.41(br.s,1H),7.22(s,1H),4.76(s,1H),4.34–4.24(m,2H),3.80(s,2H),3.52–3.49(m,6H),2.45–2.22(m,8H),2.13(s,3H),2.08–2.05(m,1H),1.61(br.s,3H),1.23(br.s,1H),0.63(t,J＝5.1Hz,2H),0.41(t,J＝5.1Hz,2H)。Use 1-((4-methylpiperazin-1-yl)methyl)cyclopropyl)methanol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrole Azin-7-ylmethanol is synthesized according to step HJ of Example 9 to obtain Example 32 containing A formic acid salt (5.15 mg, 0.007 mmol). LCMS: m/z 650.6(M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.24 (s, 1H), 7.99 (t, J = 7.5Hz, 1H), 7.48 (t, J = 9.0Hz, 1H), 7.41 (br.s, 1H),7.22(s,1H),4.76(s,1H),4.34–4.24(m,2H),3.80(s,2H),3.52–3.49(m,6H),2.45–2.22(m,8H) ,2.13(s,3H),2.08–2.05(m,1H),1.61(br.s,3H),1.23(br.s,1H),0.63(t,J＝5.1Hz,2H),0.41(t ,J=5.1Hz,2H).
实施例33制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-(((S)-1-异丙基吡咯烷-2-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基--6-氟萘-2-酚
Example 33 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((( S)-1-isopropylpyrrolidin-2-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl--6-fluoronaphthalen-2-phenol
用(S)-(1-异丙基吡咯烷-2-基)甲醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，按到实施例9步骤H-J进行合成，得到实施例33为含一个甲酸的盐(5.97mg，0.009mmol)。LCMS:m/z 609.6(M+H)。1H NMR(400MHz,Methanol-d4)δ8.55(s,1H),7.90(dd,J＝9.2,5.7Hz,1H),7.40–7.32(m,2H),7.25(t,J＝2.8Hz,1H),4.69–4.59(m,2H),4.33(s,1H),4.00–3.79(m,3H),3.72–3.58(m,3H),3.45–3.35(m,2H),3.23–3.13(m,2H),2.28–2.17(m,2H),2.05(br.s,3H),1.82(br.s,3H),1.65–1.50(m,1H),1.38(d,J＝6.6Hz,3H),1.33(d,J＝6.5Hz,3H)。Use (S)-(1-isopropylpyrrolidin-2-yl)methanol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-yl Methanol was synthesized according to step HJ of Example 9, and Example 33 was obtained as a salt containing a formic acid (5.97 mg, 0.009 mmol). LCMS: m/z 609.6(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.55 (s, 1H), 7.90 (dd, J = 9.2, 5.7Hz, 1H), 7.40–7.32 (m, 2H), 7.25 (t, J = 2.8 Hz,1H),4.69–4.59(m,2H),4.33(s,1H),4.00–3.79(m,3H),3.72–3.58(m,3H),3.45–3.35(m,2H),3.23– 3.13(m,2H),2.28–2.17(m,2H),2.05(br.s,3H),1.82(br.s,3H),1.65–1.50(m,1H),1.38(d,J＝6.6 Hz, 3H), 1.33 (d, J = 6.5 Hz, 3H).
实施例34制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((S)-1-乙基吡咯烷-2-基)甲氧基)-5-乙炔基-8-氟-吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基--6-氟萘-2-酚
Example 34 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((S)-1-ethylpyrrolidine) -2-yl)methoxy)-5-ethynyl-8-fluoro-pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl--6-fluoronaphthalen-2-phenol
用(S)-(1-乙基吡咯烷-2-基)甲醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，按到实施例9步骤H-J进行合成，得到实施例34为含一个甲酸的盐(3.72mg，23％收率)。LCMS:m/z 595.6(M+H)。1H NMR(400MHz,Methanol-d4)δ8.52(s,1H),7.90(dd,J＝9.2,5.7Hz,1H),7.40–7.33(m,2H),7.25(t,J＝2.8Hz,1H),4.80–4.72(m,1H),4.70–4.58(m,2H),4.35(s,1H),4.09–3.84(m,2H),3.77(br.s,3H),3.66–3.47(m,3H),3.14–3.02(m,2H),2.39–2.27(m,1H),2.17–1.95(m,4H),1.92–1.72(m,3H),1.69–1.57(m,1H),1.36(t,J＝7.2Hz,3H)。Use (S)-(1-ethylpyrrolidin-2-yl)methanol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol , proceed to step HJ of Example 9 for synthesis, and obtain Example 34 as a salt containing a formic acid (3.72 mg, 23% yield). LCMS: m/z 595.6(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.52 (s, 1H), 7.90 (dd, J = 9.2, 5.7Hz, 1H), 7.40–7.33 (m, 2H), 7.25 (t, J = 2.8 Hz,1H),4.80–4.72(m,1H),4.70–4.58(m,2H),4.35(s,1H),4.09–3.84(m,2H),3.77(br.s,3H),3.66– 3.47(m,3H),3.14–3.02(m,2H),2.39–2.27(m,1H),2.17–1.95(m,4H),1.92–1.72(m,3H),1.69–1.57(m,1H ), 1.36 (t, J = 7.2Hz, 3H).
实施例35制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-((1-(((S)-2-甲基吗啉基)甲基)环丙基)甲氧基)吡啶 并[4,3-d]嘧啶-7-基)-5-乙炔基--6-氟萘-2-酚
Example 35 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-8-fluoro-2-((1 -(((S)-2-methylmorpholinyl)methyl)cyclopropyl)methoxy)pyridine And[4,3-d]pyrimidin-7-yl)-5-ethynyl--6-fluoronaphthalene-2-phenol
用(S)-(1-((2-甲基吗啉基)甲基)环丙基)甲醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，按到实施例9步骤H-J进行合成，得到实施例35为含一个甲酸的盐(3.09mg，0.004mmol)。LCMS:m/z 651.6(M+H)。1H NMR(600MHz,Methanol-d4)δ8.48(s,1H),7.89(dd,J＝9.1,5.6Hz,1H),7.39–7.33(m,2H),7.24(s,1H),4.67–4.57(m,1H),4.47(s,2H),4.32(s,1H),4.10–3.89(m,4H),3.82(d,J＝11.2Hz,1H),3.64–3.54(m,2H),3.38(d,J＝2.7Hz,1H),3.01–2.93(m,2H),2.55(d,J＝12.6Hz,1H),2.47–2.41(m,1H),2.14(t,J＝11.5Hz,1H),2.00–1.88(m,3H),1.88–1.73(m,3H),1.12(dd,J＝6.3,3.5Hz,3H),0.76(br.s,2H),0.56(d,J＝4.7Hz,2H)。Using (S)-(1-((2-methylmorpholinyl)methyl)cyclopropyl)methanol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizine-7-ylmethanol, the synthesis was carried out according to steps HJ of Example 9 to obtain Example 35 as a salt containing a formic acid (3.09 mg, 0.004 mmol). LCMS: m/z 651.6 (M+H). 1 H NMR (600 MHz, Methanol-d 4 )δ8.48(s,1H),7.89(dd,J＝9.1,5.6Hz,1H),7.39–7.33(m,2H),7.24(s,1H),4.67–4.57(m,1H),4.47(s,2H),4.32(s,1H),4.10–3.89(m,4H),3.82(d,J＝11.2Hz,1H),3.64–3.54(m,2H),3.38(d,J＝2.7H z, 1H), 3.01–2.93 (m, 2H), 2.55 (d, J = 12.6 Hz, 1H), 2.47–2.41 (m, 1H), 2.14 (t, J = 11.5 Hz, 1H), 2.00–1.88 (m, 3H), 1.88–1.73 (m, 3H), 1.12 (dd, J = 6.3, 3.5 Hz, 3H), 0.76 (br. s, 2H), 0.56 (d, J = 4.7 Hz, 2H).
实施例36制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-8-氟-2-(((R)-1-((R)-3-氟吡咯烷-1-基)丙-2-基)醇)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基--6-氟萘-2-酚
Example 36 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-ethynyl-8-fluoro-2-(((R)-1-((R)-3-fluoropyrrolidin-1-yl)propan-2-yl)alcohol)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
用(R)-1-((R)-3-氟吡咯烷-1-基)丙-2-醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，按到实施例9步骤H-J进行合成，得到实施例36为含两个甲酸的盐(2.46mg，5％收率)。LCMS:m/z 613.6(M+H)。1H NMR(600MHz,Methanol-d4)δ8.44(s,2H),7.89(dd,J＝9.1,5.6Hz,1H),7.39–7.34(m,2H),7.24(t,J＝2.5Hz,1H),5.62(s,1H),5.26–5.13(m,1H),4.49(br.s,1H),4.33(s,1H),4.14–3.95(m,4H),3.19–3.10(m,2H),3.07–2.87(m,3H),2.74–2.66(m,1H),2.26–2.12(m,2H),2.08–1.82(m,6H),1.46(d,J＝5.8Hz,3H)。Use (R)-1-((R)-3-fluoropyrrolidin-1-yl)propan-2-ol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7- Hexahydropyrrozin-7-ylmethanol was synthesized according to step HJ of Example 9, and Example 36 was obtained as a salt containing two formic acids (2.46 mg, 5% yield). LCMS: m/z 613.6(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.44 (s, 2H), 7.89 (dd, J = 9.1, 5.6Hz, 1H), 7.39–7.34 (m, 2H), 7.24 (t, J = 2.5 Hz,1H),5.62(s,1H),5.26–5.13(m,1H),4.49(br.s,1H),4.33(s,1H),4.14–3.95(m,4H),3.19–3.10( m,2H),3.07–2.87(m,3H),2.74–2.66(m,1H),2.26–2.12(m,2H),2.08–1.82(m,6H),1.46(d,J＝5.8Hz, 3H).
实施例37制备8-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-5-甲基吡啶并[4,3-d]嘧啶-7-基)-1-萘甲酰胺
Example 37 Preparation of 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyridinyl-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-1-naphthylcarboxamide
反应式如下：
The reaction formula is as follows:
步骤A.(1R,5S)-3-(7-(8-氰基萘-1-基)-8-氟-5-甲基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯：将(1R,5S)-3-(7-氯-8-氟-5-甲基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(500mg，0.907mmol)，8-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-1-萘腈(380mg,1.361mmol)，甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(66mg，0.091mmol)，磷酸钾(385mg，1.815mmol)，在THF/H2O＝4/1的溶液中氮气保护加热至65℃搅拌3小时。反应混合物用乙酸乙酯(200ml)稀释并用水(200ml×3)萃取，有机相用饱和NaCl洗涤，经Na2SO4干燥，通过旋转蒸发浓缩，得到残余物。然后通过柱色谱(SiO2，二氯甲烷/甲醇＝10/1)纯化残余物，得到产物(370mg，59％收率)为黄色固体。LCMS:m/z 571.6(M+H)。Step A. (1R,5S)-3-(7-(8-cyanonaphth-1-yl)-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d ]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(7-chloro-8-fluoro-5- Methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester ( 500mg, 0.907mmol), 8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1-naphthalenenitrile (380mg, 1.361mmol), Methane [n-Butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium sulfonate (66 mg, 0.091 mmol), potassium phosphate (385 mg, 1.815 mmol), In a solution of THF/H 2 O = 4/1, it was heated to 65°C under nitrogen protection and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (200 ml) and extracted with water (200 ml x 3), the organic phase was washed with saturated NaCl, dried over Na 2 SO 4 and concentrated by rotary evaporation to give a residue. The residue was then purified by column chromatography (SiO 2 , dichloromethane/methanol = 10/1) to obtain the product (370 mg, 59% yield) as a yellow solid. LCMS: m/z 571.6(M+H).
步骤B.(1R,5S)-3-(7-(8-胺基甲酰基萘-1-基)-8-氟-5-甲基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯：(1R,5S)-3-(7-(8-氰基萘-1-基)-8-氟-5-甲基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯(20mg，0.035mmol)的浓硫酸溶液加热至95℃搅拌2小时。将反应混合物用10M的氢氧化钠溶液冰浴下淬灭，并用二氯甲烷/甲醇＝10/1的混合液萃取(100ml×3)，经Na2SO4干燥，通过旋转蒸发浓缩，得到粗品。不做后处理即用与下一步。Step B. (1R,5S)-3-(7-(8-carbamoylnaphthalen-1-yl)-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3 -d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-carboxylic acid tert-butyl ester: (1R,5S)-3-(7-(8-cyanonaphthalene- 1-yl)-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] A concentrated sulfuric acid solution of octyl-8-carboxylic acid tert-butyl ester (20 mg, 0.035 mmol) was heated to 95°C and stirred for 2 hours. The reaction mixture was quenched with 10M sodium hydroxide solution in an ice bath, extracted with a mixture of dichloromethane/methanol=10/1 (100ml×3), dried over Na2SO4 , and concentrated by rotary evaporation to obtain the crude product . Ready to use without any post-processing.
步骤C.(1R,5S)-3-(7-(8-胺基甲酰基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-5-甲基吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯：向(1R,5S)-3-(7-(8-胺基甲酰基萘-1-基)-8-氟-5-甲基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯(20mg，0.034mmol)的二氯甲烷溶液(2ml)中加入间氯过氧苯甲酸(11mg，0.051mmol)，在25℃中搅拌2小时。饱和硫代硫酸钠水溶液淬灭反应液，并用二氯甲烷(50ml)和碳酸钠水溶液萃取，经Na2SO4干燥，通过旋转蒸发浓缩，得到粗品不做纯化即用于下一步。向粗品(0.034mmol)，[(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(0.068mmol)的THF溶液(1ml)中在氮气环境下0℃缓慢加入双三甲基硅基胺基锂 (0.102mmol，3当量)并在0℃下搅拌1小时。将反应混合物用乙酸乙酯(100,ml)稀释并用水(200ml×3)萃取，经Na2SO4干燥，通过旋转蒸发浓缩，得到残余物。然后通过柱色谱(SiO2，二氯甲烷/甲醇＝10/1)纯化残余物，得到产物(15mg，65％收率)为黄色固体。LCMS:m/z 699.8(M+H)。Step C. (1R,5S)-3-(7-(8-carbamoylnaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: To (1R,5S)-3-(7-( To a solution of tert-butyl (2-(4-(2-aminoformylnaphthyl)naphthyl)-8-fluoro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.034 mmol) in dichloromethane (2 ml) was added m-chloroperbenzoic acid (11 mg, 0.051 mmol) and stirred at 25°C for 2 hours. The reaction solution was quenched with saturated aqueous sodium thiosulfate solution, extracted with dichloromethane (50 ml) and aqueous sodium carbonate solution, dried over Na 2 SO 4 , and concentrated by rotary evaporation to obtain a crude product that was used in the next step without purification. To a THF solution (1 ml) of the crude product (0.034 mmol) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (0.068 mmol) was slowly added lithium bis(trimethylsilyl)amide at 0°C under nitrogen atmosphere. (0.102mmol, 3 equivalents) and stirred at 0°C for 1 hour. The reaction mixture was diluted with ethyl acetate (100ml) and extracted with water (200ml×3), dried over Na 2 SO 4 , and concentrated by rotary evaporation to obtain a residue. The residue was then purified by column chromatography (SiO 2 , dichloromethane/methanol=10/1) to give the product (15mg, 65% yield) as a yellow solid. LCMS: m/z 699.8 (M+H).
步骤D.8-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-5-甲基吡啶并[4,3-d]嘧啶-7-基)-1-萘甲酰胺：将(1R,5S)-3-(7-(8-胺基甲酰基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-5-甲基吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯(10mg，0.014mmol)在二氯甲烷(2mL)中的溶液逐滴加入盐酸二氧六环溶液(4M)。室温搅拌40min。浓缩，将残余物倒入饱和NaHCO3(20mL)和DCM/MeOH＝10/1(15mL)的混合物中。用DCM/MeOH＝10/1(2×15mL)萃取水层，合并的有机层用盐水(15mL)洗涤，经Na2SO4干燥，过滤并真空浓缩。通过快速柱色谱纯化残余物，用0-20％MeOH/CH2Cl、2％NH4OH洗脱，然后通过制备型HPLC(5-95％ACN/水/0.1％FA，经20min)纯化。浓缩，冻干，得到实施例37为含一个甲酸的盐(1mg,0.002mmol)。LCMS:m/z 600.6(M+H)。Step D. 8-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyridinyl-7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-7-yl)-1-naphthylcarboxamide: (1R,5S)-3-(7-(8-carbamoylnaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine ring -7a(5H)-yl)methoxy)-5-methylpyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- A solution of tert-butyl formate (10 mg, 0.014 mmol) in dichloromethane (2 mL) was added dropwise to a solution of dioxane hydrochloride (4 M). Stir at room temperature for 40 minutes. Concentrate and pour the residue into a mixture of saturated NaHCO 3 (20 mL) and DCM/MeOH=10/1 (15 mL). The aqueous layer was extracted with DCM/MeOH = 10/1 (2 x 15 mL) and the combined organic layers were washed with brine (15 mL), dried over Na2SO4 , filtered and concentrated in vacuo . The residue was purified by flash column chromatography, eluting with 0-20% MeOH/ CH2Cl , 2% NH4OH , then by preparative HPLC (5-95% ACN/water/0.1% FA over 20 min). Concentrate and freeze-dry to obtain Example 37 as a salt containing a formic acid (1 mg, 0.002 mmol). LCMS: m/z 600.6(M+H).
1H NMR(400MHz,DMSO-d6)δ8.25(s,1H),8.13–8.07(m,2H),7.69(br.s,1H),7.67–7.61(m,2H),7.61–7.58(m,1H),7.56(d,J＝7.2Hz,1H),6.68(br.s,1H),5.38–5.22(m,1H),4.18–4.08(m,2H),4.08–3.99(m,2H),3.15–3.08(m,4H),3.06–3.01(m,2H),2.88–2.80(m,2H),2.47(br.s,3H),2.14(d,J＝4.2Hz,1H),2.06(d,J＝4.2Hz,1H),2.04–1.97(m,2H),1.89–1.74(m,4H),1.58–1.49(m,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.25(s,1H),8.13–8.07(m,2H),7.69(br.s,1H),7.67–7.61(m,2H),7.61–7.58 (m,1H),7.56(d,J＝7.2Hz,1H),6.68(br.s,1H),5.38–5.22(m,1H),4.18–4.08(m,2H),4.08–3.99(m ,2H),3.15–3.08(m,4H),3.06–3.01(m,2H),2.88–2.80(m,2H),2.47(br.s,3H),2.14(d,J＝4.2Hz,1H ), 2.06 (d, J = 4.2Hz, 1H), 2.04–1.97 (m, 2H), 1.89–1.74 (m, 4H), 1.58–1.49 (m, 2H).
实施例38制备4-(4-(3，6-二氮杂双环[3.1.1]庚烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡呤嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 38 Preparation of 4-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-Pyrazine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphth-2-phenol
反应式如下：
The reaction formula is as follows:
步骤A.7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶：向5，7-二氯-8-氟-2-(甲硫基)-4-(2，2，2-三氟乙氧基)吡啶并并[4,3-d]嘧啶(2.0g，5.5mmol)1,4-dioxane(20mL)溶液中加入双(三苯基膦)醋酸钯(374.5mg，0.5mmol)，三乙胺(1.6g，16.5mmol)和丙炔(1M)(8.2mL，8.2mmol)在氮气环境下105℃搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％乙酸乙酯/石油醚洗脱,得到产物(2g,4.3mmol,99％收率)，LCMS:m/z 366.0(M+H)。Step A. 7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d ]pyrimidine: to 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine ( 2.0g, 5.5mmol) 1,4-dioxane (20mL) solution was added with bis(triphenylphosphine)palladium acetate (374.5mg, 0.5mmol), triethylamine (1.6g, 16.5mmol) and propyne (1M) (8.2 mL, 8.2 mmol) was stirred at 105°C for 1 h under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluted with 0-10% ethyl acetate/petroleum ether to obtain the product (2g, 4.3mmol, 99% yield), LCMS: m/z 366.0 (M+H).
步骤B.3-(7-氯-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯：向7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶(2.0g，5.5mmol)的DMF(8mL)溶液中加入碳酸钾(2.2g，16.5mmol)和6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷(1.6g，8.2mmol)在室温搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％乙酸乙酯/石油醚洗脱,得到产物(2.0g,4.4mmol,25％收率)，LCMS:m/z 464.1(M+H)。Step B. tert-Butyl 3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate: To a solution of 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.0 g, 5.5 mmol) in DMF (8 mL) were added potassium carbonate (2.2 g, 16.5 mmol) and 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (1.6 g, 8.2 mmol) and stirred at room temperature for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl , dried over Na2S04 , the combined organic phases were filtered, dry loaded onto silica gel and purified by flash column chromatography eluting with 0-10% ethyl acetate in petroleum ether to give the product (2.0 g, 4.4 mmol, 25% yield), LCMS: m/z 464.1 (M+H).
步骤C.3-(8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯：将3-(7-氯-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯(2.0g，4.4mmol)、((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(2.9g，5.7mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(320.0mg，0.44mmol)、磷酸钾(2.8g，13.2mmol)在四氢呋喃(10mL)和水(1mL)中的溶液。氮气环境下65℃搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到化合物11(1.5g,1.8mmol,42％收率)。 Step C. 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2- (Methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl Esters: 3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-di Azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (2.0g, 4.4mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (2.9g, 5.7mmol), methanesulfonic acid [ n-Butylbis(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (320.0 mg, 0.44 mmol), potassium phosphate (2.8 g, 13.2 mmol) in tetrahydrofuran (10 mL) and water (1 mL). Stir at 65°C for 2 hours under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluted with 0-10% MeOH/DCM to obtain compound 11 (1.5 g, 1.8 mmol, 42% yield).
步骤D.3-(8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯：向3-(8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯(200mg，0.2mmol)的DCM(10mL)溶液中加入间氯过氧苯甲酸(51.6mg，0.3mmol)室温搅拌1h。加入硫代硫酸钠水溶液淬灭，使残余物在二氯甲烷与碳酸氢钠水溶液之间分配,并用二氯甲烷萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，浓缩，得到粗品(200mg)，直接用于下一步。LCMS:m/z 830.4(M+H)。Step D. 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyridazine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine- 4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester: to 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl) Ether)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidine- To a solution of 4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (200 mg, 0.2 mmol) in DCM (10 mL) was added m-chloroperoxybenzoic acid (51.6 mg , 0.3 mmol) and stirred at room temperature for 1 h. Aqueous sodium thiosulfate solution was added to quench, the residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution, and the aqueous layer was extracted with dichloromethane and the organic phase was washed with saturated NaCl, dried over Na2SO4 , and concentrated , The crude product (200 mg) was obtained and used directly in the next step. LCMS: m/z 830.4(M+H).
氮气环境和0℃下，向粗品(200mg，0.2mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(47.0mg，0.3mmol)的THF(3mL)溶液中逐滴加入LiHMDS(0.4ml,0.4mmol)搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(100.0mg,0.1mmol,45％收率)，LCMS:m/z 925.5(M+H)。Under nitrogen atmosphere and 0°C, add crude product (200 mg, 0.2 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-yl]methanol (47.0 mg, 0.3 mmol) in THF (3 mL) was added dropwise LiHMDS (0.4 ml, 0.4 mmol) and stirred for 1 h. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluted with 0-10% MeOH/DCM to obtain the product (100.0 mg, 0.1 mmol, 45% yield), LCMS: m/z 925.5 (M+H).
步骤E.3-(7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡呤嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯：将3-(8-氟-7-(7-氟-3-(甲氧基甲醚)-8-((三异丙基硅基)乙炔基)萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯(100.0mg，0.1mmol)、氟化铯(60.0mg，0.4mmol)在DMF(3mL)中的溶液。氮气环境下室温搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(80mg,0.1mmol,96％收率)，LCMS:m/z 769.3(M+H)。Step E. 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethyl ether)naphthalen-1-yl)8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrimidin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diaza Heterobicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester: 3-(8-fluoro-7-(7-fluoro-3-(methoxymethyl ether)-8-(triisopropyl Silyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridazin-7a(5H)-yl)methoxy)-5-( Propargyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (100.0 mg, 0.1 mmol), Cesium fluoride (60.0 mg, 0.4 mmol) in DMF (3 mL). Stir at room temperature for 1 hour under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluted with 0-10% MeOH/DCM to obtain the product (80 mg, 0.1 mmol, 96% yield), LCMS: m/z 769.3 (M+H).
步骤F.4-(4-(3，6-二氮杂双环[3.1.1]庚烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡呤嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚：向3-(7-(8-乙炔基-7-氟-3-(甲氧基甲醚)萘-1-基)8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡呤嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯(80.0mg，0.1mmol)的二氯甲烷(3mL)溶液中逐滴加入三氟乙酸(0.5ml)。室温搅拌20min。浓缩，将残余物倒入饱和NaHCO3(20mL)和DCM:MeOH(10:1)(15mL)的混合物中。用DCM:MeOH(10:1)(2×15mL)萃取水层，合并的有机层用盐水(15mL)洗涤，经Na2SO4干燥，过滤并真空浓缩。然后通过制备型HPLC(5-95％ACN/水/0.1％FA，经20min)纯化。冻干，得到实施例38为含一个甲酸的盐(7.32mg,0.01mmol)。LCMS:m/z 625.2(M+H)。1H NMR(600MHz,Methanol-d4)δ8.53(s,1H),7.89(dd,J＝9.1,5.6Hz,1H),7.38 (d,J＝2.5Hz,1H),7.35(t,J＝8.9Hz,1H),7.25(t,J＝2.6Hz,1H),5.46–5.33(m,1H),5.05–4.96(m,1H),4.58–4.36(m,4H),4.16(br.s,3H),3.50(s,1H),3.46–3.36(m,2H),3.16(br.s,1H),2.94(br.s,1H),2.48–2.28(m,3H),2.22(br.s,1H),2.20(s,3H),2.11(br.s,2H),1.96(t,J＝13.4Hz,2H)。Step F. 4-(4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrazine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene -2-Phenol: To 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethylether)naphth-1-yl)8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrimidin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6 - To a solution of diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (80.0 mg, 0.1 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 ml) dropwise. Stir at room temperature for 20 minutes. Concentrate and pour the residue into a mixture of saturated NaHCO3 (20 mL) and DCM:MeOH (10:1) (15 mL). The aqueous layer was extracted with DCM:MeOH (10:1) (2 x 15 mL) and the combined organic layers were washed with brine (15 mL), dried over Na2SO4 , filtered and concentrated in vacuo . It was then purified by preparative HPLC (5-95% ACN/water/0.1% FA over 20 min). After lyophilization, Example 38 was obtained as a salt containing a formic acid (7.32 mg, 0.01 mmol). LCMS: m/z 625.2(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.53 (s, 1H), 7.89 (dd, J = 9.1, 5.6Hz, 1H), 7.38 (d,J＝2.5Hz,1H),7.35(t,J＝8.9Hz,1H),7.25(t,J＝2.6Hz,1H),5.46–5.33(m,1H),5.05–4.96(m, 1H),4.58–4.36(m,4H),4.16(br.s,3H),3.50(s,1H),3.46–3.36(m,2H),3.16(br.s,1H),2.94(br. s,1H),2.48–2.28(m,3H),2.22(br.s,1H),2.20(s,3H),2.11(br.s,2H),1.96(t,J＝13.4Hz,2H) .
实施例39制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-(环丙烷乙炔基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 39 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-(cyclopropaneethynyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
反应式如下：
The reaction formula is as follows:
步骤H.7-氯-5-(环丙烷乙炔基)-8-氟-2-(甲硫基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶：将5，7-二氯-8-氟-2-(甲硫基)-4-(2，2，2-三氟乙氧基)吡啶并并[4,3-d]嘧啶(2.0g，5.5mmol)在1,4-dioxane(20mL)中的溶液加入双(三苯基膦)醋酸钯(374.5mg，0.5mmol)，三乙胺(1.6g，16.5mmol)和环丙乙炔(561.0mg，8.2mmol)在氮气环境下105℃搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％乙酸乙酯/石油醚洗脱,得到产物(2g,5.1mmol,90％收率)，LCMS:m/z 392.0(M+H)。Step H. 7-Chloro-5-(cyclopropaneethynyl)-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine: 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.0 g, 5.5 mmol) in 1,4-dioxane (20 mL) was added bis(triphenylphosphine)palladium acetate (374.5 mg, 0.5 mmol), triethylamine (1.6 g, 16.5 mmol) and cyclopropyl Acetylene (561.0 mg, 8.2 mmol) was stirred at 105°C for 1 h under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluted with 0-10% ethyl acetate/petroleum ether to obtain the product (2g, 5.1mmol, 90% yield), LCMS: m/z 392.0 (M+H).
以7-氯-5-(环丙烷乙炔基)-8-氟-2-(甲硫基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶为原料，按到实施例26的步骤C至G的方法合成实施例39为含一个甲酸的盐(20.2mg,0.03mmol)。LCMS:m/z 665.4(M+H)。1H NMR(600MHz,DMSO-d6)δ8.24(s,1H),7.99(dd,J＝9.2,5.9Hz,1H),7.48(t,J＝9.0Hz,1H),7.40(d,J＝2.5Hz,1H),7.20(s,1H),5.35–5.22(m,1H),4.13(dd,J＝10.3,5.6Hz,1H),4.02(dd,J＝10.3,3.9Hz,1H),3.78(s,1H),3.60–3.50(m,5H),3.12–3.04(m,3H),3.03(d,J＝2.4Hz,1H),2.86–2.80(m,2H),2.11(d,J＝3.8Hz,1H),2.06(d,J＝3.9Hz,1H),2.02–1.97(m,1H),1.88–1.83(m,1H),1.82–1.72(m,3H),1.71–1.64(m,1H),1.61–1.54(m,2H),1.01–0.97(m,2H),0.85–0.81(m,2H)。7-Chloro-5-(cyclopropaneethynyl)-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d] Pyrimidine was used as raw material, and the method of steps C to G of Example 26 was followed to synthesize Example 39 into a salt containing a formic acid (20.2 mg, 0.03 mmol). LCMS: m/z 665.4(M+H). 1 H NMR (600MHz, DMSO-d 6 ) δ8.24 (s, 1H), 7.99 (dd, J = 9.2, 5.9Hz, 1H), 7.48 (t, J = 9.0Hz, 1H), 7.40 (d, J＝2.5Hz,1H),7.20(s,1H),5.35–5.22(m,1H),4.13(dd,J＝10.3,5.6Hz,1H),4.02(dd,J＝10.3,3.9Hz,1H ),3.78(s,1H),3.60–3.50(m,5H),3.12–3.04(m,3H),3.03(d,J＝2.4Hz,1H),2.86–2.80(m,2H),2.11( d,J＝3.8Hz,1H),2.06(d,J＝3.9Hz,1H),2.02–1.97(m,1H),1.88–1.83(m,1H),1.82–1.72(m,3H),1.71 –1.64(m,1H),1.61–1.54(m,2H),1.01–0.97(m,2H),0.85–0.81(m,2H).
实施例40 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-8-基)-8-氟-2- (((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 40 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine-7 -yl)-5-ethynyl-6-fluoronaphthalene-2-phenol
反应式如下：
The reaction formula is as follows:
步骤A.(1R，5S)-8-(7-氯-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯：将7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶(120mg，0.355mmol)，3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯(113mg,0.533mmol)，碳酸钾(98mg，0.71mmol)的N,N-二甲基甲酰胺溶液在室温下搅拌2小时。反应混合物用乙酸乙酯稀释并加水萃取，有机相用饱和NaCl洗涤，经Na2SO4干燥，通过旋转蒸发浓缩，得到残余物。然后通过柱色谱(SiO2，石油醚/乙酸乙酯＝6/1)纯化残余物，得到产物(80mg，51％收率)为黄色固体。Step A. (1R,5S)-8-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl) -3,8-Diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester: 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4- (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (120mg, 0.355mmol), tert. 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid A solution of butyl ester (113 mg, 0.533 mmol) and potassium carbonate (98 mg, 0.71 mmol) in N,N-dimethylformamide was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and extracted with water, the organic phase was washed with saturated NaCl, dried over Na 2 SO 4 and concentrated by rotary evaporation to give a residue. The residue was then purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate = 6/1) to obtain the product (80 mg, 51% yield) as a yellow solid.
LCMS:m/z478.4(M+H)。LCMS: m/z478.4(M+H).
以(1R，5S)-8-(7-氯-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯为原料，按到实施例38的步骤C至F的合成方法合成实施例40为含一个甲酸的盐(12.18mg,0.018mmol),LCMS:m/z 639.7(M+H)。1H NMR(400MHz,Methanol-d4)δ8.52(s,1H),7.89(dd,J＝9.1,5.6Hz,1H),7.38(d,J＝2.3Hz,1H),7.34(d,J＝9.0Hz,1H),7.24(t,J＝2.3Hz,1H),5.53–5.36(m,1H),5.10–4.95(m,3H),4.56–4.40(m,2H),3.70–3.48(m,4H),3.28–3.11(m,2H),2.95(br.s,2H),2.60–2.25(m,5H),2.22(s,3H),2.20–2.11(m,3H),2.10–1.95(m,2H)。With (1R,5S)-8-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3 , 8-diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester was used as raw material, and the synthesis method of steps C to F in Example 38 was used to synthesize Example 40 into a salt containing a formic acid (12.18 mg, 0.018mmol), LCMS: m/z 639.7 (M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.52 (s, 1H), 7.89 (dd, J = 9.1, 5.6Hz, 1H), 7.38 (d, J = 2.3Hz, 1H), 7.34 (d, J＝9.0Hz,1H),7.24(t,J＝2.3Hz,1H),5.53–5.36(m,1H),5.10–4.95(m,3H),4.56–4.40(m,2H),3.70–3.48 (m,4H),3.28–3.11(m,2H),2.95(br.s,2H),2.60–2.25(m,5H),2.22(s,3H),2.20–2.11(m,3H),2.10 –1.95(m,2H).
实施例41 4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-(吗啉甲基)环丙烷基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 41 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(morpholinylmethyl)cyclopropane)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
反应式如下：
The reaction formula is as follows:
步骤A.(1R，5S)-3-(7-氯-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯：将7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶(120mg，0.355mmol)，(1R，5S)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(113mg,0.533mmol)，碳酸钾(98mg，0.71mmol)的N,N-二甲基甲酰胺溶液在室温下搅拌2小时。反应混合物用乙酸乙酯稀释并加水萃取，有机相用饱和NaCl洗涤，经Na2SO4干燥，通过旋转蒸发浓缩，得到残余物。然后通过柱色谱(SiO2，石油醚/乙酸乙酯＝6/1)纯化残余物，得到产物(80mg，51％收率)为黄色固体。LCMS:m/z478.4(M+H)。Step A. (1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl) -3,8-Diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester: 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4- (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (120mg, 0.355mmol), (1R,5S)-3,8-diazabicyclo[3.2.1]octane A solution of alkane-8-carboxylic acid tert-butyl ester (113 mg, 0.533 mmol) and potassium carbonate (98 mg, 0.71 mmol) in N,N-dimethylformamide was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and extracted with water, the organic phase was washed with saturated NaCl, dried over Na 2 SO 4 and concentrated by rotary evaporation to give a residue. The residue was then purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate = 6/1) to obtain the product (80 mg, 51% yield) as a yellow solid. LCMS: m/z478.4(M+H).
步骤B.4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚：将(1R，5S)-3-(7-氯-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯(2.0g，4.2mmol)、((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷(2.9g，5.7mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(320.0mg，0.44mmol)、磷酸钾(2.8g，13.2mmol)在四氢呋喃(10mL)和水(1mL)中的溶液。氮气环境下65℃搅拌2h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥装载到硅胶上并通过快速柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(1.7g,2.49mmol,60％收率)。Step B. 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)-5-(propanol) Alkynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphth-2-phenol: (1R,5S)- 3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo [3.2.1] Octyl-8-carboxylic acid tert-butyl ester (2.0g, 4.2mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetrahydrofuran) Methyl-1,3,2-dioxaborane-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (2.9g, 5.7mmol), methanesulfonic acid [n-butyldi (1-Adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium (320.0 mg, 0.44 mmol), potassium phosphate (2.8 g, 13.2 mmol) in tetrahydrofuran (10 mL) and Solution in water (1 mL). Stir at 65°C for 2 hours under nitrogen atmosphere. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc and the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried loaded onto silica gel and purified by flash column chromatography , eluting with 0-10% MeOH/DCM, the product (1.7g, 2.49mmol, 60% yield) was obtained.
以4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚为原料，用(1-(吗啉甲基)环丙基)甲醇代替(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基甲醇，按照实施例38的步骤D至F的合成方法制备实施例41为含一个甲酸的盐(16.2mg,0.023mmol)。LCMS:m/z 651.3(M+H)。1H NMR(400MHz,DMSO-d6)δ8.27(s,1H),7.99(dd,J＝9.2,5.9Hz,1H),7.48(t,J＝9.0Hz,1H),7.40(d,J＝2.6Hz,1H),7.21(d,J＝2.5Hz,1H),4.30(dd,J＝16.0,10.9Hz,2H),3.81–3.77(br.s,3H),3.56–3.50(m,7H),2.40–2.35(m,4H),2.33–2.23(m,3H),2.16(s,3H),1.70–1.36(m,4H),0.63(t,J＝5.1Hz,2H), 0.42(t,J＝5.2Hz,2H)。4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl) )pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphth-2-phenol as raw material, using (1-(morpholine Methyl)cyclopropyl)methanol instead of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrozin-7-ylmethanol, follow steps D to F of Example 38 The synthetic method of Preparation Example 41 contains a formic acid salt (16.2 mg, 0.023 mmol). LCMS: m/z 651.3(M+H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.27 (s, 1H), 7.99 (dd, J = 9.2, 5.9Hz, 1H), 7.48 (t, J = 9.0Hz, 1H), 7.40 (d, J＝2.6Hz,1H),7.21(d,J＝2.5Hz,1H),4.30(dd,J＝16.0,10.9Hz,2H),3.81–3.77(br.s,3H),3.56–3.50(m ,7H),2.40–2.35(m,4H),2.33–2.23(m,3H),2.16(s,3H),1.70–1.36(m,4H),0.63(t,J＝5.1Hz,2H), 0.42(t,J=5.2Hz,2H).
实施例42制备5-乙炔基-6-氟-4-(8-氟-2(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-((1S,5R)-1-甲基-3,8-二氮杂双环[3.2.1]辛-3-基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 42 Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy )-4-((1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-(propynyl)pyrido[4,3- d]pyrimidin-7-yl)naphth-2-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶为原料，用(1S,5R)-1-甲基-3,8-二氮杂双环[3.2.1]辛-甲酸叔丁酯代替6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷，按照实施例38的步骤B至F的合成方法制备实施例42为含一个甲酸的盐(6.7mg,0.01mmol)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine As raw material, use (1S,5R)-1-methyl-3,8-diazabicyclo[3.2.1]octyl-carboxylic acid tert-butyl ester instead of 6-(tert-butoxycarbonyl)-3,6-diaza Heterobicyclo[3.1.1]heptane was prepared according to the synthesis method of steps B to F of Example 38. Example 42 was a salt containing a formic acid (6.7 mg, 0.01 mmol).
LCMS:m/z 653.3(M+H)。1H NMR(400MHz,Methanol-d4)δ8.49(s,1H),7.88(dd,J＝9.1,5.7Hz,1H),7.38–7.31(m,2H),7.22(d,J＝10.9Hz,1H),5.51–5.34(m,1H),4.54–4.38(m,3H),3.88–3.76(m,2H),3.70–3.43(m,5H),3.29–3.17(m,2H),2.46–2.35(m,2H),2.32–2.24(m,2H),2.20(s,3H),2.18–2.11(m,2H),2.07–1.94(m,2H),1.64–1.53(m,2H),1.42(s,3H)。LCMS: m/z 653.3(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.49 (s, 1H), 7.88 (dd, J = 9.1, 5.7Hz, 1H), 7.38–7.31 (m, 2H), 7.22 (d, J = 10.9 Hz,1H),5.51–5.34(m,1H),4.54–4.38(m,3H),3.88–3.76(m,2H),3.70–3.43(m,5H),3.29–3.17(m,2H), 2.46–2.35(m,2H),2.32–2.24(m,2H),2.20(s,3H),2.18–2.11(m,2H),2.07–1.94(m,2H),1.64–1.53(m,2H ),1.42(s,3H).
实施例43制备5-乙炔基-6-氟-4-(8-氟-2(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(哌嗪-1-基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 43 Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy )-4-(piperazin-1-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶为原料，用1-叔丁氧羰基哌嗪代替6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷，按照实施例38的步骤B至F的合成方法制备实施例43为含一个甲酸的盐(4.76mg,0.007mmol)，LCMS:m/z 613.3(M+H)。1H NMR(400MHz,Methanol-d4)δ8.49(s,1H),7.88(dd,J＝9.2,5.7Hz,1H),7.40–7.29(m,2H),7.24(s,1H),5.50–5.33(m,1H),4.50–4.36(m,3H),4.08–3.93(m,4H),3.58–3.35(m,4H),3.12–3.00(m,4H),2.40–2.33(m,2H),2.23(s,3H),2.17–1.97(m,4H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine As the raw material, use 1-tert-butoxycarbonylpiperazine instead of 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane, and follow the synthesis method of steps B to F in Example 38 Preparation Example 43 is a salt containing a formic acid (4.76 mg, 0.007 mmol), LCMS: m/z 613.3 (M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.49 (s, 1H), 7.88 (dd, J = 9.2, 5.7Hz, 1H), 7.40–7.29 (m, 2H), 7.24 (s, 1H), 5.50–5.33(m,1H),4.50–4.36(m,3H),4.08–3.93(m,4H),3.58–3.35(m,4H),3.12–3.00(m,4H),2.40–2.33(m ,2H),2.23(s,3H),2.17–1.97(m,4H).
实施例44制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙炔基-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 44 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethynyl-2-(((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -phenol
反应式如下：
The reaction formula is as follows:
步骤A.6-氯-4-((4-甲氧基苄基)氨基)-2-甲基烟酸乙酯：向4，6-二氯-2-甲基烟酸乙酯(10.0g，42.7mmol)的DMSO(50mL)溶液中加入PMBNH2(10.5g，76.9mmol)和DIEA(16.5g，128.2mmol),50℃搅拌12h。使残余物在DCM与水之间分配,并用DCM萃取水层，将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-10％EtOAc/石油醚洗脱,得到产物(9.6g,28.7mmol,67％收率)，LCMS:m/z 335.1(M+H)。Step A. 6-Chloro-4-((4-methoxybenzyl)amino)-2-methylnicotinic acid ethyl ester: To 4,6-dichloro-2-methylnicotinic acid ethyl ester (10.0g , 42.7mmol) in DMSO (50mL) solution, PMBNH 2 (10.5g, 76.9mmol) and DIEA (16.5g, 128.2mmol) were added, and stirred at 50°C for 12h. The residue was partitioned between DCM and water, and the aqueous layer was extracted with DCM, the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography , eluting with 0-10% EtOAc/petroleum ether, the product (9.6g, 28.7mmol, 67% yield) was obtained, LCMS: m/z 335.1 (M+H).
步骤B.4-胺基-6-氯-2-甲基烟酸乙酯：将6-氯-4-((4-甲氧基苄基)氨基)-2-甲基烟酸乙酯(9.6g，28.7mmol)中加入TFA(100mL)，将混合物在65℃搅拌12h。浓缩，用饱和NaHCO3溶液调节pH＝8-9，过滤，收集滤饼，得到产物(5.6g,26.4mmol,92％收率)，LCMS:m/z 215.2(M+H)。Step B. 4-Amino-6-chloro-2-methylnicotinic acid ethyl ester: 6-chloro-4-((4-methoxybenzyl)amino)-2-methylnicotinic acid ethyl ester ( TFA (100 mL) was added to 9.6 g, 28.7 mmol), and the mixture was stirred at 65°C for 12 h. Concentrate, adjust pH=8-9 with saturated NaHCO 3 solution, filter, and collect the filter cake to obtain product (5.6 g, 26.4 mmol, 92% yield), LCMS: m/z 215.2 (M+H).
步骤C.4-胺基-6-氯-2-甲基烟酸：将4-胺基-6-氯-2-甲基烟酸乙酯(5.6g,26.4mmol)在MeOH/THF/H2O(20/20/20mL)的溶液中加入LiOH·H2O(5.5g，132.0mmol)在50℃搅拌6h。浓缩，用4M盐酸调节pH＝5-6，真空浓缩，装载到硅胶上并通过柱色谱纯化，得到产物(4.0g,21.6mmol,82％收率)，LCMS:m/z 187.0(M+H)。Step C. 4-Amino-6-chloro-2-methylnicotinic acid: 4-Amino-6-chloro-2-methylnicotinic acid ethyl ester (5.6g, 26.4mmol) was dissolved in MeOH/THF/H LiOH·H 2 O (5.5g, 132.0mmol) was added to the solution of 2O (20/20/20mL) and stirred at 50°C for 6h. Concentrate, adjust pH=5-6 with 4M hydrochloric acid, concentrate in vacuo, load onto silica gel and purify by column chromatography to obtain product (4.0g, 21.6mmol, 82% yield), LCMS: m/z 187.0 (M+H ).
步骤D.7-氯-2-巯基-5-甲基吡啶酮[4,3-d]嘧啶-4-醇：将4-胺基-6-氯-2-甲基烟酸(4.0g,21.6mmol)在二氯亚砜(120mL)的溶液50℃搅拌6h。浓缩。使残余物在0℃加入到硫氰酸铵(4.9g，64.8mmol)的丙酮(120mL)溶液中。室温搅拌1h。通过滤纸过滤混合物，滤液浓缩，得到粗品(3.7g)，LCMS:m/z228.0(M+H)。Step D.7-Chloro-2-mercapto-5-methylpyridone[4,3-d]pyrimidin-4-ol: A solution of 4-amino-6-chloro-2-methylnicotinic acid (4.0 g, 21.6 mmol) in dichlorothionyl (120 mL) was stirred at 50°C for 6 h. Concentrated. The residue was added to a solution of ammonium thiocyanate (4.9 g, 64.8 mmol) in acetone (120 mL) at 0°C. Stirred at room temperature for 1 h. The mixture was filtered through filter paper and the filtrate was concentrated to give a crude product (3.7 g), LCMS: m/z 228.0 (M+H).
步骤E.7-氯-5-甲基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇：将7-氯-2-巯基-5-甲基吡啶酮[4,3-d]嘧啶-4-醇(3.7g，16.3mmol)、氢氧化钠(1.3g，32.6mmol)在MeOH(100mL)和水(25mL)中的溶液。在0℃下加入碘甲烷(4.6g，32.6mmol)在室温搅拌1h。使残余物加入水(100ml)中,用4M盐酸调PH＝5-6。将混合物过滤，滤饼中加入乙腈(50ml)搅拌0.5h，过滤收集滤饼，得到产物(3.2g,13.3mmol,62％收率)，LCMS:m/z 242.0(M+H)。 Step E. 7-Chloro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol: 7-chloro-2-mercapto-5-methylpyridone[ 4,3-d]pyrimidin-4-ol (3.7 g, 16.3 mmol), sodium hydroxide (1.3 g, 32.6 mmol) in MeOH (100 mL) and water (25 mL). Methyl iodide (4.6g, 32.6mmol) was added at 0°C and stirred at room temperature for 1 h. The residue was added to water (100 ml), and the pH was adjusted to 5-6 with 4M hydrochloric acid. The mixture was filtered, acetonitrile (50 ml) was added to the filter cake and stirred for 0.5 h. The filter cake was collected by filtration to obtain the product (3.2 g, 13.3 mmol, 62% yield), LCMS: m/z 242.0 (M+H).
步骤F.(1R，5S)-3-(7-氯-5-甲基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：将7-氯-5-甲基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-醇(3.2g,13.3mmol)在乙腈(50mL)中的溶液加入三氯氧磷(3.1g，20.0mmol)和DIEA(3.4g，26.6mmol)在80℃搅拌2h，浓缩得到粗品。在0℃下向该粗品的乙腈溶液中加入DIEA(3.4g，26.6mmol)和3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(4.2g，20.0mmol)。室温搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水相，将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-20％乙酸乙酯/石油醚洗脱,得到化合物7(3.5g,8.1mmol,61％收率)LCMS:m/z 436.1(M+H)。Step F. (1R,5S)-3-(7-chloro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diaza Heterobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: 7-chloro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (3.2 g, 13.3 mmol) in acetonitrile (50 mL) was added with phosphorus oxychloride (3.1 g, 20.0 mmol) and DIEA (3.4 g, 26.6 mmol), stirred at 80°C for 2 h, and concentrated to obtain a crude product. To the acetonitrile solution of the crude product were added DIEA (3.4g, 26.6mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.2g, 20.0mmol) at 0°C. ). Stir at room temperature for 1 hour. The residue was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried , loaded onto silica gel and purified by column chromatography , eluted with 0-20% ethyl acetate/petroleum ether to obtain compound 7 (3.5g, 8.1mmol, 61% yield) LCMS: m/z 436.1 (M+H).
以(1R，5S)-3-(7-氯-5-甲基-2-(甲硫基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯为原料，按到实施例9的步骤D至J的合成方法制备实施例44为含一个甲酸的盐(8.9mg,0.014mmol)。LCMS:m/z607.3(M+H)。With (1R,5S)-3-(7-chloro-5-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo [3.2.1] Octane-8-carboxylic acid tert-butyl ester was used as the raw material, and Example 44 was prepared as a salt containing a formic acid (8.9 mg, 0.014 mmol) according to the synthesis method of steps D to J of Example 9. LCMS:m/z607.3(M+H).
1HNMR(600MHz,Methanol-d4)δ8.49(s,1H),7.87(dd,J＝9.2,5.6Hz,1H),7.48(s,1H),7.37–7.32(m,2H),7.22(s,1H),5.48–5.36(m,1H),4.44(d,J＝11.0Hz,1H),4.39(d,J＝10.9Hz,1H),4.36(s,1H),4.11(br.s,1H),3.97–3.80(m,4H),3.52–3.43(m,3H),3.26–3.14(m,2H),2.47(d,J＝15.6Hz,1H),2.42–2.32(m,2H),2.28–2.22(m,1H),2.19–2.10(m,2H),2.06–1.88(m,4H),1.71–1.60(m,1H)。 1 HNMR (600MHz, Methanol-d 4 ) δ8.49 (s, 1H), 7.87 (dd, J = 9.2, 5.6Hz, 1H), 7.48 (s, 1H), 7.37–7.32 (m, 2H), 7.22 (s,1H),5.48–5.36(m,1H),4.44(d,J＝11.0Hz,1H),4.39(d,J＝10.9Hz,1H),4.36(s,1H),4.11(br. s,1H),3.97–3.80(m,4H),3.52–3.43(m,3H),3.26–3.14(m,2H),2.47(d,J＝15.6Hz,1H),2.42–2.32(m, 2H),2.28–2.22(m,1H),2.19–2.10(m,2H),2.06–1.88(m,4H),1.71–1.60(m,1H).
实施例45制备3-(4-((1R,5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)酚
Example 45 Preparation of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5- Chloro-4-(trifluoromethyl)phenol
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(3-氯-5-(甲氧基甲氧基)-2-(三氟甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷为原料，根据实施例20的步骤F和H进行合成实施例45为含一个甲酸的盐。LCMS:m/z 649.2(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(3-chloro- 5-(methoxymethoxy)-2-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane is used as raw material, according to Steps F and H of Example 20 were carried out to synthesize Example 45 as a salt containing a formic acid. LCMS: m/z 649.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.53(s,1H),7.15(d,J＝2.3Hz,1H),6.77(s,1H),5.50–5.31(m,1H),4.52–4.31(m,3H),4.00–3.69(m,4H),3.59–3.38(m,4H),3.24–3.12(m,1H),2.50–2.30(m,2H),2.23(s,3H),2.27–2.17(m,1H),2.16–2.07(m,2H),2.05–1.95(m,1H),1.91–1.62(m,4H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.53 (s, 1H), 7.15 (d, J = 2.3Hz, 1H), 6.77 (s, 1H), 5.50–5.31 (m, 1H), 4.52– 4.31(m,3H),4.00–3.69(m,4H),3.59–3.38(m,4H),3.24–3.12(m,1H),2.50–2.30(m,2H),2.23(s,3H), 2.27–2.17(m,1H),2.16–2.07(m,2H),2.05–1.95(m,1H),1.91–1.62(m,4H).
实施例46制备4-(3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)7-(萘基)-5-(丙炔基)吡啶并[4,3-d]嘧啶
Example 46 Preparation of 4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole) Azin-7a(5H)-yl)methoxy)7-(naphthyl)-5-(propynyl)pyrido[4,3-d]pyrimidine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-萘硼酸为原料，根据实施例20的步骤F和H进行合成实施例46为含一个甲酸的盐。LCMS:m/z 581.2(M+H)。1H NMR(400MHz,Methanol-d4)δ8.51(s,1H),8.07(dd,J＝6.6,2.9Hz,1H),8.03–7.99(m,1H),7.74(d,J＝8.4Hz,1H),7.68–7.63(m,2H),7.59–7.55(m,1H),7.54–7.48(m,1H),5.52–5.35(m,1H),4.58–4.41(m,3H),4.06–3.80(m,4H),3.65–3.42(m,4H),3.26–3.15(m,1H),2.55–2.34(m,2H),2.30–2.20(m,1H),2.23(s,3H),2.19–2.11(m,2H),2.09–1.75(m,5H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-naphthaleneboronic acid are used as raw materials, The synthesis of Example 46 was carried out according to steps F and H of Example 20 as a salt containing a formic acid. LCMS: m/z 581.2(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.51 (s, 1H), 8.07 (dd, J = 6.6, 2.9 Hz, 1H), 8.03–7.99 (m, 1H), 7.74 (d, J = 8.4 Hz,1H),7.68–7.63(m,2H),7.59–7.55(m,1H),7.54–7.48(m,1H),5.52–5.35(m,1H),4.58–4.41(m,3H), 4.06–3.80(m,4H),3.65–3.42(m,4H),3.26–3.15(m,1H),2.55–2.34(m,2H),2.30–2.20(m,1H),2.23(s,3H ),2.19–2.11(m,2H),2.09–1.75(m,5H).
实施例47制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((2S,4R)-1-乙基-4-氟吡咯烷-2基)甲氧基)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 47 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2S,4R)-1-ethyl -4-fluoropyrrolidin-2yl)methoxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphth-2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和((2S,4R)-1-乙基-4-氟吡咯-2-基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例47为含一个甲酸的盐。LCMS:m/z 627.3(M+H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and ((2S , 4R)-1-ethyl-4-fluoropyrrol-2-yl)methanol was used as raw material, and Example 47 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid. LCMS: m/z 627.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.51(s,1H),7.89(dd,J＝9.1,5.7Hz,1H),7.40–7.32(m,2H),7.23(t,J＝2.8Hz,1H),5.35–5.16(m,1H),4.68–4.53(m,3H),4.06–3.81(m,4H),3.64–3.39(m,3H),3.24–3.14(m,1H),2.96–2.82(m,1H),2.75–2.65(m,1H),2.45–2.31(m,1H),2.22(s,3H),1.98–1.70(m,5H),1.39–1.29(m,1H),1.18(td,J＝7.2,2.4Hz,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.51 (s, 1H), 7.89 (dd, J = 9.1, 5.7Hz, 1H), 7.40–7.32 (m, 2H), 7.23 (t, J = 2.8 Hz,1H),5.35–5.16(m,1H),4.68–4.53(m,3H),4.06–3.81(m,4H),3.64–3.39(m,3H),3.24–3.14(m,1H), 2.96–2.82(m,1H),2.75–2.65(m,1H),2.45–2.31(m,1H),2.22(s,3H),1.98–1.70(m,5H),1.39–1.29(m,1H ), 1.18 (td, J = 7.2, 2.4Hz, 3H).
实施例48制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((S)-1-甲基吡咯烷-2基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 48 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1- Methylpyrrolidin-2yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和((S)-1-甲基吡咯-2-基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例47为含一个甲酸的盐。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and ((S )-1-methylpyrrol-2-yl)methanol was used as raw material, and Example 47 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid.
LCMS:m/z 595.3(M+H)。LCMS: m/z 595.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.50(s,1H),7.89(dd,J＝9.2,5.7Hz,1H),7.39–7.32(m,2H),7.23(t,J＝2.4Hz,1H),4.77(dt,J＝12.2,3.6Hz,1H),4.67–4.60(m,1H),4.03–3.76(m,5H),3.62–3.48(m,2H),3.04–2.96(m,2H),2.93(s,3H),2.40–2.28(m,2H),2.22(s,3H),2.15–1.95(m,4H),1.93–1.84(m,2H),1.67–1.57(m,1H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.50 (s, 1H), 7.89 (dd, J = 9.2, 5.7Hz, 1H), 7.39–7.32 (m, 2H), 7.23 (t, J = 2.4 Hz,1H),4.77(dt,J＝12.2,3.6Hz,1H),4.67–4.60(m,1H),4.03–3.76(m,5H),3.62–3.48(m,2H),3.04–2.96( m,2H),2.93(s,3H),2.40–2.28(m,2H),2.22(s,3H),2.15–1.95(m,4H),1.93–1.84(m,2H),1.67–1.57( m,1H).
实施例49制备4-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-5-(丙炔基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 49 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-(propynyl)-2- ((Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和(四氢-1H-吡咯嗪-7a(5H)-基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例49为含一个甲酸的盐。LCMS:m/z 621.3(M+H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and (tetrahydrogen -1H-Pyrrozine-7a(5H)-yl)methanol was used as raw material, and Example 49 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid. LCMS: m/z 621.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.51(s,1H),7.90(dd,J＝9.2,5.7Hz,1H),7.39–7.33(m,2H),7.23(d,J＝2.5Hz,1H),4.70–4.61(m,2H),4.00–3.83(m,2H),3.80–3.64(m,4H),3.34–3.25(m,4H),2.39–2.30(m,2H),2.29–2.24(m,1H),2.22(s,3H),2.22–2.01(m,6H),1.90–1.82(m,3H),1.66–1.58(m,1H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.51 (s, 1H), 7.90 (dd, J = 9.2, 5.7Hz, 1H), 7.39–7.33 (m, 2H), 7.23 (d, J = 2.5 Hz,1H),4.70–4.61(m,2H),4.00–3.83(m,2H),3.80–3.64(m,4H),3.34–3.25(m,4H),2.39–2.30(m,2H), 2.29–2.24(m,1H),2.22(s,3H),2.22–2.01(m,6H),1.90–1.82(m,3H),1.66–1.58(m,1H).
实施例50制备4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)7-(8-乙炔基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶
Example 50 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)7-(8-ethynylnaphthalen-1-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和三异丙基((8-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)萘-1-基)乙炔基)硅烷为原料，根据实施例20的步骤F-H进行合成实施例50为含一个甲酸的盐。LCMS:m/z 605.2(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and triisopropyl ((8 -(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphth-1-yl)ethynyl)silane as raw material, according to the steps F-H of Example 20 The synthesis of Example 50 was carried out as a salt containing a formic acid. LCMS: m/z 605.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.47(s,1H),8.14(dd,J＝8.3,1.4Hz,1H),8.09(dd,J＝8.3,1.3Hz,1H),7.79(dd,J＝7.2,1.4Hz,1H),7.70(dd,J＝8.3,7.0Hz,1H),7.61(d,J＝7.2Hz,1H),7.56(dd,J＝8.3,7.2Hz,1H),5.56–5.39(m,1H),4.61–4.44(m,3H),4.10–3.88(m,4H),3.72–3.55(m,3H),3.31–3.24(m,1H),3.11(d,J＝5.1Hz,1H),2.62–2.54(m,1H),2.46(t,J＝10.8Hz,2H),2.31(d,J＝9.7Hz,1H),2.22(s,3H),2.21–2.16(m,2H),2.12–1.72(m,5H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.47 (s, 1H), 8.14 (dd, J = 8.3, 1.4Hz, 1H), 8.09 (dd, J = 8.3, 1.3Hz, 1H), 7.79 ( dd,J＝7.2,1.4Hz,1H),7.70(dd,J＝8.3,7.0Hz,1H),7.61(d,J＝7.2Hz,1H),7.56(dd,J＝8.3,7.2Hz,1H ),5.56–5.39(m,1H),4.61–4.44(m,3H),4.10–3.88(m,4H),3.72–3.55(m,3H),3.31–3.24(m,1H),3.11(d ,J＝5.1Hz,1H),2.62–2.54(m,1H),2.46(t,J＝10.8Hz,2H),2.31(d,J＝9.7Hz,1H),2.22(s,3H),2.21 –2.16(m,2H),2.12–1.72(m,5H).
实施例51制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(3-羟基-3-甲基丁炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 51 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(3-hydroxy-3-methylbutynyl)pyrido[4,3-d]pyrimidine-7 -yl)-5-ethynyl-6-fluoronaphthalene-2-phenol
以5，7-二氯-8-氟-2-(甲硫基)-4-(2，2，2-三氟乙氧基)吡啶并并[4,3-d]嘧啶为原料，用2-甲基-3-丁炔-2醇替代环丙基乙炔，参照合成实施例39的方法制备实施例51为含一个甲酸的盐。LCMS:m/z 683.3(M+H)。Using 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine as raw material, use 2-Methyl-3-butyn-2ol was used instead of cyclopropylacetylene, and Example 51 was prepared as a salt containing a formic acid by referring to the method of Synthetic Example 39. LCMS: m/z 683.3(M+H).
1H NMR(600MHz,DMSO-d6)δ8.26(s,1H),7.98(dd,J＝9.2,5.9Hz,1H),7.48(t,J＝9.0Hz,1H),7.40(d,J＝2.6Hz,1H),7.22(s,1H),5.77(s,1H),5.34–5.22(m,1H),4.15–4.11(m,1H),4.04–3.99(m,1H),3.80–3.72(m,2H),3.12–2.99(m,5H),2.86–2.79(m,2H),2.14–2.04(m,3H),2.00–1.96(m,1H),1.88–1.82(m,1H),1.81–1.72(m,3H),1.62–1.54(m,3H),1.49(s,6H)。 1 H NMR (600MHz, DMSO-d 6 ) δ8.26 (s, 1H), 7.98 (dd, J = 9.2, 5.9Hz, 1H), 7.48 (t, J = 9.0Hz, 1H), 7.40 (d, J＝2.6Hz,1H),7.22(s,1H),5.77(s,1H),5.34–5.22(m,1H),4.15–4.11(m,1H),4.04–3.99(m,1H),3.80 –3.72(m,2H),3.12–2.99(m,5H),2.86–2.79(m,2H),2.14–2.04(m,3H),2.00–1.96(m,1H),1.88–1.82(m, 1H),1.81–1.72(m,3H),1.62–1.54(m,3H),1.49(s,6H).
实施例52制备(S)-5-乙炔基-6-氟-4-(8-氟-2((1-甲基吡咯烷-2-基)甲氧基)-4-(哌嗪-1-基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 52 Preparation of (S)-5-ethynyl-6-fluoro-4-(8-fluoro-2((1-methylpyrrolidin-2-yl)methoxy)-4-(piperazine-1) -yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶为原料，参照合成实施例43的方法制备实施例52为含一个甲酸的盐。LCMS:m/z 569.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine As a raw material, refer to the method of Synthetic Example 43 to prepare Example 52, which is a salt containing a formic acid. LCMS: m/z 569.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.50(s,1H),7.89(dd,J＝9.2,5.7Hz,1H),7.40–7.33(m,2H),7.25(t,J＝2.3Hz,1H),4.83(dd,J＝12.4,3.3Hz,1H),4.68(dd,J＝12.4,6.4Hz,1H),4.14–3.98(m,4H),3.72–3.56(m,2H),3.30–3.19(m,4H),3.13–3.04(m,1H),2.98(s,3H),2.42–2.32(m,1H),2.25(s,3H),2.17–1.98(m,3H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.50 (s, 1H), 7.89 (dd, J = 9.2, 5.7Hz, 1H), 7.40–7.33 (m, 2H), 7.25 (t, J = 2.3 Hz,1H),4.83(dd,J＝12.4,3.3Hz,1H),4.68(dd,J＝12.4,6.4Hz,1H),4.14–3.98(m,4H),3.72–3.56(m,2H) ,3.30–3.19(m,4H),3.13–3.04(m,1H),2.98(s,3H),2.42–2.32(m,1H),2.25(s,3H),2.17–1.98(m,3H) .
实施例53制备4-(4-(3，6-二氮杂双环[3.1.1]庚烷-6-基)-8-氟-2-(((2R,7aS))-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 53 Preparation of 4-(4-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-8-fluoro-2-(((2R,7aS))-2-fluorotetra Hydrogen-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphth-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶为原料，用3,6-二氮杂双环[3.1.1]庚烷-3-羧酸叔丁酯替代6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷，参照合成实施例38的方法制备实施例53为含2个甲酸的盐。LCMS:m/z 625.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine As raw material, use 3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester instead of 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1] Heptane, refer to the method of Synthesis Example 38 to prepare Example 53 as a salt containing 2 formic acids. LCMS: m/z 625.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.54(s,2H),7.89(dd,J＝9.2,5.7Hz,1H),7.39–7.32(m,2H),7.23(d,J＝2.5Hz,1H),5.50–5.32(m,1H),5.22–5.13(m,2H),4.47–4.37(m,2H),3.58–3.39(m,5H),3.29–3.14(m,3H),3.07–2.99(m,1H),2.54–2.45(m,1H),2.44–2.29(m,2H),2.29–2.24(m,1H),2.23(s,3H),2.18–2.08(m,2H),2.05–1.96(m,2H)。 1 H NMR (400MHz, Methanol-d 4 )δ8.54(s,2H),7.89(dd,J＝9.2,5.7Hz,1H),7.39–7.32(m,2H),7.23(d,J＝2.5Hz,1H),5.50–5.32(m,1H),5.22–5.13(m,2H),4.47–4.37(m,2H),3.58–3.39(m,5H),3.29–3.14(m,3H),3.07–2.99(m,1H),2.54–2.45(m,1H),2.44–2.29(m,2H),2.29–2.24(m,1H),2.23(s,3H),2.18–2.08(m,2H),2.05–1.96(m,2H).
实施例54制备4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)7-(3-氯-2-环丙烷基苯基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶
Example 54 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)7-(3-chloro-2-cyclopropylphenyl)-8- Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d ]pyrimidine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a (5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(3-氯-2-环丙烷基苯基)-4，4，5，5-四甲基-1，3，2-二氧杂硼烷为原料，根据实施例20的步骤F和H进行合成实施例54为含一个甲酸的盐。LCMS:m/z 605.2(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrozine-7a (5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert. Butyl ester and 2-(3-chloro-2-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane were used as raw materials, according to Example 20 Steps F and H were carried out to synthesize Example 54 as a salt containing a formic acid. LCMS: m/z 605.2(M+H).
1H NMR(600MHz,Methanol-d4)δ8.48(s,1H),7.58–7.55(t,J＝4.7Hz,1H),7.40(d,J＝5.2Hz,2H),5.54–5.42(m,1H),4.51(q,J＝11.2Hz,2H),4.06–3.89(m,4H),3.70–3.54(m,3H),3.32–3.25(m,1H),2.59–2.39(m,3H),2.35–2.28(m,1H),2.24(s,3H),2.23–2.17(m,2H),2.11–2.03(m,1H),2.03–1.89(m,4H),1.88–1.71(m,2H),0.78–0.71(m,2H),0.20–0.13(m,2H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.48 (s, 1H), 7.58–7.55 (t, J = 4.7Hz, 1H), 7.40 (d, J = 5.2Hz, 2H), 5.54–5.42 ( m,1H),4.51(q,J＝11.2Hz,2H),4.06–3.89(m,4H),3.70–3.54(m,3H),3.32–3.25(m,1H),2.59–2.39(m, 3H),2.35–2.28(m,1H),2.24(s,3H),2.23–2.17(m,2H),2.11–2.03(m,1H),2.03–1.89(m,4H),1.88–1.71( m,2H),0.78–0.71(m,2H),0.20–0.13(m,2H).
实施例55制备4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-(3，3-二甲基-1-丁炔-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 55 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-(3,3-dimethyl-1-butyn-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
以5，7-二氯-8-氟-2-(甲硫基)-4-(2，2，2-三氟乙氧基)吡啶并并[4,3-d]嘧啶为原料，用3，3-二甲基-1-丁炔替代环丙基乙炔，参照合成实施例39的方法制备实施例55为含一个甲酸的盐。LCMS:m/z 681.3(M+H)。Using 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine as raw material, use 3,3-dimethyl-1-butyne was substituted for cyclopropylacetylene, and Example 55 was prepared as a salt containing a formic acid by referring to the method of Synthetic Example 39. LCMS: m/z 681.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.54(s,1H),7.89(dd,J＝9.2,5.6Hz,1H),7.39–7.33(m,2H),7.24(br.s,1H),5.46–5.34(m,1H),4.45–4.35(m,2H),3.80–3.65(m,3H),3.53–3.36(m,4H),3.19–3.13(m,1H),2.49–2.30(m,3H),2.27–2.19(m,2H),2.15–2.07(m,3H),2.03–1.94(m,2H),1.88–1.77(m,3H),1.41(s,9H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.54 (s, 1H), 7.89 (dd, J = 9.2, 5.6Hz, 1H), 7.39–7.33 (m, 2H), 7.24 (br.s, 1H) ),5.46–5.34(m,1H),4.45–4.35(m,2H),3.80–3.65(m,3H),3.53–3.36(m,4H),3.19–3.13(m,1H),2.49–2.30 (m,3H),2.27–2.19(m,2H),2.15–2.07(m,3H),2.03–1.94(m,2H),1.88–1.77(m,3H),1.41(s,9H).
实施例56制备2-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-3-氟苯酚
Example 56 Preparation of 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-3-fluorophenol
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-氟-6-羟基苯硼酸频哪醇酯为原料，根据实施例20的步骤F和H进行合成实施例56。LCMS:m/z 565.2(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-fluoro-6-hydroxy Pinacol phenylboronic acid was used as raw material, and Example 56 was synthesized according to steps F and H of Example 20. LCMS: m/z 565.2(M+H).
1H NMR(400MHz,Methanol-d4)δ7.35(td,J＝8.3,6.6Hz,1H),6.80(d,J＝8.3Hz,1H),6.75(t,J＝8.9Hz,1H),5.48–5.30(m,1H),4.38(q,J＝10.8Hz, 2H),3.97–3.65(m,4H),3.53–3.33(m,5H),3.19–3.08(m,1H),2.49–2.28(m,2H),2.23(s,3H),2.28–2.17(m,1H),2.14–2.04(m,2H),2.03–1.58(m,5H)。 1 H NMR (400 MHz, Methanol-d 4 )δ7.35(td, J＝8.3,6.6 Hz,1H),6.80(d, J＝8.3 Hz,1H),6.75(t, J＝8.9 Hz,1H),5.48–5.30(m,1H),4.38(q, J＝10.8 Hz, 2H), 3.97–3.65(m,4H),3.53–3.33(m,5H),3.19–3.08(m,1H),2.49–2.28(m,2H),2.23(s,3H),2.28–2.17(m,1H),2.14–2.04(m,2H),2.03–1.58(m,5H).
实施例57制备2-((S)-4-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS))-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌嗪-2-基)乙腈
Example 57 Preparation of 2-((S)-4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS))) -2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperazine-2 -Acetonitrile
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶为原料，用(S)-2-(氰基甲基)哌嗪-1-羧酸叔丁酯替代6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷，参照合成实施例38的方法制备实施例57为含一个甲酸的盐。LCMS:m/z 652.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine As raw material, use (S)-2-(cyanomethyl)piperazine-1-carboxylic acid tert-butyl ester instead of 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane Alkane, refer to the method of Synthetic Example 38 to prepare Example 57 as a salt containing a formic acid. LCMS: m/z 652.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.48(s,1H),7.89(ddd,J＝9.1,5.7,2.0Hz,1H),7.38(t,J＝2.5Hz,1H),7.35(t,J＝8.9Hz,1H),7.27–7.20(m,1H),5.55–5.43(m,1H),4.61(d,J＝11.6Hz,1H),4.50(dd,J＝11.5,6.4Hz,1H),4.31–4.18(m,1H),3.80–3.57(m,5H),3.40(d,J＝10.0Hz,1H),3.34–3.26(m,3H),3.14–3.06(m,1H),2.77–2.67(m,2H),2.65–2.50(m,2H),2.50–2.40(m,1H),2.38–2.31(m,1H),2.23(s,3H),2.26–2.16(m,2H),2.11–2.04(m,1H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.48 (s, 1H), 7.89 (ddd, J = 9.1, 5.7, 2.0 Hz, 1H), 7.38 (t, J = 2.5 Hz, 1H), 7.35 ( t,J＝8.9Hz,1H),7.27–7.20(m,1H),5.55–5.43(m,1H),4.61(d,J＝11.6Hz,1H),4.50(dd,J＝11.5,6.4Hz ,1H),4.31–4.18(m,1H),3.80–3.57(m,5H),3.40(d,J＝10.0Hz,1H),3.34–3.26(m,3H),3.14–3.06(m,1H ),2.77–2.67(m,2H),2.65–2.50(m,2H),2.50–2.40(m,1H),2.38–2.31(m,1H),2.23(s,3H),2.26–2.16(m ,2H),2.11–2.04(m,1H).
实施例58制备4-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 58 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl -6-fluoronaphthalene-2-phenol
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷为原料，根据实施例20的步骤F-H进行合成实施例58为含一个甲酸的盐。LCMS:m/z 643.2(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(8-ethyl -7-Fluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane is used as raw material, according to the implementation Steps F-H of Example 20 were carried out to synthesize Example 58 as a salt containing a formic acid. LCMS: m/z 643.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.52(s,1H),7.68(dd,J＝9.1,5.8Hz,1H),7.30(d,J＝2.6Hz,1H),7.25(t,J＝9.4Hz,1H),7.07(s,1H),5.46–5.29(m,1H),4.45–4.32(m,2H),4.02–3.67(m,4H),3.53–3.44(m,4H),3.20–3.08(m,1H),2.50–2.28(m,3H),2.26–2.21(m,2H),2.20(s,3H),2.13–2.04(m,2H),2.02–1.92(m,2H),1.88–1.78(m,4H),0.82(t,J＝7.3Hz,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.52 (s, 1H), 7.68 (dd, J = 9.1, 5.8Hz, 1H), 7.30 (d, J = 2.6Hz, 1H), 7.25 (t, J＝9.4Hz,1H),7.07(s,1H),5.46–5.29(m,1H),4.45–4.32(m,2H),4.02–3.67(m,4H),3.53–3.44(m,4H) ,3.20–3.08(m,1H),2.50–2.28(m,3H),2.26–2.21(m,2H),2.20(s,3H),2.13–2.04(m,2H),2.02–1.92(m, 2H), 1.88–1.78 (m, 4H), 0.82 (t, J = 7.3Hz, 3H).
实施例59制备4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-7-(8-氟萘-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶
Example 59 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(8-fluoronaphthalene-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(8-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷为原料，根据实施例20的步骤F和H进行合成实施例59。LCMS:m/z 599.3(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(8-fluoronaphthalene -1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane was used as raw material, and Example 59 was synthesized according to steps F and H of Example 20. LCMS: m/z 599.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.18–8.13(m,1H),7.91–7.86(m,1H),7.73(dd,J＝8.3,7.1Hz,1H),7.63(d,J＝7.4Hz,1H),7.57(td,J＝8.0,5.1Hz,1H),7.22(dd,J＝13.2,7.7Hz,1H),5.69–5.53(m,1H),4.78–4.67(m,2H),4.26–4.00(m,5H),3.99–3.87(m,2H),3.55–3.46(m,1H),2.71–2.57(m,2H),2.53–2.32(m,4H),2.32–2.16(m,2H),2.24(s,3H),2.12–1.92(m,4H)。 1 H NMR (400 MHz, Methanol-d 4 )δ8.18–8.13 (m, 1H), 7.91–7.86 (m, 1H), 7.73 (dd, J＝8.3, 7.1 Hz, 1H), 7.63 (d, J =7.4 Hz, 1H), 7.57 (td, J = 8.0, 5.1 Hz, 1H), 7.22 (dd, J = 13.2, 7.7 Hz, 1H), 5.69–5.53 (m, 1H ),4.78–4.67(m,2H),4.26–4.00(m,5H),3.99–3.87(m,2H),3.55–3.46(m,1H),2.71–2.57(m,2H),2.53–2.32 (m, 4H), 2.32–2.16 (m, 2H), 2.24 (s, 3H), 2.12–1.92 (m, 4H).
实施例60制备3-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-氯-4-(三氟甲基)苯胺
Example 60 Preparation of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro- 4-(trifluoromethyl)aniline
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和3-氯-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-4-(三氟甲基)苯胺为原料，根据实施例20的步骤F和H进行合成实施例60为含一个甲酸的盐。LCMS:m/z 648.2(M+H)。1H NMR(400MHz,Methanol-d4)δ8.49(s,1H),6.93(d,J＝2.3Hz,1H),6.51(d,J＝2.4Hz,1H),5.54–5.36(m,1H),4.55–4.42(m,3H),4.02–3.82(m,4H),3.71–3.47(m,3H),3.30–3.20(m,1H),2.59–2.34(m,2H),2.32–2.13(m,4H),2.23(s,3H),2.11–1.67(m,5H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 3-chloro-5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-4-(trifluoromethyl)aniline was used as raw material, according to steps F and H of Example 20 The synthesis of Example 60 was carried out as a salt containing a formic acid. LCMS: m/z 648.2(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.49 (s, 1H), 6.93 (d, J = 2.3Hz, 1H), 6.51 (d, J = 2.4Hz, 1H), 5.54–5.36 (m, 1H),4.55–4.42(m,3H),4.02–3.82(m,4H),3.71–3.47(m,3H),3.30–3.20(m,1H),2.59–2.34(m,2H),2.32– 2.13(m,4H),2.23(s,3H),2.11–1.67(m,5H).
实施例61制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((2S,4R)-1-甲基-4-羟基吡咯烷-2基)甲氧基)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 61 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2S,4R)-1-methyl -4-hydroxypyrrolidin-2yl)methoxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphth-2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和((2S,4R)-1-甲基-4-羟基吡咯-2-基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例61为含一个甲酸的盐。LCMS:m/z 611.3(M+H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and ((2S , 4R)-1-methyl-4-hydroxypyrrol-2-yl)methanol was used as raw material, and Example 61 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid. LCMS: m/z 611.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.47(s,1H),7.89(dd,J＝9.1,5.7Hz,1H),7.38(d,J＝2.3Hz,1H),7.34(d,J＝8.9Hz,1H),7.24–7.21(m,1H),4.78(dt,J＝12.2,3.8Hz,1H),4.63(ddd,J＝12.2,6.3,4.3Hz,1H),4.51(s,1H),4.08–3.85(m,5H),3.76(dd,J＝12.4,4.6Hz,1H),3.66(dd,J＝11.6,4.8Hz,1H),3.53–3.47(m,1H),3.37–3.35(m,1H),3.28–3.20(m,1H),2.94(s,3H),2.93–2.88(m,1H),2.44–2.38(m,1H),2.22(s,3H),2.21–2.11(m,1H),2.01–1.66(m,5H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.47 (s, 1H), 7.89 (dd, J = 9.1, 5.7Hz, 1H), 7.38 (d, J = 2.3Hz, 1H), 7.34 (d, J＝8.9Hz,1H),7.24–7.21(m,1H),4.78(dt,J＝12.2,3.8Hz,1H),4.63(ddd,J＝12.2,6.3,4.3Hz,1H),4.51(s ,1H),4.08–3.85(m,5H),3.76(dd,J＝12.4,4.6Hz,1H),3.66(dd,J＝11.6,4.8Hz,1H),3.53–3.47(m,1H), 3.37–3.35(m,1H),3.28–3.20(m,1H),2.94(s,3H),2.93–2.88(m,1H),2.44–2.38(m,1H),2.22(s,3H), 2.21–2.11(m,1H),2.01–1.66(m,5H).
实施例62制备4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-7-(8-氯萘-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶
Example 62 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(8-chloronaphthyl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(8-氯萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷为原料，根据实施例20的步骤F和H进行合成实施例62为含一个甲酸的盐。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(8-chloronaphthalene -1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane is used as raw material, and is synthesized according to steps F and H of Example 20. Example 62 contains a formic acid. of salt.
LCMS:m/z 615.2(M+H)。LCMS: m/z 615.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.53(s,1H),8.16(dd,J＝8.2,1.4Hz,1H),8.03(dd,J＝8.2,1.3Hz,1H),7.71(t,J＝7.6Hz,1H),7.65–7.61(m,2H),7.53(t,J＝7.8Hz,1H),5.48–5.31(m,1H),4.47–4.33(m,2H),4.05–3.69(m,5H),3.55–3.48(m,1H),3.47–3.36(m,2H),3.21–3.10(m,2H),2.47(dd,J＝15.1,4.5Hz,1H),2.42–2.23(m,2H),2.21(s,3H),2.16–2.06(m,2H),2.00(dd,J＝15.5,8.1Hz,1H),1.90–1.54(m,4H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.53 (s, 1H), 8.16 (dd, J = 8.2, 1.4Hz, 1H), 8.03 (dd, J = 8.2, 1.3Hz, 1H), 7.71 ( t,J＝7.6Hz,1H),7.65–7.61(m,2H),7.53(t,J＝7.8Hz,1H),5.48–5.31(m,1H),4.47–4.33(m,2H),4.05 –3.69(m,5H),3.55–3.48(m,1H),3.47–3.36(m,2H),3.21–3.10(m,2H),2.47(dd,J＝15.1,4.5Hz,1H),2.42 –2.23(m,2H),2.21(s,3H),2.16–2.06(m,2H),2.00(dd,J＝15.5,8.1Hz,1H),1.90–1.54(m,4H).
实施例63制备3-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-氯-4-环丙烷基苯胺
Example 63 Preparation of 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro- 4-Cyclopropylaniline
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和3-氯-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-4-环丙烷基苯胺为原料，根据实施例20的步骤F和H进行合成实施例63为含一个甲酸的盐。LCMS:m/z 620.3(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 3-chloro-5-( Using 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-4-cyclopropanylaniline as raw material, the synthesis was carried out according to steps F and H of Example 20 Example 63 is a salt containing a formic acid. LCMS: m/z 620.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.43(s,1H),6.89(d,J＝2.4Hz,1H),6.68(d,J＝2.4Hz,1H),5.57–5.42(m,1H),4.54(q,J＝11.6Hz,2H),4.04–3.92(m,4H),3.79–3.59(m,4H),2.64–2.58(m,1H),2.54–2.41(m,2H),2.37–2.30(m,2H),2.23(s,3H),2.28–2.18(m,2H),2.14–2.06(m,2H),1.99–1.90(m,2H),1.84–1.77(m,2H),0.61(d,J＝8.3Hz,2H),0.07(d,J＝5.4Hz,2H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.43 (s, 1H), 6.89 (d, J = 2.4Hz, 1H), 6.68 (d, J = 2.4Hz, 1H), 5.57–5.42 (m, 1H),4.54(q,J＝11.6Hz,2H),4.04–3.92(m,4H),3.79–3.59(m,4H),2.64–2.58(m,1H),2.54–2.41(m,2H) ,2.37–2.30(m,2H),2.23(s,3H),2.28–2.18(m,2H),2.14–2.06(m,2H),1.99–1.90(m,2H),1.84–1.77(m, 2H), 0.61 (d, J = 8.3Hz, 2H), 0.07 (d, J = 5.4Hz, 2H).
实施例64制备4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-7-(8-氯-7-氟萘-1-基)-8-氟-7-(8-氯萘-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶
Example 64 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-chloro-7-fluoronaphthalen-1-yl)- 8-Fluoro-7-(8-chloronaphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5- (propynyl)pyrido[4,3-d]pyrimidine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(8-氯-7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷为原料，根据实施例20的步骤F和H进行合成实施例63为含0.5个甲酸的盐。LCMS:m/z 633.2(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(8-chloro- Using 7-fluoronaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane as raw material, the synthesis of Example 63 was carried out according to steps F and H of Example 20. It is a salt containing 0.5 formic acid. LCMS: m/z 633.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.54(s,0.5H),8.20–8.16(m,1H),8.10(dd,J＝9.1,5.6Hz,1H),7.73–7.67(m,2H),7.55(t,J＝8.9Hz,1H),5.48–5.31(m,1H),4.39(q,J＝10.6Hz,2H),4.01–3.68(m,4H),3.52–3.36(m,3H),3.21–3.10(m,1H),2.49–2.29(m,3H),2.22(s,3H),2.14–1.93(m,4H),1.90–1.58(m,5H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.54 (s, 0.5H), 8.20–8.16 (m, 1H), 8.10 (dd, J = 9.1, 5.6Hz, 1H), 7.73–7.67 (m, 2H),7.55(t,J＝8.9Hz,1H),5.48–5.31(m,1H),4.39(q,J＝10.6Hz,2H),4.01–3.68(m,4H),3.52–3.36(m ,3H),3.21–3.10(m,1H),2.49–2.29(m,3H),2.22(s,3H),2.14–1.93(m,4H),1.90–1.58(m,5H).
实施例65制备2-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氯-4-氟苯胺
Example 65 Preparation of 2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-chloro- 4-fluoroaniline
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-氯-4-氟-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺为原料，根据实施例20的步骤F和H进行合成实施例65为含一个甲酸的盐。LCMS:m/z 598.2(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-chloro-4-fluoro -6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)aniline is used as raw material, and the synthesis of Example 65 is carried out according to steps F and H of Example 20 It is a salt containing a formic acid. LCMS: m/z 598.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.51(s,1H),7.27(dd,J＝8.1,2.9Hz,1H),7.17(dt,J＝9.1,2.5Hz,1H),5.51–5.34(m,1H),4.43(q,J＝11.1Hz,2H),3.99–3.74(m,4H),3.56–3.43(m,3H),3.26–3.17(m,1H),2.54–2.46(m,1H),2.46–2.30(m,2H),2.29–2.25(m,1H),2.23(s,3H),2.19–2.09(m,2H),2.07–1.96(m,2H),1.89–1.66(m,4H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.51 (s, 1H), 7.27 (dd, J = 8.1, 2.9Hz, 1H), 7.17 (dt, J = 9.1, 2.5Hz, 1H), 5.51– 5.34(m,1H),4.43(q,J＝11.1Hz,2H),3.99–3.74(m,4H),3.56–3.43(m,3H),3.26–3.17(m,1H),2.54–2.46( m,1H),2.46–2.30(m,2H),2.29–2.25(m,1H),2.23(s,3H),2.19–2.09(m,2H),2.07–1.96(m,2H),1.89– 1.66(m,4H).
实施例66制备4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-7-(8-乙基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶
Example 66 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(8-ethylnaphthalen-1-yl)-8-fluoro -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d] pyrimidine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(8-乙基萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷为原料，根据实施例20的步骤F和H进行合成实施例66。LCMS:m/z 609.3(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(8-ethyl Naphthyl-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane was used as raw material, and Example 66 was synthesized according to steps F and H of Example 20. LCMS: m/z 609.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.06(d,J＝8.2Hz,1H),7.87(d,J＝8.1Hz,1H),7.58(t,J＝7.6Hz,1H),7.50(t,J＝7.7Hz,2H),7.42(d,J＝7.1Hz,1H),5.41–5.30(m,1H),4.62(s,2H),4.37(d,J＝10.7Hz,1H),4.31(d,J＝10.6Hz,1H),3.69–3.62(m,3H),3.38–3.35(m,2H),3.11–3.05(m,1H),2.49–2.24(m,5H),2.20(s,3H),2.19–2.15(m,1H),2.09–2.02(m,3H),1.98–1.90(m,2H),1.86–1.76(m,3H),0.95(t,J＝7.5Hz,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.06 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.50 (t,J＝7.7Hz,2H),7.42(d,J＝7.1Hz,1H),5.41–5.30(m,1H),4.62(s,2H),4.37(d,J＝10.7Hz,1H) ,4.31(d,J＝10.6Hz,1H),3.69–3.62(m,3H),3.38–3.35(m,2H),3.11–3.05(m,1H),2.49–2.24(m,5H),2.20 (s,3H),2.19–2.15(m,1H),2.09–2.02(m,3H),1.98–1.90(m,2H),1.86–1.76(m,3H),0.95(t,J＝7.5Hz ,3H).
实施例67制备4-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 67 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和(3-(甲氧基甲氧基)萘-1-基)硼酸为原料，根据实施例20的步骤F和H进行合成实施例67为含一个甲酸的盐。LCMS:m/z 597.3(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and (3-(methoxy Methoxy)naphthalen-1-yl)boronic acid was used as raw material, and was synthesized according to steps F and H of Example 20. Example 67 is a salt containing a formic acid. LCMS: m/z 597.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.49(s,1H),7.78(d,J＝8.3Hz,1H),7.58(d,J＝8.5Hz,1H),7.45(ddd,J＝8.1,6.8,1.1Hz,1H),7.31(d,J＝2.4Hz,1H),7.29–7.25(m,2H),5.49–5.38(m,1H),4.52–4.42(m,2H),4.02–3.81(m,5H),3.62–3.47(m,3H),3.28–3.18(m,1H),2.53–2.34(m,3H),2.27(d,J＝9.9Hz,1H),2.23(s,3H),2.20–2.11(m,2H),2.07–1.98(m,2H),1.94–1.74(m,4H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.49 (s, 1H), 7.78 (d, J = 8.3Hz, 1H), 7.58 (d, J = 8.5Hz, 1H), 7.45 (ddd, J = 8.1,6.8,1.1Hz,1H),7.31(d,J＝2.4Hz,1H),7.29–7.25(m,2H),5.49–5.38(m,1H),4.52–4.42(m,2H),4.02 –3.81(m,5H),3.62–3.47(m,3H),3.28–3.18(m,1H),2.53–2.34(m,3H),2.27(d,J＝9.9Hz,1H),2.23(s ,3H),2.20–2.11(m,2H),2.07–1.98(m,2H),1.94–1.74(m,4H).
实施例68制备氮-2-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氯-4-氟苯基)乙酰胺
Example 68 Preparation of nitrogen-2-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS) )-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6- Chloro-4-fluorophenyl)acetamide
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和氮-(2-氯-4-氟-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)乙酰胺为原料，根据实施例20的步骤F和H进行合成实施例68为含一个甲酸的盐。LCMS:m/z 640.2(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and nitrogen-(2-chloro- 4-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)acetamide was used as raw material, according to step F of Example 20 Synthesis Example 68 with H is a salt containing a formic acid. LCMS: m/z 640.2(M+H).
1H NMR(600MHz,Methanol-d4)δ8.50(s,1H),7.55(dd,J＝8.0,2.9Hz,1H),7.42(dd,J＝8.5,2.9Hz,1H),5.52–5.39(m,1H),4.52–4.42(m,2H),4.03–3.85(s,4H),3.67–3.51(m,4H),3.28–3.21(m,1H),2.55–2.37(m,3H),2.31–2.26(m,1H),2.23(s,3H),2.21–2.14(m,2H),2.08–2.01(m,1H),1.96–1.87(m,2H),1.92(s,3H),1.82–1.68(m,2H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.50 (s, 1H), 7.55 (dd, J＝8.0, 2.9Hz, 1H), 7.42 (dd, J＝8.5, 2.9Hz, 1H), 5.52– 5.39(m,1H),4.52–4.42(m,2H),4.03–3.85(s,4H),3.67–3.51(m,4H),3.28–3.21(m,1H),2.55–2.37(m,3H ),2.31–2.26(m,1H),2.23(s,3H),2.21–2.14(m,2H),2.08–2.01(m,1H),1.96–1.87(m,2H),1.92(s,3H ),1.82–1.68(m,2H).
实施例69制备4-(4-((1R,5S)-3，8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 69 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2S,4R) -4-Fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6 -Fluoronaphen-2-phenol
反应式如下：
The reaction formula is as follows:
步骤A.(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：将(1R，5S)-3-(7-氯-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-甲酸叔丁酯(200mg，0.42mmol)、2-(8-乙基-7-氟-3-(甲氧基甲氧基)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(302mg，0.84mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(31mg，0.042mmol)、磷酸钾(267mg，1.26mmol)的四氢呋喃(10mL)和水(2mL)的混合溶液在氮气环境下60℃搅拌5h。TLC监测原料反应完全，EtOAc稀释后加水混合,并用EtOAc萃取水层,将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用10-50％乙酸乙酯/石油醚洗脱,得到产物(130mg,0.19mmol,47％收率)LCMS:m/z 676.3(M+H)。Step A. (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxy ether)naphthyl-1-yl)-8-fluoro-2-(methylthio) )-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester: ( 1R,5S)-3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octyl-8-carboxylic acid tert-butyl ester (200 mg, 0.42 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1 -yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (302 mg, 0.84 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine ](2-Amino-1,1'-biphenyl-2-yl)palladium (31 mg, 0.042 mmol), potassium phosphate (267 mg, 1.26 mmol) mixed solution in tetrahydrofuran (10 mL) and water (2 mL) in a nitrogen environment Stir at 60°C for 5 hours. TLC monitors the complete reaction of the raw materials. After diluting with EtOAc, add water and mix, and extract the aqueous layer with EtOAc. Wash the organic phase with saturated NaCl and dry it over Na 2 SO 4. Filter the combined organic phase, dry it, load it onto silica gel and pass it through column chromatography. Purification, eluting with 10-50% ethyl acetate/petroleum ether, gave the product (130 mg, 0.19 mmol, 47% yield) LCMS: m/z 676.3 (M+H).
步骤B.3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯：向(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(40.0mg，0.059mmol)的DCM(5mL)溶液中加入间氯过氧苯甲酸(15.0mg，0.089mmol)，0℃搅拌1h。加入硫代硫酸钠水溶液淬灭，使残余物在二氯甲烷与碳酸氢钠水溶液之间分配,并用二氯甲烷萃取水层并且将有机相用饱和NaCl洗涤，经Na2SO4干燥，浓缩，得到粗品，直接用于下一步。0℃条件下，向粗品(40.0mg，0.059mmol)、((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲醇(16.0mg，0.12mmol)的THF(3mL)溶液中逐滴加入LiHMDS(0.177ml,0.177mmol)，搅拌1h。使残余物在EtOAc与水之间分配,并用EtOAc萃取水层,将有机相用饱和NaCl洗涤，经Na2SO4干燥，将合并的有机相过滤，干燥，装载到硅胶上并通过柱色谱纯化，用0-10％MeOH/DCM洗脱,得到产物(35.0mg,0.046mmol,78％收率)，LCMS:m/z 761.2(M+H)。Step B. 3-(7-(8-ethyl-7-fluoro-3-(methoxy ether)naphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4- Fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[ 3.2.1] Octane-8-carboxylic acid tert-butyl ester: to (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthalene-1-yl )-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] To a solution of octane-8-carboxylic acid tert-butyl ester (40.0 mg, 0.059 mmol) in DCM (5 mL), m-chloroperoxybenzoic acid (15.0 mg, 0.089 mmol) was added, and the mixture was stirred at 0°C for 1 hour. Aqueous sodium thiosulfate solution was added to quench, the residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution, and the aqueous layer was extracted with dichloromethane and the organic phase was washed with saturated NaCl, dried over Na2SO4 , and concentrated , The crude product is obtained and used directly in the next step. To the crude product (40.0 mg, 0.059 mmol), ((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methanol (16.0 mg, 0.12 mmol) in THF (3 mL) at 0°C LiHMDS (0.177ml, 0.177mmol) was added dropwise to the solution and stirred for 1 hour. The residue was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc, the organic phase was washed with saturated NaCl, dried over Na2SO4 , the combined organic phases were filtered, dried, loaded onto silica gel and purified by column chromatography , eluted with 0-10% MeOH/DCM to obtain the product (35.0 mg, 0.046 mmol, 78% yield), LCMS: m/z 761.2 (M+H).
步骤C.4-(4-((1R,5S)-3，8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚：向3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(35.0mg,0.046mmol)的二氯甲烷溶液中逐滴加入三氟乙酸(0.5ml)。室温搅拌40分钟。浓缩，将残余物倒入饱和NaHCO3(20mL)和DCM:MeOH(10:1)(15mL)的混合物中。用DCM:MeOH(10:1)(2×15mL)萃取水层，合并的有机层用盐水(15mL)洗涤，经Na2SO4干燥，过滤并真空浓缩。然后通过制备型 HPLC(5-95％ACN/水/0.1％FA，经20min)纯化。冻干，得到产物(9.0mg,0.014mmol,32％收率)为含一个甲酸的盐。LCMS:m/z 617.3(M+H)。Step C. 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2S,4R)- 4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6- Fluoronaphthyl-2-phenol: To 3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(((2S, 4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- To a solution of diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35.0 mg, 0.046 mmol) in dichloromethane was added dropwise trifluoroacetic acid (0.5 ml). Stir at room temperature for 40 minutes. Concentrate and pour the residue into a mixture of saturated NaHCO3 (20 mL) and DCM:MeOH (10:1) (15 mL). The aqueous layer was extracted with DCM:MeOH (10:1) (2 x 15 mL) and the combined organic layers were washed with brine (15 mL), dried over Na2SO4 , filtered and concentrated in vacuo . Then pass the preparation HPLC (5-95% ACN/water/0.1% FA over 20 min) purification. After lyophilization, the product (9.0 mg, 0.014 mmol, 32% yield) was obtained as a salt containing a formic acid. LCMS: m/z 617.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.51(s,1H),7.69(dd,J＝9.0,5.8Hz,1H),7.32(d,J＝2.6Hz,1H),7.27(t,J＝9.3Hz,1H),7.09(s,1H),5.29–5.17(m,1H),4.64–4.52(m,2H),4.07–3.82(m,4H),3.63–3.52(m,1H),3.28–3.23(m,1H),2.81–2.72(m,1H),2.63(s,3H),2.50–2.42(m,1H),2.40–2.32(m,1H),2.28–2.18(m,1H),2.22(s,3H),2.13–2.01(m,2H),1.97–1.60(m,5H),0.85(t,J＝7.4Hz,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.51 (s, 1H), 7.69 (dd, J = 9.0, 5.8Hz, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.27 (t, J＝9.3Hz,1H),7.09(s,1H),5.29–5.17(m,1H),4.64–4.52(m,2H),4.07–3.82(m,4H),3.63–3.52(m,1H) ,3.28–3.23(m,1H),2.81–2.72(m,1H),2.63(s,3H),2.50–2.42(m,1H),2.40–2.32(m,1H),2.28–2.18(m, 1H), 2.22 (s, 3H), 2.13–2.01 (m, 2H), 1.97–1.60 (m, 5H), 0.85 (t, J = 7.4Hz, 3H).
实施例70制备4-(4-((1R,5S)-3，8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 70 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1 -methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2- phenol
以(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和N-甲基-L-脯氨醇为原料，参照实施例69的步骤B和C的制备方法合成实施例70为含两个甲酸的盐。LCMS:m/z 599.3(M+H)。With (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and N-methyl -L-prolinol is used as raw material, and the salt of Example 70 containing two formic acids is synthesized by referring to the preparation method of Steps B and C of Example 69. LCMS: m/z 599.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.53(s,2H),7.70(dd,J＝9.0,5.8Hz,1H),7.33(d,J＝2.6Hz,1H),7.27(t,J＝9.3Hz,1H),7.10(s,1H),4.78–4.74(m,1H),4.70–4.65(m,1H),4.10–3.82(m,5H),3.58–3.51(m,2H),3.01–2.95(m,1H),2.92(s,3H),2.49–2.41(m,1H),2.36–2.30(m,1H),2.29–2.24(m,1H),2.23(s,3H),2.13–1.88(m,6H),1.86–1.60(m,2H),0.84(t,J＝7.4Hz,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.53 (s, 2H), 7.70 (dd, J = 9.0, 5.8Hz, 1H), 7.33 (d, J = 2.6Hz, 1H), 7.27 (t, J＝9.3Hz,1H),7.10(s,1H),4.78–4.74(m,1H),4.70–4.65(m,1H),4.10–3.82(m,5H),3.58–3.51(m,2H) ,3.01–2.95(m,1H),2.92(s,3H),2.49–2.41(m,1H),2.36–2.30(m,1H),2.29–2.24(m,1H),2.23(s,3H) ,2.13–1.88(m,6H),1.86–1.60(m,2H),0.84(t,J=7.4Hz,3H).
实施例71制备4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)7-(3-氯-2-(三氟甲基)苯基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶
Example 71 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)7-(3-chloro-2-(trifluoromethyl)phenyl) -8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4, 3-d]pyrimidine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(3-氯-2-(三氟甲基)苯基)-4，4，5，5-四甲基-1，3，2-二氧杂硼烷为原料，根据实施例20的步骤F和H进行合成实施例71为含两个甲酸的盐。LCMS:m/z 633.2(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(3-chloro- 2-(Trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane was used as raw material, and the synthesis was carried out according to steps F and H of Example 20. Example 71 is a salt containing two formic acids. LCMS: m/z 633.2(M+H).
1H NMR(600MHz,Methanol-d4)δ8.50(d,J＝1.0Hz,2H),7.83(d,J＝8.1Hz,1H),7.75(t,J＝7.9Hz,1H),7.46(d,J＝7.8Hz,1H),5.50–5.38(m,1H), 4.49(d,J＝11.2Hz,1H),4.44(d,J＝11.2Hz,1H),4.05–3.84(m,5H),3.64–3.47(m,2H),3.24–3.19(m,1H),2.54–2.34(m,3H),2.31–2.25(m,1H),2.24(s,3H),2.20–2.12(m,2H),2.08–2.00(m,1H),1.95–1.87(m,2H),1.85–1.67(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.50 (d, J = 1.0 Hz, 2H), 7.83 (d, J = 8.1 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.46 (d,J＝7.8Hz,1H),5.50–5.38(m,1H), 4.49(d,J＝11.2Hz,1H),4.44(d,J＝11.2Hz,1H),4.05–3.84(m,5H),3.64–3.47(m,2H),3.24–3.19(m,1H) ,2.54–2.34(m,3H),2.31–2.25(m,1H),2.24(s,3H),2.20–2.12(m,2H),2.08–2.00(m,1H),1.95–1.87(m, 2H),1.85–1.67(m,3H).
实施例72制备1-(7-4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-胺基-1H-吲哚-1-基)乙烷基-1-酮
Example 72 Preparation of 1-(7-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2R,7aS )-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5- Amino-1H-indol-1-yl)ethyl-1-one
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和1-(5-胺基-7-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-1H-吲哚-1-基)乙烷基-1-酮为原料，根据实施例20的步骤F和H进行合成实施例72为含五个甲酸的盐。LCMS:m/z 627.3(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 1-(5-amino -7-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-indol-1-yl)ethanyl-1-one is Raw materials were synthesized according to steps F and H of Example 20. Example 72 was a salt containing five formic acids. LCMS: m/z 627.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.54(s,5H),8.01(d,J＝1.9Hz,1H),7.92(d,J＝1.9Hz,1H),7.40(d,J＝3.2Hz,1H),6.56(d,J＝3.2Hz,1H),5.50–5.33(m,1H),4.45(d,J＝11.0Hz,1H),4.39(d,J＝11.0Hz,1H),3.97–3.73(m,5H),3.51–3.42(m,3H),3.21–3.14(m,1H),2.52–2.32(m,4H),2.28(s,3H),2.19(s,3H),2.17–2.08(m,2H),2.05–1.94(m,2H),1.88–1.67(m,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.54 (s, 5H), 8.01 (d, J = 1.9 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 3.2Hz,1H),6.56(d,J＝3.2Hz,1H),5.50–5.33(m,1H),4.45(d,J＝11.0Hz,1H),4.39(d,J＝11.0Hz,1H) ,3.97–3.73(m,5H),3.51–3.42(m,3H),3.21–3.14(m,1H),2.52–2.32(m,4H),2.28(s,3H),2.19(s,3H) ,2.17–2.08(m,2H),2.05–1.94(m,2H),1.88–1.67(m,3H).
实施例73制备7-4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-1H-吲哚-5-胺
Example 73 Preparation of 7-4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-1H-indole- 5-amine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和7-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-1H-吲哚-5-胺为原料，根据实施例20的步骤F和H进行合成实施例73为含一个甲酸的盐。LCMS:m/z 585.3(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 7-(4,4, Using 5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-indole-5-amine as raw material, the synthesis of Example 73 was carried out according to steps F and H of Example 20. It is a salt containing a formic acid. LCMS: m/z 585.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.49(s,1H),7.44(d,J＝2.0Hz,1H),7.32(d,J＝3.1Hz,1H),7.22(d,J＝2.1Hz,1H),6.42(d,J＝3.1Hz,1H),5.52–5.41(m,1H),4.51(d,J＝11.2Hz,1H),4.46(d,J＝11.2Hz,1H),4.01–3.83(m,5H),3.69–3.52(m,3H),3.29–3.24(m,1H),2.58–2.39(m,2H),2.32–2.29(m, 1H),2.28(s,3H),2.22–2.16(m,2H),2.10–2.02(m,1H),1.96–1.86(m,3H),1.83–1.70(m,2H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.49 (s, 1H), 7.44 (d, J = 2.0Hz, 1H), 7.32 (d, J = 3.1Hz, 1H), 7.22 (d, J = 2.1Hz,1H),6.42(d,J＝3.1Hz,1H),5.52–5.41(m,1H),4.51(d,J＝11.2Hz,1H),4.46(d,J＝11.2Hz,1H) ,4.01–3.83(m,5H),3.69–3.52(m,3H),3.29–3.24(m,1H),2.58–2.39(m,2H),2.32–2.29(m, 1H),2.28(s,3H),2.22–2.16(m,2H),2.10–2.02(m,1H),1.96–1.86(m,3H),1.83–1.70(m,2H).
实施例74制备4-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-甲基-5-(三氟甲基)吡啶-2-胺
Example 74 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-methyl -5-(trifluoromethyl)pyridin-2-amine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-5-(三氟甲基)吡啶-2-胺为原料，根据实施例20的步骤F和H进行合成实施例74为含两个甲酸的盐。LCMS:m/z 629.3(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 6-methyl-4- (4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-5-(trifluoromethyl)pyridin-2-amine was used as raw material, according to Example 20 Steps F and H were carried out to synthesize Example 74 for a salt containing two formic acids. LCMS: m/z 629.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.51(s,2H),6.37(s,1H),5.48–5.36(m,1H),4.48–4.38(m,2H),3.98–3.74(m,5H),3.54–3.44(m,3H),3.22–3.17(m,1H),2.57(s,3H),2.51–2.32(m,3H),2.23(s,3H),2.18–2.09(m,2H),2.06–1.97(m,2H),1.93–1.82(m,2H),1.78–1.65(m,2H)。 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.51 (s, 2H), 6.37 (s, 1H), 5.48–5.36 (m, 1H), 4.48–4.38 (m, 2H), 3.98–3.74 (m, 5H), 3.54–3.44 (m, 3H), 3.22–3.17 (m, 1H), 2.57 (s, 3H), 2.51–2.32 (m, 3H), 2.23 (s, 3H), 2.18–2.09 (m, 2H), 2.06–1.97 (m, 2H), 1.93–1.82 (m, 2H), 1.78–1.65 (m, 2H).
实施例75制备4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-7-(5-氯异喹啉-4-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶
Example 75 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(5-chloroisoquinolin-4-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d ]pyrimidine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和5-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)异喹啉为原料，根据实施例20的步骤F和H进行合成实施例75为含三个甲酸的盐。LCMS:m/z 616.2(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 5-chloro-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)isoquinoline is used as raw material, and is synthesized according to steps F and H of Example 20. Example 75 contains Three salts of formic acid. LCMS: m/z 616.2(M+H).
1H NMR(600MHz,Methanol-d4)δ9.51(s,1H),8.54(s,1H),8.46(s,3H),8.30(d,J＝8.2Hz,1H),7.95(d,J＝7.5Hz,1H),7.78(t,J＝7.8Hz,1H),5.56–5.43(m,1H),4.66–4.46(m,2H),4.18–3.84(m,4H),3.78–3.54(m,4H),3.31–3.26(m,1H),2.65–2.39(m,3H),2.37–2.26(m,2H),2.23(s,3H),2.14–1.72(m,6H)。 1 H NMR (600MHz, Methanol-d 4 ) δ9.51 (s, 1H), 8.54 (s, 1H), 8.46 (s, 3H), 8.30 (d, J = 8.2Hz, 1H), 7.95 (d, J＝7.5Hz,1H),7.78(t,J＝7.8Hz,1H),5.56–5.43(m,1H),4.66–4.46(m,2H),4.18–3.84(m,4H),3.78–3.54 (m,4H),3.31–3.26(m,1H),2.65–2.39(m,3H),2.37–2.26(m,2H),2.23(s,3H),2.14–1.72(m,6H).
实施例76制备4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-7-(5-氟异喹啉-4-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基) 甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶
Example 76 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-7-(5-fluoroisoquinolin-4-yl)-8- Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) Methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和5-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)异喹啉为原料，根据实施例20的步骤F和H进行合成实施例76为含一个甲酸的盐。LCMS:m/z 600.3(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 5-fluoro-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)isoquinoline is used as raw material, and is synthesized according to steps F and H of Example 20. Example 76 contains A salt of formic acid. LCMS: m/z 600.3(M+H).
1H NMR(600MHz,Methanol-d4)δ9.49(s,1H),8.58(s,1H),8.52(s,1H),8.15(dd,J＝8.3,1.0Hz,1H),7.80(td,J＝8.0,4.6Hz,1H),7.58(dd,J＝12.2,7.7Hz,1H),5.49–5.38(m,1H),4.53–4.43(m,2H),4.08–3.83(m,4H),3.65–3.46(m,3H),3.26–3.17(m,1H),2.55–2.33(m,3H),2.31–2.26(m,1H),2.24(s,3H),2.20–2.12(m,2H),2.08–1.72(m,6H)。 1 H NMR (600MHz, Methanol-d 4 ) δ9.49 (s, 1H), 8.58 (s, 1H), 8.52 (s, 1H), 8.15 (dd, J = 8.3, 1.0Hz, 1H), 7.80 ( td,J＝8.0,4.6Hz,1H),7.58(dd,J＝12.2,7.7Hz,1H),5.49–5.38(m,1H),4.53–4.43(m,2H),4.08–3.83(m, 4H),3.65–3.46(m,3H),3.26–3.17(m,1H),2.55–2.33(m,3H),2.31–2.26(m,1H),2.24(s,3H),2.20–2.12( m,2H),2.08–1.72(m,6H).
实施例77制备5-乙基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-(哌嗪-1-基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 77 Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy yl)-4-(piperazin-1-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol
参照实施例43的制备方法，使用相应的原料和试剂可制备实施例77为含一个甲酸的盐。LCMS:m/z 617.3(M+H)。Referring to the preparation method of Example 43, using corresponding raw materials and reagents, Example 77 can be prepared as a salt containing a formic acid. LCMS: m/z 617.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.55(s,1H),7.69(dd,J＝9.0,5.8Hz,1H),7.32(d,J＝2.6Hz,1H),7.27(t,J＝9.4Hz,1H),7.08(t,J＝2.2Hz,1H),5.44–5.27(m,1H),4.42–4.27(m,2H),4.05–3.89(m,4H),3.30–3.26(m,1H),3.13–3.02(m,5H),2.49–2.35(m,2H),2.34–2.25(m,2H),2.23(s,3H),2.21–2.15(m,1H),2.11–1.88(m,5H),0.84(t,J＝7.4Hz,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.55 (s, 1H), 7.69 (dd, J = 9.0, 5.8Hz, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.27 (t, J＝9.4Hz,1H),7.08(t,J＝2.2Hz,1H),5.44–5.27(m,1H),4.42–4.27(m,2H),4.05–3.89(m,4H),3.30–3.26 (m,1H),3.13–3.02(m,5H),2.49–2.35(m,2H),2.34–2.25(m,2H),2.23(s,3H),2.21–2.15(m,1H),2.11 –1.88(m,5H),0.84(t,J＝7.4Hz,3H).
实施例78制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-胺
Example 78 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl -6-fluoronaphthalene-2-amine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a (5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和((2-氟-6-氨基-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷为原料，根据实施例20的步骤F-H进行合成实施例78为含一个甲酸的盐。LCMS:m/z 638.3(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrozine-7a (5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert. Butyl ester and ((2-fluoro-6-amino-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphthalene-1-yl) Ethynyl)triisopropylsilane was used as raw material, and was synthesized according to step FH of Example 20. Example 78 is a salt containing a formic acid. LCMS: m/z 638.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.41(s,1H),7.74(dd,J＝9.2,5.7Hz,1H),7.24(t,J＝8.9Hz,1H),7.19(d,J＝2.4Hz,1H),7.12(s,1H),5.50–5.38(m,1H),4.53–4.43(m,2H),4.08–3.84(m,5H),3.68–3.51(m,3H),3.27–3.22(m,1H),2.56–2.35(m,2H),2.31–2.23(m,2H),2.19(s,3H),2.18–2.13(m,2H),2.09–1.65(m,5H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.41 (s, 1H), 7.74 (dd, J = 9.2, 5.7Hz, 1H), 7.24 (t, J = 8.9Hz, 1H), 7.19 (d, J＝2.4Hz,1H),7.12(s,1H),5.50–5.38(m,1H),4.53–4.43(m,2H),4.08–3.84(m,5H),3.68–3.51(m,3H) ,3.27–3.22(m,1H),2.56–2.35(m,2H),2.31–2.23(m,2H),2.19(s,3H),2.18–2.13(m,2H),2.09–1.65(m, 5H).
实施例79制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((2S,4R)-1-甲基-4-氟吡咯烷-2基)甲氧基)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 79 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2S,4R)-1-methyl -4-fluoropyrrolidin-2yl)methoxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphth-2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和((2S,4R)-1-甲基-4-氟吡咯-2-基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例79为含一个甲酸的盐。LCMS:m/z 613.2(M+H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and ((2S , 4R)-1-methyl-4-fluoropyrrol-2-yl)methanol was used as raw material, and Example 79 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid. LCMS: m/z 613.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.45(s,1H),7.89(dd,J＝9.1,5.7Hz,1H),7.39–7.32(m,2H),7.23(d,J＝2.2Hz,1H),5.34–5.16(m,1H),4.69–4.55(m,2H),4.14–3.86(m,5H),3.67–3.55(m,1H),2.90–2.71(m,2H),2.66(s,3H),2.43–2.31(m,2H),2.22(s,3H),2.04–1.75(m,5H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.45 (s, 1H), 7.89 (dd, J = 9.1, 5.7Hz, 1H), 7.39–7.32 (m, 2H), 7.23 (d, J = 2.2 Hz,1H),5.34–5.16(m,1H),4.69–4.55(m,2H),4.14–3.86(m,5H),3.67–3.55(m,1H),2.90–2.71(m,2H), 2.66(s,3H),2.43–2.31(m,2H),2.22(s,3H),2.04–1.75(m,5H).
实施例80制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((2S,4S)-1-甲基-4-氟吡咯烷-2基)甲氧基)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 80 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((2S,4S)-1-methyl -4-fluoropyrrolidin-2yl)methoxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphth-2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和((2S,4S)-1-甲基-4-氟吡咯-2-基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例80为含一个甲酸的盐。LCMS:m/z 613.2(M+H)。 Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and ((2S , 4S)-1-methyl-4-fluoropyrrol-2-yl)methanol was used as raw material, and Example 80 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid. LCMS: m/z 613.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.50(s,1H),7.86(dd,J＝9.1,5.7Hz,1H),7.38–7.33(m,2H),7.26(d,J＝2.2Hz,1H),5.36–5.18(m,1H),4.69–4.57(m,2H),4.15–3.86(m,5H),3.68–3.57(m,1H),2.92–2.73(m,2H),2.68(s,3H),2.43–2.31(m,2H),2.23(s,3H),2.06–1.78(m,5H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.50 (s, 1H), 7.86 (dd, J = 9.1, 5.7Hz, 1H), 7.38–7.33 (m, 2H), 7.26 (d, J = 2.2 Hz,1H),5.36–5.18(m,1H),4.69–4.57(m,2H),4.15–3.86(m,5H),3.68–3.57(m,1H),2.92–2.73(m,2H), 2.68(s,3H),2.43–2.31(m,2H),2.23(s,3H),2.06–1.78(m,5H).
实施例81制备4-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-氯萘-2-酚
Example 81 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-chloronaphthalene-2-ol
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(8-氯-3-(甲氧基甲醚)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷为原料，根据实施例20的步骤F和H进行合成实施例81为含一个甲酸的盐。LCMS:m/z 631.2(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(8-chloro- 3-(methoxymethyl ether)naphthyl-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane was used as raw material, according to steps F and 2 of Example 20 H was used to synthesize Example 81 as a salt containing a formic acid. LCMS: m/z 631.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.45(s,1H),7.78(dd,J＝7.8,1.7Hz,1H),7.42–7.34(m,3H),7.19(t,J＝2.0Hz,1H),5.58–5.42(m,1H),4.62–4.50(m,2H),4.12–3.94(m,4H),3.82–3.59(m,4H),2.66–2.44(m,2H),2.39–2.30(m,2H),2.27–2.24(m,2H),2.23(s,3H),2.15–2.05(m,1H),2.01–1.72(m,5H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.45 (s, 1H), 7.78 (dd, J = 7.8, 1.7Hz, 1H), 7.42–7.34 (m, 3H), 7.19 (t, J = 2.0 Hz,1H),5.58–5.42(m,1H),4.62–4.50(m,2H),4.12–3.94(m,4H),3.82–3.59(m,4H),2.66–2.44(m,2H), 2.39–2.30(m,2H),2.27–2.24(m,2H),2.23(s,3H),2.15–2.05(m,1H),2.01–1.72(m,5H).
实施例82制备4-(4-((1R,5S)-3，8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-((1-(吗啉甲基)环丙烷基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 82 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-(morpholine) Methyl)cyclopropyl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-phenol
以(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和(1-(吗啉甲基)环丙烷基)甲醇为原料，参照实施例69的步骤B和C的制备方法合成实施例82为含一个甲酸的盐。LCMS:m/z 655.3(M+H)。With (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and (1-( Using morpholinomethyl)cyclopropyl)methanol as raw material, the salt of Example 82 containing a formic acid was synthesized by referring to the preparation method of Steps B and C of Example 69. LCMS: m/z 655.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.39(s,1H),7.70(dd,J＝9.0,5.8Hz,1H),7.32(d,J＝2.6Hz,1H),7.27(t,J＝9.4Hz,1H),7.08(d,J＝2.6Hz,1H),4.66–4.41(m,4H),4.14–3.98(m,3H),3.70(t,J＝4.6Hz,4H),2.74–2.64(m,4H),2.61(s,2H),2.52–2.41(m,1H),2.31–2.25(m,1H),2.23(s,3H),2.10– 1.79(m,5H),0.85(t,J＝7.4Hz,3H),0.79(t,J＝5.6Hz,2H),0.60(t,J＝5.7Hz,2H)。 1 H NMR (400 MHz, Methanol-d 4 )δ8.39(s,1H),7.70(dd,J＝9.0,5.8Hz,1H),7.32(d,J＝2.6Hz,1H),7.27(t,J＝9.4Hz,1H),7.08(d,J＝2.6Hz,1H),4.66–4.41(m,4H),4.14–3.98(m,3H),3.70(t,J＝4.6Hz,4H),2.74–2.64(m,4H),2.61(s,2H),2.52–2.41(m,1H),2.31–2.25(m,1H),2.23(s,3H),2.10– 1.79 (m, 5H), 0.85 (t, J = 7.4 Hz, 3H), 0.79 (t, J = 5.6 Hz, 2H), 0.60 (t, J = 5.7 Hz, 2H).
实施例83制备4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-7-(7-氟萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶
Example 83 Preparation of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-7-(7-fluoronaphthalene-1-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidine
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(7-氟萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷为原料，根据实施例20的步骤F和H进行合成实施例83为含0.5个甲酸的盐。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(7-fluoronaphthalene -1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane is used as raw material, and is synthesized according to steps F and H of Example 20. Example 83 contains 0.5 Formic acid salt.
LCMS:m/z 599.3(M+H)。LCMS: m/z 599.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.55(s,0.5H),8.12–8.09(m,1H),8.08–8.05(m,1H),7.73(d,J＝7.0Hz,1H),7.64(dd,J＝8.2,7.1Hz,1H),7.45–7.38(m,2H),5.43–5.32(m,1H),4.40(d,J＝10.6Hz,1H),4.33(d,J＝10.6Hz,1H),3.96–3.81(m,2H),3.77–3.61(m,3H),3.45–3.35(m,2H),3.16–3.06(m,1H),2.45–2.27(m,3H),2.23(s,3H),2.22–2.15(m,1H),2.14–2.03(m,3H),2.00–1.92(m,1H),1.87–1.68(m,4H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.55 (s, 0.5H), 8.12–8.09 (m, 1H), 8.08–8.05 (m, 1H), 7.73 (d, J = 7.0Hz, 1H) ,7.64(dd,J＝8.2,7.1Hz,1H),7.45–7.38(m,2H),5.43–5.32(m,1H),4.40(d,J＝10.6Hz,1H),4.33(d,J ＝10.6Hz,1H),3.96–3.81(m,2H),3.77–3.61(m,3H),3.45–3.35(m,2H),3.16–3.06(m,1H),2.45–2.27(m,3H ),2.23(s,3H),2.22–2.15(m,1H),2.14–2.03(m,3H),2.00–1.92(m,1H),1.87–1.68(m,4H).
实施例84制备4-(4-((1R,5S)-3，8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-(4，4-二氟哌啶-1-基)丙烷-2-基)氧)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 84 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-1-(4, 4-Difluoropiperidin-1-yl)propan-2-yl)oxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl 6-fluoronaphthalene-2-phenol
以(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和(S)-1-(4，4-二氟哌啶-1-基)丙烷-2-醇为原料，参照实施例69的步骤B和C的制备方法合成实施例84为含有0.5个甲酸的盐。LCMS:m/z663.3(M+H)。With (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and (S)- Using 1-(4,4-difluoropiperidin-1-yl)propan-2-ol as raw material, the salt of Example 84 containing 0.5 formic acid was synthesized by referring to the preparation method of Steps B and C of Example 69. LCMS:m/z663.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.53(s,0.5H),7.69(dd,J＝9.0,5.7Hz,1H),7.32(d,J＝2.6Hz,1H),7.27(t,J＝9.3Hz,1H),7.09(d,J＝13.9Hz,1H),5.64–5.58(m,1H),4.06–3.75(m,5H),2.88–2.71(m,4H),2.69–2.59(m,3H), 2.49–2.43(m,1H),2.29–2.43(m,2H),2.21(s,3H),1.97–1.71(m,7H),1.42(t,J＝6.6Hz,3H),0.85(td,J＝7.4,3.8Hz,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.53 (s, 0.5H), 7.69 (dd, J = 9.0, 5.7Hz, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.27 (t ,J＝9.3Hz,1H),7.09(d,J＝13.9Hz,1H),5.64–5.58(m,1H),4.06–3.75(m,5H),2.88–2.71(m,4H),2.69– 2.59(m,3H), 2.49–2.43(m,1H),2.29–2.43(m,2H),2.21(s,3H),1.97–1.71(m,7H),1.42(t,J＝6.6Hz,3H),0.85(td, J=7.4,3.8Hz,3H).
实施例85制备4-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟萘-2-酚
Example 85 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalene -2-phenol
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(7-氟-3-(甲氧基甲醚)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷为原料，根据实施例20的步骤F和H进行合成实施例85为含0.5个甲酸的盐。LCMS:m/z 615.2(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(7-fluoro- 3-(methoxymethyl ether)naphthyl-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane was used as raw material, according to steps F and 2 of Example 20 H was used to synthesize Example 85 as a salt containing 0.5 formic acid. LCMS: m/z 615.2(M+H).
1H NMR(600MHz,Methanol-d4)δ8.46(s,0.5H),7.83(dd,J＝9.4,5.5Hz,1H),7.36–7.32(m,2H),7.31–7.21(m,2H),5.53–5.39(m,1H),4.56–4.46(m,2H),4.06–3.87(m,4H),3.66–3.52(m,3H),3.29–3.22(m,1H),2.57–2.38(m,3H),2.33–2.27(m,1H),2.24(s,3H),2.22–2.13(m,2H),2.10–2.01(m,2H),1.98–1.77(m,4H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.46 (s, 0.5H), 7.83 (dd, J = 9.4, 5.5Hz, 1H), 7.36–7.32 (m, 2H), 7.31–7.21 (m, 2H),5.53–5.39(m,1H),4.56–4.46(m,2H),4.06–3.87(m,4H),3.66–3.52(m,3H),3.29–3.22(m,1H),2.57– 2.38(m,3H),2.33–2.27(m,1H),2.24(s,3H),2.22–2.13(m,2H),2.10–2.01(m,2H),1.98–1.77(m,4H).
实施例86制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-((4-甲基哌嗪-1-基)甲基)环丙烷基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 86 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-((4-methylpiperazin-1-yl)methyl)cyclopropane)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和(1-((4-甲基哌嗪-1-基)甲基)环丙烷基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例86为含0.5个甲酸的盐。LCMS:m/z 664.3(M+H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and (1- ((4-methylpiperazin-1-yl)methyl)cyclopropyl)methanol was used as raw material, and Example 86 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing 0.5 formic acid. LCMS: m/z 664.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.54(s,0.5H),7.89(dd,J＝9.1,5.6Hz,1H),7.39–7.32(m,2H),7.23(d,J＝2.4Hz,1H),4.61(s,1H),4.47(d,J＝10.9Hz,1H),4.40(d,J＝10.9Hz,1H),4.05–3.90(m,2H),3.86–3.68(m,3H),2.97–2.62(m,7H),2.51(d,J＝13.9Hz,4H),2.41–2.33(m,1H),2.21(s,3H),1.85(s,3H),1.68–1.58(m,2H),0.75(d,J＝4.8Hz,2H),0.55(d,J＝5.2Hz,2H)。 1 H NMR (600 MHz, Methanol-d 4 )δ8.54(s,0.5H),7.89(dd,J＝9.1,5.6Hz,1H),7.39–7.32(m,2H),7.23(d,J＝ 2.4Hz,1H),4.61(s,1H),4.47(d,J＝10.9Hz,1H),4.40(d,J＝10.9Hz,1H),4.05–3.90(m,2H),3 .86–3.68(m,3H),2.97–2.62(m,7H),2.51(d,J＝13.9Hz,4H),2.41–2.33(m,1H),2.21(s,3H),1.85(s , 3H), 1.68–1.58 (m, 2H), 0.75 (d, J＝4.8Hz, 2H), 0.55 (d, J＝5.2Hz, 2H).
实施例87制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((S)-2-((S)-3-氟吡咯烷-1-基)丙氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 87 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((S)-2-( (S)-3-fluoropyrrolidin-1-yl)propoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoro Naphth-2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和((S)-2-((S)-3-氟吡咯烷-1-基)丙醇为原料，参照实施例38的步骤D至F的合成方法制备实施例87为含0.5个甲酸的盐。LCMS:m/z 627.3(M+H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and ((S )-2-((S)-3-fluoropyrrolidin-1-yl)propanol as raw material, refer to the synthesis method of steps D to F of Example 38 to prepare Example 87 as a salt containing 0.5 formic acid. LCMS: m/z 627.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.50(s,0.5H),7.88(dd,J＝9.2,5.6Hz,1H),7.38–7.32(m,2H),7.24–7.21(m,1H),5.66–5.56(m,1H),5.27–5.12(m,1H),4.71–4.55(m,2H),4.10–3.81(m,5H),3.19–2.87(m,4H),2.83–2.63(m,2H),2.22(s,3H),2.20–2.12(m,1H),2.10–1.70(m,5H),1.45(br.s,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.50 (s, 0.5H), 7.88 (dd, J = 9.2, 5.6Hz, 1H), 7.38–7.32 (m, 2H), 7.24–7.21 (m, 1H),5.66–5.56(m,1H),5.27–5.12(m,1H),4.71–4.55(m,2H),4.10–3.81(m,5H),3.19–2.87(m,4H),2.83– 2.63(m,2H),2.22(s,3H),2.20–2.12(m,1H),2.10–1.70(m,5H),1.45(br.s,3H).
实施例88制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((S)-1-(4，4-二氟哌啶-1-基)丙烷-2-基)氧)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 88 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(((S)-1-(4,4 -Difluoropiperidin-1-yl)propan-2-yl)oxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl -6-fluoronaphthalene-2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和(S)-1-(4，4-二氟哌啶-1-基)丙烷-2-醇为原料，参照实施例38的步骤D至F的合成方法制备实施例88为含3个甲酸的盐。LCMS:m/z 659.3(M+H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and (S) -1-(4,4-difluoropiperidin-1-yl)propan-2-ol was used as raw material, and Example 88 was prepared by referring to the synthesis method of steps D to F of Example 38, which was a salt containing three formic acids. LCMS: m/z 659.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.54(s,3H),7.88(dd,J＝9.1,5.7Hz,1H),7.38–7.32(m,2H),7.23(dd,J＝10.0,2.5Hz,1H),5.63–5.57(m,1H),4.07–3.88(m,3H),3.84–3.76(m,3H),2.84(td,J＝13.6,8.0Hz,2H),2.80–2.73(m,2H),2.72–2.59(m,3H),2.21(s,3H),1.98–1.82(m,7H),1.42(dd,J＝6.3,5.2Hz,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.54 (s, 3H), 7.88 (dd, J = 9.1, 5.7Hz, 1H), 7.38–7.32 (m, 2H), 7.23 (dd, J = 10.0 ,2.5Hz,1H),5.63–5.57(m,1H),4.07–3.88(m,3H),3.84–3.76(m,3H),2.84(td,J＝13.6,8.0Hz,2H),2.80– 2.73(m,2H),2.72–2.59(m,3H),2.21(s,3H),1.98–1.82(m,7H),1.42(dd,J＝6.3,5.2Hz,3H).
实施例89制备4-(4-((1R,5S)-3，8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-(哌啶-1-基)丙烷-2-基)氧)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 89 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((S)-1-(piperidine) -1-yl)propan-2-yl)oxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene -2-phenol
以(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和(S)-1-(哌啶-1-基)丙烷-2-醇为原料，参照实施例69的步骤B和C的制备方法合成实施例89为含有一个甲酸的盐。LCMS:m/z 627.3(M+H)。With (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and (S)- Using 1-(piperidin-1-yl)propan-2-ol as raw material, the salt of Example 89 containing a formic acid was synthesized by referring to the preparation method of Steps B and C of Example 69. LCMS: m/z 627.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.53(s,1H),7.70(dd,J＝9.0,5.8Hz,1H),7.32(d,J＝2.7Hz,1H),7.27(t,J＝9.4Hz,1H),7.09(dd,J＝5.8,2.6Hz,1H),5.72–5.63(m,1H),4.06–3.71(m,5H),3.29–3.20(m,1H),3.14–2.95(m,6H),2.52–2.40(m,1H),2.29–2.23(m,1H),2.21(s,3H),1.93–1.81(m,3H),1.78–1.68(m,5H),1.62–1.55(m,2H),1.48(t,J＝6.0Hz,3H),0.85(t,J＝7.4Hz,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.53 (s, 1H), 7.70 (dd, J = 9.0, 5.8Hz, 1H), 7.32 (d, J = 2.7Hz, 1H), 7.27 (t, J＝9.4Hz,1H),7.09(dd,J＝5.8,2.6Hz,1H),5.72–5.63(m,1H),4.06–3.71(m,5H),3.29–3.20(m,1H),3.14 –2.95(m,6H),2.52–2.40(m,1H),2.29–2.23(m,1H),2.21(s,3H),1.93–1.81(m,3H),1.78–1.68(m,5H) ,1.62–1.55(m,2H),1.48(t,J＝6.0Hz,3H),0.85(t,J＝7.4Hz,3H).
实施例90制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-(哌啶甲基)环丙烷基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 90 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(piperidinemethyl) (yl)cyclopropyl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和(1-(哌啶甲基)环丙烷基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例90为含一个甲酸的盐。LCMS:m/z 649.3(M+H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and (1- (Piperidinylmethyl)cyclopropyl)methanol was used as raw material, and Example 90 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid. LCMS: m/z 649.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.57(s,1H),7.88(dd,J＝9.2,5.7Hz,1H),7.38–7.32(m,2H),7.23(d,J＝2.5Hz,1H),4.51–4.40(m,2H),3.88–3.58(m,6H),3.08–2.79(m,7H),2.21(s,3H),1.86–1.69(m,7H),1.66–1.54(m,3H),0.88(d,J＝8.5Hz,2H),0.71(d,J＝8.4Hz,2H)。 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.57 (s, 1H), 7.88 (dd, J＝9.2, 5.7 Hz, 1H), 7.38–7.32 (m, 2H), 7.23 (d, J＝2.5 Hz, 1H), 4.51–4.40 (m, 2H), 3.88–3.58 (m, 6H), 3.08–2.79 (m, 7H), 2.21 (s, 3H), 1.86–1.69 (m, 7H), 1.66–1.54 (m, 3H), 0.88 (d, J＝8.5 Hz, 2H), 0.71 (d, J＝8.4 Hz, 2H).
实施例91制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((S)-1-(哌啶-1-基)丙烷-2-基)氧)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 91 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1- (Piperidin-1-yl)propan-2-yl)oxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- 2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和(S)-1-(哌啶-1-基)丙烷-2-醇为原料，参照实施例38的步骤D至F的合成方法制备实施例91为含一个甲酸的盐。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and (S) -1-(piperidin-1-yl)propan-2-ol was used as raw material, and Example 91 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid.
LCMS:m/z 623.3(M+H)。LCMS: m/z 623.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,1H),7.88(dd,J＝9.1,5.7Hz,1H),7.39–7.31(m,2H),7.23(dd,J＝5.1,2.5Hz,1H),5.68–5.59(m,1H),4.02–3.61(m,5H),3.13–3.02(m,1H),2.94–2.73(m,5H),2.21(s,3H),1.88–1.76(m,3H),1.72–1.59(m,5H),1.56–1.49(m,3H),1.45(t,J＝6.0Hz,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.56 (s, 1H), 7.88 (dd, J = 9.1, 5.7Hz, 1H), 7.39–7.31 (m, 2H), 7.23 (dd, J = 5.1 ,2.5Hz,1H),5.68–5.59(m,1H),4.02–3.61(m,5H),3.13–3.02(m,1H),2.94–2.73(m,5H),2.21(s,3H), 1.88–1.76(m,3H),1.72–1.59(m,5H),1.56–1.49(m,3H),1.45(t,J=6.0Hz,3H).
实施例92制备5-乙基-6-氟-4-(8-氟-4-((1R,5S)-1-甲基-3,8-二氮杂双环[3.2.1]辛-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 92 Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]octane-3 -yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl) Naphth-2-phenol
参照实施例42的制备方法，使用相应的原料和试剂可制备实施例92为含一个甲酸的盐。LCMS:m/z 613.3(M+H)。Referring to the preparation method of Example 42, Example 92 can be prepared as a salt containing one formic acid using corresponding raw materials and reagents. LCMS: m/z 613.3 (M+H).
1H NMR(400MHz,Methanol-d4)δ8.53(s,1H),7.70(dd,J＝9.0,5.8Hz,1H),7.32(d,J＝2.6Hz,1H),7.27(t,J＝9.4Hz,1H),7.14–7.08(m,1H),4.73–4.58(m,3H),3.73–3.66(m,2H),3.47–3.37(m,3H),2.91–2.79(m,4H),2.52–2.36(m,2H),2.36–2.24(m,3H),2.21(s,3H),2.09–1.89(m,5H),1.56–1.44(m,2H),1.36(d,J＝10.7Hz,3H),0.84(td,J＝7.3,5.0Hz,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.53 (s, 1H), 7.70 (dd, J = 9.0, 5.8Hz, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.27 (t, J＝9.4Hz,1H),7.14–7.08(m,1H),4.73–4.58(m,3H),3.73–3.66(m,2H),3.47–3.37(m,3H),2.91–2.79(m, 4H),2.52–2.36(m,2H),2.36–2.24(m,3H),2.21(s,3H),2.09–1.89(m,5H),1.56–1.44(m,2H),1.36(d, J=10.7Hz, 3H), 0.84 (td, J=7.3, 5.0Hz, 3H).
实施例93制备5-乙基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-4-((1R，5S)-1-甲基-3，8-二氮杂双环[3.2.1]辛-3-基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 93 Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy base)-4-((1R,5S)-1-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-(propynyl)pyrido[4,3 -d]pyrimidin-7-yl)naphth-2-ol
参照实施例42的制备方法，使用相应的原料和试剂可制备实施例93为含一个甲酸的盐。LCMS:m/z 657.3(M+H)。Referring to the preparation method of Example 42, using corresponding raw materials and reagents, Example 93 can be prepared as a salt containing a formic acid. LCMS: m/z 657.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.53(s,1H),7.69(dd,J＝9.0,5.8Hz,1H),7.32(d,J＝2.6Hz,1H),7.27(t,J＝9.4Hz,1H),7.11(d,J＝7.1Hz,1H),5.47–5.30(m,1H),4.47–4.31(m,2H),3.76–3.64(m,2H),3.45–3.36(m,3H),3.20–3.10(m,1H),2.52–2.27(m,4H),2.21(s,4H),2.15–2.05(m,2H),2.02–1.91(m,2H),1.56–1.46(m,2H),1.42–1.27(m,3H),0.89–0.77(m,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.53 (s, 1H), 7.69 (dd, J = 9.0, 5.8Hz, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.27 (t, J＝9.4Hz,1H),7.11(d,J＝7.1Hz,1H),5.47–5.30(m,1H),4.47–4.31(m,2H),3.76–3.64(m,2H),3.45–3.36 (m,3H),3.20–3.10(m,1H),2.52–2.27(m,4H),2.21(s,4H),2.15–2.05(m,2H),2.02–1.91(m,2H),1.56 –1.46(m,2H),1.42–1.27(m,3H),0.89–0.77(m,3H).
实施例94制备4-(4-((1R,5S)-3，8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-2-(((S)-1-((S)-3-氟吡咯烷-1-基)丙烷-2-基)氧)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 94 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((S)-1-((S)-3-fluoropyrrolidin-1-yl)propan-2-yl)oxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol
以(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和((S)-1-((S)-3-氟吡咯烷-1-基)丙烷-2-醇为原料，参照实施例69的步骤B和C的制备方法合成实施例94为含有一个甲酸的盐。LCMS:m/z 631.3(M+H)。With (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and ((S) -1-((S)-3-fluoropyrrolidin-1-yl)propan-2-ol is used as raw material, and the salt of Example 94 containing a formic acid is synthesized by referring to the preparation method of steps B and C of Example 69. LCMS :m/z 631.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.46(s,1H),7.69(dd,J＝9.1,5.8Hz,1H),7.32(d,J＝2.6Hz,1H),7.27(t,J＝9.4Hz,1H),7.09(d,J＝2.6Hz,1H),5.60(br.s,1H),5.28–5.09(m,1H),4.71–4.38(m,2H),4.16–3.83(m,4H),3.24–2.83(m,5H),2.74–2.61(m,1H),2.52–2.42(m,1H),2.31–2.24(m,2H),2.22(s,3H),2.08–1.73(m,5H),1.45(s,3H),0.85(t,J＝7.3Hz,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.46 (s, 1H), 7.69 (dd, J = 9.1, 5.8Hz, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.27 (t, J＝9.4Hz,1H),7.09(d,J＝2.6Hz,1H),5.60(br.s,1H),5.28–5.09(m,1H),4.71–4.38(m,2H),4.16–3.83 (m,4H),3.24–2.83(m,5H),2.74–2.61(m,1H),2.52–2.42(m,1H),2.31–2.24(m,2H),2.22(s,3H),2.08 –1.73(m,5H),1.45(s,3H),0.85(t,J=7.3Hz,3H).
实施例95制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((S)-1-((S)-3-氟吡咯烷-1-基)丙烷-2-基)氧)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 95 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1- ((S)-3-fluoropyrrolidin-1-yl)propan-2-yl)oxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyne 6-fluoronaphthalene-2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和((S)-1-((S)-3-氟吡咯烷-1-基)丙烷-2-醇为原料，参照实施例38的步骤D至F的合成方法制备实施例95为含一个甲酸的盐。LCMS:m/z 627.3(M+H)。 Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and ((S )-1-((S)-3-fluoropyrrolidin-1-yl)propan-2-ol was used as raw material, and the salt containing a formic acid was prepared in Example 95 by referring to the synthesis method of steps D to F of Example 38. LCMS: m/z 627.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.54(s,1H),7.88(dd,J＝9.2,5.7Hz,1H),7.40–7.29(m,2H),7.23(t,J＝2.3Hz,1H),5.62–5.53(m,1H),5.27–5.08(m,1H),4.66–4.36(m,2H),4.04–3.81(m,4H),3.13–3.02(m,2H),2.99–2.90(m,2H),2.89–2.81(m,2H),2.66–2.56(m,1H),2.21(s,3H),2.20–2.10(m,1H),2.08–1.70(m,5H),1.44(dd,J＝6.4,4.1Hz,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.54 (s, 1H), 7.88 (dd, J = 9.2, 5.7Hz, 1H), 7.40–7.29 (m, 2H), 7.23 (t, J = 2.3 Hz,1H),5.62–5.53(m,1H),5.27–5.08(m,1H),4.66–4.36(m,2H),4.04–3.81(m,4H),3.13–3.02(m,2H), 2.99–2.90(m,2H),2.89–2.81(m,2H),2.66–2.56(m,1H),2.21(s,3H),2.20–2.10(m,1H),2.08–1.70(m,5H ), 1.44 (dd, J = 6.4, 4.1Hz, 3H).
实施例96制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-甲基哌啶-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 96 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-methylpiperidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和(1-甲基哌啶-2-基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例96为含一个甲酸的盐。LCMS:m/z609.3(M+H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and (1- Methylpiperidin-2-yl)methanol was used as raw material, and Example 96 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid. LCMS:m/z609.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.55(s,1H),7.89(dd,J＝9.2,5.7Hz,1H),7.39–7.32(m,2H),7.23(d,J＝2.6Hz,1H),4.77–4.71(m,1H),4.67–4.60(m,1H),4.03–3.65(m,6H),3.30–3.24(m,1H),3.09–3.01(m,1H),2.76(s,3H),2.21(s,3H),2.01(d,J＝13.4Hz,2H),1.96–1.71(m,8H),1.63–1.50(m,2H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.55 (s, 1H), 7.89 (dd, J = 9.2, 5.7Hz, 1H), 7.39–7.32 (m, 2H), 7.23 (d, J = 2.6 Hz,1H),4.77–4.71(m,1H),4.67–4.60(m,1H),4.03–3.65(m,6H),3.30–3.24(m,1H),3.09–3.01(m,1H), 2.76(s,3H),2.21(s,3H),2.01(d,J＝13.4Hz,2H),1.96–1.71(m,8H),1.63–1.50(m,2H).
实施例97制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2S,4R)-4-甲氧基-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 97 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2S,4R)- 4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl- 6-fluoronaphthalene-2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和((2S,4R)-4-甲氧基-1-甲基吡咯烷-2-基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例97为含一个甲酸的盐。LCMS:m/z 625.3(M+H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and ((2S , 4R)-4-methoxy-1-methylpyrrolidin-2-yl)methanol was used as the raw material, and Example 97 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid. LCMS: m/z 625.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.51(s,1H),7.89(dd,J＝9.2,5.7Hz,1H),7.37(d,J＝2.3Hz,1H),7.34(d,J＝9.0Hz,1H),7.23(t,J＝2.3Hz,1H), 4.70–4.55(m,3H),4.09–4.01(m,1H),4.00–3.78(m,4H),3.58–3.45(m,2H),3.36(s,3H),2.83–2.79(m,1H),2.78(s,3H),2.57–2.49(m,1H),2.22(s,3H),2.08–1.59(m,6H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.51 (s, 1H), 7.89 (dd, J = 9.2, 5.7Hz, 1H), 7.37 (d, J = 2.3Hz, 1H), 7.34 (d, J＝9.0Hz,1H),7.23(t,J＝2.3Hz,1H), 4.70–4.55(m,3H),4.09–4.01(m,1H),4.00–3.78(m,4H),3.58–3.45(m,2H),3.36(s,3H),2.83–2.79(m,1H ),2.78(s,3H),2.57–2.49(m,1H),2.22(s,3H),2.08–1.59(m,6H).
实施例98制备4-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-5-(丙炔基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 98 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-(propynyl)-2- ((Tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-phenol
以(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和(六氢-1H-吡咯啉-7a-基)甲醇为原料，参照实施例69的步骤B和C的制备方法合成实施例98为含有0.5个甲酸的盐。LCMS:m/z 625.3(M+H)。With (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and (hexahydro- Using 1H-pyrrolin-7a-yl)methanol as raw material, the salt of Example 98 containing 0.5 formic acid was synthesized by referring to the preparation method of Steps B and C of Example 69. LCMS: m/z 625.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.57(s,0.5H),7.69(dd,J＝9.1,5.8Hz,1H),7.32(d,J＝2.6Hz,1H),7.27(t,J＝9.4Hz,1H),7.10(s,1H),4.49(s,2H),3.66–3.57(m,3H),3.46–3.38(m,2H),3.07–3.00(m,2H),2.49–2.40(m,2H),2.27–2.22(m,2H),2.21(s,3H),2.15–2.01(m,6H),1.99–1.91(m,3H),1.83–1.77(m,2H),1.38–1.30(m,2H),0.84(t,J＝7.4Hz,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.57 (s, 0.5H), 7.69 (dd, J = 9.1, 5.8Hz, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.27 (t ,J＝9.4Hz,1H),7.10(s,1H),4.49(s,2H),3.66–3.57(m,3H),3.46–3.38(m,2H),3.07–3.00(m,2H), 2.49–2.40(m,2H),2.27–2.22(m,2H),2.21(s,3H),2.15–2.01(m,6H),1.99–1.91(m,3H),1.83–1.77(m,2H ),1.38–1.30(m,2H),0.84(t,J=7.4Hz,3H).
实施例99制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((S)-4-甲基吗啉-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 99 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-4- Methylmorpholin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和((S)-4-甲基吗啉-2-基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例99为含两个甲酸的盐。LCMS:m/z 611.3(M+H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol of Example 41 and ((S)-4-methylmorpholin-2-yl)methanol as raw materials, the salt containing two formic acids of Example 99 was prepared by referring to the synthetic method of steps D to F of Example 38. LCMS: m/z 611.3 (M+H).
1H NMR(600MHz,Methanol-d4)δ8.50(s,2H),7.88(dd,J＝9.1,5.7Hz,1H),7.40–7.32(m,2H),7.22(t,J＝2.3Hz,1H),4.56–4.50(m,2H),4.05–3.88(m,6H),3.75–3.69(m,2H),2.99(d,J＝11.5Hz,1H),2.80(d,J＝11.7Hz, 1H),2.39(s,3H),2.35–2.26(m,2H),2.22(s,3H),2.21–2.17(m,1H),1.98–1.74(m,5H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.50 (s, 2H), 7.88 (dd, J = 9.1, 5.7Hz, 1H), 7.40–7.32 (m, 2H), 7.22 (t, J = 2.3 Hz,1H),4.56–4.50(m,2H),4.05–3.88(m,6H),3.75–3.69(m,2H),2.99(d,J＝11.5Hz,1H),2.80(d,J＝ 11.7Hz, 1H),2.39(s,3H),2.35–2.26(m,2H),2.22(s,3H),2.21–2.17(m,1H),1.98–1.74(m,5H).
实施例100制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((S)-1-异丙基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 100 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1-isopropylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和((S)-1-异丙基吡咯烷-2-基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例100为含0.5个甲酸的盐。LCMS:m/z 623.3(M+H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and ((S )-1-isopropylpyrrolidin-2-yl)methanol was used as raw material, and Example 100 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing 0.5 formic acid. LCMS: m/z 623.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.48(s,0.5H),7.90(dd,J＝9.2,5.6Hz,1H),7.40–7.33(m,2H),7.23(t,J＝3.4Hz,1H),4.78–4.65(m,2H),4.17–4.09(m,2H),4.03–3.75(m,6H),3.55–3.48(m,1H),2.37–2.28(m,2H),2.22(s,3H),2.15–2.06(m,3H),1.94–1.84(m,5H),1.43(dd,J＝6.6,3.5Hz,3H),1.39(d,J＝6.5Hz,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.48 (s, 0.5H), 7.90 (dd, J＝9.2, 5.6Hz, 1H), 7.40–7.33 (m, 2H), 7.23 (t, J＝ 3.4Hz,1H),4.78–4.65(m,2H),4.17–4.09(m,2H),4.03–3.75(m,6H),3.55–3.48(m,1H),2.37–2.28(m,2H) ,2.22(s,3H),2.15–2.06(m,3H),1.94–1.84(m,5H),1.43(dd,J＝6.6,3.5Hz,3H),1.39(d,J＝6.5Hz,3H ).
实施例101制备4-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-氟萘-2-酚
Example 101 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthalene -2-phenol
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(8-氟-3-(甲氧基甲醚)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷为原料，根据实施例20的步骤F和H进行合成实施例101为含一个甲酸的盐。LCMS:m/z 615.3(M+H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(8-fluoro- 3-(methoxymethyl ether)naphthyl-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane was used as raw material, according to steps F and 2 of Example 20 H was used to synthesize Example 101 as a salt containing a formic acid. LCMS: m/z 615.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.52(s,1H),7.61(d,J＝8.3Hz,1H),7.41(td,J＝8.0,5.0Hz,1H),7.35(t,J＝2.3Hz,1H),7.18(s,1H),6.95(dd,J＝13.1,7.6Hz,1H),5.48–5.36(m,1H),4.46(d,J＝11.1Hz,1H),4.41(d,J＝11.0Hz,1H),4.02–3.77(m,3H),3.60–3.41(m,4H),3.24–3.14(m,2H),2.51– 2.32(m,3H),2.28–2.25(m,1H),2.22(s,3H),2.18–2.09(m,2H),2.04–1.97(m,1H),1.92–1.70(m,4H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.52 (s, 1H), 7.61 (d, J = 8.3Hz, 1H), 7.41 (td, J = 8.0, 5.0Hz, 1H), 7.35 (t, J＝2.3Hz,1H),7.18(s,1H),6.95(dd,J＝13.1,7.6Hz,1H),5.48–5.36(m,1H),4.46(d,J＝11.1Hz,1H), 4.41(d,J＝11.0Hz,1H),4.02–3.77(m,3H),3.60–3.41(m,4H),3.24–3.14(m,2H),2.51– 2.32(m,3H),2.28–2.25(m,1H),2.22(s,3H),2.18–2.09(m,2H),2.04–1.97(m,1H),1.92–1.70(m,4H).
实施例102制备4-(4-(3，6-二氮杂双环[3.2.1]庚烷-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 102 Preparation of 4-(4-(3,6-diazabicyclo[3.2.1]heptan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene -2-phenol
以3-(7-氯-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，6-二氮杂双环[3.1.1]庚烷-6-甲酸叔丁酯和相应试剂为原料，参照实施例38的步骤C、D和F的合成方法制备实施例102为含三个甲酸的盐。LCMS:m/z629.3(M+H)。1H NMR(400MHz,Methanol-d4)δ8.55(s,3H),7.70(dd,J＝9.1,5.8Hz,1H),7.33(d,J＝2.5Hz,1H),7.27(t,J＝9.4Hz,1H),7.09(s,1H),5.45–5.29(m,1H),4.66–4.53(m,3H),4.48–4.33(m,3H),4.12–4.02(m,2H),3.78–3.71(m,2H),3.14–3.09(m,1H),2.94–2.86(m,2H),2.47–2.38(m,2H),2.36–2.25(m,3H),2.19(s,3H),2.12–2.04(m,3H),1.92–1.83(m,2H),0.86(t,J＝7.4Hz,3H)。3-(7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,6-diaza Bicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester and corresponding reagents were used as raw materials, and the salt containing three formic acids was prepared in Example 102 by referring to the synthesis method of steps C, D and F of Example 38. LCMS:m/z629.3(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.55 (s, 3H), 7.70 (dd, J = 9.1, 5.8Hz, 1H), 7.33 (d, J = 2.5Hz, 1H), 7.27 (t, J＝9.4Hz,1H),7.09(s,1H),5.45–5.29(m,1H),4.66–4.53(m,3H),4.48–4.33(m,3H),4.12–4.02(m,2H) ,3.78–3.71(m,2H),3.14–3.09(m,1H),2.94–2.86(m,2H),2.47–2.38(m,2H),2.36–2.25(m,3H),2.19(s, 3H), 2.12–2.04 (m, 3H), 1.92–1.83 (m, 2H), 0.86 (t, J = 7.4Hz, 3H).
实施例103制备4-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5，6-二氟萘-2-酚
Example 103 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5,6- Difluoronaphthalene-2-phenol
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(7，8-二氟-3-(甲氧基甲醚)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷为原料，根据实施例20的步骤F和H进行合成实施例103为含0.5个甲酸的盐。LCMS:m/z 633.3(M+H)。1H NMR(400MHz,Methanol-d4)δ8.54(s,0.5H),7.63(ddd,J＝9.3,4.8,1.6Hz,1H),7.45–7.40(m,1H),7.35(t,J＝2.2Hz,1H),7.26(s,1H),5.48–5.30(m,1H),4.48–4.31(m,3H),4.01–3.80(m,2H),3.73(s,2H),3.53–3.37(m,3H),3.18–3.10(m,1H),2.51–2.26(m,3H),2.22(s,3H),2.16–2.03(m,3H),2.03–1.93(m,2H),1.89–1.60(m,5H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(7,8- Difluoro-3-(methoxymethyl ether)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane was used as raw material, according to Example 20 Steps F and H were carried out to synthesize Example 103 as a salt containing 0.5 formic acid. LCMS: m/z 633.3(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.54 (s, 0.5H), 7.63 (ddd, J = 9.3, 4.8, 1.6Hz, 1H), 7.45–7.40 (m, 1H), 7.35 (t, J＝2.2Hz,1H),7.26(s,1H),5.48–5.30(m,1H),4.48–4.31(m,3H),4.01–3.80(m,2H),3.73(s,2H),3.53 –3.37(m,3H),3.18–3.10(m,1H),2.51–2.26(m,3H),2.22(s,3H),2.16–2.03(m,3H),2.03–1.93(m,2H) ,1.89–1.60(m,5H).
实施例104制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((R)-2-甲基吗啉)甲基)环丙烷基)甲氧基)-5-(丙炔基)吡啶并 [4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 104 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((R)-2- Methylmorpholine)methyl)cyclopropyl)methoxy)-5-(propynyl)pyrido [4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和(R)-(1-((2-甲基吗啉)甲基)环丙烷基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例104为含0.5个甲酸的盐。LCMS:m/z 665.3(M+H)。1H NMR(400MHz,Methanol-d4)δ8.52(s,1H),7.88(dd,J＝9.2,5.7Hz,1H),7.37(d,J＝2.4Hz,1H),7.33(d,J＝9.0Hz,1H),7.22(d,J＝2.5Hz,1H),4.46(s,2H),4.01–3.74(m,5H),3.65–3.52(m,3H),2.93(d,J＝11.4Hz,2H),2.52(dd,J＝12.6,5.5Hz,1H),2.40(dd,J＝12.6,7.0Hz,1H),2.35(d,J＝2.8Hz,1H),2.21(s,3H),2.16–2.06(m,1H),1.96–1.62(m,6H),1.11(dt,J＝6.3,1.8Hz,3H),0.77–0.71(m,2H),0.59–0.49(m,2H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and (R) -(1-((2-methylmorpholine)methyl)cyclopropyl)methanol was used as raw material, and the salt containing 0.5 formic acid was prepared in Example 104 by referring to the synthesis method of steps D to F in Example 38. LCMS: m/z 665.3(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.52 (s, 1H), 7.88 (dd, J = 9.2, 5.7Hz, 1H), 7.37 (d, J = 2.4Hz, 1H), 7.33 (d, J＝9.0Hz,1H),7.22(d,J＝2.5Hz,1H),4.46(s,2H),4.01–3.74(m,5H),3.65–3.52(m,3H),2.93(d,J ＝11.4Hz,2H),2.52(dd,J＝12.6,5.5Hz,1H),2.40(dd,J＝12.6,7.0Hz,1H),2.35(d,J＝2.8Hz,1H),2.21(s ,3H),2.16–2.06(m,1H),1.96–1.62(m,6H),1.11(dt,J＝6.3,1.8Hz,3H),0.77–0.71(m,2H),0.59–0.49(m ,2H).
实施例105制备4-(4-((1R，5S)-3，8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-氯-6-氟萘-2-酚
Example 105 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-6-fluoronaphthalene-2-ol
以(1R,5S)-3-(7-氯-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和2-(8-氯-7-氟-3-(甲氧基甲醚)萘-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷为原料，根据实施例20的步骤F和H进行合成实施例105为含一个甲酸的盐。LCMS:m/z 649.2(M+H)。1H NMR(400MHz,Methanol-d4)δ7.84(dd,J＝9.2,5.5Hz,1H),7.43(d,J＝8.9Hz,1H),7.40(d,J＝2.3Hz,1H),7.24(s,1H),5.59–5.41(m,1H),4.65–4.48(m,3H),4.15–3.87(m,4H),3.79–3.59(m,3H),2.60–2.30(m,5H),2.29–2.15(m,5H),2.14–1.72(m,5H)。With (1R,5S)-3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy) -5-(propynyl)pyrido[4,3-d]pyrimidine)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-(8-chloro- 7-Fluoro-3-(methoxymethyl ether)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane was used as raw material, according to Example 20 Steps F and H were carried out to synthesize Example 105 containing a formic acid salt. LCMS: m/z 649.2(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ7.84 (dd, J = 9.2, 5.5 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H) ,7.24(s,1H),5.59–5.41(m,1H),4.65–4.48(m,3H),4.15–3.87(m,4H),3.79–3.59(m,3H),2.60–2.30(m, 5H),2.29–2.15(m,5H),2.14–1.72(m,5H).
实施例106制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((2S,4R)-4-甲氧基-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 106 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2S,4R)- 4-methoxy-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl- 6-fluoronaphthalene-2-phenol
以(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和((2S,4R)-4-甲氧基-1-甲基吡咯烷-2-基)甲醇为原料，参照实施例69的步骤B和C的制备方法合成实施例106为含有一个甲酸的盐。LCMS:m/z 629.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.53(s,1H),7.69(dd,J＝9.1,5.8Hz,1H),7.32(d,J＝2.6Hz,1H),7.27(t,J＝9.3Hz,1H),7.10(s,1H),4.65–4.53(m,2H),4.07–3.98(m,2H),3.88–3.70(m,3H),3.52(dd,J＝11.3,5.5Hz,1H),3.41(d,J＝11.3Hz,1H),3.35(s,3H),3.27–3.19(m,1H),2.74–2.61(m,3H),2.56–2.40(m,2H),2.21(s,3H),2.07–2.00(m,1H),1.95–1.71(m,4H),0.84(t,J＝7.4Hz,3H).With (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and ((2S, 4R)-4-Methoxy-1-methylpyrrolidin-2-yl)methanol was used as raw material, and Example 106 was synthesized by referring to the preparation method of Steps B and C of Example 69 to prepare a salt containing a formic acid. LCMS: m/z 629.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.53 (s, 1H), 7.69 (dd, J = 9.1, 5.8Hz, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.27 (t, J＝9.3Hz,1H),7.10(s,1H),4.65–4.53(m,2H),4.07–3.98(m,2H),3.88–3.70(m,3H),3.52(dd,J＝11.3, 5.5Hz,1H),3.41(d,J＝11.3Hz,1H),3.35(s,3H),3.27–3.19(m,1H),2.74–2.61(m,3H),2.56–2.40(m,2H ),2.21(s,3H),2.07–2.00(m,1H),1.95–1.71(m,4H),0.84(t,J=7.4Hz,3H).
实施例107制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((S)-1-异丙基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 107 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1- Isopropylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2- phenol
以(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和((S)-1-异丙基吡咯烷-2-基)甲醇为原料，参照实施例69的步骤B和C的制备方法合成实施例107为含有一个甲酸的盐。LCMS:m/z 627.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.55(s,1H),7.70(dd,J＝9.1,5.7Hz,1H),7.33(d,J＝2.6Hz,1H),7.27(t,J＝9.3Hz,1H),7.10(s,1H),4.64(s,2H),3.97(s,2H),3.72–3.62(m,4H),3.44–3.38(m,1H),3.23–3.17(s,2H),2.49–2.41(m,2H),2.28–2.23(m,2H),2.21(s,3H),2.10–2.02(m,4H),1.86–1.78(m,3H),1.39(d,J＝6.7Hz,3H),1.33(d,J＝6.4Hz,3H),0.84(t,J＝7.4Hz,3H)。With (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and ((S) -1-isopropylpyrrolidin-2-yl)methanol was used as raw material, and the salt containing a formic acid was synthesized in Example 107 by referring to the preparation method of Steps B and C of Example 69. LCMS: m/z 627.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.55 (s, 1H), 7.70 (dd, J = 9.1, 5.7Hz, 1H), 7.33 (d, J = 2.6Hz, 1H), 7.27 (t, J＝9.3Hz,1H),7.10(s,1H),4.64(s,2H),3.97(s,2H),3.72–3.62(m,4H),3.44–3.38(m,1H),3.23–3.17 (s,2H),2.49–2.41(m,2H),2.28–2.23(m,2H),2.21(s,3H),2.10–2.02(m,4H),1.86–1.78(m,3H),1.39 (d, J=6.7Hz, 3H), 1.33 (d, J=6.4Hz, 3H), 0.84 (t, J=7.4Hz, 3H).
实施例108制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((1-((二甲胺基)甲基)环丙烷基)甲氧基)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 108 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((dimethylamino)methyl)cyclopropane)methoxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol
以(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和1-((二甲胺基)甲基)环丙烷基)甲醇为原料，参照实施例69的步骤B和C的制备方法合成实施例108为含有0.5个甲酸的盐。LCMS:m/z613.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.56(s,0.5H),7.69(dd,J＝9.1,5.7Hz,1H),7.32(d,J＝2.6Hz,1H),7.27(t,J＝9.3Hz,1H),7.11(s,1H),4.58(s,1H),4.43(t,J＝9.1Hz,2H),4.01–3.73(m,3H),3.64(s,2H),2.93(s,2H),2.76–2.62(m,5H),2.50–2.41(m,2H),2.21(s,3H),1.81(s,3H),1.70–1.52(m,2H),0.89(s,2H),0.84(t,J＝7.4Hz,3H),0.74(s,2H)。With (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 1-(( Dimethylamino)methyl)cyclopropyl)methanol was used as raw material, and Example 108 was synthesized into a salt containing 0.5 formic acid by referring to the preparation method of Steps B and C of Example 69. LCMS:m/z613.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 0.5H), 7.69 (dd, J = 9.1, 5.7Hz, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.27 (t ,J＝9.3Hz,1H),7.11(s,1H),4.58(s,1H),4.43(t,J＝9.1Hz,2H),4.01–3.73(m,3H),3.64(s,2H) ,2.93(s,2H),2.76–2.62(m,5H),2.50–2.41(m,2H),2.21(s,3H),1.81(s,3H),1.70–1.52(m,2H),0.89 (s, 2H), 0.84 (t, J = 7.4Hz, 3H), 0.74 (s, 2H).
实施例109制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-(((R)-2-甲基吗啉)甲基)环丙烷基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 109 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(((R )-2-methylmorpholinyl)methyl)cyclopropyl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6 -Fluoronaphen-2-phenol
以(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和(R)-(1-((2-甲基吗啉)甲基)环丙烷基)甲醇为原料，参照实施例69的步骤B和C的制备方法合成实施例109。LCMS:m/z 669.3(M+H)。1H NMR(600MHz,Methanol-d4)δ7.70(dd,J＝9.1,5.7Hz,1H),7.33(d,J＝2.7Hz,1H),7.28(t,J＝9.4Hz,1H),7.07(d,J＝2.6Hz,1H),4.63(s,2H),4.52(t,J＝8.4Hz,2H),4.28–4.18(m,3H),4.16–4.05(m,3H),3.95–3.88(m,2H),3.84–3.70(m,3H),3.12(t,J＝11.8Hz,1H),2.83(t,J＝11.5Hz,1H),2.46(dd,J＝14.8,7.6Hz,1H),2.32–2.25(m,1H),2.22(s,3H),2.09(s,2H),1.97(s,2H),1.27(d,J＝6.3Hz,3H),1.02(d,J＝5.1Hz,2H),0.91(d,J＝6.1Hz,2H),0.85(t,J＝7.4Hz,3H)。With (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and (R)- (1-((2-methylmorpholine)methyl)cyclopropyl)methanol was used as raw material, and Example 109 was synthesized by referring to the preparation method of Steps B and C of Example 69. LCMS: m/z 669.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ7.70 (dd, J = 9.1, 5.7Hz, 1H), 7.33 (d, J = 2.7Hz, 1H), 7.28 (t, J = 9.4Hz, 1H) ,7.07(d,J＝2.6Hz,1H),4.63(s,2H),4.52(t,J＝8.4Hz,2H),4.28–4.18(m,3H),4.16–4.05(m,3H), 3.95–3.88(m,2H),3.84–3.70(m,3H),3.12(t,J＝11.8Hz,1H),2.83(t,J＝11.5Hz,1H),2.46(dd,J＝14.8, 7.6Hz,1H),2.32–2.25(m,1H),2.22(s,3H),2.09(s,2H),1.97(s,2H),1.27(d,J＝6.3Hz,3H),1.02( d, J＝5.1Hz, 2H), 0.91 (d, J＝6.1Hz, 2H), 0.85 (t, J＝7.4Hz, 3H).
实施例110制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((S)-4-甲基吗啉-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 110 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-4- Methylmorpholin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-phenol
以(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和((S)-4-甲基吗啉-2-基)甲醇为原料，参照实施例69的步骤B和C的制备方法合成实施例110。LCMS:m/z 615.3(M+H)。1H NMR(600MHz,Methanol-d4)δ7.70(dd,J＝9.1,5.8Hz,1H),7.33(d,J＝2.7Hz,1H),7.28(t,J＝9.4Hz,1H),7.07(d,J＝2.6Hz,1H),4.70(dt,J＝12.0,3.5Hz,2H),4.62(d,J＝12.2Hz,2H),4.28–4.06(m,6H),3.89(d,J＝12.9Hz,1H),3.69(d,J＝12.4Hz,1H),3.51(d,J＝12.9Hz,1H),3.22(d,J＝6.8Hz,2H),3.00(s,3H),2.47(dd,J＝14.6,7.6Hz,1H),2.30–2.25(m,1H),2.22(s,3H),2.07(t,J＝11.2Hz,2H),2.12–2.06(m,2H),0.85(t,J＝7.4Hz,3H)。With (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and ((S) -4-methylmorpholin-2-yl)methanol was used as raw material, and Example 110 was synthesized by referring to the preparation method of steps B and C of Example 69. LCMS: m/z 615.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ7.70 (dd, J = 9.1, 5.8 Hz, 1H), 7.33 (d, J = 2.7 Hz, 1H), 7.28 (t, J = 9.4 Hz, 1H) ,7.07(d,J＝2.6Hz,1H),4.70(dt,J＝12.0,3.5Hz,2H),4.62(d,J＝12.2Hz,2H),4.28–4.06(m,6H),3.89( d,J＝12.9Hz,1H),3.69(d,J＝12.4Hz,1H),3.51(d,J＝12.9Hz,1H),3.22(d,J＝6.8Hz,2H),3.00(s, 3H),2.47(dd,J＝14.6,7.6Hz,1H),2.30–2.25(m,1H),2.22(s,3H),2.07(t,J＝11.2Hz,2H),2.12–2.06(m ,2H),0.85(t,J=7.4Hz,3H).
实施例111制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((1-((二甲胺基)甲基)环丙烷基)甲氧基)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 111 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((1-((dimethylamino)methyl) (yl)cyclopropyl)methoxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2- phenol
以实施例41的中间体4-(4-((1R，5S)3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-((三异丙基硅基)乙炔基)萘-2-酚和1-((二甲胺基)甲基)环丙烷基)甲醇为原料，参照实施例38的步骤D至F的合成方法制备实施例111为含一个甲酸的盐。LCMS:m/z 609.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.56(s,1H),7.89(dd,J＝9.1,5.8Hz,1H),7.41–7.31(m,3H),7.24(s,1H),4.45(d,J＝11.4Hz,1H),4.40(d,J＝11.5Hz,1H),3.70–3.61(m,3H),3.55–3.51(m,1H),3.32–3.28(m,1H),3.06–2.93(m,2H),2.82–2.66(m,5H),2.36–2.32(m,1H),2.21(s,3H),1.81(s,3H),1.73–1.52(m,3H),0.96–0.85(m,2H),0.76(s,2H)。Using the intermediate 4-(4-((1R,5S)3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene-2-phenol and 1-( (Dimethylamino)methyl)cyclopropyl)methanol was used as raw material, and Example 111 was prepared by referring to the synthesis method of steps D to F of Example 38 to prepare a salt containing a formic acid. LCMS: m/z 609.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 1H), 7.89 (dd, J = 9.1, 5.8Hz, 1H), 7.41–7.31 (m, 3H), 7.24 (s, 1H), 4.45(d,J＝11.4Hz,1H),4.40(d,J＝11.5Hz,1H),3.70–3.61(m,3H),3.55–3.51(m,1H),3.32–3.28(m,1H) ,3.06–2.93(m,2H),2.82–2.66(m,5H),2.36–2.32(m,1H),2.21(s,3H),1.81(s,3H),1.73–1.52(m,3H) ,0.96–0.85(m,2H),0.76(s,2H).
实施例112制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟萘-2-酚
Example 112 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1- Methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalene-2-phenol
参照实施例69的制备方法，使用相应的原料和试剂可制备实施例112为含一个甲酸的盐。LCMS:m/z 571.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.55(s,1H),7.82(dd,J＝9.8,5.6Hz,1H),7.35–7.31(m,2H),7.29(dd,J＝9.9,5.5Hz,2H),4.66(dd,J＝11.6,4.3Hz,1H),4.59(dd,J＝11.7,6.3Hz,1H),4.00–3.78(m,3H),3.69(s,2H),3.39–3.35(m,2H),3.30–3.23(m,1H),2.77(s,3H),2.29–2.24(m,1H),2.23(s,3H),2.04–1.87(m,3H),1.86–1.67(m,5H)。Referring to the preparation method of Example 69, using corresponding raw materials and reagents, Example 112 can be prepared as a salt containing a formic acid. LCMS: m/z 571.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.55 (s, 1H), 7.82 (dd, J = 9.8, 5.6 Hz, 1H), 7.35–7.31 (m, 2H), 7.29 (dd, J = 9.9 ,5.5Hz,2H),4.66(dd,J＝11.6,4.3Hz,1H),4.59(dd,J＝11.7,6.3Hz,1H),4.00–3.78(m,3H),3.69(s,2H) ,3.39–3.35(m,2H),3.30–3.23(m,1H),2.77(s,3H),2.29–2.24(m,1H),2.23(s,3H),2.04–1.87(m,3H) ,1.86–1.67(m,5H).
实施例113制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-(((S)-1-异丙基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟萘-2-酚
Example 113 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((S)-1- Isopropylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalene-2-phenol
参照实施例69的制备方法，使用相应的原料和试剂可制备实施例113为含一个甲酸的盐。LCMS:m/z 599.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.50(s,1H),7.83(dd,J＝9.4,5.6Hz,1H),7.35(d,J＝2.4Hz,1H),7.33(d,J＝2.5Hz,1H),7.32–7.27(m,2H),4.74(d,J＝11.9Hz,1H),4.68(dd,J＝12.3,6.6Hz,1H),4.10(s,1H),3.99–3.83(m,2H),3.82–3.72(m,3H),3.54–3.46(m,2H),2.34–2.27(m,1H),2.24(s,3H),2.14–2.05(m,3H),1.90–1.81(m,3H),1.79–1.66(m,2H),1.43(d,J＝6.6Hz,3H),1.38(d,J＝6.5Hz,3H)。Referring to the preparation method of Example 69 and using corresponding raw materials and reagents, Example 113 can be prepared as a salt containing a formic acid. LCMS: m/z 599.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.50 (s, 1H), 7.83 (dd, J = 9.4, 5.6Hz, 1H), 7.35 (d, J = 2.4Hz, 1H), 7.33 (d, J＝2.5Hz,1H),7.32–7.27(m,2H),4.74(d,J＝11.9Hz,1H),4.68(dd,J＝12.3,6.6Hz,1H),4.10(s,1H), 3.99–3.83(m,2H),3.82–3.72(m,3H),3.54–3.46(m,2H),2.34–2.27(m,1H),2.24(s,3H),2.14–2.05(m,3H ),1.90–1.81(m,3H),1.79–1.66(m,2H),1.43(d,J＝6.6Hz,3H),1.38(d,J＝6.5Hz,3H).
实施例114制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-(哌啶-1-基甲基)环丙烷基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟萘-2-酚
Example 114 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(piperidin-1-ylmethyl)cyclopropane)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol
参照实施例69的制备方法，使用相应的原料和试剂可制备实施例114为含一个甲酸的盐。LCMS:m/z 625.3(M+H)。1H NMR(400MHz,Methanol-d4)δ7.83(dd,J＝8.9,5.7Hz,1H),7.37–7.31(m,2H),7.28(dt,J＝10.6,3.7Hz,2H),4.60–4.46(m,3H),4.09–3.85(m,6H),3.30–3.22(m,2H),3.10–2.90(m, 2H),2.24(s,3H),2.03–1.60(m,11H),1.00(d,J＝5.2Hz,2H),0.88(s,2H)。Referring to the preparation method of Example 69, using corresponding raw materials and reagents, Example 114 can be prepared as a salt containing a formic acid. LCMS: m/z 625.3(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ7.83 (dd, J＝8.9, 5.7Hz, 1H), 7.37–7.31 (m, 2H), 7.28 (dt, J＝10.6, 3.7Hz, 2H), 4.60–4.46(m,3H),4.09–3.85(m,6H),3.30–3.22(m,2H),3.10–2.90(m, 2H), 2.24 (s, 3H), 2.03–1.60 (m, 11H), 1.00 (d, J = 5.2Hz, 2H), 0.88 (s, 2H).
实施例115制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((1-(哌啶-1-基甲基)环丙烷基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 115 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((1-(piperidine- 1-ylmethyl)cyclopropyl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2- phenol
以(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和((1-(哌啶-1-基)甲基)环丙烷基)甲醇为原料，参照实施例69的步骤B和C的制备方法合成实施例115为含0.5个甲酸的盐。With (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyl ether)naphthyl-1-yl)-8-fluoro-2-(methylthio)- 5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and ((1- (Piperidin-1-yl)methyl)cyclopropyl)methanol was used as raw material, and the salt containing 0.5 formic acid was synthesized in Example 115 by referring to the preparation method of Steps B and C of Example 69.
LCMS:m/z 653.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.53(s,0.5H),7.70(dd,J＝9.1,5.7Hz,1H),7.32(d,J＝2.6Hz,1H),7.27(t,J＝9.3Hz,1H),7.09(s,1H),4.46(s,2H),4.06–3.74(m,5H),3.68(s,2H),3.20–3.08(m,4H),2.48–2.41(m,2H),2.21(s,3H),1.96–1.77(m,6H),1.76–1.53(m,5H),0.96(s,2H),0.84(t,J＝7.5Hz,5H)。LCMS: m/z 653.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.53 (s, 0.5H), 7.70 (dd, J = 9.1, 5.7Hz, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.27 (t ,J＝9.3Hz,1H),7.09(s,1H),4.46(s,2H),4.06–3.74(m,5H),3.68(s,2H),3.20–3.08(m,4H),2.48– 2.41(m,2H),2.21(s,3H),1.96–1.77(m,6H),1.76–1.53(m,5H),0.96(s,2H),0.84(t,J＝7.5Hz,5H) .
实施例116制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-5-(丙炔基)-2-((1-(吡咯烷-1-基)甲基)环丙烷基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 116 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-(propynyl)-2-((1-(pyrrolidin-1-yl)methyl)cyclopropane)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol
以(1R,5S)-3-(7-(8-乙基-7-氟-3-(甲氧基基醚)萘-1-基)-8-氟-2-(甲硫基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3，8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯和((1-(吡咯烷-1-基)甲基)环丙烷基)甲醇为原料，参照实施例69的步骤B和C的制备方法合成实施例116为含一个甲酸的盐。Using (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-(methoxyether)naphthalen-1-yl)-8-fluoro-2-(methylthio)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and ((1-(pyrrolidin-1-yl)methyl)cyclopropane)methanol as raw materials, referring to the preparation method of steps B and C of Example 69 to synthesize Example 116 which is a salt containing a formic acid.
LCMS:m/z 639.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.52(m,1H),7.69(dd,J＝9.1,5.7Hz,1H),7.33(d,J＝2.6Hz,1H),7.27(t,J＝9.3Hz,1H),7.10(s,1H),4.47(s,2H),4.07–3.65(m,6H),3.51–3.41(m,2H),2.49–2.40(m,3H),2.36–2.24(m,3H),2.21(s,3H),2.14–2.06(m,3H),1.96–1.69(m,5H),0.96(s,2H),0.90(t,J＝7.5Hz,5H)。LCMS: m/z 639.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.52 (m, 1H), 7.69 (dd, J = 9.1, 5.7Hz, 1H), 7.33 (d, J = 2.6Hz, 1H), 7.27 (t, J＝9.3Hz,1H),7.10(s,1H),4.47(s,2H),4.07–3.65(m,6H),3.51–3.41(m,2H),2.49–2.40(m,3H),2.36 –2.24(m,3H),2.21(s,3H),2.14–2.06(m,3H),1.96–1.69(m,5H),0.96(s,2H),0.90(t,J＝7.5Hz,5H ).
实施例117制备4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-5-(丙炔基)-2-((1-(吡咯烷-1-基)甲基)环丙烷基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟萘-2-酚
Example 117 Preparation of 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-(propynyl)-2- ((1-(pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalene-2-phenol
参照实施例69的制备方法，使用相应的原料和试剂可制备实施例117为含0.5个甲酸的盐。LCMS:m/z 611.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.56(s,0.5H),7.83(dd,J＝9.1,5.6Hz,1H),7.36–7.32(m,2H),7.32–7.26(m,2H),4.46(s,2H),4.05–3.71(m,3H),3.70–3.58(m,3H),3.29–3.11(m,4H),2.23(s,3H),2.11–2.00(m,4H),1.86–1.54(m,6H),0.93(s,2H),0.84(s,2H)。Referring to the preparation method of Example 69, using corresponding raw materials and reagents, Example 117 can be prepared as a salt containing 0.5 formic acid. LCMS: m/z 611.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 0.5H), 7.83 (dd, J = 9.1, 5.6Hz, 1H), 7.36–7.32 (m, 2H), 7.32–7.26 (m, 2H),4.46(s,2H),4.05–3.71(m,3H),3.70–3.58(m,3H),3.29–3.11(m,4H),2.23(s,3H),2.11–2.00(m, 4H),1.86–1.54(m,6H),0.93(s,2H),0.84(s,2H).
实施例118制备4-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1，4-噁吖庚环-6-醇
Example 118 Preparation of 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例118为含一个甲酸的盐。LCMS:m/z 658.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.51(s,1H),7.87(dd,J＝9.1,5.6Hz,1H),7.37(d,J＝2.6Hz,1H),7.34(t,J＝8.8Hz,1H),7.28(t,J＝2.2Hz,1H),5.51–538(m,1H),4.54–4.38(m,4H),4.03–3.90(m,3H),3.90–3.77(m,2H),3.65–3.44(m,4H),3.27–3.21(m,1H),2.57–2.34(m,3H),2.31–2.23(m,1H),2.20(s,3H),2.19–2.11(m,2H),2.08–1.97(m,1H),1.11(d,J＝1.9Hz,3H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 118. LCMS: m/z 658.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.51 (s, 1H), 7.87 (dd, J = 9.1, 5.6Hz, 1H), 7.37 (d, J = 2.6Hz, 1H), 7.34 (t, J＝8.8Hz,1H),7.28(t,J＝2.2Hz,1H),5.51–538(m,1H),4.54–4.38(m,4H),4.03–3.90(m,3H),3.90–3.77 (m,2H),3.65–3.44(m,4H),3.27–3.21(m,1H),2.57–2.34(m,3H),2.31–2.23(m,1H),2.20(s,3H),2.19 –2.11(m,2H),2.08–1.97(m,1H),1.11(d,J=1.9Hz,3H).
实施例119制备4-(7-(8-乙基-7-氟-3-羟基萘-1-基)8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1，4-噁吖庚环-6-醇
Example 119 Preparation of 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepine cyclo-6-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例119为含0.5个甲酸的盐。LCMS:m/z 662.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.53(s,0.5H),7.69(dt,J＝9.0,5.5Hz,1H),7.32(t,J＝2.4 Hz,1H),7.27(td,J＝9.4,4.1Hz,1H),7.11(dt,J＝6.8,2.4Hz,1H),5.45–5.34(m,1H),4.61(s,1H),4.49–4.40(m,2H),4.40–4.34(m,1H),4.18–4.03(m,2H),3.97(d,J＝12.0Hz,1H),3.90(d,J＝14.8Hz,1H),3.71(d,J＝12.4Hz,1H),3.65(s,1H),3.55–3.37(m,4H),3.19–3.13(m,1H),2.47–2.29(m,3H),2.27–2.22(m,2H),2.21(s,3H),2.14–2.07(m,2H),2.03–1.95(m,1H),1.14(d,J＝22.3Hz,3H),0.89–0.80(m,3H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 119. LCMS: m/z 662.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.53 (s, 0.5H), 7.69 (dt, J = 9.0, 5.5Hz, 1H), 7.32 (t, J = 2.4 Hz,1H),7.27(td,J＝9.4,4.1Hz,1H),7.11(dt,J＝6.8,2.4Hz,1H),5.45–5.34(m,1H),4.61(s,1H),4.49 –4.40(m,2H),4.40–4.34(m,1H),4.18–4.03(m,2H),3.97(d,J＝12.0Hz,1H),3.90(d,J＝14.8Hz,1H), 3.71(d,J＝12.4Hz,1H),3.65(s,1H),3.55–3.37(m,4H),3.19–3.13(m,1H),2.47–2.29(m,3H),2.27–2.22( m,2H),2.21(s,3H),2.14–2.07(m,2H),2.03–1.95(m,1H),1.14(d,J＝22.3Hz,3H),0.89–0.80(m,3H) .
实施例120制备1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 120 Preparation of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H) -Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例120为含0.5个甲酸的盐。LCMS:m/z 646.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.53(s,0.5H),7.69(ddd,J＝9.5,5.8,4.1Hz,1H),7.32(d,J＝2.6Hz,1H),7.26(q,J＝9.1Hz,1H),7.14–7.05(m,1H),5.46–5.35(m,1H),4.50–4.33(m,3H),3.93–3.72(m,3H),3.55–3.37(m,2H),3.19–3.14(m,1H),2.52–2.29(m,4H),2.28–2.22(m,1H),2.20(s,3H),2.16–2.09(m,3H),2.03–1.96(m,1H),1.83–1.65(m,4H),1.17(s,3H),0.90–0.82(m,3H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 120. LCMS: m/z 646.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.53 (s, 0.5H), 7.69 (ddd, J＝9.5, 5.8, 4.1Hz, 1H), 7.32 (d, J＝2.6Hz, 1H), 7.26 (q,J＝9.1Hz,1H),7.14–7.05(m,1H),5.46–5.35(m,1H),4.50–4.33(m,3H),3.93–3.72(m,3H),3.55–3.37 (m,2H),3.19–3.14(m,1H),2.52–2.29(m,4H),2.28–2.22(m,1H),2.20(s,3H),2.16–2.09(m,3H),2.03 –1.96(m,1H),1.83–1.65(m,4H),1.17(s,3H),0.90–0.82(m,3H).
实施例121制备5-乙基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)-4-(1-氧杂-6-氮杂螺[3.5]壬-6-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 121 Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy yl)-5-(propynyl)-4-(1-oxa-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene- 2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例121为含一个甲酸的盐。LCMS:m/z 658.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.54(s,0.5H),7.70(dd,J＝9.1,5.7Hz,1H),7.33(t,J＝3.1Hz,1H),7.27(td,J＝9.4,5.5Hz,1H),7.18–7.08(m,1H),5.46–5.33(m,1H),4.49–4.31(m,4H),4.23–3.94(m,2H),3.53–3.38(m,3H),3.19–3.12(m,2H),2.52–2.28(m,5H),2.27–2.19(m,4H),2.15–2.07(m,3H),2.04–1.87(m,3H),1.82–1.69(m,2H),1.39–1.29(m,1H),0.89–0.84(m,3H)。 7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and the corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 121. LCMS: m/z 658.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.54 (s, 0.5H), 7.70 (dd, J = 9.1, 5.7Hz, 1H), 7.33 (t, J = 3.1Hz, 1H), 7.27 (td ,J＝9.4,5.5Hz,1H),7.18–7.08(m,1H),5.46–5.33(m,1H),4.49–4.31(m,4H),4.23–3.94(m,2H),3.53–3.38 (m,3H),3.19–3.12(m,2H),2.52–2.28(m,5H),2.27–2.19(m,4H),2.15–2.07(m,3H),2.04–1.87(m,3H) ,1.82–1.69(m,2H),1.39–1.29(m,1H),0.89–0.84(m,3H).
实施例122制备5-乙基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)-4-(1，6-二氧杂-9-氮杂螺[3.6]癸-9-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 122 Preparation of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy base)-5-(propynyl)-4-(1,6-dioxa-9-azaspiro[3.6]dec-9-yl)pyrido[4,3-d]pyrimidin-7-yl )naphthalene-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例122为含0.3个甲酸的盐。LCMS:m/z 674.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.3 formic acid in Example 122. LCMS: m/z 674.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.55(s,0.3H),7.70(ddd,J＝8.8,5.9,1.8Hz,1H),7.33(dd,J＝4.1,2.6Hz,1H),7.27(q,J＝9.0Hz,1H),7.15–7.03(m,1H),5.42–5.31(m,1H),4.61(s,1H),4.44–4.30(m,4H),4.25–4.14(m,3H),4.05–3.96(m,2H),3.90–3.79(m,2H),3.42–3.35(m,2H),3.14–3.08(m,1H),2.61–2.38(m,4H),2.38–2.25(m,2H),2.23(d,J＝4.6Hz,3H),2.21–2.17(m,1H),2.17–2.03(m,3H),1.99–1.93(m,1H),0.88–0.81(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.55 (s, 0.3H), 7.70 (ddd, J = 8.8, 5.9, 1.8Hz, 1H), 7.33 (dd, J = 4.1, 2.6Hz, 1H) ,7.27(q,J＝9.0Hz,1H),7.15–7.03(m,1H),5.42–5.31(m,1H),4.61(s,1H),4.44–4.30(m,4H),4.25–4.14 (m,3H),4.05–3.96(m,2H),3.90–3.79(m,2H),3.42–3.35(m,2H),3.14–3.08(m,1H),2.61–2.38(m,4H) ,2.38–2.25(m,2H),2.23(d,J＝4.6Hz,3H),2.21–2.17(m,1H),2.17–2.03(m,3H),1.99–1.93(m,1H),0.88 –0.81(m,3H).
实施例123制备1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基六氢氮杂卓-3-醇
Example 123 Preparation of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H) -Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylhexahydroazepine-3 -alcohol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例123为含0.5个甲酸的盐。LCMS:m/z 660.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 123. LCMS: m/z 660.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,0.5H),7.68(dt,J＝9.0,6.0Hz,1H),7.32(t,J＝3.0Hz,1H),7.26(td,J＝9.4,3.8Hz,1H),7.14–7.09(m,1H),5.39–5.28(m,1H),4.60(s,1H),4.42–4.24(m,4H),3.96–3.70(m,2H),3.30–3.23(m,2H),3.08–3.03(m,1H),2.44–2.33(m,2H),2.30–2.20(m,2H),2.19(d,J＝2.5Hz,3H),2.18–2.09(m,2H),2.05–1.99(m,2H),1.96–1.87(m,2H),1.83–1.73(m,2H),1.70–1.64(m,1H),1.61–1.53(m,1H),1.17(d,J＝11.1Hz,3H),0.89–0.82(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 0.5H), 7.68 (dt, J = 9.0, 6.0 Hz, 1H), 7.32 (t, J = 3.0 Hz, 1H), 7.26 (td ,J＝9.4,3.8Hz,1H),7.14–7.09(m,1H),5.39–5.28(m,1H),4.60(s,1H),4.42–4.24(m,4H),3.96–3.70(m ,2H),3.30–3.23(m,2H),3.08–3.03(m,1H),2.44–2.33(m,2H),2.30–2.20(m,2H),2.19(d,J＝2.5Hz,3H ),2.18–2.09(m,2H),2.05–1.99(m,2H),1.96–1.87(m,2H),1.83–1.73(m,2H),1.70–1.64(m,1H),1.61–1.53 (m,1H),1.17(d,J＝11.1Hz,3H),0.89–0.82(m,3H).
实施例124制备3-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-氮杂双环[3.2.1]辛烷-6-醇
Example 124 Preparation of 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H) -Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane alkan-6-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例124为含0.3个甲酸的盐。LCMS:m/z 658.3(M+H)7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.3 formic acid in Example 124. LCMS:m/z 658.3(M+H)
1H NMR(600MHz,Methanol-d4)δ8.55(s,0.3H),7.70–7.66(m,1H),7.31(dd,J＝4.2,2.6Hz,1H),7.28–7.22(m,1H),7.16–6.99(m,1H),5.43–5.31(m,1H),4.59(s,1H),4.43–4.24(m,3H),4.18–3.92(m,3H),3.42–3.33(m,3H),3.14–3.08(m,1H),2.49–2.25(m,5H),2.19(s,3H),2.15–2.04(m,5H),2.01–1.92(m,2H),1.86–1.77(m,1H),1.54–1.46(m,1H),0.85(t,J＝7.3Hz,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.55 (s, 0.3H), 7.70–7.66 (m, 1H), 7.31 (dd, J = 4.2, 2.6Hz, 1H), 7.28–7.22 (m, 1H),7.16–6.99(m,1H),5.43–5.31(m,1H),4.59(s,1H),4.43–4.24(m,3H),4.18–3.92(m,3H),3.42–3.33( m,3H),3.14–3.08(m,1H),2.49–2.25(m,5H),2.19(s,3H),2.15–2.04(m,5H),2.01–1.92(m,2H),1.86– 1.77(m,1H),1.54–1.46(m,1H),0.85(t,J＝7.3Hz,3H).
实施例125制备4-(4-((R)-3-氨基哌啶-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-酚
Example 125 Preparation of 4-(4-((R)-3-aminopiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine- 7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例125为含一个甲酸的盐。LCMS:m/z 631.3(M+H)。1H NMR(400MHz,Methanol-d4)δ8.50(d,J＝5.1Hz,1H),7.70(dd,J＝9.0,5.8Hz,1H),7.33(d,J＝2.7Hz,1H),7.27(t,J＝9.4Hz,1H),7.07(dd,J＝5.4,2.7Hz,1H),5.47–5.30(m,1H),4.59(s,2H),4.49–4.22(m,4H),3.61–3.36(m,6H),3.20–3.09(m,1H),2.50–2.28(m,4H),2.28–2.19(m,5H),2.15–2.04(m,2H),2.01–1.90(m,2H),1.80–1.68(m,2H),0.88–0.81(m,3H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 125. LCMS: m/z 631.3(M+H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.50 (d, J = 5.1Hz, 1H), 7.70 (dd, J = 9.0, 5.8Hz, 1H), 7.33 (d, J = 2.7Hz, 1H) ,7.27(t,J＝9.4Hz,1H),7.07(dd,J＝5.4,2.7Hz,1H),5.47–5.30(m,1H),4.59(s,2H),4.49–4.22(m,4H ),3.61–3.36(m,6H),3.20–3.09(m,1H),2.50–2.28(m,4H),2.28–2.19(m,5H),2.15–2.04(m,2H),2.01–1.90 (m,2H),1.80–1.68(m,2H),0.88–0.81(m,3H).
实施例126制备6-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-6-氮杂双环[3.2.1]辛烷-2-醇
Example 126 Preparation of 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H) -Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-azabicyclo[3.2.1]octane Alkan-2-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方 法制备实施例126。LCMS:m/z 658.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F in Example 38. Preparation Example 126. LCMS: m/z 658.3(M+H).
实施例127制备(R)-1-(7-(7，8-二氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 127 Preparation of (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例127为含0.3个甲酸的盐。LCMS:m/z 636.3(M+H)。1H NMR(600MHz,Methanol-d4)δ8.54(s,0.3H),7.63(dd,J＝9.4,4.6Hz,1H),7.42(q,J＝8.9Hz,1H),7.35(s,1H),7.31–7.19(m,1H),5.46–5.34(m,1H),4.60(s,1H),4.46(d,J＝10.9Hz,1H),4.36(d,J＝11.4Hz,1H),3.88(d,J＝10.5Hz,1H),3.77(d,J＝11.0Hz,1H),3.53–3.37(m,3H),3.19–3.12(m,1H),2.53–2.28(m,3H),2.22(d,J＝5.2Hz,4H),2.18–2.05(m,3H),2.01–1.94(m,1H),1.85–1.76(m,2H),1.75–1.68(m,1H),1.23–1.13(m,3H).7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.3 formic acid in Example 127. LCMS: m/z 636.3(M+H). 1 H NMR (600MHz, Methanol-d 4 ) δ8.54 (s, 0.3H), 7.63 (dd, J = 9.4, 4.6Hz, 1H), 7.42 (q, J = 8.9Hz, 1H), 7.35 (s ,1H),7.31–7.19(m,1H),5.46–5.34(m,1H),4.60(s,1H),4.46(d,J＝10.9Hz,1H),4.36(d,J＝11.4Hz, 1H),3.88(d,J＝10.5Hz,1H),3.77(d,J＝11.0Hz,1H),3.53–3.37(m,3H),3.19–3.12(m,1H),2.53–2.28(m ,3H),2.22(d,J＝5.2Hz,4H),2.18–2.05(m,3H),2.01–1.94(m,1H),1.85–1.76(m,2H),1.75–1.68(m,1H) ),1.23–1.13(m,3H).
实施例128-P1制备(R)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 128-P1 Preparation of (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例128-P1为含0.5个甲酸的盐。LCMS:m/z 632.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare Example 128-P1 as a salt containing 0.5 formic acid. LCMS: m/z 632.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.54(s,0.5H),7.69(dd,J＝9.1,5.8Hz,1H),7.33–7.31(m,1H),7.27(td,J＝9.4,4.4Hz,1H),7.13–7.04(m,1H),5.49–5.32(m,1H),4.61(s,2H),4.47(dd,J＝10.9,4.0Hz,1H),4.36(d,J＝10.9Hz,1H),3.93–3.79(m,2H),3.54–3.38(m,3H),3.20–3.12(m,1H),2.52–2.30(m,4H),2.21(s,3H),2.16–1.92(m,6H),1.77–1.59(m,3H),0.89–0.81(m,3H)。 1 H NMR (400 MHz, Methanol-d 4 )δ8.54(s,0.5H),7.69(dd,J＝9.1,5.8Hz,1H),7.33–7.31(m,1H),7.27(td,J＝ 9.4,4.4 Hz,1H),7.13–7.04 (m,1H),5.49–5.32 (m,1H),4.61 (s,2H),4.47 (dd,J＝10.9,4.0 Hz,1H ),4.36(d,J＝10.9Hz,1H),3.93–3.79(m,2H),3.54–3.38(m,3H),3.20–3.12(m,1H),2.52–2.30(m,4H), 2.21(s,3H),2.16–1.92(m,6H),1.77–1.59(m,3H),0.89–0.81(m,3H).
实施例128-P2制备(S)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 128-P2 Preparation of (S)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例128-P2为含0.5个甲酸的盐。LCMS:m/z 632.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare Example 128-P2 as a salt containing 0.5 formic acid. LCMS: m/z 632.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.54(s,0.5H),7.69(dd,J＝9.0,5.8Hz,1H),7.32(d,J＝2.6Hz,1H),7.26(td,J＝9.3,6.3Hz,1H),7.13–7.04(m,1H),5.44–5.33(m,1H),4.61(s,1H),4.44–4.35(m,2H),3.90–3.77(m,2H),3.50–3.36(m,4H),3.17–3.10(m,1H),2.51–2.28(m,4H),2.21(s,3H),2.14–1.93(m,6H),1.76–1.59(m,3H),0.89–0.83(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.54 (s, 0.5H), 7.69 (dd, J = 9.0, 5.8Hz, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.26 (td ,J＝9.3,6.3Hz,1H),7.13–7.04(m,1H),5.44–5.33(m,1H),4.61(s,1H),4.44–4.35(m,2H),3.90–3.77(m ,2H),3.50–3.36(m,4H),3.17–3.10(m,1H),2.51–2.28(m,4H),2.21(s,3H),2.14–1.93(m,6H),1.76–1.59 (m,3H),0.89–0.83(m,3H).
实施例129制备4-(8-氟-7-(7-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1，4-噁吖庚环-6-醇
Example 129 Preparation of 4-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepine-6- alcohol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例129为含一个甲酸的盐。LCMS:m/z 634.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 129. LCMS: m/z 634.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.55(s,1H),7.82(dd,J＝9.0,5.7Hz,1H),7.34(q,J＝2.5Hz,2H),7.28(tt,J＝10.3,4.8Hz,2H),5.45–5.28(m,1H),4.60(s,1H),4.48–4.25(m,4H),4.05–3.89(m,4H),3.70(d,J＝12.6Hz,1H),3.53–3.35(m,3H),3.15–3.08(m,1H),2.44–2.27(m,2H),2.23(s,3H),2.22–2.16(m,1H),2.13–2.03(m,2H),2.01–1.92(m,1H),1.19(s,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.55 (s, 1H), 7.82 (dd, J = 9.0, 5.7Hz, 1H), 7.34 (q, J = 2.5Hz, 2H), 7.28 (tt, J＝10.3,4.8Hz,2H),5.45–5.28(m,1H),4.60(s,1H),4.48–4.25(m,4H),4.05–3.89(m,4H),3.70(d,J＝ 12.6Hz,1H),3.53–3.35(m,3H),3.15–3.08(m,1H),2.44–2.27(m,2H),2.23(s,3H),2.22–2.16(m,1H),2.13 –2.03(m,2H),2.01–1.92(m,1H),1.19(s,3H).
实施例130制备1-(8-氟-7-(7-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 130 Preparation of 1-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例130为含一个甲酸的盐。LCMS:m/z 618.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and the corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 130. LCMS: m/z 618.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.51(s,1H),7.83(dd,J＝9.3,5.6Hz,1H),7.34(d,J＝2.5Hz,1H),7.32(d,J＝2.3Hz,1H),7.29(d,J＝2.0Hz,1H),7.27(s,1H),5.53–5.34(m,1H),4.69–4.39(m,4H),3.91(d,J＝13.6Hz,1H),3.79(d,J＝13.5Hz,1H),3.70–3.47(m,3H),3.28–3.20(m,1H),2.59–2.25(m,4H),2.23(s,3H),2.21–2.13(m,2H),2.10–1.96(m,1H),1.79(q,J＝3.9,3.3Hz,2H),1.69(d,J＝13.4Hz,1H),1.18(s,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.51 (s, 1H), 7.83 (dd, J = 9.3, 5.6Hz, 1H), 7.34 (d, J = 2.5Hz, 1H), 7.32 (d, J＝2.3Hz,1H),7.29(d,J＝2.0Hz,1H),7.27(s,1H),5.53–5.34(m,1H),4.69–4.39(m,4H),3.91(d,J ＝13.6Hz,1H),3.79(d,J＝13.5Hz,1H),3.70–3.47(m,3H),3.28–3.20(m,1H),2.59–2.25(m,4H),2.23(s, 3H),2.21–2.13(m,2H),2.10–1.96(m,1H),1.79(q,J＝3.9,3.3Hz,2H),1.69(d,J＝13.4Hz,1H),1.18(s ,3H).
实施例131制备6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)-4-(1-氧杂-6-氮杂螺[3.5]壬-6-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 131 Preparation of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5- (propynyl)-4-(1-oxa-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例131为含0.5个甲酸的盐。LCMS:m/z 630.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 131. LCMS: m/z 630.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.54(s,0.3H),7.83(dd,J＝9.1,5.6Hz,1H),7.34(t,J＝2.2Hz,2H),7.29(td,J＝8.7,2.6Hz,1H),7.23(d,J＝10.9Hz,1H),5.44–5.33(m,1H),4.44(d,J＝10.7Hz,2H),4.37(d,J＝10.8Hz,2H),4.30–3.96(m,4H),3.49–3.37(m,3H),3.18–3.09(m,1H),2.47–2.28(m,5H),2.23(s,3H),2.20–1.92(m,7H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.54 (s, 0.3H), 7.83 (dd, J = 9.1, 5.6Hz, 1H), 7.34 (t, J = 2.2Hz, 2H), 7.29 (td ,J＝8.7,2.6Hz,1H),7.23(d,J＝10.9Hz,1H),5.44–5.33(m,1H),4.44(d,J＝10.7Hz,2H),4.37(d,J＝ 10.8Hz,2H),4.30–3.96(m,4H),3.49–3.37(m,3H),3.18–3.09(m,1H),2.47–2.28(m,5H),2.23(s,3H),2.20 –1.92(m,7H).
实施例132制备(R)-1-(8-氟-2(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-7-(7-氟-3-羟基萘-1-基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 132 Preparation of (R)-1-(8-fluoro-2(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(7-fluoro) -3-Hydroxynaphth-1-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例132为含一个甲酸的盐。LCMS:m/z 592.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 132. LCMS: m/z 592.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.50(s,0.3H),7.82(dd,J＝9.8,5.7Hz,1H),7.35–7.26(m,4H),5.33–5.14(m,1H),4.64–4.54(m,2H),3.91(d,J＝13.6Hz,1H),3.77(d,J＝13.5Hz,1H),3.64–3.52(m,1H),3.30–3.25(m,1H), 2.81(d,J＝11.7Hz,1H),2.74(d,J＝12.0Hz,1H),2.63(s,3H),2.43–2.30(m,2H),2.23(s,3H),2.15–1.98(m,2H),1.83–1.75(m,2H),1.73–1.65(m,1H),1.18(s,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.50 (s, 0.3H), 7.82 (dd, J = 9.8, 5.7Hz, 1H), 7.35–7.26 (m, 4H), 5.33–5.14 (m, 1H),4.64–4.54(m,2H),3.91(d,J＝13.6Hz,1H),3.77(d,J＝13.5Hz,1H),3.64–3.52(m,1H),3.30–3.25(m ,1H), 2.81(d,J＝11.7Hz,1H),2.74(d,J＝12.0Hz,1H),2.63(s,3H),2.43–2.30(m,2H),2.23(s,3H),2.15–1.98 (m,2H),1.83–1.75(m,2H),1.73–1.65(m,1H),1.18(s,3H).
实施例133制备(R)-1-(8-氟-7-(7-氟-3-羟基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 133 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl) )methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例133为含0.5个甲酸的盐。LCMS:m/z 574.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 133. LCMS: m/z 574.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.55(s,0.5H),7.82(dd,J＝9.5,5.6Hz,1H),7.34(d,J＝2.4Hz,1H),7.32(d,J＝2.2Hz,1H),7.29(t,J＝8.4Hz,2H),4.62(d,J＝20.8Hz,3H),3.92(d,J＝13.7Hz,1H),3.78(d,J＝13.6Hz,1H),3.40–3.27(m,2H),2.77(s,4H),2.29–2.24(m,2H),2.23(s,3H),2.03–1.89(m,4H),1.83–1.76(m,2H),1.72–1.66(m,1H),1.18(s,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.55 (s, 0.5H), 7.82 (dd, J = 9.5, 5.6Hz, 1H), 7.34 (d, J = 2.4Hz, 1H), 7.32 (d ,J＝2.2Hz,1H),7.29(t,J＝8.4Hz,2H),4.62(d,J＝20.8Hz,3H),3.92(d,J＝13.7Hz,1H),3.78(d,J ＝13.6Hz,1H),3.40–3.27(m,2H),2.77(s,4H),2.29–2.24(m,2H),2.23(s,3H),2.03–1.89(m,4H),1.83– 1.76(m,2H),1.72–1.66(m,1H),1.18(s,3H).
实施例134制备(R)-1-(2-((1-((二甲氨基)亚甲基)环丙烷基)甲氧基)-8-氟-7-(7-氟-3-羟基萘-1-基)5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 134 Preparation of (R)-1-(2-((1-((dimethylamino)methylene)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-hydroxy Naphth-1-yl)5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例134为含0.5个甲酸的盐。LCMS:m/z 588.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 134. LCMS: m/z 588.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.57(s,0.5H),7.82(dd,J＝9.4,5.6Hz,1H),7.36–7.26(m,4H),4.60(s,2H),4.43(q,J＝11.4Hz,2H),3.90(d,J＝13.5Hz,1H),3.78(d,J＝13.4Hz,1H),2.88–2.66(m,2H),2.57(s,6H),2.22(s,3H),2.00–2.13(m,1H),1.83–1.76(m,2H),1.69(d,J＝13.1Hz,1H),1.18(s,3H),0.84(s,2H),0.68(s,2H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.57 (s, 0.5H), 7.82 (dd, J = 9.4, 5.6Hz, 1H), 7.36–7.26 (m, 4H), 4.60 (s, 2H) ,4.43(q,J＝11.4Hz,2H),3.90(d,J＝13.5Hz,1H),3.78(d,J＝13.4Hz,1H),2.88–2.66(m,2H),2.57(s, 6H),2.22(s,3H),2.00–2.13(m,1H),1.83–1.76(m,2H),1.69(d,J＝13.1Hz,1H),1.18(s,3H),0.84(s ,2H),0.68(s,2H).
实施例135制备(R)-1-(2-((1-(氨基亚甲基)环丙烷基)甲氧基)-8-氟-7-(7-氟-3-羟基萘-1-基)5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 135 Preparation of (R)-1-(2-((1-(aminomethylene)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-hydroxynaphthalene-1- (yl)5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例135为含0.3个甲酸的盐。LCMS:m/z 560.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.3 formic acid in Example 135. LCMS: m/z 560.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.43(s,0.3H),7.81(dd,J＝9.5,5.6Hz,1H),7.40–7.22(m,4H),4.61(s,1H),3.89–3.44(m,6H),2.20(s,3H),1.83–1.63(m,3H),1.37–1.21(m,1H),1.19(s,3H),0.95–0.84(m,1H),0.55(t,J＝28.3Hz,4H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.43 (s, 0.3H), 7.81 (dd, J = 9.5, 5.6Hz, 1H), 7.40–7.22 (m, 4H), 4.61 (s, 1H) ,3.89–3.44(m,6H),2.20(s,3H),1.83–1.63(m,3H),1.37–1.21(m,1H),1.19(s,3H),0.95–0.84(m,1H) ,0.55(t,J＝28.3Hz,4H).
实施例136制备1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟--2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)六氢氮杂卓-4-腈
Example 136 Preparation of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)hexahydroazepine-4-carbonitrile
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例136为含一个甲酸的盐。LCMS:m/z 655.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents were used as raw materials, and the salt containing a formic acid was prepared in Example 136 by referring to the synthesis method of synthesis steps B to F of Example 38. LCMS: m/z 655.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.54(s,1H),7.69(dt,J＝9.4,5.1Hz,1H),7.32(d,J＝2.6Hz,1H),7.26(td,J＝9.4,6.7Hz,1H),7.14–7.07(m,1H),5.44–5.33(m,1H),4.60(s,2H),4.47–4.33(m,2H),4.23–4.15(m,1H),4.05–3.98(m,1H),3.86–3.79(m,1H),3.43–3.36(m,2H),3.20–3.11(m,1H),2.47–2.27(m,5H),2.25–2.20(m,2H),2.18(d,J＝2.6Hz,3H),2.13–2.07(m,2H),2.02–1.93(m,3H),1.38–1.30(m,H),0.89–0.83(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.54 (s, 1H), 7.69 (dt, J = 9.4, 5.1Hz, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.26 (td, J＝9.4,6.7Hz,1H),7.14–7.07(m,1H),5.44–5.33(m,1H),4.60(s,2H),4.47–4.33(m,2H),4.23–4.15(m, 1H),4.05–3.98(m,1H),3.86–3.79(m,1H),3.43–3.36(m,2H),3.20–3.11(m,1H),2.47–2.27(m,5H),2.25– 2.20(m,2H),2.18(d,J＝2.6Hz,3H),2.13–2.07(m,2H),2.02–1.93(m,3H),1.38–1.30(m,H),0.89–0.83( m,3H).
实施例137制备(R)-1-(8-氟-7-(7-氟-3-羟基-8-甲基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 137 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-methylnaphthalene-1-yl)-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine- 3-alcohol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方 法制备实施例137为含0.3个甲酸的盐。LCMS:m/z 632.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F in Example 38. Preparation Example 137 is a salt containing 0.3 formic acid. LCMS: m/z 632.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.54(s,0.3H),7.68(t,J＝7.5Hz,1H),7.31(s,1H),7.26(td,J＝9.1,4.6Hz,1H),7.17–7.09(m,1H),5.45–5.34(m,1H),4.60(s,1H),4.46(d,J＝10.6Hz,1H),4.35(d,J＝11.6Hz,1H),3.93–3.72(m,3H),3.53–3.37(m,3H),3.18–3.12(m,1H),2.51–2.28(m,3H),2.27–2.23(m,1H),2.21(s,3H),2.15–2.06(m,2H),2.02–1.95(m,1H),1.87(d,J＝8.9Hz,3H),1.82–1.77(m,2H),1.74–1.67(m,1H),1.20–1.12(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.54 (s, 0.3H), 7.68 (t, J = 7.5Hz, 1H), 7.31 (s, 1H), 7.26 (td, J = 9.1, 4.6Hz ,1H),7.17–7.09(m,1H),5.45–5.34(m,1H),4.60(s,1H),4.46(d,J＝10.6Hz,1H),4.35(d,J＝11.6Hz, 1H),3.93–3.72(m,3H),3.53–3.37(m,3H),3.18–3.12(m,1H),2.51–2.28(m,3H),2.27–2.23(m,1H),2.21( s,3H),2.15–2.06(m,2H),2.02–1.95(m,1H),1.87(d,J＝8.9Hz,3H),1.82–1.77(m,2H),1.74–1.67(m, 1H),1.20–1.12(m,3H).
实施例138制备(R)-1-(2-(((2S,4R)-1-乙基-4-氟吡咯烷-2-基)甲氧基)-8-氟-7-(7-氟-3-羟基萘-1-基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 138 Preparation of (R)-1-(2-(((2S,4R)-1-ethyl-4-fluoropyrrolidin-2-yl)methoxy)-8-fluoro-7-(7- Fluoro-3-hydroxynaphthalen-1-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例138为含0.1个甲酸的盐。LCMS:m/z 606.3(M+H)。Using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, Example 138 was prepared according to the synthetic method of synthetic steps B to F of Example 38 as a salt containing 0.1 formic acid. LCMS: m/z 606.3 (M+H).
1H NMR(600MHz,Methanol-d4)δ8.54(s,0.1H),7.82(dd,J＝9.7,5.6Hz,1H),7.34(d,J＝2.4Hz,1H),7.32(d,J＝2.5Hz,1H),7.31–7.26(m,2H),5.30–5.18(m,1H),4.65–4.59(m,2H),4.53(dd,J＝11.2,5.3Hz,1H),3.91(d,J＝13.4Hz,1H),3.77(d,J＝13.7Hz,1H),3.59–3.49(m,1H),3.47–3.39(m,1H),3.23–3.13(m,1H),2.89–2.79(m,1H),2.70–2.63(m,1H),2.41–2.33(m,1H),2.22(s,3H),2.21–2.17(m,1H),2.12–1.99(m,2H),1.84–1.75(m,2H),1.72–1.66(m,1H),1.22–1.13(m,6H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.54 (s, 0.1H), 7.82 (dd, J = 9.7, 5.6Hz, 1H), 7.34 (d, J = 2.4Hz, 1H), 7.32 (d ,J＝2.5Hz,1H),7.31–7.26(m,2H),5.30–5.18(m,1H),4.65–4.59(m,2H),4.53(dd,J＝11.2,5.3Hz,1H), 3.91(d,J＝13.4Hz,1H),3.77(d,J＝13.7Hz,1H),3.59–3.49(m,1H),3.47–3.39(m,1H),3.23–3.13(m,1H) ,2.89–2.79(m,1H),2.70–2.63(m,1H),2.41–2.33(m,1H),2.22(s,3H),2.21–2.17(m,1H),2.12–1.99(m, 2H),1.84–1.75(m,2H),1.72–1.66(m,1H),1.22–1.13(m,6H).
实施例139制备(R)-1-(8-氟-7-(7-氟-3-羟基萘-1-基)-5-(丙炔基)-2-((1-(吡咯烷-1-基)甲基)环丙烷基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 139 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-5-(propynyl)-2-((1-(pyrrolidine- 1-yl)methyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例139为含一个甲酸的盐。LCMS:m/z 614.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F in Example 38 to prepare a salt containing a formic acid in Example 139. LCMS: m/z 614.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.57(s,1H),7.83(dd,J＝9.0,5.6Hz,1H),7.35(d,J＝2.4Hz,1H),7.32(d,J＝2.5Hz,1H),7.32–7.27(m,2H),4.61(s,1H),4.53(d,J＝11.6Hz,1H),4.41(d,J＝11.6Hz,1H),3.91(d,J＝13.5Hz,1H),3.77(d,J＝13.7Hz,1H),3.23–2.98(m,6H),2.23(s,3H),2.22–2.16(m, 1H),2.04–1.95(m,4H),1.81–1.77(m,2H),1.71–1.66(m,1H),1.36–1.30(m,1H),1.18(s,3H),0.88(s,2H),0.78(s,2H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.57 (s, 1H), 7.83 (dd, J = 9.0, 5.6Hz, 1H), 7.35 (d, J = 2.4Hz, 1H), 7.32 (d, J＝2.5Hz,1H),7.32–7.27(m,2H),4.61(s,1H),4.53(d,J＝11.6Hz,1H),4.41(d,J＝11.6Hz,1H),3.91( d,J＝13.5Hz,1H),3.77(d,J＝13.7Hz,1H),3.23–2.98(m,6H),2.23(s,3H),2.22–2.16(m, 1H),2.04–1.95(m,4H),1.81–1.77(m,2H),1.71–1.66(m,1H),1.36–1.30(m,1H),1.18(s,3H),0.88(s, 2H),0.78(s,2H).
实施例140制备(R)-1-(8-氟-7-(7-氟-3-羟基萘-1-基)-2-((1-(哌啶-1-基甲基)环丙烷基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 140 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphth-1-yl)-2-((1-(piperidin-1-ylmethyl)cyclopropane) (yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例140为含一个甲酸的盐。LCMS:m/z 628.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and the corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 140. LCMS: m/z 628.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,1H),7.82(dd,J＝9.0,5.6Hz,1H),7.34(d,J＝2.4Hz,1H),7.32(d,J＝2.5Hz,1H),7.29(tt,J＝9.1,4.1Hz,2H),4.60(s,1H),4.52(d,J＝11.3Hz,1H),4.40(d,J＝11.3Hz,1H),3.89(d,J＝13.5Hz,1H),3.77(d,J＝13.7Hz,1H),3.02–2.62(m,6H),2.23(s,3H),2.22–2.16(m,1H),1.85–1.49(m,10H),1.18(s,3H),0.85(s,2H),0.68(s,2H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 1H), 7.82 (dd, J = 9.0, 5.6Hz, 1H), 7.34 (d, J = 2.4Hz, 1H), 7.32 (d, J＝2.5Hz,1H),7.29(tt,J＝9.1,4.1Hz,2H),4.60(s,1H),4.52(d,J＝11.3Hz,1H),4.40(d,J＝11.3Hz, 1H),3.89(d,J＝13.5Hz,1H),3.77(d,J＝13.7Hz,1H),3.02–2.62(m,6H),2.23(s,3H),2.22–2.16(m,1H ),1.85–1.49(m,10H),1.18(s,3H),0.85(s,2H),0.68(s,2H).
实施例141制备(R)-1-(8-氟-7-(7-氟-3-羟基萘-1-基)-5-(丙炔基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 141 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-5-(propynyl)-2-((tetrahydro-1H-pyrrole) Azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例141为含一个甲酸的盐。LCMS:m/z 600.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 141. LCMS: m/z 600.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,1H),7.83(dd,J＝9.0,5.6Hz,1H),7.35(d,J＝2.4Hz,1H),7.32(d,J＝2.5Hz,1H),7.32–7.27(m,2H),4.62–4.54(m,4H),3.92(d,J＝13.6Hz,1H),3.79(d,J＝13.6Hz,1H),3.60–3.52(m,2H),3.19–3.12(m,2H),2.33–2.25(m,2H),2.23(s,3H),2.21–2.07(m,5H),2.06–2.00(m,2H),1.82–1.78(m,2H),1.72–1.67(m,1H),1.19(s,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 1H), 7.83 (dd, J = 9.0, 5.6Hz, 1H), 7.35 (d, J = 2.4Hz, 1H), 7.32 (d, J＝2.5Hz,1H),7.32–7.27(m,2H),4.62–4.54(m,4H),3.92(d,J＝13.6Hz,1H),3.79(d,J＝13.6Hz,1H), 3.60–3.52(m,2H),3.19–3.12(m,2H),2.33–2.25(m,2H),2.23(s,3H),2.21–2.07(m,5H),2.06–2.00(m,2H ),1.82–1.78(m,2H),1.72–1.67(m,1H),1.19(s,3H).
实施例142制备(R)-1-(8-氟-7-(7-氟-3-羟基萘-1-基)-2-(((S)-1-(哌啶-1-基)丙烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 142 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S)-1-(piperidin-1-yl)propan-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例142为含0.2个甲酸的盐。LCMS:m/z 602.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.2 formic acid in Example 142. LCMS: m/z 602.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,0.2H),7.82(dd,J＝9.0,5.6Hz,1H),7.34(d,J＝2.4Hz,1H),7.32(d,J＝2.5Hz,1H),7.31–7.26(m,2H),5.66(s,1H),4.60(s,1H),3.91(d,J＝13.5Hz,1H),3.77(d,J＝13.1Hz,1H),3.11–2.68(m,7H),2.23(s,3H),2.21–2.16(m,1H),1.84–1.77(m,2H),1.74–1.61(m,5H),1.57–1.50(m,2H),1.45(d,J＝5.8Hz,3H),1.18(s,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 0.2H), 7.82 (dd, J = 9.0, 5.6Hz, 1H), 7.34 (d, J = 2.4Hz, 1H), 7.32 (d ,J＝2.5Hz,1H),7.31–7.26(m,2H),5.66(s,1H),4.60(s,1H),3.91(d,J＝13.5Hz,1H),3.77(d,J＝ 13.1Hz,1H),3.11–2.68(m,7H),2.23(s,3H),2.21–2.16(m,1H),1.84–1.77(m,2H),1.74–1.61(m,5H),1.57 –1.50(m,2H),1.45(d,J=5.8Hz,3H),1.18(s,3H).
实施例143制备(R)-1-(8-氟-7-(8-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 143 Preparation of (R)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例143为含0.5个甲酸的盐。LCMS:m/z 618.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 143. LCMS: m/z 618.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.55(s,0.5H),7.61(d,J＝8.3Hz,1H),7.41(td,J＝8.0,5.1Hz,1H),7.34(q,J＝2.3Hz,1H),7.23–7.12(m,1H),6.99–6.91(m,1H),5.47–5.31(m,1H),4.62(s,1H),4.45(d,J＝10.8Hz,1H),4.34(d,J＝10.7Hz,1H),3.90–3.74(m,2H),3.52–3.37(m,3H),3.18–3.09(m,1H),2.51–2.26(m,3H),2.21(d,J＝4.3Hz,3H),2.15–1.91(m,4H),1.84–1.66(m,4H),1.17(d,J＝14.7Hz,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.55 (s, 0.5H), 7.61 (d, J = 8.3Hz, 1H), 7.41 (td, J = 8.0, 5.1Hz, 1H), 7.34 (q ,J＝2.3Hz,1H),7.23–7.12(m,1H),6.99–6.91(m,1H),5.47–5.31(m,1H),4.62(s,1H),4.45(d,J＝10.8 Hz,1H),4.34(d,J＝10.7Hz,1H),3.90–3.74(m,2H),3.52–3.37(m,3H),3.18–3.09(m,1H),2.51–2.26(m, 3H), 2.21 (d, J = 4.3Hz, 3H), 2.15–1.91 (m, 4H), 1.84–1.66 (m, 4H), 1.17 (d, J = 14.7Hz, 3H).
实施例144制备1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-甲酰胺
Example 144 Preparation of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H) -Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxamide
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶 并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例144为含0.2个甲酸的盐。LCMS:m/z 659.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyridine Using [4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.2 formic acid in Example 144. LCMS: m/z 659.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.54(s,0.3H),7.69(dd,J＝9.1,5.8Hz,1H),7.32(d,J＝2.7Hz,1H),7.26(td,J＝9.4,2.1Hz,1H),7.10(dd,J＝13.7,2.7Hz,1H),5.46–5.29(m,1H),4.60(s,1H),4.50–4.32(m,3H),3.81–3.56(m,3H),3.16–3.09(m,1H),2.76–2.61(m,2H),2.49–2.25(m,4H),2.22(s,3H),2.14–2.04(m,3H),2.02–1.86(m,3H),1.83–1.62(m,2H),1.37–1.30(m,1H),0.91–0.80(m,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.54 (s, 0.3H), 7.69 (dd, J = 9.1, 5.8Hz, 1H), 7.32 (d, J = 2.7Hz, 1H), 7.26 (td ,J＝9.4,2.1Hz,1H),7.10(dd,J＝13.7,2.7Hz,1H),5.46–5.29(m,1H),4.60(s,1H),4.50–4.32(m,3H), 3.81–3.56(m,3H),3.16–3.09(m,1H),2.76–2.61(m,2H),2.49–2.25(m,4H),2.22(s,3H),2.14–2.04(m,3H ),2.02–1.86(m,3H),1.83–1.62(m,2H),1.37–1.30(m,1H),0.91–0.80(m,3H).
实施例145制备2-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-2-氮杂双环[2.2.1]庚烷-6-醇
Example 145 Preparation of 2-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H) -Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-2-azabicyclo[2.2.1]hepta alkan-6-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例145为含0.4个甲酸的盐。LCMS:m/z 644.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.4 formic acid in Example 145. LCMS: m/z 644.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.54(s,0.4H),7.69(dd,J＝9.1,5.8Hz,1H),7.32(t,J＝2.4Hz,1H),7.26(td,J＝9.4,2.8Hz,1H),7.13–7.03(m,1H),5.47–5.29(m,1H),5.00(d,J＝6.9Hz,1H),4.60(s,1H),4.47–4.32(m,2H),4.12–3.97(m,2H),3.49–3.35(m,2H),3.17–3.09(m,1H),2.53–2.20(m,6H),2.18(s,3H),2.15–2.03(m,3H),2.02–1.82(m,3H),1.54(d,J＝13.5Hz,1H),1.35–1.29(m,1H),0.91–0.80(m,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.54 (s, 0.4H), 7.69 (dd, J = 9.1, 5.8Hz, 1H), 7.32 (t, J = 2.4Hz, 1H), 7.26 (td ,J＝9.4,2.8Hz,1H),7.13–7.03(m,1H),5.47–5.29(m,1H),5.00(d,J＝6.9Hz,1H),4.60(s,1H),4.47– 4.32(m,2H),4.12–3.97(m,2H),3.49–3.35(m,2H),3.17–3.09(m,1H),2.53–2.20(m,6H),2.18(s,3H), 2.15–2.03(m,3H),2.02–1.82(m,3H),1.54(d,J=13.5Hz,1H),1.35–1.29(m,1H),0.91–0.80(m,3H).
实施例146制备2-(1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-基)乙腈
Example 146 Preparation of 2-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)acetonitrile
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例146为含0.2个甲酸的盐。LCMS:m/z 655.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.2 formic acid in Example 146. LCMS: m/z 655.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.54(s,0.2H),7.69(dd,J＝9.0,5.8Hz,1H),7.32(t,J＝2.4Hz,1H),7.27(td,J＝9.4,2.7Hz,1H),7.13–7.04(m,1H),5.47–5.30(m,1H),4.60(s,1H),4.52–4.35(m,3H),4.33–4.23(m,1H),3.69–3.52(m,2H),3.45–3.37(m,2H),3.16–3.09(m,1H),2.64–2.44(m,3H),2.43 –2.24(m,4H),2.21(s,3H),2.13–1.94(m,4H),1.93–1.84(m,1H),1.63–1.51(m,2H),1.36–1.30(m,1H),0.88–0.81(m,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.54 (s, 0.2H), 7.69 (dd, J = 9.0, 5.8Hz, 1H), 7.32 (t, J = 2.4Hz, 1H), 7.27 (td ,J＝9.4,2.7Hz,1H),7.13–7.04(m,1H),5.47–5.30(m,1H),4.60(s,1H),4.52–4.35(m,3H),4.33–4.23(m ,1H),3.69–3.52(m,2H),3.45–3.37(m,2H),3.16–3.09(m,1H),2.64–2.44(m,3H),2.43 –2.24(m,4H),2.21(s,3H),2.13–1.94(m,4H),1.93–1.84(m,1H),1.63–1.51(m,2H),1.36–1.30(m,1H) ,0.88–0.81(m,3H).
实施例147制备(R)-1-(7-(5-胺基-3-氯-2-环丙烷基苯基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 147 Preparation of (R)-1-(7-(5-amino-3-chloro-2-cyclopropylphenyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-3 -alcohol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例147为含0.2个甲酸的盐。LCMS:m/z 623.3(M+H)。Using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, Example 147 was prepared as a salt containing 0.2 formic acid by referring to the synthesis method of synthesis steps B to F of Example 38. LCMS: m/z 623.3 (M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,0.2H),6.87(d,J＝2.4Hz,1H),6.67(s,1H),5.42–5.26(m,1H),4.62(s,1H),4.37(d,J＝10.5Hz,1H),4.25(d,J＝10.6Hz,1H),3.87–3.72(m,3H),3.29–3.22(m,2H),3.09–3.02(m,1H),2.44–2.25(m,4H),2.21(s,3H),2.18–2.13(m,1H),2.08–1.98(m,3H),1.95–1.63(m,6H),1.13(s,3H),0.71–0.54(m,2H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.56 (s, 0.2H), 6.87 (d, J = 2.4Hz, 1H), 6.67 (s, 1H), 5.42–5.26 (m, 1H), 4.62 (s,1H),4.37(d,J＝10.5Hz,1H),4.25(d,J＝10.6Hz,1H),3.87–3.72(m,3H),3.29–3.22(m,2H),3.09– 3.02(m,1H),2.44–2.25(m,4H),2.21(s,3H),2.18–2.13(m,1H),2.08–1.98(m,3H),1.95–1.63(m,6H), 1.13(s,3H),0.71–0.54(m,2H).
实施例148制备(R)-1-(7-(3-氯-5-羟基-2-(三氟甲基)苯基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 148 Preparation of (R)-1-(7-(3-chloro-5-hydroxy-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine -3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例148为含0.2个甲酸的盐。LCMS:m/z 652.2(M+H)。Using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, Example 148 was prepared according to the synthetic method of synthetic steps B to F of Example 38 as a salt containing 0.2 formic acid. LCMS: m/z 652.2 (M+H).
1H NMR(400MHz,Methanol-d4)δ8.55(s,0.2H),7.14(d,J＝2.5Hz,1H),6.81–6.70(m,1H),5.45–5.28(m,1H),4.62(s,1H),4.40(d,J＝10.7Hz,1H),4.29(d,J＝10.7Hz,1H),3.78(q,J＝13.4Hz,3H),3.46–3.36(m,2H),3.15–3.04(m,1H),2.48–2.25(m,3H),2.22(s,3H),2.18(d,J＝9.1Hz,2H),2.11–2.02(m,2H),2.00–1.89(m,1H),1.78(t,J＝5.8Hz,2H),1.73–1.64(m,1H),1.15(s,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.55 (s, 0.2H), 7.14 (d, J = 2.5Hz, 1H), 6.81–6.70 (m, 1H), 5.45–5.28 (m, 1H) ,4.62(s,1H),4.40(d,J＝10.7Hz,1H),4.29(d,J＝10.7Hz,1H),3.78(q,J＝13.4Hz,3H),3.46–3.36(m, 2H),3.15–3.04(m,1H),2.48–2.25(m,3H),2.22(s,3H),2.18(d,J＝9.1Hz,2H),2.11–2.02(m,2H),2.00 –1.89(m,1H),1.78(t,J＝5.8Hz,2H),1.73–1.64(m,1H),1.15(s,3H).
实施例149制备(R)-1-(8-氟-7-(8-氟-3-羟基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 149 Preparation of (R)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例149为含0.5个甲酸的盐。LCMS:m/z 574.3(M+H)。Using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, Example 149 was prepared according to the synthetic method of synthetic steps B to F of Example 38 as a salt containing 0.5 formic acid. LCMS: m/z 574.3 (M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,0.5H),7.61(d,J＝8.3Hz,1H),7.43–7.39(m,1H),7.34(q,J＝2.5Hz,1H),7.23–7.11(m,1H),6.98–6.93(m,1H),4.66–4.58(m,3H),3.93–3.74(m,3H),3.30–3.23(m,1H),2.76(s,3H),2.29–2.23(m,1H),2.21(d,J＝6.3Hz,4H),2.04–1.87(m,4H),1.84–1.76(m,2H),1.74–1.68(m,1H),1.37–1.30(m,1H),1.22–1.13(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 0.5H), 7.61 (d, J = 8.3Hz, 1H), 7.43–7.39 (m, 1H), 7.34 (q, J = 2.5Hz ,1H),7.23–7.11(m,1H),6.98–6.93(m,1H),4.66–4.58(m,3H),3.93–3.74(m,3H),3.30–3.23(m,1H),2.76 (s,3H),2.29–2.23(m,1H),2.21(d,J＝6.3Hz,4H),2.04–1.87(m,4H),1.84–1.76(m,2H),1.74–1.68(m ,1H),1.37–1.30(m,1H),1.22–1.13(m,3H).
实施例150制备(R)-1-(8-氟-2-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-7-(8-氟-3-羟基萘-1-基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 150 Preparation of (R)-1-(8-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-7-(8- Fluoro-3-hydroxynaphthalen-1-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例150为含0.5个甲酸的盐。LCMS:m/z 592.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 150. LCMS: m/z 592.2(M+H).
1H NMR(600MHz,Methanol-d4)δ8.50(s,0.5H),7.61(d,J＝8.3Hz,1H),7.43–7.39(m,1H),7.34(q,J＝2.5Hz,1H),7.23–7.12(m,1H),6.98–6.93(m,1H),5.31–5.18(m,1H),4.64–4.56(m,3H),3.92–3.74(m,3H),3.65–3.54(m,1H),2.85–2.74(m,1H),2.65(s,3H),2.41–2.33(m,1H),2.21(d,J＝6.1Hz,3H),2.18–2.03(m,2H),1.83–1.76(m,2H),1.75–1.68(s,1H),1.38–1.30(m,1H),1.21–1.12(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.50 (s, 0.5H), 7.61 (d, J = 8.3Hz, 1H), 7.43–7.39 (m, 1H), 7.34 (q, J = 2.5Hz ,1H),7.23–7.12(m,1H),6.98–6.93(m,1H),5.31–5.18(m,1H),4.64–4.56(m,3H),3.92–3.74(m,3H),3.65 –3.54(m,1H),2.85–2.74(m,1H),2.65(s,3H),2.41–2.33(m,1H),2.21(d,J＝6.1Hz,3H),2.18–2.03(m ,2H),1.83–1.76(m,2H),1.75–1.68(s,1H),1.38–1.30(m,1H),1.21–1.12(m,3H).
实施例151制备(R)-1-(2-(((2S,4R)-1-乙基-4-氟吡咯烷-2-基)甲氧基)-8-氟-7-(8-氟-3-羟基萘-1-基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 151 Preparation of (R)-1-(2-(((2S,4R)-1-ethyl-4-fluoropyrrolidin-2-yl)methoxy)-8-fluoro-7-(8- Fluoro-3-hydroxynaphthalen-1-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶 并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例151为含一个甲酸的盐。LCMS:m/z 606.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyridine Using [4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 151. LCMS: m/z 606.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.57(s,1H),7.59–7.54(m,1H),7.37(q,J＝7.4Hz,1H),7.32–7.27(m,1H),7.21–7.10(m,1H),6.93–6.87(m,1H),5.27–5.16(m,1H),4.62–4.57(m,1H),4.49(dd,J＝11.0,5.6Hz,1H),3.90–3.74(m,3H),3.53–3.42(m,2H),3.14–3.09(m,1H),2.78–2.69(m,1H),2.62–2.56(m,1H),2.38–2.29(m,1H),2.21(d,J＝6.3Hz,3H),2.18–1.98(m,3H),1.83–1.68(m,3H),1.35–1.30(m,1H),1.23–1.08(m,5H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.57 (s, 1H), 7.59–7.54 (m, 1H), 7.37 (q, J = 7.4Hz, 1H), 7.32–7.27 (m, 1H), 7.21–7.10(m,1H),6.93–6.87(m,1H),5.27–5.16(m,1H),4.62–4.57(m,1H),4.49(dd,J＝11.0,5.6Hz,1H), 3.90–3.74(m,3H),3.53–3.42(m,2H),3.14–3.09(m,1H),2.78–2.69(m,1H),2.62–2.56(m,1H),2.38–2.29(m ,1H),2.21(d,J＝6.3Hz,3H),2.18–1.98(m,3H),1.83–1.68(m,3H),1.35–1.30(m,1H),1.23–1.08(m,5H ).
实施例152制备(R)-1-(2-((1-((二甲氨基)亚甲基)环丙烷基)甲氧基)-8-氟-7-(8-氟-3-羟基萘-1-基)5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 152 Preparation of (R)-1-(2-((1-((dimethylamino)methylene)cyclopropyl)methoxy)-8-fluoro-7-(8-fluoro-3-hydroxy Naphth-1-yl)5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例152为含一个甲酸的盐。LCMS:m/z 588.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents were used as raw materials, and Example 152 was prepared by referring to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid. LCMS: m/z 588.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,1H),7.62(d,J＝8.3Hz,1H),7.42(td,J＝8.0,5.0Hz,1H),7.35(dt,J＝4.4,2.2Hz,1H),7.25–7.12(m,1H),6.95(dt,J＝13.5,7.1Hz,1H),4.51–4.36(m,3H),3.93–3.74(m,3H),2.82(s,6H),2.21(d,J＝7.8Hz,3H),2.18–2.12(m,1H),1.80(d,J＝6.9Hz,2H),1.75–1.67(m,2H),1.36–1.30(m,1H),1.22–1.13(m,3H),0.93(s,2H),0.80(s,2H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 1H), 7.62 (d, J = 8.3Hz, 1H), 7.42 (td, J = 8.0, 5.0Hz, 1H), 7.35 (dt, J＝4.4,2.2Hz,1H),7.25–7.12(m,1H),6.95(dt,J＝13.5,7.1Hz,1H),4.51–4.36(m,3H),3.93–3.74(m,3H) ,2.82(s,6H),2.21(d,J＝7.8Hz,3H),2.18–2.12(m,1H),1.80(d,J＝6.9Hz,2H),1.75–1.67(m,2H), 1.36–1.30(m,1H),1.22–1.13(m,3H),0.93(s,2H),0.80(s,2H).
实施例153制备(R)-1-(2-((1-(氨基亚甲基)环丙烷基)甲氧基)-8-氟-7-(8-氟-3-羟基萘-1-基)5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 153 Preparation of (R)-1-(2-((1-(aminomethylene)cyclopropyl)methoxy)-8-fluoro-7-(8-fluoro-3-hydroxynaphthalene-1- (yl)5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例153为含两个甲酸的盐。LCMS:m/z 560.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare Example 153 as a salt containing two formic acids. LCMS: m/z 560.2(M+H).
1H NMR(600MHz,Methanol-d4)δ8.55(s,2H),7.61(d,J＝8.3Hz,1H),7.41(ddd,J＝12.6,8.3,5.0Hz,1H),7.35(dt,J＝4.3,2.2Hz,1H),7.24–7.16(m,1H),6.98–6.93(m,1H),4.49–4.38(m,3H),3.93–3.76(m,3H),3.17–3.08(m,1H),2.21(d,J＝7.2Hz,3H),1.85–1.67(m,5H),1.23–1.13(m,3H),0.91(s,2H),0.85(s,2H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.55 (s, 2H), 7.61 (d, J = 8.3Hz, 1H), 7.41 (ddd, J = 12.6, 8.3, 5.0Hz, 1H), 7.35 ( dt,J＝4.3,2.2Hz,1H),7.24–7.16(m,1H),6.98–6.93(m,1H),4.49–4.38(m,3H),3.93–3.76(m,3H),3.17– 3.08(m,1H),2.21(d,J＝7.2Hz,3H),1.85–1.67(m,5H),1.23–1.13(m,3H),0.91(s,2H),0.85(s,2H) .
实施例154制备(R)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 154 Preparation of (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrole) Alk-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例154为含0.3个甲酸的盐。LCMS:m/z 602.3(M+H)。Using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, Example 154 was prepared as a salt containing 0.3 formic acid by referring to the synthesis method of synthesis steps B to F of Example 38. LCMS: m/z 602.3 (M+H).
1H NMR(400MHz,Methanol-d4)δ8.55(s,0.3H),7.72–7.67(m,1H),7.32(d,J＝2.7Hz,1H),7.26(td,J＝9.4,5.8Hz,1H),7.14–7.05(m,1H),4.71–4.57(m,3H),3.92(d,J＝13.4Hz,1H),3.83–3.69(m,2H),3.46–3.36(m,2H),2.81(s,3H),2.52–2.43(m,1H),2.37–2.23(m,3H),2.20(s,3H),2.08–1.90(m,3H),1.85–1.65(m,3H),1.36–1.30(m,1H),1.19–1.10(m,3H),0.87(q,J＝7.2Hz,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.55 (s, 0.3H), 7.72–7.67 (m, 1H), 7.32 (d, J = 2.7Hz, 1H), 7.26 (td, J = 9.4, 5.8Hz,1H),7.14–7.05(m,1H),4.71–4.57(m,3H),3.92(d,J＝13.4Hz,1H),3.83–3.69(m,2H),3.46–3.36(m ,2H),2.81(s,3H),2.52–2.43(m,1H),2.37–2.23(m,3H),2.20(s,3H),2.08–1.90(m,3H),1.85–1.65(m ,3H),1.36–1.30(m,1H),1.19–1.10(m,3H),0.87(q,J=7.2Hz,3H).
实施例155制备(R)-1-(7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2S，4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 155 Preparation of (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2S,4R)-4-fluoro -1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例155为含0.1个甲酸的盐。LCMS:m/z 620.3(M+H)。Using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, Example 155 was prepared as a salt containing 0.1 formic acid by referring to the synthetic method of synthetic steps B to F of Example 38. LCMS: m/z 620.3 (M+H).
1H NMR(600MHz,Methanol-d4)δ8.41(s,0.1H),7.71–7.67(m,1H),7.32(d,J＝2.6Hz,1H),7.26(q,J＝9.1Hz,1H),7.14–7.06(m,1H),5.34–5.22(m,1H),4.65–4.57(m,3H),3.91(d,J＝13.5Hz,1H),3.83–3.60(m,3H),3.46–3.40(m,1H),2.96–2.86(m,1H),2.71(s,3H),2.52–2.23(m,4H),2.20(s,3H),2.18–2.08(m,1H),1.84–1.66(m,3H),1.17(s,3H),0.87(dt,J＝9.0,7.4Hz,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.41 (s, 0.1H), 7.71–7.67 (m, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.26 (q, J = 9.1Hz ,1H),7.14–7.06(m,1H),5.34–5.22(m,1H),4.65–4.57(m,3H),3.91(d,J＝13.5Hz,1H),3.83–3.60(m,3H) ),3.46–3.40(m,1H),2.96–2.86(m,1H),2.71(s,3H),2.52–2.23(m,4H),2.20(s,3H),2.18–2.08(m,1H ),1.84–1.66(m,3H),1.17(s,3H),0.87(dt,J=9.0,7.4Hz,3H).
实施例156制备(R)-1-(2-(((2S,4R)-1-乙基-4-氟吡咯烷-2-基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 156 Preparation of (R)-1-(2-(((2S,4R)-1-ethyl-4-fluoropyrrolidin-2-yl)methoxy)-7-(8-ethyl-7 -Fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例156为含一个甲酸的盐。LCMS:m/z 634.3(M+H)。Using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, Example 156 was prepared as a salt containing a formic acid by referring to the synthesis method of synthesis steps B to F of Example 38. LCMS: m/z 634.3 (M+H).
1H NMR(600MHz,Methanol-d4)δ8.47(s,1H),7.71–7.67(m,1H),7.32(d,J＝2.6Hz,1H),7.26(q,J＝9.1Hz,1H),7.14–7.06(m,1H),5.35–5.24(m,1H),4.67–4.56(m,3H),3.91(d,J＝13.7Hz,1H),3.87–3.70(m,2H),3.67–3.56(m,2H),3.29–3.22(m,1H),3.05–2.96(m,1H),2.80(dd,J＝12.6,6.9Hz,1H),2.51–2.24(m,4H),2.20(s,3H),2.17–2.07(m,1H),1.83–1.66(m,3H),1.22(td,J＝7.2,5.0Hz,3H),1.17(s,3H),0.86(dt,J＝9.8,7.4Hz,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.47 (s, 1H), 7.71–7.67 (m, 1H), 7.32 (d, J = 2.6Hz, 1H), 7.26 (q, J = 9.1Hz, 1H),7.14–7.06(m,1H),5.35–5.24(m,1H),4.67–4.56(m,3H),3.91(d,J＝13.7Hz,1H),3.87–3.70(m,2H) ,3.67–3.56(m,2H),3.29–3.22(m,1H),3.05–2.96(m,1H),2.80(dd,J＝12.6,6.9Hz,1H),2.51–2.24(m,4H) ,2.20(s,3H),2.17–2.07(m,1H),1.83–1.66(m,3H),1.22(td,J＝7.2,5.0Hz,3H),1.17(s,3H),0.86(dt ,J=9.8,7.4Hz,3H).
实施例157制备(R)-1-(2-((1-((二甲氨基)亚甲基)环丙烷基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 157 Preparation of (R)-1-(2-((1-((dimethylamino)methylene)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3- Hydroxynaphth-1-yl)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例157为含0.5个甲酸的盐。LCMS:m/z 616.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 157. LCMS: m/z 616.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,0.5H),7.71–7.66(m,1H),7.32(d,J＝2.7Hz,1H),7.29–7.23(m,1H),7.14–7.06(m,1H),4.59(s,1H),4.48–4.37(m,2H),3.94–3.70(m,3H),2.93–2.74(m,2H),2.61(s,6H),2.51–2.24(m,3H),2.20(s,3H),1.84–1.65(m,3H),1.16(s,3H),0.89–0.83(m,5H),0.70(s,2H)。 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.56 (s, 0.5H), 7.71–7.66 (m, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.29–7.23 (m, 1H), 7.14–7.06 (m, 1H), 4.59 (s, 1H), 4.48–4.37 (m, 2H), 3.94–3.70 (m, 3H), 2.93–2.74 (m, 2H), 2.61 (s, 6H), 2.51–2.24 (m, 3H), 2.20 (s, 3H), 1.84–1.65 (m, 3H), 1.16 (s, 3H), 0.89–0.83 (m, 5H), 0.70 (s, 2H).
实施例158制备(R)-1-(2-((1-((胺基甲基)环丙烷基)甲氧基)-7-(8-乙基-7-氟-3-羟基萘-1-基)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 158 Preparation of (R)-1-(2-((1-((aminomethyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene- 1-yl)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方 法制备实施例158为含0.5个甲酸的盐。LCMS:m/z 588.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F in Example 38. Preparation Example 158 is a salt containing 0.5 formic acid. LCMS: m/z 588.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,0.5H),7.71–7.68(m,1H),7.33(d,J＝2.7Hz,1H),7.30–7.26(m,1H),7.14–7.05(m,1H),4.59(s,1H),4.49–4.40(m,2H),3.93–3.72(m,3H),3.11–3.03(m,1H),2.48(dd,J＝14.8,7.8Hz,1H),2.37–2.23(m,2H),2.20(s,3H),1.83–1.66(m,4H),1.18(s,3H),0.90–0.87(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 0.5H), 7.71–7.68 (m, 1H), 7.33 (d, J = 2.7Hz, 1H), 7.30–7.26 (m, 1H) ,7.14–7.05(m,1H),4.59(s,1H),4.49–4.40(m,2H),3.93–3.72(m,3H),3.11–3.03(m,1H),2.48(dd,J＝ 14.8,7.8Hz,1H),2.37–2.23(m,2H),2.20(s,3H),1.83–1.66(m,4H),1.18(s,3H),0.90–0.87(m,3H).
实施例159制备(R)-1-(7-(5-胺基-3-氯-2-(三氟甲基)苯基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 159 Preparation of (R)-1-(7-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-8-fluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiper din-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例159为含两个甲酸的盐。LCMS:m/z 651.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents were used as raw materials, and Example 159 was prepared by referring to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing two formic acids. LCMS: m/z 651.2(M+H).
1H NMR(600MHz,Methanol-d4)δ8.55(s,2H),6.92(d,J＝2.4Hz,1H),6.56–6.46(m,1H),5.43–5.32(m,1H),4.41(d,J＝10.7Hz,1H),4.31(d,J＝10.9Hz,1H),3.85–3.72(m,3H),3.42–3.35(m,2H),3.14–3.09(m,1H),2.47–2.25(m,4H),2.21(s,3H),2.11–2.04(m,3H),2.00–1.91(m,2H),1.81–1.75(m,2H),1.72–1.66(m,1H),1.16(s,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.55 (s, 2H), 6.92 (d, J = 2.4Hz, 1H), 6.56–6.46 (m, 1H), 5.43–5.32 (m, 1H), 4.41(d,J＝10.7Hz,1H),4.31(d,J＝10.9Hz,1H),3.85–3.72(m,3H),3.42–3.35(m,2H),3.14–3.09(m,1H) ,2.47–2.25(m,4H),2.21(s,3H),2.11–2.04(m,3H),2.00–1.91(m,2H),1.81–1.75(m,2H),1.72–1.66(m, 1H),1.16(s,3H).
实施例160制备(R)-1-(8-氟-7-(8-氟-3-羟基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 160 Preparation of (R)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl) )methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例160为含0.5个甲酸的盐。LCMS:m/z 560.2(M+H)。Using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, Example 160 was prepared as a salt containing 0.5 formic acid by referring to the synthetic method of synthetic steps B to F of Example 38. LCMS: m/z 560.2 (M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,0.5H),7.61(d,J＝8.3Hz,1H),7.43–7.38(m,1H),7.36–7.33(m,1H),7.23–7.13(m,1H),6.97–6.92(m,1H),4.65–4.57(m,3H),3.90–3.80(m,2H),3.22–3.14(m,1H),2.72(s,3H),2.72–2.64(m,1H),2.22(d,J＝3.2Hz,4H),2.10–2.02(m,3H),2.02–1.84(m,4H),1.75–1.62(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 0.5H), 7.61 (d, J = 8.3Hz, 1H), 7.43–7.38 (m, 1H), 7.36–7.33 (m, 1H) ,7.23–7.13(m,1H),6.97–6.92(m,1H),4.65–4.57(m,3H),3.90–3.80(m,2H),3.22–3.14(m,1H),2.72(s, 3H),2.72–2.64(m,1H),2.22(d,J＝3.2Hz,4H),2.10–2.02(m,3H),2.02–1.84(m,4H),1.75–1.62(m,3H) .
实施例161制备(R)-1-(8-氟-7-(8-氟-3-羟基萘-1-基)-5-(丙炔基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)哌啶 -3-醇
Example 161 Preparation of (R)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-5-(propynyl)-2-((tetrahydro-1H-pyrrole) Azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine -3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例161为含0.3个甲酸的盐。LCMS:m/z 586.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.3 formic acid in Example 161. LCMS: m/z 586.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,0.3H),7.61(dd,J＝8.4,1.0Hz,1H),7.44–7.38(m,1H),7.35(q,J＝2.2Hz,1H),7.23–7.12(m,1H),6.94(dd,J＝13.1,7.6Hz,1H),4.61–4.52(m,3H),3.91–3.79(m,2H),3.60–3.52(m,2H),3.19–3.11(m,2H),2.33–2.24(m,2H),2.22(d,J＝2.4Hz,3H),2.19–1.98(m,9H),1.77–1.61(m,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.56 (s, 0.3H), 7.61 (dd, J＝8.4, 1.0Hz, 1H), 7.44–7.38 (m, 1H), 7.35 (q, J＝ 2.2Hz,1H),7.23–7.12(m,1H),6.94(dd,J＝13.1,7.6Hz,1H),4.61–4.52(m,3H),3.91–3.79(m,2H),3.60–3.52 (m,2H),3.19–3.11(m,2H),2.33–2.24(m,2H),2.22(d,J＝2.4Hz,3H),2.19–1.98(m,9H),1.77–1.61(m ,3H).
实施例162制备(R)-1-(8-氟-7-(8-氟-3-羟基萘-1-基)-5-(丙炔基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 162 Preparation of (R)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-5-(propynyl)-2-((tetrahydro-1H-pyrrole) Azin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例162为含0.5个甲酸的盐。LCMS:m/z 600.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 162. LCMS: m/z 600.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.57(s,0.5H),7.61(d,J＝8.3Hz,1H),7.43–7.39(m,1H),7.36–7.34(m,1H),7.24–7.12(m,1H),6.98–6.93(m,1H),4.63–4.53(m,3H),3.92–3.77(m,3H),3.57–3.50(m,2H),3.17–3.11(m,2H),2.32–2.24(m,2H),2.22(d,J＝6.6Hz,3H),2.19–2.06(m,5H),2.05–1.98(m,2H),1.80(d,J＝6.0Hz,2H),1.74–1.68(m,1H),1.22–1.14(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.57 (s, 0.5H), 7.61 (d, J = 8.3Hz, 1H), 7.43–7.39 (m, 1H), 7.36–7.34 (m, 1H) ,7.24–7.12(m,1H),6.98–6.93(m,1H),4.63–4.53(m,3H),3.92–3.77(m,3H),3.57–3.50(m,2H),3.17–3.11( m,2H),2.32–2.24(m,2H),2.22(d,J＝6.6Hz,3H),2.19–2.06(m,5H),2.05–1.98(m,2H),1.80(d,J＝ 6.0Hz,2H),1.74–1.68(m,1H),1.22–1.14(m,3H).
实施例163制备6-氟-4-(8-氟-5-(丙炔基)-4-(1-氧杂-6-氮杂螺[3.5]壬-6-基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 163 Preparation of 6-fluoro-4-(8-fluoro-5-(propynyl)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)-2-(( Tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方 法制备实施例163为含0.3个甲酸的盐。LCMS:m/z 612.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F in Example 38. Preparation Example 163 is a salt containing 0.3 formic acid. LCMS: m/z 612.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,0.3H),7.83(dd,J＝9.1,5.6Hz,1H),7.34(s,2H),7.29(td,J＝8.7,2.5Hz,1H),7.23(d,J＝10.9Hz,1H),4.48–4.15(m,6H),4.10–3.96(m,1H),3.30–3.25(m,2H),2.93–2.87(m,2H),2.42(t,J＝7.8Hz,2H),2.23(s,3H),2.21–2.13(m,3H),2.08–1.94(m,6H),1.90–1.84(m,2H),1.79–1.71(m,1H),1.36–1.28(m,1H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 0.3H), 7.83 (dd, J = 9.1, 5.6Hz, 1H), 7.34 (s, 2H), 7.29 (td, J = 8.7, 2.5Hz,1H),7.23(d,J＝10.9Hz,1H),4.48–4.15(m,6H),4.10–3.96(m,1H),3.30–3.25(m,2H),2.93–2.87(m ,2H),2.42(t,J＝7.8Hz,2H),2.23(s,3H),2.21–2.13(m,3H),2.08–1.94(m,6H),1.90–1.84(m,2H), 1.79–1.71(m,1H),1.36–1.28(m,1H).
实施例164制备6-氟-4-(8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)-4-(1-氧杂-6-氮杂螺[3.5]壬-6-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 164 Preparation of 6-fluoro-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)-4-( 1-oxa-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例164为含0.3个甲酸的盐。LCMS:m/z 586.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.3 formic acid in Example 164. LCMS: m/z 586.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.55(s,0.3H),7.83(dd,J＝9.1,5.6Hz,1H),7.35(s,2H),7.29(td,J＝8.7,2.6Hz,1H),7.23(d,J＝10.9Hz,1H),4.69–4.57(m,4H),4.48–4.24(m,4H),4.07–3.98(m,1H),3.39–3.35(m,1H),2.77(s,3H),2.42(t,J＝7.8Hz,2H),2.29–2.25(m,1H),2.24(s,3H),2.22–2.15(m,1H),2.10–1.89(m,6H),1.79–1.72(m,1H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.55 (s, 0.3H), 7.83 (dd, J = 9.1, 5.6Hz, 1H), 7.35 (s, 2H), 7.29 (td, J = 8.7, 2.6Hz,1H),7.23(d,J＝10.9Hz,1H),4.69–4.57(m,4H),4.48–4.24(m,4H),4.07–3.98(m,1H),3.39–3.35(m ,1H),2.77(s,3H),2.42(t,J＝7.8Hz,2H),2.29–2.25(m,1H),2.24(s,3H),2.22–2.15(m,1H),2.10– 1.89(m,6H),1.79–1.72(m,1H).
实施例165制备5-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)-4-(1-氧杂-6-氮杂螺[3.5]壬-6-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 165 Preparation of 5-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5- (propynyl)-4-(1-oxa-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例165为含一个甲酸的盐。LCMS:m/z 630.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 165. LCMS: m/z 630.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,1H),7.61(d,J＝8.2Hz,1H),7.44–7.37(m,1H),7.36–7.34(m,1H),7.27–7.16(m,1H),6.98–6.90(m,1H),5.47–5.31(m,1H),4.60(s,1H),4.49–4.22(m,5H),4.20–3.95(m,2H),3.45–3.37(m,2H),3.19–3.11(m,1H),2.52–2.28(m,5H),2.22(s,3H),2.18–1.88(m,7H),1.81–1.68(m,1H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.56 (s, 1H), 7.61 (d, J = 8.2Hz, 1H), 7.44–7.37 (m, 1H), 7.36–7.34 (m, 1H), 7.27–7.16(m,1H),6.98–6.90(m,1H),5.47–5.31(m,1H),4.60(s,1H),4.49–4.22(m,5H),4.20–3.95(m,2H ),3.45–3.37(m,2H),3.19–3.11(m,1H),2.52–2.28(m,5H),2.22(s,3H),2.18–1.88(m,7H),1.81–1.68(m ,1H).
实施例166制备4-(8-氟-7-(8-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟 四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1，4-噁吖庚环-6-醇
Example 166 Preparation of 4-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1, 4-oxazepine-6-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例166为含0.5个甲酸的盐。LCMS:m/z 634.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents were used as raw materials, and a salt containing 0.5 formic acid was prepared in Example 166 by referring to the synthesis method of synthesis steps B to F of Example 38. LCMS: m/z 634.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,0.5H),7.61(d,J＝8.3Hz,1H),7.44–7.38(m,1H),7.34(d,J＝2.2Hz,1H),7.22–7.15(m,1H),6.98–6.91(m,1H),5.44–5.27(m,1H),4.45–4.14(m,5H),4.07–3.91(m,4H),3.52–3.44(m,1H),3.13–3.06(m,1H),2.47–2.24(m,3H),2.21(s,3H),2.20–2.14(m,1H),2.12–1.89(m,4H),1.35–1.29(m,1H),1.22–1.13(m,3H)。 1 H NMR (400 MHz, Methanol-d 4 )δ8.56(s,0.5H),7.61(d,J＝8.3Hz,1H),7.44–7.38(m,1H),7.34(d,J＝2.2Hz ,1H),7.22–7.15(m,1H),6.98–6.91(m,1H),5.44–5.27(m,1H),4.45–4.14(m,5H),4.0 7–3.91(m,4H),3.52–3.44(m,1H),3.13–3.06(m,1H),2.47–2.24(m,3H),2.21(s,3H),2.20–2.14(m,1H ),2.12–1.89(m,4H),1.35–1.29(m,1H),1.22–1.13(m,3H).
实施例167制备4-(8-氟-7-(8-氟-3-羟基萘-1-基)-5-(丙炔基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1，4-噁吖庚环-6-醇
Example 167 Preparation of 4-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-5-(propynyl)-2-((tetrahydro-1H-pyrrolazine-7a( 5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例167为含0.5个甲酸的盐。LCMS:m/z 616.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 167. LCMS: m/z 616.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,0.5H),7.61(d,J＝8.3Hz,1H),7.43–7.39(m,1H),7.36–7.34(m,1H),7.22–7.16(m,1H),6.97–6.92(m,1H),4.50(d,J＝10.9Hz,1H),4.45–4.39(m,1H),4.28–4.19(m,1H),4.08–3.92(m,5H),3.73–3.63(m,2H),3.52–3.44(m,1H),3.01–2.95(m,2H),2.22(s,3H),2.21–2.15(m,2H),2.12–1.97(m,5H),1.95–1.89(m,2H),1.22–1.12(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 0.5H), 7.61 (d, J = 8.3Hz, 1H), 7.43–7.39 (m, 1H), 7.36–7.34 (m, 1H) ,7.22–7.16(m,1H),6.97–6.92(m,1H),4.50(d,J＝10.9Hz,1H),4.45–4.39(m,1H),4.28–4.19(m,1H),4.08 –3.92(m,5H),3.73–3.63(m,2H),3.52–3.44(m,1H),3.01–2.95(m,2H),2.22(s,3H),2.21–2.15(m,2H) ,2.12–1.97(m,5H),1.95–1.89(m,2H),1.22–1.12(m,3H).
实施例168制备4-(8-氟-7-(8-氟-3-羟基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1，4-噁吖庚环-6-醇
Example 168 Preparation of 4-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy )-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepin-6-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例168为含0.3个甲酸的盐。LCMS:m/z 590.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.3 formic acid in Example 168. LCMS: m/z 590.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,0.3H),7.61(dd,J＝8.3,1.1Hz,1H),7.44–7.38(m,1H),7.35(t,J＝2.2Hz,1H),7.22–7.16(m,1H),6.98–6.91(m,1H),4.66–4.51(m,2H),4.33–4.17(m,2H),4.08–3.92(m,4H),3.67(t,J＝12.2Hz,1H),3.53–3.43(m,1H),3.29–3.23(m,1H),3.12–3.04(m,1H),2.67(s,3H),2.64–2.56(m,1H),2.21(s,3H),1.98–1.79(m,4H),1.22–1.11(m,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.56 (s, 0.3H), 7.61 (dd, J＝8.3, 1.1Hz, 1H), 7.44–7.38 (m, 1H), 7.35 (t, J＝ 2.2Hz,1H),7.22–7.16(m,1H),6.98–6.91(m,1H),4.66–4.51(m,2H),4.33–4.17(m,2H),4.08–3.92(m,4H) ,3.67(t,J＝12.2Hz,1H),3.53–3.43(m,1H),3.29–3.23(m,1H),3.12–3.04(m,1H),2.67(s,3H),2.64–2.56 (m,1H),2.21(s,3H),1.98–1.79(m,4H),1.22–1.11(m,3H).
实施例169制备4-(8-氟-7-(7-氟-3-羟基萘-1-基)-5-(丙炔基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1，4-噁吖庚环-6-醇
Example 169 Preparation of 4-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-5-(propynyl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例169为含4个甲酸的盐。LCMS:m/z 616.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 4 formic acids in Example 169. LCMS: m/z 616.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.57(s,4H),7.83(dd,J＝9.1,5.5Hz,1H),7.36–7.33(m,2H),7.31–7.25(m,2H),4.62–4.54(m,2H),4.50(d,J＝11.5Hz,1H),4.41(d,J＝14.0Hz,1H),4.31(d,J＝14.7Hz,1H),4.08–3.92(m,4H),3.71(d,J＝12.6Hz,1H),3.52–3.40(m,2H),3.09–3.03(m,2H),2.23(s,3H),2.16–2.03(m,4H),2.01–1.94(m,2H),1.38–1.29(m,2H),1.19(s,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.57 (s, 4H), 7.83 (dd, J = 9.1, 5.5Hz, 1H), 7.36–7.33 (m, 2H), 7.31–7.25 (m, 2H) ),4.62–4.54(m,2H),4.50(d,J＝11.5Hz,1H),4.41(d,J＝14.0Hz,1H),4.31(d,J＝14.7Hz,1H),4.08–3.92 (m,4H),3.71(d,J＝12.6Hz,1H),3.52–3.40(m,2H),3.09–3.03(m,2H),2.23(s,3H),2.16–2.03(m,4H ),2.01–1.94(m,2H),1.38–1.29(m,2H),1.19(s,3H).
实施例170制备4-(8-氟-7-(7-氟-3-羟基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1，4-噁吖庚环-6-醇
Example 170 Preparation of 4-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy )-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepin-6-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例170为含一个甲酸的盐。LCMS:m/z 590.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 170. LCMS: m/z 590.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,1H),7.83(dd,J＝8.9,5.7Hz,1H),7.36–7.33(m,2H),7.32–7.24(m,2H),4.73–4.65(m,1H),4.64–4.52(m,2H),4.40(d,J＝13.9Hz,1H),4.30(d,J＝14.7Hz,1H),4.09–3.90(m,4H),3.70(d,J＝12.6Hz,1H),3.52–3.43(m,1H),3.28–3.20(m,1H),2.75(s,3H), 2.74–2.68(m,1H),2.29–2.24(m,1H),2.23(s,3H),2.03–1.84(m,3H),1.18(d,J＝2.2Hz,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.56 (s, 1H), 7.83 (dd, J = 8.9, 5.7Hz, 1H), 7.36–7.33 (m, 2H), 7.32–7.24 (m, 2H) ),4.73–4.65(m,1H),4.64–4.52(m,2H),4.40(d,J＝13.9Hz,1H),4.30(d,J＝14.7Hz,1H),4.09–3.90(m, 4H),3.70(d,J＝12.6Hz,1H),3.52–3.43(m,1H),3.28–3.20(m,1H),2.75(s,3H), 2.74–2.68(m,1H),2.29–2.24(m,1H),2.23(s,3H),2.03–1.84(m,3H),1.18(d,J＝2.2Hz,3H).
实施例171制备(R)-1-(8-氟-7-(7-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 171 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例171为含一个甲酸的盐。LCMS:m/z 604.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and the corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 171. LCMS: m/z 604.2(M+H).
1H NMR(600MHz,Methanol-d4)δ8.55(s,1H),7.82(dd,J＝9.1,5.6Hz,1H),7.34(d,J＝2.4Hz,1H),7.31(d,J＝2.5Hz,1H),7.31–7.23(m,2H),5.45–5.34(m,1H),4.60(s,1H),4.46(d,J＝10.8Hz,1H),4.35(d,J＝10.8Hz,1H),3.85(s,2H),3.51–3.36(m,3H),3.17–3.12(m,1H),2.49–2.28(m,3H),2.23(s,3H),2.14–1.93(m,6H),1.77–1.62(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.55 (s, 1H), 7.82 (dd, J = 9.1, 5.6Hz, 1H), 7.34 (d, J = 2.4Hz, 1H), 7.31 (d, J＝2.5Hz,1H),7.31–7.23(m,2H),5.45–5.34(m,1H),4.60(s,1H),4.46(d,J＝10.8Hz,1H),4.35(d,J ＝10.8Hz,1H),3.85(s,2H),3.51–3.36(m,3H),3.17–3.12(m,1H),2.49–2.28(m,3H),2.23(s,3H),2.14– 1.93(m,6H),1.77–1.62(m,3H).
实施例172制备(R)-1-(8-氟-7-(7-氟-3-羟基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 172 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphth-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl) )methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例172为含0.5个甲酸的盐。LCMS:m/z 560.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 172. LCMS: m/z 560.2(M+H).
1H NMR(600MHz,Methanol-d4)δ8.53(s,0.5H),7.81(dd,J＝9.1,5.6Hz,1H),7.32(d,J＝2.4Hz,1H),7.30(d,J＝2.5Hz,1H),7.29–7.22(m,2H),4.69–4.64(m,1H),4.63–4.56(m,2H),4.31–4.20(m,1H),3.84(s,2H),3.46–3.37(m,2H),2.80(s,3H),2.30–2.24(m,1H),2.21(s,3H),2.15–1.88(m,6H),1.76–1.60(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.53 (s, 0.5H), 7.81 (dd, J = 9.1, 5.6Hz, 1H), 7.32 (d, J = 2.4Hz, 1H), 7.30 (d ,J＝2.5Hz,1H),7.29–7.22(m,2H),4.69–4.64(m,1H),4.63–4.56(m,2H),4.31–4.20(m,1H),3.84(s,2H ),3.46–3.37(m,2H),2.80(s,3H),2.30–2.24(m,1H),2.21(s,3H),2.15–1.88(m,6H),1.76–1.60(m,3H ).
实施例173(R)-1-(8-氟-7-(7-氟-3-羟基萘-1-基)-5-(丙炔基)-2-((四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 173 (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphth-1-yl)-5-(propynyl)-2-((tetrahydro-1H-pyrrolizine) -7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例173为含0.5个甲酸的盐。LCMS:m/z 586.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare Example 173 as a salt containing 0.5 formic acid. LCMS: m/z 586.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,0.5H),7.83(dd,J＝9.0,5.7Hz,1H),7.33(dd,J＝9.8,2.5Hz,2H),7.30–7.23(m,2H),4.55–4.46(m,2H),4.36–4.20(m,2H),3.93–3.80(m,1H),3.48–3.38(m,2H),3.09–2.97(m,2H),2.29–2.19(m,5H),2.16–1.89(m,9H),1.80–1.59(m,3H)。 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.56 (s, 0.5H), 7.83 (dd, J=9.0, 5.7 Hz, 1H), 7.33 (dd, J=9.8, 2.5 Hz, 2H), 7.30–7.23 (m, 2H), 4.55–4.46 (m, 2H), 4.36–4.20 (m, 2H), 3.93–3.80 (m, 1H), 3.48–3.38 (m, 2H), 3.09–2.97 (m, 2H), 2.29–2.19 (m, 5H), 2.16–1.89 (m, 9H), 1.80–1.59 (m, 3H).
实施例174制备(R)-1-(8-氟-7-(8-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 174 Preparation of (R)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例174为含0.5个甲酸的盐。LCMS:m/z 604.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare Example 174 as a salt containing 0.5 formic acid. LCMS: m/z 604.2(M+H).
1H NMR(600MHz,Methanol-d4)δ8.54(s,0.5H),7.61(d,J＝8.3Hz,1H),7.44–7.39(m,1H),7.37–7.34(m,1H),7.22–7.12(m,1H),6.94(dd,J＝13.3,7.7Hz,1H),5.46–5.34(m,1H),4.59(s,1H),4.49–4.35(m,2H),3.89–3.78(m,1H),3.47–3.40(m,2H),3.19–3.11(m,1H),2.51–2.28(m,4H),2.26–2.18(m,4H),2.15–1.95(m,6H),1.76–1.60(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.54 (s, 0.5H), 7.61 (d, J = 8.3Hz, 1H), 7.44–7.39 (m, 1H), 7.37–7.34 (m, 1H) ,7.22–7.12(m,1H),6.94(dd,J＝13.3,7.7Hz,1H),5.46–5.34(m,1H),4.59(s,1H),4.49–4.35(m,2H),3.89 –3.78(m,1H),3.47–3.40(m,2H),3.19–3.11(m,1H),2.51–2.28(m,4H),2.26–2.18(m,4H),2.15–1.95(m, 6H),1.76–1.60(m,3H).
实施例175制备(R)-1-(7-(7，8-二氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 175 Preparation of (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro -1H-Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例175为含0.2个甲酸的盐。LCMS:m/z 622.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare Example 175 as a salt containing 0.2 formic acid. LCMS: m/z 622.2(M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,0.2H),7.63(dd,J＝9.5,4.6Hz,1H),7.41(q,J＝8.8Hz,1H),7.35(t,J＝2.3Hz,1H),7.29–7.19(m,1H),5.42– 5.31(m,1H),4.41(d,J＝10.6Hz,1H),4.31(d,J＝10.6Hz,1H),3.84(s,2H),3.43–3.38(m,2H),3.12–3.07(m,2H),2.45–2.25(m,3H),2.22(s,3H),2.21–2.16(m,1H),2.12–2.01(m,4H),1.99–1.91(m,2H),1.75–1.61(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 0.2H), 7.63 (dd, J = 9.5, 4.6Hz, 1H), 7.41 (q, J = 8.8Hz, 1H), 7.35 (t ,J＝2.3Hz,1H),7.29–7.19(m,1H),5.42– 5.31(m,1H),4.41(d,J＝10.6Hz,1H),4.31(d,J＝10.6Hz,1H),3.84(s,2H),3.43–3.38(m,2H),3.12–3.07 (m,2H),2.45–2.25(m,3H),2.22(s,3H),2.21–2.16(m,1H),2.12–2.01(m,4H),1.99–1.91(m,2H),1.75 –1.61(m,3H).
实施例176制备6-氟-4-(8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)-4-(1，6-二氧杂-9-氮杂螺[3.6]癸-9-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 176 Preparation of 6-fluoro-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)-4-( 1,6-dioxa-9-azaspiro[3.6]dec-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例176为含0.5个甲酸的盐。LCMS:m/z 602.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 176. LCMS: m/z 602.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,0.5H),7.83(dd,J＝9.1,5.6Hz,1H),7.34(q,J＝2.5Hz,2H),7.29(td,J＝8.7,2.6Hz,1H),7.20(d,J＝10.9Hz,1H),4.67–4.52(m,4H),4.42–4.37(m,1H),4.33–4.22(m,3H),4.06–3.98(m,3H),3.86–3.74(m,2H),3.20–3.15(m,1H),2.77–2.57(m,5H),2.52–2.46(m,1H),2.25(s,3H),2.24–2.19(m,1H),1.99–1.84(m,3H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 0.5H), 7.83 (dd, J = 9.1, 5.6Hz, 1H), 7.34 (q, J = 2.5Hz, 2H), 7.29 (td ,J＝8.7,2.6Hz,1H),7.20(d,J＝10.9Hz,1H),4.67–4.52(m,4H),4.42–4.37(m,1H),4.33–4.22(m,3H), 4.06–3.98(m,3H),3.86–3.74(m,2H),3.20–3.15(m,1H),2.77–2.57(m,5H),2.52–2.46(m,1H),2.25(s,3H ),2.24–2.19(m,1H),1.99–1.84(m,3H).
实施例177制备6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)-4-(1，6-二氧杂-9-氮杂螺[3.6]癸-9-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 177 Preparation of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5- (propynyl)-4-(1,6-dioxa-9-azaspiro[3.6]dec-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2- phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例177为含0.5个甲酸的盐。LCMS:m/z 646.3(M+H)。Using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, Example 177 was prepared as a salt containing 0.5 formic acid by referring to the synthesis method of synthesis steps B to F of Example 38. LCMS: m/z 646.3 (M+H).
1H NMR(600MHz,Methanol-d4)δ8.57(s,0.5H),7.82(dd,J＝9.1,5.6Hz,1H),7.34(q,J＝2.5Hz,2H),7.28(td,J＝8.7,2.6Hz,1H),7.19(d,J＝10.9Hz,1H),5.38–5.27(m,1H),4.59(s,1H),4.44–4.20(m,6H),4.03(d,J＝12.3Hz,2H),3.82–3.72(m,2H),3.31–3.22(m,3H),3.09–3.03(m,1H),2.68–2.62(m,1H),2.52–2.45(m,1H),2.37–2.33(m,1H),2.32–2.26(m,1H),2.24(s,3H),2.17–2.13(m,1H),2.06–1.98(m,2H),1.96–1.89(m,2H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.57 (s, 0.5H), 7.82 (dd, J = 9.1, 5.6Hz, 1H), 7.34 (q, J = 2.5Hz, 2H), 7.28 (td ,J＝8.7,2.6Hz,1H),7.19(d,J＝10.9Hz,1H),5.38–5.27(m,1H),4.59(s,1H),4.44–4.20(m,6H),4.03( d,J＝12.3Hz,2H),3.82–3.72(m,2H),3.31–3.22(m,3H),3.09–3.03(m,1H),2.68–2.62(m,1H),2.52–2.45( m,1H),2.37–2.33(m,1H),2.32–2.26(m,1H),2.24(s,3H),2.17–2.13(m,1H),2.06–1.98(m,2H),1.96– 1.89(m,2H).
实施例178制备(3R)-1-(8-氟-7-(7-氟-3-羟基萘-1-基)-2-((2-亚甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基) -3-甲基哌啶-3-醇
Example 178 Preparation of (3R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-((2-methylenetetrahydro-1H-pyrrolazine-7a) (5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl) -3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例178为含0.3个甲酸的盐。LCMS:m/z 612.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare Example 178 as a salt containing 0.3 formic acid. LCMS: m/z 612.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,0.3H),7.82(dd,J＝9.8,5.7Hz,1H),7.34(d,J＝2.5Hz,1H),7.32(d,J＝2.5Hz,1H),7.31–7.26(m,2H),5.10(s,2H),4.51–4.38(m,3H),3.97–3.86(m,2H),3.78(d,J＝13.6Hz,1H),3.55–3.49(m,1H),3.39–3.35(m,1H),2.93–2.85(m,2H),2.63–2.56(m,1H),2.28–2.23(m,2H),2.23(s,3H),2.12–1.91(m,4H),1.83–1.76(m,2H),1.72–1.64(m,1H),1.18(s,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.56 (s, 0.3H), 7.82 (dd, J = 9.8, 5.7Hz, 1H), 7.34 (d, J = 2.5Hz, 1H), 7.32 (d ,J＝2.5Hz,1H),7.31–7.26(m,2H),5.10(s,2H),4.51–4.38(m,3H),3.97–3.86(m,2H),3.78(d,J＝13.6 Hz,1H),3.55–3.49(m,1H),3.39–3.35(m,1H),2.93–2.85(m,2H),2.63–2.56(m,1H),2.28–2.23(m,2H), 2.23(s,3H),2.12–1.91(m,4H),1.83–1.76(m,2H),1.72–1.64(m,1H),1.18(s,3H).
实施例179制备(R)-1-(8-氟-7-(7-氟-3-羟基萘-1-基)-2-(((R)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 179 Preparation of (R)-1-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((R)-1-methylpyrrolidin-2-yl) )methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例179为含0.5个甲酸的盐。LCMS:m/z 574.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare Example 179 as a salt containing 0.5 formic acid. LCMS: m/z 574.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,0.5H),7.82(dd,J＝9.8,5.7Hz,1H),7.34(d,J＝2.5Hz,1H),7.32(d,J＝2.5Hz,1H),7.31–7.26(m,2H),4.67(dd,J＝11.7,4.6Hz,1H),4.59(dd,J＝11.7,6.1Hz,1H),3.92(d,J＝13.5Hz,1H),3.78(d,J＝13.5Hz,1H),3.39–3.35(m,1H),3.30–3.22(m,1H),2.76(s,3H),2.74–2.69(m,1H),2.30–2.23(m,2H),2.22(s,3H),2.05–1.86(m,4H),1.86–1.75(m,2H),1.73–1.65(m,2H),1.18(s,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.56 (s, 0.5H), 7.82 (dd, J = 9.8, 5.7Hz, 1H), 7.34 (d, J = 2.5Hz, 1H), 7.32 (d ,J＝2.5Hz,1H),7.31–7.26(m,2H),4.67(dd,J＝11.7,4.6Hz,1H),4.59(dd,J＝11.7,6.1Hz,1H),3.92(d, J＝13.5Hz,1H),3.78(d,J＝13.5Hz,1H),3.39–3.35(m,1H),3.30–3.22(m,1H),2.76(s,3H),2.74–2.69(m ,1H),2.30–2.23(m,2H),2.22(s,3H),2.05–1.86(m,4H),1.86–1.75(m,2H),1.73–1.65(m,2H),1.18(s ,3H).
实施例180制备(3R)-1-(8-氟-7-(8-氟-3-羟基萘-1-基)-2-((2-亚甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 180 Preparation of (3R)-1-(8-fluoro-7-(8-fluoro-3-hydroxynaphthalen-1-yl)-2-((2-methylenetetrahydro-1H-pyrrolazine-7a) (5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例180为含0.3个甲酸的盐。LCMS:m/z 612.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.3 formic acid in Example 180. LCMS: m/z 612.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,0.3H),7.61(d,J＝8.3Hz,1H),7.43–7.38(m,1H),7.34(q,J＝2.2Hz,1H),7.23–7.12(m,1H),6.98–6.92(m,1H),5.09(s,2H),4.49–4.35(m,3H),3.89(t,J＝14.3Hz,2H),3.82–3.75(m,1H),3.53–3.46(m,1H),2.92–2.83(m,2H),2.58(d,J＝15.9Hz,1H),2.28–2.23(m,1H),2.21(d,J＝4.1Hz,3H),2.19–2.13(m,1H),2.12–1.90(m,4H),1.83–1.66(m,4H),1.17(d,J＝15.5Hz,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.56 (s, 0.3H), 7.61 (d, J = 8.3Hz, 1H), 7.43–7.38 (m, 1H), 7.34 (q, J = 2.2Hz ,1H),7.23–7.12(m,1H),6.98–6.92(m,1H),5.09(s,2H),4.49–4.35(m,3H),3.89(t,J＝14.3Hz,2H), 3.82–3.75(m,1H),3.53–3.46(m,1H),2.92–2.83(m,2H),2.58(d,J＝15.9Hz,1H),2.28–2.23(m,1H),2.21( d,J＝4.1Hz,3H),2.19–2.13(m,1H),2.12–1.90(m,4H),1.83–1.66(m,4H),1.17(d,J＝15.5Hz,3H).
实施例181制备4-(8-氟-7-(7-氟-3-羟基萘-1-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-1，4-噁吖庚环-6-醇
Example 181 Preparation of 4-(8-fluoro-7-(7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例181为含三个甲酸的盐。LCMS:m/z 620.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing three formic acids in Example 181. LCMS: m/z 620.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,3H),7.82(dd,J＝9.0,5.6Hz,1H),7.35–7.31(m,2H),7.31–7.23(m,2H),5.44–5.28(m,1H),4.43–4.27(m,4H),4.22–4.00(m,4H),3.89–3.82(m,2H),3.70–3.64(m,1H),3.13–3.06(m,1H),2.46–2.25(m,4H),2.22(s,3H),2.20–2.16(m,1H),2.11–1.91(m,4H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.56 (s, 3H), 7.82 (dd, J = 9.0, 5.6Hz, 1H), 7.35–7.31 (m, 2H), 7.31–7.23 (m, 2H) ),5.44–5.28(m,1H),4.43–4.27(m,4H),4.22–4.00(m,4H),3.89–3.82(m,2H),3.70–3.64(m,1H),3.13–3.06 (m,1H),2.46–2.25(m,4H),2.22(s,3H),2.20–2.16(m,1H),2.11–1.91(m,4H).
实施例182制备4-(4-(3-胺基-3-甲基哌啶-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 182 Preparation of 4-(4-(3-amino-3-methylpiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole) Azin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例182为含一个甲酸的盐。LCMS:m/z 641.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents were used as raw materials, and Example 182 was prepared by referring to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid. LCMS: m/z 641.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.52(s,1H),7.91–7.86(m,1H),7.39–7.37(m,1H),7.34(d,J＝9.0Hz,1H),7.29–7.18(m,1H),5.47–5.30(m,1H),4.46–4.37(m,2H),4.13–3.74(m,5H),3.47–3.36(m,2H),3.19–3.13(m,1H), 2.48–2.30(m,3H),2.23(s,3H),2.15–2.05(m,2H),2.04–1.81(m,6H),1.46–1.31(m,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.52 (s, 1H), 7.91–7.86 (m, 1H), 7.39–7.37 (m, 1H), 7.34 (d, J = 9.0Hz, 1H), 7.29–7.18(m,1H),5.47–5.30(m,1H),4.46–4.37(m,2H),4.13–3.74(m,5H),3.47–3.36(m,2H),3.19–3.13(m ,1H), 2.48–2.30(m,3H),2.23(s,3H),2.15–2.05(m,2H),2.04–1.81(m,6H),1.46–1.31(m,3H).
实施例183制备4-(4-(3-胺基-3-甲基哌啶-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-6-氟萘-2-酚
Example 183 Preparation of 4-(4-(3-amino-3-methylpiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例183为含两个甲酸的盐。LCMS:m/z 617.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing two formic acids in Example 183. LCMS: m/z 617.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.55(s,2H),7.83(dd,J＝9.0,5.7Hz,1H),7.35(d,J＝2.4Hz,1H),7.32(d,J＝2.7Hz,1H),7.31–7.23(m,2H),5.45–5.29(m,1H),4.45–4.34(m,2H),4.15–3.81(m,4H),3.46–3.40(m,1H),3.15–3.08(m,1H),2.47–2.27(m,3H),2.24(s,3H),2.23–2.15(m,1H),2.13–2.02(m,3H),2.02–1.82(m,5H),1.39–1.27(m,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.55 (s, 2H), 7.83 (dd, J = 9.0, 5.7Hz, 1H), 7.35 (d, J = 2.4Hz, 1H), 7.32 (d, J＝2.7Hz,1H),7.31–7.23(m,2H),5.45–5.29(m,1H),4.45–4.34(m,2H),4.15–3.81(m,4H),3.46–3.40(m, 1H),3.15–3.08(m,1H),2.47–2.27(m,3H),2.24(s,3H),2.23–2.15(m,1H),2.13–2.02(m,3H),2.02–1.82( m,5H),1.39–1.27(m,3H).
实施例184制备4-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1，4-噁吖庚环-6-醇
Example 184 Preparation of 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidine-2- (yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例184为含一个甲酸的盐。LCMS:m/z 614.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 184. LCMS: m/z 614.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,1H),7.87(dd,J＝9.1,5.8Hz,1H),7.37(d,J＝2.6Hz,1H),7.36–7.30(m,1H),7.27(dd,J＝13.8,2.6Hz,1H),4.68–4.55(m,3H),4.51–4.40(m,2H),4.02–3.90(m,3H),3.84–3.77(m,2H),3.51(d,J＝12.6Hz,1H),3.26–3.17(m,1H),2.73(d,J＝8.0Hz,4H),2.29–2.23(m,1H),2.22(s,3H),2.02–1.84(m,4H),1.12(s,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.56 (s, 1H), 7.87 (dd, J = 9.1, 5.8Hz, 1H), 7.37 (d, J = 2.6Hz, 1H), 7.36–7.30 ( m,1H),7.27(dd,J＝13.8,2.6Hz,1H),4.68–4.55(m,3H),4.51–4.40(m,2H),4.02–3.90(m,3H),3.84–3.77( m,2H),3.51(d,J＝12.6Hz,1H),3.26–3.17(m,1H),2.73(d,J＝8.0Hz,4H),2.29–2.23(m,1H),2.22(s ,3H),2.02–1.84(m,4H),1.12(s,3H).
实施例185制备(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 185 Preparation of (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine- 3-alcohol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例185为含0.5个甲酸的盐。LCMS:m/z 642.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 185. LCMS: m/z 642.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.53(s,0.5H),7.86(dd,J＝9.1,5.7Hz,1H),7.37(d,J＝2.5Hz,1H),7.35–7.29(m,2H),5.50–5.34(m,1H),4.52(d,J＝11.1Hz,1H),4.37(dd,J＝11.2,5.6Hz,1H),4.03(d,J＝13.6Hz,1H),3.98–3.91(m,1H),3.70(d,J＝13.6Hz,1H),3.54–3.43(m,3H),3.24–3.16(m,2H),2.43–2.35(m,2H),2.29–2.23(m,2H),2.20(d,J＝5.4Hz,3H),2.17–2.09(m,2H),2.06–1.95(m,2H),1.83–1.74(m,2H),1.65(d,J＝13.8Hz,1H),1.15(s,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.53 (s, 0.5H), 7.86 (dd, J = 9.1, 5.7Hz, 1H), 7.37 (d, J = 2.5Hz, 1H), 7.35–7.29 (m,2H),5.50–5.34(m,1H),4.52(d,J＝11.1Hz,1H),4.37(dd,J＝11.2,5.6Hz,1H),4.03(d,J＝13.6Hz, 1H),3.98–3.91(m,1H),3.70(d,J＝13.6Hz,1H),3.54–3.43(m,3H),3.24–3.16(m,2H),2.43–2.35(m,2H) ,2.29–2.23(m,2H),2.20(d,J＝5.4Hz,3H),2.17–2.09(m,2H),2.06–1.95(m,2H),1.83–1.74(m,2H),1.65 (d,J=13.8Hz,1H),1.15(s,3H).
实施例186制备(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)吡咯烷-3-醇
Example 186 Preparation of (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例186为含一个甲酸的盐。LCMS:m/z 614.2(M+H)。Using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, Example 186, a salt containing one formic acid, was prepared by referring to the synthetic method of synthetic steps B to F of Example 38. LCMS: m/z 614.2 (M+H).
1H NMR(400MHz,Methanol-d4)δ8.55(s,1H),7.88(dd,J＝9.1,5.7Hz,1H),7.39–7.33(m,2H),7.32–7.30(m,1H),5.48–5.31(m,1H),4.59–4.45(m,3H),4.38–4.31(m,2H),3.84–3.70(m,2H),3.46–3.38(m,2H),3.19–3.12(m,1H),2.43–2.30(m,2H),2.25–2.19(m,2H),2.17(d,J＝2.8Hz,3H),2.14–2.04(m,3H),2.03–1.92(m,2H),1.35–1.29(m,1H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.55 (s, 1H), 7.88 (dd, J = 9.1, 5.7Hz, 1H), 7.39–7.33 (m, 2H), 7.32–7.30 (m, 1H) ),5.48–5.31(m,1H),4.59–4.45(m,3H),4.38–4.31(m,2H),3.84–3.70(m,2H),3.46–3.38(m,2H),3.19–3.12 (m,1H),2.43–2.30(m,2H),2.25–2.19(m,2H),2.17(d,J＝2.8Hz,3H),2.14–2.04(m,3H),2.03–1.92(m ,2H),1.35–1.29(m,1H).
实施例187制备(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-3-甲基哌啶-3-醇
Example 187 Preparation of (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrole) Alk-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶 并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例187为含一个甲酸的盐。LCMS:m/z 598.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyridine Using [4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 187. LCMS: m/z 598.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,1H),7.89–7.84(m,1H),7.40–7.34(m,2H),7.33–7.30(m,1H),4.65–4.53(m,3H),4.03(d,J＝13.5Hz,1H),3.99–3.91(m,1H),3.70(d,J＝13.5Hz,1H),3.31–3.27(m,1H),3.23–3.14(m,1H),2.72(s,3H),2.70–2.62(m,1H),2.30–2.22(m,2H),2.20(d,J＝7.6Hz,3H),2.02–1.84(m,4H),1.83–1.73(m,2H),1.65(d,J＝13.5Hz,1H),1.15(s,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.56(s,1H),7.89–7.84(m,1H),7.40–7.34(m,2H),7.33–7.30(m,1H),4.65–4.53 (m,3H),4.03(d,J＝13.5Hz,1H),3.99–3.91(m,1H),3.70(d,J＝13.5Hz,1H),3.31–3.27(m,1H),3.23– 3.14(m,1H),2.72(s,3H),2.70–2.62(m,1H),2.30–2.22(m,2H),2.20(d,J＝7.6Hz,3H),2.02–1.84(m, 4H), 1.83–1.73 (m, 2H), 1.65 (d, J = 13.5Hz, 1H), 1.15 (s, 3H).
实施例188制备(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 188 Preparation of (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例188为含一个甲酸的盐。LCMS:m/z 628.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 188. LCMS: m/z 628.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.51(s,0.3H),7.90–7.85(m,1H),7.37(d,J＝2.5Hz,1H),7.35–7.19(m,2H),5.53–5.36(m,1H),4.55(d,J＝11.1Hz,1H),4.41(d,J＝11.4Hz,1H),3.94–3.89(m,2H),3.61–3.47(m,4H),3.29–3.21(m,1H),2.60–2.36(m,3H),2.33–2.24(m,2H),2.20(d,J＝4.2Hz,3H),2.19–2.13(m,2H),2.10–1.95(m,3H),1.85–1.59(m,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.51 (s, 0.3H), 7.90–7.85 (m, 1H), 7.37 (d, J = 2.5Hz, 1H), 7.35–7.19 (m, 2H) ,5.53–5.36(m,1H),4.55(d,J＝11.1Hz,1H),4.41(d,J＝11.4Hz,1H),3.94–3.89(m,2H),3.61–3.47(m,4H ),3.29–3.21(m,1H),2.60–2.36(m,3H),2.33–2.24(m,2H),2.20(d,J＝4.2Hz,3H),2.19–2.13(m,2H), 2.10–1.95(m,3H),1.85–1.59(m,3H).
实施例189制备(R)-1-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 189 Preparation of (R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrole) Alk-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例189为含一个甲酸的盐。LCMS:m/z 584.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 189. LCMS: m/z 584.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.54(s,1H),7.90–7.85(m,1H),7.39–7.37(m,1H),7.36–7.20(m,2H),4.72–4.60(m,3H),4.12–3.99(m,1H),3.95–3.89(m,1H),3.85–3.74(m,1H),3.49–3.39(m,2H),2.92–2.81(m,4H),2.34–2.24(m,2H),2.20(d,J＝4.2Hz,3H),2.12–1.90(m,5H),1.85–1.59(m,3H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.54(s,1H),7.90–7.85(m,1H),7.39–7.37(m,1H),7.36–7.20(m,2H),4.72–4.60 (m,3H),4.12–3.99(m,1H),3.95–3.89(m,1H),3.85–3.74(m,1H),3.49–3.39(m,2H),2.92–2.81(m,4H) ,2.34–2.24(m,2H),2.20(d,J＝4.2Hz,3H),2.12–1.90(m,5H),1.85–1.59(m,3H).
实施例190制备5-乙炔基-6-氟-4-(8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)-4-(1-氧杂-6-氮杂螺[3.5]壬-6-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 190 Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy yl)-5-(propynyl)-4-(1-oxa-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalene- 2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例190为含0.3个甲酸的盐。LCMS:m/z 654.3(M+H)。Using 7-chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, Example 190 was prepared as a salt containing 0.3 formic acid by referring to the synthetic method of synthetic steps B to F of Example 38. LCMS: m/z 654.3 (M+H).
1H NMR(400MHz,Methanol-d4)δ8.55(s,0.3H),7.91–7.86(m,1H),7.38(dd,J＝5.4,2.5Hz,1H),7.36–7.21(m,2H),5.45–5.28(m,1H),4.51–4.38(m,3H),4.35–4.16(m,3H),4.06–3.92(m,2H),3.46–3.36(m,2H),3.15–3.06(m,1H),2.53–2.27(m,5H),2.21(s,3H),2.19–2.16(m,1H),2.14–1.87(m,6H),1.81–1.72(m,2H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.55 (s, 0.3H), 7.91–7.86 (m, 1H), 7.38 (dd, J = 5.4, 2.5Hz, 1H), 7.36–7.21 (m, 2H),5.45–5.28(m,1H),4.51–4.38(m,3H),4.35–4.16(m,3H),4.06–3.92(m,2H),3.46–3.36(m,2H),3.15– 3.06(m,1H),2.53–2.27(m,5H),2.21(s,3H),2.19–2.16(m,1H),2.14–1.87(m,6H),1.81–1.72(m,2H).
实施例191制备5-乙炔基-6-氟-4-(8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)-4-(1-氧杂-6-氮杂螺[3.5]壬-6-基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 191 Preparation of 5-ethynyl-6-fluoro-4-(8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl )-4-(1-oxa-6-azaspiro[3.5]non-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例191为含0.3个甲酸的盐。LCMS:m/z 610.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.3 formic acid in Example 191. LCMS: m/z 610.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.57(s,0.3H),7.91–7.86(m,1H),7.40–7.22(m,3H),4.65–4.44(m,4H),4.41–4.15(m,3H),4.07–3.91(m,2H),3.30–3.21(m,1H),3.13–3.03(m,1H),2.67(s,3H),2.65–2.29(m,5H),2.21(s,3H),2.13–2.01(m,1H),2.00–1.72(m,5H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.57(s,0.3H),7.91–7.86(m,1H),7.40–7.22(m,3H),4.65–4.44(m,4H),4.41– 4.15(m,3H),4.07–3.91(m,2H),3.30–3.21(m,1H),3.13–3.03(m,1H),2.67(s,3H),2.65–2.29(m,5H), 2.21(s,3H),2.13–2.01(m,1H),2.00–1.72(m,5H).
实施例192制备(R)-1-(2-((1-((二甲氨基)亚甲基)环丙烷基)甲氧基)-8-氟-7-(8-氟-3-羟基萘-1-基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 192 Preparation of (R)-1-(2-((1-((dimethylamino)methylene)cyclopropyl)methoxy)-8-fluoro-7-(8-fluoro-3-hydroxy Naphth-1-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例192为含2.5个甲酸的盐。LCMS:m/z 574.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare Example 192 as a salt containing 2.5 formic acids. LCMS: m/z 574.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.53(s,2.5H),7.60(d,J＝8.3Hz,1H),7.42–7.38(m,1H),7.33(dt,J＝3.9,2.2Hz,1H),7.22–7.11(m,1H),6.93(dd,J＝13.1,7.6Hz,1H),4.58(s,1H),4.48–4.37(m,2H),3.86–3.79(m,1H),3.17–3.06(m,2H),2.87(s,6H),2.20(d,J＝4.5Hz,3H),2.07–2.01(m,3H),1.74–1.60(m,4H),0.94(s,2H),0.82(d,J＝7.4Hz,2H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.53 (s, 2.5H), 7.60 (d, J = 8.3Hz, 1H), 7.42–7.38 (m, 1H), 7.33 (dt, J = 3.9, 2.2Hz,1H),7.22–7.11(m,1H),6.93(dd,J＝13.1,7.6Hz,1H),4.58(s,1H),4.48–4.37(m,2H),3.86–3.79(m ,1H),3.17–3.06(m,2H),2.87(s,6H),2.20(d,J＝4.5Hz,3H),2.07–2.01(m,3H),1.74–1.60(m,4H), 0.94(s,2H),0.82(d,J=7.4Hz,2H).
实施例193制备(R)-1-(2-((1-((二甲氨基)亚甲基)环丙烷基)甲氧基)-8-氟-7-(7-氟-3-羟基萘-1-基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 193 Preparation of (R)-1-(2-((1-((dimethylamino)methylene)cyclopropyl)methoxy)-8-fluoro-7-(7-fluoro-3-hydroxy Naphth-1-yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例193为含一个甲酸的盐。LCMS:m/z 574.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 193. LCMS: m/z 574.3(M+H).
1H NMR(400MHz,Methanol-d4)δ8.56(s,1H),7.83(dd,J＝9.0,5.7Hz,1H),7.34(d,J＝2.5Hz,1H),7.33–7.31(m,1H),7.31–7.23(m,2H),4.61(s,1H),4.48–4.39(m,2H),4.35–4.18(m,1H),3.96–3.76(m,2H),3.01–2.83(m,2H),2.68(s,6H),2.23(s,3H),2.15–1.99(m,2H),1.79–1.59(m,3H),0.88(d,J＝4.8Hz,2H),0.74(d,J＝4.8Hz,2H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.56 (s, 1H), 7.83 (dd, J = 9.0, 5.7Hz, 1H), 7.34 (d, J = 2.5Hz, 1H), 7.33–7.31 ( m,1H),7.31–7.23(m,2H),4.61(s,1H),4.48–4.39(m,2H),4.35–4.18(m,1H),3.96–3.76(m,2H),3.01– 2.83(m,2H),2.68(s,6H),2.23(s,3H),2.15–1.99(m,2H),1.79–1.59(m,3H),0.88(d,J＝4.8Hz,2H) ,0.74(d,J＝4.8Hz,2H).
实施例194制备(R)-1-(7-(7，8-二氟-3-羟基萘-1-基)-2-((1-((二甲氨基)亚甲基)环丙烷基)甲氧基)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 194 Preparation of (R)-1-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-2-((1-((dimethylamino)methylene)cyclopropanyl) )methoxy)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例194为含0.5个甲酸的盐。LCMS:m/z 592.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 194. LCMS: m/z 592.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.57(s,0.5H),7.66–7.61(m,1H),7.42(q,J＝9.0Hz,1H),7.35(q,J＝2.2Hz,1H),7.31–7.20(m,1H),4.61(s,1H),4.42(d,J＝2.6Hz,2H),4.35–4.22(m,1H),4.12–3.75(m,3H),2.94–2.75(m,2H),2.62(s,6H),2.22(d,J＝1.7Hz,3H),2.11–2.00(m,2H),1.76–1.61(m,2H),0.86(d,J＝4.9Hz,2H),0.70(d,J＝4.9Hz,2H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.57 (s, 0.5H), 7.66–7.61 (m, 1H), 7.42 (q, J = 9.0Hz, 1H), 7.35 (q, J = 2.2Hz ,1H),7.31–7.20(m,1H),4.61(s,1H),4.42(d,J＝2.6Hz,2H),4.35–4.22(m,1H),4.12–3.75(m,3H), 2.94–2.75(m,2H),2.62(s,6H),2.22(d,J＝1.7Hz,3H),2.11–2.00(m,2H),1.76–1.61(m,2H),0.86(d, J=4.9Hz, 2H), 0.70 (d, J=4.9Hz, 2H).
实施例195制备(R)-1-(2-((1-((二甲氨基)亚甲基)环丙烷基)甲氧基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)哌啶-3-醇
Example 195 Preparation of (R)-1-(2-((1-((dimethylamino)methylene)cyclopropane)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例195为含一个甲酸的盐。LCMS:m/z 598.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing a formic acid in Example 195. LCMS: m/z 598.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,1H),7.90–7.86(m,1H),7.38(d,J＝2.4Hz,1H),7.36–7.20(m,2H),4.60(s,1H),4.49(dd,J＝15.7,11.7Hz,1H),4.39(t,J＝12.3Hz,1H),3.95–3.89(m,1H),3.09–2.96(m,2H),2.88–2.75(m,4H),2.21(d,J＝5.5Hz,3H),2.05(s,6H),2.02–1.96(m,1H),1.83–1.62(m,3H),0.96–0.90(m,2H),0.84–0.76(m,2H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 1H), 7.90–7.86 (m, 1H), 7.38 (d, J = 2.4Hz, 1H), 7.36–7.20 (m, 2H), 4.60(s,1H),4.49(dd,J＝15.7,11.7Hz,1H),4.39(t,J＝12.3Hz,1H),3.95–3.89(m,1H),3.09–2.96(m,2H) ,2.88–2.75(m,4H),2.21(d,J＝5.5Hz,3H),2.05(s,6H),2.02–1.96(m,1H),1.83–1.62(m,3H),0.96–0.90 (m,2H),0.84–0.76(m,2H).
实施例196制备4-(4-(3-胺基-3-甲基哌啶-1-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-酚
Example 196 Preparation of 4-(4-(3-amino-3-methylpiperidin-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl) Methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例196为含两个甲酸的盐。LCMS:m/z 597.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents were used as raw materials, and the salt containing two formic acids was prepared in Example 196 by referring to the synthesis method of synthesis steps B to F of Example 38. LCMS: m/z 597.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.53(s,2H),7.91–7.87(m,1H),7.39–7.37(m,1H),7.37–7.19(m,2H),4.75–4.68(m,1H),4.65–4.58(m,2H),4.05–3.80(m,3H),3.43–3.38(m,1H),2.78(d,J＝9.5Hz,3H),2.23(s,3H),2.05–1.83(m,6H),1.46–1.27(m,3H)。 1 H NMR (600 MHz, Methanol-d 4 ) δ 8.53 (s, 2H), 7.91–7.87 (m, 1H), 7.39–7.37 (m, 1H), 7.37–7.19 (m, 2H), 4.75–4.68 (m, 1H), 4.65–4.58 (m, 2H), 4.05–3.80 (m, 3H), 3.43–3.38 (m, 1H), 2.78 (d, J=9.5 Hz, 3H), 2.23 (s, 3H), 2.05–1.83 (m, 6H), 1.46–1.27 (m, 3H).
实施例197制备4-(2-((1-((二甲氨基)亚甲基)环丙烷基)甲氧基)-8-氟-7-(8-氟-3-羟基萘-1-基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-6-甲基-1，4-噁吖庚环-6-醇
Example 197 Preparation of 4-(2-((1-((dimethylamino)methylene)cyclopropyl)methoxy)-8-fluoro-7-(8-fluoro-3-hydroxynaphthalene-1- yl)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-6-methyl-1,4-oxazepan-6-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例197为含0.5个甲酸的盐。LCMS:m/z 604.3(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents as raw materials, refer to the synthesis method of synthesis steps B to F of Example 38 to prepare a salt containing 0.5 formic acid in Example 197. LCMS: m/z 604.3(M+H).
1H NMR(600MHz,Methanol-d4)δ8.56(s,0.5H),7.63–7.60(m,1H),7.43–7.39(m,1H),7.35(d,J＝2.3Hz,1H),7.22–7.17(m,1H),6.97–6.92(m,1H),4.60(s,1H),4.45–4.35(m,3H),4.06–3.93(m,4H),3.68(t,J＝14.8Hz,1H),3.49(t,J＝13.7Hz,1H),2.79(s,2H),2.59(s,6H),2.22(s,3H),1.20–1.11(m,3H),0.85(s,2H),0.68(s,2H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.56 (s, 0.5H), 7.63–7.60 (m, 1H), 7.43–7.39 (m, 1H), 7.35 (d, J = 2.3Hz, 1H) ,7.22–7.17(m,1H),6.97–6.92(m,1H),4.60(s,1H),4.45–4.35(m,3H),4.06–3.93(m,4H),3.68(t,J＝ 14.8Hz,1H),3.49(t,J＝13.7Hz,1H),2.79(s,2H),2.59(s,6H),2.22(s,3H),1.20–1.11(m,3H),0.85( s,2H),0.68(s,2H).
实施例198制备4-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-1，4-噁吖庚环-6-醇
Example 198 Preparation of 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H) -Pyrrozine-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6- alcohol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例198。LCMS:m/z 644.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents were used as raw materials, and Example 198 was prepared by referring to the synthesis method of synthesis steps B to F of Example 38. LCMS: m/z 644.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.54(s,1H),7.91–7.85(m,1H),7.37(t,J＝2.2Hz,1H),7.33(d,J＝9.0Hz,1H),7.25–7.19(m,1H),5.54–5.38(m,1H),4.62(s,1H),4.56–4.41(m,3H),4.36–4.23(m,1H),4.19–3.99(m,3H),3.97–3.85(m,3H),3.78–3.54(m,5H),2.50–2.27(m,4H),2.21(s,3H),2.10–2.01(m,2H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.54 (s, 1H), 7.91–7.85 (m, 1H), 7.37 (t, J = 2.2Hz, 1H), 7.33 (d, J = 9.0Hz, 1H),7.25–7.19(m,1H),5.54–5.38(m,1H),4.62(s,1H),4.56–4.41(m,3H),4.36–4.23(m,1H),4.19–3.99( m,3H),3.97–3.85(m,3H),3.78–3.54(m,5H),2.50–2.27(m,4H),2.21(s,3H),2.10–2.01(m,2H).
实施例199制备4-(7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-4-基)-1，4-噁吖庚环-6-醇
Example 199 Preparation of 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazepan-6-ol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例199。LCMS:m/z 600.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents were used as raw materials, and Example 199 was prepared by referring to the synthesis method of synthesis steps B to F of Example 38. LCMS: m/z 600.2(M+H).
1H NMR(400MHz,Methanol-d4)δ8.52(s,1H),7.91–7.85(m,1H),7.38(d,J＝2.4Hz,1H),7.36–7.31(m,1H),7.30–7.19(m,1H),4.80–4.74(m,2H),4.65–4.59(m,3H),4.48–4.42(m,1H),4.18–4.00(m,3H),3.96–3.85(m,3H), 3.78–3.71(m,1H),3.60–3.52(m,2H),2.92(d,J＝5.0Hz,3H),2.37–2.29(m,1H),2.21(s,3H),2.09(s,1H),2.04–1.94(m,2H)。 1 H NMR (400MHz, Methanol-d 4 ) δ8.52 (s, 1H), 7.91–7.85 (m, 1H), 7.38 (d, J = 2.4Hz, 1H), 7.36–7.31 (m, 1H), 7.30–7.19(m,1H),4.80–4.74(m,2H),4.65–4.59(m,3H),4.48–4.42(m,1H),4.18–4.00(m,3H),3.96–3.85(m ,3H), 3.78–3.71(m,1H),3.60–3.52(m,2H),2.92(d,J＝5.0Hz,3H),2.37–2.29(m,1H),2.21(s,3H),2.09(s, 1H),2.04–1.94(m,2H).
实施例200制备6-氟-4-(8-氟-4-(6-氟-1，4-噁吖庚环-4-基)-2-(((2R,7aS)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(丙炔基)吡啶并[4,3-d]嘧啶-7-基)萘-2-酚
Example 200 Preparation of 6-fluoro-4-(8-fluoro-4-(6-fluoro-1,4-oxazepan-4-yl)-2-(((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrrozin-7a(5H)-yl)methoxy)-5-(propynyl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-phenol
以7-氯-8-氟-2-(甲硫基)-5-(丙炔基)-4-(2，2，2-三氟乙氧基)吡啶并[4,3-d]嘧啶和相应试剂为原料，参照实施例38的合成步骤B至F的合成方法制备实施例200。LCMS:m/z 622.2(M+H)。7-Chloro-8-fluoro-2-(methylthio)-5-(propynyl)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine and corresponding reagents were used as raw materials, and Example 200 was prepared by referring to the synthesis method of synthesis steps B to F of Example 38. LCMS: m/z 622.2(M+H).
1H NMR(600MHz,Methanol-d4)δ8.54(s,0.5H),7.83(dd,J＝9.1,5.6Hz,1H),7.35–7.32(m,2H),7.29(td,J＝8.7,2.6Hz,1H),7.24(d,J＝10.9Hz,1H),5.45–5.34(m,1H),5.27–5.15(m,1H),4.46–4.36(m,3H),4.23(s,2H),4.19–4.05(m,3H),3.83–3.72(m,1H),3.69–3.63(m,1H),3.52–3.38(m,3H),3.18–3.13(m,1H),2.48–2.29(m,3H),2.23(s,3H),2.14–2.08(m,2H),2.03–1.95(m,1H)。 1 H NMR (600MHz, Methanol-d 4 ) δ8.54 (s, 0.5H), 7.83 (dd, J＝9.1, 5.6Hz, 1H), 7.35–7.32 (m, 2H), 7.29 (td, J＝ 8.7,2.6Hz,1H),7.24(d,J＝10.9Hz,1H),5.45–5.34(m,1H),5.27–5.15(m,1H),4.46–4.36(m,3H),4.23(s ,2H),4.19–4.05(m,3H),3.83–3.72(m,1H),3.69–3.63(m,1H),3.52–3.38(m,3H),3.18–3.13(m,1H),2.48 –2.29(m,3H),2.23(s,3H),2.14–2.08(m,2H),2.03–1.95(m,1H).
下表中的实施例201-310可参照实施例38的步骤B至F的合成方法及相应的试剂制备






Examples 201-310 in the table below can be prepared by referring to the synthesis method and corresponding reagents of steps B to F in Example 38.






实验例1本发明化合物的GDP-KRasG12D酶抑制活性测定Experimental Example 1 Determination of GDP-KRas G12D enzyme inhibitory activity of the compounds of the present invention
KRas蛋白是一种GTP酶，可以使蛋白由GTP状态(激活状态)转变为GDP状态(失活状态)。本实验中使用GDP状态的蛋白，加入鸟嘌呤核苷酸交换因子以及GTP促使GDP变为GTP，从而激活蛋白，同时加入的RAF蛋白可以与活性状态的蛋白相连，后续加入的Alpha检测珠子分别与RAF蛋白和活性蛋白相连，进而检测实验室化合物的分子活性。KRas protein is a GTPase that can convert the protein from the GTP state (activated state) to the GDP state (inactivated state). In this experiment, the protein in the GDP state is used, and the addition of guanine nucleotide exchange factor and GTP causes GDP to become GTP, thereby activating the protein. The RAF protein added at the same time can be connected to the protein in the active state. The Alpha detection beads added later are connected to the RAF protein and the active protein respectively, thereby detecting the molecular activity of the laboratory compound.
1试剂准备:1Reagent preparation:
1.1酶缓冲液的配制：1.1 Preparation of enzyme buffer:
25mM HEPES,10mM MgCl2,0.01％Triton X-100，1mM DTT。25mM HEPES, 10mM MgCl2 , 0.01% Triton X-100, 1mM DTT.
1.2 GDP-KRas G12D工作液配制：1.2 Preparation of GDP-KRas G12D working fluid:
以34.77μM GDP-KRas G12D蛋白作为母液，配置为240nM的工作液，体系中浓度为40nM。Use 34.77μM GDP-KRas G12D protein as the mother solution, configure it as a 240nM working solution, and the concentration in the system is 40nM.
1.3 GTP/SOS1混合工作液配制：1.3 Preparation of GTP/SOS1 mixed working fluid:
以100mM GTP和7.7μM SOS1作为母液，配置成3.75μM和1.5μM的混合工作液，体系中浓度分别为625nM以及250nM。Use 100mM GTP and 7.7μM SOS1 as the mother solution to prepare mixed working solutions of 3.75μM and 1.5μM. The concentrations in the system are 625nM and 250nM respectively.
1.4 RAF工作液配制：1.4 Preparation of RAF working fluid:
将38.1μM的RAF母液配置成300nM的工作液，体系中浓度为50nM。Configure 38.1 μM RAF stock solution into a 300 nM working solution, and the concentration in the system is 50 nM.
1.5 Donor beads/Acceptor beads工作液配置：1.5 Donor beads/Acceptor beads working fluid configuration:
以5mg/ml的Donor beads和5mg/ml的Acceptor beads溶液作为母液，配置成60μg/ml的工作液，体系中浓度分别为60μg/ml以及60μg/ml。Use 5 mg/ml Donor beads and 5 mg/ml Acceptor beads solutions as the mother solution to prepare a 60 μg/ml working solution. The concentrations in the system are 60 μg/ml and 60 μg/ml respectively.
1.6供试化合物和标准品PC-1工作液的配制；1.6 Preparation of test compounds and standard PC-1 working solution;
1.6.1配制标准品PC-1工作液(化合物溶于DMSO配置成10mM母液浓度)1.6.1 Preparation of standard PC-1 working solution (the compound is dissolved in DMSO and prepared into a 10 mM stock solution concentration)
化合物终浓度从高至低依次为2500nM,625nM,156.25nM,39.06nM,9.77nM,2.44nM,0.61nM,0.15nM,0.04nM,0nM。化合物浓度为0nM组为空白组，DMSO最终含量为0.5％。The final concentrations of the compounds from high to low are 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, 0.15nM, 0.04nM, 0nM. The group with a compound concentration of 0 nM was the blank group, and the final DMSO content was 0.5%.
1.6.2配制化合物工作液(化合物溶于DMSO配置成10mM母液浓度)1.6.2 Prepare compound working solution (compound is dissolved in DMSO and prepared into 10mM mother solution concentration)
化合物工作液可按照标准品PC-1的方法进行配制。化合物浓度为0nM组为空白组，DMSO最终含量为0.5％。The compound working solution can be prepared according to the method of standard PC-1. The group with a compound concentration of 0 nM was the blank group, and the final DMSO content was 0.5%.
1.7实验步骤：1.7 Experimental steps:
1.7.1取384孔Alpha plate白板，每孔加入5μL蛋白酶工作液、5μL稀 释好的化合物工作液(按上述顺序加入)，室温25°摇板机孵育60min。1.7.1 Take the 384-well Alpha plate and add 5 μL of protease working solution and 5 μL of diluted protein to each well. The released compound working solution (added in the above order) was incubated with a plate shaker at room temperature 25° for 60 minutes.
1.6.2每孔加入5μL GTP/SOS1混合工作液，室温25°摇板机孵育60min。1.6.2 Add 5 μL of GTP/SOS1 mixed working solution to each well, and incubate with a shaker at room temperature 25° for 60 minutes.
1.6.3每孔加入5μL RAF工作液以及10μL Donor beads/Acceptor beads混合工作液(体系总体积为30μL)，室温25℃摇板机孵育60min。1.6.3 Add 5 μL of RAF working solution and 10 μL of Donor beads/Acceptor beads mixed working solution to each well (the total volume of the system is 30 μL), and incubate for 60 minutes with a shaker at room temperature of 25°C.
1.6.4使用多功能酶联免疫仪检测并记录数据。1.6.4 Use a multifunctional enzyme-linked immunosorbent instrument to detect and record data.
1.7数据处理：1.7 Data processing:
按如下公式计算各化合物在各浓度点的抑制率，并通过软件Graphpad Prism 8.0进行曲线拟合得到IC50值。(需要先扣除空白孔的数值，第十一孔)
The inhibition rate of each compound at each concentration point was calculated according to the following formula, and the IC 50 value was obtained by curve fitting using the software Graphpad Prism 8.0. (You need to deduct the value of the blank hole first, the eleventh hole)
1.8检测结果：1.8 Test results:
由专利WO2022042630公开的PC-1以及实施例1-197的化合物对GDP-KRasG12D酶的抑制作用，具体结果如下表所示：


The inhibitory effect of PC-1 disclosed by patent WO2022042630 and the compounds of Examples 1-197 on GDP-KRasG12D enzyme is as follows:


备注：“NA”表示无可用数据。Note: "NA" means no data available.
基于上表中数据，多数实施例对GDP-KRasG12D酶具有显著地抑制活性， 特别是实施例19(IC50＝1.1nM)、实施例42(IC50＝2.5nM)、实施例43(IC50＝2.4nM)、实施例45(IC50＝2.0nM)和实施例80(IC50＝1.5nM)等实施例优于化合物PC-1(IC50＝13.7nM)。Based on the data in the above table, most embodiments have significant inhibitory activity against GDP-KRas G12D enzyme, In particular, Example 19 (IC 50 =1.1 nM), Example 42 (IC 50 =2.5 nM), Example 43 (IC 50 =2.4 nM), Example 45 (IC 50 =2.0 nM) and Example 80 ( Examples such as IC 50 =1.5 nM) are better than compound PC-1 (IC 50 =13.7 nM).
实验例2本发明化合物的人胰腺癌ASPC-1细胞的增值抑制活性测定Experimental Example 2 Measurement of the proliferation inhibitory activity of the compound of the present invention on human pancreatic cancer ASPC-1 cells
通过体外细胞试验对本实验发明的化合物对人胰腺癌ASPC-1细胞增殖抑制的影响利用CELL TITER-GLO(CTG)发光法进行评估，该CTG发光法可通过对ATP进行定量测定来检测活细胞数目。The effect of the compound invented in this experiment on the inhibition of human pancreatic cancer ASPC-1 cell proliferation was evaluated through in vitro cell testing using the CELL TITER-GLO (CTG) luminescence method. The CTG luminescence method can detect the number of viable cells by quantitatively measuring ATP. .
1实验材料:1Experimental materials:
人胰腺癌ASPC-1细胞和均购于美国细胞库-ATCC货号CRL-1682。Human pancreatic cancer ASPC-1 cells were purchased from the American Cell Bank-ATCC Cat. No. CRL-1682.
2实验准备:2Experimental preparation:
2.1培养基的配制：2.1 Preparation of culture medium:
1640高糖培养基+10％FBS+1％Penicillin-Streptomycin(青霉素/链霉素)。1640 high glucose medium + 10% FBS + 1% Penicillin-Streptomycin (penicillin/streptomycin).
2.2细胞铺板：2.2 Cell plating:
ASPC-1细胞培养：ASPC-1 cell culture:
取一瓶/一皿处于对数生长期的ASPC-1细胞，消化重悬细胞后计数，调整细胞密度后接种到96孔平底透明板中，每孔接种2000个细胞/100μL，板置于37℃、5％CO2的培养箱中培养24h后加入化合物进行处理。Take a bottle/dish of ASPC-1 cells in the logarithmic growth phase, digest and resuspend the cells, count them, adjust the cell density and inoculate them into a 96-well flat-bottomed transparent plate. Inoculate 2000 cells/100 μL in each well, and place the plate at 37 After culturing for 24 h in an incubator at ℃ and 5% CO2 , compounds were added for treatment.
2.3供试化合物和标准品PC-1溶液的配制；2.3 Preparation of test compound and standard PC-1 solutions;
(1)配制标准品PC-1溶液(化合物溶于DMSO配置成10mM母液浓度)(1) Prepare standard PC-1 solution (the compound is dissolved in DMSO to prepare a 10mM mother solution concentration)
用于ASPC-1细胞的化合物终浓度从高至低依次为10000nM、1666.67nM、277.78nM、46.30nM、7.72nM、1.29nM、0.21nM、0.036nM、0.0060nM和0nM,化合物浓度为0nM组为空白组，DMSO最终含量为0.5％。The final concentrations of compounds used for ASPC-1 cells were 10000nM, 1666.67nM, 277.78nM, 46.30nM, 7.72nM, 1.29nM, 0.21nM, 0.036nM, 0.0060nM and 0nM from high to low. The compound concentration group was 0nM. For the blank group, the final DMSO content was 0.5%.
加入对应化合物后将细胞板分别置于细胞培养箱培养120h。After adding the corresponding compounds, the cell plates were placed in a cell culture incubator and cultured for 120 h.
(2)配制化合物溶液(化合物溶于DMSO配置成10mM母液浓度)(2) Prepare compound solution (compound is dissolved in DMSO to prepare a mother solution concentration of 10mM)
化合物溶液按照与上述标准品PC-1相同的方法配制。The compound solution was prepared in the same manner as the above standard PC-1.
将上述稀释好的标准品溶液和化合物溶液分别以20μL/孔加入至接种有细胞的培养板中，恒温37℃，5％CO2和90％相对湿度下培养120h。Add the above-mentioned diluted standard solution and compound solution to the culture plate seeded with cells at 20 μL/well respectively, and incubate for 120 h at a constant temperature of 37°C, 5% CO 2 and 90% relative humidity.
2.4 CTG检测：2.4 CTG detection:
细胞培养120h后每孔加入60μL的CellTiter-Glo 2.0 Cell Ⅵability溶液，置于摇板机上室温孵育30min，之后将对应孔中的100μL溶液转移至96孔平底白板中并使用多功能酶联免疫仪读取各孔的数值。After the cells were cultured for 120 hours, add 60 μL of CellTiter-Glo 2.0 Cell VIability solution to each well, place it on a shaker and incubate at room temperature for 30 minutes, then transfer 100 μL of the solution in the corresponding well to a 96-well flat-bottomed white plate and read using a multifunctional enzyme-linked immunosorbent instrument. Get the value of each hole.
2.5数据处理：2.5 Data processing:
按如下公式计算各化合物在各浓度点的抑制率，并通过软件Graphpad
Calculate the inhibition rate of each compound at each concentration point according to the following formula, and use the software Graphpad
Prism 8.0进行曲线拟合得到IC50值。Prism 8.0 was used to perform curve fitting to obtain the IC 50 value.
2.6检测结果：2.6 Test results:
2.6.1化合物PC-1以及本发明实施例的化合物对人胰腺癌ASPC-1细胞的抑制作用分别进行检测，具体检测结果如下表所示：
2.6.1 The inhibitory effects of compound PC-1 and the compounds of the embodiments of the present invention on human pancreatic cancer ASPC-1 cells were tested respectively. The specific test results are as shown in the following table:
备注：“NA”表示无可用数据。Note: “NA” means no data available.
基于上表中数据，本发明提供的实施例1-43的化合物均对人胰腺癌ASPC-1细胞显示出显著的抑制活性，且大多数化合物具有比化合物PC-1更优的抑制活性，尤其是实施例20(IC50＝2.3nM)、35(IC50＝3.1nM)、41(IC50＝1.3nM)、42(IC50＝2.7nM)、58(IC50＝1.4nM)、103(IC50＝2.0nM)、104(IC50＝1.5nM)和129(IC50＝2.4nM)等实施例显著优于化合物PC-1(IC50＝36.5nM)。Based on the data in the above table, the compounds of Examples 1-43 provided by the present invention all showed significant inhibitory activity on human pancreatic cancer ASPC-1 cells, and most of the compounds had better inhibitory activity than compound PC-1, especially Examples 20 (IC 50 =2.3nM), 35 (IC 50 =3.1nM), 41 (IC 50 =1.3nM), 42 (IC 50 =2.7nM), 58 (IC 50 =1.4nM), 103 (IC 50 =2.0nM), 104 (IC 50 =1.5nM) and 129 (IC 50 =2.4nM) were significantly better than compound PC-1 (IC 50 =36.5nM).
实验例3本发明化合物的肝微粒体稳定性实验测试Experimental Example 3 Experimental test of liver microsome stability of the compound of the present invention
一、溶液配制1. Solution preparation
1.PB缓冲溶液配制：1. Preparation of PB buffer solution:
用电子天平精确称量K2HPO41.3475g,KH2PO46.9845g，用去离子水配成终浓度为100mM的缓冲液备用。Use an electronic balance to accurately weigh K 2 HPO 4 1.3475g and KH 2 PO 4 6.9845g, and use deionized water to prepare a buffer with a final concentration of 100mM for later use.
2.化合物的溶解： 2. Dissolution of compounds:
称取适量化合物用DMSO溶解成浓度为10mM的母液储藏，再用DMSO和PB缓冲液将10mM的化合物进一步稀释成浓度为400μM的中间液(使化合物在体系中的终浓度为1μM)。Weigh an appropriate amount of the compound and dissolve it in DMSO into a mother solution with a concentration of 10mM for storage. Then use DMSO and PB buffer to further dilute the 10mM compound into an intermediate solution with a concentration of 400μM (so that the final concentration of the compound in the system is 1μM).
3.NADPH再生系统的配制：3. Preparation of NADPH regeneration system:
将NADPH试剂盒中的A液和B液以5:1的比例添加并混合均匀。Add solution A and solution B in the NADPH kit at a ratio of 5:1 and mix evenly.
4.配制PB与肝微粒体的混合液4. Preparation of a mixture of PB and liver microsomes
实验设置样品孔和阴性对照孔(无NADPH)，样品孔：取适量100mM PB缓冲液，加入浓度为20mg/ml的肝微粒体，配成终浓度为0.535mg/ml的肝微粒体混合液备用；阴性对照孔：取适量100mM PB缓冲液，加入浓度为20mg/ml的肝微粒体，配成终浓度为0.538mg/ml的肝微粒体混合液备用(使肝微粒体的终浓度在两个体系中均为0.5mg/ml)。The experiment set up sample wells and negative control wells (without NADPH): For sample wells: take an appropriate amount of 100mM PB buffer, add liver microsomes at a concentration of 20mg/ml, and prepare a liver microsome mixture with a final concentration of 0.535mg/ml for use; for negative control wells: take an appropriate amount of 100mM PB buffer, add liver microsomes at a concentration of 20mg/ml, and prepare a liver microsome mixture with a final concentration of 0.538mg/ml for use (so that the final concentration of liver microsomes is 0.5mg/ml in both systems).
5.终止液的配制。5. Preparation of stop solution.
含200ng/ml拉贝洛尔、甲苯磺丁脲和酮洛芬的冷乙腈，即为终止液。Cold acetonitrile containing 200 ng/ml of labetalol, tolbutamide and ketoprofen was used as the stop solution.
二、液质仪器参数2. Liquid quality instrument parameters
1.色谱柱：Waters XSELECT HSS T3,100×2.1mm，1.8μM。1. Chromatographic column: Waters XSELECT HSS T3, 100×2.1mm, 1.8μM.
2.流动相成份：A相：水(0.1％甲酸)；B相：乙腈(0.1％甲酸)；流速：0.5ml/min。2. Mobile phase components: Phase A: water (0.1% formic acid); Phase B: acetonitrile (0.1% formic acid); flow rate: 0.5ml/min.
洗脱梯度：0-1.5min,5％B；1.5-9min,5％-40％B；9-12min,40％-100％B；12-14min,100％B；14-14.3min,100-5％B；14.3-15min,5％B。Elution gradient: 0-1.5min, 5%B; 1.5-9min, 5%-40%B; 9-12min, 40%-100%B; 12-14min, 100%B; 14-14.3min, 100- 5%B; 14.3-15min, 5%B.
3.质谱条件：3. Mass spectrometry conditions:
电离模式：正电模式；离子源电压：5500V；扫描模式：IDA；喷气温度：550℃；碰撞电压：10V。Ionization mode: positive mode; ion source voltage: 5500V; scanning mode: IDA; jet temperature: 550°C; collision voltage: 10V.
三、实验步骤3. Experimental steps
1.实验设置样品孔和阴性对照孔，样品孔：每孔加入374μL肝微粒体PB混合液，阴性对照孔：每孔加入186μL肝微粒体PB混合液；将96孔深孔板放置于37℃恒温振荡器孵育10min；加入2μL化合物的中间液，再孵育10min，向样品孔加入24μL NADPH再生系统的混合液，向阴性对照孔加入12μLPB溶液，混匀立即吸取50μL于150μL终止液，终止反应。剩余反应液继续于37℃恒温振荡器孵育，分别在15min、30min、45min和60min吸取50μL反应液，用150μL终止液，终止反应。1. Experimental setup of sample wells and negative control wells: 374μL liver microsome PB mixture was added to each well of the sample wells, and 186μL liver microsome PB mixture was added to each well of the negative control wells; the 96-well deep-well plate was placed in a 37°C constant temperature oscillator for incubation for 10 min; 2μL of the intermediate solution of the compound was added, and then incubated for another 10 min. 24μL of the mixture of the NADPH regeneration system was added to the sample wells, and 12μLPB solution was added to the negative control wells. After mixing, 50μL was immediately aspirated into 150μL of stop solution to terminate the reaction. The remaining reaction solution was continued to be incubated in a 37°C constant temperature oscillator, and 50μL of the reaction solution was aspirated at 15min, 30min, 45min, and 60min, respectively, and 150μL of stop solution was used to terminate the reaction.
2.混匀样品，3000rpm，4℃，离心20min，吸取上清液体100μL，于100μL水混匀，制备成检测样品。2. Mix the sample, centrifuge at 3000 rpm, 4°C for 20 minutes, absorb 100 μL of the supernatant liquid, mix it with 100 μL of water, and prepare a test sample.
3.用LC-MS/MS仪器中的MRM模块检测。3. Detect with the MRM module in the LC-MS/MS instrument.
四、数据分析4. Data Analysis
1.使用内标化合物做校准，用SCIEX OS软件提取离子色谱图确定化合物的峰面积。1. Use internal standard compounds for calibration, and use SCIEX OS software to extract the ion chromatogram to determine the peak area of the compound.
2.将各个时间点化合物的峰面积导入到Excel表中，计算化合物的半衰期(in Ⅵtro t1/2)60min时样品剩余率(％Remaining)和化合物的体外清除率(In Ⅵtro Clint)，计算公式如下所示。2. Import the peak area of the compound at each time point into the Excel table, and calculate the half-life of the compound (in Ⅵtro t 1/2 ), the sample remaining rate (%Remaining) at 60 minutes and the in vitro clearance rate of the compound (In Ⅵtro Cl int ). The calculation formula is as follows.
in Ⅵtro t1/2＝-(0.693/k)
in VItro t 1/2 = -(0.693/k)
注释：斜率值k由母药剩余百分比与孵育时间曲线的自然对数线性回归确定。volume of incubation(μL)是整个孵育体系的体积，amount of proteins(mg)是整个孵育体系中微粒体的含量。Note: The slope value k is determined by linear regression of the natural logarithm of the remaining percentage of parent drug versus incubation time. Volume of incubation (μL) is the volume of the entire incubation system, and amount of proteins (mg) is the content of microsomes in the entire incubation system.
五、检测结果5. Test results
以专利WO2022042630公开的PC-1为对照化合物，检测根据本发明提供的化合物对人的肝微粒体稳定性，检测结果如下表所示：
Using PC-1 disclosed in patent WO2022042630 as a control compound, the stability of the compound provided according to the present invention to human liver microsomes was tested. The test results are as shown in the following table:
基于此表数据可以看到，根据本发明制备的化合物中大多数在人的肝微粒体中的稳定性均优于PC-1，其中，实施例6(T1/2＝337min)、实施例23(T1/2＝166.2min)、实施例70(T1/2＝247.2min)、实施例85(T1/2＝298.8min)、实施例98(T1/2＝475.8min)和实施例102(T1/2＝172.3min)等实施例在人肝微粒体中的稳定性显著优于PC-1(T1/2＝36.1min)。Based on the data in this table, it can be seen that most of the compounds prepared according to the present invention are more stable than PC-1 in human liver microsomes. Among them, Example 6 (T 1/2 =337 min), Example 23 (T 1/2 =166.2min), Example 70 (T 1/2 =247.2min), Example 85 (T 1/2 =298.8min), Example 98 (T 1/2 =475.8min) and The stability of examples such as Example 102 (T 1/2 =172.3 min) in human liver microsomes is significantly better than that of PC-1 (T 1/2 =36.1 min).
实验例4本发明化合物对不同突变型细胞的增殖抑制实验Experimental Example 4 Proliferation Inhibition Experiment of Compounds of the Invention on Different Mutated Cells
使用体外细胞试验评估本实验发明的化合物对人胰腺癌AsPC-1(KRAS G12D)、人胃癌MKN1(KRAS WT)、人非小细胞肺癌NCI-H358(KRAS G12C)、人非小细胞肺癌A549(KRAS G12S)、人结肠癌SW480(KRAS G12V)、人多发性骨髓瘤MM.1S(KRAS G12A)、人结肠癌HCT116(KRAS G13D)等细胞增殖抑制的影响。试验中所用的检测方法是CELL TITER-GLO(CTG)发光法，该法可通过对ATP进行定量测定来检测活细胞数目。In vitro cell tests were used to evaluate the effects of the compounds of the present invention on the inhibition of cell proliferation in human pancreatic cancer AsPC-1 (KRAS G 12D ), human gastric cancer MKN1 (KRAS WT), human non-small cell lung cancer NCI-H358 (KRAS G 12C ), human non-small cell lung cancer A549 (KRAS G 12S ), human colon cancer SW480 (KRAS G 12V ), human multiple myeloma MM.1S (KRAS G 12A ), human colon cancer HCT116 (KRAS G 13D ), etc. The detection method used in the test was the CELL TITER-GLO (CTG) luminescence method, which can detect the number of viable cells by quantitatively measuring ATP.
1实验材料:1Experimental materials:
人胃癌MKN1、人非小细胞肺癌A549、人结肠癌SW480细胞购于Cobioer；人结肠癌HCT116细胞购于Cyagen；人胰腺癌AsPC-1、人非小细胞肺癌NCI-H358、人多发性骨髓瘤MM.1S购于ATCC。Human gastric cancer MKN1, human non-small cell lung cancer A549, and human colon cancer SW480 cells were purchased from Cobioer; human colon cancer HCT116 cells were purchased from Cyagen; human pancreatic cancer AsPC-1, human non-small cell lung cancer NCI-H358, and human multiple myeloma MM.1S were purchased from ATCC.
2实验准备:2Experimental preparation:
2.1培养基的配制：1640高糖培养基+10％FBS+1％ Penicillin-Streptomycin(青霉素/链霉素)，Mc Coy’s 5a+10％FBS+1％Penicillin-Streptomycin(青霉素/链霉素)，F12K+10％FBS+1％Penicillin-Streptomycin(青霉素/链霉素)，。2.1 Preparation of medium: 1640 high sugar medium + 10% FBS + 1% Penicillin-Streptomycin (penicillin/streptomycin), Mc Coy's 5a+10% FBS+1% Penicillin-Streptomycin (penicillin/streptomycin), F12K+10% FBS+1% Penicillin-Streptomycin (penicillin/streptomycin) ,.
2.2细胞铺板：取一瓶/一皿处于对数生长期的各突变型细胞，(消化)重悬细胞后计数，调整细胞密度后接种到96孔平底透明板中，每孔接种2000个细胞/100μL，板置于37℃、5％CO2的培养箱中培养24h后加入化合物进行处理；2.2 Cell plating: Take a bottle/dish of each mutant cell in the logarithmic growth phase, (digest), resuspend the cells and count them, adjust the cell density and inoculate them into a 96-well flat-bottomed transparent plate, seeding 2000 cells/well in each well. 100 μL, place the plate in an incubator at 37°C and 5% CO2 and incubate for 24 hours before adding compounds for treatment;
2.3供试化合物和标准品MRTX1133溶液的配制；2.3 Preparation of test compound and standard MRTX1133 solution;
(1)配制标准品MRTX1133溶液(化合物溶于DMSO配置成10mM母液浓度)(1) Prepare standard MRTX1133 solution (the compound is dissolved in DMSO to a 10 mM stock solution concentration)
ASPC-1细胞：化合物终浓度从高至低依次为10000nM、1666.67nM、277.78nM、46.30nM、7.72nM、1.29nM、0.21nM、0.036nM、0.0060nM和0nM,化合物浓度为0nM组为空白组，DMSO最终含量为0.5％。ASPC-1 cells: The final concentrations of compounds from high to low are 10000nM, 1666.67nM, 277.78nM, 46.30nM, 7.72nM, 1.29nM, 0.21nM, 0.036nM, 0.0060nM and 0nM. The group with compound concentration of 0nM is the blank group. , the final DMSO content is 0.5%.
其余细胞：化合物终浓度从高至低依次为50000nM、8333.33nM、1388.89nM、231.48nM、38.58nM、6.43nM、1.07nM、0.18nM、0.03nM和0nM,化合物浓度为0nM组为空白组，DMSO最终含量为0.5％。Remaining cells: The final concentrations of compounds from high to low are 50000nM, 8333.33nM, 1388.89nM, 231.48nM, 38.58nM, 6.43nM, 1.07nM, 0.18nM, 0.03nM and 0nM. The group with compound concentration of 0nM is the blank group, DMSO The final content is 0.5%.
(2)配制化合物溶液(化合物溶于DMSO配置成10mM母液浓度)(2) Prepare compound solution (compound is dissolved in DMSO to prepare a mother solution concentration of 10mM)
化合物溶液可按照标准品MRTX1133的方法进行配制。The compound solution can be prepared according to the method of standard MRTX1133.
将上述稀释好的标准品溶液和化合物溶液分别以20μL/孔加入至接种有细胞的培养板中，恒温37℃，5％CO2和90％相对湿度下培养120h。Add the above-mentioned diluted standard solution and compound solution to the culture plate seeded with cells at 20 μL/well respectively, and incubate for 120 h at a constant temperature of 37°C, 5% CO 2 and 90% relative humidity.
2.4 CTG检测：2.4 CTG detection:
细胞培养120h后每孔加入60μL的CellTiter-Glo 2.0 Cell Viability溶液，置于摇板机上室温孵育30min，之后将对应孔中的100μL溶液转移至96孔平底白板中并使用多功能酶联免疫仪读取各孔的数值。After the cells were cultured for 120 hours, 60 μL of CellTiter-Glo 2.0 Cell Viability solution was added to each well, placed on a shaker and incubated at room temperature for 30 min. Then, 100 μL of the solution in the corresponding well was transferred to a 96-well flat-bottomed white plate and read using a multifunctional enzyme-linked immunosorbent instrument. Get the value of each hole.
2.5数据处理：2.5 Data processing:
按如下公式计算各化合物在各浓度点的抑制率，并通过软件Graphpad Prism 8.0进行曲线拟合得到IC50值。
Calculate the inhibition rate of each compound at each concentration point according to the following formula, and perform curve fitting using the software Graphpad Prism 8.0 to obtain the IC50 value.
结果如下表所示：


The results are shown in the table below:


备注：“NA”表示无可用数据。Note: "NA" means no data available.
基于上表中数据，本发明提供的实施例118-191的化合物对人胰腺癌AsPC-1(KRAS G12D)、人胃癌MKN1(KRAS WT)、人非小细胞肺癌NCI-H358(KRAS G12C)、人非小细胞肺癌A549(KRAS G12S)、人结肠癌SW480(KRAS G12V)、人多发性骨髓瘤MM.1S(KRAS G12A)、人结肠癌HCT116(KRAS G13D)等癌细胞均显示出显著的抑制活性，相对于对照化合物MRTX1133，我们发明的多数化合物不仅对人胰腺癌AsPC-1(KRAS G12D)细胞具有显著的抑制活性，而且对不同KRAS突变的癌细胞均有较好的抑制活性。Based on the data in the above table, the compounds of Examples 118-191 provided by the present invention are effective against human pancreatic cancer AsPC-1 (KRAS G 12D ), human gastric cancer MKN1 (KRAS WT), and human non-small cell lung cancer NCI-H358 (KRAS G 12C) . ), human non-small cell lung cancer A549 (KRAS G 12S ), human colon cancer SW480 (KRAS G 12V ), human multiple myeloma MM.1S (KRAS G 12A ), human colon cancer HCT116 (KRAS G 13D ) and other cancer cells All showed significant inhibitory activity. Compared with the control compound MRTX1133, most of the compounds we invented not only had significant inhibitory activity against human pancreatic cancer AsPC-1 (KRAS G 12D ) cells, but also had better inhibitory activity against cancer cells with different KRAS mutations. Good inhibitory activity.
本发明已经通过上述实施例进行了说明，但应当理解的是，上述实施例只是用于举例和说明的目的，而非意在将本发明限制于所描述的实施例范围内。此外本领域技术人员可以理解的是，本发明并不局限于上述实施例，根据本发明的教导还可以做出更多种的变型和修改，这些变型和修改均落在本发明所要求保护的范围以内。本发明的保护范围由附属的权利要求书及其等效范围所界定。 The present invention has been described through the above-mentioned embodiments, but it should be understood that the above-mentioned embodiments are only for the purpose of illustration and illustration, and are not intended to limit the present invention to the scope of the described embodiments. In addition, those skilled in the art can understand that the present invention is not limited to the above embodiments, and more variations and modifications can be made according to the teachings of the present invention. These variations and modifications all fall within the scope of the protection claimed by the present invention. within the range. The protection scope of the present invention is defined by the appended claims and their equivalent scope.

Claims (20)

  1. 一种式Ⅰ化合物，或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，其中，
    A compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein,
    其中，R1为CR1a或N；R1a选自氢、卤素、氰基、羟基、巯基、羟基亚烷基、-COO烷基、羧基、氨基、-CONH2、-NHCO烷基、烷基、亚烷基氰基、烯基和炔基；优选地，R1a选自氢、卤素、氰基、羟基、巯基、羟甲基、-COOC1-6烷基、羧基、氨基、-CONH2、-NHCOC1-6烷基、C1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基；Wherein, R 1 is CR 1a or N; R 1a is selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxyalkylene, -COO alkyl, carboxyl, amino, -CONH 2 , -NHCO alkyl, alkyl , alkylene cyano, alkenyl and alkynyl; preferably, R 1a is selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, -COOC 1-6 alkyl, carboxyl, amino, -CONH 2 , -NHCOC 1-6 alkyl, C 1-6 alkyl, C 1-6 alkylenecyano, C 2-6 alkenyl and C 2-6 alkynyl;
    R2为至少含1个N原子的3-12元饱和或部分饱和的单环、桥环、稠环或螺环，其中所述饱和或部分饱和的单环、桥环、稠环或螺环任选地被一个、两个或更多个R2a取代；优选地，R2为含1、2或3个环N的3-12元饱和或部分饱和的单环、桥环、稠环或螺环，其中所述饱和或部分饱和的单环、桥环、稠环或螺环任选地被一个或多个R2a取代；优选地，R2为含1或2个环N的饱和或部分饱和的3-10元单环、6-12元桥环、4-10元稠环或5-12元螺环，其中所述饱和或部分饱和的单环、桥环、稠环或螺环任选地被一个或多个R2a取代；优选地，R2为含1或2个环N，并且含0、1、2或3个独立选自O和S的环杂原子的饱和或部分饱和的3、5、6、7、或8元单环、6、7、8、9、或10元桥环、4、5、6、7、8、9、或10元稠环、或5、6、7、8、9、10、11或12元螺环，其中所述饱和或部分饱和的单环、桥环、稠环或螺环任选地被一个或多个R2a取代；每次R2a出现时各自独立地选自卤素、氰基、羟基、巯基、羟基亚烷基、羧基、氨基、-CONH2、-NHCO烷基、烷基、亚烷基氰基、亚烷基炔基、亚烷基COO烷基、-NHCOC1-6烷基、烯基、氧代基(＝O)、环烷基、杂环基和炔基，任选地，所述亚烷基、烷基、炔基、烯基、环烷基、和杂环基被一个、两个或更多个选自卤素、氰基、氨基、羟基、羟亚烷基、巯基、-C(O)O-烷基、-OC(O)-烷基、羧基、氧代基、(＝CH2)、-CONH2、-NHC(O)C1-6烷基、C1-6烷基-NHCOC1-6亚烷基、烷基、烷基氨基、C1-6卤代烷基、C1-6烷氧基、亚芳基C1-6烷基、芳基C1-6亚烷基、(C1-6烷氧基)C1-6亚烷基-、(C1-6烷基)C(＝O)-、(C1-6卤代烷基)C(＝O)-、-CH2NHCOC1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基的取代基所取代；优选地，每次R2a出现时各自独立地选自F、Cl、Br、I、氰基、羟基、巯基、羟基C1-6亚烷基、羧基、氨基、-CONH2、-NHCOC1-6烷基、C1-6烷基、C1-6亚烷基氰基、C1-6亚烷基炔基、C1-6亚烷基COO C1-6烷基、-NHCOC1-6烷基、C2-6烯基、氧代基(＝O)和C2-6炔基，任选地，所述C1-6亚烷基、C1-6烷基、C2-6炔基、和C2-6烯基被一个、两个或更多个选自卤素、氰基、氨基、羟基、羟亚烷基、巯基、-C(O)O-烷基、-OC(O)-烷基、羧基、氧代基、(＝CH2)、-CONH2、-NHC(O)C1-6烷基、C1-6烷基-NHCOC1-6亚烷基、C1-6烷基、C1-6烷基氨基、C1-6卤代烷基、C1-6烷氧基、亚芳基C1-6 烷基、芳基C1-6亚烷基、(C1-6烷氧基)C1-6亚烷基-、(C1-6烷基)C(＝O)-、(C1-6卤代烷基)C(＝O)-、-CH2NHCOC1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基的取代基所取代；R 2 is a 3-12 membered saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring containing at least 1 N atom, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring optionally substituted by one, two or more R 2a ; preferably, R 2 is a 3-12 membered saturated or partially saturated monocyclic ring, bridged ring, fused ring or containing 1, 2 or 3 ring N Spiro ring, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spiro ring is optionally substituted by one or more R 2a ; preferably, R 2 is a saturated or spiro ring containing 1 or 2 ring N Partially saturated 3-10-membered monocyclic ring, 6-12-membered bridged ring, 4-10-membered fused ring or 5-12-membered spirocyclic ring, wherein the saturated or partially saturated monocyclic ring, bridged ring, fused ring or spirocyclic ring Optionally substituted by one or more R 2a ; preferably, R 2 is a saturated or partial ring containing 1 or 2 ring N's and containing 0, 1, 2 or 3 ring heteroatoms independently selected from O and S Saturated 3, 5, 6, 7, or 8-membered monocyclic ring, 6, 7, 8, 9, or 10-membered bridged ring, 4, 5, 6, 7, 8, 9, or 10-membered fused ring, or 5 , 6, 7, 8, 9, 10, 11 or 12 membered spirocyclic rings, wherein the saturated or partially saturated monocyclic, bridged, fused or spirocyclic rings are optionally substituted by one or more R 2a ; each Each R 2a occurrence is independently selected from halogen, cyano, hydroxy, mercapto, hydroxyalkylene, carboxyl, amino, -CONH 2 , -NHCO alkyl, alkyl, alkylenecyano, alkylene alkyne base, alkylene COO alkyl, -NHCOC 1-6 alkyl, alkenyl, oxo (=O), cycloalkyl, heterocyclyl and alkynyl, optionally, the alkylene, alkyl The base, alkynyl, alkenyl, cycloalkyl, and heterocyclyl groups are one, two or more selected from halogen, cyano, amino, hydroxyl, hydroxyalkylene, mercapto, -C(O)O- Alkyl, -OC(O)-alkyl, carboxyl, oxo, (=CH 2 ), -CONH 2 , -NHC(O)C 1-6 alkyl, C 1-6 alkyl -NHCOC 1- 6 alkylene, alkyl, alkylamino, C 1-6 haloalkyl, C 1-6 alkoxy, arylene C 1-6 alkyl, aryl C 1-6 alkylene, (C 1 -6 alkoxy)C 1-6 alkylene-, (C 1-6 alkyl)C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH 2 NHCOC 1 -6 alkyl, C 1-6 alkylene cyano, C 2-6 alkenyl and C 2-6 alkynyl substituents; preferably, each occurrence of R 2a is independently selected from F, Cl, Br, I, cyano group, hydroxyl group, mercapto group, hydroxyl C 1-6 alkylene group, carboxyl group, amino group, -CONH 2 , -NHCOC 1-6 alkyl group, C 1-6 alkyl group, C 1-6 alkylene group Alkyl cyano group, C 1-6 alkylene alkynyl group, C 1-6 alkylene COO C 1-6 alkyl group, -NHCOC 1-6 alkyl group, C 2-6 alkenyl group, oxo group (= O) and C 2-6 alkynyl, optionally, the C 1-6 alkylene, C 1-6 alkyl, C 2-6 alkynyl, and C 2-6 alkenyl are replaced by one or two or more selected from halogen, cyano, amino, hydroxyl, hydroxyalkylene, mercapto, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, oxo, (=CH 2 ), -CONH 2 , -NHC(O)C 1-6 alkyl, C 1-6 alkyl -NHCOC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 alkoxy, arylene C 1-6 Alkyl, aryl C 1-6 alkylene, (C 1-6 alkoxy) C 1-6 alkylene-, (C 1-6 alkyl) C (=O)-, (C 1- 6 haloalkyl) C(=O)-, -CH 2 NHCOC 1-6 alkyl, C 1-6 alkylene cyano, C 2-6 alkenyl and C 2-6 alkynyl substituents substituted;
    Y为CRxRy、O、S、S＝O、S(＝O)2或NRx，Rx和Ry每次出现时分别独立地选自氢、烷基、环烷基、杂环基、亚烷基氨基烷基、芳基和亚烷基芳基；优选地，Rx和Ry每次出现时分别独立地选自氢、和C1-6烷基；Y is CR x R y , O, S, S=O, S(=O) 2 or NR x , R x and R y are independently selected from hydrogen, alkyl, cycloalkyl, heterocycle each time they appear. group, alkyleneaminoalkyl, aryl and alkylenearyl; preferably, R x and R y are independently selected from hydrogen, and C 1-6 alkyl each time they appear;
    R3选自烷基、亚烷基羟基、-L-杂环基、-L-芳基、-L-亚芳基-L-杂环基、-L-亚杂芳基-L-杂环基、-L-杂芳基、-L-亚杂环基-L-OCO-N(R5)2、-L-亚杂环基-L-NR5-CO-N(R5)2、-L-亚杂环基-L-NR5-CO-R5、-L-环烷基、-L-亚环烷基-L-N(R5)2、-L-亚环烷基-L-杂环基和-L-亚环烷基-L-N(R5)2，其中，所述杂环基、亚杂芳基、杂芳基、和亚杂环基各自独立地含有1、2、3或4个各自独立选自N、O和S的杂原子，所述烷基、烷基羟基、杂环基、芳基、亚芳基、亚杂芳基、杂芳基、亚杂环基、环烷基和亚环烷基可任选被一个、两个或更多个选自卤素、氰基、氨基、羟基、羟烷基、巯基、-C(O)O-烷基、-OC(O)-烷基、羧基、氧代基、(＝CH2)、-CONH2、-NHC(O)C1-6烷基、C1-6烷基-NHCOC1-6亚烷基、烷基、烷基氨基、C1-6卤代烷基、C1-6烷氧基、C1-6烷基取代的吡唑基、亚芳基C1-6烷基、芳基C1-6亚烷基、(C1-6烷氧基)C1-6亚烷基-、(C1-6烷基)C(＝O)-、(C1-6卤代烷基)C(＝O)-、-CH2NHCOC1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基的取代基所取代；优选地，R3选自C1-6烷基、C1-6烷基羟基、-L-(3-12元杂环基)、-L-(6-10元亚芳基)、-L-(6-10元亚芳基)-L-(3-12元杂环基)、-L-(5-12元亚杂芳基)-L-(3-12元杂环基)、-L-(5-12元杂芳基)、-L-(3-12元亚杂环基)-L-OCO-N(R5)2、-L-(3-12元亚杂环基)-L-NR5-CO-N(R5)2、-L-(3-12元亚杂环基)-L-NR5-CO-R5、-L-(3-10元环烷基)、-L-(3-10元亚环烷基)-L-N(R5)2、-L-(3-10元亚环烷基)-L-(3-12元杂环基)和-L-(3-10元亚环烷基)-L-N(R5)2，其中，所述3-12元杂环基、3-12元亚杂环基、5-12元亚杂芳基和5-12元杂芳基，各自独立地含有1、2、或3个各自独立选自N、O和S的杂原子，所述C1-6烷基、C1-6亚烷基羟基、3-12元杂环基、6-10元芳基、6-10元亚芳基、5-12元亚杂芳基、5-12元杂芳基、3-12元亚杂环基、3-10元环烷基和3-10元亚环烷基可任选被一个、两个或更多个选自F、Cl、Br、I、氰基、氨基、羟基、C1-6羟烷基、巯基、-C(O)O-C1-6烷基、-OC(O)-C1-6烷基、羧基、氧代基、(＝CH2)、-CONH2、-NHC(O)C1-6烷基、C1-6烷基-NHCOC1-6亚烷基、C1-6烷基、C1-6烷基氨基、C1-6卤代烷基、C1-6烷氧基、C1-6烷基取代的吡唑基、亚芳基C1-6烷基、芳基C1-6亚烷基、(C1-6烷氧基)C1-6亚烷基-、(C1-6烷基)C(＝O)-、(C1-6卤代烷基)C(＝O)-、-CH2NHCOC1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基的取代基所取代；R 3 is selected from alkyl, alkylenehydroxy, -L-heterocyclyl, -L-aryl, -L-arylene-L-heterocyclyl, -L-heteroarylene-L-heterocycle base, -L-heteroaryl, -L-heterocyclylene-L-OCO-N(R 5 ) 2 , -L-heterocyclylene-L-NR 5 -CO-N(R 5 ) 2 , -L-Heterocyclylene-L-NR 5 -CO-R 5 , -L-cycloalkyl, -L-cycloalkylene-LN(R 5 ) 2 , -L-cycloalkylene-L- Heterocyclyl and -L-cycloalkylene-LN(R 5 ) 2 , wherein the heterocyclyl, heteroarylene, heteroarylene, and heterocyclylene each independently contain 1, 2, 3 Or 4 heteroatoms each independently selected from N, O and S, the alkyl group, alkylhydroxy group, heterocyclylene group, aryl group, arylene group, heteroarylene group, heteroaryl group, heterocyclylene group, Cycloalkyl and cycloalkylene groups may optionally be substituted by one, two or more selected from halogen, cyano, amino, hydroxyl, hydroxyalkyl, mercapto, -C(O)O-alkyl, -OC( O)-alkyl, carboxyl, oxo, (=CH 2 ), -CONH 2 , -NHC(O)C 1-6 alkyl, C 1-6 alkyl -NHCOC 1-6 alkylene, alkyl group, alkylamino, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkyl substituted pyrazolyl, arylene C 1-6 alkyl, aryl C 1-6 alkyl Alkyl, (C 1-6 alkoxy) C 1-6 alkylene-, (C 1-6 alkyl) C (=O)-, (C 1-6 haloalkyl) C (=O)- , -CH 2 NHCOC 1-6 alkyl, C 1-6 alkylene cyano, C 2-6 alkenyl and C 2-6 alkynyl substituents substituted; preferably, R 3 is selected from C 1- 6 alkyl group, C 1-6 alkyl hydroxyl group, -L-(3-12 membered heterocyclyl group), -L-(6-10 membered arylene group), -L-(6-10 membered arylene group) -L-(3-12 membered heterocyclyl), -L-(5-12 membered heteroarylene) -L-(3-12 membered heterocyclyl), -L-(5-12 membered heteroarylene) ), -L-(3-12 membered heterocyclylene)-L-OCO-N(R 5 ) 2 , -L-(3-12 membered heterocyclylene)-L-NR 5 -CO-N( R 5 ) 2 , -L-(3-12 membered heterocyclylene)-L-NR 5 -CO-R 5 , -L-(3-10 membered cycloalkyl), -L-(3-10 membered Cycloalkylene)-LN(R 5 ) 2 , -L-(3-10-membered cycloalkylene)-L-(3-12-membered heterocyclylene) and -L-(3-10-membered cycloalkylene) base)-LN(R 5 ) 2 , wherein the 3-12-membered heterocyclyl group, 3-12-membered heterocyclylene group, 5-12-membered heteroarylene group and 5-12-membered heteroarylene group are each independently contains 1, 2, or 3 heteroatoms each independently selected from N, O and S, the C 1-6 alkyl group, C 1-6 alkylene hydroxyl group, 3-12 membered heterocyclyl group, 6- 10-membered aryl, 6-10-membered arylene, 5-12-membered heteroarylene, 5-12-membered heteroarylene, 3-12-membered heterocyclylene, 3-10-membered cycloalkyl and 3-10 The one-membered cycloalkylene group may be optionally replaced by one, two or more members selected from F, Cl, Br, I, cyano, amino, hydroxyl, C 1-6 hydroxyalkyl, mercapto, -C(O)OC 1-6 alkyl, -OC(O)-C 1-6 alkyl, carboxyl, oxo group, (=CH 2 ), -CONH 2 , -NHC(O)C 1-6 alkyl, C 1- 6 alkyl-NHCOC 1-6 alkylene, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkyl substituted Pyrazolyl , arylene C 1-6 alkyl, aryl C 1-6 alkylene, (C 1-6 alkoxy) C 1-6 alkylene-, (C 1-6 alkyl) C(=O)-, (C 1-6 haloalkyl)C(=O)-, -CH 2 NHCOC 1-6 alkyl, C 1-6 alkylenecyano, C 2-6 alkenyl and C Substituted by 2-6 alkynyl substituents;
    L每次出现时各自独立地选自共价键、C1-6亚烷基、C1-6羟亚烷基、-C(O)C1-6亚烷基、-C(O)O-、-OC(O)-、C1-6氘代亚烷基、C1-6卤代亚烷基、亚环烷基、亚杂环基、亚芳基和亚杂芳基，任选地，所述C1-6亚烷基、C1-6羟亚烷基、C1-6氘代亚烷基、C1-6卤代亚烷基、亚环烷基、亚杂环基、亚芳基和亚 杂芳基被一个、两个或更多个选自F、Cl、Br、I、氰基、氨基、羟基、C1-6羟烷基、巯基、-C(O)O-C1-6烷基、-OC(O)-C1-6烷基、羧基、氧代基、(＝CH2)、-CONH2、-NHC(O)C1-6烷基、C1-6烷基-NHCOC1-6亚烷基、C1-6烷基、C1-6烷基氨基、C1-6卤代烷基、C1-6烷氧基、亚芳基C1-6烷基、芳基C1-6亚烷基、(C1-6烷氧基)C1-6亚烷基-、(C1-6烷基)C(＝O)-、(C1-6卤代烷基)C(＝O)-、-CH2NHCOC1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基的取代基所取代；Each occurrence of L is independently selected from covalent bond, C 1-6 alkylene, C 1-6 hydroxyalkylene, -C(O)C 1-6 alkylene, -C(O)O -, -OC(O)-, C 1-6 deuterated alkylene, C 1-6 haloalkylene, cycloalkylene, heterocyclylene, arylene and heteroarylene, optional Ground, the C 1-6 alkylene group, C 1-6 hydroxyalkylene group, C 1-6 deuterated alkylene group, C 1-6 haloalkylene group, cycloalkylene group, heterocyclylene group , arylene and arylene The heteroaryl group is one, two or more selected from F, Cl, Br, I, cyano, amino, hydroxyl, C 1-6 hydroxyalkyl, mercapto, -C(O)OC 1-6 alkyl , -OC(O)-C 1-6 alkyl, carboxyl, oxo group, (=CH 2 ), -CONH 2 , -NHC(O)C 1-6 alkyl, C 1-6 alkyl-NHCOC 1-6 alkylene, C 1-6 alkyl , C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 alkoxy, arylene C 1-6 alkyl , aryl C 1-6 alkylene, (C 1-6 alkoxy) C 1-6 alkylene-, (C 1-6 alkyl) C (=O)-, (C 1-6 haloalkyl) C ( =O)-, -CH 2 NHCOC 1-6 alkyl, C 1-6 alkylene cyano, C 2-6 alkenyl and C 2-6 alkynyl substituents substituted;
    R5每次出现独立地选自氢、卤素、氰基、氨基、羟基、羟基亚烷基、巯基、-C(O)O-烷基、-OC(O)-烷基、羧基、氧代基、(＝CH2)、-CONH2、-NHC(O)C1-6烷基、C1-6烷基-NHCOC1-6烷基、烷基、烷基氨基、C1-6卤代烷基、C1-6烷氧基、C1-6烷基取代的吡唑基、亚芳基C1-6烷基、芳基C1-6亚烷基、(C1-6烷氧基)C1-6亚烷基-、(C1-6烷基)C(＝O)-、(C1-6卤代烷基)C(＝O)-、-CH2NHCO C1-6烷基、C1-6亚烷基氰基、C2-6烯基和C2-6炔基；Each occurrence of R 5 is independently selected from hydrogen, halogen, cyano, amino, hydroxyl, hydroxyalkylene, mercapto, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, oxo Base, (=CH 2 ), -CONH 2 , -NHC(O)C 1-6 alkyl, C 1-6 alkyl -NHCOC 1-6 alkyl, alkyl, alkylamino, C 1-6 haloalkyl base, C 1-6 alkoxy group, C 1-6 alkyl substituted pyrazolyl group, arylene C 1-6 alkyl group, aryl C 1-6 alkylene group, (C 1-6 alkoxy group )C 1-6 alkylene-, (C 1-6 alkyl)C (=O)-, (C 1-6 haloalkyl) C (=O)-, -CH 2 NHCO C 1-6 alkyl , C 1-6 alkylene cyano group, C 2-6 alkenyl group and C 2-6 alkynyl group;
    Cy2为与Cy1稠合连接的芳基、饱和或部分不饱和的环烷基、含有1、2或3个各自独立选自N、O和S的杂原子的杂芳基、含有1、2或3个各自独立选自N、O和S的杂原子的饱和的杂环烷基、或含有1、2或3个各自独立选自N、O和S的杂原子的部分不饱和的杂环烷基，所述芳基、饱和或部分不饱和的环烷基、杂芳基、杂环烷基可任选地被1个、2个、3个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、烷氧基、烷基氨基、亚烷基羟基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基的取代基所取代，任选地，所述烷基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基被1个、2个、3个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、烷氧基、烷基氨基、亚烷基羟基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基的取代基所取代；Cy2为与Cy1稠合连接的6-10元芳基、饱和或部分不饱和的3-10元环烷基、含有1、2或3个各自独立选自N、O和S的杂原子的5-10元杂芳基、含有1、2或3个各自独立选自N、O和S的杂原子的5-10元饱和杂环烷基、或含有1、2或3个各自独立选自N、O和S的杂原子的5-10元部分不饱和杂环烷基，所述芳基、饱和或部分不饱和的环烷基、杂芳基、杂环烷基可任选地被1个、2个、3个或多个选自F、Cl、Br、I、C1-6烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、C6-10芳基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、和C5-10杂芳基的取代基所取代，任选地，所述C1-6烷基、C6-10芳基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、和C5-10杂芳基被1个、2个、3个或多个选自F、Cl、Br、I、C1-6烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、C6-10芳基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、和C5-10杂芳基的取代基所取代；优选地，Cy2选 自其中表示与R4的连接位点，表示Cy2与Cy1稠合位置；Cy 2 is an aryl group fused to Cy 1 , a saturated or partially unsaturated cycloalkyl group, a heteroaryl group containing 1, 2 or 3 heteroatoms each independently selected from N, O and S, containing 1, A saturated heterocycloalkyl group with 2 or 3 heteroatoms each independently selected from N, O and S, or a partially unsaturated heterocycloalkyl group containing 1, 2 or 3 heteroatoms each independently selected from N, O and S. Cycloalkyl, the aryl, saturated or partially unsaturated cycloalkyl, heteroaryl, heterocycloalkyl can optionally be 1, 2, 3 or more selected from halogen, alkyl, Hydroxy, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl , heterocyclyl, and heteroaryl substituents, optionally, the alkyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl groups are substituted by 1, 2 One, three or more selected from halogen, alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylene Substituted with hydroxyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents; Cy 2 is a 6-10 membered aryl group fused to Cy 1 , saturated or partially un Saturated 3-10 membered cycloalkyl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms each independently selected from N, O and S, 5-10 membered heteroaryl containing 1, 2 or 3 each independently selected from N , a 5-10 membered saturated heterocycloalkyl group with heteroatoms of O and S, or a 5-10 membered partially unsaturated heterocycloalkyl group containing 1, 2 or 3 heteroatoms each independently selected from N, O and S , the aryl group, saturated or partially unsaturated cycloalkyl group, heteroaryl group, heterocycloalkyl group can optionally be 1, 2, 3 or more selected from F, Cl, Br, I, C 1-6 alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl Amino, C 1-6 alkylenehydroxy, C 6-10 aryl, C 2-6 alkynyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl , and C 5-10 heteroaryl substituents, optionally, the C 1-6 alkyl, C 6-10 aryl, C 2-6 alkynyl, C 2-6 alkenyl, C 3-10 Cycloalkyl, C 3-10 heterocyclyl, and C 5-10 heteroaryl are 1, 2, 3 or more selected from F, Cl, Br, I, C 1-6 alkyl, hydroxyl , cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylene Substitution of hydroxyl, C 6-10 aryl, C 2-6 alkynyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, and C 5-10 heteroaryl Substituted with radicals; preferably, Cy 2 is selected since in Indicates the connection site with R 4 , Indicates the fused position of Cy 2 and Cy 1 ;
    q为0，1，或2；q is 0, 1, or 2;
    Ra每次出现时各自独立地选自氢、卤素、烷基、炔基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、芳基、C2-6烯基、环烷基、杂环基、和杂芳基，任选地，所述烷基、炔基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、芳基、C2-6烯基、环烷基、杂环基、和杂芳基被被1个、2个、3个或多个选自F、Cl、Br、I、C1-6烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、C6-10芳基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、和C5-10杂芳基的取代基所取代；当R2含有2个环N原子时，Cy2为且Ra为H时，R4是R3是当Cy2是且Ra为H时，R4是R3是 Each occurrence of R a is independently selected from hydrogen, halogen, alkyl, alkynyl, hydroxy, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, C 1-6 Alkoxy, C 1-6 alkylamino, C 1-6 alkylenehydroxy, aryl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, and heteroaryl, optionally, the Alkyl, alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylenehydroxy, aryl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, and The heteroaryl group is 1, 2, 3 or more selected from F, Cl, Br, I, C 1-6 alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl Base, -CO-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylene hydroxy, C 6-10 aryl, C 2-6 alkynyl , C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, and C 5-10 heteroaryl substituents; when R 2 contains 2 ring N atoms, Cy 2 for And when R a is H, R 4 is R 3 is When Cy 2 is And when R a is H, R 4 is R 3 is
    当与Rb连接的为双键时，Rb每次出现时各自独立地为O、S或者C(R5)2；当与Rb连接的为单键时，Rb每次出现时各自独立地选自氢、卤素、烷基、烷氧基、羟基、氰基、氨基、氨基烷基、亚烷基氨基、环烷基、杂环基、-CONH2、-NHCOC1-6烷基、-CO-烷基、亚烷基羟基、芳基、炔基、烯基、和杂芳基，优选地，Rb每次出现时各自独立地选自氢、F、Cl、Br、I，C1-6烷基、C1-6烷氧基、羟基、氰基、氨基、氨基C1-6烷基、C1-6亚烷基氨基、C3-10环烷基、C3-10杂环基、-CONH2、-NHCOC1-6烷基、-CO-C1-6烷基、C1-6亚烷基羟基、C6-10芳基、C2-6炔基、C2-6烯基、和C5-10杂芳基；When connected to R b When it is a double bond, R b is independently O, S or C(R 5 ) 2 each time it appears; when it is connected to R b When it is a single bond, each occurrence of R b is independently selected from hydrogen, halogen, alkyl, alkoxy, hydroxyl, cyano, amino, aminoalkyl, alkyleneamino, cycloalkyl, heterocyclyl , -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkylenehydroxy, aryl, alkynyl, alkenyl, and heteroaryl, preferably, each occurrence of R b is independently Selected from hydrogen, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, cyano, amino, amino C 1-6 alkyl, C 1-6 alkylene amino , C 3-10 cycloalkyl, C 3-10 heterocyclyl, -CONH 2 , -NHCOC 1-6 alkyl, -CO-C 1-6 alkyl, C 1-6 alkylene hydroxyl, C 6 -10 aryl, C 2-6 alkynyl, C 2-6 alkenyl, and C 5-10 heteroaryl;
    Rc选自H、C1-6烷基、-CN、-≡-Rca、-CONH2和-OCONH2；当R2含有2个环N原子时，且当Rc为C1-6烷基或H时，R1为N时，R4为 当R2含有2个环N原子时，当Rc为H时，R1为CR1a，R1a为 CN时，R4为R3为 R c is selected from H, C 1-6 alkyl, -CN, -≡-R ca , -CONH 2 and -OCONH 2 ; when R 2 contains 2 ring N atoms, and when R c is C 1-6 When R 1 is N, R 4 is When R 2 contains 2 ring N atoms, when R c is H, R 1 is CR 1a , and R 1a is When CN, R 4 is R 3 is
    Rca每次出现时，每个Rca各自独立地选自氢、氨基、羟基、卤素、氰基、-CONH2、-NHC(O)C1-6烷基、-CO-C1-6烷基、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基氨基、C1-6亚烷基NHC1-6烷基、C1-6亚烷基羟基、C2-6炔基、C2-6烯基、环烷基、杂环基、和杂芳基，任选地，所述C1-6烷基、C1-6亚烷基、C2-6炔基、C2-6烯基、环烷基、杂环基、芳基和杂芳基被1个、2个、3个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、烷氧基、烷基氨基、亚烷基羟基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基的取代基所取代；优选地，Rca每次出现时，每个Rca各自独立地选自氢、氨基、羟基、F、Cl、Br、I、氰基、-CONH2、-NHC(O)C1-6烷基、-CO-C1-6烷基、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基氨基、C1-6亚烷基NHC1-6烷基、C1-6亚烷基羟基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、C6-10芳基和C5-10杂芳基，任选地，所述C1-6烷基、C1-6亚烷基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、C6-10芳基和C5-10杂芳基被1个、2个、3个或多个选自F、Cl、Br、I、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、烷氧基、烷基氨基、亚烷基羟基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基的取代基所取代；优选地，Rca每次出现时，每个Rca各自独立地选自氢、-CH3、-C(CH3)3、-C(CH3)2OH、-CH(CH3)OH、-C2H5、-C3H7、-C4H9、-CH2OH、-C2H4OH、-C3H6OH、-CH2NH2、-CH2NHCH3、和环丙基；Each occurrence of R ca , each R ca is independently selected from hydrogen, amino, hydroxyl, halogen, cyano, -CONH 2 , -NHC(O)C 1-6 alkyl, -CO-C 1-6 Alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylene amino, C 1-6 alkylene NHC 1-6 alkyl, C 1-6 alkylene hydroxyl, C 2-6 alkynyl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, and heteroaryl, optionally, the C 1-6 alkyl, C 1 -6 alkylene, C 2-6 alkynyl, C 2-6 alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are 1, 2, 3 or more selected from halogen, Alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylenehydroxy, aryl, alkynyl, alkenyl, Substituted with cycloalkyl, heterocyclyl, and heteroaryl substituents; preferably, each time R ca occurs, each R ca is independently selected from hydrogen, amino, hydroxyl, F, Cl, Br, I , cyano group, -CONH 2 , -NHC(O)C 1-6 alkyl, -CO-C 1-6 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl amino group, C 1-6 alkylene amino group, C 1-6 alkylene NHC 1-6 alkyl group, C 1-6 alkylene hydroxyl group, C 2-6 alkynyl group, C 2-6 alkenyl group, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl and C 5-10 heteroaryl, optionally, the C 1-6 alkyl, C 1-6 alkylene , C 2-6 alkynyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl and C 5-10 heteroaryl are replaced by 1, 2 One, three or more selected from F, Cl, Br, I, alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkyl substituted with substituents of amino, alkylenehydroxy, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl; preferably, each time R ca appears, each R ca is Independently selected from hydrogen, -CH 3 , -C(CH 3 ) 3 , -C(CH 3 ) 2 OH, -CH(CH 3 )OH, -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -CH 2 OH, -C 2 H 4 OH, -C 3 H 6 OH, -CH 2 NH 2 , -CH 2 NHCH 3 , and cyclopropyl;
    当R2为R4为 且当Rca 为氢时，Rd为氟时，Y为O时，R3不为 When R 2 is R 4 is And when R ca When it is hydrogen, when R d is fluorine, when Y is O, when R 3 is not
    Rd每次出现时各自独立地选自氢、氟、氯、溴、碘、氰基、羟基、巯基、羟基亚烷基、羧基、氧代基、烷氧基、氨基、-CONH2、-NHC(O)烷基、烷基、C1-6亚烷基氰基、-CO-烷基、烷基氨基、亚烷基氨基、亚烷基NH烷基、芳基、环烷基、杂环基、杂芳基、烯基和炔基，任选地，所述烷基、亚烷基、炔基、烯基、环烷基、杂环基、芳基和杂芳基被1个、2个、3个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、烷氧基、烷基氨基、亚烷基羟基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基的取代基所取代；优选地，Rd每次出现时各自独立地选自氢、氟、氯、溴、碘、氰基、羟基、巯基、羟基C1-6亚烷基、羧基、氧代基、C1-6烷氧基、氨基、-CONH2、-NHC(O)C1-6烷基、C1-6烷基、C1-6亚烷基氰基、-CO-C1-6烷基、C1-6烷基氨基、C1-6亚烷基氨基、C1-6亚烷基NH烷基、C6-10芳基、C3-10环烷基、C3-10杂环基、C5-10杂芳基、C2-6烯基和C2-6炔基，任选地，所述C1-6烷基、C1-6亚烷基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、C6-10芳基和C5-10杂芳基被1个、2个、3个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、C6-10芳基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、和C5-10杂芳基的取代基所取代；Each occurrence of R d is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, hydroxy, mercapto, hydroxyalkylene, carboxyl, oxo, alkoxy, amino, -CONH 2 , - NHC(O)alkyl, alkyl, C 1-6 alkylenecyano, -CO-alkyl, alkylamino, alkyleneamino, alkyleneNHalkyl, aryl, cycloalkyl, hetero Cyclic group, heteroaryl group, alkenyl group and alkynyl group, optionally, the alkyl group, alkylene group, alkynyl group, alkenyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are replaced by 1, 2, 3 or more selected from halogen, alkyl, hydroxyl, cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylene hydroxyl, aryl, alkynyl, alkenyl, cycloalkyl, heterocyclyl, and heteroaryl substituents; preferably, each occurrence of R d is independently selected from hydrogen, fluorine, chlorine, Bromine, iodine, cyano, hydroxyl, mercapto, hydroxy C 1-6 alkylene, carboxyl, oxo, C 1-6 alkoxy, amino, -CONH 2 , -NHC(O)C 1-6 alkane group, C 1-6 alkyl, C 1-6 alkylene cyano, -CO-C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkylene amino, C 1-6 Alkylene NH alkyl, C 6-10 aryl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 5-10 heteroaryl, C 2-6 alkenyl and C 2-6 alkyne base, optionally, the C 1-6 alkyl group, C 1-6 alkylene group, C 2-6 alkynyl group, C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 3-10 hetero group The ring group, C 6-10 aryl group and C 5-10 heteroaryl group are 1, 2, 3 or more selected from halogen, alkyl, hydroxyl, cyano group, amino, -CONH 2 , -NHCOC 1 -6 alkyl, -CO-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylene hydroxy, C 6-10 aryl, C 2- Substituted with substituents of 6 alkynyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, and C 5-10 heteroaryl;
    R4选自被0、1、2、3、4、5、或更多个R4a取代的芳基和杂芳基，所述杂芳基包含1、2、3或4个各自独立选自N、O和S的杂原子；优选地，R4选自被0、1、2、3、4、5、或更多个R4a取代的6-12元芳基和5-12元杂芳基，所述5-12元杂芳基包含1、2、3或4个各自独立选自N、O和S的杂原子；优选地，R4选自被0、1、2、3、4、5、或更多个R4a取代的苯基、萘基、5-6元杂芳基、7-8元杂芳基、9-10元杂芳基、和苯并5-6元杂芳基，所述5-6元杂芳基、7-8元杂芳基、9-10元杂芳基、和苯并5-6元杂芳基包含1、2、3或4个各自独立选自N、O和S的杂原子；R4a每次出现时各自独立地选自卤素、炔基、烯基、亚炔基烷基、亚烯基烷基、亚烷基氰基、烷氧基、-OH、-SH、-NH2、-NH-R4c、-CN、-CO-烷基、-CON(R4c)2、烷基-CO-NR4c-、烷基、卤代烷基、卤代烷氧基、烷基氨基、亚烷基氨基、环烷基、亚环烷基烷基、芳基、杂芳基、杂环烷基和亚杂环烷基烷基，任选地，所述炔基、烯基、亚炔基、 亚烯基、亚烷基、烷氧基、烷基、环烷基、芳基、杂芳基、杂环烷基和亚杂环烷基被一个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-烷基、烷氧基、烷基氨基、亚烷基羟基、芳基、炔基、烯基、环烷基、杂环基、和杂芳基的取代基所取代；优选地，R4a每次出现独立地选自C1-6烷基、F、Cl、Br、I、C2-6炔基、C2-6烯基、C2-6亚炔基C1-6烷基、C2-6亚烯基C1-6烷基、C1-6亚烷基氰基、C1-6烷氧基、-OH、-SH、-NH2、-NH-R4c、-CN、-CO 1-6烷基、-CON(R4c)2、C1-6烷基-CO-NR4c-、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基氨基、3-10元环烷基、3-10元亚环烷基C1-6烷基、3-10元杂环烷基和3-10元亚杂环烷基C1-6烷基，任选地，所述C2-6炔基、C2-6烯基、C2-6亚炔基、C2-6亚烯基、C1-6亚烷基、C1-6烷氧基、C1-6烷基、C3-10环烷基、C6-10芳基、C5-10杂芳基、C3-10杂环烷基和C3-10亚杂环烷基被一个或多个选自卤素、烷基、羟基、氰基、氨基、-CONH2、-NHCOC1-6烷基、-CO-C1-6烷基、C1-6烷氧基、C1-6烷基氨基、C1-6亚烷基羟基、C6-10芳基、C2-6炔基、C2-6烯基、C3-10环烷基、C3-10杂环基、和C5-10杂芳基的取代基所取代；R 4 is selected from aryl and heteroaryl substituted by 0, 1, 2, 3, 4, 5, or more R 4a , and the heteroaryl contains 1, 2, 3 or 4 each independently selected from Heteroatoms of N, O and S; preferably, R 4 is selected from 6-12-membered aryl and 5-12-membered heteroaryl substituted by 0, 1, 2, 3, 4, 5, or more R 4a base, the 5-12 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S; preferably, R 4 is selected from 0, 1, 2, 3, 4 , 5, or more R 4a substituted phenyl, naphthyl, 5-6 membered heteroaryl, 7-8 membered heteroaryl, 9-10 membered heteroaryl, and benzo 5-6 membered heteroaryl base, the 5-6-membered heteroaryl, 7-8-membered heteroaryl, 9-10-membered heteroaryl, and benzo 5-6-membered heteroaryl include 1, 2, 3 or 4 independently selected heteroatoms from N, O, and S; each occurrence of R 4a is independently selected from halogen, alkynyl, alkenyl, alkynylenealkyl, alkenylenealkyl, alkylenecyano, alkoxy , -OH, -SH, -NH 2 , -NH-R 4c , -CN, -CO-alkyl, -CON(R 4c ) 2 , alkyl-CO-NR 4c -, alkyl, haloalkyl, haloalkyl Oxy, alkylamino, alkyleneamino, cycloalkyl, cycloalkylenealkyl, aryl, heteroaryl, heterocycloalkyl and heterocycloalkylenealkyl, optionally, the alkyne base, alkenyl, alkynylene, Alkenylene, alkylene, alkoxy, alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl and heterocycloalkylene are substituted by one or more selected from halogen, alkyl, hydroxyl, Cyano, amino, -CONH 2 , -NHCOC 1-6 alkyl, -CO-alkyl, alkoxy, alkylamino, alkylene hydroxy, aryl, alkynyl, alkenyl, cycloalkyl, hetero Substituted with cyclic and heteroaryl substituents; preferably, each occurrence of R 4a is independently selected from C 1-6 alkyl, F, Cl, Br, I, C 2-6 alkynyl, C 2- 6 alkenyl, C 2-6 alkynylene C 1-6 alkyl, C 2-6 alkenylene C 1-6 alkyl, C 1-6 alkylene cyano, C 1-6 alkoxy, -OH, -SH, -NH 2 , -NH-R 4c , -CN, -CO 1-6 alkyl, -CON(R 4c ) 2 , C 1-6 alkyl -CO-NR 4c -, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylene amino, 3-10-membered cycloalkyl, 3-10-membered cycloalkylene C 1-6 alkyl, 3-10 membered heterocycloalkyl and 3-10 membered heterocycloalkylene C 1-6 alkyl, optionally, the C 2-6 alkynyl, C 2-6 alkene Base , C 2-6 alkynylene, C 2-6 alkenylene, C 1-6 alkylene, C 1-6 alkoxy, C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 5-10 heteroaryl, C 3-10 heterocycloalkyl and C 3-10 heterocycloalkylene are one or more selected from halogen, alkyl, hydroxyl, cyano, amino , -CONH 2 , -NHCOC 1-6 alkyl, -CO-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylene hydroxyl, C 6 -Substituted with substituents of -10 aryl, C 2-6 alkynyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, and C 5-10 heteroaryl;
    R4c每次出现各自独立地选自氢、卤素、氰基、羟基、巯基、羟基亚烷基、-C(O)O-烷基、-OC(O)-烷基、羧基、氨基、-CONH2、-NHCOC1-6烷基、烷基、C1-6亚烷基氰基、烯基和炔基；Each occurrence of R 4c is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxyalkylene, -C(O)O-alkyl, -OC(O)-alkyl, carboxyl, amino, - CONH 2 , -NHCOC 1-6 alkyl, alkyl, C 1-6 alkylenecyano, alkenyl and alkynyl;
    式Ⅰ化合物不为：

    Compounds of formula I are not:

  2. 一种式Ⅰ化合物，或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，其中，
    A compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein,
    其中，R1为CR1a或N；R1a独立地选自氢、卤素、氰基、羟基、巯基、羟甲基、酯基、羧基、-CONH2、氨基、-NHCOC1-6烷基、烷基、C1-4烷基氰基、烯基和炔基；Wherein, R 1 is CR 1a or N; R 1a is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester group, carboxyl, -CONH 2 , amino, -NHCOC 1-6 alkyl, Alkyl, C 1-4 alkylcyano, alkenyl and alkynyl;
    R2为至少含1个N的3-12元饱和或部分饱和的单环、桥环或螺环，其中所述饱和或部分饱和的单环、桥环或螺环任选地被一个或多个R2a取代；每次R2a出现时，每个R2a分别独立地选自卤素、氰基、羟基、巯基、羟甲基、酯基、羧基、羰基、氨基、-CONH2-NHCOC1-6烷基、烷基、C1-4烷基氰基、烯基和炔基；优选地，R2为含1个环N的3-12元饱和或部分饱和的单环、桥环或螺环，其中所述饱和或部分饱和的单环、桥环或螺环任选地被一个或多个R2a取代；优选地，R2为含1个环N，并且含0、1、2或3个独立选自O和S的环杂原子的饱和或部分饱和的3、5、6、7、或8元单环、6、7、8、9、或10元桥环、4、5、6、7、8、9、或10元稠环、或5、6、7、8、9、10、11或12元螺环，其中所述饱和或部分饱和的单环、桥环、稠环或螺环任选地被一个或多个R2a取代；每次R2a出现时，每个R2a分别独立地选自卤素、氰基、羟基、巯基、羟甲基、-COO烷基、羧基、氧代基、-NH2、-CONH2、-NHC(O)C1-6烷基、烷基、C1-4烷基氰基、烯基和炔基；R 2 is a 3-12 membered saturated or partially saturated monocyclic ring, bridged ring or spirocyclic ring containing at least 1 N, wherein the saturated or partially saturated monocyclic ring, bridged ring or spirocyclic ring is optionally replaced by one or more Each R 2a is substituted; each time R 2a appears, each R 2a is independently selected from halogen, cyano, hydroxyl, sulfhydryl, hydroxymethyl, ester, carboxyl, carbonyl, amino, -CONH 2 -NHCOC 1- 6 alkyl, alkyl, C 1-4 alkyl cyano, alkenyl and alkynyl; preferably, R 2 is a 3-12 membered saturated or partially saturated monocyclic ring, bridged ring or spiro ring containing 1 ring N Ring, wherein the saturated or partially saturated monocyclic, bridged or spirocyclic ring is optionally substituted by one or more R 2a ; preferably, R 2 contains 1 ring N, and contains 0, 1, 2 or 3 saturated or partially saturated 3, 5, 6, 7, or 8-membered monocyclic rings, 6, 7, 8, 9, or 10-membered bridged rings, 4, 5, 6, 7, 8, 9 or 10-membered fused ring, or 5, 6, 7, 8, 9, 10, 11 or 12-membered spiro ring, wherein the saturated or partially saturated single ring, bridged ring or fused ring Or the spiro ring is optionally substituted by one or more R2a; each time R2a occurs, each R2a is independently selected from halogen, cyano, hydroxyl, mercapto, hydroxymethyl, -COO alkyl, carboxyl, Oxo, -NH 2 , -CONH 2 , -NHC(O)C 1-6 alkyl, alkyl, C 1-4 alkylcyano, alkenyl and alkynyl;
    Y为-CRxRy-、-O-、-S-、-S＝O-、-S(＝O)2-或-NRx-，Rx和Ry分别独立地选自氢、烷基、环烷基、杂环基、烷基氨基烷基、芳基和烷基芳基；Y is -CR x R y -, -O-, -S-, -S=O-, -S(=O) 2 - or -NR x -, R x and R y are independently selected from hydrogen, alkane base, cycloalkyl, heterocyclyl, alkylaminoalkyl, aryl and alkylaryl;
    R3为各自独立地选自氢、烷基、羟基烷基、二羟基烷基、烷基胺基烷基、二烷基胺基烷基、环烷基、杂环基、-L-N(R5)2、-L-NHC(＝NH)NH2、-L-C(O)N(R5)2、-L-NR5C(O)-芳基、-L-C1-6卤代烷基、-L-OR5、-L-杂环基、-L- 芳基、-L-杂芳基、-L-环烷基、氮杂饱和或部分饱和的单环或并环、和氧杂饱和或部分饱和的单环或稠环，其中所述杂芳基、芳基、饱和或部分饱和的单环或稠环部分以及-L-杂环基的所述杂环基部分和-L-环烷基的所述环烷基部分可任选被一个或多个R5取代；R 3 is each independently selected from hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, heterocyclyl, -LN (R 5 ) 2 , -L-NHC(=NH)NH 2 , -LC(O)N(R 5 ) 2 , -L-NR 5 C(O)-aryl, -LC 1-6 haloalkyl, -L- OR 5 , -L-heterocyclyl, -L- Aryl, -L-heteroaryl, -L-cycloalkyl, aza-saturated or partially saturated monocyclic or fused rings, and oxa-saturated or partially saturated monocyclic or condensed rings, wherein said heteroaryl , an aryl group, a saturated or partially saturated monocyclic or fused ring moiety and the heterocyclyl moiety of -L-heterocyclyl and the cycloalkyl moiety of -L-cycloalkyl may optionally be replaced by one or more R 5 substitution;
    每个L独立地选自C1-6亚烷基、C1-6羟烷基和杂芳基；Each L is independently selected from C 1-6 alkylene, C 1-6 hydroxyalkyl and heteroaryl;
    R5每次出现时，每个R5独立地选自氢、卤素、氰基、羟基、巯基、羟甲基、酯基、羧基、羰基、-NH2、-CONH2、-NHC(O)C1-6烷基、烷基、C1-4卤代烷基、C1-4烷氧基、C1-4烷基取代的吡唑基、芳基C1-4烷基、(C1-4烷氧基)C1-4烷基-、(C1-4烷基)C(＝O)-、(C1-4卤代烷基)C(＝O)-、-CH2NHCO C1-6烷基、C1-4烷基氰基、C2-6烯基和C2-6炔基；Each time R 5 occurs, each R 5 is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, carbonyl, -NH 2 , -CONH 2 , -NHC(O) C 1-6 alkyl, alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkyl substituted pyrazolyl, aryl C 1-4 alkyl, (C 1- 4Alkoxy )C 1-4 alkyl-, (C 1-4 alkyl)C(=O)-, (C 1-4 haloalkyl)C(=O)-, -CH 2 NHCO C 1- 6 alkyl, C 1-4 alkyl cyano, C 2-6 alkenyl and C 2-6 alkynyl;
    Cy2与Cy1稠合连接，且Cy2为芳基或含有1或2个杂原子的5-7元杂芳基、5-7元饱和杂环烷基或5-7元不饱和杂环烷基；且当Cy2为芳基或吡啶基时，具有结构式Ra每次出现时，每个Ra独立地选自氢、卤基、烷基、炔基、羟基、氰基、-CONH2、-NHCOC1-6烷基、-CO-烷基、C1-4烷氧基、C1-4烷基氨基、C1-4烷基羟基、芳基、C2-4炔基、C2-6烯基、环烷基、杂环基、杂芳基；Rc选自-CN、-≡-Rca、Rca每次出现时，每个Rca独立地选自氢、卤素、氰基、-COO-烷基、-NHC(O)C1-6烷基、-CO-烷基、C1-4烷基、C1-4烷氧基、C1-4烷基氨基、C1-4烷基羟基、芳基、C2-4炔基、C2-6烯基、环烷基、杂环基和杂芳基；Cy 2 is fused to Cy 1 , and Cy 2 is an aryl group or a 5-7-membered heteroaryl group containing 1 or 2 heteroatoms, a 5-7-membered saturated heterocycloalkyl group, or a 5-7-membered unsaturated heterocycle Alkyl; and when Cy 2 is aryl or pyridyl, it has the structural formula Each occurrence of R a is independently selected from hydrogen, halo, alkyl, alkynyl, hydroxy, cyano, -CONH 2 , -NHCOC 1-6 alkyl, -CO - alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylhydroxy, aryl, C 2-4 alkynyl, C 2-6 alkenyl , cycloalkyl, heterocyclyl, heteroaryl Base; R c is selected from -CN, -≡-R ca , Each occurrence of R ca , each R ca is independently selected from hydrogen, halogen, cyano, -COO-alkyl, -NHC(O)C 1-6 alkyl, -CO-alkyl, C 1-4 Alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylhydroxy, aryl, C 2-4 alkynyl, C 2-6 alkenyl, cycloalkyl, heterocycle base and heteroaryl;
    每次Rd出现时各自独立地选自氢、卤素、氰基、羟基、巯基、羟甲基、酯基、羧基、氧代、氧烷基、氨基、-CONH2、-NHC(O)C1-6烷基、烷基、C1-4烷基氰基、烯基和炔基；Each occurrence of R d is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, oxo, oxyalkyl, amino, -CONH 2 , -NHC(O)C 1-6 alkyl, alkyl, C 1-4 alkylcyano, alkenyl and alkynyl;
    R4选自被1、2、或3个R4a或1、2或3个R4b取代的苯基、萘基、5-6元杂芳基、苯并5-6元杂环基、苯并5-6元环烯基和苯并5-6元杂芳基；每个R4a独立地选自卤基、-OH、-SH、-NH2、-CN、-CO-烷基、-CON(R4c)2、C1-4烷基、卤代C1-4烷基、卤代C1-4烷氧基、C1-4烷基氨基、二C1-4烷基氨基、3-7元环烷基、4-7元杂环烷基和4-7元杂环烷基C1-4烷基；每个R4b分别各自独立地选自卤基、-OH、-SH、-NH2、-NO2、-CN、-CO-烷基、-CON(R4c)2、三唑基、C1-6烷基、C2-6烯基、C2-4炔基、C1-6烷氧基、C1-6的烷硫基、C1-6的烷基氨基、C1-6的烷基氰基、二C1-6烷基氨基、氨基C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6的烷基氨基、卤代C1-6烷硫基、二(卤代C1-6烷基)氨基；R4c每次出现时，每个R4c各自独立地选自氢、卤素、氰基、羟基、巯基、羟甲基、酯基、羧基、氨基、-CONH2、-NHCOC1-6烷基、烷基、C1-4烷基氰基、烯基和炔基，或者由两个连接到同一个C原子的R4c形成＝O； R 4 is selected from phenyl, naphthyl, 5-6 membered heteroaryl, benzo 5-6 membered heterocyclyl, benzene substituted with 1, 2, or 3 R 4a or 1, 2 or 3 R 4b and 5-6 membered cycloalkenyl and benzo 5-6 membered heteroaryl; each R 4a is independently selected from halo, -OH, -SH, -NH 2 , -CN, -CO-alkyl, - CON(R 4c ) 2 , C 1-4 alkyl, halo C 1-4 alkyl, halo C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl and 4-7 membered heterocycloalkyl C 1-4 alkyl; each R 4b is independently selected from halo, -OH, -SH , -NH 2 , -NO 2 , -CN, -CO-alkyl, -CON(R 4c ) 2 , triazolyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-4 alkynyl , C 1-6 alkoxy group, C 1-6 alkylthio group, C 1-6 alkylamino group, C 1-6 alkylcyano group, di-C 1-6 alkylamino group, amino C 1- 6 alkyl, halo C 1-6 alkyl , halo C 1-6 alkoxy, halo C 1-6 alkylamino, halo C 1-6 alkylthio, di(halo C 1 -6 alkyl) amino; each time R 4c appears, each R 4c is independently selected from hydrogen, halogen, cyano, hydroxyl, mercapto, hydroxymethyl, ester, carboxyl, amino, -CONH 2 , - NHCOC 1-6 alkyl, alkyl, C 1-4 alkylcyano, alkenyl and alkynyl, or formed from two R 4c attached to the same C atom =O;
    当R4为时，m为0至6的整数，每次R4a出现时，每个R4a独立地选自H、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、卤素、-OH、-SH、-CN、-COR5、-CON(R5)2、-OCON(R5)2和-≡-Rca；When R 4 is When, m is an integer from 0 to 6, each time R 4a appears, each R 4a is independently selected from H, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl , halogenated C 1-4 alkoxy, halogen, -OH, -SH, -CN, -COR 5 , -CON(R 5 ) 2 , -OCON(R 5 ) 2 and -≡-R ca ;
    每次Rca出现时，每个Rca独立地选自氢、卤素、-CN、-COO-烷基、-CONH2、-NHCOC1-6烷基、-CO-烷基、C1-4烷基、C1-4烷氧基、C1-4烷基氨基、C1-4烷基羟基、芳基、C2-4炔基、C2-6烯基、环烷基、杂环基和杂芳基；Each occurrence of Rca is independently selected from hydrogen, halogen, -CN, -COO- alkyl , -CONH2 , -NHCOC1-6alkyl, -CO-alkyl, C1-4alkyl , C1-4alkoxy , C1-4alkylamino, C1-4alkylhydroxy, aryl, C2-4alkynyl , C2-6alkenyl , cycloalkyl , heterocyclyl, and heteroaryl;
    每次R6出现时，R6独立地选自H和C1-4烷基；Each time R 6 occurs, R 6 is independently selected from H and C 1-4 alkyl;
    优选地，式Ⅰ化合物不为：

    Preferably, the compound of formula I is not:

  3. 如权利要求1或2所述的化合物，或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，其特征在于，R4选自


    The compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, Characteristically, R 4 is selected from


  4. 如权利要求1所述的化合物，或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，其特征在于，R2选自 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein R 2 is selected from
  5. 如权利要求1所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，其中，R3选自C1-6烷基、 The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein R 3 Selected from C 1-6 alkyl,
    其中，n＝0、1、2或3；每次R3b出现时独立地选自共价键、-COC1-6亚烷基、C1-6亚烷基、C1-6氘代亚烷基、亚环烷基、C1-6卤代亚烷基、亚杂环基、亚芳基和亚杂芳基；和wherein n=0, 1, 2 or 3; each occurrence of R 3b is independently selected from a covalent bond, -COC 1-6 alkylene, C 1-6 alkylene, C 1-6 deuterated alkylene, cycloalkylene, C 1-6 haloalkylene, heterocyclylene, arylene and heteroarylene; and
    每次R3c出现时，每个R3c独立地选自氢、氘原子、卤基、C1-6烷基、-CONH2、-NHCOC1-6烷基、C1-6烷基-NHCOC1-6烷基、羟基、氨基、羟基亚烷基、氰基、烷基氨基、卤代烷基、C1-6烷氧基。Each time R 3c occurs, each R 3c is independently selected from hydrogen, a deuterium atom, a halogen group, a C 1-6 alkyl group, -CONH 2 , -NHCOC 1-6 alkyl group, a C 1-6 alkyl group-NHCOC 1-6 alkyl group, a hydroxyl group, an amino group, a hydroxyalkylene group, a cyano group, an alkylamino group, a haloalkyl group, and a C 1-6 alkoxy group.
  6. 如权利要求1或5所述的化合物，或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，其特征在于，R3选自


    The compound of claim 1 or 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, Characteristically, R 3 is selected from


  7. 如权利要求1所述的化合物，或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，其特征在于，选自 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, characterized in that , selected from
    优选地，所述化合物的药学上可接受的盐为所述化合物的酸式盐，优选所述化合物的药学上可接受的盐为所述化合物的有机酸式盐，优选所述化合物的药学上可接受的盐为所述化合物的甲酸盐，优选每摩尔所述化合物的甲酸盐含0.1-3摩尔的甲酸离子，优选每摩尔所述化合物的甲酸盐含0.1、0.2、0.3、0.4、0.5、1、2或3摩尔甲酸离子。 Preferably, the pharmaceutically acceptable salt of the compound is an acid salt of the compound, preferably the pharmaceutically acceptable salt of the compound is an organic acid salt of the compound, preferably the pharmaceutically acceptable salt of the compound is a formate salt of the compound, preferably the formate salt contains 0.1-3 moles of formate ions per mole of the compound, preferably the formate salt contains 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2 or 3 moles of formate ions per mole of the compound.
  8. 如权利要求1所述的化合物，或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，其特征在于，所述化合物选自 The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, characterized in that , the compound is selected from
    优选地，所述化合物的药学上可接受的盐为所述化合物的酸式盐，优选所述化合物的药学上可接受的盐为所述化合物的有机酸式盐，优选所述化合物的药学上可接受的盐为所述化合物的甲酸盐，优选每摩尔所述化合物的甲酸盐含0.1-3摩尔的甲酸离子，优选每摩尔所述化合物的甲酸盐含0.1、0.2、0.3、0.4、0.5、1、2或3摩尔甲酸离子。Preferably, the pharmaceutically acceptable salt of the compound is an acid salt of the compound. Preferably, the pharmaceutically acceptable salt of the compound is an organic acid salt of the compound. Preferably, the pharmaceutically acceptable salt of the compound is an organic acid salt of the compound. Acceptable salts are formate salts of the compound, preferably each mole of the formate salt of the compound contains 0.1-3 moles of formate ions, preferably each mole of the formate salt of the compound contains 0.1, 0.2, 0.3, 0.4 , 0.5, 1, 2 or 3 moles of formate ions.
  9. 如权利要求1-8中任一项所述的化合物，或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物的制备方法，其特征在于，包括：The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterium thereof The preparation method of generation compound is characterized in that it includes:
    方案a):在碱和DMF的作用下，以含氮杂环R2，与中间体化合物进行选择性亲核取代得到化合物然后，将含有R4基团的丙烯基胺与甲酯化合物Ⅲ-4在LiHMDS的作用下发生胺酯交换得到 酰胺化合物再利用具有式H-Y-R3的亲核试剂，在碳酸铯和1,4-二氧六环为溶剂下，取代酰胺化合物III-5中的氯并引入取代基-Y-R3得到化合物随后，化合物Ⅲ-6在钯催化剂和有机碱的作用下进行Heck反应，得到含环外双键的中间体化合物，然后，将所述含环外双键的中间体化合物经脱保护即得式Ⅰ化合物；Scheme a): Under the action of base and DMF, nitrogen-containing heterocycle R 2 is used with the intermediate compound Selective nucleophilic substitution gives compounds Then, the allylamine containing R 4 group and the methyl ester compound III-4 undergo amine ester exchange under the action of LiHMDS to obtain Amide compounds Then use the nucleophile with the formula HYR 3 , in the presence of cesium carbonate and 1,4-dioxane as the solvent, replace the chlorine in the amide compound III-5 and introduce the substituent -YR 3 to obtain the compound Subsequently, compound III-6 undergoes Heck reaction under the action of palladium catalyst and organic base to obtain an intermediate compound containing exocyclic double bonds. Then, the intermediate compound containing exocyclic double bonds is deprotected to obtain the formula ⅠCompound;
    和/或方案b):或者，将中间体化合物与PyBOP、DIEA和含氮杂环R2化合物共混后，进行反应得到化合物然后将含有R4基团的丙烯基胺与氯代物Ⅳ-4在K2CO3和乙腈加热下进行取代反应得到化合物再利用钯催化剂进行Heck反应关环得到环外双键化合物之后再利用硫醚化合物与IV-6在m-CPBA的氧化下得到亚砜，再与式H-Y-R3的亲核试剂，在以碳酸铯和1,4-二氧六环为溶剂的条件下，取代亚砜嘧啶化合物的亚砜基团来引入取代基-Y-R3得到中间体化合物，该中间体化合物再经脱保护即得目标化合物 and/or scheme b): Alternatively, the intermediate compound After being mixed with PyBOP, DIEA and a nitrogen-containing heterocyclic compound R2 , a reaction is performed to obtain a compound Then the allylamine containing R 4 group and the chlorinated compound IV-4 are subjected to substitution reaction under heating with K 2 CO 3 and acetonitrile to obtain the compound Then use palladium catalyst to carry out Heck reaction to obtain an exocyclic double bond compound Then, the sulfide compound is used to oxidize IV-6 with m-CPBA to obtain sulfoxide, and then the sulfoxide group of the sulfoxide pyrimidine compound is replaced with a nucleophilic reagent of the formula HYR 3 under the conditions of cesium carbonate and 1,4-dioxane as solvent to introduce the substituent -YR 3 to obtain an intermediate compound, and the intermediate compound is then deprotected to obtain the target compound.
    和/或方案c):将中间体化合物与PyBOP、DIEA和含氮杂环R2共混后，进行反应得到化合物然后利用钯催化剂进行Heck反应关环得到环内双键化合物再利用Chan-Lam偶联反应将含R4基团偶联到V-6中得到随后，再利用硫醚化合物、V-7在m-CPBA的氧化下得到亚砜，再与结构式为H-Y-R3的亲核试剂，在碳酸铯和1,4-二氧六环的溶剂条件下，取代亚砜嘧啶化合物的亚砜基团并引入取代基-Y-R3得到中间体化合物，该中间体在步骤H的脱保护就可以得到 and/or scheme c): the intermediate compound After blending with PyBOP, DIEA and nitrogen-containing heterocycle R2 , the reaction is carried out to obtain the compound Then a palladium catalyst is used to perform Heck reaction ring closure to obtain an intracyclic double bond compound. Then use Chan-Lam coupling reaction to couple the R 4 -containing group to V-6 to obtain Subsequently, the thioether compound and V-7 were used to obtain sulfoxide under the oxidation of m-CPBA, and then with the nucleophile with the structural formula HYR 3 , under the solvent conditions of cesium carbonate and 1,4-dioxane, Substitute the sulfoxide group of the sulfoxide pyrimidine compound and introduce the substituent -YR 3 to obtain an intermediate compound, which can be obtained by deprotection in step H
    和/或方案d):利用三氯氧磷将中间体化合物进行羟基的氯代后再与含氮杂环R2进行亲核反应得到然后基于Suzuki 偶联反应引入甲基制得化合物随后再利用Suzuki偶联或Stille偶联反应制备含有R4的化合物再利用二氧化硒对甲基进行氧化得到醛再使用(1-重氮基-2-氧代丙基)膦酸二甲酯试剂(Ohira-Bestman试剂)与醛VI-5在碳酸钾和甲醇的作用下生成炔然后，利用硫醚化合物VI-6在m-CPBA的氧化下得到亚砜，再与式H-Y-R3的亲核试剂，在含有LiHMDS和THF的溶剂中，取代亚砜嘧啶化合物的亚砜基团来引入取代基-Y-R3得到中间体化合物，该中间体化合物再经脱保护处理，即得化合物 and/or scheme d): using phosphorus oxychloride to convert the intermediate compound After chlorination of the hydroxyl group, the nucleophilic reaction with nitrogen-containing heterocycle R 2 is obtained. Then based on Suzuki Coupling reaction introduces methyl group to prepare compound Subsequently, Suzuki coupling or Stille coupling reactions are used to prepare compounds containing R 4 Selenium dioxide is then used to oxidize the methyl group to obtain the aldehyde Then use (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester reagent (Ohira-Bestman reagent) and aldehyde VI-5 under the action of potassium carbonate and methanol to generate alkyne Then, the thioether compound VI-6 is oxidized with m-CPBA to obtain sulfoxide, and then the nucleophile of formula HYR 3 is used to replace the sulfoxide group of the sulfoxide pyrimidine compound in a solvent containing LiHMDS and THF. The substituent -YR 3 is introduced to obtain an intermediate compound, which is then deprotected to obtain the compound
    和/或方案e):and/or option e):
    将在盐酸羟胺和碳酸钾作用下制备得到中间体肟再将所述中间体肟Ⅶ-1在醋酸酐的作用下脱水形成氰基 得到然后，利用硫醚化合物VII-2在m-CPBA的氧化下得到亚砜，再与式H-Y-R3的亲核试剂反应，随后在含LiHMDS和THF的溶剂条件下，取代亚砜嘧啶化合物的亚砜基团并引入取代基-Y-R3得到中间体化合物，该中间体化合物经脱保护即得化合物 Will The intermediate oxime was prepared under the action of hydroxylamine hydrochloride and potassium carbonate. Then the intermediate oxime VII-1 is dehydrated under the action of acetic anhydride to form a cyano group get Then, the thioether compound VII-2 is oxidized with m-CPBA to obtain the sulfoxide, and then reacted with the nucleophile of formula HYR 3 , and then replaces the sulfoxide of the sulfoxide pyrimidine compound in a solvent containing LiHMDS and THF. group and introduce the substituent -YR 3 to obtain an intermediate compound, which can be deprotected to obtain the compound
    和/或方案f):在低温下，在LiHMDS的无水THF中，夺取的端炔的H后与含R基团的亲电试剂反应生成取代的炔基化合物然后，利用硫醚化合物VII-2在m-CPBA的氧化下得到亚砜，再与式H-Y-R3的亲核试剂反应，随后在含LiHMDS和THF的溶剂条件下，取代亚砜嘧啶化合物的亚砜基团并引入取代基-Y-R3得到中间体化合物，该中间体化合物经脱保护即得化合物；and/or solution f): capture in LiHMDS in anhydrous THF at low temperature The H of the terminal alkyne reacts with an electrophile containing an R group to form a substituted alkynyl compound Then, the thioether compound VII-2 is oxidized with m-CPBA to obtain the sulfoxide, and then reacted with the nucleophile of formula HYR 3 , and then replaces the sulfoxide of the sulfoxide pyrimidine compound in a solvent containing LiHMDS and THF. group and introduce the substituent -YR 3 to obtain an intermediate compound, which is deprotected to obtain the compound;
    和/或，方案g)：利用三氟甲磺酸三氟乙酯与中间体化合物在DMF和碱的作用下反应生成中间体化合物然后利用Rca取代的乙炔试剂在钯催化下发生偶联反应，制得化合物使用含氮杂环R2在碱的作用下与化合物VIII-2进行亲核取代反 应得到化合物VIII-3化合物再通过含R4基团的硼酸酯或硼酸，或有机锡试剂与氯吡啶Ⅵ-3在钯试剂的催化下发生Suzuki偶联或Stille偶联反应得到含有R4的化合物然后，利用硫醚化合物Ⅷ-4在m-CPBA的氧化下得到亚砜，再与式H-Y-R3的亲核试剂，在含有LiHMDS和THF的溶剂中，取代亚砜嘧啶化合物的亚砜基团来引入取代基-Y-R3得到中间体化合物，该中间体化合物再经脱保护处理，即得化合物 and/or, scheme g): using trifluoroethyl trifluoromethanesulfonate and intermediate compounds Reaction under the action of DMF and base produces intermediate compounds Then the Rca-substituted acetylene reagent is used to undergo a coupling reaction under palladium catalysis to prepare the compound Use nitrogen-containing heterocycle R 2 to carry out nucleophilic substitution with compound VIII-2 under the action of a base. Compound VIII-3 compound should be obtained Then, the compound containing R 4 is obtained by Suzuki coupling or Stille coupling reaction between the boronic acid ester or boric acid containing R 4 group, or the organotin reagent and chloropyridine VI-3 under the catalysis of palladium reagent. Then, the thioether compound VIII-4 is oxidized with m-CPBA to obtain sulfoxide, and then the nucleophile of formula HYR 3 is used to replace the sulfoxide group of the sulfoxide pyrimidine compound in a solvent containing LiHMDS and THF. The substituent -YR 3 is introduced to obtain an intermediate compound, which is then deprotected to obtain the compound
    其中，R2如权利要求1-6任一权利要求所定义，含氮杂环R2的化合物优选为含哌嗪基、桥环哌嗪基、吗啉基、哌啶基的杂环化合物；所述有机碱优选为三乙胺；所述亲电试剂优选为氘水、卤代烃、醛或酮类化合物。Wherein, R 2 is as defined in any one of claims 1 to 6, and the compound of nitrogen-containing heterocyclic R 2 is preferably a heterocyclic compound containing piperazinyl, bridged ring piperazinyl, morpholinyl or piperidinyl; The organic base is preferably triethylamine; the electrophile is preferably deuterated water, halogenated hydrocarbons, aldehydes or ketone compounds.
  10. 如权利要求9所述的制备方法，其特征在于，包括：The preparation method according to claim 9, characterized in that it includes:
    所述是通过包括下述步骤的方法制备得到的：described It is prepared by a method including the following steps:
    将乳清酸甲酯与卤素X’反应发生卤代得到然后利用三卤氧磷和DIEA进行羟基的卤代，得到III-3；优选地，所述卤素X’为溴素，所述三卤氧磷为三氯氧磷；更优选地，所述Ⅲ-3为 Halogenation is obtained by reacting methyl orotate with halogen X' Then use phosphorus oxyhalide and DIEA to perform halogenation of the hydroxyl group to obtain III-3; preferably, the halogen X' is bromine, and the phosphorus oxyhalide is phosphorus oxychloride; more preferably, the III -3 for
    和/或，是通过包括下述步骤的方法制备得到的:and / or, It is prepared by a method including the following steps:
    将与S-甲基异硫脲硫酸盐反应得到然后再以含卤素X’的N-卤代丁二酰亚胺进行取代反应得到化合物Ⅳ-3；优选地，所述Ⅳ-1为氯代乙酰乙酸乙酯，所述N-卤代丁二酰亚胺为N-溴代丁二酰亚胺(NBS)；更优选地，所述Ⅳ-3为 Will React with S-methylisothiourea sulfate to obtain Then, a substitution reaction is performed with N-halogenated succinimide containing halogen The imide is N-bromosuccinimide (NBS); more preferably, the IV-3 is
    和/或，是通过包括下述步骤的方法制备得到的：and / or, It is prepared by a method including the following steps:
    以草酰乙酸二乙酯钠盐与S-甲基异硫脲硫酸盐于强碱性条件下反应得到再以N-卤代丁二酰亚胺进行卤代反应得到然后，Ⅴ-3与烯丙基胺进行酰胺缩合反应得到V-4；优选地，所述N-卤代丁二酰亚胺为N-溴代丁二酰亚胺(NBS)；更优选地，V-4为 diethyl oxaloacetate sodium salt with S-methylisothiourea sulfate Reacted under strongly alkaline conditions to obtain Then carry out halogenation reaction with N-halogenated succinimide to obtain Then, V-3 undergoes amide condensation reaction with allylamine to obtain V-4; preferably, the N-halosuccinimide is N-bromosuccinimide (NBS); more preferably , V-4 is
  11. 一种药物组合物，其特征在于，包含治疗有效量的如权利要求1-8中任一项所述的化合物、其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，以及药学上可接受的赋形剂。 A pharmaceutical composition, characterized in that it contains a therapeutically effective amount of the compound according to any one of claims 1 to 8, its pharmaceutically acceptable salts, stereoisomers, tautomers, and solvents compounds, metabolites, prodrugs, polymorphs or deuterated compounds, and pharmaceutically acceptable excipients.
  12. 如权利要求1-8中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，或者如权利要求9所述的药物组合物在制备用于抑制KRas突变蛋白活性的药物中的应用，优选，在制备用于抑制KRas G12D活性的药物中的应用。The compound of any one of claims 1-8 or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated form The compound, or the application of the pharmaceutical composition according to claim 9 in the preparation of a medicament for inhibiting the activity of KRas mutant protein, preferably, the application in the preparation of a medicament for inhibiting the activity of KRas G12D.
  13. 如权利要求1-8中任一项所述的化合物或其药学上可接受的盐，立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，或者如权利要求9所述的药物组合物在制备用于治疗KRas突变蛋白相关癌症的药物中的用途，优选在制备用于治疗KRas G12D相关癌症的药物中的用途。The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated form The use of a compound, or a pharmaceutical composition as claimed in claim 9, in the preparation of a medicament for the treatment of KRas mutant protein-related cancers, preferably in the preparation of a medicament for the treatment of KRas G12D-related cancers.
  14. 如权利要求13所述的用途，其特征在于，所述KRas突变蛋白相关癌症选自：The use according to claim 13, wherein the KRas mutant protein-related cancer is selected from:
    非小细胞肺癌、结肠腺癌、多发性骨髓瘤、结肠癌和胰腺癌；支气管癌、肺泡癌、肉瘤、淋巴瘤、支气管腺瘤、软骨瘤错构瘤、间皮瘤；食管鳞状细胞癌、食管平滑肌肉瘤、食管腺癌、食管淋巴瘤、胃癌、胃淋巴瘤、胃平滑肌肉瘤、胰腺导管腺癌、胰岛素瘤、胃泌素瘤、类癌瘤、胰高血糖素瘤、血管活性肠肽瘤、小肠腺癌、小肠淋巴瘤、小肠类癌瘤、小肠平滑肌瘤、小肠血管瘤、小肠卡波西肉瘤、小肠脂肪瘤、小肠纤维瘤、小肠神经纤维瘤、大肠腺癌、大肠管状腺瘤、大肠错构瘤、大肠绒毛状腺瘤、大肠平滑肌瘤；心脏肉瘤、心脏血管肉瘤、心脏纤维肉瘤、心脏脂肪肉瘤、心脏横纹肌肉瘤、心脏粘液瘤、心脏纤维瘤、心脏横纹肌瘤、心脏脂肪瘤和心脏畸胎瘤；肝细胞瘤或肝细胞癌、胆管癌、肝母细胞瘤、肝脏血管肉瘤、肝细胞腺瘤、肝脏血管瘤；胆囊癌、胆管癌、壶腹癌；威尔姆氏瘤、肾母细胞瘤、淋巴瘤、白血病、鳞状细胞癌、移行细胞癌、肾腺癌、前列腺腺癌、肉瘤、睾丸精原细胞瘤、睾丸畸胎瘤、睾丸畸胎癌、睾丸肉瘤、睾丸胚胎性癌、睾丸绒毛膜癌、睾丸间质细胞癌、睾丸纤维腺瘤、睾丸纤维瘤、睾丸腺瘤样瘤、睾丸脂肪瘤；骨肉瘤、纤维肉瘤、软骨肉瘤、尤文氏肉瘤、恶性纤维性组织细胞瘤、网织细胞肉瘤、良性软骨瘤、恶性巨细胞肿瘤脊索瘤、软骨母细胞瘤、骨软骨瘤、骨软骨外生骨疣、软骨黏液样纤维瘤、骨样骨瘤和巨细胞肿瘤；骨瘤、黄色瘤、血管瘤、肉芽肿、畸形性骨炎、脑膜瘤、胶质瘤、脑膜肉瘤、脑星形细胞瘤、髓母细胞瘤、室管膜瘤、神经胶质瘤、生殖细胞瘤、松果体瘤、神经鞘瘤、少突胶质细胞瘤、多形性胶质母细胞瘤、视网膜母细胞瘤、神经胶质瘤、先天性肿瘤、脑膜瘤、脊髓神经纤维瘤、肉瘤；子宫内膜癌、浆液性囊腺癌、粘液性囊腺癌、粒层细胞-鞘细胞瘤、恶性畸胎瘤、外阴腺癌、外阴鳞状细胞癌、外阴上皮内癌、外阴纤维肉瘤、外阴黑色素瘤、阴道鳞状细胞癌、阴道透明细胞癌、阴道葡萄状肉瘤、胚胎性横纹肌肉瘤、输卵管癌；急性骨髓性白血病、慢性骨髓性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病、骨髓增殖性疾病、多发性骨髓瘤、骨髓增生异常综合征、霍奇金病、非霍奇金淋巴瘤、恶性淋巴瘤；皮肤恶性黑色素瘤、皮肤卡波西肉瘤、皮肤基底细胞癌、皮肤鳞状细胞癌、皮肤发育不良痣、皮肤脂肪瘤、皮肤血 管瘤、皮肤纤维瘤、皮肤瘢痕疙瘩、牛皮癣；肾上腺成神经细胞瘤中的一种或多种。Non-small cell lung cancer, colon adenocarcinoma, multiple myeloma, colon cancer, and pancreatic cancer; bronchial carcinoma, alveolar carcinoma, sarcoma, lymphoma, bronchial adenoma, enchondromatous hamartoma, mesothelioma; esophageal squamous cell carcinoma , Esophageal leiomyosarcoma, esophageal adenocarcinoma, esophageal lymphoma, gastric cancer, gastric lymphoma, gastric leiomyosarcoma, pancreatic ductal adenocarcinoma, insulinoma, gastrinoma, carcinoid tumor, glucagonoma, vasoactive intestinal peptide neoplasm, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, small intestinal leiomyoma, small intestinal hemangioma, small intestinal Kaposi's sarcoma, small intestinal lipoma, small intestinal fibroma, small intestinal neurofibroma, large intestinal adenocarcinoma, large intestinal tubular glands tumor, colorectal hamartoma, colorectal villous adenoma, colorectal leiomyoma; cardiac sarcoma, cardiac angiosarcoma, cardiac fibrosarcoma, cardiac liposarcoma, cardiac rhabdomyosarcoma, cardiac myxoma, cardiac fibroma, cardiac rhabdomyosarcoma, cardiac Lipomas and cardiac teratomas; hepatoma or hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hepatic angiosarcoma, hepatocellular adenoma, hepatic hemangioma; gallbladder carcinoma, cholangiocarcinoma, ampullary carcinoma; Wilm Nephroblastoma, nephroblastoma, lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, renal adenocarcinoma, prostate adenocarcinoma, sarcoma, testicular seminoma, testicular teratoma, testicular teratoma, testicular sarcoma , Testicular embryonal carcinoma, testicular choriocarcinoma, testicular Leydig cell carcinoma, testicular fibroadenoma, testicular fibroma, testicular adenomatoid tumor, testicular lipoma; osteosarcoma, fibrosarcoma, chondrosarcoma, Ewing's sarcoma, malignant Fibrous histiocytoma, reticulocytic sarcoma, benign chondroma, malignant giant cell tumor chordoma, chondroblastoma, osteochondroma, osteochondral exostoses, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor Cellular neoplasms; osteomas, xanthomas, hemangiomas, granulomas, osteitis deformans, meningiomas, gliomas, meningosarcoma, cerebral astrocytoma, medulloblastoma, ependymoma, glioma , germ cell tumor, pineal tumor, schwannoma, oligodendroglioma, glioblastoma multiforme, retinoblastoma, glioma, congenital tumors, meningiomas, spinal nerve fibers tumors, sarcomas; endometrial carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa cell-theca cell tumor, malignant teratoma, vulvar adenocarcinoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulva Fibrosarcoma, vulvar melanoma, vaginal squamous cell carcinoma, vaginal clear cell carcinoma, vaginal botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tube cancer; acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia Cellular leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma; cutaneous malignant melanoma, cutaneous Kaposi's sarcoma, cutaneous basal cell Carcinoma, cutaneous squamous cell carcinoma, cutaneous dysplastic nevus, cutaneous lipoma, cutaneous hematoma One or more of angiomas, dermatofibromas, keloids, psoriasis; adrenal neuroblastoma.
  15. 如权利要求1-8中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，或者如权利要求9所述的药物组合物，其用于抑制KRas突变蛋白活性，优选，其用于抑制KRas G12D活性。The compound of any one of claims 1-8 or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated form A compound, or a pharmaceutical composition as claimed in claim 9, which is used to inhibit KRas mutein activity, preferably, it is used to inhibit KRas G12D activity.
  16. 如权利要求1-8中任一项所述的化合物或其药学上可接受的盐，立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，或者如权利要求9所述的药物组合物，其用于治疗KRas突变蛋白相关癌症，优选用于治疗KRas G12D相关癌症。The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated form Compounds, or pharmaceutical compositions as claimed in claim 9, which are used for the treatment of KRas mutant protein-related cancers, preferably for the treatment of KRas G12D-related cancers.
  17. 如权利要求16所述用途的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，其中，所述KRas突变蛋白相关癌症选自非小细胞肺癌、结肠腺癌、多发性骨髓瘤、结肠癌和胰腺癌；支气管癌、肺泡癌、肉瘤、淋巴瘤、支气管腺瘤、软骨瘤错构瘤、间皮瘤；食管鳞状细胞癌、食管平滑肌肉瘤、食管腺癌、食管淋巴瘤、胃癌、胃淋巴瘤、胃平滑肌肉瘤、胰腺导管腺癌、胰岛素瘤、胃泌素瘤、类癌瘤、胰高血糖素瘤、血管活性肠肽瘤、小肠腺癌、小肠淋巴瘤、小肠类癌瘤、小肠平滑肌瘤、小肠血管瘤、小肠卡波西肉瘤、小肠脂肪瘤、小肠纤维瘤、小肠神经纤维瘤、大肠腺癌、大肠管状腺瘤、大肠错构瘤、大肠绒毛状腺瘤、大肠平滑肌瘤；心脏肉瘤、心脏血管肉瘤、心脏纤维肉瘤、心脏脂肪肉瘤、心脏横纹肌肉瘤、心脏粘液瘤、心脏纤维瘤、心脏横纹肌瘤、心脏脂肪瘤和心脏畸胎瘤；肝细胞瘤或肝细胞癌、胆管癌、肝母细胞瘤、肝脏血管肉瘤、肝细胞腺瘤、肝脏血管瘤；胆囊癌、胆管癌、壶腹癌；威尔姆氏瘤、肾母细胞瘤、淋巴瘤、白血病、鳞状细胞癌、移行细胞癌、肾腺癌、前列腺腺癌、肉瘤、睾丸精原细胞瘤、睾丸畸胎瘤、睾丸畸胎癌、睾丸肉瘤、睾丸胚胎性癌、睾丸绒毛膜癌、睾丸间质细胞癌、睾丸纤维腺瘤、睾丸纤维瘤、睾丸腺瘤样瘤、睾丸脂肪瘤；骨肉瘤、纤维肉瘤、软骨肉瘤、尤文氏肉瘤、恶性纤维性组织细胞瘤、网织细胞肉瘤、良性软骨瘤、恶性巨细胞肿瘤脊索瘤、软骨母细胞瘤、骨软骨瘤、骨软骨外生骨疣、软骨黏液样纤维瘤、骨样骨瘤和巨细胞肿瘤；骨瘤、黄色瘤、血管瘤、肉芽肿、畸形性骨炎、脑膜瘤、胶质瘤、脑膜肉瘤、脑星形细胞瘤、髓母细胞瘤、室管膜瘤、神经胶质瘤、生殖细胞瘤、松果体瘤、神经鞘瘤、少突胶质细胞瘤、多形性胶质母细胞瘤、视网膜母细胞瘤、神经胶质瘤、先天性肿瘤、脑膜瘤、脊髓神经纤维瘤、肉瘤；子宫内膜癌、浆液性囊腺癌、粘液性囊腺癌、粒层细胞-鞘细胞瘤、恶性畸胎瘤、外阴腺癌、外阴鳞状细胞癌、外阴上皮内癌、外阴纤维肉瘤、外阴黑色素瘤、阴道鳞状细胞癌、阴道透明细胞癌、阴道葡萄状肉瘤、胚胎性横纹肌肉瘤、输卵管癌；急性骨髓性白血病、慢性骨髓性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病、骨髓增殖性疾病、多发性骨髓瘤、骨髓增生异常综合征、霍奇金病、非霍奇金淋巴瘤、恶性淋巴瘤； 皮肤恶性黑色素瘤、皮肤卡波西肉瘤、皮肤基底细胞癌、皮肤鳞状细胞癌、皮肤发育不良痣、皮肤脂肪瘤、皮肤血管瘤、皮肤纤维瘤、皮肤瘢痕疙瘩、牛皮癣；肾上腺成神经细胞瘤中的一种或多种。The compound for use according to claim 16 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, metabolite, prodrug, polymorph or deuterated compound thereof, wherein, The KRas mutant protein-related cancers are selected from non-small cell lung cancer, colon adenocarcinoma, multiple myeloma, colon cancer and pancreatic cancer; bronchial carcinoma, alveolar carcinoma, sarcoma, lymphoma, bronchial adenoma, enchondromatous hamartoma, mesenchymal carcinoma, Skin tumors; esophageal squamous cell carcinoma, esophageal leiomyosarcoma, esophageal adenocarcinoma, esophageal lymphoma, gastric cancer, gastric lymphoma, gastric leiomyosarcoma, pancreatic ductal adenocarcinoma, insulinoma, gastrinoma, carcinoid tumor, pancreatic high Glucagonoma, vasoactive intestinal peptide tumor, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, small intestinal leiomyoma, small intestinal hemangioma, small intestinal Kaposi's sarcoma, small intestinal lipoma, small intestinal fibroma, small intestinal neurofibroma , colorectal adenocarcinoma, colorectal tubular adenoma, colorectal hamartoma, colorectal villous adenoma, colorectal leiomyoma; cardiac sarcoma, cardiac angiosarcoma, cardiac fibrosarcoma, cardiac liposarcoma, cardiac rhabdomyosarcoma, cardiac myxoma, heart Fibromas, cardiac rhabdomyomas, cardiac lipomas, and cardiac teratomas; hepatoma or hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hepatic angiosarcoma, hepatocellular adenoma, hepatic hemangioma; gallbladder cancer, cholangiocarcinoma , ampullary cancer; Wilms' tumor, nephroblastoma, lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, renal adenocarcinoma, prostate adenocarcinoma, sarcoma, testicular seminoma, testicular teratoma , testicular teratoma, testicular sarcoma, testicular embryonal carcinoma, testicular choriocarcinoma, testicular interstitial cell carcinoma, testicular fibroadenoma, testicular fibroma, testicular adenomatoid tumor, testicular lipoma; osteosarcoma, fibrosarcoma, Chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma, reticulocyte sarcoma, benign enchondroma, malignant giant cell tumor chordoma, chondroblastoma, osteochondroma, osteochondral exostosis, chondromyxoid fibrosis tumors, osteoid osteomas and giant cell tumors; osteomas, xanthomas, hemangiomas, granulomas, osteitis deformans, meningiomas, gliomas, meningiosarcomas, cerebral astrocytoma, medulloblastoma, ventricular Angiomangiomas, gliomas, germ cell tumors, pineal tumors, schwannomas, oligodendrogliomas, glioblastoma multiforme, retinoblastoma, gliomas, congenital Tumors, meningiomas, spinal neurofibromas, sarcomas; endometrial cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa cell-theca cell tumor, malignant teratoma, vulvar adenocarcinoma, vulvar squamous cell Carcinoma, vulvar intraepithelial carcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal squamous cell carcinoma, vaginal clear cell carcinoma, vaginal botryoid sarcoma, embryonal rhabdomyosarcoma, fallopian tube cancer; acute myeloid leukemia, chronic myelogenous leukemia, acute Lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma; Cutaneous malignant melanoma, cutaneous Kaposi's sarcoma, cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, cutaneous dysplastic nevus, cutaneous lipoma, cutaneous hemangioma, dermatofibroma, cutaneous keloid, psoriasis; adrenal neuroblastoma one or more of them.
  18. 一种治疗对KRas突变蛋白活性的抑制具有反应的疾病的方法，其包括对患有所述疾病的受试者施用治疗有效量的权利要求1-8中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，或者如权利要求9所述的药物组合物。A method of treating a disease responsive to inhibition of KRas mutant protein activity, comprising administering to a subject suffering from the disease a therapeutically effective amount of a compound or pharmaceutical thereof according to any one of claims 1-8. acceptable salts, stereoisomers, tautomers, solvates, metabolites, prodrugs, polymorphs or deuterated compounds, or the pharmaceutical composition of claim 9.
  19. 一种治疗KRas突变蛋白相关癌症的方法，其包括对患有所述KRas突变蛋白相关癌症的受试者施用治疗有效量的权利要求1-8中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、代谢产物、前药、多晶型物或氘代化合物，或者如权利要求9所述的药物组合物，优选，所述KRas突变蛋白相关癌症为KRas G12D相关癌症。A method of treating KRas mutant protein-related cancer, which includes administering a therapeutically effective amount of the compound of any one of claims 1-8 or a pharmaceutically acceptable compound thereof to a subject suffering from the KRas mutant protein-related cancer. Acceptable salts, stereoisomers, tautomers, solvates, metabolites, prodrugs, polymorphs or deuterated compounds, or the pharmaceutical composition of claim 9, preferably, the KRas Mutated protein-related cancers are KRas G12D-related cancers.
  20. 如权利要求19所述的方法，其特征在于，所述KRas突变蛋白相关癌症选自：非小细胞肺癌、结肠腺癌、多发性骨髓瘤、结肠癌和胰腺癌；支气管癌、肺泡癌、肉瘤、淋巴瘤、支气管腺瘤、软骨瘤错构瘤、间皮瘤；食管鳞状细胞癌、食管平滑肌肉瘤、食管腺癌、食管淋巴瘤、胃癌、胃淋巴瘤、胃平滑肌肉瘤、胰腺导管腺癌、胰岛素瘤、胃泌素瘤、类癌瘤、胰高血糖素瘤、血管活性肠肽瘤、小肠腺癌、小肠淋巴瘤、小肠类癌瘤、小肠平滑肌瘤、小肠血管瘤、小肠卡波西肉瘤、小肠脂肪瘤、小肠纤维瘤、小肠神经纤维瘤、大肠腺癌、大肠管状腺瘤、大肠错构瘤、大肠绒毛状腺瘤、大肠平滑肌瘤；心脏肉瘤、心脏血管肉瘤、心脏纤维肉瘤、心脏脂肪肉瘤、心脏横纹肌肉瘤、心脏粘液瘤、心脏纤维瘤、心脏横纹肌瘤、心脏脂肪瘤和心脏畸胎瘤；肝细胞瘤或肝细胞癌、胆管癌、肝母细胞瘤、肝脏血管肉瘤、肝细胞腺瘤、肝脏血管瘤；胆囊癌、胆管癌、壶腹癌；威尔姆氏瘤、肾母细胞瘤、淋巴瘤、白血病、鳞状细胞癌、移行细胞癌、肾腺癌、前列腺腺癌、肉瘤、睾丸精原细胞瘤、睾丸畸胎瘤、睾丸畸胎癌、睾丸肉瘤、睾丸胚胎性癌、睾丸绒毛膜癌、睾丸间质细胞癌、睾丸纤维腺瘤、睾丸纤维瘤、睾丸腺瘤样瘤、睾丸脂肪瘤；骨肉瘤、纤维肉瘤、软骨肉瘤、尤文氏肉瘤、恶性纤维性组织细胞瘤、网织细胞肉瘤、良性软骨瘤、恶性巨细胞肿瘤脊索瘤、软骨母细胞瘤、骨软骨瘤、骨软骨外生骨疣、软骨黏液样纤维瘤、骨样骨瘤和巨细胞肿瘤；骨瘤、黄色瘤、血管瘤、肉芽肿、畸形性骨炎、脑膜瘤、胶质瘤、脑膜肉瘤、脑星形细胞瘤、髓母细胞瘤、室管膜瘤、神经胶质瘤、生殖细胞瘤、松果体瘤、神经鞘瘤、少突胶质细胞瘤、多形性胶质母细胞瘤、视网膜母细胞瘤、神经胶质瘤、先天性肿瘤、脑膜瘤、脊髓神经纤维瘤、肉瘤；子宫内膜癌、浆液性囊腺癌、粘液性囊腺癌、粒层细胞-鞘细胞瘤、恶性畸胎瘤、外阴腺癌、外阴鳞状细胞癌、外阴上皮内癌、外阴纤维肉瘤、外阴黑色素瘤、阴道鳞状细胞癌、阴道透明细胞癌、阴道葡萄状肉瘤、胚胎性横纹肌肉瘤、输卵管癌；急性骨髓性白血病、慢性骨髓性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞 性白血病、骨髓增殖性疾病、多发性骨髓瘤、骨髓增生异常综合征、霍奇金病、非霍奇金淋巴瘤、恶性淋巴瘤；皮肤恶性黑色素瘤、皮肤卡波西肉瘤、皮肤基底细胞癌、皮肤鳞状细胞癌、皮肤发育不良痣、皮肤脂肪瘤、皮肤血管瘤、皮肤纤维瘤、皮肤瘢痕疙瘩、牛皮癣；肾上腺成神经细胞瘤中的一种或多种。 The method of claim 19, wherein the KRas mutant protein-related cancer is selected from: non-small cell lung cancer, colon adenocarcinoma, multiple myeloma, colon cancer and pancreatic cancer; bronchial cancer, alveolar cancer, sarcoma , lymphoma, bronchial adenoma, enchondromatous hamartoma, mesothelioma; esophageal squamous cell carcinoma, esophageal leiomyosarcoma, esophageal adenocarcinoma, esophageal lymphoma, gastric cancer, gastric lymphoma, gastric leiomyosarcoma, pancreatic ductal adenocarcinoma , insulinoma, gastrinoma, carcinoid tumor, glucagonoma, vasoactive intestinal peptide tumor, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, small intestinal leiomyoma, small intestinal hemangioma, small intestinal kapos Western sarcoma, small intestinal lipoma, small intestinal fibroma, small intestinal neurofibroma, colorectal adenocarcinoma, colorectal tubular adenoma, colorectal hamartoma, colorectal villous adenoma, colorectal leiomyoma; cardiac sarcoma, cardiac angiosarcoma, cardiac fibrosis Sarcoma, cardiac liposarcoma, cardiac rhabdomyosarcoma, cardiac myxoma, cardiac fibroma, cardiac rhabdomyomas, cardiac lipoma, and cardiac teratoma; hepatoma or hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hepatic angiosarcoma , Hepatocellular adenoma, liver hemangioma; gallbladder cancer, cholangiocarcinoma, ampullary cancer; Wilms' tumor, Wilms tumor, lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, renal adenocarcinoma, prostate Adenocarcinoma, sarcoma, testicular seminoma, testicular teratoma, testicular teratocarcinoma, testicular sarcoma, testicular embryonal carcinoma, testicular choriocarcinoma, testicular Leydig cell carcinoma, testicular fibroadenoma, testicular fibroma, testis Adenomatoid tumor, testicular lipoma; osteosarcoma, fibrosarcoma, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma, reticulocyte sarcoma, benign enchondroma, malignant giant cell tumor chordoma, chondroblastoma, Osteochondroma, osteochondral exostoses, chondromyxoid fibroma, osteoid osteoma and giant cell tumors; osteomas, xanthomas, hemangiomas, granulomas, osteitis deformans, meningiomas, gliomas, Meningeal sarcoma, cerebral astrocytoma, medulloblastoma, ependymoma, glioma, germ cell tumor, pineal tumor, schwannoma, oligodendroglioma, glioblastoma multiforme Cytomas, retinoblastoma, glioma, congenital tumors, meningiomas, spinal neurofibromas, sarcomas; endometrial cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, granulosa cell-theca cell tumor, malignant teratoma, vulvar adenocarcinoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal squamous cell carcinoma, vaginal clear cell carcinoma, vaginal botryoid sarcoma, embryonal rhabdomyosarcoma , fallopian tube cancer; acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma; cutaneous malignant melanoma, cutaneous Kaposi's sarcoma, cutaneous basal cell carcinoma , cutaneous squamous cell carcinoma, cutaneous dysplastic nevus, cutaneous lipoma, cutaneous hemangioma, dermatofibroma, cutaneous keloid, psoriasis; one or more of adrenal neuroblastoma.
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