WO2024061333A1 - Inhibiteur de protéine mutante kras, son procédé de préparation et son utilisation - Google Patents

Inhibiteur de protéine mutante kras, son procédé de préparation et son utilisation 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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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

L'invention concerne un composé de formule I ayant une activité inhibitrice de KRas, une composition pharmaceutique comprenant le composé, son procédé de préparation et son utilisation. Le composé a de remarquables sélectivité et activité inhibitrice et présente de meilleures perspectives médicales.
PCT/CN2023/120527 2022-09-21 2023-09-21 Inhibiteur de protéine mutante kras, son procédé de préparation et son utilisation WO2024061333A1 (fr)

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CN115974896A (zh) * 2021-10-15 2023-04-18 广东东阳光药业有限公司 新的嘧啶并吡啶化合物、其药物组合物及其用途
WO2023138583A1 (fr) * 2022-01-21 2023-07-27 上海湃隆生物科技有限公司 Composé hétérocyclique, composition pharmaceutique et utilisation associée
WO2023143312A1 (fr) * 2022-01-28 2023-08-03 上海艾力斯医药科技股份有限公司 Composé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation

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