Pyridopyrimidine derivatives and their use

Abstract

The present invention belongs to the field of pharmaceutical technology and relates to pyridopyrimidine derivatives and their use, more specifically to pyridopyrimidine derivatives and pharmaceutical compositions containing the compound, and their use in the preparation of pharmaceuticals for treating diseases related to the PD-1 / PD-L1 signaling pathway.

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceuticals, and more specifically to pyridopyrimidine derivatives and pharmaceutical compositions comprising these compounds, as well as their use in the preparation of pharmaceuticals for treating diseases related to the PD-1 / PD-L1 signaling pathway. [Background technology]

[0002] Programmed cell death receptor-1 (PD-1), also known as CD279, is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells, and macrophages (Greenwald et al., Annu. Rev. Immunol 2005, 23:515~548; Okazaki and Honjo, Trends Immunol 2006, (4):195~201). It is a type I transmembrane protein composed of 268 amino acids and belongs to the CD28 family. Structurally, PD-1 consists of three parts: an extracellular immunoglobulin variable domain, a hydrophobic transmembrane region, and an intracellular domain (Parry et al., Mol Cell Biol 2005, 9543~9553). The intracellular domain contains two phosphorylation sites located at the immunoreceptor tyrosine repression motif (ITIM) and the immunoreceptor tyrosine translation motif (ITSM), suggesting that PD-1 negatively modulates T cell receptor-mediated signaling. As a unique negative feedback system, PD-1 prevents T cell activation, thereby reducing autoimmunity and promoting self-tolerance. Furthermore, PD-1 is also thought to play an important role in suppressing antigen-specific T cell responses in diseases such as cancer and viral infections (Sharpe et al., Nat Immunol 2007, 8, 239-245; Postow et al., J. Clinical Oncol 2015, 33, 1-9).

[0003] Under normal conditions, the PD-1 / PD-L1 signaling pathway can prevent excessive inflammation and autoimmune diseases induced by an overreaction of the immune system against tissues. Under abnormal conditions, such as tumor tissue and chronic HBV-infected tissue, PD-L1 is overexpressed. Overexpression of PD-1 / PD-L1 and activation of the signaling pathway inhibits the activation and proliferation of functional T cells, suppresses the anti-tumor immune response, and causes the immune system to lose its inhibitory effect on tumorigenesis, thereby accelerating tumor development and progression. Various drugs have been approved for this pathway. Among them, PD-L1 monoclonal antibodies, such as atezolizumab, have been approved for indications including urothelial carcinoma and non-small cell lung cancer, and ongoing clinical studies are investigating additional oncological applications. However, biologics exhibit significant limitations compared to small molecule drugs in terms of tissue penetration, pharmacokinetic properties, cost, and administration methods. As a result, the development of small-molecule oral drugs that target the PD-1 / PD-L1 pathway remains a significant market opportunity, addressing an unmet clinical need.

[0004] Bristol-Myers Squibb (BMS) was one of the first pharmaceutical companies to investigate small molecule PD-L1 inhibitors, disclosing a series of compounds capable of directly blocking PD-1 / PD-L1 interactions in patent documents (e.g., International Publication No. 2017066227 and International Publication No. 2018044963) and related academic publications. Notable small molecule inhibitors that have entered clinical development include Incyte Corporation's oral PD-L1 inhibitor (INCB-086550), which received Phase I clinical trial approval in December 2018 for advanced solid tumors; Gilead Sciences' GS-4224, which began clinical trials in the United States on August 8, 2019; and Maxinovel Pharmaceuticals' MAX-10181, the third small molecule PD-L1 inhibitor to enter clinical trials worldwide, which began Phase I trials in Australia on October 10, 2019. Furthermore, IMMH-010, licensed by the Chinese Academy of Medical Sciences and manufactured by Chase Sun Pharmaceutical, received IND approval for clinical trials in China in April 2020.

[0005] Currently, several monoclonal antibody drugs targeting PD-1 or PD-L1 are commercially available, and PD-1 / PD-L1 blockers have been shown to be usable for the clinical treatment of various tumors. However, antibody drugs have their own unique characteristics, such as high manufacturing costs, insufficient stability, the need for administration by injection, and easy immunogenicity. Small molecule drugs have advantages such as good tissue permeability, convenient storage and transport, low manufacturing costs, and non-immunogenicity, and can usually be administered orally. Therefore, the development of small molecule inhibitors of PD-1 / PD-L1 has significant application and social value. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2017066227 [Patent Document 2] International Publication No. 2018044963

Non-licensed literature

[0007] [Non-licensed document 1] Greenwald, Annu.Rev.Immunol 2005, 23:515~548 [Non-licensed document 2] Okazaki and Honjo, Trends Immunol 2006, (4): 195~201 [Non-licensed document 3] Parryら、Mol Cell Biol 2005、9543~9553

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Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

[0008] The present invention provides pyridopyrimidine derivatives having the ability to inhibit PD-1 / PD-L1 interaction, which can be used as novel oral small-molecule immunomodulators. The compounds of the present invention have good in vivo exposure and sustained exposure time and are targeted to tumor tissue. They are concentrated in tumor tissue and can be increased to higher tumor tissue exposure concentrations, which helps to exert better antitumor activity during treatment, thereby achieving a better therapeutic effect.

[0009] In one embodiment, the present invention relates to a compound having formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0010] [ka]

[0011] (In the formula, L1 is a combination, -NR z -, -O-, -(CH2) t -, -HC=CH-, -S-, or -SO2- are selected; R z H, D, -OH, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C1~6 haloalkyl, C 1~6 alkoxy or C 1~6 haloalkoxy; R 1 , R 2 , R 1a and R 2a are independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~6 alkyl or C 1~6 haloalkyl; Ring A is selected from C 3~8 cycloalkyl, a heterocyclic ring consisting of 3 to 8 atoms, C 6~10 aryl, or heteroaryl consisting of 5 to 6 atoms; Each R 3a is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, C 1~6 alkoxy or C 1~6 haloalkoxy, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl and C 1~6 alkoxy are independently and optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, oxo, -NO2, -CN, -OH, -NH2, -COOCH3 and -COOH; R 4 is H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~6 alkyl, C 1~6 haloalkyl or C 3~8 cycloalkyl, C 1~6 alkyl and C 3~8 cycloalkyl are independently and optionally D, F, Cl, Br, I, C 1~6 alkyl, C 1~6Substituting with 1, 2, 3, or 4 substituents selected from haloalkyl, oxo, -NO2, -CN, -OH, -NH2, -COOCH3, and -COOH; L2 is a bond, -C 1~6 Alkylene- or -C 1~6 Alkilen-NR w -C 1~6 It is alkylene-, and each -C 1~6 Alkylenes are independently and optionally selected as D, F, Cl, Br, I, oxo, -OH, C 1~6 Alkyl and C 1~6 Substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups; R w H, D, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl or C 2~6 It is alkinyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl and C 2~6 Alkynnyls are independently and optionally selected as D, F, Cl, Br, I, oxo, -OH, C 1~6 Alkyl and C 1~6 Substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups; R 3 -NR 5 R 6 , C 3~12 A cycloalkyl or heterocycle consisting of 3 to 12 atoms, C 3~12 Cycloalkyls and heterocycles consisting of 3 to 12 atoms are independently and optionally selected as D, halogen, -NO2, -CN, -OH, -NH2, oxo, C 1~6 Alkyl, -C(O)CH3, -C(O)OH, -C 1~4 Alkylene C(O)OH, -C(O)OCH3, -NHC(O)-C 1~4 Substituting with 1, 2, 3, or 4 substituents selected from alkyl, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3, -S(O)2NH2, and -C(O)NHS(O)2CH3; R5 and R 6 are each independently H, D, C 1~6 alkyl, C 3~10 cycloalkyl or a heterocyclic ring consisting of 3 to 12 atoms, and C 1~6 alkyl, C 3~10 cycloalkyl and the heterocyclic ring consisting of 3 to 12 atoms are independently and optionally D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~6 alkyl, C 1~6 haloalkyl, hydroxy C 1~6 alkyl, amino C 1~6 alkyl, carboxy C 1~6 alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b , -C(O)NR a R b , -S(O)2R a , -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b substituted with 1, 2, 3 or 4 substituents selected from; or R 5 and R 6 together with the atom to which they are attached form a heterocyclic ring consisting of 3 to 12 atoms, and the heterocyclic ring consisting of 3 to 12 atoms optionally contains 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, or nitrogen, and optionally D, F, Cl, Br, I, -NO2, -CN, oxo, C 1~6 alkyl, C 1~6 haloalkyl, hydroxy C 1~6 alkyl, amino C 1~6 alkyl, carboxy C 1~6 alkyl, -OR a , -C(O)Ra , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b Substituted with 1, 2, 3, or 4 substituents independently selected from; R a , R b , R c and R d Each of these is independently H, D, C 1~6 Alkyl, C 3~8 A cycloalkyl or heterocycle consisting of 3 to 8 atoms, C 1~6 Alkyl, C 3~8 Cycloalkyls and heterocycles consisting of 3 to 8 atoms are independently and optionally selected as D, F, Cl, Br, I, C 1~6 Substituting with 1, 2, 3, or 4 substituents selected from alkyl, -NO2, -CN, -OH, -NH2, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3, and -S(O)2NH2; R 7 is C 3~10 A cycloalkyl or heterocycle consisting of 3 to 12 atoms, C 3~10 Cycloalkyls and heterocycles consisting of 3 to 12 atoms are independently and optionally selected as D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, -OR e , -C(O)R e , -C(O)OR e , -NRe R f , -NR e C(O)R f , -NR e C(O)OR f and -C(O)NR e R f Substituted with 1, 2, 3, or 4 substituents selected from; R e and R f Each of them is H, D, C 1~6 Alkyl or C 3~8 It is a cycloalkyl, C 1~6 Alkyl and C 3~8 The cycloalkyl group is independently and optionally substituted with one, two, three, or four substituents selected from D, F, Cl, Br, I, oxo, -NO2, -CN, -OH, -NH2, -C(O)CH3, -COOCH3, and -COOH; (Each of m, n, q, p, and t is independently 0, 1, 2, or 3.) To provide.

[0012] In some embodiments, R 1 , R 2 , R 1a and R 2a Each of these is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~4 Alkyl or C 1~4 It is a haloalkyl; Each R 3a These are independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 It is a haloalkoxy, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl and C 1~4 Alkoxy compounds are D, F, Cl, Br, I, C, independently and optionally. 1~4 Alkyl, C 2~4 Alkenil, C2~4 Substituting with one, two, three, or four substituents selected from alkynyl, oxo, -NO2, -CN, -OH, -NH2, -COOCH3, and -COOH; R 4 H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~4 Alkyl, C 1~4 Haloalkyl or C 3~6 It is a cycloalkyl, C 1~4 Alkyl and C 3~6 Cycloalkyls are independently and optionally selected as D, F, Cl, Br, I, C 1~4 Alkyl, C 1~4 It is substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, oxo, -NO2, -CN, -OH, -NH2, -COOCH3, and -COOH.

[0013] In some embodiments, R 1 , R 2 , R 1a and R 2a Each of these is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH2Cl, -CHCl2, -CH2CHCl2, -CH2Br, -CHBr2, or -CH2CHBr2; R 3aEach of these is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethinyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CHF2, or -OCH2CF3, and methyl, ethyl, n-propyl Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, -OCH3, -OCH2CH3, -OCH2CH2CH3 and -OCH(CH3)2 are independently and optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, oxo, -NO2, -CN, -OH, -NH2, -COOCH3 and -COOH; R 4These are H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclo Ropropyl, cyclobutyl, cyclopentyl, and cyclohexyl are independently and optionally substituted with one, two, three, or four substituents selected from D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, oxo, -NO2, -CN, -OH, -NH2, -COOCH3, and -COOH.

[0014] In some embodiments, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidyl, pyrazinyl, or pyridazinyl.

[0015] In some embodiments, R 3 -NR 5 R 6 , C 3~10 A cycloalkyl or heterocycle consisting of 3 to 10 atoms, C 3~10 Cycloalkyls and heterocycles consisting of 3 to 10 atoms are independently and optionally selected as D, halogen, -NO2, -CN, -OH, -NH2, oxo, C 1~4 Alkyl, -C(O)CH3, -C(O)OH, -C 1~4 Alkylene C(O)OH, -C(O)CH3, -NHC(O)-C 1~4Substituting with 1, 2, 3, or 4 substituents selected from alkyl, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3, -S(O)2NH2, and -C(O)NHS(O)2CH3; R 5 and R 6 These are H, D, and C, respectively, independently. 1~4 Alkyl, C 3~8 A cycloalkyl or heterocycle consisting of 3 to 10 atoms, C 1~4 Alkyl, C 3~8 Cycloalkyls and heterocycles consisting of 3 to 10 atoms are independently and optionally selected as D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, HydroxyC 1~4 Alkyl, amino C 1~4 Alkyl, CarboxyC 1~4 Alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b Substituted with 1, 2, 3, or 4 substituents selected from; or R 5 and R 6 These atoms, together with the atoms to which they are bonded, form a heterocycle consisting of 3 to 10 atoms, and the heterocycle consisting of 3 to 10 atoms optionally contains 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, or nitrogen, and optionally contains D, F, Cl, Br, I, -NO2, -CN, oxo, C 1~4 Alkyl, C 1~4Haloalkyl, HydroxyC 1~4 Alkyl, amino C 1~4 Alkyl, CarboxyC 1~4 Alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b Substituted with 1, 2, 3, or 4 substituents independently selected from; R a , R b , R c and R d Each of these is independently H, D, C 1~4 Alkyl, C 3~6 A cycloalkyl or heterocycle consisting of 3 to 6 atoms, C 1~4 Alkyl, C 3~6 Cycloalkyls and heterocycles consisting of 3 to 6 atoms are independently and optionally selected as D, F, Cl, Br, I, C 1~4 It is substituted with 1, 2, 3, or 4 substituents selected from alkyl, -NO2, -CN, -OH, -NH2, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3, and -S(O)2NH2.

[0016] In some embodiments, R 3 -NR 5 R 6 , C 5~8 A cycloalkyl or heterocycle consisting of 4 to 9 atoms, C 5~8Cycloalkyls and heterocycles consisting of 4 to 9 atoms are independently and optionally selected as D, halogen, -NO2, -CN, -OH, -NH2, oxo, C 1~4 Alkyl, -C(O)CH3, -C(O)OH, -C 1~4 Alkylene C(O)OH, -C(O)OCH3, -NHC(O)-C 1~4 Substituting with 1, 2, 3, or 4 substituents selected from alkyl, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3, -S(O)2NH2, and -C(O)NHS(O)2CH3; R 5 and R 6 These are H, D, and C, respectively, independently. 1~4 Alkyl, C 5~8 A cycloalkyl or heterocycle consisting of 4 to 9 atoms, C 1~4 Alkyl, C 5~8 Cycloalkyls and heterocycles consisting of 4 to 9 atoms are independently and optionally selected as D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, HydroxyC 1~4 Alkyl, amino C 1~4 Alkyl, CarboxyC 1~4 Alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b Substituted with 1, 2, 3, or 4 substituents selected from; or R 5 and R 6These atoms, together with the atoms to which they are bonded, form a heterocycle consisting of 4 to 9 atoms, and this heterocycle, consisting of 4 to 9 atoms, optionally contains 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, or nitrogen, and optionally contains D, F, Cl, Br, I, -NO2, -CN, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, HydroxyC 1~4 Alkyl, amino C 1~4 Alkyl, CarboxyC 1~4 Alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b Substituted with 1, 2, 3, or 4 substituents independently selected from; R a , R b , R c and R d Each of these is independently H, D, C 1~4 Alkyl, C 3~6 A cycloalkyl or heterocycle consisting of 3 to 6 atoms, C 1~4 Alkyl, C 3~6 Cycloalkyls and heterocycles consisting of 3 to 6 atoms are independently and optionally selected as D, F, Cl, Br, I, C 1~4 It is substituted with 1, 2, 3, or 4 substituents selected from alkyl, -NO2, -CN, -OH, -NH2, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3, and -S(O)2NH2.

[0017] In some embodiments, R 3 -NR 5 R 6 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.1.0]hexyl, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azabi Spiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 1,7-diazaspiro[4.4]nonyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl, or morpholinyl, and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.1] Heptan-5-yl, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.1.0]hexyl, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azazspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 1,7-diazaspiro[4.4]nonyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl, and morpholinil are independently and optionally selected as D, F, Substituted with one, two, three, or four substituents selected from Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -C(O)CH3, -C(O)OH, -methyleneC(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3, -S(O)2NH2 and -C(O)NHS(O)2CH3; R 5 and R 6Each of these is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl, or morpholinyl, and each of these is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1] Pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl and morpholinil are independently and optionally selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH2OH, -CH2CH2OH, -CH2NH2, -CH2CH2NH2, -CH2COOH, -CH2CH2COOH, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b Substituted with 1, 2, 3, or 4 substituents selected from; or R 5 and R 6Together with the atoms to which they are bonded, the following occurs:

[0018] [ka]

[0019] Form a structure selected from,

[0020] [ka]

[0021] These are, independently and at will, D, F, Cl, Br, I, -NO2, -CN, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH2OH, -CH2CH2OH, -CH2NH2, -CH2CH2NH2, -CH2COOH, -CH2CH2COOH, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b Substituted with 1, 2, 3, or 4 substituents selected from; R a , R b , R c and R dEach of these is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl, or morpholinyl, and each of these is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl Tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl are independently and optionally substituted with one, two, three, or four substituents selected from D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -NO2, -CN, -OH, -NH2, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3, and -S(O)2NH2.

[0022] In some embodiments, L2 is coupled, -C 1~3 Alkylene- or -C 1~3 Alkilen-NR w -C 1~3 It is alkylene-, and each -C 1~3 Alkylenes are independently and optionally selected as D, F, Cl, Br, I, oxo, -OH, C 1~4 Alkyl and C 1~4 Substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups; R w H, D, -OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl or C 2~4 It is alkinyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl and C 2~4 Alkynnyls are independently and optionally selected as D, F, Cl, Br, I, oxo, -OH, C 1~4 Alkyl and C1~4 Substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups; R z H, D, -OH, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 It is a haloalkoxy; R 7 is C 3~8 A cycloalkyl or heterocycle consisting of 3 to 10 atoms, C 3~8 Cycloalkyls and heterocycles consisting of 3 to 10 atoms are independently and optionally selected as D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, -OR e , -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f and -C(O)NR e R f Substituted with 1, 2, 3, or 4 substituents selected from; R e and R f Each of them is H, D, C 1~4 Alkyl or C 3~6 It is a cycloalkyl, C 1~4 Alkyl and C 3~6 The cycloalkyl group is independently and optionally substituted with 1, 2, 3, or 4 substituents selected from D, F, Cl, Br, I, oxo, -NO2, -CN, -OH, -NH2, -C(O)CH3, -COOCH3, and -COOH.

[0023] In some embodiments, L2 is a bonded methylene-, ethylene-, methylene-NR w-methylene-, or -ethylene-NR w -ethylene-, where -methylene- and -ethylene- are independently and optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, oxo, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F and -CH2CF3; R w These are H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, vinyl, propenyl, allyl, ethinyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, or 3-butynyl, and methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CH2CHF 2, -CHFCH2F, -CH2CF3, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl and 3-butynyl are independently and optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, oxo, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F and -CH2CF3; R z These are H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethinyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CHF2, or -OCH2CF3; R 7These are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranil, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, or morpholinyl, and are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[ 2.2.1]heptyl, bicyclo[2.2.2]octyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl and morpholinyl are independently and optionally selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -OR e , -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f and -C(O)NR e R f Substituted with 1, 2, 3, or 4 substituents selected from; R e and R fEach of these is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and each of these is independently and optionally substituted with one, two, three, or four substituents selected from D, F, Cl, Br, I, oxo, -NO2, -CN, -OH, -NH2, -C(O)CH3, -COOCH3, and -COOH.

[0024] In some embodiments, the present invention relates to a compound of formula (II) or its stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0025] [ka]

[0026] (In the formula, X is CR x or N; Y is CR y or N; R x and R y These are independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 It is a haloalkoxy; R 1 , R 2 , R 3 , R 3a , R 4 , R 7 (Each of L2 is as defined herein) To provide.

[0027] In some embodiments, R x and R yEach of these is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CHF2, or -OCH2CF3.

[0028] In some embodiments, the present invention relates to a compound of formula (III) or its stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0029] [ka]

[0030] (In the formula, X, Y, R 1 , R 2 , R 3 , R 3a (and L2 is as defined herein) To provide.

[0031] In some embodiments, the present invention relates to the compound of formula (IV) or its stereoisomers, geometric iomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0032] [ka]

[0033] (In the formula, n1 is 0, 1, 2, 3, 4, or 5; R g H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, C1-6 hydroxyalkyl, -OR e, -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f and -C(O)NR e R f and; X, Y, R 1 , R 2 , R 3 , R 3a , R 4 , R e , R f (Each of L2 is as defined herein) To provide.

[0034] In some embodiments, R g H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, -OR e , -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f and -C(O)NR e R f and; R e and R f Each of these is as defined herein.

[0035] In some embodiments, R g H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -ORe , -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f or -C(O)NR e R f and; R e and R f Each of these is as defined herein.

[0036] In one embodiment, pharmaceutical compositions comprising a compound of formula (I), (II), (III), or (IV), or its stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts, or prodrugs are provided herein.

[0037] In some embodiments, the pharmaceutical compositions disclosed herein further include pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or combinations thereof.

[0038] In other embodiments, the use of compounds of formula (I), (II), (III), or (IV) or pharmaceutical compositions disclosed herein in the manufacture of a medicament for treating a disease mediated by the PD-1 / PD-L1 signaling pathway is provided herein.

[0039] In some embodiments, the diseases mediated by the PD-1 / PD-L1 signaling pathway disclosed herein are cancer, infectious diseases, or autoimmune diseases.

[0040] In other embodiments, the cancers disclosed herein are selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, T-cell lymphoma, B-cell lymphoma, Waldenström macroglobulinemia, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, cervical cancer, stomach cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, or bone cancer.

[0041] In other embodiments, the infectious diseases disclosed herein are selected from acquired immunodeficiency syndrome (HIV), hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpesvirus infection, papillomavirus infection, or influenza virus infection.

[0042] In other embodiments, the autoimmune disease according to the present invention is selected from chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia due to chronic atrophic gastritis, Goodpasture syndrome, primary biliary cholangitis, multiple sclerosis, acute idiopathic polyneuritis, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, or autoimmune hemolytic anemia.

[0043] In another aspect, the present invention provides a method for modulating an immune response mediated by the PD-1 / PD-L1 signaling pathway in a patient, comprising the step of administering a therapeutically effective amount of the compound of the present invention to a target, thereby modulating the immune response in the patient.

[0044] In a further embodiment, the present invention relates to a method for preparing, separating, and purifying compounds of formula (I), (II), (III), or (IV).

[0045] The foregoing is merely a summary of certain aspects disclosed herein and is not intended to be limiting in nature. These aspects, as well as other aspects and embodiments, are described more fully below. [Modes for carrying out the invention]

[0046] Definitions and General Terminology Herein, we refer in detail to certain embodiments of the present invention, as illustrated in the accompanying structures and formulas. The present invention is intended to encompass all alternatives, modifications, and equivalents that may fall within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that may be used in carrying out the present invention. The present invention is by no means limited to the methods and materials described herein. If one or more incorporated documents, patents, and similar materials differ from or conflict with this application (including, but not limited to, defined terms, terminology usage, and described techniques), this application shall prevail.

[0047] It is further understood that certain features of the present invention, described in the context of separate embodiments for clarity, can also be provided in combination in a single embodiment. Conversely, various features of the present invention, described in the context of a single embodiment for brevity, can also be provided separately or in any suitable subcombination.

[0048] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention pertains. All patents and publications referenced herein are incorporated by reference in their entirety.

[0049] As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of this invention, chemical elements are identified in accordance with the Periodic Table, CAS versions, and Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, the general principles of organic chemistry are described in their entirety in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, which are incorporated herein by reference in their entirety.

[0050] The grammatical articles “a,” “an,” and “the,” as used herein, are intended to include “at least one” or “one or more,” unless otherwise indicated herein or unless clearly inconsistent with the context. Thus, these articles are used herein to refer to the grammatical object of one or more (i.e., at least one) articles. For example, “a component” means one or more components, and therefore, perhaps two or more components may be considered and employed or used in the implementation of the embodiments described herein.

[0051] As used herein, the term “subject” refers to an animal. Typically, an animal is a mammal. A subject can also refer to, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0052] As used herein, “patient” refers to a human being (including adults and children) or another animal. In one embodiment, “patient” refers to a human being.

[0053] The term "contains" is an open expression meaning that it contains the contents disclosed herein, but does not exclude other contents.

[0054] The term "stereoisomer" refers to compounds that have the same chemical composition but differ in the arrangement of atoms or groups in space. Examples of stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric (cis / trans) isomers, and atropisomers.

[0055] The term "chiral molecule" refers to a molecule that cannot be superimposed onto its mirror image; on the other hand, an "achiral molecule" is a molecule that can be superimposed onto its mirror image.

[0056] The term "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other but cannot be superimposed.

[0057] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical procedures, such as electrophoresis and chromatography, for example, under HPLC.

[0058] The definitions and conventions of stereochemistry used herein generally follow those of SP. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994.

[0059] Many organic compounds exist in an optically active form, that is, they have the ability to rotate the plane of polarization. When describing optically active compounds, prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the rotation of plane polarization by the compound, with (-) or l meaning the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. Certain stereoisomers are sometimes called enantiomers, and mixtures of such stereoisomers are called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is neither stereoselectivity nor stereospecificity in a chemical reaction or process.

[0060] Any chiral atom (e.g., carbon) of the compounds disclosed herein may exist in a racemic or enantiomerically concentrated configuration, such as (R)-, (S)-, or (R,S)-. In certain embodiments, each chiral atom in the (R)- or (S)- configuration has an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%.

[0061] Depending on the selection of starting materials and procedures, the compound may exist in one of the possible stereoisomers, or as a mixture thereof, such as a racemate and a mixture of diastereoisomers, depending on the number of chiral carbon atoms. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or they can be divided using conventional techniques. If the compound contains a double bond, the substituent may be in an E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans- configuration.

[0062] Any resulting mixture of stereoisomers can be separated, for example, by chromatography and / or fractional crystallization into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the physicochemical differences of their constituents. Cis and trans isomers are diastereomers.

[0063] Any resulting racemic mixture of the final product or intermediate can be optically separated by methods known to those skilled in the art, for example, by separation of its diastereomer salts. The racemic product can also be separated by chiral chromatography, for example, high-performance liquid chromatography (HPLC) using a chiral adsorbent. Preferred enantiomers can also be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd edition, Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions, p. 268 (EL Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); and Chiral Separation Techniques: A Practical Approach (Subramanian, G., ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0064] The term "tautomer" or "tautomer" refers to structural isomers of different energies that can be interconverted across a low energy barrier. If tautomerization is possible (e.g., in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversion via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversion through the rearrangement of some of the bonded electrons. Specific examples of keto-enol tautomerization are the interconversion of pentane-2,4-dione tautomers and 4-hydroxypenta-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. Specific examples of phenol-keto tautomerization are the tautomerization of pyridine-4-ol and pyridine-4(1H)-one. Unless otherwise specified, all tautomers of the compounds disclosed herein fall within the scope of the present invention.

[0065] The term "optionally substituted with..." can be used interchangeably with the term "unsubstituted or substituted with...", and means that the structure is unsubstituted or substituted with one or more substituents according to the present invention. Examples of substituents according to the present invention include, but are not limited to, D, F, Cl, Br, I, -CHF2, -CF3, -CH2CF3, -OH, -COOH, -CONH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)-alkyl, -C(=O)-alkoxy, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -alkylene-cycloalkyl, -alkylene-heterocyclyl, -alkylene-aryl, or -alkylene-heteroaryl.

[0066] Generally, the term “substituted” refers to the replacement of one or more hydrogen groups within a given structure or group with a specified substituent. Unless otherwise indicated, a substituted group may have substituents at each of its substituted positions. If two or more positions within a given structure can be substituted by one or more specified substituents of selection, the substituents may be identical or different and can be substituted at each chemically feasible position within the structure.

[0067] The term "unsubstituted" means that the specified group does not have substituents.

[0068] Furthermore, it is necessary to explain that the phrases "each... is independent" and "each of... and... is independent" should be understood broadly unless otherwise specified. Specific options represented by the same symbol are independent of each other under different bases; or specific options represented by the same symbol are independent of each other under the same base.

[0069] Throughout this specification, substituents of the compounds disclosed herein are disclosed in groups or ranges. It is specifically intended that the present invention includes all individual subcombinations of members of such groups and ranges. For example, "C1-C6 alkyl" or "C 1~6 The term "alkyl" is intended to specifically disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups individually.

[0070] The term "D" refers to a single deuterium atom.

[0071] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0072] The terms "alkyl" or "alkyl group" refer to a saturated linear or branched monovalent hydrocarbon group having 1 to 20 carbon atoms, and the alkyl group may be optionally and independently substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In other embodiments, the alkyl group contains 1 to 8 carbon atoms. In other embodiments, the alkyl group contains 1 to 6 carbon atoms. In yet another embodiment, the alkyl group contains 1 to 4 carbon atoms. In yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.

[0073] Some non-limiting examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), 2-methyl-propyl or isobutyl (i-Bu, -CH2CH(CH3)2), 1-methyl-propyl or sec-butyl (s-Bu, -CH(CH3)CH2CH3), t ert-butyl(t-Bu, -C(CH3)3), n-pentyl(-CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-l-butyl(-CH2CH2CH(CH3)2), 2-methyl-l-butyl(-CH2CH(C H3)CH2CH3), n-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl(-CH(CH3)CH2CH(CH3)2), 3 Examples include -methyl-3-pentyl(-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl(-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl(-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl(-CH(CH3)C(CH3)3), n-heptyl, and n-octyl. The term "alkyl" or the prefix "alk-" includes both straight-chain saturated carbon chains and branched saturated carbon chains.

[0074] The term "alkenyl" refers to at least one unsaturated site, i.e., carbon-carbon sp 2This refers to a linear or branched monovalent hydrocarbon group having a double bond and comprising 2 to 12 carbon atoms. The alkenyl group may optionally be independently substituted with one or more substituents described herein, and may include groups having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, and allyl.

[0075] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms having at least one unsaturated site, i.e., a carbon-carbon sp triple bond, and the alkynyl group may be optionally independently substituted with one or more substituents described herein. In some embodiments, the alkynyl contains 2 to 8 carbon atoms. In other embodiments, the alkynyl contains 2 to 6 carbon atoms. In yet another embodiment, the alkynyl contains 2 to 4 carbon atoms. Some non-limiting examples of alkynyl groups include ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), 1-butynyl (-CH2CH2C≡CH), 2-butynyl (-CH2C≡CCH3), 3-butynyl (-C≡CCH2CH3), and the like.

[0076] The term "haloalkyl" refers to an alkyl group substituted with one or more identical or different halogen atoms. Alkyl groups are as defined herein. Some non-exclusive examples of haloalkyl groups include trifluoromethyl, difluoromethyl, fluoromethyl, 2,2-chloroethyl, and 3,3,3-trifluoropropyl. Haloalkyl groups may optionally be substituted with one or more substituents disclosed herein.

[0077] The term "alkoxy" refers to an alkyl group, as previously defined, bonded to the parent molecule via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms. In another embodiment, the alkoxy group contains 1 to 4 carbon atoms. In yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may optionally be substituted with one or more substituents disclosed herein. Some non-restrictive examples of alkoxy groups include methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), and 2-methyl-2-propoxy ( Examples include, but are not limited to, t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), and 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3).

[0078] The term "haloalkoxy" refers to an alkoxy group that is, in some cases, substituted with one or more halogen atoms, where alkoxy is defined as described herein. Examples of such groups include, but are not limited to, difluoromethoxy (-OCHF2), trifluoromethoxy (-OCF3), 2,2-difluoroethoxy (-OCH2CHF2), and 2,2,2-trifluoroethoxy (-OCH2CF3).

[0079] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with one, two, three, or four hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted with one or two hydroxyl groups. In some embodiments, hydroxyalkyl refers to a hydroxyC 1~6 Alkyl, i.e., C substituted with one or more hydroxyl groups 1~6 This refers to an alkyl group, preferably "hydroxy C 1~6 "Alkyl" refers to a C molecule substituted with one hydroxyl group. 1~6 This refers to an alkyl group. In some embodiments, hydroxyalkyl refers to hydroxyC 1~4 Refers to alkyl. In some embodiments, hydroxyalkyl refers to hydroxyC 1~3 This refers to alkyl groups. Some non-exclusive examples of hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH(OH)CH3, -CH2CH2OH, and -CH2CH(OH)CH2CH2OH.

[0080] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups, wherein the alkyl group is as defined herein. In some embodiments, aminoalkyl is amino C 1~6 Alkyl, i.e., C substituted with one or more amino groups 1~6 This refers to an alkyl group, preferably "amino C 1~6 "Alkyl" refers to a C molecule substituted with one amino group. 1~6 This refers to alkyl groups. Some non-exclusive examples of such groups include aminomethyl (-CH2NH2) and aminoethyl (e.g., -CH2CH2NH2).

[0081] The term "carboxyalkyl" refers to an alkyl group substituted with one or two carboxy substituents, where carboxy is -COOH and alkyl is as defined herein. In some embodiments, carboxyalkyl refers to an alkyl group substituted with one or two carboxyl groups. In some embodiments, carboxyalkyl refers to a carboxyC 1~6 Alkyl, i.e., C substituted with one or more carboxyl groups 1~6 This refers to an alkyl group, preferably "carboxyC 1~6 "Alkyl" refers to a C molecule substituted with one carboxyl group. 1~6 This refers to alkyl groups. Some non-exclusive examples of such groups include -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, etc.

[0082] The term "cycloalkyl" refers to monovalent or polyvalent saturated or partially unsaturated, non-aromatic saturated monocyclic, bicyclic, tricyclic, or tetracyclic carbocyclic systems containing 3 to 12 ring carbon atoms, where bicyclic, tricyclic, or tetracyclic carbocyclic systems are formed by condensation, crosslinking, or spiro-condensation configurations. In some embodiments, cycloalkyls contain 3 to 10 ring carbon atoms. In other embodiments, cycloalkyls contain 3 to 8 ring carbon atoms. In yet another embodiment, cycloalkyls contain 3 to 6 ring carbon atoms. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, and bicyclo[2.2.2]octanyl. Cycloalkyls are optionally substituted with one or more substituents described herein.

[0083] The terms “heterocyclyl” and “heterocyclic” are used interchangeably herein to refer to monovalent or polyvalent saturated or partially unsaturated non-aromatic monocyclic, bicyclic, or tricyclic systems containing 3 to 12 ring atoms, with at least one ring atom selected from nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, heterocyclyl groups may be carbon-bonded or nitrogen-bonded, and the -CH2- group may optionally be replaced by a -C(=O)- group. The sulfur of the ring atom may optionally be oxygenated to an S-oxide. The nitrogen of the ring atom may optionally be oxygenated to an N-oxide. Heterocyclic groups include saturated heterocyclic groups (i.e., heterocycloalkyl groups) and partially unsaturated heterocyclic groups. In some embodiments, the heterocyclyl group is a heterocyclyl group consisting of 3 to 8 atoms; in other embodiments, the heterocyclyl group is a heterocyclyl group consisting of 3 to 6 atoms. Some non-limiting examples of heterocyclyl groups include oxyranil, azetidinil, oxetanil, pyrrolidinil, tetrahydrofuranil, tetrahydrothiophenyl, thiazolidinil, pyrazolidinil, oxazolidinil, imidazolidinil, isoxazolidinil, piperidinil, piperazinil, or morpholinil. As described in the present invention, the heterocyclic group may consist of 3 to 12 atoms, 3 to 8 atoms, or 3 to 6 atoms, the atoms being optionally selected from C, N, O, or S, with at least one atom being N, O, or S; the heterocyclic group consisting of 3 to 8 atoms includes the heterocyclic group consisting of 3 to 6 atoms; and the heterocyclic group consisting of 3 to 6 atoms includes the heterocyclic group consisting of 3 to 5 atoms. Specifically, heterocyclic groups composed of 3 to 6 atoms include, but are not limited to, oxyranil, azilidinil, azetidinil, oxetanil, pyrrolidinil, tetrahydrofuranil, tetrahydrothiophenyl, thiazolidinil, pyrazolidinil, pyrazolinil, oxazolidinil, imidazolidinil, piperidinil, piperazinil, or morpholinil.

[0084] A heterocyclyl can be a carbon atom or a heteroatom atom. Heterocyclyl groups also include heterocyclic groups, bridged heterocyclic groups, or spiroheterocyclic groups formed by the fusion, bridging, or spirobonding of a heterocyclic group with a saturated or partially unsaturated carbocyclic or heterocyclic ring. Some non-restrictive examples of heterocyclyl groups include pyrrolidinyl, tetrahydrofuranil, dihydrofuranil, tetrahydrothienyl, tetrahydropyranil, dihydropyranil, tetrahydrothiopyranil, N-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, thioxayl, azetidinyl, oxetanil, thietanil, homopiperidinyl, oxyranil, azepanil, oxepanil, thiepanil, N-morpholinil, 2-morpholinil, 3-morpholinil, thiomorpholinil, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazinyl, 1,2,3,6-tetrahydropyrida-1-yl, oxazepinyl, diazepinyl, thiazepinyl, pyrrolin-1-yl, 2-pyrrolinil, 3-pyrrolinil, dihydro Loindyl, 2-Indolinyl, 2H-Pyranyl, 4H-Pyranyl, Dioxanyl, 1,3-Dioxolanyl, Pyrazolinyl, Dithianyl, Dithiolanyl, Dihydrothienyl, Imidazolidinyl, 1,2,3,4-Tetrahydroisoquinolinyl, 1,2,6-Thidiadin-1,1-Dioxo-2-yl, Hexahydro-2H-[1,4]Dioxin[2,3-c]Pyrrolyl, Quinolidinyl, 1,1-Dioxothiomorpholinyl, 2,3,3a,7a-Tetrahydro-1H-Isoindyl, Isoindolinyl, 1,2,3,4-Tetrahydroquinolyl, Dibenzofuranyl, Dihydrobenzoisothiadinyl, Dihydrobenzoisooxazinyl, Dioxolanyl, Dihydropyrazine, Dihydropyridyl, Dihydropyrazolyl, Dihydropyrimidinyl, Dihydropyrrolyl, 1,4-Dithianyl, Furanolyl, Furyl, Imidazolidinyl, Imidazolinyl, Imidazolyl, Imidazopyridyl, Imidazothiazolyl, Indazolyl, Dihydroindolyl, Indolidinyl, Isobenzotetrahydrofuryl, Isobenzotetrahydrothienyl, Isobenzothienyl, Isobenzodihydropyranyl, Isocumalinyl, Isoindlinyl, Isothiazolidinyl, Isoxazolidinyl, Morpholinyl, Decahydroindolyl, Decahydroisoindolyl, Oxadiazolyl, Oxazolidenedionyl, Oxazolidinyl, Oxazolopyridinyl, Oxyranyl, 4-Piperidonyl, Pyrrolyl, Quinolyl, Tetrahydroisoquinolinyl, Tetrahydrothienyl, Thiomorpholinyl, Thiazolidinyl, 1,3,5-Tritianyl, 2-Oxopyrrolidyl, Oxy So-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, 1,2,3,4-tetrahydroisoquinolyl, 1,3-benzodioxyl, 2-oxa-5-azabicyclo[2.2.1]hepta-5-yl, 2-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.1.0]hexanyl, 2,6-diazaspiro[3.3]he Examples include butanyl, 2,6-diazaspiro[3.4]octanyl, 1,7-diazaspiro[4.4]nonanyl, 4-oxomorpholinyl, 2,6-diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2-oxa-6-azaspiro[3.4]octanyl, 1,7-diazaspiro[4.4]nonanyl, 1,9-diazaspiro[5.5]undecanyl, and pyrimidinedionyl.

[0085] The phrases "consisting of j-k ring atoms," "consisting of j-k atoms," or "j-k members" mean that the cyclic group is formed by j-k atoms that form a ring, and the ring atoms include carbon atoms and / or heteroatoms, e.g., O, N, S, P, etc. j and k are each any non-zero natural number independently, where k > j; "j-k" includes j, k, and any natural numbers between j and k (including the ends). For example, "consisting of 3-8 atoms or 3-8 members," "consisting of 3-6 atoms or 3-6 members," "consisting of 5-10 atoms or 5-10 members," or "consisting of 5-6 atoms or 5-6 members" mean that the cyclic group is formed by 3-8, 3-6, 5-10, or 5-6 ring atoms, respectively. The ring atoms include carbon atoms and / or heteroatoms, e.g., O, N, S, P, etc. Specifically, for example, "heteroaryl group consisting of 5 to 10 ring atoms" or "5 to 10-membered heteroaryl group" refers to a heteroaryl group having 5, 6, 7, 8, 9, or 10 ring atoms, where 5, 6, 7, 8, 9, or 10 refers to the number of atoms forming the ring. For example, pyridinyl is a heteroaryl group or 6-membered heteroaryl group composed of 6 ring atoms.

[0086] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, and silicon, including any oxidized form of nitrogen, sulfur, or phosphorus; any quaternized form of basic nitrogen; or a substituteable nitrogen in a heterocyclic ring, e.g., N (such as 3,4-dihydro-2H-pyrrolyl), NH (such as pyrrolidinyl), or NR (such as N-substituted pyrrolidinyl, where R is a substituent as defined herein).

[0087] The term "aryl" refers to monocyclic, bicyclic, and tricyclic aromatic unsaturated carbocyclic systems containing 6 to 14 ring atoms, 6 to 12 ring atoms, or 6 to 10 ring atoms, where each ring system contains a ring of 3 to 7 atoms and has one or more bonding sites with the rest of the molecule. The terms "aryl" and "aromatic ring" may be used interchangeably herein. Examples of aryl rings include phenyl, naphthyl, and anthryl. The aryl group may be optionally and independently substituted with one or more substituents disclosed herein.

[0088] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 5 to 12 ring atoms, 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one ring contains 1, 2, 3, or 4 ring heteroatoms selected from nitrogen, oxygen, and sulfur, and the heteroaryl has one or more bonding sites with the rest of the molecule. If a -CH2- group is present in the heteroaryl group, the -CH2- group may optionally be replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group may be bonded to the rest of the molecule (e.g., the main structure of the general formula) via any suitable position (e.g., C of CH, or N of NH). The terms "hetreroaryl" and "heteroaromatic ring" or "heteroaromatic compound" may be used interchangeably herein. Some non-limiting examples of heteroaryl groups include furyl, imidazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidyl, and pyrazinyl. The heteroaryl group may optionally be substituted with one or more substituents disclosed herein. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 to 10 atoms, meaning it includes 1 to 9 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from O, S, and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5 to 6 atoms, meaning it includes 1 to 5 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from O, S, and N. Examples of heteroaryl groups consisting of 5 to 6 atoms include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyridazinyl, thienyl, thiazolyl, and others.

[0089] In other embodiments, some non-limiting examples of heteroaryl systems (including heteroaryl and heteroaromatic rings) include furan-2-yl, furan-3-yl, N-imidazolyl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl, oxazole-2-yl, oxazole-4-yl, oxazole-5-yl, 4-methylisoxazole-5-yl, N-pyrrolyl, pyrrole-2-yl Pyrrole-3-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, pyridazinyl (e.g., pyridazin-3-yl), thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, tetrazolyl (e.g., tetrazolyl-5-yl), triazolyl (e.g., triazol-2-yl and triazol-5-yl), thiophene-2-yl, thiophene-3-yl, pyrazolyl (e.g., pyrazol- 2-yl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazole-2-yl, pyrazinyl, pyrazine-2-yl, 1,3,5-triazinyl, benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridine-6-yl, benzimidazolyl, benzoxazolyl, quinoxalinyl, 1,8-Naphthilidinyl, Benzothienyl, Benzothiazolyl, Indolyl (e.g., Indole-2-yl), Purinyl, Quinolinyl (e.g., Quinoline-2-yl, Quinoline-3-yl and Quinoline-4-yl), Isoquinolyl (e.g., Isoquinola-1-yl, Isoquinola-3-yl or Isoquinola-4-yl), Benzopyrazolyl, Acridinyl, Benzenimidazolyl, Benzoindolyl, Benzoisooxazinyl, Benzo[4,6]imidazo[1,2-a]pyridinyl, Benzo[d]imidazo[2,1-b] Thiazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzothiopyranil, benzoxazinyl, benzoxazolyl, benzothiazolyl, β-carbolinyl, carbazolyl, sinnolinyl, dibenzofuranil, imidazopyridinyl, imidazothiazolyl, indazolyl, indolidinyl, indolyl, isobenzothienyl, isoquinolinyl, isothiazolidinyl, isoth Azolyl, naphthilidinyl, oxazolidinedionyl, oxazolidinyl, oxazolopyridinyl, oxazolyl, perimidinyl, phenanthiazinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalanidyl, pteridinyl, pyridopyridyl, quinazolinyl, quinoxalinyl, thiophenyl, triazinyl, 2H-pyrrolo[3,4-c] Pyridinyl, pyrazolo[2',1':2,3]oxazolo[4,5-c]pyridinyl, imidazo[2',1':2,3]thiazolo[4,5-c]pyridinyl, imidazo[2',1':2,3]thiazolo[4,5-b]pyridinyl, imidazo[2',1':2,3]thiazolo[5,4-b]pyridinyl, pyrazolo[2',1':2,3]thiazolo[4,5-b]pyridinyl, 1H-benzo[4,5]thieno[2,3-d]imida Examples include zolyl, 1H-benzo[4,5]thieno[2,3-d]imidazolyl, benzo[4,5]thieno[2,3-d]imidazolyl, imidazo[2',1':2,3]thiazolo[4,5-b]pyradinyl, imidazo[2',1':2,3]thiazolo[5,4-b]pyridinyl, imidazo[2',1':2,3]thiazolo[4,5-c]pyridinyl, and 1H-benzo[f]imidazo[4,5-b][1,4]thiazepinyl. The heteroaryl group may be substituted with substituents disclosed herein.

[0090] The terms "-alkylene-cycloalkyl," "-alkylene-heterocyclyl," "-alkylene-aryl," and "-alkylene-heteroaryl" refer to cycloalkyl, heterocyclyl, aryl, and heteroaryl groups bonded to the rest of the molecule through an alkylene group, each having the meanings defined herein. The alkylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups in "-alkylene-cycloalkyl," "-alkylene-heterocyclyl," "-alkylene-aryl," and "-alkylene-heteroaryl" are each optionally substituted with one or more substituents described herein.

[0091] The term "pharmaceutically acceptable" means that it is physiologically acceptable and, when administered to humans, generally does not cause allergic reactions or similar adverse reactions, such as gastrointestinal upset or dizziness. Preferably, as used herein, the term "pharmaceutically acceptable" means that it is approved by a federal or state regulatory authority for use in animals, and especially in humans, or is listed in the United States Pharmacopeia or other generally recognized pharmacopoeias.

[0092] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a compound is administered. Suitable pharmaceutical carriers are listed in "Remington's Pharmaceutical Sciences," EW Martin.

[0093] "Hydrate" refers to a compound or salt thereof disclosed herein that further contains a stoichiometric or non-stoichiometric amount of water bonded by non-covalent intermolecular forces, and also refers to a complex in which the solvent molecule is water.

[0094] The term "solvate" refers to the association or complex of one or more solvent molecules with a compound disclosed herein. Some non-limiting examples of solvents that form solvates include water, isopropanol, ethanol, MeOH, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0095] "Ester" refers to an in vivo hydrolyzable ester of a compound of formula (I), (II), (III), or (IV) containing a hydroxyl group, such as a pharmaceutically acceptable ester that is hydrolyzed in the body of a human or animal to produce a parent alcohol. Examples of in vivo hydrolyzable ester groups of compounds of formula (I), (II), (III), or (IV) containing a hydroxyl group include, but are not limited to, phosphates, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl, and N-(dialkylaminoethyl)-N-alkylcarbamoyl.

[0096] An "N-oxide" refers to one or more nitrogen atoms that are oxidized to form an N-oxide when a compound contains several amine functional groups. Specific examples of N-oxides are those of tertiary amines or nitrogen atoms of nitrogen-containing heterocyclic compounds. N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid) (see Advanced Organic Chemistry, Jerry March, 4th edition, Wiley Interscience, pp. 509-514). In particular, N-oxides can be prepared, for example, by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA) in an inert solvent, such as dichloromethane.

[0097] Compounds can exist in several different geometric isomers and tautomers, and compounds of formula (I), (II), (III), or (IV) encompass all such forms. To avoid doubt, if a compound can exist in one of several geometric isomers or tautomers, and only one is specifically described or shown, then all the others are still encompassed by formula (I), (II), (III), or (IV).

[0098] The term "prodrug" refers to a compound that is converted in vivo to a compound of formula (I), (II), (III), or (IV). Such conversion may be achieved, for example, by hydrolysis of the prodrug form in the blood or by enzymatic conversion to the parent form in the blood or tissue. Prodrugs of the compounds disclosed herein may be, for example, esters. Some common esters used as prodrugs are phenyl esters, aliphatic (C) esters. 1~24These include esters, acyloxymethyl esters, carbonate esters, carbamic acid esters, and amino acid esters. For example, compounds disclosed herein that contain a hydroxyl group may be acylated to their prodrug form at this position. Other prodrug forms include phosphates, such as phosphate compounds derived from the phosphonation of a hydroxyl group on the parent compound. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, ACS Symposium Series Vol. 14; Edward B. Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, all of which are incorporated herein by reference.

[0099] Unless otherwise specified, all tautomers of the compounds disclosed herein fall within the scope of the present invention.

[0100] Furthermore, unless otherwise specified, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. The present invention includes isotope-labeled compounds that are identical to those enumerated in formulas (I), (II), (III), or (IV), but in which one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl is an example. Compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of the said compounds or prodrugs containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotope-labeled compounds of the present invention, for example, radioisotopes, for example 3 H or 14 Compounds incorporating C are useful in drug and / or substrate tissue distribution assays. The isotope-labeled compounds of formula (I), (II), (III), or (IV) of the present invention and their prodrugs can generally be prepared by performing the procedures disclosed in the following schemes and / or examples, using readily available isotope-labeling reagents in place of non-isotope-labeling reagents.

[0101] A “metabolite” is a product produced through the metabolism of a specified compound or a salt thereof in the body. Metabolites of a compound may be identified using routine techniques known in the art, and their activity may be determined using tests, such as those described herein. Such products may arise, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds disclosed herein, including metabolites produced by contacting the compounds disclosed herein with mammals for a sufficient period of time.

[0102] The compounds disclosed herein are useful in a variety of pharmaceutically acceptable salt forms. The term “pharmaceutically acceptable salt” refers to a salt form that would be apparent to a pharmacist, i.e., substantially nontoxic and providing the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism, or excretion. Other factors of more practical nature, equally important in the selection, are the cost of the raw materials, ease of crystallization, yield, stability of the resulting active pharmaceutical ingredient, hygroscopicity, and flowability.

[0103] "Pharmacologically acceptable salts" refers to organic or inorganic salts of the compounds disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., incorporated herein by reference, describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1977, 66:1-19. Examples of pharmaceutically acceptable non-toxic salts include, but are not limited to, salts of amino groups formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, and nitric acid, or organic acids, such as acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid, or salts obtained by other methods used in the art, such as ion exchange.

[0104] Other pharmaceutically acceptable salts include adipine, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptaneate, hexanoate, and yo Examples include hydrochloride, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4 Examples include alkyl(4) salts.

[0105] The present invention also envisions the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Products soluble or dispersible in water or oil can be obtained by such quaternization. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, ferric salts, zinc salts, copper salts, manganese salts, and aluminum salts. Further pharmaceutically acceptable salts may include, where appropriate, counterions such as halides, hydroxides, carboxylic acids, sulfuric acids, phosphoric acids, nitric acids, and C2. 1~8Examples include non-toxic ammonium compounds, quaternary ammonium compounds, and amine cations formed using sulfonates or aryl sulfonates. Examples of amine salts include, but are not limited to, N,N-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, diethylamine and other alkylamines, piperazine, and tris(hydroxymethyl)aminomethane. Examples of alkaline earth metal salts include, but are not limited to, barium, calcium, and magnesium. Examples of transition metal salts include, but are not limited to, zinc.

[0106] The terms "protecting group" or "PG" refer to substituents commonly used to block or protect specific functional groups while reacting with other functional groups on a compound. For example, an "amino protecting group" is a substituent attached to an amino group that blocks or protects an amino functional group in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent on a hydroxyl group that blocks or protects a hydroxyl functional group. Suitable protecting groups include acetyl and silyl. A "carboxy protecting group" refers to a substituent on a carboxyl group that blocks or protects a carboxyl functional group. Common carboxyl protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenylphosphinol)ethyl, and nitroethyl. For a general explanation of protecting groups and their uses, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0107] In this invention, "room temperature" refers to a temperature of 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature of 20°C to 30°C; in other embodiments, "room temperature" refers to 25°C.

[0108] In this invention, if the chemical name of a compound does not match the corresponding structure, the compound is characterized by the corresponding structure.

[0109] Where used herein, any abbreviations for protecting groups, amino acids, and other compounds shall, unless otherwise indicated, follow their common use, recognized abbreviations, or those of the IUPAC-IUB Committee on Biochemical Nomenclature (see Biochem. 1972, 11:942-944).

[0110] The terms “to treat,” “to treat,” or “to treat” any disease or disorder mean, in one embodiment, improving the disease or disorder (i.e., slowing, stopping, or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, “to treat,” “to treat,” or “to treat” means mitigating or improving at least one physical parameter, including one that may not be recognizable to the patient. In yet another embodiment, “to treat,” “to treat,” or “to treat” means regulating the disease or disorder physically (e.g., stabilizing recognizable symptoms), physiologically (e.g., stabilizing physical parameters), or together. In yet another embodiment, “to treat,” “to treat,” or “to treat” means preventing or delaying the onset, onset, or progression of the disease or disorder.

[0111] Description of the compound of the present invention The present invention provides pyridopyrimidine derivatives or pharmaceutical compositions thereof that can be used as PD-1 / PD-L1 inhibitors. The present invention further relates to the use of compounds or pharmaceutical compositions thereof for preparing pharmaceuticals for treating diseases and / or disorders by inhibiting the activity of PD-1 / PD-L1 by the compound. The present invention further describes a method for synthesizing the compounds. The compounds of the present invention exhibit good PD-1 / PD-L1 inhibitory activity and pharmacokinetic properties.

[0112] In one embodiment, the present invention relates to a pyridopyrimidine derivative having the ability to inhibit PD-1 / PD-L1 interaction, which is a structure represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt, or prodrug of the structure represented by formula (I).

[0113] [ka]

[0114] (In the formula, R 1 , R 2 , R 1a , R 2a , R 3 , R 3a , R 4 , R 7 (L1, L2, A, m, n, q, and p are as defined herein.) To provide.

[0115] In some embodiments, m is 0, 1, 2, or 3.

[0116] In some embodiments, n is 0, 1, 2, or 3.

[0117] In some embodiments, q is 0, 1, 2, or 3.

[0118] In some embodiments, p is 0, 1, 2, or 3.

[0119] In some embodiments, t is 0, 1, 2, or 3.

[0120] In some embodiments, L1 is coupled, -NR z -, -O-, -(CH2) t -, -HC=CH-, -S- or -SO2- are selected; R z Each of t is as defined herein.

[0121] In some embodiments, R z H, D, -OH, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 It is a haloalkoxy.

[0122] In some embodiments, R z H, D, -OH, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 It is a haloalkoxy.

[0123] In other embodiments, R z These are H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethinyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CHF2, or -OCH2CF3.

[0124] In some embodiments, R 1 , R 2 , R 1a and R 2a Each of these is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~6 Alkyl or C 1~6 It is a haloalkyl group.

[0125] In some embodiments, R 1 , R 2 , R 1a and R 2a Each of these is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~4 Alkyl or C 1~4 It is a haloalkyl group.

[0126] In other embodiments, R 1 , R 2 , R 1a and R 2aEach of these is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH2Cl, -CHCl2, -CH2CHCl2, -CH2Br, -CHBr2, or -CH2CHBr2.

[0127] In some embodiments, ring A is C 3~8 Cycloalkyl, heterocycle consisting of 3 to 8 atoms, C 6~10 It is selected from aryls or heteroaryls consisting of 5 to 6 atoms.

[0128] In some embodiments, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidyl, pyrazinyl, or pyridazinyl.

[0129] In some implementations, each R 3a These are independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 It is a haloalkoxy, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl and C 1~6 Alkoxy compounds are D, F, Cl, Br, I, C, independently and optionally. 1~6 Alkyl, C 2~6 Alkenil, C 2~6It is substituted with 1, 2, 3, or 4 substituents selected from alkynyl, oxo, -NO2, -CN, -OH, -NH2, -COOCH3, and -COOH.

[0130] In some implementations, each R 3a These are independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 It is a haloalkoxy, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl and C 1~4 Alkoxy compounds are D, F, Cl, Br, I, C, independently and optionally. 1~4 Alkyl, C 2~4 Alkenil, C 2~4 It is substituted with 1, 2, 3, or 4 substituents selected from alkynyl, oxo, -NO2, -CN, -OH, -NH2, -COOCH3, and -COOH.

[0131] In other embodiments, R 3aEach of these is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethinyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CHF2, or -OCH2CF3, and methyl, ethyl, n-propyl Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, -OCH3, -OCH2CH3, -OCH2CH2CH3 and -OCH(CH3)2 are independently and optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, oxo, -NO2, -CN, -OH, -NH2, -COOCH3 and -COOH.

[0132] In some embodiments, R 4 H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~8 It is a cycloalkyl, C 1~6 Alkyl and C 3~8 Cycloalkyls are independently and optionally selected as D, F, Cl, Br, I, C 1~6 Alkyl, C 1~6 It is substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, oxo, -NO2, -CN, -OH, -NH2, -COOCH3, and -COOH.

[0133] In some embodiments, R 4 H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C1~4 Alkyl, C 1~4 Haloalkyl or C 3~6 It is a cycloalkyl, C 1~4 Alkyl and C 3~6 Cycloalkyls are independently and optionally selected as D, F, Cl, Br, I, C 1~4 Alkyl, C 1~4 It is substituted with 1, 2, 3, or 4 substituents selected from haloalkyl, oxo, -NO2, -CN, -OH, -NH2, -COOCH3, and -COOH.

[0134] In other embodiments, R 4 These are H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclo Ropropyl, cyclobutyl, cyclopentyl, and cyclohexyl are independently and optionally substituted with one, two, three, or four substituents selected from D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, oxo, -NO2, -CN, -OH, -NH2, -COOCH3, and -COOH.

[0135] In some embodiments, L2 is coupled, -C 1~6 Alkylene- or -C 1~6 Alkilen-NR w -C 1~6 It is alkylene-, and each -C 1~6 Alkylenes are independently and optionally selected as D, F, Cl, Br, I, oxo, -OH, C 1~6 Alkyl and C 1~6 Substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups; Rw This is defined herein.

[0136] In some embodiments, L2 is coupled, -C 1~3 Alkylene- or -C 1~3 Alkilen-NR w -C 1~3 It is alkylene-, and each -C 1~3 Alkylenes are independently and optionally selected as D, F, Cl, Br, I, oxo, -OH, C 1~4 Alkyl and C 1~4 Substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups; R w This is defined herein.

[0137] In some embodiments, L2 is a bonded methylene-, ethylene-, methylene-NR w -methylene-, or -ethylene-NR w -ethylene-, where -methylene- and -ethylene- are independently and optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, oxo, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F and -CH2CF3; R w This is defined herein.

[0138] In some embodiments, R w H, D, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl or C 2~6 It is alkinyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl and C 2~6 Alkynnyls are independently and optionally selected as D, F, Cl, Br, I, oxo, -OH, C 1~6 Alkyl and C 1~6It is substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups.

[0139] In some embodiments, R w H, D, -OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl or C 2~4 It is alkinyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkenyl and C 2~4 Alkynnyls are independently and optionally selected as D, F, Cl, Br, I, oxo, -OH, C 1~4 Alkyl and C 1~4 It is substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups.

[0140] In other embodiments, R w These are H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, vinyl, propenyl, allyl, ethinyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, or 3-butynyl, and methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CH2CHF 2, -CHFCH2F, -CH2CF3, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl and 3-butynyl are independently and optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, oxo, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F and -CH2CF3.

[0141] In some embodiments, R 3 -NR 5 R 6, C 3~12 A cycloalkyl or heterocycle consisting of 3 to 12 atoms, C 3~12 Cycloalkyls and heterocycles consisting of 3 to 12 atoms are independently and optionally selected as D, halogen, -NO2, -CN, -OH, -NH2, oxo, C 1~6 Alkyl, -C(O)CH3, -C(O)OH, -C 1~4 Alkylene C(O)OH, -C(O)OCH3, -NHC(O)-C 1~4 Substituting with 1, 2, 3, or 4 substituents selected from alkyl, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3, -S(O)2NH2, and -C(O)NHS(O)2CH3; R 5 and R 6 Each of these is as defined herein.

[0142] In some embodiments, R 3 -NR 5 R 6 , C 3~10 A cycloalkyl or heterocycle consisting of 3 to 10 atoms, C 3~10 Cycloalkyls and heterocycles consisting of 3 to 10 atoms are independently and optionally selected as D, halogen, -NO2, -CN, -OH, -NH2, oxo, C 1~4 Alkyl, -C(O)CH3, -C(O)OH, -C 1~4 Alkylene C(O)OH, -C(O)OCH3, -NHC(O)-C 1~4 Substituting with 1, 2, 3, or 4 substituents selected from alkyl, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3, -S(O)2NH2, and -C(O)NHS(O)2CH3; R 5 and R 6 Each of these is as defined herein.

[0143] In some embodiments, R 3 -NR 5 R 6 , C 5~8 A cycloalkyl or heterocycle consisting of 4 to 9 atoms, C 5~8Cycloalkyls and heterocycles consisting of 4 to 9 atoms are independently and optionally selected as D, halogen, -NO2, -CN, -OH, -NH2, oxo, C 1~4 Alkyl, -C(O)CH3, -C(O)OH, -C 1~4 Alkylene C(O)OH, -C(O)OCH3, -NHC(O)-C 1~4 Substituting with 1, 2, 3, or 4 substituents selected from alkyl, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3, -S(O)2NH2, and -C(O)NHS(O)2CH3; R 5 and R 6 Each of these is as defined herein.

[0144] In some embodiments, R 3 -NR 5 R 6Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.1.0]hexyl, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azabi Spiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 1,7-diazaspiro[4.4]nonyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl, or morpholinyl, and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.1] Heptan-5-yl, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.1.0]hexyl, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azazspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 1,7-diazaspiro[4.4]nonyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl, and morpholinil are independently and optionally selected as D, F, Substituted with 1, 2, 3 or 4 substituents selected from Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -C(O)CH3, -C(O)OH, -methyleneC(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3, -S(O)2NH2 and -C(O)NHS(O)2CH3; R 5 and R 6 Each of these is as defined herein.

[0145] In some embodiments, R 5 and R 6These are H, D, and C, respectively, independently. 1~6 Alkyl, C 3~10 A cycloalkyl or heterocycle consisting of 3 to 12 atoms, C 1~6 Alkyl, C 3~10 Cycloalkyls and heterocycles consisting of 3 to 12 atoms are independently and optionally selected as D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, HydroxyC 1~6 Alkyl, amino C 1~6 Alkyl, CarboxyC 1~6 Alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b Substituted with 1, 2, 3, or 4 substituents selected from; R a , R b , R c and R d Each of these is as defined herein.

[0146] In some embodiments, R 5 and R 6 These are H, D, and C, respectively, independently. 1~4 Alkyl, C 5~8 A cycloalkyl or heterocycle consisting of 4 to 9 atoms, C 1~4 Alkyl, C 5~8 Cycloalkyls and heterocycles consisting of 4 to 9 atoms are independently and optionally selected as D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~4Alkyl, C 1~4 Haloalkyl, HydroxyC 1~4 Alkyl, amino C 1~4 Alkyl, CarboxyC 1~4 Alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b Substituted with 1, 2, 3, or 4 substituents selected from; R a , R b , R c and R d Each of these is as defined herein.

[0147] In some embodiments, R 5 and R 6 These are H, D, and C, respectively, independently. 1~4 Alkyl, C 3~8 A cycloalkyl or heterocycle consisting of 3 to 10 atoms, C 1~4 Alkyl, C 3~8 Cycloalkyls and heterocycles consisting of 3 to 10 atoms are independently and optionally selected as D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, HydroxyC 1~4 Alkyl, amino C 1~4 Alkyl, CarboxyC 1~4 Alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NRc C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b Substituted with 1, 2, 3, or 4 substituents selected from; R a , R b , R c and R d Each of these is as defined herein.

[0148] In some embodiments, R 5 and R 6 These atoms, together with the atoms to which they are bonded, form a heterocycle consisting of 4 to 9 atoms, and this heterocycle, consisting of 4 to 9 atoms, optionally contains 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, or nitrogen, and optionally contains D, F, Cl, Br, I, -NO2, -CN, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, HydroxyC 1~4 Alkyl, amino C 1~4 Alkyl, CarboxyC 1~4 Alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R bIt is substituted with 1, 2, 3, or 4 substituents independently selected from; R a , R b , R c and R d Each of these is as defined herein.

[0149] In some embodiments, R 5 and R 6 Each of these is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl, or morpholinyl, and each of these is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1] Pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl and morpholinil are independently and optionally selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH2OH, -CH2CH2OH, -CH2NH2, -CH2CH2NH2, -CH2COOH, -CH2CH2COOH, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2Ra -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b Substituted with 1, 2, 3, or 4 substituents selected from; R a , R b , R c and R d Each of these is as defined herein.

[0150] In some embodiments, R 5 and R 6 These atoms, together with the atoms to which they are bonded, form a heterocycle consisting of 3 to 12 atoms, and the heterocycle consisting of 3 to 12 atoms optionally contains 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, or nitrogen, and optionally contains D, F, Cl, Br, I, -NO2, -CN, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, HydroxyC 1~6 Alkyl, amino C 1~6 Alkyl, CarboxyC 1~6 Alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b It is substituted with 1, 2, 3, or 4 substituents independently selected from; R a , R b , R c and R dEach is as defined herein.

[0151] In some embodiments, R 5 and R 6 together with the atoms to which they are attached form a heterocyclic ring consisting of 3 to 10 atoms, and the heterocyclic ring consisting of 3 to 10 atoms optionally contains 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, or nitrogen, and optionally contains D, F, Cl, Br, I, -NO2, -CN, oxo, C 1~4 alkyl, C 1~4 haloalkyl, hydroxyC 1~4 alkyl, aminoC 1~4 alkyl, carboxyC 1~4 alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b , -C(O)NR a R b , -S(O)2R a , -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b is substituted with 1, 2, 3 or 4 substituents independently selected from; R a , R b , R c and R d Each is as defined herein.

[0152] In other embodiments, R 5 and R 6 together with the atoms to which they are attached are as follows:

[0153]

Chemical formula

[0154] Form a structure selected from,

[0155] [ka]

[0156] These are, independently and at will, D, F, Cl, Br, I, -NO2, -CN, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH2OH, -CH2CH2OH, -CH2NH2, -CH2CH2NH2, -CH2COOH, -CH2CH2COOH, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b -S(O)2R a -S(O)2NR a R b , -NR a S(O)2R b and -C(O)NR a S(O)2R b Substituted with 1, 2, 3, or 4 substituents selected from; R a , R b , R c and R d Each of these is as defined herein.

[0157] In one embodiment, the present invention-NR 5 R 6 The structure is as follows:

[0158] [ka]

[0159] is selected from

[0160] In some embodiments, R a , R b , R c and R d each independently is H, D, C 1~6 alkyl, C 3~8 cycloalkyl or a heterocyclic ring consisting of 3 to 8 atoms, and C 1~6 alkyl, C 3~8 cycloalkyl and the heterocyclic ring consisting of 3 to 8 atoms are independently and optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, C 1~6 alkyl, -NO2, -CN, -OH, -NH2, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

[0161] In some embodiments, R a , R b , R c and R d each independently is H, D, C 1~4 alkyl, C 3~6 cycloalkyl or a heterocyclic ring consisting of 3 to 6 atoms, and C 1~4 alkyl, C 3~6 cycloalkyl and the heterocyclic ring consisting of 3 to 6 atoms are independently and optionally substituted with 1, 2, 3 or 4 substituents selected from D, F, Cl, Br, I, C 1~4 alkyl, -NO2, -CN, -OH, -NH2, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3 and -S(O)2NH2.

[0162] In other embodiments, R a , R b , R c and R dEach of these is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl, or morpholinyl, and each of these is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl Tetrahydrofuranyl, piperidinyl, piperazinyl, and morpholinyl are independently and optionally substituted with one, two, three, or four substituents selected from D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -NO2, -CN, -OH, -NH2, -C(O)CH3, -C(O)OH, -C(O)OCH3, -NHC(O)CH3, -NHC(O)OCH3, -C(O)NH2, -S(O)2CH3, and -S(O)2NH2.

[0163] In some embodiments, R 7 is C 3~10 A cycloalkyl or heterocycle consisting of 3 to 12 atoms, C 3~10 Cycloalkyls and heterocycles consisting of 3 to 12 atoms are independently and optionally selected as D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, C1-6 hydroxyalkyl, -OR e , -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f and -C(O)NR e R f Substituted with 1, 2, 3, or 4 substituents selected from; R e and R f This is defined herein.

[0164] In some embodiments, R 7 is C 3~8 A cycloalkyl or heterocycle consisting of 3 to 10 atoms, C 3~8 Cycloalkyls and heterocycles consisting of 3 to 10 atoms are independently and optionally selected as D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, -OR e , -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f and -C(O)NR e R f Substituted with 1, 2, 3, or 4 substituents selected from; R e and R f Each of these is as defined herein.

[0165] In other embodiments, R 7These are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranil, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, or morpholinyl, and are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[ 2.2.1]heptyl, bicyclo[2.2.2]octyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl and morpholinyl are independently and optionally selected from D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -OR e , -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f and -C(O)NR e R f Substituted with 1, 2, 3, or 4 substituents selected from; R e and R f Each of these is as defined herein.

[0166] In some embodiments, R e and R f Each of them is H, D, C 1~6Alkyl or C 3~8 It is a cycloalkyl, C 1~6 Alkyl and C 3~8 The cycloalkyl group is independently and optionally substituted with 1, 2, 3, or 4 substituents selected from D, F, Cl, Br, I, oxo, -NO2, -CN, -OH, -NH2, -C(O)CH3, -COOCH3, and -COOH.

[0167] In some embodiments, R e and R f Each of them is H, D, C 1~4 Alkyl or C 3~6 It is a cycloalkyl, C 1~4 Alkyl and C 3~6 The cycloalkyl group is independently and optionally substituted with 1, 2, 3, or 4 substituents selected from D, F, Cl, Br, I, oxo, -NO2, -CN, -OH, -NH2, -C(O)CH3, -COOCH3, and -COOH.

[0168] In some embodiments, R e and R f Each of these is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and each of these is independently and optionally substituted with one, two, three, or four substituents selected from D, F, Cl, Br, I, oxo, -NO2, -CN, -OH, -NH2, -C(O)CH3, -COOCH3, and -COOH.

[0169] In some embodiments, the present invention relates to a compound of formula (II) or its stereoisomers, geometric isomers, tautomers, N-oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts, or prodrugs.

[0170] [ka]

[0171] (In the formula, X, Y, R 1 , R 2 , R 3 , R 3a , R 4 , R 7 (Each of L2 is as defined herein) To provide.

[0172] In some embodiments, X is CR x or N; R x This is defined herein.

[0173] In some embodiments, Y is CR y or N; R y This is defined herein.

[0174] In some embodiments, R x and R y Each of these is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 It is a haloalkoxy.

[0175] In some embodiments, R x and R y Each of these is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy or C 1~4 It is a haloalkoxy.

[0176] In other embodiments, R x and R yEach of these is independently H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CHF2, or -OCH2CF3.

[0177] In some embodiments, the present invention relates to a compound of formula (III) or its stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0178] [ka]

[0179] (In the formula, X, Y, R 1 , R 2 , R 3 , R 3a (and L2 is as defined herein) To provide.

[0180] In some embodiments, the present invention relates to a compound of formula (IV) or its stereoisomers, geometric isomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs.

[0181] [ka]

[0182] (In the formula, n1 is 0, 1, 2, 3, 4, or 5; R g H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, -ORe , -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f and -C(O)NR e R f and; X, Y, R 1 , R 2 , R 3 , R 3a , R 4 , R e , R f (Each of L2 is as defined herein) To provide.

[0183] In some embodiments, R g H, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, -OR e , -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f and -C(O)NR e R f and; R e and R f Each of these is as defined herein.

[0184] In some embodiments, R gH, D, F, Cl, Br, I, -NO2, -CN, -OH, -NH2, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH2F, -CHF2, -CF3, -CH2CHF2, -CHFCH2F, -CH2CF3, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -OR e , -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f or -C(O)NR e R f and; R e and R f Each of these is as defined herein.

[0185] In other embodiments, the present invention relates in no way to any one of the following compounds or to stereoisomers, tautomers, N-oxides, solvates, hydrates, metabolites, esters, pharmaceutically acceptable salts or prodrugs thereof:

[0186] [ka]

[0187] [ka]

[0188] [ka]

[0189] In one embodiment, pharmaceutical compositions comprising a compound of formula (I), (II), (III), or (IV), or its stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs are provided herein.

[0190] In some embodiments, the pharmaceutical compositions disclosed herein further include pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or combinations thereof.

[0191] In one embodiment, the present invention relates to the use of a compound represented by formula (I), (II), (III), or (IV) or a pharmaceutical composition thereof in the preparation of a drug for treating a disease mediated by the PD-1 / PD-L1 signaling pathway.

[0192] In some embodiments, the diseases mediated by the PD-1 / PD-L1 signaling pathway disclosed herein are cancer, infectious diseases, or autoimmune diseases.

[0193] In some embodiments, the cancers disclosed herein are selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, T-cell lymphoma, B-cell lymphoma, Waldenström macroglobulinemia, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, cervical cancer, stomach cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, or bone cancer.

[0194] In some embodiments, the infectious diseases disclosed herein include acquired immunodeficiency syndrome (HIV), hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpesvirus infection, papillomavirus infection, or influenza virus infection.

[0195] In some embodiments, the autoimmune disease according to the present invention is selected from Hashimoto's disease, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia due to chronic atrophic gastritis, Goodpasture syndrome, primary biliary cholangitis, multiple sclerosis, acute idiopathic polyneuritis, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, or autoimmune hemolytic anemia.

[0196] In another aspect, the present invention provides a method for modulating an immune response mediated by the PD-1 / PD-L1 signaling pathway in a patient, comprising the step of administering a therapeutically effective amount of the compound of the present invention to a target, thereby modulating the immune response in the patient.

[0197] In a further embodiment, the present invention relates to a method for preparing, separating, and purifying compounds of formula (I), (II), (III), or (IV).

[0198] Pharmaceutical composition of the compound of the present invention, preparation, and administration As described in the present invention, the pharmaceutical compositions of the present invention comprise one of the compounds represented by formula (I), formula (II), formula (III), or formula (IV) of the present invention, and further comprise pharmaceutically acceptable excipients. These excipients include, for example, any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring agent, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, or lubricant, as used in the present invention, suitable for a specific target dosage form. As described below: Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988–1999, Marcel Dekker, New York, both of which are incorporated herein by reference in their entirety, disclose various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation. Except for any conventional adjuvants incompatible with the compounds disclosed herein by, for example, producing any undesirable biological effect or otherwise interacting adversely with any other components of a pharmaceutically acceptable composition, their use is considered to be within the scope of the invention.

[0199] Some non-limiting examples of materials that can function as pharmaceutically acceptable carriers include: ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, e.g., human serum albumin; buffering substances, e.g., phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; lanolin; sugars, e.g., lactose, glucose and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., cellulose Examples of suitable luboxymethylcellulose sodium, ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol; and phosphate buffer, as well as other non-toxic, suitable lubricants, such as sodium lauryl sulfate and magnesium stearate, and colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants. When the compounds of the present invention are administered as pharmaceuticals to mammals, such as humans, they may be given alone or as pharmaceutical compositions containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0200] "Therapeutic dose" or "effective dose" means one or more of the compounds of the present invention in an amount sufficient to treat, prevent, alleviate, improve or eliminate one or more symptoms of a particular disease, disorder or syndrome, or to halt or delay the onset of one or more symptoms of a particular disease, disorder or syndrome described herein. In the case of cancer treatment, a therapeutic dose of the drug can reduce the number of cancer cells; inhibit (i.e., slow or halt to some extent) the invasion of cancer cells into surrounding organs; inhibit tumor metastasis; inhibit tumor growth to some extent; and / or alleviate to some extent one or more symptoms associated with cancer. In the case of infectious disease conditions, a therapeutic dose is an amount sufficient to reduce or alleviate the symptoms of an infectious disease (an infection caused by bacteria, viruses and fungi).

[0201] The administration regimen may affect the components that constitute the effective dose. The compounds of the present invention may be administered to an individual before or after the onset of a disorder related to the PD-1 / PD-L1 signaling pathway. Furthermore, several divided doses and staggered dosages may be administered daily or sequentially, or the dose may be infused continuously or administered as a bolus injection. Moreover, the dosage of the compounds of the present invention may be increased or decreased proportionally, as indicated by the urgency of the therapeutic or preventive situation.

[0202] The compounds of the present invention may be used in the treatment of conditions, disorders, or diseases described herein, or in the preparation of pharmaceutical compositions for use in the treatment of these diseases. Methods of using the compounds of the present invention in the treatment of these diseases, or pharmaceutical preparations having the compounds of the present invention for the treatment of these diseases.

[0203] A "pharmaceutically acceptable carrier" includes a pharmaceutically acceptable material, composition, or vehicle that is recognized in the art and suitable for administering the compounds of the present invention to mammals. The carrier includes liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that are involved in holding the pharmaceutically active ingredient or transferring it from one organ or part of the body to another. Each carrier must be "acceptable" in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic, suitable substances used in pharmaceutical formulations.

[0204] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants may also be present in the composition.

[0205] Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bicarbonate, sodium pyrosulfite, and sodium sulfite; oil-soluble antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0206] The formulations of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal, and / or parenteral administration. The formulations can be conveniently provided in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to make a single dosage form will generally be the amount of the compound that produces the therapeutic effect. Generally, out of 100 percent, this amount will be in the range of about 1 percent to about 99 percent of the active ingredient, preferably about 5 percent to about 70 percent, and most preferably about 10 percent to about 30 percent.

[0207] Methods for preparing these formulations or compositions include the step of associating the compound of the present invention with a carrier and, optionally, one or more minor components. Generally, formulations are prepared by homogeneously and closely associating the compound of the present invention with a liquid carrier or a micronized solid carrier, or both, and then, if necessary, shaping the product.

[0208] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (flavored basis, usually using sucrose and acacia or tragacanth), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as flavored tablets (using an inert base, e.g., gelatin and glycerin, or sucrose and acacia), and / or as mouthwashes, etc., each containing a predetermined amount of the compound of the present invention as an active ingredient. The compound of the present invention may also be administered as a bolus, lick, or paste.

[0209] In the solid dosage forms of the present invention for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; and water-retaining agents, such as glycerides. Rolls; disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; dissolution retarders, such as paraffin; absorption enhancers, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also include buffers. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

[0210] Tablets may be prepared by compression or molding using one or more optional auxiliary components. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), a surfactant, or a dispersant. Wet tablets may be prepared by molding a mixture of powder compounds moistened with an inert liquid diluent in a suitable machine.

[0211] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as sugar-coated tablets, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may also be formulated to provide delayed or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres that provide a desired release profile. They may be sterilized, for example, by filtration through a bacterial capture filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injection medium immediately before use. These compositions may also optionally contain opacifying agents and may be compositions that release the active ingredient only in or preferentially in a specific part of the gastrointestinal tract, and optionally delayed. Examples of embedding compositions that can be used include polymer substances and waxes. The active ingredient may also, where appropriate, be in the form of microencapsulation with one or more of the above excipients.

[0212] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, as well as mixtures thereof.

[0213] Oral compositions may also include, in addition to inert diluents, adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances and preservatives.

[0214] In addition to the active compound, the suspension may contain a suspending agent, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or mixtures thereof.

[0215] Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration may be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate, and may be provided as suppositories that are solid at room temperature but liquid at body temperature, and therefore melt in the rectal or vaginal cavity to release the active compound.

[0216] Formulations of the present invention suitable for vaginal administration include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known to be suitable in the art.

[0217] Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compounds can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives, buffers, or propellants.

[0218] The ointments, pastes, creams, and gels may contain, in addition to the active compound of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0219] The powders and sprays may contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. The sprays may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0220] Transdermal patches offer the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flow of the compounds across the skin. The rate of such flow can be controlled by providing a rate-controlled membrane or by dispersing the active compounds in a polymer matrix or gel.

[0221] Ophthalmic preparations, ophthalmic ointments, powders, solutions, etc., are also considered to fall within the scope of the present invention.

[0222] A pharmaceutical composition of the present invention suitable for parenteral administration comprises one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injection solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostatic agents, solutes or suspending agents or thickeners to make the formulation isotonic with the blood of the intended recipient.

[0223] Suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and organic esters for injection (e.g., ethyl oleate). Appropriate fluidity can be maintained, for example, by the use of coating materials (e.g., lecithin), by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0224] These compositions may also contain adjuvants, such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid. It may also be desirable to include isotonic agents, such as sugars and sodium chloride, in the composition. Furthermore, sustained absorption of the injectable pharmaceutical form can be achieved by including absorption-delaying agents, such as aluminum monostearate and gelatin.

[0225] In some cases, it is desirable to slow down the absorption of a drug from subcutaneous or intramuscular injection in order to prolong its effects. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. In this case, the rate of drug absorption depends on its dissolution rate, which may depend on the crystal size and morphology. Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0226] Depot formulations for injection are prepared by forming a microcapsule matrix of the drug in a biodegradable polymer, such as polylactide-polyglycolide. The drug release rate can be controlled depending on the ratio of the drug to the polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(acid anhydrides). Depot injection formulations are also prepared by capturing the drug in liposomes or microemulsions compatible with body tissues.

[0227] The preparations of the present invention may be administered orally, parenterally, topically, or rectally. These may, of course, be administered in a form suitable for each route of administration. For example, they may be administered by injection, infusion, or inhalation in the form of tablets or capsules, such as in injection, inhalation, eye drops, ointments, or suppositories; topically by lotion or ointment; and rectally by suppositories. Oral and / or IV administration is preferred.

[0228] When used herein, the phrases “parenteral administration” and “administered parenterally” mean, but are not limited to, injections, other modes of administration other than enteral and topical administration, but typically include intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injections and infusions.

[0229] When used herein, the phrases “systemic administration,” “administered systemically,” “peripheral administration,” and “administered peripherally” mean the administration of a compound, drug, or other material other than directly into the central nervous system, such as subcutaneous administration, in which the compound, drug, or other material enters the patient’s system and is therefore subject to metabolism and other similar processes.

[0230] These compounds can be administered to humans and other animals for therapeutic purposes by any suitable route of administration, including, for example, orally by spray, nasally, as powder, ointment or droplets, rectally, vaginally, parenterally, intravesically and topically, buccally and sublingually.

[0231] Regardless of the selected route of administration, the compounds of the present invention, and / or the pharmaceutical compositions of the present invention, which can be used in an appropriate hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0232] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of the active ingredient effective in achieving a desired therapeutic response for a particular patient, composition, and mode of administration without becoming toxic to the patient.

[0233] The selected dosage level depends on a variety of factors, including the activity of the specific compound of the present invention being employed, or its ester, salt, or amide; the route of administration; the time of administration; the elimination rate of the specific compound being employed; the duration of treatment; other drugs, compounds, and / or materials used in combination with the specific compound being employed; the age, sex, weight, condition, overall health, and medical history of the patient being treated; and similar factors well known in the medical field.

[0234] A physician or veterinarian with ordinary skill in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can start the dose of the compound of the invention used in the pharmaceutical composition at a level lower than the level required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0235] Generally, the appropriate daily dose of the compound of the present invention is the amount of the compound that is the minimum effective dose to produce a therapeutic effect. Such an effective dose generally depends on the factors mentioned above. Generally, the dosage of the compound of the present invention for a patient is about 0.001 to about 100 mg / kg body weight / day, more preferably about 0.01 to about 80 mg / kg body weight / day, and even more preferably about 1.0 to about 50 mg / kg body weight / day.

[0236] If desired, the effective daily dose of the active compound may be administered separately in unit dosage forms at appropriate intervals throughout the day, in two, three, four, five, six, or more divided doses.

[0237] The pharmaceutical compositions or combinations of the present invention may have a unit dose of about 1 to 1000 mg of the active ingredient for a subject weighing about 50 to 70 kg, preferably about 1 to 500 mg, about 1 to 250 mg, about 1 to 150 mg, about 1 to 100 mg, or about 1 to 50 mg of the active ingredient. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity. A physician, clinician, or veterinarian skilled in the art can easily determine the effective amount of each active ingredient necessary to prevent, treat, or inhibit the progression of the disorder or disease.

[0238] The dosage characteristics cited above can be advantageously demonstrated in in vitro and in vivo studies using mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues, and preparations thereof. The compounds of the present invention can be administered in vitro in the form of a solution, for example, preferably an aqueous solution, and in vivo enterally, parenterally, advantageously intravenously, for example, as a suspension or in an aqueous solution. The therapeutically effective dose in vivo may range between about 0.1 and 500 mg / kg, or between about 1 and 100 mg / kg, depending on the route of administration.

[0239] As used herein, the term “subject” refers to an animal. Typically, an animal is a mammal. A subject can also refer to, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0240] The compounds of the present invention can be administered alone, but are preferably administered in the form of a pharmaceutical composition of the compounds.

[0241] Drug combinations To treat the diseases and conditions described herein, combination therapies are used in which one or more compounds or compositions provided by the present invention, or pharmaceutically acceptable derivatives thereof, are used in combination with other drug activators, such as the ALK inhibitor ceritinib, the NTRK inhibitor entrectinib, cisplatin, and carboplatin.

[0242] In carrying out this method, an effective amount or therapeutically effective concentration of the compound is administered to an individual exhibiting symptoms of the disease or disorder being treated, either by systemic delivery including oral, parenteral, or intravenous delivery, or by formulation for local or topical application. The amount is effective in treating, managing, or improving the disease, or improving or eliminating one or more symptoms of the disease or disorder.

[0243] Furthermore, it will be understood by those skilled in the art that the compounds, isomers, prodrugs, and pharmaceutically acceptable derivatives provided herein, including pharmaceutical compositions and formulations containing these compounds, can be used in a variety of combination therapies to treat the above-mentioned conditions and diseases. Accordingly, the use of the compounds, isomers, prodrugs, and pharmaceutically acceptable derivatives provided herein in combination with other active pharmaceutical products to treat the diseases / conditions described herein is also given due consideration herein.

[0244] General synthesis procedure In general, the compounds disclosed herein may be prepared by the methods described herein, and the substituents are as defined for formulas (I), (II), (III), or (IV) above, unless otherwise specified. The following non-limiting schemes and examples are provided to further illustrate the invention.

[0245] Those skilled in the art will recognize that the chemical reactions described can be readily adapted to prepare several other compounds disclosed herein, and that alternative methods for preparing the compounds disclosed herein are considered to be within the scope of disclosure. For example, the synthesis of compounds not exemplified by the present invention can be successfully carried out by modifications obvious to those skilled in the art, for example, by appropriately protecting interfering groups, by using other suitable reagents known in the art other than those described, and / or by making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as applicable for preparing other compounds disclosed herein.

[0246] In the examples described below, all temperatures are given in degrees Celsius (°C) unless otherwise specified. Reagents were purchased from commercial suppliers, such as Aldrich Chemical Company, Arco Chemical Company, and Alfa Chemical Company, and were used without further purification unless otherwise specified. Common solvents were purchased from commercial suppliers, such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., Qingdao Tenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.

[0247] Anhydrous THF, anhydrous dioxane, anhydrous toluene, and anhydrous ether were obtained by refluxing the solvent with sodium. Anhydrous CH2Cl2 and anhydrous CHCl3 were obtained by refluxing the solvent with CaH2. Anhydrous ÃO, anhydrous PE, anhydrous hexane, anhydrous DMAC, and anhydrous DMF were treated with anhydrous Na2SO4 before use.

[0248] The reactions described below were generally carried out under positive pressure of nitrogen or argon, or in anhydrous solvent using a drying tube (unless otherwise specified), with the reaction flask typically fitted with a rubber diaphragm for introducing the substrate and reagents via syringe. The glassware was oven-dried and / or heat-dried.

[0249] Column chromatography was performed using silica gel columns. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used, with a specification of 0.4mm-0.5mm for thin-layer chromatography separation and purification products.

[0250] ¹H NMR spectra were obtained using CDCl3, DMSO-d6, CD3OD, or acetone-d6 solutions with TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard (reported in ppm). When reporting peak multiplicity, the following abbreviations are used: s (singular), d (double), t (tripular), q (quadruplicate), m (multiple), br (broad), dd (double double), ddd (double double double), dt (double triple), dq (double quadruplicate). The coupling constant J was reported in Hertz (Hz) if given.

[0251] Low-resolution mass spectral (MS) data were also measured using an Agilent 6120 series LC-MS spectrometer equipped with a G1311B binary pump, G1316A TCC (column temperature controlled, maintained at 30°C), G1329B autosampler, and G1315D DAD detector. An ESI source was used with the LC-MS spectrometer.

[0252] Both LC-MS spectrometers were equipped with Agilent Zorbax SB-C18, 2.1 × 30 mm, 5 μm columns. The injection volume was determined by the sample concentration. The flow rate was 0.6 mL / min. HPLC peaks were recorded at UV-Vis wavelengths of 210 nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (Phase A) and 0.1% formic acid in ultrapure water (Phase B). The gradient elution conditions are shown in Table 1.

[0253] [Table 1]

[0254] The purity of the compounds was evaluated by Agilent 1100 series high-performance liquid chromatography (HPLC) using UV detection at 210 nm and 254 nm (Zorbax SB-C18, 2.1 × 30 mm, 4 micorns, 10 min, 0.6 mL / min flow rate, 5-95% (0.1% formic acid in CH3CN) in (0.1% formic acid in H2O). The column was operated at 40°C.

[0255] Throughout this specification, the following abbreviations will be used:

[0256] [Table 2]

[0257] The following synthesis schemes and synthesis intermediate schemes describe the steps for preparing the compounds disclosed in this invention, and unless otherwise specified, R 1 , R 2 , R 3a , R 4 , R 5 , R 6 , R g n1, X, and Y are as defined herein.

[0258] [ka]

[0259] In the formula, v is 0, 1, 2, or 3.

[0260] The compound of formula (13) can be prepared by synthesis scheme 1: The compound of formula (1) and the compound of formula (2) undergo reductive amination to obtain the compound of formula (3). The compound of formula (3) undergoes a coupling reaction with the compound of formula (4) to obtain the compound of formula (5). The compound of formula (5) and the compound of formula (6) undergo a nucleophilic substitution reaction to obtain the compound of formula (7). The compound of formula (7) and the compound of formula (8) are reacted by a coupling reaction to obtain the compound of formula (9). The compound of formula (9) is subjected to an oxidation reaction to obtain the compound of formula (10). The compound of formula (10) undergoes reductive amination with the compound of formula (11) to obtain the compound of formula (12). The compound of formula (12) undergoes ester hydrolysis to obtain the compound of formula (13).

[0261] [ka]

[0262] The compound of formula (20) can be prepared by synthesis scheme 2: The compound represented by formula (1) and the compound represented by formula (14) undergo a reductive amination reaction to obtain the compound represented by formula (15). The compound of formula (15) undergoes a coupling reaction with the compound of formula (4) to obtain the compound of formula (16). The compound of formula (16) and the compound of formula (6) undergo a nucleophilic substitution reaction to obtain the compound of formula (17). The compound of formula (17) and the compound of formula (8) are reacted by a coupling reaction to obtain the compound of formula (18). The compound of formula (18) is subjected to an oxidation reaction to obtain the compound of formula (19). The compound of formula (19) undergoes reductive amination with the compound of formula (11) to obtain the compound of formula (20).

[0263] [ka]

[0264] The compound of formula (20) can be prepared by synthesis scheme 3: The compound of formula (1) and the compound of formula (4) undergo a coupling reaction to obtain the compound of formula (21). The compound of formula (21) and the compound of formula (6) undergo a nucleophilic substitution reaction to obtain the compound of formula (22). The compound of formula (22) and the compound of formula (8) are reacted by a coupling reaction to obtain the compound of formula (23). The compound of formula (23) undergoes reductive amination with the compound of formula (14) to obtain the compound of formula (18). The compound of formula (18) is subjected to an oxidation reaction to obtain the compound of formula (19). The compound of formula (19) undergoes reductive amination with the compound of formula (11) to obtain the compound of formula (20).

[0265] [ka]

[0266] The compound of formula (13-a) can be prepared by synthesis scheme 4: the compound of formula (10) and the compound of formula (11-a) undergo reductive amination to obtain the compound of formula (12-a). The compound of formula (12-a) undergoes ester hydrolysis to obtain the compound of formula (13-a).

[0267] [ka]

[0268] The compound of formula (20-a) can be prepared by synthesis scheme 5: the compound of formula (19) and the compound of formula (11-a) undergo a reductive amination reaction to obtain the compound of formula (20-a).

[0269] The following examples disclosed herein are provided to further illustrate the present invention. However, these examples should not be used to limit the scope of the present invention. In the event of any inconsistency between the structure and the name of a compound of the present invention, the structure of the compound shall prevail. [Examples]

[0270] Intermediate fragment 1: 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde

[0271] [ka]

[0272] (3-bromo-2-chlorophenyl)boronic acid (50 g, 212.5 mmol), 6-chloro-2-methoxynicotinaldehyde (36.5 g, 212.5 mmol), Pd(PPh3)2Cl2 (7.46 g, 10.63 mmol), (o-tol)3P (3.2 g, 10.6 mmol), and K2CO3 (58.7 g, 425.0 mmol) were dissolved in 1,4-dioxane (1000 mL) and water (200 mL). The reaction mixture was stirred overnight at 65°C under an N2 atmosphere. After cooling the reaction solution, it was filtered through a Celite pad. The filtrate was concentrated under reduced pressure, washed with an appropriate amount of ethyl acetate, and filtered to obtain 63 g of a white solid product in 62% yield. MS (ESI, positive ion) m / z: 326.1 [M+H] + .

[0273] (Example 1) (1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylic acid

[0274] [ka]

[0275] Step 1: Synthesis of methyl(1r,4r)-4-(((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylate

[0276] [ka]

[0277] In a 500 mL bottle, 6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-aldehyde (7.5 g, 22.97 mmol), methyl(1r,4r)-4-aminocyclohexane-1-carboxylate hydrochloride (11.12 g, 57.42 mmol), DCM (100 mL), methanol (100 mL), triethylamine (3.49 g, 34.45 mmol), and acetic acid (2.07 g, 34.45 mmol) were added in order, and the mixture was stirred at 50°C for 3 hours. Sodium cyanoborohydride (2.89 g, 45.94 mmol) was added, and the reaction was continued for 2 hours. After the reaction was complete, the pH was adjusted to 7-8 with saturated potassium carbonate aqueous solution, the solution was concentrated under reduced pressure, then extracted with DCM (240 mL), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 10.5 g of a pale yellow oily liquid product in 97.7% yield. MS (ESI, positive ion) m / z: 467.1 [M+H] + .

[0278] Step 2: Synthesis of methyl(1r,4r)-4-(((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0279] [ka]

[0280] In a 500 mL bottle, methyl(1r,4r)-4-(((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylate (10.5 g, 22.45 mmol), formaldehyde (5.06 g, 67.35 mmol), DCM (100 mL), methanol (100 mL), triethylamine (2.50 g, 24.70 mmol), and acetic acid (1.48 g, 24.70 mmol) were added in order, and the mixture was stirred at 50°C for 3.5 hours. Sodium cyanoborohydride (4.23 g, 67.35 mmol) was added, and the reaction was continued for 2 hours. After the reaction was complete, the pH was adjusted to 7-8 with saturated potassium carbonate aqueous solution, the solution was concentrated under reduced pressure, then extracted with DCM (240 mL), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE / siRNA (v / v) = 3 / 1 to obtain a white solid product (10.10 g, yield 93.4%). MS (ESI, positive ion) m / z: 481.1 [M+H] + .

[0281] Step 3: Synthesis of methyl(1r,4r)-4-(((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0282] [ka]

[0283] Methyl(1r,4r)-4-(((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (1.5 g, 3.11 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.94 g, 4.04 mmol), potassium carbonate (1.29 g, 9.33 mmol), Pd(dppf)Cl2CH2Cl2 (0.25 g, 0.31 mmol), 1,4-dioxane (15 mL), and water (3 mL) were added in order to a 30 mL microwave tube. The tube was sealed and reacted at 130 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the product was purified by silica gel column chromatography (eluent: PE / Â(v / v)=2 / 1) to obtain 1.32 g of a pale yellow oily product in 83.5% yield. MS (ESI, positive ion) m / z: 508.5 [M+H] + .

[0284] Step 4: Synthesis of methyl(1r,4r)-4-(((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0285] [ka]

[0286] Methyl(1r,4r)-4-(((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (1.2 g, 2.36 mmol), 7-bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (0.69 g, 2.36 mmol), and tert-butanol (20 mL) were added sequentially to a 50 mL bottle and reacted at 130 °C for 3 hours. After the reaction, the mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography with PE / siRNA(v / v) = 2 / 1, and the product was obtained as a pale yellow oily substance (533.0 mg, yield 29.5%). MS (ESI, positive ion) m / z: 765.6 [M+H] + .

[0287] Step 5: Synthesis of methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0288] [ka]

[0289] In a 30 mL microwave tube, add methyl(1r,4r)-4-(((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (0.48 g, 0.63 0.29 g, 1.89 mmol) of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane, 0.33 g, 1.57 mmol of potassium phosphate, 0.051 g, 0.063 mmol of Pd(dppf)Cl2CH2Cl2, 10 mL of 1,4-dioxane, and 2 mL of water were added in sequence. The tube was sealed, and the reaction was carried out at 120°C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: PE / siRNA = 1 / 1) to obtain 324.0 mg of a pale yellow solid product in yield of 72.5%. MS (ESI, positive ion) m / z: 713.2 [M+H] + .

[0290] Step 6: Synthesis of methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0291] [ka]

[0292] Methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (324 mg, 0.45 mmol), 1,4-dioxane (20 mL), water (8 mL), potassium osmate dihydrate (16.58 mg, 0.045 mmol), and sodium periodate (481.25 mg, 2.25 mmol) were added in sequence to a 50 mL bottle and reacted at room temperature for 1.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the dioxane, water (100 mL) was added, and then the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 1), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 30 / 1) to obtain 255.0 mg of a pale yellow solid product in yield of 78.5%. MS (ESI, positive ion) m / z: 715.6 [M+H] + .

[0293] Step 7: Synthesis of methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0294] [ka]

[0295] Methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (255 mg, 0.36 mmol), (R)-pyrrolidine-3-ol hydrochloride (222.44 mg, 1.80 mmol), DCM (15 mL), DMF (15 mL), triethylamine (43.71 mg, 0.43 mmol), and acetic acid (25.94 mg, 0.43 mmol) were added in order to a 100 mL bottle and reacted at 50°C for 2 hours. Sodium borohydride (45.24 mg, 0.72 mmol) was added, and the reaction was continued at room temperature. After the reaction was complete, the pH was adjusted to 7-8 with saturated potassium carbonate aqueous solution, then extracted with DCM (20 mL x 3), the organic phases were combined, washed with saturated brine (50 mL x 1), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 15 / 1) to obtain 30.0 mg of a pale yellow solid product in yield of 10.70%. MS (ESI, positive ion) m / z: 786.7 [M+H] + .

[0296] Step 8: Synthesis of (1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylic acid

[0297] [ka]

[0298] Methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (30 mg, 0.038 mmol), 1,4-dioxane (6 mL), water (2 mL), and lithium hydroxide monohydrate (7.97 mg, 0.19 mmol) were added in order to a 25 mL bottle and reacted at 50°C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, a mixture of dichloromethane and methanol (DCM / MeOH(v / v)=1:1) was added to dissolve the mixture, the pH was adjusted to 7-8 with 1M aqueous HCl, and the mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=7.5 / 1) to obtain 13.3 mg of a white solid product in a yield of 45.2%. MS (ESI, positive ion) m / z: 772.31 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.33 (s, 1H), 8.94 (s, 1H), 8.16 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.42 - 7.32 (m, 2H), 7.27 (d, J = 7.4 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 6.70 (t, J = 54.6 Hz, 1H), 4.26 - 4.19 (m, 1H), 3.90 (s, 3H), 3.88 - 3.80 (m, 1H), 3.54 (s, 4H), 2.76 - 2.64 (m, 2H), 2.43 - 2.38 (m, 2H), 2.17 (s, 3H), 2.04 (s, 3H), 1.99 - 1.76 (m, 6H), 1.65 - 1.52 (m, 1H), 1.40 - 1.25 (m, 6H).

[0299] (Example 2) (1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylic acid

[0300] [ka]

[0301] Step 1: Synthesis of 6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-aldehyde

[0302] [ka]

[0303] In a 100 mL bottle, 6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-aldehyde (1.0 g, 2.83 mmol), tert-butanol (50 mL), and 7-bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (1.25 g, 4.25 mmol) were added in sequence and reacted at 100°C. After the reaction was complete, the mixture was concentrated under reduced pressure, diluted with water (100 mL), and then extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 1), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: PE / siRNA(v / v)=5 / 1), yielding 1.68 g of a pale yellow solid product in 97.03% yield. MS (ESI, positive ion) m / z: 610.4 [M+H] + .

[0304] Step 2: Synthesis of methyl(1r,4r)-4-(((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylate

[0305] [ka]

[0306] In a 100 mL bottle, 6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-aldehyde (1.68 g, 2.75 mmol), DCM (20 mL), methanol (20 mL), methyl(1r,4r)-4-aminocyclohexane-1-carboxylate hydrochloride (1.60 g, 8.25 mmol), triethylamine (0.42 g, 4.13 mmol), and acetic acid (0.25 g, 4.13 mmol) were added in order, and the mixture was reacted at 50°C for 4 hours. After the reaction, the pH was adjusted to 7-8 with saturated potassium carbonate aqueous solution, and the mixture was concentrated. The residue was purified by silica gel chromatography using DCM / MeOH(v / v)=20 / 1, yielding a pale yellow solid (1.7g, 82.2%). MS (ESI, positive ion) m / z: 751.2 [M+H] + .

[0307] Step 3: Synthesis of methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylate

[0308] [ka]

[0309] Methyl(1r,4r)-4-(((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylate (1.1 g, 1.46 mmol), vinylboronic acid pinacol ester (0.67 g, 4.38 mmol), potassium phosphate (0.77 g, 3.65 mmol), Pd(dppf)Cl2CH2Cl2 (0.12 g, 0.15 mmol), 1,4-dioxane (10 mL), and water (2 mL) were added to a 25 mL bottle and reacted at 130 °C under a nitrogen atmosphere. After the reaction, the mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography using DCM / MeOH(v / v)=20 / 1, yielding a pale yellow solid (0.98 g, 95.8%). MS (ESI, positive ion) m / z: 699.3 [M+H] + .

[0310] Step 4: Synthesis of methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylate

[0311] [ka]

[0312] Methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylate (760 mg, 1.09 mmol), 1,4-dioxane (37.5 mL), water (15 mL), potassium osmate dihydrate (40.16 mg, 0.11 mmol), and sodium periodate (1165.70 mg, 5.45 mmol) were added in order to a 100 mL bottle and the mixture was allowed to react at room temperature. After the reaction was complete, the reaction product was quenched with saturated sodium sulfite aqueous solution (10 mL) and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=30 / 1), yielding 650.0 mg of a pale yellow solid product in 85.29% yield. MS (ESI, positive ion) m / z: 701.6 [M+H] + .

[0313] Step 5: Synthesis of methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylate

[0314] [ka]

[0315] Methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylate (450 mg, 0.64 mmol), (R)-pyrrolidine-3-ol (278.78 mg, 3.2 mmol), triethylamine (97.14 mg, 0.96 mmol), DCM (15 mL), methanol (15 mL), and acetic acid (57.65 mg, 0.96 mmol) were added in order to a 100 mL bottle, and the reaction was carried out at 50 °C for 5 hours. Sodium borohydride (80.44 mg, 1.28 mmol) was added, and the reaction was continued at room temperature. After the reaction was complete, the pH was adjusted to 7-8 with saturated potassium carbonate aqueous solution, the mixed solution was concentrated under reduced pressure, water (150 mL) was added, and then the mixture was extracted with DCM (20 mL x 3), the organic phases were combined, washed with water (100 mL x 1), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) to obtain 398.0 mg of a pale yellow solid product in yield of 80.3%. MS (ESI, positive ion) m / z: 772.8 [M+H] + .

[0316] Step 6: Synthesis of (1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylic acid

[0317] [ka]

[0318] Methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylate (53 mg, 0.069 mmol), 1,4-dioxane (6 mL), water (2 mL), and lithium hydroxide monohydrate (5.79 mg, 0.14 mmol) were added in order to a 5 mL bottle and reacted at 50°C. After the reaction was complete, the mixture was concentrated under reduced pressure, the residue was separated, and the residue was purified by preparative silica gel thin-layer chromatography (eluent: DCM / MeOH(v / v)=4 / 1) to obtain 27.6 mg of a pale yellow solid product in a yield of 53.04%. MS (ESI, positive ion) m / z: 758.30 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 10.36 (s, 1H), 8.95 (s, 1H), 8.17 (s, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 7.6, 1.5 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.43 - 7.30 (m, 3H), 7.15 (d, J = 7.4 Hz, 1H), 6.70 (t, J = 54.5 Hz, 1H), 4.23 (s, 1H), 4.02 (s, 1H), 3.95 (s, 1H), 3.93 - 3.83 (m, 3H), 3.63 - 3.57 (m, 2H), 2.79 - 2.63 (m, 3H), 2.22 - 2.08 (m, 3H), 2.04 (s, 3H), 2.02 - 1.94 (m, 4H), 1.41 - 1.30 (m, 6H).

[0319] (Example 3) N-((R)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl-pyrrolidine-3-yl)acetamide

[0320] [ka]

[0321] Step 1: Synthesis of 6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde

[0322] [ka]

[0323] To a mixture of 6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-aldehyde (1.52 g, 4.65 mmol) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.30 g, 5.58 mmol) in water (8 mL) and 1,4-dioxane (40 mL), potassium carbonate (1.29 g, 9.3 mmol) and Pd(dppf)Cl2CH2Cl2 (0.38 g, 0.47 mmol) were added sequentially. The mixture was protected with nitrogen and heated at 90°C for 15 hours. After the reaction was complete, the product was filtered and the filtrate was concentrated. The remaining liquid was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (DCM / MeOH(v / v)=4 / 1), yielding 1.64 g of yellow powder in 99.9% yield. MS (ESI, positive ion) m / z: 353.4 [M+H] + .

[0324] Step 2: Synthesis of (R)-N-(1-((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-yl)acetamide

[0325] [ka]

[0326] 6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (1.64 g, 4.65 mmol) and (R)-N-(pyrrolidine-3-yl)acetamide (2.38 g, 18.6 mmol) were dissolved in a mixed solvent of 2,2,2-trifluoroethanol (50 mL) and DCM (50 mL). After stirring at 50°C for 30 minutes, sodium borohydride (146.10 mg, 2.33 mmol) was added to the system, and the reaction was continued at room temperature for 10 minutes. After the reaction was complete, the system was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: DCM / MeOH (v / v) = 15 / 1) to obtain 1.12 g of a yellow viscous substance in 51.8% yield. MS (ESI, positive ion) m / z: 465.5 [M+H] + .

[0327] Step 3: Synthesis of (R)-N-(1-((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-yl)acetamide

[0328] [ka]

[0329] 7-Bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (400 mg, 1.36 mmol) and (R)-N-(1-((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-yl)acetamide (758.86 mg, 1.63 mmol) were dissolved in tert-butanol (60 mL) and stirred under nitrogen at 130°C for 3 hours. After the reaction was complete, the system was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: DCM / MeOH(v / v)=20 / 1) to obtain 773 mg of yellow powder in yield 78.7%. MS (ESI, positive ion) m / z: 722.1 [M+H] + .

[0330] Step 4: Synthesis of (R)-N-(1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-yl)acetamide

[0331] [ka]

[0332] (R)-N-(1-((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-yl)acetamide (773 mg, 1.07 mmol) was dissolved in a mixed solvent of 1,4-dioxane (50 mL) and water (5 mL). Vinylboronic acid pinacol ester (823.95 mg, 5.35 mmol), Pd(dppf)Cl2CH2Cl2 (305.83 mg, 0.37 mmol), and potassium phosphate (454.26 mg, 2.14 mmol) were added in sequence. The mixture was stirred at 100°C for 3 hours under nitrogen protection. After the reaction was complete, the system was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: DCM / MeOH(v / v)=19 / 1) to obtain 556 mg of a yellowish-brown solid in a yield of 77.6%. MS (ESI, positive ion) m / z: 670.2 [M+H] + .

[0333] Step 5: Synthesis of (R)-N-(1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-yl)acetamide

[0334] [ka]

[0335] (R)-N-(1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-yl)acetamide (400 mg, 0.60 mmol) was dissolved in 1,4-dioxane (40 mL) and water (16 mL). Potassium osmate dihydrate (22.11 mg, 0.060 mmol) and sodium periodate (641.67 mg, 3 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the system was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: DCM / MeOH(v / v)=10 / 1) to obtain 306 mg of yellow powder in a yield of 76.3%. MS (ESI, positive ion) m / z: 672.6 [M+H] + .

[0336] Step 6: Synthesis of N-((R)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-yl)acetamide

[0337] [ka]

[0338] (R)-N-(1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-yl)acetamide (336 mg, 0.50 mmol) and (R)-pyrrolidine-3-ol (217.80 mg, 2.5 mmol) were dissolved in methanol (30 mL) and DCM (10 mL), and then acetic acid (150.13 mg, 2.5 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, and then sodium borocyanohydride (94.26 mg, 1.5 mmol) was added, and the reaction mixture was stirred for 4 hours. After the reaction was complete, the system was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: DCM / MeOH(v / v)=12 / 1) to obtain 10 mg of yellow powder in a yield of 2.69%. MS (ESI, positive ion) m / z: 743.30 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 10.36 (s, 1H), 8.98 (s, 1H), 8.20 (s, 1H), 8.08 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 7.7, 1.8 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 7.4 Hz, 1H), 7.19 - 7.12 (m, 2H), 6.71 (d, J = 2.5 Hz, 1H), 4.85 - 4.77 (m, 1H), 4.59 (t, J = 5.3 Hz, 1H), 4.27 - 4.22 (m, 1H), 4.20 - 4.15 (m, 1H), 3.92 (s, 3H), 3.69 - 3.57 (m, 3H), 2.84 - 2.66 (m, 6H), 2.15 - 2.07 (m, 2H), 2.04 (s, 3H), 1.78 (s, 3H), 1.65 - 1.58 (m, 2H), 1.36 (d, J = 8.8 Hz, 2H).

[0339] (Example 4) (S)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-ol

[0340] [ka]

[0341] Step 1: Synthesis of (S)-1-((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-ol

[0342] [ka]

[0343] In a 250 mL bottle, 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (4 g, 12.25 mmol), (S)-pyrrolidine-3-ol hydrochloride (3.03 g, 24.5 mmol), DCM (50 mL), DMF (50 mL), triethylamine (1.86 g, 18.38 mmol), and acetic acid (1.10 g, 18.38 mmol) were added in order, and the reaction mixture was stirred overnight at 50°C. Then, sodium borocyanohydride (1.54 g, 24.5 mmol) was added, and the reaction was continued at room temperature. After the reaction was complete, the pH was adjusted to 7-8 with saturated potassium carbonate aqueous solution, diluted with water (500 mL), then extracted with DCM (80 mL x 3), the organic phases were combined, washed with water (500 mL x 2), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 40 / 1) to obtain 2.66 g of a white solid product in yield of 54.61%. MS (ESI, positive ion) m / z: 397.3 [M+H] + .

[0344] Step 2: Synthesis of (S)-1-((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-ol

[0345] [ka]

[0346] (S)-1-((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-ol (1.3 g, 3.27 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.99 g, 4.25 mmol), potassium carbonate (1.13 g, 8.18 mmol), Pd(dppf)Cl2CH2Cl2 (0.27 g, 0.33 mmol), 1,4-dioxane (10 mL), and water (2 mL) were added in sequence to a 20 mL microwave tube. The tube was sealed and reacted at 130 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the dioxane, water (150 mL) was added, and then the solution was extracted with DCM (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 1), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 15 / 1) to obtain 813.0 mg of a brown solid product in yield of 58.67%. MS (ESI, positive ion) m / z: 424.2 [M+H] + .

[0347] Step 3: Synthesis of (S)-1-((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-ol

[0348] [ka]

[0349] (S)-1-((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-ol (500 mg, 1.18 mmol), 7-bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (416.98 mg, 1.42 mmol), tert-butanol (30 mL), and acetic acid (70.86 mg, 1.18 mmol) were added in order to a 100 mL bottle, and the reaction mixture was stirred at 120 °C. After the reaction was complete, the pH was adjusted to 7-8 with saturated potassium carbonate aqueous solution, the mixed solution was concentrated under reduced pressure, water (100 mL) was added, then extracted with DCM (20 mL x 3), the organic phases were combined, washed with water (100 mL x 1), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 20 / 1) to obtain 605.0 mg of a pale yellow solid product in yield of 75.2%. MS (ESI, positive ion) m / z: 681.5 [M+H] + .

[0350] Step 4: Synthesis of (S)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-ol

[0351] [ka]

[0352] (S)-1-((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-ol (400 mg, 0.59 mmol), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (227.16 mg, 1.47 mmol), potassium phosphate (313.10 mg, 1.47 mmol), Pd(dppf)Cl2CH2Cl2 (48.18 mg, 0.059 mmol), 1,4-dioxane (7.5 mL), and water (1.5 mL) were added to a 20 mL microwave tube and reacted at 130 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove dioxane, water (100 mL) was added, and then the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 1), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) to obtain 340.0 mg of a pale yellow solid product in 92.1% yield. MS (ESI, positive ion) m / z: 629.6 [M+H] + .

[0353] Step 5: Synthesis of (S)-4-((2'-chloro-3'-(5-((3-hydroxypyrrolidine-1-yl)methyl)-6-methoxypyridine-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-carbaldehyde

[0354] [ka]

[0355] (S)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-ol (244 mg, 0.39 mmol), 1,4-dioxane (15 mL), water (6 mL), potassium osmate dihydrate (14.37 mg, 0.039 mmol), and sodium periodate (417.09 mg, 1.95 mmol) were added in order to a 50 mL bottle, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the dioxane, water (100 mL) was added, and then the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 1), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 15 / 1) to obtain 215.0 mg of a pale yellow solid product in yield of 87.8%. MS (ESI, positive ion) m / z: 631.6 [M+H] + .

[0356] Step 6: Synthesis of (S)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-ol

[0357] [ka]

[0358] (S)-4-((2'-chloro-3'-(5-((3-hydroxypyrrolidine-1-yl)methyl)-6-methoxypyrrolidine-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-carbaldehyde (142 mg, 0.23 mmol), (R)-pyrrolidine-3-ol (50.09 mg, 0.58 mmol), DCM (5 mL), DMF (5 mL), triethylamine (34.91 mg, 0.35 mmol), and acetic acid (20.72 mg, 0.35 mmol) were added in order to a 25 mL bottle, and the mixture was reacted overnight at 50°C. Then sodium borocyanohydride (28.91 mg, 0.46 mmol) was added, and the reaction was continued to stir at room temperature. After the reaction was complete, the pH was adjusted to 7-8 with saturated potassium carbonate aqueous solution, diluted with water (100 mL), then extracted with DCM (15 mL x 3), the organic phases were combined, washed with water (100 mL x 2), dried on anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative silica gel thin-layer chromatography (eluent: DCM / MeOH (v / v) = 7.5 / 1) to obtain 10.0 mg of a yellow solid product in yield of 6.33%. MS (ESI, positive ion) m / z: 702.27 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.36 (s, 1H), 8.96 (s, 1H), 8.20 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.0 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.70 (t, J = 54.6 Hz, 1H), 5.10 - 4.98 (m, 1H), 4.86 (s, 1H), 3.93 (s, 3H), 3.63 - 3.52 (m, 6H), 3.04 - 2.67 (m, 8H), 2.03 (s, 3H), 1.76 - 1.40 (m, 4H).

[0359] (Example 5) (R)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-carboxylic acid

[0360] [ka]

[0361] Step 1: Synthesis of methyl(R)-1-((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-carboxylate

[0362] [ka]

[0363] 6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-aldehyde (0.2 g, 0.57 mmol) and methyl(R)-pyrrolidine-3-carboxylate hydrochloride (0.28 g, 1.71 mmol) were dissolved in 2,2,2-trifluoroethanol (15 mL) and DCM (15 mL). The mixture was stirred at 50°C for 30 minutes. After the reaction was complete, the system was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: DCM / MeOH(v / v)=15 / 1) to obtain 0.26 g of a yellow viscous substance in 98.4% yield. MS (ESI, positive ion) m / z: 466.1 [M+H] + .

[0364] Step 2: Synthesis of methyl(R)-1-((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-carboxylate

[0365] [ka]

[0366] 7-Bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (180 mg, 0.61 mmol) and methyl(R)-1-((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-carboxylate (0.26 g, 0.55 mmol) were dissolved in tert-butanol (15 mL) and stirred at 130 °C for 3 hours. After the reaction was complete, the system was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: DCM / MeOH (v / v) = 40 / 1) to obtain 186 mg of yellow powder in a yield of 42.03%. MS (ESI, positive ion) m / z: 723.6 [M+H] + .

[0367] Step 3: Synthesis of methyl(R)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-carboxylate

[0368] [ka]

[0369] Methyl(R)-1-((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-carboxylate (186 mg, 0.26 mmol) was dissolved in a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL). 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200.21 mg, 1.3 mmol), Pd(dppf)Cl2CH2Cl2 (74.31 mg, 0.091 mmol), and potassium phosphate (110.38 mg, 0.52 mmol) were added in sequence. The mixture was stirred at 100°C for 3 hours. After the reaction was complete, the system was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: DCM / MeOH(v / v)=30 / 1) to obtain 172 mg of a yellowish-brown solid in 99.76% yield. MS (ESI, positive ion) m / z: 671.2 [M+H] + .

[0370] Step 4: Synthesis of methyl(R)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-carboxylate

[0371] [ka]

[0372] Methyl(R)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-carboxylate (152 mg, 0.23 mmol) was dissolved in 1,4-dioxane (30 mL) and water (12 mL). Sodium periodate (245.97 mg, 1.15 mmol) and potassium osmate dihydrate (8.47 mg, 0.023 mmol) were added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the system was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: DCM / MeOH(v / v)=10 / 1) to obtain 48 mg of yellow powder in a yield of 31.5%. MS (ESI, positive ion) m / z: 675.0 [M+H] + .

[0373] Step 5: Synthesis of methyl(R)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-carboxylate

[0374] [ka]

[0375] Methyl(R)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-carboxylate (56 mg, 0.083 mmol) and (R)-pyrrolidine-3-ol (36.15 mg, 0.42 mmol) were dissolved in methanol (10 mL) and DCM (3 mL). The mixture was stirred at room temperature for 3 hours. Sodium borocyanohydride (15.65 mg, 0.25 mmol) was added, and the reaction was continued at room temperature for 1.5 hours. After the reaction was complete, the system was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: DCM / MeOH(v / v)=12 / 1) to obtain 22 mg of yellow powder in a yield of 35.5%. MS (ESI, positive ion) m / z: 644.6 [M+H] + .

[0376] Step 6: Synthesis of (R)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-carboxylic acid

[0377] [ka]

[0378] Methyl(R)-1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)pyrrolidine-3-carboxylate (22 mg, 0.030 mmol) was dissolved in a mixed solution of 1,4-dioxane (3 mL) and water (3 mL), and lithium hydroxide monohydrate (15.11 mg, 0.36 mmol) was added. The reaction mixture was stirred at room temperature for 3.5 hours. After the reaction was complete, the system was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: DCM / MeOH(v / v)=6 / 1) to obtain 10 mg of yellow powder in a yield of 46.3%. MS (ESI, positive ion) m / z: 730.26 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 10.34 (s, 1H), 8.95 (s, 1H), 8.17 (s, 1H), 7.76 (dd, J = 13.5, 7.7 Hz, 2H), 7.64 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.74 - 6.65 (m, 1H), 4.24 - 4.20 (m, 1H), 3.91 (s, 3H), 3.60 (dd, J = 9.3, 4.9 Hz, 4H), 2.99 - 2.92 (m, 2H), 2.78 - 2.67 (m, 5H), 2.62 - 2.55 (m, 3H), 2.04 (s, 3H), 1.99 - 1.96 (m, 2H), 1.62 - 1.55 (m, 1H), 1.49 - 1.41 (m, 1H).

[0379] (Example 6) (R)-2-(1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl)acetic acid

[0380] [ka]

[0381] Step 1: Synthesis of methyl 2-(1-((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl)acetate

[0382] [ka]

[0383] 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (1.5 g, 4.59 mmol) was dissolved in a mixed solvent of DCM (15 mL) and trifluoroethanol (15 mL). Methyl 2-(piperidine-4-yl) acetate (2.67 g, 13.77 mmol) and triethylamine (2.32 g, 22.95 mmol) were added, and the mixture was heated and stirred overnight at 60°C. Sodium borocyanohydride (0.58 g, 9.18 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. After the reaction of the starting materials was complete, the mixture was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: PE / siRNA(v / v)=7 / 1) to obtain 1.38 g of a yellow solid product in 64.2% yield. MS (ESI, positive ion) m / z: 467.1 [M+H] + .

[0384] Step 2: Synthesis of methyl 2-(1-((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl)acetate

[0385] [ka]

[0386] Methyl 2-(1-((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl)acetate (1.38 g, 2.95 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.06 g, 8.85 mmol), Pd(dppf)Cl2CH2Cl2 (0.60 g, 0.74 mmol), and potassium carbonate (1.43 g, 10.33 mmol) were dissolved in a mixed solvent of 1,4-dioxane (20 mL) and water (4 mL), and heated overnight at 90°C under nitrogen protection. After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the product was purified by silica gel column chromatography (eluent: PE / SiO(v / v) = 3 / 2) to obtain 1.38 g of a yellow liquid product in a yield of 94.7%. MS (ESI, positive ion) m / z: 594.5 [M+H] + .

[0387] Step 3: Synthesis of methyl 2-(1-((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl)acetate

[0388] [ka]

[0389] Methyl 2-(1-((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl)acetate (1.38 g, 2.79 mmol) and 7-bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (0.99 g, 3.35 mmol) were dissolved in tert-butanol (20 mL), acetic acid (0.17 g, 2.79 mmol) was added, the mixture was protected with N2, and stirred at 100°C for 5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the mixture was purified by silica gel column chromatography (eluent: PE / siRNA(v / v)=3 / 2) to obtain 1.34 g of a yellow solid product in 63.8% yield. MS (ESI, positive ion) m / z: 751.2 [M+H] + .

[0390] Step 4: Synthesis of methyl 2-(1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl)acetate

[0391] [ka]

[0392] Methyl 2-(1-((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl)acetate (1.34 g, 1.78 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.37 g, 8.90 mmol), Pd(dppf)Cl2CH2Cl2 (0.51 g, 0.62 mmol), and potassium phosphate (0.76 g, 3.56 mmol) were dissolved in a mixed solvent of 1,4-dioxane (40 mL) and water (8 mL) and heated at 100 °C for 5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the solution was purified by silica gel column chromatography (eluent: PE / siRNA(v / v)=3 / 2) to obtain 1.24 g of a yellow solid product in 99.5% yield. MS (ESI, positive ion) m / z: 699.3 [M+H] + .

[0393] Step 5: Synthesis of methyl 2-(1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl)acetate

[0394] [ka]

[0395] Methyl 2-(1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl)acetate (1.24 g, 1.77 mmol) was dissolved in a mixed solvent of 1,4-dioxane (62.5 mL) and water (25 mL). Then, potassium osmate dihydrate (0.065 g, 0.18 mmol) and subsequently sodium periodate (1.89 g, 8.85 mmol) were added, and the mixture was reacted at room temperature for 1.5 hours. After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the product was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=33 / 1) to obtain 0.67 g of a yellow liquid product in a yield of 53.9%. MS (ESI, positive ion) m / z: 701.3 [M+H] + .

[0396] Step 6: Synthesis of Methyl(R)-2-(1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl)acetate

[0397] [ka]

[0398] Methyl 2-(1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl)acetate (0.147 g, 0.21 mmol) was dissolved in a mixed solvent of DCM (10 mL) and MeOH (10 mL), and (R)-pyrrolidine-3-ol (0.091 g, 1.05 mmol) and acetic acid (0.1 mL) were added, and the mixture was stirred overnight at room temperature. Sodium borocyanohydride (0.026 g, 0.42 mmol) was added, and the mixture was stirred for 1 hour at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the solution was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=20 / 1) to obtain 0.16 g of a yellow oily product in 98.8% yield. MS (ESI, positive ion) m / z: 732.3 [M+H] + .

[0399] Step 7: Synthesis of (R)-2-(1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl)acetic acid

[0400] [ka]

[0401] Methyl(R)-2-(1-((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)piperidine-4-yl) acetate (0.16 g, 0.21 mmol) was dissolved in 1,4-dioxane (12.5 mL) and water (2.5 mL), lithium hydroxide monohydrate (0.088 g, 2.1 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction of the raw materials was complete, the pH of the system was adjusted to approximately 5 with acetic acid, the reaction solution was concentrated under reduced pressure, the residue was separated, and the residue was purified by preparative thin-layer chromatography (eluent: DCM / MeOH(v / v)=4 / 1) to obtain 37 mg of a yellow solid product in a yield of 21.7%. MS (ESI, positive ion) m / z: 758.3024 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 10.36 (s, 1H), 8.98 (s, 1H), 8.21 (d, J = 6.2 Hz, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 7.7, 1.7 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.30 (d, J = 7.4 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.27 - 4.24 (m, 1H), 3.91 (s, 3H), 3.57 (s, 4H), 2.89 (d, J = 7.7 Hz, 1H), 2.75 - 2.73 (m, 1H), 2.63 - 2.61 (m, 1H), 2.53 (d, J = 2.2 Hz, 5H), 2.41 - 2.38 (m, 1H), 2.16 (d, J = 6.6 Hz, 2H), 2.04 (s, 3H), 1.69 - 1.66 (m, 2H), 1.35 - 1.33 (m, 5H).

[0402] (Example 7) (R)-2-((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylic acid

[0403] [ka]

[0404] Step 1: Synthesis of methyl 2-azabicyclo[2.2.2]octane-4-carboxylate 2,2,2-trifluoroacetate

[0405] [ka]

[0406] 2-(Tert-butyl)4-methyl-2-azabicyclo[2.2.2]octane-2,4-dicarboxylate (0.9 g, 3.34 mmol) was dissolved in DCM (20 mL), and TFA (11.42 g, 100.20 mmol) was added. The mixture was reacted at room temperature for 5 hours. After the reaction of the starting materials was complete, the reaction solution was concentrated under reduced pressure to obtain 0.94 g of a yellow liquid product in 99.3% yield. MS (ESI, positive ion) m / z: 170.4 [M+H] + .

[0407] Step 2: Synthesis of methyl 2-((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylate

[0408] [ka]

[0409] The compound 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (0.5 g, 1.53 mmol) was dissolved in a mixed solvent of DCM (10 mL) and trifluoroethanol (10 mL). Methyl 2-azabicyclo[2.2.2]octane-4-carboxylate 2,2,2-trifluoroacetate (0.93 g, 3.29 mmol) and triethylamine (0.77 g, 7.65 mmol) were added, and the mixture was heated and stirred overnight at 60°C. After cooling to room temperature, sodium borohydride (0.19 g, 3.06 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: PE / siRNA(v / v)=2 / 1) to obtain 0.73 g of a yellow solid product in 99.4% yield. MS (ESI, positive ion) m / z: 479.1 [M+H] + .

[0410] Step 3: Synthesis of methyl 2-((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylate

[0411] [ka]

[0412] Methyl 2-((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylate (0.73 g, 1.52 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.06 g, 4.56 mmol), Pd(dppf)Cl2CH2Cl2 (0.31 g, 0.38 mmol), and potassium carbonate (0.74 g, 5.32 mmol) were dissolved in a mixed solvent of 1,4-dioxane (30 mL) and water (6 mL), and heated overnight at 90°C under nitrogen protection. After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the product was purified by silica gel column chromatography (eluent: PE / SiO(v / v)=2 / 1) to obtain 0.76 g of a yellow liquid product in a yield of 98.7%. MS (ESI, positive ion) m / z: 506.5 [M+H] + .

[0413] Step 4: Methyl 2-((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino) -2-chloro Synthesis of -2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylate

[0414] [ka]

[0415] Methyl 2-((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylate (0.76 g, 1.50 mmol) and 7-bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (0.53 g, 1.80 mmol) were dissolved in tert-butanol (20 mL), acetic acid (0.09 g, 1.50 mmol) was added, and the mixture was reacted at 100°C for 5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, the residue was separated, and the mixture was purified by silica gel column chromatography (eluent: PE / siRNA(v / v)=3 / 1) to obtain 0.88 g of a yellow solid product in 76.7% yield. MS (ESI, positive ion) m / z: 763.6 [M+H] + .

[0416] Step 5: Synthesis of methyl 2-((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylate

[0417] [ka]

[0418] Methyl 2-((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino) -2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylate (0.88 g, 1.15 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.89 g, 5.75 mmol), Pd(dppf)Cl2CH2Cl2 (0.33 g, 0.40 mmol), and potassium phosphate (0.49 g, 2.3 mmol) were dissolved in a mixed solvent of 1,4-dioxane (35 mL) and water (7 mL), and heated at 100 °C for 5 hours under nitrogen protection. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the solution was purified by silica gel column chromatography (eluent: PE / SiO(v / v)=3 / 2) to obtain 0.719 g of a yellow solid product in 87.78% yield. MS (ESI, positive ion) m / z: 711.7 [M+H] + .

[0419] Step 6: Synthesis of methyl 2-((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylate

[0420] [ka]

[0421] Methyl 2-((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylate (0.72 g, 1.01 mmol) was dissolved in a mixed solvent of 1,4-dioxane (30 mL) and water (12 mL), then potassium osmate dihydrate (0.037 g, 0.1 mmol), followed by sodium periodate (1.08 g, 5.05 mmol), and the mixture was reacted at room temperature for 3.5 hours. After the reaction of the raw materials was complete, the mixture was filtered through celite, the filtrate was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=33 / 1) to obtain 0.11 g of a yellow liquid product in a yield of 15.2%. MS (ESI, positive ion) m / z: 713.7 [M+H] + .

[0422] Step 7: Synthesis of methyl(R)-2-((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylate

[0423] [ka]

[0424] Methyl 2-((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylate (0.108 g, 0.15 mmol) was dissolved in a mixed solvent of DCM (5 mL) and MeOH (5 mL), and (R)-pyrrolidine-3-ol (0.065 g, 0.75 mmol) and 2 drops of acetic acid were added. The mixture was stirred overnight at room temperature. Sodium borocyanohydride (0.019 g, 0.3 mmol) was added, and the mixture was stirred for 1 hour at room temperature. After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the product was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=20 / 1) to obtain 0.077 g of a yellow liquid product in a yield of 64.8%. MS (ESI, positive ion) m / z: 784.3 [M+H] + .

[0425] Step 8: Synthesis of (R)-2-((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylic acid

[0426] [ka]

[0427] Methyl(R)-2-((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)-2-azabicyclo[2.2.2]octane-4-carboxylate (0.077 g, 0.098 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL), lithium hydroxide monohydrate (0.041 g, 0.98 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction of the raw materials was complete, the pH of the system was adjusted to approximately 5 with acetic acid, the reaction solution was concentrated under reduced pressure, the residue was separated, and the residue was purified by preparative thin-layer chromatography (eluent: DCM / MeOH(v / v)=2 / 1) to obtain 44 mg of a yellow solid product in a yield of 58.18%. MS (ESI, positive ion) m / z: 770.3060 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.34 (s, 1H), 8.95 (s, 1H), 8.16 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.28 (d, J = 7.4 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 6.71 (s, 1H), 4.24 - 4.20 (m, 1H), 3.91 (s, 3H), 3.88 (s, 1H), 3.85 (s, 1H), 3.66 (s, 2H), 2.75 - 2.71 (m, 3H), 2.68 (d, J = 7.3 Hz, 1H), 2.62 - 2.59 (m, 1H), 2.41 (dd, J = 9.7, 3.6 Hz, 2H), 2.03 (s, 3H), 1.71 - 1.67 (m, 3H), 1.61 - 1.55 (m, 1H), 1.50 - 1.45 (m, 2H), 1.35 - 1.32 (m, 5H).

[0428] (Example 8) (R)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid

[0429] [ka]

[0430] Step 1: Synthesis of methyl 4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylate

[0431] [ka]

[0432] At room temperature, 6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-aldehyde (1.2 g, 2.15 mmol) and methyl 4-aminobicyclo[2.2.1]heptane-1-carboxylate (1.09 g, 6.45 mmol) were added to 2,2,2-trifluoroethanol (8 mL) and DCM (8 mL). The mixture was stirred at 45°C for 0.5 hours, and then sodium borocyanohydride (0.14 g, 2.15 mmol) was slowly added while continuing to stir the reaction. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: CH2Cl2 / MeOH (v / v) = 25 / 1) yielded 1.50 g of a yellow solid product in 98.07% yield. MS (ESI, positive ion) m / z: 711.3 [M+H] + .

[0433] Step 2: Synthesis of methyl 4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)bicyclo[2.2.1]heptane-1-carboxylate

[0434] [ka]

[0435] At room temperature, methyl 4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylate (0.90 g, 1.27 mmol) and aqueous formaldehyde solution (0.11 g, 3.81 mmol) were added to DCM (5 mL) and 2,2,2-trifluoroethanol (5 mL), and the reaction mixture was stirred at 45°C for 30 minutes. Then, sodium borocyanohydride (0.020 g, 0.32 mmol) was slowly added and the reaction was continued. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: CH2Cl2 / MeOH (v / v) = 20 / 1) yielded 0.80 g of a yellow solid product in 87.17% yield. MS (ESI, positive ion) m / z: 725.3 [M+H] + .

[0436] Step 3: Synthesis of methyl 4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)bicyclo[2.2.1]heptane-1-carboxylate

[0437] [ka]

[0438] At room temperature, methyl 4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)bicyclo[2.2.1]heptane-1-carboxylate (0.75 g, 1.03 mmol), potassium osmate dihydrate (0.038 g, 0.10 mmol), and sodium periodate (1.10 g, 5.15 mmol) were added to 1,4-dioxane (33 mL) and water (13 mL), and the reaction mixture was stirred at room temperature. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: CH2Cl2 / MeOH (v / v) = 30 / 1) yielded 0.30 g of a yellow oily product in a yield of 39.89%. MS (ESI, positive ion) m / z: 727.0 [M+H] + .

[0439] Step 4: Synthesis of methyl(R)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)bicyclo[2.2.1]heptane-1-carboxylate

[0440] [ka]

[0441] At room temperature, methyl 4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)bicyclo[2.2.1]heptan-1-carboxylate (0.29 g, 0.40 mmol) and (3R)-pyrrolidine-3-ol (0.070 g, 0.80 mmol) were added to methanol (5 mL) and DCM (5 mL). The reaction mixture was stirred overnight at room temperature. Then, sodium borocyanohydride (0.025 g, 0.40 mmol) was slowly added, and the reaction mixture was continued to stir. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) yielded 0.20 g of a yellow solid product in a yield of 62.82%. MS (ESI, positive ions) m / z: 798.0 [M+H] + .

[0442] Step 5: Synthesis of (R)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid

[0443] [ka]

[0444] At room temperature, methyl(R)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)bicyclo[2.2.1]heptane-1-carboxylate (0.2 g, 0.25 mmol) and lithium hydroxide monohydrate (0.031 g, 0.75 mmol) were added to 1,4-dioxane (6 mL) and water (1.5 mL), and the reaction mixture was stirred at 45°C. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: DCM / MeOH(v / v)=8 / 1) yielded 0.15 g of a yellow solid product in a yield of 76.34%. MS (ESI, positive ion) m / z: 784.3290 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 7.7, 1.8 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.28 (d, J = 7.4 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.71 (t, J = 54.5 Hz, 1H), 4.76 (s, 1H), 4.23 (dq, J = 7.0, 3.3 Hz, 1H), 3.91 (s, 3H), 3.90 - 3.80 (m, 2H), 2.78 - 2.64 (m, 2H), 2.47 (d, J = 11.6 Hz, 1H), 2.42 (dd, J = 9.7, 3.5 Hz, 1H), 2.16 (s, 3H), 2.05 (s, 3H), 1.99 (q, J = 12.7, 9.8 Hz, 3H), 1.82 - 1.72 (m, 2H), 1.67 (s, 4H), 1.58 (q, J = 8.3, 7.4 Hz, 3H), 1.22 (s, 2H).

[0445] (Example 9) (R)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid

[0446] [ka]

[0447] Step 1: Synthesis of ethyl 4-(((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylate

[0448] [ka]

[0449] At room temperature, 6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (2.6 g, 4.26 mmol) and ethyl 4-aminobicyclo[2.2.1]heptane-1-carboxylate (1.56 g, 8.52 mmol) were added to DCM (10 mL) and 2,2,2-trifluoroethanol (10 mL). The mixture was stirred at 45°C for 1 hour, and then sodium borohydride (0.27 g, 4.26 mmol) was slowly added while continuing to stir the reaction. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: DCM / MeOH(v / v)=25 / 1) yielded 0.80 g of a yellow solid product in a yield of 24.16%. MS (ESI, positive ion) m / z: 772.2 [M+H] + .

[0450] Step 2: Synthesis of ethyl 4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylate

[0451] [ka]

[0452] At room temperature, ethyl 4-(((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)bicyclo[2.2.1]heptan-1-carboxylate (0.78 g, 1.00 mmol), vinylboronic acid pinacol ester (0.77 g, 5 mmol), Pd(dppf)Cl2·DCM (0.12 g, 0.15 mmol), and potassium phosphate (0.42 g, 2 mmol) were added to 1,4-dioxane (10 mL) and water (2.5 mL), and the reaction mixture was stirred at 90°C. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) yielded 0.65 g of a yellow solid product in 89.41% yield. MS (ESI, positive ion) m / z: 725.0 [M+H] + .

[0453] Step 3: Synthesis of ethyl 4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylate

[0454] [ka]

[0455] At room temperature, ethyl 4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylate (0.65 g, 0.90 mmol) was added to 1,4-dioxane (33 mL) and water (13 mL). Then, sodium periodate (0.96 g, 4.5 mmol) and potassium osmate dihydrate (0.033 g, 0.090 mmol) were slowly added, and the reaction mixture was stirred at room temperature for 30 minutes. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: PE / siRNA(v / v)=1 / 1) yielded 0.36 g of a yellow solid product in a yield of 55.23%. MS (ESI, positive ion) m / z: 727.7 [M+H] + .

[0456] Step 4: Synthesis of ethyl(R)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylate

[0457] [ka]

[0458] At room temperature, ethyl 4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)bicyclo[2.2.1]heptan-1-carboxylate (0.35 g, 0.48 mmol) and (3R)-pyrrolidine-3-ol (0.13 g, 1.44 mmol) were added to DCM (5 mL) and 2,2,2-trifluoroethanol (5 mL). The reaction mixture was stirred at 45°C for 30 minutes. Then, sodium borocyanohydride (0.030 g, 0.48 mmol) was slowly added, and the reaction mixture was continued to stir. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) yielded 0.35 g of a yellow solid product in 91.09% yield. MS (ESI, positive ion) m / z: 798.8 [M+H] + .

[0459] Step 5: Synthesis of (R)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid

[0460] [ka]

[0461] At room temperature, ethyl(R)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)bicyclo[2.2.1]heptane-1-carboxylate (0.2 g, 0.25 mmol) and lithium hydroxide monohydrate (0.031 g, 0.75 mmol) were added to 1,4-dioxane (6 mL) and water (1.5 mL), and the reaction mixture was stirred at 45°C. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) yielded 0.080 g of a yellow solid product in a yield of 40.73%. MS (ESI, positive ion) m / z: 770.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.95 (d, J = 1.9 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.63 (dd, J = 7.8, 1.8 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.38 (dd, J = 9.3, 6.9 Hz, 2H), 7.26 (d, J = 7.5 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 6.71 (t, J = 54.5 Hz, 1H), 4.23 (dq, J = 6.8, 3.4 Hz, 1H), 3.92 (s, 3H), 3.90 - 3.81 (m, 2H), 3.73 (s, 3H), 2.77 - 2.65 (m, 2H), 2.47 (d, J = 9.6 Hz, 1H), 2.42 (dd, J = 9.7, 3.5 Hz, 1H), 2.05 (s, 3H), 1.97 - 1.86 (m, 2H), 1.76 - 1.66 (m, 2H), 1.64 - 1.59 (m, 2H), 1.56 (s, 3H), 1.49 (dd, J = 10.5, 3.7 Hz, 2H).

[0462] (Example 10) (R)-4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid

[0463] [ka]

[0464] Step 1: Synthesis of methyl 4-((((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)amino)methyl)bicyclo[2.2.1]heptan-1-carboxylate

[0465] [ka]

[0466] 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (3 g, 9.19 mmol) and methyl 4-(aminomethyl)bicyclo[2.2.1]heptane-1-carboxylate (3.03 g, 16.54 mmol) were dissolved in 2,2,2-trifluoroethanol (30 mL) and DCM (30 mL), and triethylamine (2 mL) was added dropwise. The mixture was stirred at 50°C for 15 hours. Sodium borohydride (866.3 mg, 13.8 mmol) was added, and the reaction was continued at room temperature. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (DCM / MeOH(v / v)=20 / 1) to obtain 4.53 g of a pale yellow viscous product in 99.86% yield. MS (ESI, positive ion) m / z: 493.1 [M+H] + .

[0467] Step 2: Synthesis of methyl 4-((((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptane-1-carboxylate

[0468] [ka]

[0469] Methyl 4-((((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)amino)methyl)bicyclo[2.2.1]heptane-1-carboxylate (4.69 g, 9.50 mmol) and aqueous formaldehyde solution (3.08 g, 38 mmol) were dissolved in methanol (120 ml), and then acetic acid (713.09 mg, 11.88 mmol) was added and the mixture was stirred at room temperature for 20 hours. Sodium borocyanohydride (2984.9 mg, 47.5 mmol) was slowly added and the mixture was stirred at room temperature for 1 hour. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (DCM / MeOH(v / v)=40 / 1) to obtain 3.16 g of a pale yellow viscous product in 65.52% yield. MS (ESI, positive ion) m / z: 507.4 [M+H] + .

[0470] Step 3: Synthesis of methyl 4-((((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptane-1-carboxylate

[0471] [ka]

[0472] Methyl 4-((((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptane-1-carboxylate (0.5 g, 0.98 mmol) and 2-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.46 g, 1.96 mmol) were dissolved in a mixed solvent of water (4 mL) and 1,4-dioxane (20 mL). Then, potassium carbonate (0.31 g, 2.94 mmol) and Pd(dppf)Cl2·DCM (0.074 g, 0.098 mmol) were added in sequence, the mixture was protected with nitrogen, and heated at 90°C for 15 hours. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, the residue was separated, and the product was purified by silica gel column chromatography (PE / siRNA(v / v)=6 / 1) to obtain 0.525 g of a pale yellow viscous product in 99.84% yield. MS (ESI, positive ion) m / z: 534.5 [M+H] + .

[0473] Step 4: Synthesis of methyl 4-((((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptan-1-carboxylate

[0474] [ka]

[0475] 7-Bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (400 mg, 1.36 mmol) and methyl 4-((((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptane-1-carboxylate (0.52 g, 0.98 mmol) were dissolved in n-butanol (30 mL) and stirred at 130°C under N2 for 3 hours. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (DCM / MeOH(v / v)=20 / 1) to obtain 0.433 g of a brown-yellow powder product in a yield of 40.24%. MS (ESI, positive ion) m / z: 791.2 [M+H] + .

[0476] Step 5: Synthesis of methyl 4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptane-1-carboxylate

[0477] [ka]

[0478] Methyl 4-((((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptane-1-carboxylate (0.433 g, 0.55 mmol) was dissolved in a mixed solvent of 1,4-dioxane (25 mL) and water (5 mL). 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (423.53 mg, 2.75 mmol), Pd(dppf)Cl2·DCM (157.20 mg, 0.19 mmol), and potassium phosphate (233.50 mg, 1.1 mmol) were added in sequence. The mixture was stirred at 100°C under N2 for 3 hours. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (DCM / MeOH(v / v)=20 / 1) to obtain 0.4 g of a brown-yellow viscous product in 98.98% yield. MS (ESI, positive ion) m / z: 739.3 [M+H] + .

[0479] Step 6: Synthesis of methyl 4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptane-1-carboxylate

[0480] [ka]

[0481] Methyl 4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptane-1-carboxylate (0.4 g, 0.54 mmol) was dissolved in 1,4-dioxane (18 mL) and water (6 mL), and potassium osmate dihydrate (9.95 mg, 0.027 mmol) and sodium periodate (0.29 g, 1.35 mmol) were added in sequence, and the system was stirred at room temperature for 2 hours. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (DCM / MeOH(v / v)=20 / 1) yielded 0.253 g of a brown-yellow viscous product in a yield of 63.08%. MS (ESI, positive ion) m / z: 741.3 [M+H] + .

[0482] Step 7: Synthesis of methyl(R)-4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptane-1-carboxylate

[0483] [ka]

[0484] Methyl 4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptan-1-carboxylate (0.253 g, 0.34 mmol) and (3R)-pyrrolidine-3-ol (148.10 mg, 1.70 mmol) were dissolved in methanol (30 mL) and DCM (10 mL), and acetic acid (102.09 mg, 1.70 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride cyanohydride (64.10 mg, 1.02 mmol) was added, and the reaction was continued at room temperature for 1.5 hours. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, the residue was separated, and the product was purified by silica gel column chromatography (DCM / MeOH(v / v)=12 / 1) to obtain 0.15 g of a pale yellow powder product in a yield of 54.10%. MS (ESI, positive ion) m / z: 812.6 [M+H] + .

[0485] Step 8: Synthesis of (R)-4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptane-1-carboxylic acid

[0486] [ka]

[0487] Methyl(R)-4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)bicyclo[2.2.1]heptane-1-carboxylate (0.15 g, 0.18 mmol) was dissolved in a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL), lithium hydroxide monohydrate (90.63 mg, 2.16 mmol) was added, and the mixture was heated to 60°C and stirred for 4 hours. After the raw materials were consumed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (DCM / MeOH=12 / 1) yielded 70 mg of a pale yellow powder product in a yield of 47.49%. MS (ESI, positive ion) m / z: 798.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.94 (s, 1H), 8.15 (s, 1H), 7.80 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.44 - 7.19 (m, 4H), 7.14 (d, J = 7.7 Hz, 1H), 6.69 (t, J = 54.5 Hz, 1H), 4.23 (dd, J = 10.7, 6.7 Hz, 1H), 3.88 (s, 3H), 3.86 - 3.77 (m, 4H), 2.76 - 2.63 (m, 3H), 2.53 (s, 2H), 2.44 - 2.36 (m, 2H), 2.21 (s, 3H), 2.03 (s, 4H), 1.78 (s, 3H), 1.65 - 1.57 (m, 3H), 1.52 - 1.43 (m, 3H), 1.41 - 1.37 (m, 2H).

[0488] (Example 11) (1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylic acid

[0489] [ka]

[0490] Step 1: Synthesis of methyl(1r,4r)-4-(((5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-yl)methyl)amino)cyclohexane-1-carboxylate

[0491] [ka]

[0492] 5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-carboxyaldehyde (0.66 g, 2.01 mmol), methyl(1r,4r)-4-aminocyclohexane-1-carboxylate hydrochloride (1.17 g, 6.03 mmol), DCM (20 mL), methanol (20 mL), triethylamine (0.31 g, 3.01 mmol), and acetic acid (0.12 g, 2.01 mmol) were added sequentially to a 100 mL bottle, and the mixture was reacted overnight at 50°C. Sodium cyanoborohydride (0.25 g, 4.02 mmol) was added, and the reaction was continued at room temperature. After the reaction was complete, the filtrate was concentrated under reduced pressure to remove the solvent, yielding 830.0 mg of a white solid product in a yield of 87.87%. MS (ESI, positive ion) m / z: 467.9 [M+H] + .

[0493] Step 2: Synthesis of methyl(1r,4r)-4-(((5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-yl)methyl(methyl))amino)cyclohexane-1-carboxylate

[0494] [ka]

[0495] Methyl(1r,4r)-4-(((5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (800 mg, 1.71 mmol), formaldehyde (385.13 mg, 5.13 mmol), DCM (15 mL), methanol (15 mL), triethylamine (259.55 mg, 2.56 mmol), and acetic acid (123.22 mg, 2.05 mmol) were added sequentially to a 100 mL bottle, and the mixture was reacted at 50°C for 8 hours. Sodium borohydride (429.83 mg, 6.84 mmol) was added, and the reaction was continued at room temperature. After the reaction was complete, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: PE / Â(v / v)=1 / 1) yielded 750.0 mg of a pale yellow solid product in 91.03% yield. MS (ESI, positive ion) m / z: 481.9 [M+H] + .

[0496] Step 3: Synthesis of methyl(1r,4r)-4-(((5-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0497] [ka]

[0498] Methyl(1r,4r)-4-(((5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (790 mg, 1.64 mmol), 2-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (477.88 mg, 2.05 mmol), potassium carbonate (566.66 mg, 4.1 mmol), Pd(dppf)Cl2·DCM (133.93 mg, 0.16 mmol), 1,4-dioxane (10 mL), and water (2 mL) were added in order to a 30 mL microwave tube. The tube was sealed and reacted at 130 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: DCM / MeOH(v / v)=20 / 1) yielded 750.0 mg of a pale yellow solid product in 90.04% yield. MS (ESI, positive ion) m / z: 509.2 [M+H] + .

[0499] Step 4: Synthesis of methyl(1r,4r)-4-(((5-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0500] [ka]

[0501] Methyl(1r,4r)-4-(((5-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (790 mg, 1.55 mmol), tert-butanol (50 mL), and 7-bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (593.38 mg, 2.02 mmol) were added sequentially to a 100 mL bottle and reacted at 100 °C under N2. After the reaction was complete, the solvent was removed by concentration under reduced pressure, yielding 1.13 g of a pale yellow solid product in 94.92% yield. MS (ESI, positive ion) m / z: 765.9 [M+H] + .

[0502] Step 5: Synthesis of methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0503] [ka]

[0504] In a 30 mL microwave tube, add methyl(1r,4r)-4-(((5-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (1.13 g, 1.4 7 mmol) of 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.68 g, 4.41 mmol), potassium phosphate (0.78 g, 3.67 mmol), Pd(dppf)Cl2·DCM (0.12 g, 0.15 mmol), 1,4-dioxane (15 mL), and water (3 mL) were added in sequence. The tube was sealed, and the reaction was carried out at 130°C for 1.5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 40 / 1) yielded 935.0 mg of a white solid product in 88.87% yield. MS (ESI, positive ion) m / z: 714.3 [M+H] + .

[0505] Step 6: Synthesis of methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0506] [ka]

[0507] Methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (935 mg, 1.31 mmol), 1,4-dioxane (75 mL), water (30 mL), potassium osmate dihydrate (48 mg, 0.13 mmol), and sodium periodate (1400 mg, 6.55 mmol) were added in order to a 250 mL bottle and reacted at room temperature. After the reaction was complete, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: DCM / MeOH(v / v)=30 / 1) yielded 270.0 mg of a pale yellow solid product in a yield of 28.80%. MS (ESI, positive ion) m / z: 716.2 [M+H] + .

[0508] Step 7: Synthesis of methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0509] [ka]

[0510] In a 100mL single-mouth bottle, methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (210mg, 0.29mmol), (3R)-pyrrolidine-3-ol Hydrochloride (179.19 mg, 1.45 mmol), DCM (15 mL), methanol (15 mL), triethylamine (44 mg, 0.43 mmol), and acetic acid (26 mg, 0.43 mmol) were added in sequence and the mixture was reacted overnight at 50°C. Sodium borohydride cyanohydride (36 mg, 0.57 mmol) was added and the reaction was continued at room temperature. After the reaction was complete, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) yielded 200.0 mg of a pale yellow solid product in 86.63% yield. MS (ESI, positive ion) m / z: 787.4 [M+H] + .

[0511] Step 8: Synthesis of (1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylic acid

[0512] [ka]

[0513] Methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (170 mg, 0.22 mmol), 1,4-dioxane (15 mL), water (5 mL), and lithium hydroxide monohydrate (18 mg, 0.43 mmol) were added in sequence to a 50 mL bottle and reacted at 50°C. After the reaction was complete, the solvent was removed by concentrating under reduced pressure, and the mixture was dissolved in DCM (15 mL) and MeOH (15 mL). Acetic acid (1 mL) was added, and the solvent was removed by concentrating under reduced pressure. The residue was separated and purified by preparative silica gel thin-layer chromatography (eluent: DCM / MeOH(v / v)=5 / 1), yielding 66.0 mg of a pale yellow solid product in a yield of 39.53%. MS (ESI, positive ion) m / z: 773.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.95 (d, J = 1.9 Hz, 1H), 8.42 (s, 1H), 8.18 (d, J = 1.9 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 7.7, 1.7 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.44 (dd, J = 7.6, 1.7 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 6.71 (t, J = 54.5 Hz, 1H), 4.74 (s, 1H), 4.23 (dp, J = 7.0, 3.4 Hz, 1H), 3.96 (s, 3H), 3.87 (q, J = 14.0 Hz, 2H), 3.71 (s, 2H), 2.74 (dd, J = 9.7, 6.1 Hz, 2H), 2.48 (d, J = 3.3 Hz, 2H), 2.42 (dd, J = 9.6, 3.6 Hz, 1H), 2.22 (s, 3H), 2.13 (d, J = 8.3 Hz, 1H), 2.05 (s, 3H), 2.04 - 1.99 (m, 1H), 1.96 (d, J = 7.7 Hz, 2H), 1.87 (d, J = 7.6 Hz, 2H), 1.59 (dddd, J = 13.1, 8.1, 5.4, 3.1 Hz, 1H), 1.41 - 1.27 (m, 4H).

[0514] (Example 12) (S)-5-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)methyl)pyrrolidine-2-one

[0515] [ka]

[0516] Step 1: Synthesis of 6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde

[0517] [ka]

[0518] 6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-aldehyde (2 g, 6.12 mmol), 2-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.71 g, 7.34 mmol), potassium carbonate (2.11 g, 15.3 mmol), Pd(dppf)Cl2·DCM (0.50 g, 0.61 mmol), 1,4-dioxane (20 mL), and water (4 mL) were added sequentially to a 50 mL microwave tube. The mixture was reacted overnight at 100 °C. After the reaction was complete, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: PE / siRNA(v / v)=3 / 1) yielded 1.95 g of a yellow solid product in 90.25% yield. MS (ESI, positive ion) m / z: 353.1 [M+H] + .

[0519] Step 2: Synthesis of 6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde

[0520] [ka]

[0521] 6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (800 mg, 2.27 mmol), tert-butanol (50 mL), and 7-bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (802.16 mg, 2.72 mmol) were added sequentially to a 100 mL bottle and reacted overnight at 100 °C under N2. After the reaction was complete, the solvent was removed by concentration under reduced pressure, yielding 1.30 g of a pale yellow solid product in 93.86% yield. MS (ESI, positive ion) m / z: 609.8 [M+H] + .

[0522] Step 3: Synthesis of (S)-5-((((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)methyl)pyrrolidine-2-one

[0523] [ka]

[0524] 6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxynicotinaldehyde (800 mg, 1.31 mmol), (5S)-5-(aminomethyl)pyrrolidine-2-one hydrochloride (986.50 mg, 6.55 mmol), DCM (15 mL), methanol (15 mL), triethylamine (198.84 mg, 1.97 mmol), and acetic acid (94.40 mg, 1.57 mmol) were added sequentially to a 100 mL bottle and reacted at 50°C for 9 hours. Sodium borocyanohydride (164.64 mg, 2.62 mmol) was added and the reaction was continued at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: DCM / MeOH(v / v)=30 / 1) yielded 850.0 mg of a pale yellow solid product in 91.54% yield. MS (ESI, positive ion) m / z: 708.6 [M+H] + .

[0525] Step 4: Synthesis of (S)-5-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)methyl)pyrrolidine-2-one

[0526] [ka]

[0527] (S)-5-((((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)methyl)pyrrolidine-2-one (523 mg, 0.74 mmol), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (341.90 mg, 2.22 mmol), potassium phosphate (392.70 mg, 1.85 mmol), Pd(dppf)Cl2·DCM (60.43 mg, 0.074 mmol), 1,4-dioxane (15 mL), and water (3 mL) were added to a 50 mL bottle and reacted at 130 °C. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: DCM / MeOH(v / v)=20 / 1) yielded 460.0 mg of a pale yellow solid product in 95.04% yield. MS (ESI, positive ion) m / z: 656.0 [M+H] + .

[0528] Step 5: Synthesis of (S)-4-((2'-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidine2-yl)methyl)amino)methyl)pyridine-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-carbaldehyde

[0529] [ka]

[0530] (S)-5-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)methyl)pyrrolidine-2-one (443.0 mg, 0.68 mmol), 1,4-dioxane (50 mL), water (20 mL), potassium osmate dihydrate (25.05 mg, 0.068 mmol), and sodium periodate (727.23 mg, 3.40 mmol) were added in order to a 250 mL bottle, and the reaction mixture was stirred at room temperature for 2.5 hours. After the reaction was complete, the reaction mixture was quenched with saturated sodium sulfite aqueous solution (5 mL) and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=20 / 1), yielding 155.0 mg of a pale yellow solid product in a yield of 34.88%. MS (ESI, positive ion) m / z: 658.0 [M+H] + .

[0531] Step 6: Synthesis of (S)-5-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)amino)methyl)pyrrolidine-2-one

[0532] [ka]

[0533] (S)-4-((2'-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidine-2-yl)methyl)amino)methyl)pyridine-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)amino)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-7-carbaldehyde (100 mg, 0.15 mmol), (R)-pyrrolidine-3-ol (65.34 mg, 0.75 mmol), DCM (7.5 mL), and 2,2,2-trifluoroethanol (7.5 mL) were added in order and reacted overnight at 50°C. Sodium borocyanohydride (18.85 mg, 0.30 mmol) was added and the reaction was continued at room temperature. After the reaction was complete, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: DCM / MeOH(v / v)=15 / 1) yielded 10.1 mg of a pale yellow solid product in a yield of 9.11%. MS (ESI, positive ion) m / z: 729.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 10.36 (s, 1H), 8.96 (s, 1H), 8.19 (s, 1H), 7.86 (d, J = 7.1 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.30 (d, J = 6.8 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.71 (t, J = 54.4 Hz, 1H), 4.80 (s, 1H), 4.24 (s, 1H), 3.93 (s, 3H), 3.90 - 3.50 (m, 6H), 2.85 - 2.63 (m, 4H), 2.21 - 2.08 (m, 3H), 2.04 (s, 3H), 2.01 - 1.95 (m, 1H), 1.77 - 1.42 (m, 4H).

[0534] (Example 13) (1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylic acid

[0535] [ka]

[0536] Step 1: Synthesis of methyl(1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylate

[0537] [ka]

[0538] Methyl(1r,4r)-4-aminocyclohexane-1-carboxylate hydrochloride (10 g, 51.62 mmol) was dissolved in dichloromethane (300 mL). Di-tert-butyl dicarbonate (14.23 mL, 61.94 mmol) and triethylamine (14.35 mL, 103.24 mmol) were added sequentially, and the system was stirred at room temperature for 6.5 hours. The stirring of the system was stopped, and the system was diluted with water (100 mL). The liquid was separated, and the aqueous phase was extracted with dichloromethane (60 mL x 3). The organic phases were combined and dried on anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain 13.28 g of a white solid in 99.95% yield. MS (ESI, positive ion) m / z: 202.2 [M+H] + .

[0539] Step 2: Synthesis of methyl(1r,4r)-4-((tert-butoxycarbonyl)(methyl-d3)amino)cyclohexane-1-carboxylate

[0540] [ka]

[0541] Methyl(1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylate (5 g, 19.43 mmol) was dissolved in DMF (30 mL), deuterated iodomethane (1.81 mL, 29.14 mmol) was added, and sodium hydride (2.33 g, 58.29 mmol) was slowly added in an ice bath and stirred for 0.5 hours. The mixture was stirred at room temperature for 12 hours. Stirring of the system was stopped, saturated ammonium chloride aqueous solution (40 mL) was added to the system to quench the reaction products, ethyl acetate (40 mL x 3) was added for extraction, the organic phase was combined, washed sequentially with water (30 mL) and saturated brine (30 mL), the organic phase was recovered, dried on anhydrous sodium sulfate, filtered under reduced pressure, washed with ethyl acetate (20 mL), the filtrate was concentrated under reduced pressure, and the residue was used directly in the next step. MS (ESI, positive ion) m / z: 219.4 [M+H] + .

[0542] Step 3: Synthesis of methyl(1r,4r)-4-((methyl-d3)amino)cyclohexane-1-carboxylate

[0543] [ka]

[0544] Methyl(1r,4r)-4-((tert-butoxycarbonyl)(methyl-d3)amino)cyclohexane-1-carboxylate (5.3 g, 19.32 mmol) was dissolved in dichloromethane (100 mL), and trifluoroacetic acid (20.09 mL, 270.48 mmol) was slowly added. The system was stirred at room temperature for 4.5 hours. The reaction was stopped and stirred, and the system was concentrated under reduced pressure. The residue was diluted by adding water (20 mL) and dichloromethane (20 mL). The pH of the system was adjusted to 8-9 by adding saturated potassium carbonate aqueous solution (10 mL). Dichloromethane (20 mL x 3) was used for extraction. The organic phases were combined, dried on anhydrous sodium sulfate, filtered under reduced pressure, and washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure, and the residue was used directly in the next step. MS (ESI, positive ion) m / z: 175.2 [M+H] + .

[0545] Step 4: Synthesis of methyl(1r,4r)-4-(((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylate

[0546] [ka]

[0547] 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (3 g, 9.19 mmol) and methyl(1r,4r)-4-((methyl-d3)amino)cyclohexane-1-carboxylate (2.08 g, 11.95 mmol) were dissolved in a mixed solvent of dichloromethane (50 mL) and 2,2,2-trifluoroethanol (100 mL). Acetic acid (1.05 mL, 18.38 mmol) and triethylamine (5.11 mL, 36.76 mmol) were added, and the system was stirred at 60°C for 7 hours. The system was cooled to room temperature, sodium borocyanohydride (1.73 g, 27.57 mmol) was added, and the system was stirred overnight at room temperature. The reaction was stopped and the mixture was stirred. The system was concentrated under reduced pressure, and the residue was diluted with water (25 mL) and dichloromethane (25 mL). The pH of the system was adjusted to 8-9 by adding saturated potassium carbonate aqueous solution (15 mL). Dichloromethane (20 mL x 3) was added for extraction, the organic phases were combined, dried on anhydrous sodium sulfate, filtered under reduced pressure, washed with dichloromethane (10 mL), and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: PE / siRNA (v / v) = 4 / 1) to obtain 1.33 g of pale yellow solid in 30% yield. MS (ESI, positive ion) m / z: 484.4 [M+H] + .

[0548] Step 5: Synthesis of methyl(1r,4r)-4-(((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylate

[0549] [ka]

[0550] Methyl(1r,4r)-4-(((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylate (1.4 g, 2.89 mmol) and 2-methyl-3-(4,4,4,4-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.01 g, 4.33 mmol) were dissolved in a mixed solvent of 1,4-dioxane (50 mL) and water (10 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (0.24 g, 0.29 mmol) and potassium carbonate (0.80 g, 5.78 mmol) were added. The system was stirred at 90°C under N2 for 5.5 hours. The reaction was stopped and the mixture was stirred. The system was diluted with water (20 mL) and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and dried on anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: PE / ethyl(v / v) = 2 / 1) to obtain 1.25 g of yellow solid in 85% yield. MS (ESI, positive ion) m / z: 511.5 [M+H] + .

[0551] Step 6: Synthesis of methyl(1r,4r)-4-(((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylate

[0552] [ka]

[0553] Methyl(1r,4r)-4-(((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylate (1.4 g, 2.74 mmol) and 7-bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (1.05 g, 3.56 mmol) were dissolved in tert-butanol (80 mL), and hydrochloric acid (1.03 mL, 4.11 mmol) was added. The system was stirred overnight at 130°C under N2. The reaction was stopped and stirred, and the system was concentrated under reduced pressure. The system was diluted with water (25 mL) and dichloromethane (25 mL), and then saturated potassium carbonate solution (15 mL) was added. The mixture was extracted with dichloromethane (25 mL x 3). The organic phases were combined and dried on anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: PE / SiO(v / v)=2 / 1) to obtain 1.97 g of yellow solid in 94% yield. MS (ESI, positive ion) m / z: 768.5 [M+H] + .

[0554] Step 7: Synthesis of methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylate

[0555] [ka]

[0556] Methyl(1r,4r)-4-(((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylate (1.97g, 2.56mmol) to 1,4-dioxane (70m Dissolve in a mixed solvent of (L) and water (10 mL), and sequentially add 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.56 mL, 3.33 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (0.21 g, 0.26 mmol), and potassium phosphate (1.36 g, 6.4 mmol). Stir the system overnight at 100 °C. Stop the reaction and stir. Cool the system to room temperature and dilute with water (20 mL) and ethyl acetate (20 mL). Separate the liquids, extract the aqueous phase with ethyl acetate (20 mL x 3), combine with the organic phase, dry on anhydrous sodium sulfate, filter under reduced pressure, wash with ethyl acetate (10 mL), and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: PE / SiO(v / v)=1 / 1), yielding 1.57 g of yellow solid in 86% yield. MS (ESI, positive ion) m / z: 716.6 [M+H] + .

[0557] Step 8: Synthesis of methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylate

[0558] [ka]

[0559] Methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylate (1.57 g, 2.19 mmol) was dissolved in 1,4-dioxane (90 mL) and water (30 mL). Potassium osmate dihydrate (40.35 mg, 0.11 mmol) and sodium periodate (1.17 g, 5.47 mmol) were added sequentially, and the system was stirred at room temperature for 2 hours. The reaction was stopped, and the system was filtered under reduced pressure. The filtrate was separated, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and dried on anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: PE / SiO(v / v)=1 / 2) to obtain 0.64 g of green solid in 41% yield. MS (ESI, positive ion) m / z: 718.3 [M+H] + .

[0560] Step 9: Synthesis of methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylate

[0561] [ka]

[0562] Methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylate (0.64 g, 0.89 mmol) and (R)-pyrrolidine-3-ol (0.36 mL, 4.45 mmol) were dissolved in a mixed solvent of methanol (42 mL) and dichloromethane (14 mL). Acetic acid (0.15 mL, 2.67 mmol) was added, and the system was stirred at room temperature for 7 hours. Sodium borocyanohydride (0.17 g, 2.67 mmol) was added, and the system was stirred at room temperature overnight. The reaction was stopped and the mixture was stirred. The system was concentrated under reduced pressure and diluted with water (15 mL) and DCM (15 mL). Saturated potassium carbonate solution (5 mL) was added to adjust the pH of the system to 9-10. The layers were separated, and the aqueous phase was extracted with DCM (15 mL x 3). The organic phases were combined and dried on anhydrous sodium sulfate. The mixture was filtered under reduced pressure and washed with DCM (10 mL). The filtrate was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) to obtain 0.52 g of an orange-red oily substance in 74% yield. MS (ESI, positive ion) m / z: 789.4 [M+H] + .

[0563] Step 10: Synthesis of (1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylic acid

[0564] [ka]

[0565] Methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl-d3)amino)cyclohexane-1-carboxylate (0.52 g, 0.66 mmol) was dissolved in 1,4-dioxane (40 mL), and a solution of lithium hydroxide monohydrate (553.87 mg, 13.20 mmol) in water (10 mL) was added. The system was stirred at room temperature for 9 hours. The reaction was stopped, and stirring was discontinued. Acetic acid was added to the system to adjust the pH to 4-5. The system was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=2 / 1), yielding 125 mg of yellow solid in a yield of 24%. MS (ESI, positive ion) m / z: 775.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.33 (s, 1H), 8.95 (s, 1H), 8.17 (s, 1H), 7.77 (t, J = 8.3 Hz, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.27 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 7.1 Hz, 1H), 6.71 (t, J = 54.5 Hz, 1H), 4.26 - 4.20 (m, 2H), 3.91 (s, 3H), 3.89 (s, 1H), 3.85 (s, 1H), 3.81 (s, 1H), 2.76 - 2.72 (m, 1H), 2.69 - 2.66 (m, 1H), 2.42 (d, J = 6.9 Hz, 2H), 2.08 (s, 1H), 2.05 (s, 3H), 2.02 - 1.98 (m, 2H), 1.93 (s, 2H), 1.83 (s, 2H), 1.63 - 1.55 (m, 2H), 1.39 - 1.28 (m, 4H).

[0566] (Example 14) (1r,4r)-4-((((5-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylic acid

[0567] [ka]

[0568] Step 1: Synthesis of 5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-carbaldehyde

[0569] [ka]

[0570] (2-bromo-3-chlorophenyl)boronic acid (17.3 g, 73.53 mmol), 5-bromo-3-methoxypyrazine-2-carbaldehyde (19.15 g, 88.24 mmol), Pd(PPh3)Cl2 (1.55 g, 2.21 mmol), tri(o-methylphenyl)phosphine (0.67 g, 2.21 mmol), and potassium carbonate (10.16 g, 73.53 mmol) were dissolved in a mixed solvent of 1,4-dioxane (200 mL) and water (50 mL). The resulting solution was protected with nitrogen and heated to 65°C. After the reaction was complete, a large amount of water was added to the reaction system, causing a large amount of solid to precipitate. This was filtered and dried to obtain 22.01 g of a white solid product in 91.38% yield. MS (ESI, positive ion) m / z: 327.0 [M+H] + .

[0571] Step 2: Synthesis of methyl(1r,4r)-4-((((5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-yl)methyl)amino)methyl)cyclohexane-1-carboxylate

[0572] [ka]

[0573] At room temperature, 5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-carbaldehyde (5 g, 15.26 mmol) and methyl(1r,4r)-4-(aminomethyl)cyclohexane-1-carboxylate (3.92 g, 22.89 mmol) were added to 2,2,2-trifluoroethanol (20 mL) and DCM (20 mL). The mixture was stirred at 45°C for 30 minutes, and then sodium borohydride (0.96 g, 15.26 mmol) was slowly added, and the reaction was continued under stirring. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (eluent: PE / siRNA(v / v) = 10 / 1) to obtain 6.5 g of a yellow oily product in 88.2% yield. MS (ESI, positive ion) m / z: 482.0 [M+H] + .

[0574] Step 3: Synthesis of methyl(1r,4r)-4-((((5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate

[0575] [ka]

[0576] At room temperature, methyl(1r,4r)-4-((((5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-yl)methyl)aminomethyl)cyclohexane-1-carboxylate (12.9 g, 26.72 mmol) and formaldehyde (0.80 g, 26.72 mmol) were added to 2,2,2-trifluoroethanol (20 mL) and DCM (20 mL). The mixture was stirred at 45°C for 30 minutes, and then sodium borohydride (1.68 g, 26.72 mmol) was slowly added, and the reaction was continued under stirring. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (eluent: PE / siRNA(v / v)=10 / 1) to obtain 8.2 g of a yellow oily product in 61.77% yield. MS (ESI, positive ion) m / z: 496.4 [M+H] + .

[0577] Step 4: Synthesis of methyl(1r,4r)-4-((((5-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate

[0578] [ka]

[0579] At room temperature, methyl(1r,4r)-4-((((5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate (8.2 g, 16.50 mmol), 2-methyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.69 g, 33 mmol), Pd(dppf)Cl2·DCM· (0.62 g, 0.83 mmol), and potassium carbonate (4.56 g, 33 mmol) were added to 1,4-dioxane (100 mL) and water (25 mL), and the reaction mixture was stirred at 90°C. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: PE / Â(v / v)=3 / 1) yielded 8.4 g of a yellow oily product in 97.30% yield. MS (ESI, positive ion) m / z: 523.3 [M+H] + .

[0580] Step 5: Synthesis of methyl(1r,4r)-4-((((5-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate

[0581] [ka]

[0582] At room temperature, methyl(1r,4r)-4-((((5-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate (8.3 g, 15.87 mmol) and 7-bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (6.08 g, 20.63 mmol) were added to tert-butanol (100 mL) and stirred at 100 °C for the reaction. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by silica gel column chromatography (eluent: CH2Cl2 / MeOH (v / v) = 10 / 1) to obtain 11.95 g of a yellow solid product in 96.42% yield. MS (ESI, positive ion) m / z: 780.5 [M+H] + .

[0583] Step 6: Synthesis of methyl(1r,4r)-4-((((5-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate

[0584] [ka]

[0585] Methyl(1r,4r)-4-((((5-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate (8.1 g, 10.37 mmol), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.79 g, 31.1 mmol), Pd(dppf)Cl2·DCM· (1.27 g, 1.56 mmol), and potassium phosphate (4.40 g, 20.74 mmol) were added to 1,4-dioxane (150 mL) and water (30 mL) at room temperature. The reaction mixture was stirred at 100 °C. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: CH2Cl2 / MeOH (v / v) = 10 / 1) yielded 5.5 g of a yellow solid product in a yield of 72.83%. MS (ESI, positive ion) m / z: 728.1 [M+H] + .

[0586] Step 7: Synthesis of methyl(1r,4r)-4-((((5-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate

[0587] [ka]

[0588] At room temperature, methyl(1r,4r)-4-((((5-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate (3.0 g, 4.12 mmol) was added to 1,4-dioxane (200 mL) and water (75 mL). Then, potassium osmite dihydrate (0.15 g, 0.41 mmol) and sodium periodate (4.41 g, 20.6 mmol) were slowly added, and the reaction mixture was continuously stirred. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: CH2Cl2 / MeOH (v / v) = 20 / 1) yielded 1.80 g of a yellow oily product in 59.84% yield. MS (ESI, positive ion) m / z: 729.9 [M+H] + .

[0589] Step 8: Synthesis of methyl(1r,4r)-4-((((5-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate

[0590] [ka]

[0591] At room temperature, methyl(1r,4r)-4-((((5-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate (2.9 g, 3.97 mmol) and (3R)-pyrrolidine-3-ol (1.04 g, 11.91 mmol) were added to dichloromethane (20 mL) and 2,2,2-trifluoroethanol (20 mL), and the reaction mixture was stirred at 45°C. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: CH2Cl2 / MeOH (v / v) = 20 / 1) yielded 2.50 g of a yellow oily product in a yield of 78.56%. MS (ESI, positive ion) m / z: 801.8 [M+H] + .

[0592] Step 9: Synthesis of (1r,4r)-4-((((5-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylic acid

[0593] [ka]

[0594] At room temperature, methyl(1r,4r)-4-((((5-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate (2.49 g, 3.11 mmol) was added to 1,4-dioxane (30 mL) and water (5 mL), and then lithium hydroxide monohydrate (0.65 g, 15.55 mmol) was slowly added, and the reaction mixture was stirred at 50°C. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was separated. Purification by silica gel column chromatography (eluent: CH2Cl2 / MeOH (v / v) = 10 / 1) yielded 1.0 g of a white solid product in 40.88% yield. MS (ESI, positive ion) m / z: 787.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.93 (d, J = 1.9 Hz, 1H), 8.42 (s, 1H), 8.15 (d, J = 1.9 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 7.7, 1.7 Hz, 1H), 7.56 (td, J = 7.5, 1.5 Hz, 1H), 7.42 (dd, J = 7.6, 1.7 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.18 - 7.11 (m, 1H), 6.69 (t, J = 54.6 Hz, 1H), 4.21 (qd, J = 6.7, 3.3 Hz, 1H), 3.94 (s, 3H), 3.85 (q, J = 14.0 Hz, 2H), 3.59 (s, 2H), 3.16 (s, 3H), 2.78 - 2.62 (m, 2H), 2.46 (d, J = 8.3 Hz, 1H), 2.41 (dd, J = 9.7, 3.5 Hz, 1H), 2.21 (d, J = 7.0 Hz, 2H), 2.17 (s, 3H), 2.04 (s, 3H), 1.80 (d, J = 19.3 Hz, 3H), 1.59 (ddt, J = 12.5, 8.8, 3.5 Hz, 1H), 1.45 (s, 1H), 1.33 - 1.19 (m, 2H), 0.76 (q, J = 12.8, 12.4 Hz, 2H).

[0595] (Example 15) (R)-1-((5-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylic acid

[0596] [ka]

[0597] Step 1: Synthesis of methyl 1-((5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylate

[0598] [ka]

[0599] 5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-carbaldehyde (5 g, 15.26 mmol) and methylpiperidine-4-carboxylate (6.55 g, 45.78 mmol) were dissolved in a mixed solvent of dichloromethane (40 mL) and methanol (120 mL). Acetic acid (1.75 mL, 30.52 mmol) was added, and the mixture was stirred at room temperature for 8 hours. Sodium borocyanohydride (2.88 g, 45.78 mmol) was added, and the system was stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: PE / siRNA(v / v)=4 / 1) to obtain 6.9 g of an orange-yellow oily substance in 99% yield. MS (ESI, positive ion) m / z: 454.1 [M+H] + .

[0600] Step 2: Synthesis of methyl 1-((5-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylate

[0601] [ka]

[0602] Methyl 1-((5-(3-bromo-2-chlorophenyl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylate (5.3 g, 11.65 mmol) and 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4.07 g, 17.48 mmol) were dissolved in a mixed solvent of 1,4-dioxane (150 mL) and water (30 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (0.95 g, 1.17 mmol) and potassium carbonate (3.22 g, 23.3 mmol) were added. The system was stirred at 90°C under N2 for 10.5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the solution was purified by silica gel column chromatography (eluent: PE / SiO(v / v)=1 / 1) to obtain 4.5 g of a red oily substance in 80% yield. MS (ESI, positive ion) m / z: 481.5 [M+H] + .

[0603] Step 3: Synthesis of methyl 1-((5-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylate

[0604] [ka]

[0605] Methyl 1-((5-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylate (4.5 g, 9.36 mmol) and 7-bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (3.58 g, 12.17 mmol) were dissolved in tert-butanol (160 mL), and hydrochloric acid in 1,4-dioxane solution (3.51 mL, 14.04 mmol) was added. The system was stirred overnight at 130°C under N2. After the reaction was complete, the filtrate was concentrated under reduced pressure, the residue was separated, and the mixture was purified by silica gel column chromatography (eluent: PE / siRNA(v / v)=1 / 2) to obtain 6 g of yellow solid in 87% yield. MS (ESI, positive ion) m / z: 738.0 [M+H] + .

[0606] Step 4: Synthesis of methyl 1-((5-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylate

[0607] [ka]

[0608] Methyl 1-((5-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylate (6 g, 8.12 mmol) was dissolved in a mixed solvent of 1,4-dioxane (300 mL) and water (30 mL). 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.79 mL, 10.56 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (0.66 g, 0.81 mmol), and potassium phosphate (4.31 g, 20.30 mmol) were added in sequence, and the system was stirred overnight at 100°C. After the reaction was complete, the filtrate was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: PE / SiO(v / v)=1 / 2) to obtain 4.4 g of yellow solid in 81% yield. MS (ESI, positive ion) m / z: 686.6 [M+H] + .

[0609] Step 5: Synthesis of methyl 1-((5-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylate

[0610] [ka]

[0611] Methyl 1-((5-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylate (4.4 g, 6.41 mmol) was dissolved in 1,4-dioxane (270 mL) and water (90 mL). Potassium osmate dihydrate (118.09 mg, 0.32 mmol) and sodium periodate (3.43 g, 16.02 mmol) were added in sequence, and the system was stirred at room temperature for 7.5 hours. After the reaction was complete, the filtrate was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: PE / siRNA(v / v)=1 / 4) to obtain 1.63 g of a brown-yellow solid in 37% yield. MS (ESI, positive ion) m / z: 688.9 [M+H] + .

[0612] Step 6: Synthesis of methyl(R)-1-((5-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylate

[0613] [ka]

[0614] Methyl 1-((5-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylate (1.6 g, 2.33 mmol) and (3R)-pyrrolidine-3-ol (0.94 mL, 11.65 mmol) were dissolved in a mixed solvent of methanol (90 mL) and dichloromethane (30 mL), and acetic acid (0.40 mL, 6.99 mmol) was added. The system was stirred at room temperature for 6 hours. Sodium borocyanohydride (0.44 g, 6.99 mmol) was added, and the system was stirred at room temperature overnight. After the reaction was complete, the filtrate was concentrated under reduced pressure, the residue was separated, and the mixture was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=15 / 1) to obtain 0.83 g of a yellow oily substance in 47% yield. MS (ESI, positive ion) m / z: 759.3 [M+H] + .

[0615] Step 7: Synthesis of (R)-1-((5-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylic acid

[0616] [ka]

[0617] Methyl(R)-1-((5-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)piperidine-4-carboxylate (0.83 g, 1.09 mmol) was dissolved in 1,4-dioxane (60 mL), and a solution of lithium hydroxide monohydrate (914.73 mg, 21.8 mmol) in water (15 mL) was added. The system was stirred overnight at room temperature. The reaction was stopped, and stirring was discontinued. Acetic acid was added to the system to adjust the pH to 4-5. The system was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=10 / 1), yielding 337.2 mg of a yellow solid in 41% yield. MS (ESI, positive ion) m / z: 745.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.95 (s, 1H), 8.46 (s, 1H), 8.17 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.44 (d, J = 7.1 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 6.71 (t, J = 54.5 Hz, 1H), 4.25 - 4.21 (m, 1H), 3.97 (s, 3H), 3.90 (d, J = 13.9 Hz, 1H), 3.83 (d, J = 13.9 Hz, 1H), 3.62 (s, 4H), 2.86 (d, J = 10.7 Hz, 2H), 2.74 (dd, J = 9.4, 6.1 Hz, 1H), 2.68 (q, J = 7.7 Hz, 1H), 2.49 - 2.47 (m, 1H), 2.41 (dd, J = 9.4, 2.9 Hz, 1H), 2.13 (t, J = 10.8 Hz, 2H), 2.04 (s, 3H), 2.01 (dd, J = 14.9, 7.5 Hz, 1H), 1.74 (d, J = 11.4 Hz, 2H), 1.61 - 1.51 (m, 1H), 1.51 (dt, J = 12.5, 6.3 Hz, 2H).

[0618] (Example 16) (1r,4r)-4-(((6-(2,2'-Dichloro-3'-((2-(Difluoromethyl)-7-(((R)-3-Hydroxypyrrolidine-1-yl)methyl)Pyrido[3,2-d]Pyrimidine-4-yl)amino)-[1,1'-Biphenyl]-3-yl)-2-Methoxypyridine-3-yl)methyl)(Methyl)amino)Cyclohexane-1-carboxylic acid

[0619] [ka]

[0620] Step 1: Synthesis of methyl(1r,4r)-4-(((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylate

[0621] [ka]

[0622] 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (1.1 g, 3.37 mmol) and methyl(1r,4r)-4-aminocyclohexane-1-carboxylate (0.98 g, 5.05 mmol) were dissolved in 2,2,2-trifluoroethanol (15 mL) and dichloromethane (15 mL). The mixture was stirred at 50°C for 16 hours. Sodium borocyanohydride (317.66 mg, 5.05 mmol) was added to the system, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the system was concentrated and extracted with ethyl acetate (10 mL x 2). The organic phases were combined and concentrated under reduced pressure. The mixture was separated and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 15 / 1) to obtain 1.57 g of a pale yellow viscous product in 99.64% yield. MS (ESI, positive ion) m / z: 467.1 [M+H] + .

[0623] Step 2: Synthesis of methyl(1r,4r)-4-(((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0624] [ka]

[0625] Methyl(1r,4r)-4-(((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)amino)cyclohexane-1-carboxylate (0.44 g, 0.94 mmol) and formaldehyde (0.31 g, 3.76 mmol) were dissolved in methanol (40 mL), then acetic acid (70.56 mg, 1.17 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Sodium borohydride (295.35 mg, 4.70 mmol) was slowly added, and the mixture was stirred at room temperature for 2.5 hours. After the reaction was complete, saturated sodium carbonate solution (10 mL) was added to quench the reaction product, and it was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and dried on anhydrous sodium sulfate. The solution was filtered, the filtrate was concentrated, and then concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 40 / 1) yielded 0.45 g of a pale yellow viscous product in 99.29% yield. MS (ESI, positive ion) m / z: 482.9 [M+H] + .

[0626] Step 3: Synthesis of methyl(1r,4r)-4-(((6-(3'-amino-2,2'-dichloro[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0627] [ka]

[0628] Methyl(1r,4r)-4-(((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (0.66 g, 1.37 mmol) and 2-chloro-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.69 g, 2.74 mmol) were dissolved in a mixed solvent of water (4 mL) and 1,4-dioxane (20 mL). Sodium carbonate (0.44 g, 4.11 mmol) and [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II) (0.10 g, 0.14 mmol) were added in sequence. The mixture was heated at 90°C for 6 hours under N2. After the reaction was complete, the product was filtered and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 20 / 1), yielding 0.72 g of a brown-black viscous product in 99.46% yield. MS (ESI, positive ion) m / z: 528.5 [M+H] + .

[0629] Step 4: Synthesis of methyl(1r,4r)-4-(((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2,2'-dichloro[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0630] [ka]

[0631] 7-Bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (500 mg, 1.70 mmol) and methyl(1r,4r)-4-(((6-(3'-amino-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (0.72 g, 1.36 mmol) were dissolved in tert-butanol (50 mL) and stirred at 130°C under N2 for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=20 / 1) to obtain 0.5 g of a brownish-yellow powder in a yield of 46.66%. MS (ESI, positive ion) m / z: 785.5 [M+H] + .

[0632] Step 5: Synthesis of methyl(1r,4r)-4-(((6-(2,2'-dichloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0633] [ka]

[0634] Methyl(1r,4r)-4-(((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2,2'-dichloro-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (0.315g, 0.40 mmol) mixed with 1,4-dioxane (30mL) and water (6mL) The mixture was dissolved in L) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (616.04 mg, 4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (32.67 mg, 0.040 mmol), and potassium phosphate (169.82 mg, 0.80 mmol) were added in sequence. The system was stirred at 100°C under N2 for 4 hours. After the reaction was complete, the product was filtered and concentrated, and the residue was purified by column chromatography (eluent: DCM / MeOH(v / v)=20 / 1) to obtain 0.29 g of yellow solid in 98.70% yield. MS (ESI, positive ion) m / z: 733.2 [M+H] + .

[0635] Step 6: Synthesis of methyl(1r,4r)-4-(((6-(2,2'-dichloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0636] [ka]

[0637] Methyl(1r,4r)-4-(((6-(2,2'-dichloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (0.29 g, 0.40 mmol) was dissolved in 1,4-dioxane (18 mL) and water (6 mL). Potassium osmate dihydrate (7.37 mg, 0.020 mmol) and sodium periodate (0.21 g, 1 mmol) were added sequentially, and the system was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered and separated. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and dried on anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=20 / 1), yielding 0.188 g of a brown-yellow viscous product in 64.65% yield. MS (ESI, positive ion) m / z: 735.5 [M+H] + .

[0638] Step 7: Synthesis of methyl(1r,4r)-4-(((6-(2,2'-dichloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0639] [ka]

[0640] Methyl(1r,4r)-4-(((6-(2,2'-dichloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (0.188 g, 0.26 mmol) and (3R)-pyrrolidine-3-ol (113.26 mg, 1.3 mmol) were dissolved in methanol (24 mL) and DCM (7 mL), and the reaction mixture was stirred at room temperature for 21 hours. Sodium borocyanohydride (49.02 mg, 0.78 mmol) was added, and the reaction was continued at room temperature for 3 hours. After the reaction was complete, the system was concentrated, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=12 / 1) to obtain 0.14 g of brownish-yellow powder in a yield of 67.90%. MS (ESI, positive ion) m / z: 806.0 [M+H] + .

[0641] Step 8: Synthesis of (1r,4r)-4-(((6-(2,2'-dichloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylic acid

[0642] [ka]

[0643] Methyl(1r,4r)-4-(((6-(2,2'-dichloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (0.14 g, 0.17 mmol) was dissolved in a mixed solution of 1,4-dioxane (15 mL) and water (3 mL), and lithium hydroxide monohydrate (85.60 mg, 2.04 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours. After the reaction was complete, water (5 mL) was added for dilution, the pH was adjusted to 5 using dilute hydrochloric acid (5 mL), and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 8 / 1), yielding 60 mg of a bright orange powder in a yield of 43.62%. MS (ESI, positive ion) m / z: 791.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.56 (d, J = 8.3 Hz, 1H), 8.23 ​​(s, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.56 (dt, J = 14.1, 8.1 Hz, 3H), 7.41 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 7.6 Hz, 3H), 4.23 - 4.19 (m, 1H), 3.89 (s, 3H), 3.86 - 3.79 (m, 4H), 3.01 - 2.90 (m, 1H), 2.72 (d, J = 7.6 Hz, 2H), 2.67 (d, J = 5.3 Hz, 2H), 2.37 - 2.28 (m, 1H), 2.16 (s, 3H), 2.06 - 1.98 (m, 3H), 1.91 (s, 3H), 1.86 - 1.75 (m, 4H), 1.61 - 1.55 (m, 1H).

[0644] (Example 17) (1r,4r)-4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylic acid

[0645] [ka]

[0646] Step 1: Synthesis of methyl(1r,4r)-4-((((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)amino)methyl)cyclohexane-1-carboxylate

[0647] [ka]

[0648] 6-(3-bromo-2-chlorophenyl)-2-methoxynicotinaldehyde (2.0 g, 6.12 mmol) and methyl(1r,4r)-4-(aminomethyl)cyclohexane-1-carboxylate (1.36 g, 7.96 mmol) were dissolved in 2,2,2-trifluoroethanol (10 mL) and dichloromethane (20 mL). The mixture was stirred at 50°C for 2 hours. Sodium borohydride cyanohydride (380 mg, 6.12 mmol) was added to the system, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the system was concentrated and extracted with ethyl acetate (10 mL x 2). The organic phases were combined and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: PE / siRNA(v / v)=1 / 1) to obtain 2.60 g of a pale yellow viscous product in 88.11% yield. MS (ESI, positive ion) m / z: 481.4 [M+H] + .

[0649] Step 2: Synthesis of methyl(1r,4r)-4-((((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate

[0650] [ka]

[0651] Methyl(1r,4r)-4-((((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)aminomethyl)cyclohexane-1-carboxylate (3.8 g, 7.89 mmol) and formaldehyde (0.71 g, 23.67 mmol) were dissolved in 2,2,2-trifluoroethanol (20 mL) and dichloromethane (20 mL). The mixture was stirred at 50°C for 2 hours. Sodium borocyanohydride (500 mg, 7.89 mmol) was added to the system, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the product was concentrated under reduced pressure, the residue was separated, and the mixture was purified by silica gel column chromatography (eluent: PE / Â(v / v)=1 / 1) to obtain 3.65 g of a pale yellow viscous product in 93.33% yield. MS (ESI, positive ion) m / z: 495.4 [M+H] + .

[0652] Step 3: Synthesis of methyl(1r,4r)-4-((((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate

[0653] [ka]

[0654] Methyl(1r,4r)-4-((((6-(3-bromo-2-chlorophenyl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate (1.70 g, 3.43 mmol) and 2-chloro-3-(tetramethyl-1,3,2-dioxavorin-2-yl)aniline (1.2 g, 5.15 mmol) were dissolved in a mixed solvent of water (5 mL) and 1,4-dioxane (20 mL). Potassium carbonate (0.71 g, 5.15 mmol) and [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II) (0.14 g, 0.17 mmol) were added in sequence. The mixture was heated at 100 °C overnight. After the reaction was complete, the product was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: PE / siRNA(v / v)=1 / 1) to obtain 1.70 g of a brown-black viscous substance in a yield of 94.97%. MS (ESI, positive ion) m / z: 522.3 [M+H] + .

[0655] Step 4: Synthesis of methyl(1r,4r)-4-((((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate

[0656] [ka]

[0657] 7-Bromo-4-chloro-2-(difluoromethyl)pyrido[3,2-d]pyrimidine (1.18 g, 4.02 mmol) and methyl(1r,4r)-4-((((6-(3'-amino-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate (1.75 g, 3.35 mmol) were dissolved in tert-butanol (50 mL) and stirred at 120°C under N2 for 5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=20 / 1) to obtain 2.1 g of brownish-yellow powder in yield of 80.31%. MS (ESI, positive ion) m / z: 779.5 [M+H] + .

[0658] Step 5: Synthesis of methyl(1r,4r)-4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate

[0659] [ka]

[0660] Methyl(1r,4r)-4-((((6-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate (2.0g, 2.56 mmol) to 1,4-dioxane (30m The mixture was dissolved in a mixed solvent of (L) and water (6 mL), and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.99 g, 6.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane adduct (0.21 g, 0.26 mmol), and potassium phosphate (1.36 g, 6.4 mmol) were added in sequence. The system was stirred at 100°C under N2 for 4 hours. After the reaction was complete, the mixture was filtered and concentrated, and the residue was purified by column chromatography (eluent: DCM / MeOH(v / v)=20 / 1) to obtain 1.6 g of yellow solid in yield 85.81%. MS (ESI, positive ion) m / z: 727.3 [M+H] + .

[0661] Step 6: Synthesis of methyl(1r,4r)-4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate

[0662] [ka]

[0663] Methyl(1r,4r)-4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-vinylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate (2.56 g, 3.52 mmol) was dissolved in 1,4-dioxane (36 mL) and water (12 mL). Potassium osmate dihydrate (0.065 mg, 0.18 mmol) and sodium periodate (1.51 g, 7.04 mmol) were added sequentially, and the system was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered and separated. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and dried on anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=20 / 1) to obtain 0.87 g of a brown-yellow viscous product in 33.89% yield. MS (ESI, positive ion) m / z: 729.6 [M+H] + .

[0664] Step 7: Synthesis of methyl(1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate

[0665] [ka]

[0666] Methyl(1r,4r)-4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-formylpyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate (1.4 g, 1.92 mmol) and (3R)-pyrrolidine-3-ol (836.35 mg, 9.6 mmol) were dissolved in methanol (45 mL) and DCM (15 mL), and acetic acid (576.48 mg, 9.6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 13 hours. Sodium borocyanohydride (361.96 mg, 5.76 mmol) was added, and the reaction was continued at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=10 / 1) to obtain 873 mg of pale yellow powder in yield of 56.82%. MS (ESI, positive ion) m / z: 800.8 [M+H] + .

[0667] Step 8: Synthesis of (1r,4r)-4-(((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylic acid

[0668] [ka]

[0669] Methyl(1r,4r)-4-((((6-(2-chloro-3'-((2-(difluoromethyl)-7-(((R)-3-hydroxypyrrolidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-2-methoxypyridine-3-yl)methyl)(methyl)amino)methyl)cyclohexane-1-carboxylate (0.773 g, 0.97 mmol) was dissolved in a mixed solution of 1,4-dioxane (50 mL) and water (10 mL), lithium hydroxide monohydrate (488.41 mg, 11.64 mmol) was added, and the reaction mixture was stirred at room temperature for 20 hours. After the reaction was complete, the product was concentrated under reduced pressure, the residue was separated, and the product was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 9 / 1) to obtain 293.8 mg of yellow powder in a yield of 36.89%. MS (ESI, positive ion) m / z: 786.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.03 (d, J = 27.1 Hz, 1H), 8.30 (s, 1H), 7.86 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.54 (q, J = 10.4, 9.2 Hz, 1H), 7.36 (d, J = 24.6 Hz, 2H), 7.23 - 7.09 (m, 1H), 7.03 - 6.39 (m, 2H), 5.08 (s, 1H), 4.36 (d, J = 42.9 Hz, 2H), 4.19 (d, J = 22.7 Hz, 2H), 3.92 (s, 3H), 3.22 (d, J = 7.4 Hz, 1H), 3.11 (d, J = 9.9 Hz, 1H), 3.06 - 2.93 (m, 3H), 2.85 - 2.71 (m, 2H), 2.41 - 2.36 (m, 1H), 2.18 - 2.08 (m, 2H), 2.06 (s, 1H), 2.03 (s, 2H), 1.90 (s, 3H), 1.87 (s, 3H), 1.76 - 1.69 (m, 1H), 1.68 - 1.57 (m, 1H), 1.32 (d, J = 11.7 Hz, 2H), 1.27 - 1.12 (m, 2H).

[0670] (Example 18) (1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-((3-methoxyazetidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylic acid

[0671] [ka]

[0672] Step 1: Synthesis of methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-((3-methoxyazetidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0673] [ka]

[0674] At room temperature, 3-methoxyazetidine (0.34 g, 3.90 mmol), potassium bromomethyl trifluoroborate (0.78 g, 3.90 mmol), and sodium carbonate (0.83 g, 7.80 mmol) were added to acetonitrile (10 mL), stirred at 80°C for 5 hours, concentrated under reduced pressure, and then Pd(OAc)2 (0.0029 g, 0.013 mmol), X-Phos (0.012 g, 0.026 mmol), and potassium carbonate (0.54 g, 3.90 mmol) were added. The reaction mixture was stirred at 110°C with methyl(1r,4r)-4-(((5-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (1.0 g, 1.30 mmol), 1,4-dioxane (30 mL), and water (6 mL). After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the residue was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=20 / 1) to obtain 0.52 g of a yellow solid product in 50.66% yield. MS (ESI, positive ion) m / z: 787.3 [M+H] + .

[0675] Step 2: Synthesis of (1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-((3-methoxyazetidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylic acid

[0676] [ka]

[0677] At room temperature, methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-((3-methoxyazetidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (0.50 g, 0.64 mmol) and lithium hydroxide monohydrate (0.04 g, 0.96 mmol) were added to 1,4-dioxane (15 mL) and water (5 mL), and the reaction mixture was stirred at 50°C. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the solution was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=5 / 1) to obtain 0.38 g of a white solid product in 77.4% yield. MS (ESI, positive ion) m / z: 773.31 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.88 (s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.44 - 7.34 (m, 2H), 7.15 (d, J = 7.6 Hz, 1H), 6.68 (t, J = 54.5 Hz, 1H), 4.01 (q, J = 5.9 Hz, 1H), 3.94 (s, 3H), 3.85 (s, 3H), 3.57 - 3.51 (m, 2H), 3.17 (s, 3H), 3.14 (s, 2H), 2.97 (t, J = 6.6 Hz, 1H), 2.45 (d, J = 11.7 Hz, 1H), 2.20 (s, 3H), 2.12 (s, 1H), 2.02 (s, 3H), 1.94 (d, J = 7.4 Hz, 1H), 1.90 (s, 1H), 1.85 (d, J = 8.1 Hz, 2H), 1.32 (d, J = 9.7 Hz, 4H)..

[0678] (Example 19) (1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxy-3-methylazetidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylic acid

[0679] [ka]

[0680] Step 1: Synthesis of methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxy-3-methylazetidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0681] [ka]

[0682] At room temperature, 3-methylazetidine-3-ol (0.34 g, 3.90 mmol), potassium bromomethyltrifluoroborate (0.78 g, 3.90 mmol), and sodium carbonate (0.83 g, 7.80 mmol) were added to acetonitrile (10 mL), stirred at 80°C for 5 hours, concentrated under reduced pressure, and then Pd(OAc)2 (0.0029 g, 0.013 mmol), X-Phos (0.012 g, 0.026 mmol), and potassium carbonate (0.54 g, 3.9 0 mmol) methyl(1r,4r)-4-(((5-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (1.0 g, 1.30 mmol), 1,4-dioxane (30 mL), and water (6 mL) were added to the reaction mixture, which was stirred at 110°C. After the reaction, the mixture was filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography eluted with DCM / MeOH (v / v) = 20 / 1, and the product was obtained as a yellow solid (0.26 g, 25.33%). MS (ESI, positive ion) m / z: 787.4 [M+H] + .

[0683] Step 2: Synthesis of (1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxy-3-methylazetidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylic acid

[0684] [ka]

[0685] At room temperature, methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-((3-hydroxy-3-methylazetidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (0.25 g, 0.32 mmol) and lithium hydroxide monohydrate (0.02 g, 0.48 mmol) were added to 1,4-dioxane (10 mL) and water (3 mL), and the reaction mixture was stirred at 50°C. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the solution was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=5 / 1) to obtain 0.13 g of a yellow solid product in a yield of 52.9%. MS (ESI, positive ion) m / z: 773.31 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.88 (d, J = 1.8 Hz, 1H), 8.38 (s, 1H), 8.09 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.44 - 7.33 (m, 2H), 7.14 (d, J = 7.5 Hz, 1H), 6.68 (t, J = 54.5 Hz, 1H), 3.93 (s, 3H), 3.85 (s, 2H), 3.24 (d, J = 6.9 Hz, 2H), 3.17 (s, 4H), 3.01 (d, J = 6.9 Hz, 2H), 2.47 - 2.38 (m, 1H), 2.18 (s, 3H), 2.02 (s, 3H), 1.91 (d, J = 7.9 Hz, 2H), 1.85 - 1.79 (m, 2H), 1.38 (s, 3H), 1.31 - 1.25 (m, 4H).

[0686] (Example 20) (1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-(pyrrolidine-1-ylmethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylic acid

[0687] [ka]

[0688] Step 1: Synthesis of methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-(pyrrolidine-1-ylmethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0689] [ka]

[0690] At room temperature, pyrrolidine (0.28 g, 3.90 mmol), potassium bromomethyl trifluoroborate (0.78 g, 3.90 mmol), and sodium carbonate (0.41 g, 3.90 mmol) were added to acetonitrile (6 mL), stirred at 80°C for 5 hours, concentrated under reduced pressure, and then Pd(OAc)2 (15.0 mg, 0.06 mmol), X-Phos (62.0 mg, 0.13 mmol), potassium carbonate (0.54 g, 3.90 mmol), and methyl phosphate were added. The reaction mixture was stirred at 110°C with 1.0 g, 1.30 mmol of 1,4-dioxane (20 mL) and water (5 mL). After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the mixture was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) to obtain 0.31 g of a yellow solid product in 30.8% yield. MS (ESI, positive ion) m / z: 771.3 [M+H] + .

[0691] Step 2: Synthesis of (1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-(pyrrolidine-1-ylmethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylic acid

[0692] [ka]

[0693] At room temperature, methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-(pyrrolidine-1-ylmethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (280 mg, 0.36 mmol) and lithium hydroxide monohydrate (60 mg, 1.44 mmol) were added to methanol (2.0 mL), tetrahydrofuran (1.0 mL), and water (1.0 mL), and the reaction mixture was stirred at 60°C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the solution was purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 10 / 1) to obtain 70 mg of a yellow solid product in a yield of 25.5%. MS (ESI, positive ion) m / z: 773.31 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.97 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H), 7.77 - 7.67 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.46 - 7.34 (m, 2H), 7.17 (d, J = 7.5 Hz, 1H), 6.71 (t, J = 54.5 Hz, 1H), 3.96 (s, 3H), 3.89 (s, 2H), 3.71 (s, 2H), 2.59 - 2.51 (m, 7H), 2.28 - 2.09 (m, 4H), 2.00 - 1.82 (m, 5H), 1.79 - 1.70 (m, 4H), 1.39 - 1.28 (m, 4H).

[0694] (Example 21) (1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-((4-hydroxypiperidine-1-yl)methyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylic acid

[0695] [ka]

[0696] Step 1: Synthesis of methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-(hydroxymethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0697] [ka]

[0698] In a reaction flask, methyl(1r,4r)-4-(((5-(3'-((7-bromo-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2-chloro-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate (3.00 g, 3.91 mmol), 1,4-dioxane (40.0 mL), (tributylstannyl)methanol (2.01 g, 6.26 mmol), and chloro(2-dicyclohexylphosphin-2',4',6'-tri-i-propyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (0.15 g, 0.20 mmol) were added. After purging with nitrogen, the mixture was heated to 90°C and stirred overnight. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was separated, and the solution was purified by silica gel column chromatography (eluent: DCM / MeOH(v / v)=10 / 1) to obtain 2.50 g of a yellow solid product in 89.0% yield. MS (ESI, positive ion) m / z: 718.2 [M+H] + .

[0699] Step 2: Synthesis of methyl(1r,4r)-4-(((5-(2-chloro-3'-((2-(difluoromethyl)-7-(hydroxymethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-carboxylate

[0700] [ka]

[0701] Methyl(1r,4r)-4-(((5-(2-chloro-3'-((7-(chloromethyl)-2-(difluoromethyl)pyrido[3,2-d]pyrimidine-4-yl)amino)-2'-methyl-[1,1'-biphenyl]-3-yl)-3-methoxypyrazine-2-yl)methyl)(methyl)amino)cyclohexane-1-car...

Claims

1. Compounds of formula (I) or their stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts, or prodrugs 【Chemistry 1】 (In the formula, L 1 is a combination, -NR z -, -O-, -(CH 2 ) t -, -HC=CH-, -S- or -SO 2 - Selected from; R z is H, D, -OH, C 1～6 alkyl, C 2～6 alkenyl, C 2～6 alkynyl, C 1～6 haloalkyl, C 1～6 alkoxy or C 1～6 haloalkoxy; R 1 , R 2 , R 1a and R 2a Each of these is independently H, D, F, Cl, Br, I, -NO 2 -CN, -OH, -NH 2 , C 1～6 Alkyl or C 1～6 It is a haloalkyl; Ring A is C 3～8 Cycloalkyl, heterocycle consisting of 3 to 8 atoms, C 6～10 Selected from aryls or heteroaryls consisting of 5-6 atoms; Each R 3a These are independently H, D, F, Cl, Br, I, -NO 2 -CN, -OH, -NH 2 , C 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 It is a haloalkoxy, and the C 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl and C 1～6 Alkoxy compounds are D, F, Cl, Br, I, C, independently and optionally. 1～6 Alkyl, C 2～6 Alkenil, C 2～6 Alkinyl, oxo, -NO 2 -CN, -OH, -NH 2 ,-COOCH 3 Substituted with 1, 2, 3, or 4 substituents selected from -COOH; R 4 These are H, D, F, Cl, Br, I, -NO 2 -CN, -OH, -NH 2 , C 1～6 Alkyl, C 1～6 Haloalkyl or C 3～8 It is a cycloalkyl, and the C 1～6 Alkyl and C 3～8 Cycloalkyls are independently and optionally selected as D, F, Cl, Br, I, C 1～6 Alkyl, C 1～6 Haloalkyl, oxo, -NO 2 -CN, -OH, -NH 2 ,-COOCH 3 Substituted with 1, 2, 3, or 4 substituents selected from -COOH; L 2 is a combination, -C 1～6 Alkylene- or -C 1～6 Alkilen-NR w -C 1～6 Alkylene-, and each of the above C 1～6 Alkylenes are independently and optionally selected as D, F, Cl, Br, I, oxo, -OH, C 1～6 Alkyl and C 1～6 Substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups; R w H, D, -OH, C 1～6 Alkyl, C 1～6 Haloalkyl, C 2～6 Alkenyl or C 2～6 It is an alkynyl, and the C 1～6 Alkyl, C 1～6 Haloalkyl, C 2～6 Alkenyl and C 2～6 Alkynnyls are independently and optionally selected as D, F, Cl, Br, I, oxo, -OH, C 1～6 Alkyl and C 1～6 Substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups; R 3 is -NR 5 R 6 、C 3～12 is cycloalkyl or a heterocyclic ring consisting of 3 to 12 atoms, and the C 3～12 cycloalkyl and the heterocyclic ring consisting of 3 to 12 atoms are independently and optionally D, halogen, -NO 2 、-CN、-OH、-NH 2 、oxo, C 1～6 alkyl, -C(O)CH 3 、-C(O)OH、-C 1～4 alkylene C(O)OH, -C(O)OCH 3 、-NHC(O)-C 1～4 alkyl, -NHC(O)OCH 3 、-C(O)NH 2 、-S(O) 2 CH 3 、-S(O) 2 NH 2 and -C(O)NHS(O) 2 CH 3 and is substituted with 1, 2, 3 or 4 substituents selected from; R 5 and R 6 are each independently H, D, C 1～6 alkyl, C 3～10 cycloalkyl or a heterocyclic ring consisting of 3 to 12 atoms, wherein said C 1～6 alkyl, C 3～10 cycloalkyl and the heterocyclic ring consisting of 3 to 12 atoms are independently and optionally D, F, Cl, Br, I, -NO 2 , -CN, -OH, -NH 2 , oxo, C 1～6 alkyl, C 1～6 haloalkyl, hydroxy C 1～6 alkyl, amino C 1～6 alkyl, carboxy C 1～6 alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b , -C(O)NR a R b , -S(O) 2 R a , -S(O) 2 NR a R b , -NR a S(O) 2 R b and -C(O)NR a S(O) 2 R b substituted with 1, 2, 3 or 4 substituents selected from; or R 5 and R 6 These atoms, together with the atoms to which they are bonded, form a heterocycle consisting of 3 to 12 atoms, and this heterocycle, consisting of 3 to 12 atoms, optionally contains 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, or nitrogen, and optionally contains D, F, Cl, Br, I, -NO 2 ,-CN, oxo, C 1～6 Alkyl, C 1～6 Haloalkyl, HydroxyC 1～6 Alkyl, amino C 1～6 Alkyl, CarboxyC 1～6 Alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b , -S(O) 2 R a , -S(O) 2 NR a R b , -NR a S(O) 2 R b and -C(O)NR a S(O) 2 R b Substituted with 1, 2, 3, or 4 substituents independently selected from; R a , R b , R c and R d Each of these is independently H, D, C 1～6 Alkyl, C 3～8 A cycloalkyl or heterocycle consisting of 3 to 8 atoms, and the C 1～6 Alkyl, C 3～8 Cycloalkyls and heterocycles consisting of 3 to 8 atoms are independently and optionally selected as D, F, Cl, Br, I, C 1～6 Alkyl, -NO 2 -CN, -OH, -NH 2 ,-C(O)CH 3 -C(O)OH, -C(O)OCH 3 ,-NHC(O)CH 3 ,-NHC(O)OCH 3 -C(O)NH 2 , -S(O) 2 CH 3 and -S(O) 2 NH 2 Substituted with 1, 2, 3, or 4 substituents selected from; R 7 is C 3～10 A cycloalkyl or heterocycle consisting of 3 to 12 atoms, and the C 3～10 Cycloalkyls and heterocycles consisting of 3 to 12 atoms are independently and optionally selected from D, F, Cl, Br, I, and -NO. 2 -CN, -OH, -NH 2 , oxo, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, -OR e , -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f and -C(O)NR e R f Substituted with 1, 2, 3, or 4 substituents selected from; R e and R f Each of them is H, D, C 1～6 Alkyl or C 3～8 It is a cycloalkyl, and the C 1～6 Alkyl and C 3～8 Cycloalkyls are independently and optionally selected from D, F, Cl, Br, I, oxo, and -NO. 2 -CN, -OH, -NH 2 ,-C(O)CH 3 ,-COOCH 3 Substituted with 1, 2, 3, or 4 substituents selected from -COOH; (Each of m, n, q, p, and t is independently 0, 1, 2, or 3).

2. R 1 , R 2 , R 1a and R 2a Each of these independently comprises H, D, F, Cl, Br, I, and -NO. 2 -CN, -OH, -NH 2 , C 1～4 Alkyl or C 1～4 It is a haloalkyl; Each R 3a These are independently H, D, F, Cl, Br, I, -NO 2 -CN, -OH, -NH 2 , C 1～4 Alkyl, C 2～4 Alkenil, C 2～4 Alkinyl, C 1～4 Haloalkyl, C 1～4 Alkoxy or C 1～4 It is a haloalkoxy, and the C 1～4 Alkyl, C 2～4 Alkenil, C 2～4 Alkinyl and C 1～4 Alkoxys, independently and optionally, D, F, Cl, Br, I, C 1～4 Alkyl, C 2～4 Alkenil, C 2～4 Alkinyl, oxo, -NO 2 -CN, -OH, -NH 2 ,-COOCH 3 Substituted with 1, 2, 3, or 4 substituents selected from -COOH; R 4 , H, D, F, Cl, Br, I, -NO 2 -CN, -OH, -NH 2 , C 1～4 Alkyl, C 1～4 Haloalkyl or C 3～6 It is a cycloalkyl, and the C 1～4 Alkyl and C 3～6 Cycloalkyls are independently and optionally selected as D, F, Cl, Br, I, C 1～4 Alkyl, C 1～4 Haloalkyl, oxo, -NO 2 -CN, -OH, -NH 2 ,-COOCH 3 Substituted with 1, 2, 3, or 4 substituents selected from -COOH, The compound according to claim 1.

3. R 1 , R 2 , R 1a and R 2a Each of these independently comprises H, D, F, Cl, Br, I, and -NO. 2 -CN, -OH, -NH 2 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CHF 2 ,-CHFCH 2 F, -CH 2 CF 3 ,-CH 2 Cl, -CHCl 2 ,-CH 2 CHCl 2 ,-CH 2 Br, -CHBr 2 or -CH 2 CHBr 2 and; R 3a Each of these independently comprises H, D, F, Cl, Br, I, and -NO. 2 -CN, -OH, -NH 2 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethinyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CHF 2 ,-CHFCH 2 F, -CH 2 CF 3 ,-OCH 3 ,-OCH 2 CH 3 ,-OCH 2 CH 2 CH 3 ,-OCH(CH 3 ) 2 -OCHF 2 , -OCF 3 ,-OCH 2 CHF 2 or -OCH 2 CF 3 The aforementioned methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethinyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, -OCH 3 ,-OCH 2 CH 3 ,-OCH 2 CH 2 CH 3 and -OCH(CH 3 ) 2 However, independently and at will, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, oxo, -NO 2 -CN, -OH, -NH 2 ,-COOCH 3 Substituted with 1, 2, 3, or 4 substituents selected from -COOH; R 4 , H, D, F, Cl, Br, I, -NO 2 -CN, -OH, -NH 2 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CHF 2 ,-CHFCH 2 F, -CH 2 CF 3 The compounds are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are independently and optionally D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CHF 2 ,-CHFCH 2 F, -CH 2 CF 3 , oxo, -NO 2 -CN, -OH, -NH 2 ,-COOCH 3 Substituted with 1, 2, 3, or 4 substituents selected from -COOH, The compound according to claim 1 or 2.

4. Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidyl, pyrazinyl, or pyridazinyl. The compound according to any one of claims 1 to 3.

5. R 3 However, -NR 5 R 6 , C 3～10 A cycloalkyl or heterocycle consisting of 3 to 10 atoms, and the C 3～10 Cycloalkyl groups and heterocycles consisting of 3 to 10 atoms can be independently and optionally selected as D, halogens, or -NO. 2 -CN, -OH, -NH 2 , oxo, C 1～4 Alkyl, -C(O)CH 3 -C(O)OH, -C 1～4 Alkylene C(O)OH, -C(O)OCH 3 ,-NHC(O)-C 1～4 Alkyl, -NHC(O)OCH 3 -C(O)NH 2 , -S(O) 2 CH 3 , -S(O) 2 NH 2 and -C(O)NHS(O) 2 CH 3 Substituted with 1, 2, 3, or 4 substituents selected from; R 5 and R 6 Each of these is independent of H, D, and C. 1～4 Alkyl, C 3～8 A cycloalkyl or heterocycle consisting of 3 to 10 atoms, and the C 1～4 Alkyl, C 3～8 Cycloalkyls and heterocycles consisting of 3 to 10 atoms are independently and optionally selected as D, F, Cl, Br, I, -NO 2 -CN, -OH, -NH 2 , oxo, C 1～4 Alkyl, C 1～4 Haloalkyl, HydroxyC 1～4 Alkyl, amino C 1～4 Alkyl, CarboxyC 1～4 Alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b , -S(O) 2 R a , -S(O) 2 NR a R b , -NR a S(O) 2 R b and -C(O)NR a S(O) 2 R b Substituted with 1, 2, 3, or 4 substituents selected from; or R 5 and R 6 However, together with the atoms to which they are bonded, they form a heterocycle consisting of 3 to 10 atoms, and the heterocycle consisting of 3 to 10 atoms contains, optionally, 1, 2, or 3 heteroatoms independently selected from oxygen, sulfur, or nitrogen, and optionally, D, F, Cl, Br, I, -NO 2 ,-CN, oxo, C 1～4 Alkyl, C 1～4 Haloalkyl, HydroxyC 1～4 Alkyl, amino C 1～4 Alkyl, CarboxyC 1～4 Alkyl, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b , -S(O) 2 R a , -S(O) 2 NR a R b , -NR a S(O) 2 R b and -C(O)NR a S(O) 2 R b Substituted with 1, 2, 3, or 4 substituents independently selected from; R a , R b , R c and R d Each of these is independent of H, D, and C. 1～4 Alkyl, C 3～6 A cycloalkyl or heterocycle consisting of 3 to 6 atoms, and the C 1～4 Alkyl, C 3～6 Cycloalkyl groups and heterocycles consisting of 3 to 6 atoms can be independently and arbitrarily selected as D, F, Cl, Br, I, C 1～4 Alkyl, -NO 2 -CN, -OH, -NH 2 ,-C(O)CH 3 -C(O)OH, -C(O)OCH 3 ,-NHC(O)CH 3 ,-NHC(O)OCH 3 -C(O)NH 2 , -S(O) 2 CH 3 and -S(O) 2 NH 2 Substituted with 1, 2, 3, or 4 substituents selected from: The compound according to any one of claims 1 to 4.

6. R 3 However, -NR 5 R 6 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl , 3-azabicyclo[3.1.0]hexyl, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azazspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 1,7-diazaspiro[4.4]nonyl, azetidinil, pyrrolidyl, tetrahydrofuranil, piperidinil, piperazinil, or morpholinil, and the cyclopropyl, cyclob Tyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.1 .0]hexyl, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 1,7-diazaspiro[4.4]nonyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl, and morpholinil are independently and optionally selected as D, F, Cl, Br, I, -NO 2 -CN, -OH, -NH 2 Oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -C(O)CH 3 -C(O)OH, -methyleneC(O)OH, -C(O)OCH 3 ,-NHC(O)CH 3 ,-NHC(O)OCH 3 -C(O)NH 2 , -S(O) 2 CH 3 , -S(O) 2 NH 2 and -C(O)NHS(O) 2 CH 3 Substituted with 1, 2, 3, or 4 substituents selected from; R 5 and R 6 Each of these is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl, or morpholinyl, and the methyl, ethyl I, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl, and morpholinil are independently and optionally selected as D, F, Cl, Br, I, -NO 2 -CN, -OH, -NH 2 , oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CHF 2 ,-CHFCH 2 F, -CH 2 CF 3 ,-CH 2 OH, -CH 2 CH 2 OH, -CH 2 NH 2 ,-CH 2 CH 2 NH 2 ,-CH 2 COOH, -CH 2 CH 2 COOH, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b , -S(O) 2 R a , -S(O) 2 NR a R b , -NR a S(O) 2 R b and -C(O)NR a S(O) 2 R b Substituted with 1, 2, 3, or 4 substituents selected from; or R 5 and R 6 However, together with the atoms they are bonded to, the following occurs: 【Chemistry 2】 Form a structure selected from the above, 【Transformation 3】 However, independently and by arbitrary selection, D, F, Cl, Br, I, -NO 2 -CN, oxomethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CHF 2 ,-CHFCH 2 F, -CH 2 CF 3 ,-CH 2 OH, -CH 2 CH 2 OH, -CH 2 NH 2 ,-CH 2 CH 2 NH 2 ,-CH 2 COOH, -CH 2 CH 2 COOH, -OR a , -C(O)R a , -C(O)OR a , -NR a R b , -NR c C(O)R d , -NR a C(O)OR b -C(O)NR a R b , -S(O) 2 R a , -S(O) 2 NR a R b , -NR a S(O) 2 R b and -C(O)NR a S(O) 2 R b Substituted with 1, 2, 3, or 4 substituents selected from; R a , R b , R c and R d Each of these is independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl, or morpholinyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidyl, tetrahydrofuranil, piperidinyl, piperazinyl, and morpholinyl are independently and optionally D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -NO 2 -CN, -OH, -NH 2 ,-C(O)CH 3 -C(O)OH, -C(O)OCH 3 ,-NHC(O)CH 3 ,-NHC(O)OCH 3 -C(O)NH 2 , -S(O) 2 CH 3 and -S(O) 2 NH 2 Substituted with 1, 2, 3, or 4 substituents selected from: The compound according to any one of claims 1 to 5.

7. L 2 However, the combination, -C 1～3 Alkylene- or -C 1～3 Alkilen-NR w -C 1～3 Alkylene-, and each of the above-C 1～3 Alkylenes, independently and optionally selected, include D, F, Cl, Br, I, oxo, -OH, and C. 1～4 Alkyl and C 1～4 Substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups; R w However, H, D, -OH, C 1～4 Alkyl, C 1～4 Haloalkyl, C 2～4 Alkenyl or C 2～4 It is an alkynyl, and the C 1～4 Alkyl, C 1～4 Haloalkyl, C 2～4 Alkenyl and C 2～4 Alkynyl is independently and optionally selected as D, F, Cl, Br, I, oxo, -OH, C 1～4 Alkyl and C 1～4 Substituted with 1, 2, 3, or 4 substituents selected from haloalkyl groups; R z However, H, D, -OH, C 1～4 Alkyl, C 2～4 Alkenil, C 2～4 Alkinyl, C 1～4 Haloalkyl, C 1～4 Alkoxy or C 1～4 It is a haloalkoxy; R 7 C 3～8 A cycloalkyl or heterocycle consisting of 3 to 10 atoms, and the C 3～8 Cycloalkyls and heterocycles consisting of 3 to 10 atoms are independently and optionally selected as D, F, Cl, Br, I, -NO 2 -CN, -OH, -NH 2 , oxo, C 1～4 Alkyl, C 1～4 Haloalkyl, C 1～4 Hydroxyalkyl, -OR e , -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f and -C(O)NR e R f Substituted with 1, 2, 3, or 4 substituents selected from; R e and R f Each of them is H, D, C 1～4 Alkyl or C 3～6 It is a cycloalkyl, and the C 1～4 Alkyl and C 3～6 Cycloalkyls are independently and optionally selected as D, F, Cl, Br, I, oxo, -NO 2 -CN, -OH, -NH 2 ,-C(O)CH 3 ,-COOCH 3 Substituted with 1, 2, 3, or 4 substituents selected from -COOH, The compound according to any one of claims 1 to 6.

8. L 2 However, the bonds are -methylene-, -ethylene-, -methylene-NR w -methylene-, or -ethylene-NR w -ethylene-, wherein -methylene- and -ethylene- are independently and optionally D, F, Cl, Br, I, oxo, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CHF 2 ,-CHFCH 2 F and -CH 2 CF 3 Substituted with 1, 2, 3, or 4 substituents selected from; R w However, H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CHF 2 ,-CHFCH 2 F, -CH 2 CF 3 , vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl or 3-butynyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CHF 2 ,-CH 2 CHF 2 ,-CHFCH 2 F, -CH 2 CF 3 Vinyl, propenyl, allyl, ethynyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl are independently and optionally selected as D, F, Cl, Br, I, oxo, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CHF 2 ,-CHFCH 2 F and -CH 2 CF 3 Substituted with 1, 2, 3, or 4 substituents selected from; R z However, H, D, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, propenyl, allyl, ethinyl, propargyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CHF 2 ,-CHFCH 2 F, -CH 2 CF 3 ,-OCH 3 ,-OCH 2 CH 3 ,-OCH 2 CH 2 CH 3 ,-OCH(CH 3 ) 2 -OCHF 2 , -OCF 3 ,-OCH 2 CHF 2 or -OCH 2 CF 3 and; R 7 The compounds are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranil, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, or morpholinyl, and the compounds are cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranil, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, and morpholinyl are independently and optionally selected as D, F, Cl, Br, I, -NO 2 -CN, -OH, -NH 2 , oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CHF 2 ,-CHFCH 2 F, -CH 2 CF 3 ,-CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 3 , -OR e , -C(O)R e , -C(O)OR e , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f and -C(O)NR e R f Substituted with 1, 2, 3, or 4 substituents selected from; R e and R f Each of these is H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are independently and optionally D, F, Cl, Br, I, oxo, -NO 2 -CN, -OH, -NH 2 ,-C(O)CH 3 ,-COOCH 3 Substituted with 1, 2, 3, or 4 substituents selected from -COOH, The compound according to any one of claims 1 to 7.

9. A compound according to any one of claims 1 to 8, which is a compound of formula (II) or its stereoisomer, geometric isomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug: 【Chemistry 4】 (In the formula, X is CR x or N; Y is CR y or N; R x and R y These are independently H, D, F, Cl, Br, I, -NO 2 -CN, -OH, -NH 2 , C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 (It is a haloalkoxy.)

10. R x and R y Each of these independently comprises H, D, F, Cl, Br, I, and -NO. 2 -CN, -OH, -NH 2 Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 CHF 2 ,-CHFCH 2 F, -CH 2 CF 3 ,-OCH 3 ,-OCH 2 CH 3 ,-OCH 2 CH 2 CH 3 ,-OCH(CH 3 ) 2 -OCHF 2 , -OCF 3 ,-OCH 2 CHF 2 or -OCH 2 CF 3 That is, The compound according to claim 9.

11. A compound according to any one of claims 1 to 10, which is a stereoisomer, tautomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug having one of the following structures: [Chemical 5A] 【Chem.5B】 【5C】 。

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, and combination thereof.

13. Use of a compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 in the manufacture of a pharmaceutical for treating a disease mediated by the PD-1 / PD-L1 signaling pathway.

14. The use according to claim 13, wherein the disease mediated by the PD-1 / PD-L1 signaling pathway disclosed herein is cancer, an infectious disease, or an autoimmune disease.

15. The aforementioned cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, T-cell lymphoma, B-cell lymphoma, Waldenström macroglobulinemia, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, cervical cancer, stomach cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, or bone cancer; The infectious disease is selected from HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpesvirus infection, papillomavirus infection, or influenza virus infection; The use according to claim 13, wherein the autoimmune disease is selected from chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia due to chronic atrophic gastritis, Goodpasture syndrome, primary biliary cholangitis, multiple sclerosis, acute idiopathic polyneuritis, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, or autoimmune hemolytic anemia.

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