Pyrrolidone-containing fused bicyclic compounds

Abstract

The present invention is in the field of medicinal chemistry and relates to pyrrolidone-containing fused bicyclic compounds, in particular to the compound of formula (II), its stereoisomers or pharma- ceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing said compounds, and uses in the treatment of diseases (e.g., cancer). TIFF2025508437000312.tif46170

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of the following Chinese patent applications filed with the State Intellectual Property Office of the People's Republic of China, the contents of which are incorporated herein by reference in their entireties: A Chinese patent application filed on February 23, 2022, with application number CN202210166821.7, A Chinese patent application with application number CN202211272746.9 filed on October 18, 2022; and A Chinese patent application filed on February 14, 2023, with application number CN202310115154.4. [Technical Field]

[0002] This application relates to fused bicyclic compounds containing pyrrolidones, methods for their preparation, pharmaceutical compositions containing such compounds, and uses in the treatment of diseases (e.g., cancer). [Background technology]

[0003] Hematopoietic progenitor kinase 1 (HPK1), also known as mitogen-activated protein kinase 1 (MAP4K1), is a mammalian Ste20-related serine / threonine protein kinase belonging to the microtubule-associated protein family and a member of the mitogen-activated protein kinase (MAP4K) family. This family also includes five subtypes: GCK / MAP4K2, GLK / MAP4K3, HGK / MAP4K4, KHS1 / MAP4K5, and MINK1 / MAP4K6. Unlike the other five MAP4K subtypes, which are widely expressed in tissue cells, HPK1 is exclusively expressed in hematopoietic tissue cells and mediates various cell signaling pathways, including MAPK signaling, antigen receptor signaling, and cytokine signaling, thereby regulating signal transduction in the hematopoietic system, including lymphocytes.

[0004] Studies have shown that HPK1 inhibits immune cell responses primarily through the c-Jun amino-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) signaling pathways. After T cell TCR activation, HPK1 interacts with multiple TCRs and is phosphorylated by the tyrosine kinases Lck and Zap70. Activated HPK1 further phosphorylates the T cell receptor adaptor protein SLP-76, establishing a docking site for the negative regulator 14-3-3 (14-3-3). This ultimately disrupts the stabilization of the TCR signaling complex (lato-gads-SLP76), inhibiting downstream mitogen-activated protein (MAP) kinase signaling, negatively regulating TCR signaling, and subsequently inhibiting T cell proliferation. A similar negative feedback mechanism also exists in B cells, where B cell receptor (BCR) signaling inhibits downstream signaling through HPK1-mediated phosphorylation and activation of B-cell linker protein (BLNK), suppressing B cell proliferation. In addition, HPK1 also exerts a negative feedback regulatory effect on NK cells (natural killer cells) and dendritic cells (DCs).

[0005] Currently, there are no commercially available drugs directed against the HPK1 target, and there remains a need in this field to develop compounds with selective inhibitory activity or better pharmacodynamics and pharmacokinetics. Summary of the Invention

[0006] According to one aspect, the present invention relates to a compound of formula (II) below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0007] [ka] [In the formula, X is selected from N or CH; Y is a bond, -O-, -S-, or -NR a -, -C(R a )2-, -S(O)2-, -S(O)2NR a -, -S(O)-, -S(O)NR a -, -C(O)-, -C(O)O-, -C(O)NR a -, -C(O)N(R a )O-, -OC(O)-, -OC(O)NR a -, -N(R a )C(O)O-, -N(R a )C(O)-, or -N(R a )S(O)2-, Ring A is a 3- to 10-membered heterocyclyl, C 5-10 aryl, or 5- to 10-membered heteroaryl; R 1 are each independently -NH2, -NHR d , -N(R d )2, -OH, -OR d , -CN, halogen, -COOR d , -OCOR d , -N(R d )C(O)(R d ), -CONH(R d ), -CON(R d )2, -NHSO2(R d ), -SO2NH(R d ), -SO2N(R d )2, -PO(R d )2, [ka] C 1-6 Alkyl, C 5-10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein said C 1-6 Alkyl, C 5-10 An aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl may be one or more R boptionally replaced by R d are each independently, C 1-4 Alkyl or C 3-7 cycloalkyl, R 2 is selected from a 5-6 membered monocyclic heteroaryl or a 9-14 membered saturated, partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 0-6 heteroatoms independently selected from N, O or S; 2 is one or more R c optionally replaced by R 3 are each independently a halogen, C 1-4 Alkyl or haloC 1-4 selected from alkyl, R a are each independently hydrogen or C 1-4 selected from alkyl, R b are independently deuterium, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, -CN, halogen, [ka] C 1-4 alkyl, or 3- to 6-membered heterocycloalkyl, wherein said —NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl, C 1-4 Alkyl and 3- to 6-membered heterocycloalkyl may contain one or more deuterium, halogen, or [ka] optionally substituted with substituents, R c are each independently -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, halogen, [ka] or C optionally substituted with one or more deuterium atoms 1-6 selected from alkyl, n is selected from 1, 2, 3, or 4; m is selected from 0, 1, or 2; Each X, Y, ring A, R 1 , R d , R 2 , R 3 , R a , R b , or R c are each independently optionally substituted with one or more substituents.

[0008] In another aspect, the present invention relates to a compound of formula (I) below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0009] [ka] [In the formula, X is selected from N or CH; Y is a bond, -O-, -S- or -NR a -Selected from Ring A is C 5-10 aryl, or 5- to 10-membered heteroaryl; R 1 are each independently -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, -CN, halogen, C 1-6 alkyl, or 3- to 10-membered heterocycloalkyl, wherein said C 1-6 Alkyl and 3- to 10-membered heterocycloalkyl may be one or more R b optionally replaced by R 2is selected from a 5-6 membered monocyclic heteroaryl or a 9-14 membered saturated, partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 0-6 heteroatoms independently selected from N, O or S; 2 is one or more R c optionally replaced by R a is hydrogen or C 1-4 selected from alkyl, R b are each independently -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, -CN, halogen, [ka] or 3- to 6-membered heterocycloalkyl, wherein said —NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl and 3- to 6-membered heterocycloalkyl may contain one or more deuterium, halogen, or [ka] optionally substituted with substituents, R c are each independently -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, halogen, [ka] or C optionally substituted with one or more deuterium atoms 1-6 selected from alkyl, n is selected from 1, 2, 3 or 4.

[0010] In some embodiments, the present invention relates to a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, provided that: X is selected from N or CH; Y is a bond, -O-, -S-, or -NR a -Selected from Ring A is C 5-10 aryl, or 5- to 10-membered heteroaryl; R 1 are each independently -NH2, -NHR d , -N(R d )2, -OH, -OR d , -CN, halogen, -COOR d , -OCOR d , -N(R d )C(O)(R d ), -CONH(R d ), -CON(R d )2, -NHSO2(R d ), -SO2NH(R d ), -SO2N(R d )2, -PO(R d )2, [ka] C 1-6 alkyl, 3- to 10-membered heterocyclyl, wherein 1-6 Alkyl and 3- to 10-membered heterocyclyl are each independently one or more R b optionally replaced by R d are each independently, C 1-4 Alkyl or C 3-7 cycloalkyl, R 2 is selected from a 5-6 membered monocyclic heteroaryl or a 9-14 membered saturated, partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 0-6 heteroatoms independently selected from N, O or S; 2 is one or more R c optionally replaced by R 3 is a halogen, C 1-4 Alkyl or haloC 1-4 selected from alkyl, R a is hydrogen or C 1-4 selected from alkyl, R b are independently deuterium, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, -CN, halogen, [ka] C 1-4 alkyl, or 3- to 6-membered heterocycloalkyl, wherein said —NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl, C 1-4 Alkyl and 3- to 6-membered heterocycloalkyl may contain one or more deuterium, halogen, or [ka] optionally substituted with substituents, R c are each independently -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, halogen, [ka] or C optionally substituted with one or more deuterium atoms 1-6 selected from alkyl, n is selected from 1, 2, 3, or 4; m is selected from 0, 1 or 2.

[0011] In some embodiments, Y is a bond, —O—, —S—, or —NR a -, and ring A is selected from C 5-10 aryl or 5- to 10-membered heteroaryl, R 1 are each independently -NH2, -NHR d , -N(R d )2, -OH, -OR d , -CN, halogen, -COOR d , -OCOR d, -N(R d )C(O)(R d ), -CONH(R d ), -CON(R d )2, -NHSO2(R d ), -SO2NH(R d ), -SO2N(R d )2, -PO(R d )2, [ka] C 1-6 alkyl, or 3- to 10-membered heterocycloalkyl, wherein said C 1-6 Alkyl and 3- to 10-membered heterocycloalkyl may be one or more R b optionally substituted with R 3 is a halogen, C 1-4 Alkyl or haloC 1-4 alkyl, R a is hydrogen or C 1-4 is selected from alkyl.

[0012] In some embodiments, the heteroaryl and heterocycloalkyl contain 1, 2, 3, or 4 heteroatoms selected from N, O, S, or P, with the remaining ring atoms being selected from carbon. In some embodiments, the heteroaryl and heterocycloalkyl contain 1, 2, or 3 heteroatoms selected from N, O, or S, with the remaining ring atoms being selected from carbon. In some embodiments, the heteroaryl and heterocycloalkyl contain 1, 2, or 3 heteroatoms selected from N or O, with the remaining ring atoms being selected from carbon. In some embodiments, the heteroaryl and heterocycloalkyl contain 1 or 2 heteroatoms selected from N or O, with the remaining ring atoms being selected from carbon.

[0013] In some embodiments, X is selected from CH. In some embodiments, X is selected from N. In some embodiments, R a is selected from hydrogen. In some embodiments, Y is a bond, —O—, —S—, or —NR a -Selected from. In some embodiments, Y is —NR a In some embodiments, Y is selected from -NH-. In some embodiments, ring A is C 5-10 It is selected from aryl and 5- to 10-membered heteroaryl.

[0014] In some embodiments, ring A is C 5-8 It is selected from aryl and 5- to 8-membered heteroaryl. In some embodiments, ring A is C 5-6 It is selected from aryl or 5- to 6-membered heteroaryl. In some other embodiments, ring A is selected from a 3-10 membered heterocycloalkyl, or a 5-8 membered heterocycloalkyl, or a 5-6 membered heterocycloalkyl. In some other embodiments, ring A is phenyl or a 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, or S. In some embodiments, ring A is phenyl or a 6-membered heteroaryl containing 1 or 2 N atoms.

[0015] In some other embodiments, Ring A is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, imidazolyl, or oxazolyl. In some embodiments, ring A is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl. In some other embodiments, ring A is phenyl, pyridyl, or thiazolyl. In some embodiments, ring A is phenyl or pyridyl. In some embodiments, ring A is pyridyl. In some other embodiments, ring A is thiazolyl.

[0016] In some other embodiments, R 1 are each independently -NH2, -NH(R d ), -N(R d )2, halogen, -N(R d )C(O)(R d ), -NHSO2(R d ), -SO2NH(R d ), -PO(R d )2, [ka] C 1-6 alkyl, 5- to 8-membered heteroaryl, or 3- to 10-membered heterocyclyl containing a heteroatom selected from N, O, S, or P, wherein said C 1-6 Alkyl, 5- to 8-membered heteroaryl, or 3- to 10-membered heterocyclyl containing a heteroatom selected from N, O, S, or P may be substituted with one or more R b is optionally replaced by

[0017] In some other embodiments, R 1 are each independently -NH2, -NHR d , -N(R d )2, halogen, -N(R d )C(O)(R d ), -NHSO2(R d ), -SO2NH(R d ), -PO(R d )2, [ka] C 1-6 alkyl, 3- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 5- to 10-membered heterocycloalkenyl, wherein 1-6 An alkyl, 3- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 5- to 10-membered heterocycloalkenyl may be formed by one or more R b is optionally replaced by

[0018] In some embodiments, R 1 are each independently -NH2, -NHR d , -N(R d )2, -OH, -OR d , -CN, -OH, -COOR d , -OCOR d , -N(R d )C(O)(R d ), -CONH(R d ), -CON(R d )2, -NHSO2(R d ), -SO2NH(R d ), -SO2N(R d )2, -PO(R d )2, [ka] C 1-6 alkyl or 3- to 10-membered heterocycloalkyl, wherein said C 1-6 Alkyl and 3- to 10-membered heterocycloalkyl may be one or more R b is optionally replaced by

[0019] In some embodiments, R 1 are each independently -NH2, -NH(R d ), -N(R d )2, halogen, -N(R d )C(O)(R d ), -NHSO2(R d ), -SO2NH(R d ), PO(R d )2, [ka] C 1~6 alkyl or 3- to 10-membered heterocycloalkyl, wherein said C 1~6 Alkyl and 3- to 10-membered heterocycloalkyl may be one or more R b is optionally replaced by

[0020] In some other embodiments, R1 are each independently -NH2, -NH(R d ), -N(R d )2, F, Cl, Br, -N(R d )C(O)(R d ), -NHSO2(R d ), -SO2NH(R d ), -PO(R d )2, [ka] C 1-4 alkyl, 5- to 10-membered heterocycloalkyl, or 5- to 8-membered heterocycloalkenyl, wherein 1-4 An alkyl, 5- to 10-membered heterocycloalkyl, or 5- to 8-membered heterocycloalkenyl may be selected from the group consisting of one or more R b is optionally replaced by

[0021] In some embodiments, R 1 are each independently -NH2, -NH(R d ), -N(R d )2, F, Cl, Br, -N(R d )C(O)(R d ), -NHSO2(R d ), -SO2NH(R d ), -PO(R d )2, [ka] C 1-4 alkyl or 5-10 membered heterocycloalkyl, wherein said C 1-4 Alkyl and 5- to 10-membered heterocycloalkyl may be substituted by one or more R b is optionally replaced by

[0022] In some other embodiments, R 1 are each independently -NH2, -NH(R d ), -N(R d )2, -N(R d )C(O)(R d ), -NHSO2(Rd ), -SO2NH(R d ), -PO(R d )2, [ka] C 1-3 alkyl, 5- to 9-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkenyl, wherein 1-3 An alkyl, 5- to 9-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkenyl may be formed by one or more R b is optionally replaced by

[0023] In some embodiments, R 1 are each independently -NH2, -NH(R d ), -N(R d )2, -N(R d )C(O)(R d ), -NHSO2(R d ), -SO2NH(R d ), -PO(R d )2, [ka] C 1-3 alkyl, 5- to 9-membered heterocycloalkyl, wherein 1-3 Alkyl, 5- to 9-membered heterocycloalkyl may be one or more R b is optionally replaced by

[0024] In some other embodiments, R 1 The heteroatoms in the heterocyclyl, heterocycloalkyl or heterocycloalkenyl are selected from N, O, S or P; alternatively, N, O, S.

[0025] In some other embodiments, R 1are each independently -NH2, -NHCH3, -N(CH3)2, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperidinyl, piperazinyl, tetrahydroimidazolyl, aza-oxa-bicycloheptyl, aza-oxa-spirononanyl, aza-oxa-spiroheptyl, -N(CH3)C(O)CH3, -NHSO2(CH3), -SON2NH(CH3), -PO(CH3)2, [ka] oxazolidinyl, phospha-oxa-bicyclohexyl, aza-oxa-bicyclohexyl, phospha-aza-bicyclohexyl, dihydropyridyl, furanyl, or thiazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tet-butyl, t ... azahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperidinyl, piperazinyl, tetrahydroimidazolyl, aza-oxa-bicycloheptyl, aza-oxa-spirononyl, aza-oxa-spiroheptyl, oxazolidinyl, phospha-oxa-bicyclohexyl, aza-oxa-bicyclohexyl, phospha-aza-bicyclohexyl, dihydropyridyl, furanyl, or thiazinyl is a substituted or unsubstituted aryl group consisting of one or more R b is optionally replaced by

[0026] In some embodiments, R 1are each independently -NH2, -NHCH3, -N(CH3)2, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperidinyl, piperazinyl, tetrahydroimidazolyl, aza-oxa-bicycloheptyl, aza-oxa-spirononyl, aza-oxa-spiroheptyl, -N(CH3)C(O)CH3, -NHSO2(CH3), -SO2NH(CH3), -PO(CH3)2, [ka] oxazolidinyl, phospha-oxa-bicyclohexyl, aza-oxa-bicyclohexyl or phospha-aza-bicyclohexyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperidinyl, piperazinyl, tetrahydroimidazolyl, aza-oxa-bicycloheptyl, aza-oxa-spirononyl, aza-oxa-spiroheptyl, oxazolidinyl, phospha-oxa-bicyclohexyl, aza-oxa-bicyclohexyl or phospha-aza-bicyclohexyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperidinyl, piperazinyl, tetrahydroimidazolyl, aza-oxa-bicycloheptyl, aza-oxa-spirononyl, aza-oxa-spiroheptyl, oxazolidinyl, phospha-oxa-bicyclohexyl, aza-oxa-bicyclohexyl or phospha-aza-bicyclohexyl, b is optionally replaced by

[0027] In some embodiments, R 1 are each independently -NH2, F, methyl, ethyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, tetrahydroimidazolyl, -N(CH3)COCH3, aza-oxa-bicycloheptyl, aza-oxa-spirononyl, aza-oxa-spiroheptyl, phospha-oxa-bicyclohexyl, aza-oxa-bicyclohexyl, phospha-aza-bicyclohexyl, oxazolidinyl, -NHSO2(CH3), -SO2NH(CH3), -PO(CH3)2, [ka] wherein said methyl, ethyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, tetrahydroimidazolyl, aza-oxa-bicycloheptyl, aza-oxa-spirononyl, aza-oxa-spiroheptyl, phospha-oxa-bicyclohexyl, aza-oxa-bicyclohexyl, phospha-aza-bicyclohexyl or oxazolidinyl is selected from the group consisting of one, two or three R b is optionally replaced by

[0028] In some other embodiments, R 1 are each independently -NH2, F, methyl, ethyl, [ka] wherein said methyl, ethyl, [ka] is one, two or three R b is optionally replaced by

[0029] In some embodiments, R 1 are each independently -NH2, F, methyl, ethyl, [ka] wherein said methyl, ethyl, [ka] is one, two or three R b is optionally replaced by

[0030] In some embodiments, R 1 are each independently -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, halogen, C 1-6alkyl, or 3- to 10-membered heterocycloalkyl, wherein said C 1-6 Alkyl and 3- to 10-membered heterocycloalkyl may be one or more R b is optionally replaced by

[0031] In some embodiments, R 1 are each independently -NH2, -NH(C 1-2 alkyl), -N(C 1-2 Alkyl)2, halogen, C 1-4 alkyl, or 5- to 6-membered heterocycloalkyl, wherein said C 1-4 Alkyl and 5- to 6-membered heterocycloalkyl may be substituted by one or more R b is optionally replaced by

[0032] In some embodiments, R 1 are each independently selected from -NH2, -NHCH3, -N(CH3)2, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl is selected from the group consisting of one or more R b is optionally replaced by

[0033] In some embodiments, R 1 are each independently selected from —NH, F, methyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, or morpholinyl, wherein said methyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and morpholinyl are selected from the group consisting of one or more R b is optionally replaced by

[0034] In some embodiments, R 1 are each independently selected from —NH, F, methyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, or morpholinyl, wherein said methyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and morpholinyl are selected from one, two, or three R b is optionally replaced by

[0035] In some embodiments, R 1 are each independently -NH2, F, methyl, [ka] wherein said methyl, [ka] is one, two or three R b is optionally replaced by

[0036] In some embodiments, R d are each independently, C 1-4 Alkyl or C 3-6 cycloalkyl. In some embodiments, R d are each independently, C 1-2 Alkyl or C 3-4 cycloalkyl. In some embodiments, R d are each independently, C 1-2 In some embodiments, R d are each independently, C 3-4 cycloalkyl.

[0037] In some embodiments, R b are independently deuterium, -OH, C 1-4 Alkyl, halogen, [ka] -N(C 1-4 alkyl) 2- or 3- to 6-membered heterocycloalkyl, wherein said —N(C 1-4 alkyl) 2- and 3- to 6-membered heterocycloalkyl may contain one or more deuterium, halogen, or [ka] It is optionally substituted with a substituent.

[0038] In some embodiments, R b are independently deuterium, -OH, C 1-3 Alkyl, F, Cl, Br, [ka] -N(C 1-4 alkyl) 2- or 5-membered heterocycloalkyl, wherein said —N(C 1-4 alkyl) 2- and 5-membered heterocycloalkyl may be substituted with one or more deuterium, F, Cl, Br or [ka] It is optionally substituted with a substituent.

[0039] In some embodiments, R b are each independently deuterium, -OH, CH3, F, [ka] -N(CH3)2, -N(CH3CH2)2, -N(CH3CH2CH2)2, -N(CH3)CH2CH3, -N(CH3)C(CH3)2, tetrahydrofuranyl, or tetrahydrothienyl, wherein said -N(CH3)2, -N(CH3CH2)2, -N(CH3CH2CH2)2, -N(CH3)CH2CH3, -N(CH3)C(CH3)2, tetrahydropyrrolyl, tetrahydrofuranyl, and tetrahydrothienyl are selected from the group consisting of one or more deuterium, F, Cl, Br, or [ka] It is optionally substituted with a substituent.

[0040] In some embodiments, R b are each independently deuterium, -OH, CH3, F, [ka] -N(CH3)2, -N(CH3)CH2CH3, -N(CH3)C(CH3)2, or tetrahydropyrrolyl, wherein said -N(CH3)2, tetrahydropyrrolyl, or -N(CH3)CH2CH3 is selected from one or more of deuterium, F, Cl, Br, or [ka] It is optionally substituted with a substituent.

[0041] In some embodiments, R b are each independently deuterium, -OH, CH3, F, [ka] -N(CH3)2, -N(CH3)CH2CH3, -N(CH3)C(CH3)2, or tetrahydropyrrolyl, wherein said -N(CH3)2 is optionally substituted with six deuterium atoms, and said tetrahydropyrrolyl or -N(CH3)CH2CH3 is selected from two F or one [ka] It is optionally substituted with a substituent.

[0042] In some embodiments, R b are each independently deuterium, -OH, CH3, F, [ka] -N(CH3)2, -N(CD3)2, [ka] Selected from.

[0043] In some embodiments, R b are each independently -OH, halogen, [ka] -N(C 1-4 alkyl) 2- or 3- to 6-membered heterocycloalkyl, wherein said —N(C 1-4 alkyl) 2- and 3- to 6-membered heterocycloalkyl may contain one or more deuterium, halogen, or [ka] It is optionally substituted with a substituent.

[0044] In some embodiments, R b are each independently -OH, F, Cl, Br, [ka] -N(C 1-4 alkyl) 2- or 5-membered heterocycloalkyl, wherein said —N(C 1-4 alkyl) 2- and 5-membered heterocycloalkyl optionally contain one or more deuterium, halogen, or [ka] It is optionally substituted with a substituent.

[0045] In some embodiments, R b are each independently -OH, F, [ka] -N(CH3)2, -N(CH3CH2)2, -N(CH3CH2CH2)2, tetrahydrofuranyl, or tetrahydrothienyl, wherein said -N(CH3)2, -N(CH3CH2)2, -N(CH3CH2CH2)2, tetrahydropyrrolyl, tetrahydrofuranyl, and tetrahydrothienyl are selected from the group consisting of one or more deuterium, halogen, or [ka] It is optionally substituted with a substituent.

[0046] In some embodiments, R b are each independently -OH, F, [ka] -N(CH3)2 or tetrahydropyrrolyl, wherein said -N(CH3)2 and tetrahydropyrrolyl are selected from one or more of deuterium, halogen, or [ka] It is optionally substituted with a substituent.

[0047] In some embodiments, R b are each independently -OH, F, [ka] -N(CH3)2 or tetrahydropyrrolyl, wherein said -N(CH3)2 is optionally substituted with three deuterium atoms, and said tetrahydropyrrolyl is selected from two F or one [ka] is optionally replaced by

[0048] In some embodiments, R b are each independently -OH, F, [ka] -N(CH3)2, -N(CD3)2, [ka] Selected from.

[0049] In some embodiments, R 1 are each independently -NH2, F, [ka] Selected from.

[0050] In some embodiments, R 1 are each independently -NH2, F, [ka] Selected from.

[0051] In some embodiments, R 1 are each independently -NH2, F, [ka] Selected from.

[0052] In some embodiments, n is selected from 1, 2, or 3. In some embodiments, n is selected from 2. In some embodiments, m is selected from 0, 1, or 2. In some embodiments, m is selected from 0 or 1. In some embodiments, m is selected from 0.

[0053] In some embodiments, R 3 is a halogen, C 1-3 Alkyl or haloC 1-3 is selected from alkyl. In some embodiments, R 3 is F, Cl, Br or C 1-3is selected from alkyl. In some embodiments, R 3 is selected from F or methyl.

[0054] In some other embodiments, one, two, or three of the three rings are aromatic rings. In some embodiments, one or two of the three rings are aromatic rings.

[0055] In some embodiments, the tricycle of formula (I) [ka] The single ring attached to the moiety is an aromatic ring.

[0056] In some embodiments, the tricycle of formula (I) [ka] or of formula (II) [ka] The single ring attached to the moiety is an aromatic ring.

[0057] In some embodiments, the tricycle of formula (I) [ka] or of formula (II) [ka] The single ring attached to the moiety is an aromatic ring containing a N atom.

[0058] In some embodiments, any two adjacent rings of the tricycle are optionally fused, bridged, or spiro rings. In some embodiments, the tricycle of formula (I) [ka] The single ring attached to the moiety and its adjacent ring are fused rings.

[0059] In some embodiments, the tricycle of formula (I) [ka] or of formula (II) [ka] The single ring attached to the moiety and its adjacent ring are fused rings.

[0060] In some embodiments, R 2 is selected from a 6-membered monocyclic heteroaryl or a 9-14 membered saturated, partially saturated, or aromatic tricyclic ring, wherein said tricyclic ring contains 0-6 heteroatoms independently selected from N, O, or S; and said R 2 is one or more R c is optionally replaced by

[0061] In some embodiments, R 2 is selected from a 9-14 membered saturated, partially saturated, or aromatic tricycle, wherein said tricycle contains 0-6 heteroatoms independently selected from N, O, or S; 2 is one or more R c is optionally replaced by

[0062] In some embodiments, R 2 is selected from a 6-membered monocyclic heteroaryl containing 1 or 2 N atoms, or a 9-14 membered saturated, partially saturated, or aromatic tricyclic ring, wherein said tricyclic ring contains 1 to 6 heteroatoms independently selected from N, O, or S; and 2 is one or more R c is optionally replaced by

[0063] In some embodiments, R 2is selected from a 9-14 membered saturated, partially saturated, or aromatic tricycle, wherein said tricycle contains 1-6 heteroatoms independently selected from N, O, or S; 2 is one or more R c is optionally replaced by

[0064] In some other embodiments, R 2 The heteroatoms in the three rings described in are selected from N or O.

[0065] In some other embodiments, R 2 The heteroatoms in the three rings described in are selected from N.

[0066] In some embodiments, R 2 is selected from a 6-membered monocyclic heteroaryl containing 1 or 2 N atoms, or a 9-14 membered saturated, partially saturated, or aromatic tricyclic ring, wherein said tricyclic ring contains 1 to 6 heteroatoms independently selected from N or O; R 2 is one or more R c In some embodiments, R 2 is selected from a 9-14 membered saturated, partially saturated, or aromatic tricycle, wherein said tricycle contains 1-6 heteroatoms independently selected from N or O, and said R 2 is one or more R c is optionally replaced by

[0067] In some embodiments, R 2 is selected from a 6-membered monocyclic heteroaryl containing 1 or 2 N atoms, or a 9-14 membered partially saturated tricyclic ring, wherein said tricyclic ring contains 1 to 6 heteroatoms independently selected from N or O, and said R 2 is one or more R c is optionally replaced by

[0068] In some embodiments, R 2is selected from 9-14 membered partially saturated or aromatic tricycles, wherein said tricycles contain 1-6 heteroatoms independently selected from N or O, and said R 2 is one or more R c is optionally replaced by

[0069] In some embodiments, R 2 is selected from a 6-membered monocyclic heteroaryl containing one N atom, or a 9-14 membered partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 1-6 heteroatoms independently selected from N or O, and said R 2 is one or more R c is optionally replaced by

[0070] In some embodiments, R 2 is selected from a 6-membered monocyclic heteroaryl containing one N atom, or a 9-, 11-, 12-, 13-, or 14-membered partially saturated tricyclic ring, wherein said tricyclic ring contains 1 to 6 heteroatoms independently selected from N or O, and said R 2 is one or more R c is optionally replaced by

[0071] In some embodiments, R 2 is selected from a 9-, 10-, 11-, 12-, 13-, or 14-membered partially saturated or aromatic tricycle, wherein said tricycle contains 1 to 4 heteroatoms independently selected from N or O; 2 is one or more R c is optionally replaced by

[0072] In some embodiments, R 2 is selected from 9-, 11-, 12-, 13-, and 14-membered partially saturated or aromatic tricycles, wherein said tricycles contain 1 to 4 heteroatoms independently selected from N or O, and said R 2 is one or more R c is optionally replaced by

[0073] In some other embodiments, R 2The heteroatoms in the three rings described in are selected from N, O or S.

[0074] In some other embodiments, R 2 The heteroatoms in the tricycles described in are selected from N or S.

[0075] In some other embodiments, R 2 is selected from a 6-membered monocyclic heteroaryl containing 1 or 2 N atoms, or a 9-14 membered saturated, partially saturated, or aromatic tricyclic ring, wherein said tricyclic ring contains 1 to 6 heteroatoms independently selected from S; 2 is one or more R c is optionally replaced by

[0076] In some other embodiments, R 2 is selected from a 6-membered monocyclic heteroaryl containing 1 or 2 N atoms, or a 9-14 membered partially saturated tricyclic ring, wherein said tricyclic ring contains 1 to 6 heteroatoms independently selected from S, and said R 2 is one or more R c is optionally replaced by

[0077] In some other embodiments, R 2 is selected from 9-14 membered partially saturated or aromatic tricycles, wherein said tricycles contain 1-6 heteroatoms independently selected from S; 2 is one or more R c is optionally replaced by

[0078] In some other embodiments, R 2 is selected from a 6-membered monocyclic heteroaryl containing one N atom, or a 9-14 membered partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 1-6 heteroatoms independently selected from S; 2 is one or more R c is optionally replaced by

[0079] In some other embodiments, R 2is selected from a 6-membered monocyclic heteroaryl containing one N atom, or a 9-, 11-, 12-, 13-, or 14-membered partially saturated tricyclic ring, wherein said tricyclic ring contains 1 to 6 heteroatoms independently selected from S; 2 is one or more R c is optionally replaced by

[0080] In some other embodiments, R 2 is selected from a 9-, 10-, 11-, 12-, 13-, or 14-membered partially saturated or aromatic tricycle, wherein said tricycle contains 1 to 4 heteroatoms independently selected from S; 2 is one or more R c is optionally replaced by

[0081] In some other embodiments, R 2 teeth [ka] wherein R 2 is one or more R c is optionally replaced by

[0082] In some embodiments, R 2 teeth [ka] wherein R 2 is one or more R c is optionally replaced by

[0083] In some other embodiments, R 2 teeth [ka] wherein R 2 is one or more R c is optionally replaced by

[0084] In some embodiments, R 2 teeth [ka] wherein R 2 is one or more R c is optionally replaced by

[0085] In some other embodiments, R 2 teeth [ka] Selected from.

[0086] In some embodiments, R 2 teeth [ka] Selected from.

[0087] In some embodiments, R 2 teeth [ka] wherein R 2 is one or more R c is optionally replaced by

[0088] In some embodiments, R 2 teeth [ka] wherein R 2 is one or more R c is optionally replaced by

[0089] In some embodiments, R 2 teeth [ka] wherein R 2 is one or more R c is replaced by

[0090] In some embodiments, R c are each independently, [ka] or C optionally substituted with one or more deuterium atoms 1-6 is selected from alkyl.

[0091] In some embodiments, R c are each independently, [ka] or C optionally substituted with one or more deuterium atoms 1-4 is selected from alkyl.

[0092] In some embodiments, R c are each independently, [ka] or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl optionally substituted with one or more deuterium atoms.

[0093] In some embodiments, R c are each independently, [ka] or methyl optionally substituted with one or more deuterium atoms.

[0094] In some embodiments, R c are each independently, [ka] or methyl or -CD3.

[0095] In some embodiments, R 2 teeth [ka] Selected from.

[0096] In some embodiments, the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to the present invention are selected from the compound of formula (Ia), formula (Ib), formula (Ic), or formula (Id), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0097] [ka] In the formula, X, ring A, R 1 , R 2 and n is as described herein.

[0098] In some embodiments, the present invention includes the above-defined variables and embodiments thereof, and any combination thereof.

[0099] [1] On the other hand, the present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X is selected from N or CH; Y is a bond, -O-, -S- or -NR a -Selected from Ring A is C 5-10 aryl, or 5- to 10-membered heteroaryl; R 1 are each independently -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, -CN, halogen, C 1-6 alkyl, or 3- to 10-membered heterocycloalkyl, wherein said C 1-6 Alkyl and 3- to 10-membered heterocycloalkyl may be one or more Rb optionally replaced by R 2 is selected from a 5-6 membered monocyclic heteroaryl or a 9-14 membered saturated, partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 0-6 heteroatoms independently selected from N, O or S; 2 is one or more R c optionally replaced by R a is hydrogen or C 1-4 selected from alkyl, R b are each independently -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, -CN, halogen, [ka] or 3- to 6-membered heterocycloalkyl, wherein said —NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OC 1-4 Alkyl and 3- to 6-membered heterocycloalkyl may contain one or more deuterium, halogen, or [ka] optionally substituted with substituents, R c are each independently -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, halogen, [ka] or C optionally substituted with one or more deuterium atoms 1-6 selected from alkyl, n is selected from 1, 2, 3 or 4.

[0100] [2] In some embodiments, the compound of formula (I) according to the above item [1], its stereoisomer, or its pharmaceutically acceptable salt is provided, wherein X is selected from CH, or X is selected from N.

[0101] [3] In some embodiments, R a is selected from hydrogen, a compound of formula (I) according to the above item [1] or [2], a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0102] [4] In some embodiments, Y is -NR a -, or Y is selected from -NH-, or a compound of formula (I) according to any one of items [1] to [3], its stereoisomer, or its pharmaceutically acceptable salt.

[0103] [5] In some embodiments, ring A is C 5-8 aryl or 5- to 8-membered heteroaryl, or ring A is C 5-6 The present invention provides a compound of formula (I) according to any one of items [1] to [4], a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from aryl or 5- to 6-membered heteroaryl, or ring A is phenyl or 6-membered heteroaryl containing 1 or 2 N atoms, or ring A is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, or ring A is phenyl or pyridyl.

[0104] [6] In some embodiments, R 1 are each independently -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, halogen, C 1-6 alkyl, or 3- to 10-membered heterocycloalkyl, wherein said C 1-6 Alkyl and 3- to 10-membered heterocycloalkyl may be one or more R b optionally substituted with, or R 1 are each independently -NH2, -NH(C 1-2alkyl), -N(C 1-2 Alkyl)2, halogen, C 1-4 alkyl, or 5- to 6-membered heterocycloalkyl, wherein said C 1-4 Alkyl and 5- to 6-membered heterocycloalkyl may be substituted by one or more R b optionally substituted with, or R 1 are each independently selected from -NH2, -NHCH3, -N(CH3)2, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl is selected from the group consisting of one or more R b optionally substituted with, or R 1 are each independently selected from —NH, F, methyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and morpholinyl, wherein said methyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and morpholinyl are selected from one or more R b optionally substituted with, or R 1 are each independently -NH2, F, methyl, [ka] wherein said methyl, [ka] is one, two or three R b optionally substituted with, or R 1 are each independently -NH2, F, [ka] The present invention provides a compound of formula (I) according to any one of the above items [1] to [5], a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the following:

[0105] [7] In some embodiments, there is provided a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of the above items [1] to [6], wherein n is selected from 1, 2, or 3, or n is selected from 2.

[0106] [8] In some embodiments, R b are each independently -OH, halogen, [ka] -N(C 1-4 alkyl) 2- or 3- to 6-membered heterocycloalkyl, wherein said —N(C 1-4 alkyl) 2- and 3- to 6-membered heterocycloalkyl may contain one or more deuterium, halogen, or [ka] optionally substituted with a substituent, or R b are each independently -OH, F, Cl, Br, [ka] -N(C 1-4 alkyl) 2- or 5-membered heterocycloalkyl, wherein said —N(C 1-4 alkyl) 2- and 5-membered heterocycloalkyl may be substituted with one or more deuterium, halogen, or [ka] optionally substituted with a substituent, or R b are each independently -OH, F, [ka] -N(CH3)2, -N(CH3CH2)2, -N(CH3CH2CH2)2, tetrahydropyrrolyl, tetrahydrofuranyl, or tetrahydrothienyl, wherein said -N(CH3)2, -N(CH3CH2)2, -N(CH3CH2CH2)2, tetrahydropyrrolyl, tetrahydrofuranyl, and tetrahydrothienyl are selected from the group consisting of one or more deuterium, halogen, or [ka] Substituted by a substituent or R b are each independently -OH, F, [ka] -N(CH3)2 or tetrahydropyrrolyl, wherein said -N(CH3)2 and tetrahydropyrrolyl are selected from one or more of deuterium, halogen, or [ka] Substituted by a substituent or R b are each independently -OH, F, [ka] -N(CH3)2, -N(CD3)2, [ka] The present invention provides a compound of formula (I) according to any one of the above items [1] to [7], a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the following:

[0107] [9] In some embodiments, one or two of the three rings are aromatic rings, or one of the three rings of formula (I) [ka] the single ring attached to the moiety is an aromatic ring, or any two adjacent rings of said tricycle are optionally fused, bridged, or spiro rings, or the tricycle of formula (I) [ka] The present invention provides a compound of formula (I) according to any one of items [1] to [8], a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the single ring bound to the moiety and the adjacent ring are fused rings.

[0108]

[10] In some embodiments, R 2 is selected from a 6-membered monocyclic heteroaryl or a 9-14 membered saturated, partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 0-6 heteroatoms independently selected from N, O or S; 2 is one or more R c optionally substituted with, or R 2 is selected from a 6-membered monocyclic heteroaryl containing 1 or 2 N atoms, or a 9-14 membered saturated, partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 1 to 6 heteroatoms independently selected from N, O or S, and said R 2 is one or more R c optionally substituted with, or R 2 is selected from a 6-membered monocyclic heteroaryl containing 1 or 2 N atoms, or a 9-14 membered saturated, partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 1 to 6 heteroatoms independently selected from N or O, and said R 2 is one or more R c optionally substituted with, or R 2 is selected from a 6-membered monocyclic heteroaryl containing 1 or 2 N atoms, or a 9-14 membered partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 1 to 6 heteroatoms independently selected from N or O, and said R 2 is one or more R c optionally substituted with, or R 2 teeth, [ka] wherein R 2 is one or more R c optionally substituted with, or R 2 teeth [ka] wherein R 2 is one or more R c optionally substituted with, or R 2 teeth [ka] The present invention provides a compound of formula (I) according to any one of the above items [1] to [9], a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the following:

[0109]

[11] In some embodiments, R c are each independently, [ka] or C optionally substituted with one or more deuterium atoms 1-6 alkyl, or R c are each independently, [ka] or C optionally substituted with one or more deuterium atoms 1-4 alkyl, or R c are each independently, [ka] or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl optionally substituted with one or more deuterium atoms; or R c are each independently, [ka] or methyl optionally substituted with one or more deuterium atoms, or R c are each independently, [ka] The present invention provides a compound of formula (I) according to any one of the above items [1] to

[10] , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from -methyl or -CD3.

[0110]

[12] In some embodiments, the compound is selected from the group consisting of a compound of formula (Ia), formula (Ib), formula (Ic), or formula (Id), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] In the formula, X, ring A, R 1 , R 2 and n are as defined in any one of items [1] to [2] or items [5] to

[11] . The present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of items [1] to

[10] .

[0111] Any of the embodiments of the compounds of the present invention as described above, and the specific X, Y, ring A, R in the compounds of the present disclosure as described above. 1 , R 2 , R 3 It should be understood that any particular substituent described herein with respect to the substituents of X, Y, ring A, R can be independently combined with the substituents of several other embodiments and / or compounds according to the invention to form embodiments of the invention not specifically described above. Furthermore, in specific embodiments and / or claims, any particular X, Y, ring A, R 1 , R 2 , R 3 When a range of substituents is disclosed for a substituent, if one or more substituents are deleted from that range, the remaining range of substituents should also be considered an embodiment of the present invention.

[0112] In some embodiments, the heteroatoms of the heterocycloalkenyl, heterocycloalkyl, heterocyclyl, or heteroaryl are selected from N, O, S, or P; alternatively, the number of heteroatoms is selected from 1, 2, 3, 4, or 5; alternatively, the number of heteroatoms is selected from 1, 2, 3, or 4; alternatively, the number of heteroatoms is selected from 1, 2, or 3; alternatively, the number of heteroatoms is selected from 1 or 2.

[0113] In some embodiments, the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to the present invention are selected from the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0114] [ka] TIFF2025508437000113.tif221170TIFF2025508437000114.tif228170TIFF2025508437000115.tif224170TIFF2025508437000116.tif22317 0TIFF2025508437000117.tif210170TIFF2025508437000118.tif203170TIFF2025508437000119.tif230170TIFF2025508437000120.tif82170

[0115] In another aspect, the present invention provides a pharmaceutical composition comprising the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.

[0116] According to another aspect, the present invention provides a method for treating a disease associated with HPK1 kinase in a mammal, comprising administering to a mammal, preferably a human, in need of treatment a therapeutically effective amount of the above-described compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0117] In another aspect, the present invention provides use of the above-mentioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for treating a disease associated with HPK1 kinase.

[0118] In another aspect, the present invention provides use of the above compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of a disease associated with HPK1 kinase.

[0119] In another aspect, the present invention provides the above compound, its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating a disease associated with HPK1 kinase.

[0120] In some embodiments, the disease associated with HPK1 kinase is selected from cancer. Preferably, the cancer is selected from solid tumors, leukemia, lymphoma, and the like.

[0121] The compounds according to the present invention have at least one of improved or excellent HPK1 kinase inhibitory activity and Jurkat cell p-SLP76 phosphorylation inhibitory activity, improved or excellent in vivo efficacy, and favorable in vivo and in vitro pharmacokinetic properties, such as metabolic stability in mouse and human liver microsomes.

[0122] [Definition] Unless otherwise specified, the following terms and phrases used herein have the following meanings. Unless otherwise defined, a particular term is not intended to be indefinite or ambiguous and should be understood to have its general meaning in the art. When a trade name is mentioned herein, it refers to the corresponding product or its active ingredient.

[0123] The term "substituted" refers to the replacement of any one or more hydrogen atoms at a specified atom with a substituent, provided that the electronic valence state of the specified atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =0), this refers to the replacement of two hydrogen atoms with oxo, and the oxo does not occur on an aromatic group.

[0124] The "substituents" described herein include all substituents mentioned in the context of the present specification, such as "halogen", "deuterium", [ka] "-NH2", "-NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, -OH, -OC 1-4 alkyl", "-CN", "C 1-4Some non-limiting examples of said "substituents" include mercapto, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkylene, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkylene, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocycloalkylthio, acyl, acyloxy, carbame Examples of the substituent include oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH, -C(O)NH-alkyl, -C(O)N(alkyl), -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl , -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0125] In some embodiments herein, the substituents are selected from the group consisting of deuterium, tritium, hydroxy, mercapto, halogen, amino, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide, carboxy, aldehyde, imine, C 1-12 Alkyl, Halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 Alkenyl, Halo-C 2-12 Alkenyl, 3- to 12-membered cycloalkenyl, halo-3- to 12-membered cycloalkenyl, C 2-12 Alkynyl, Halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, 6- to 10-membered aryl, 6- to 10-membered aryloxy, 6- to 10-membered arylthio, 6- to 10-membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 Alkylthio, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy, 5- to 10-membered heteroarylthio, 5- to 10-membered heteroarylalkylene, 5- to 10-membered heteroarylalkoxy, 5- to 10-membered heteroarylalkylthio, 3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyloxy, 3- to 12-membered heterocyclylthio, 3- to 12-membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclylC 1-12 Alkoxy, 3-12 membered heterocyclylC 1-12 Alkylthio, C 1-12 Achill, C 1-12 Acyloxy, Carbamate, C 1-12 Amide, ureido, epoxy, C 2-12 ester and oxo, wherein the substituents are selected from oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12Alkynyl, C 1-12 Alkoxy, HaloC 1-12 Alkoxy, C 1-12 Alkylamino, DiC 1-12 Alkylamino, HaloC 1-12 Alkylamino, Halodi C 1-12 Alkylamino, carboxy, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)N(C 1-12 alkyl) 2, 3- to 12-membered cycloalkyl, 3- to 12-membered cycloalkylC 1-12 Alkylene, 3- to 12-membered cycloalkyloxy, 3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclylC 1-12 Alkylene, 3- to 12-membered heterocyclyloxy, 3- to 12-membered heterocycloalkyl, 3- to 12-membered heterocycloalkylC 1-12 Alkylene, 3- to 12-membered heterocycloalkyloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylC 1-12 Alkylene, 5- to 10-membered heteroaryloxy, 6- to 10-membered aryl, 6- to 10-membered arylC 1-12 It is optionally substituted with one or more substituents selected from alkylene or 6- to 10-membered aryloxy.

[0126] The term "optionally" or "optionally / as needed" means that the following circumstances or situations may or may not occur, and the description includes both cases where the circumstances or situations occur and cases where they do not occur. For example, "optionally" ethyl substituted with a halogen means that the ethyl may be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It should be understood by those skilled in the art that any group containing one or more substituents does not introduce any spatially impossible and / or synthetically impossible substitutions or substitution modes.

[0127] C as described herein m-n means that the moiety has an integer number of carbon atoms within a given range. For example, "C 1-6 " indicates that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms. For example, "C 1-3 " indicates that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0128] As used herein, "one or more" refers to an integer between 1 and 10. For example, "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; alternatively, "one or more" means 1, 2, 3, 4, 5, or 6; alternatively, "one or more" refers to 1, 2, or 3.

[0129] When any variable (e.g., R) occurs more than one time in any composition or structure of a compound, its definition on each occurrence is independent. So, for example, when a group is substituted with two R, each R is an independent option.

[0130] When a bond of a substituent crosses two atoms in a ring, the substituent can be linked to any atom in the ring. For example, [ka] indicates that the cyclohexyl group may be substituted at any position in the cyclohexadiene group.

[0131] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine. The term "hydroxy" refers to the group --OH. The term "amino" refers to the group --NH.sub.2. The term "nitro" refers to the group --NO.sub.2. The term "cyano" refers to the group --CN.

[0132] The term "alkyl" refers to a group of the general formula C n H 2n+1 The alkyl may be linear or branched. For example, the term "C 1-6 "Alkyl" refers to an alkyl containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portions (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definition as above.

[0133] The term "alkoxy" refers to --O-alkyl. The term "monocyclic" refers to a cyclic group containing one ring, which may be fully saturated, partially saturated, or aromatic. Said monocyclic ring may be composed entirely of C atoms and may contain one or more heteroatoms, for example selected from N, O, S, or P.

[0134] The term "bicycle" refers to a cyclic group containing two rings that may be fully saturated, partially saturated, or aromatic. The bicycle may be composed entirely of C atoms or may contain one or more heteroatoms, e.g., selected from N, O, S, or P. The bicycle may be fused, bridged, or spiro.

[0135] The term "tricyclic" refers to a cyclic group containing three rings, which may be fully saturated, partially saturated, or aromatic. The three rings may all be composed of C atoms or may contain one or more heteroatoms, e.g., selected from N, O, S, or P. Any two adjacent monocyclic rings of the three rings may be fused, bridged, or spirocyclic.

[0136] The term "cycloalkyl" refers to a fully saturated carbocyclic ring. Unless otherwise specified, the carbocyclic ring is typically 3 to 10-membered. Unless otherwise specified, the cycloalkyl may be monocyclic, bicyclic, or tricyclic. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

[0137] The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, fused, or spirocyclic ring. Unless otherwise specified, the heterocyclic ring is generally a 3- to 20-, 3- to 15-, 3- to 12-, or 3- to 10-membered ring (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered), 4- to 8-, 5- to 8-, or 5- to 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron. Non-limiting examples of heterocyclyl include, but are not limited to, ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, and the like.

[0138] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged, or spirocyclic ring. Unless otherwise specified, the carbocyclic ring is generally a 4- to 16-membered, 4- to 12-membered, 4- to 10-membered, or 4- to 8-membered ring (specifically, for example, a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, or 11-membered ring). Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptaenyl, cycloheptadienyl, and the like.

[0139] The term "monocycloalkyl" refers to a cycloalkyl present as a single ring.

[0140] The term "spirocycle" refers to a fully saturated or partially unsaturated polycyclic ring system that shares one carbon atom (called a spiroatom) between monocyclic rings, and includes carbocyclic and heterocyclic rings. Unless otherwise specified, the spirocycle has 5 to 20 ring members, preferably 6 to 14 ring members, and more preferably 9 to 14 ring members. When the spirocycle is a heterocycle, one or more ring atoms in the polycyclic ring may be N, O, S(O), or HCl. n , P(O) n wherein n is 0, 1, or 2, and the remaining ring atoms are carbon atoms.

[0141] The term "spirocycloalkyl" refers to a fully saturated polycyclic ring that shares one carbon atom (called a spiro atom) between monocyclic rings. Unless otherwise specified, spirocycloalkyls are 5 to 20-membered, preferably 6 to 14-membered, and more preferably 9 to 14-membered. Depending on the number of spiro atoms shared between the rings, spirocycloalkyls are divided into monospirocycloalkyls, bisspirocycloalkyls, or polyspirocycloalkyls, with monospirocycloalkyls and bisspirocycloalkyls being preferred, and 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyls being more preferred. Non-limiting examples of spirocycloalkyls include: [ka] Includes:

[0142] The term "spiroheterocycloalkyl" means a fully saturated polycyclic ring that shares one carbon atom (called a spiroatom) between monocyclic rings, and one or more ring atoms in the polycyclic ring are not N, O, S(O), n , P(O) n(where n is 0, 1, or 2), and the remaining ring atoms are carbon atoms. Unless otherwise specified, spiroheterocycloalkyls are 5 to 20-membered, preferably 6 to 14-membered, and more preferably 6 to 10-membered. Depending on the number of spiro atoms shared between the rings, spiroheterocycloalkyls are divided into monospiroheterocycles, bisspiroheterocycles, or polyspiroheterocycles, preferably monospiroheterocycles or bisspiroheterocycles, and more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocycles. Non-limiting examples of spiroheterocycloalkyls include: [ka] etc. are included.

[0143] The term "bridge" refers to a fully saturated or partially unsaturated polycyclic ring system in which two rings share three or more atoms, including carbocyclic and heterocyclic rings. Unless otherwise specified, the bridge has 5 to 14 ring members, preferably 6 to 14 ring members, and more preferably 6 to 10 ring members. Depending on the number of rings, the bridge is divided into bicyclic, tricyclic, tetracyclic or polycyclic rings, preferably bicyclic or tricyclic, more preferably bicyclic. If the bridge is heterocyclic, one or more ring atoms in the polycyclic ring may be N, O, S(O), or N-(O-)-. n , P(O) n wherein n is 0, 1, or 2, and the remaining ring atoms are carbon atoms.

[0144] The term "bridged alkyl" refers to a fully saturated all-carbon polycyclic ring in which two rings share three or more atoms. Unless otherwise specified, bridged alkyls are 5 to 14-membered, preferably 6 to 14-membered, and more preferably 6 to 10-membered. Depending on the number of rings, they are divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridges, preferably bicyclic or tricyclic, and more preferably bicyclic. Non-limiting examples of bridged alkyls include: [ka] etc. are included.

[0145] The term "bridged heterocycloalkyl" refers to a fully saturated polycyclic ring in which two rings share three or more atoms and one or more ring atoms is N, O, S(O), or n , P(O) n (where n is 0, 1, or 2), with the remaining ring atoms being carbon atoms. Unless otherwise specified, the bridged heterocycloalkyl has 5 to 14 ring members, preferably 6 to 14 ring members, and more preferably 6 to 10 ring members. Depending on the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridges, preferably bicyclic or tricyclic, and more preferably bicyclic. Non-limiting examples of bridged heterocycloalkyls include: [ka] etc. are included.

[0146] The term "heterocycloalkyl" refers to a fully saturated cyclic group containing heteroatoms. Unless otherwise specified, heterocycloalkyl generally refers to N, O, S(O) n , P(O) n(where n is 0, 1, or 2), and preferably a ring containing 1 to 3 heteroatoms, independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 40, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 119, 120, 121, 122, 123, 124, 125, 130, 131, 132, 140, 141, 142, 143, 144, Examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl. Examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Preferred are monocyclic heterocycloalkyls having 5 or 6 ring atoms.

[0147] The term "heterocycloalkenyl" includes cycloalkenyl in which one or more carbon atoms are replaced with a heteroatom, specifically, for example, cycloalkenyl in which three or fewer carbon atoms, two or fewer carbon atoms, and in one embodiment, one carbon atom are each independently replaced with N, O, or S(O), provided that at least one cycloalkenyl carbon-carbon double bond is retained. A heterocycloalkenyl may be a cyclic group existing as a single ring, a bridged ring, or a spiro ring, and may be a 3- to 16-membered ring (e.g., a 3- to 12-membered ring, a 5- to 8-membered ring, specifically, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, or an 11-membered ring). Examples of heterocycloalkenyl include, but are not limited to, dihydropyridyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazepine, or azaspiro-cyclooctene. The term "monoheterocycloalkyl" refers to a heterocycloalkyl existing as a single ring.

[0148] The term "fused ring" refers to a polycyclic compound formed by the parallel bonding of two or more shared carbon or heterocyclic rings, including fully saturated, partially saturated, and aromatic rings. Unless otherwise specified, the fused ring has 5 to 20 members, preferably 6 to 14 members, and more preferably 9 to 14 members. Non-limiting examples of the fused ring include naphthalene, anthracene, phenanthrene, [ka] These include, but are not limited to:

[0149] As described herein, [ka] For example, "the three rings of formula (I) [ka] The "monocyclic ring" in "the monocyclic ring bonded to the moiety is an aromatic ring" means a tricyclic ring. [ka] It also refers to pyridyl in [ka] For example, "the three rings of formula (I) [ka] The "monocyclic ring" in "the monocyclic ring bonded to the moiety is an aromatic ring" means a tricyclic ring. [ka] This refers to 1,2,4-triazolyl.

[0150] As described herein, [ka] For example, the above-mentioned "tricyclic ring of formula (I) [ka] The phrase "the monocyclic ring bonded to the moiety and the adjacent ring are fused rings" means a tricyclic ring. [ka] In the formula, pyridyl and pyrrolyl are fused together [ka] It also refers to the formation of [ka] For example, the above-mentioned "tricyclic ring of formula (I) [ka] The phrase "the monocyclic ring bonded to the moiety and the adjacent ring are fused rings" means a tricyclic ring. [ka] In the formula, pyridyl and tetrahydropyrrolyl are fused together [ka] It refers to the formation of

[0151] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. Unless otherwise specified, an aryl may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthryl, and 1,2,3,4-tetrahydronaphthalene.

[0152] The term "heteroaryl" refers to any group including N, O, S(O) n , P(O) n (where n is 0, 1, or 2), with the remaining ring atoms being C, and at least one aromatic ring. Unless otherwise specified, the heteroaryl may be a monocyclic, bicyclic, or tricyclic ring system. Unless otherwise specified, the heteroaryl may have a single 5- to 8-membered ring or multiple fused rings having 6 to 14, and more particularly 6 to 10, ring atoms. Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.

[0153] The term "treatment" means administering a compound or formulation described herein to alleviate or eliminate a disease or one or more symptoms associated with said disease, and includes the following: (i) inhibiting a disease or disease state, i.e., inhibiting its onset or progression; (ii) Alleviating the disease or disease state, i.e., causing the disease or disease state to diminish.

[0154] The term "therapeutically effective amount" refers to an amount of a compound of the present invention administered that (i) treats a specific disease, condition, or disorder described herein, (ii) reduces, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder described herein, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the administration form, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on their own knowledge and the disclosure of the present invention.

[0155] The term "pharmaceutically acceptable" applies to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0156] Pharmaceutically acceptable salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with alkaline or acidic amino acids, and the like.

[0157] The term "pharmaceutical composition" refers to a mixture of one or more compounds according to the invention or salts thereof with pharmaceutically acceptable adjuvants. Pharmaceutical compositions are intended for the advantageous administration of the compounds according to the invention to an organism.

[0158] The term "pharmaceutically acceptable adjuvant" refers to an adjuvant that does not have a significant irritating effect on the living body and does not impair the biological activity or performance of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0159] The term "comprise" and its English variants (e.g., "comprises" and "comprising") are to be interpreted in an open-ended, inclusive sense, i.e., "including, but not limited to."

[0160] Unless otherwise specified, singular terms include plural terms and plural terms include the singular term. Unless otherwise specified, the terms "a" or "one" refer to "at least one" or "at least one." Unless otherwise specified, the use of "or" refers to "and / or."

[0161] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All compounds contemplated by the present invention include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomer- or diastereomer-enriched mixtures. All of these are within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and mixtures thereof are within the scope of the present invention.

[0162] Unless otherwise specified, "(D)" or "(+)" means right-handed, "(L)" or "(-)" means left-handed, and "(DL)" or "(±)" refers to racemic.

[0163] Unless otherwise specified, the absolute configuration of one stereocenter is represented by a solid wedge bond. [ka] and wedge-shaped dashed line bond [ka] The relative configuration of the stereocenters is represented by a straight solid bond. [ka] and straight dashed bond [ka] It is expressed as:

[0164] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared by chiral synthesis or chiral reagents, or other conventional techniques. If a single enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and cleavage of the auxiliary to provide the desired pure enantiomer. Alternatively, if the molecule contains alkaline (e.g., amino) or acidic (e.g., carboxyl) functions, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by separation and subsequent recovery of the diastereomers by conventional methods well known in the art. Separation of enantiomers and diastereomers is typically accomplished by chromatography, employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., carbamate formation with amines).

[0165] The present invention also includes isotope-labeled compounds of the present invention that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 123I, 125 I, and 36 Cl etc.

[0166] Some isotopically labeled compounds according to the present invention (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. 15 O. 13 N, 11 C and 18 Positron-emitting isotopes such as F are useful in positron emission tomography (PET) studies to examine substrate occupancy. Isotopically labeled compounds of the present invention can generally be prepared following procedures analogous to those disclosed in the following schemes and / or examples, by substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0167] Additionally, heavy isotopes (e.g., deuterium, i.e. 2 Substitution with a methyl group (e.g., H or D) may be preferred in some circumstances due to certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), where deuteration can be partial or full, where partial deuteration means that at least one hydrogen is replaced with at least one deuterium, and full deuteration means that all hydrogens in the group are replaced with deuterium, e.g., methyl (-CH3) is fully replaced with deuterium, i.e., -CD3.

[0168] The compounds according to the present invention may also exist in their tautomeric forms, and all such forms are included within the scope of protection of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogen atoms.

[0169] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable auxiliaries.

[0170] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, include, but are not limited to, oral administration, topical administration, inhalation administration, parenteral administration, intranasal administration, intraocular administration, intramuscular administration, subcutaneous administration, and intravenous administration.

[0171] The pharmaceutical compositions of the present invention can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, lyophilizing, and the like.

[0172] In all methods of administration of the compounds of Formula II described herein, the daily dosage ranges from 0.001 to 2000 mg / kg body weight in single or multiple doses.

[0173] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments described below and in combination with other chemical synthetic methods, as well as equivalents well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0174] The chemical reactions of specific embodiments of the present invention are accomplished in suitable solvents, which must be compatible with the chemical transformations of the present invention and the desired reagents and materials. Those skilled in the art may need to modify or select synthetic procedures or reaction schemes based on existing embodiments to obtain compounds of the present invention.

[0175] One of the important considerations in planning any synthetic route in the art is the selection of appropriate protecting groups for reactive functionalities (such as amino in the present invention); see, for example, Greene's Protective Groups in Organic Synthesis (4th Ed.). Hoboken, New Jersey: John Wiley & Sons, Inc., all references incorporated herein in their entirety.

[0176] In some embodiments, compounds of formula II according to the present invention can be prepared by one skilled in the art of organic synthesis via the following schemes.

[0177] Scheme 1: [ka] Scheme 2: [ka] where Z is halogen, OH, NH2 or NH(C 1-6 alkyl), and R e is selected from groups such as halogen, NH, boronic acid or boronic ester. f is selected from groups such as halogen, boronic acid or boronic ester.

[0178] However, rings A and R 1 , X, Y, R 2 , R 3 , m, and n are as defined herein.

[0179] For purposes of illustration and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely for their disclosure prior to the filing date of the present invention. All statements as to the date of any such document or representation of the contents of any such document are based on the information available to applicant and do not constitute any admission as to the accuracy of the dates of any such document or the contents of any such document. Furthermore, the reference to any such publication herein does not constitute an admission that such publication has become part of the general knowledge in the art in any country or region.

[0180] Specific compounds according to the present invention are listed in the table below, and said specific compounds can be prepared by the process according to the present invention.

[0181] [ka] TIFF2025508437000149.tif215170TIFF2025508437000150.tif224170TIFF2025508 437000151.tif220170TIFF2025508437000152.tif211170TIFF2025508437000153.t if235170TIFF2025508437000154.tif227170TIFF2025508437000155.tif232170TIF F2025508437000156.tif223170TIFF2025508437000157.tif226170TIFF20255084370 00158.tif227170TIFF2025508437000159.tif230170TIFF2025508437000160.tif21 8170TIFF2025508437000161.tif218170TIFF2025508437000162.tif231170TIFF202 5508437000163.tif235170TIFF2025508437000164.tif230170TIFF20255084370001 65.tif229170TIFF2025508437000166.tif231170TIFF2025508437000167.tif164170

[0182] The following abbreviations are used in this specification: DMSO represents dimethyl sulfoxide, THF represents tetrahydrofuran, NCS represents N-chlorosuccinimide, NBS represents N-bromosuccinimide, CCl4 represents carbon tetrachloride, DMF represents N,N-dimethylformamide, HOVEYDA-GRUBBS represents (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidene)dichloro(o-isopropoxyphenylenemethyl)ruthenium, Boc represents t-butoxycarbonyl, Ms represents methanesulfonyl, Ts represents p-toluenesulfonyl, and Cbz represents benzyloxycarbonyl. DETAILED DESCRIPTION OF THE INVENTION

[0183] For clarity, the present invention is further illustrated by the following examples, which are not intended to limit the scope of the present invention. Various modifications and improvements to the specific embodiments of the present invention will be apparent to those skilled in the art without departing from the spirit and scope of the present invention. All reagents used in the present invention are commercially available and can be used without the need for further purification.

[0184] The compounds of the present invention can be obtained by similar preparation methods to those in the examples, including, but not limited to, structurally similar starting materials, reagents, or adjustment of process parameters. 1 The structural information can be obtained by H NMR. The compounds according to the present invention can also be tested by similar efficacy testing methods.

[0185] Intermediate Production Intermediate Example 1: Preparation of Intermediate 1A [ka]

[0186] Step A: Preparation of Intermediate 1A-1 The compound methyl 6-amino-3-bromopicolinate (100 g), N,N-dimethylpyridin-4-amine (10.6 g), di-t-butyl dicarbonate (170 g), and tetrahydrofuran (600 mL) were sequentially added to a reaction flask. After addition, the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was quenched by adding 10% aqueous citric acid solution (200 mL, w / w). The mixture was extracted with dichloromethane, washed with saturated brine, dried, and concentrated to obtain Intermediate 1A-1 (1201.1 g). MS (ESI, [M+H] + ) m / z: 331.1.

[0187] Step B: Preparation of Intermediate 1A-2 Intermediate 1A-1 (85 g), tetrahydrofuran (300 mL), and lithium borohydride (6.2 g) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature while reacting. After the reaction was completed, the reaction mixture was quenched by adding saturated ammonium chloride solution, extracted with dichloromethane, washed with saturated brine, dried, and concentrated to obtain Intermediate 1A-2 (60.0 g). MS (ESI, [M+H] + ) m / z: 303.1.

[0188] Step C: Preparation of Intermediate 1A-3 To a reaction flask, intermediate 1A-2 (54.2 g), N,N-diisopropylethylamine, dichloromethane (200 mL), and methanesulfonic anhydride (78 g) were sequentially added. After the addition, the mixture was reacted at −15° C. with stirring. After the reaction was completed, the reaction mixture did not need to be treated and was used directly in the next step.

[0189] Step D: Preparation of Intermediate 1A-4 Dimethylamine tetrahydrofuran solution (446 mL, 2 M), dichloromethane (200 mL), and the intermediate 1A-3 reaction solution were sequentially added to a reaction flask and allowed to react at room temperature with stirring. After the reaction was completed, the mixture was extracted with dichloromethane, washed with saturated brine, dried, and concentrated. Intermediate 1A-4 (38.2 g) was obtained by column chromatography (dichloromethane / methanol = 5 / 1). MS (ESI, [M+H] + ) m / z: 330.1.

[0190] Step E: Preparation of Intermediate 1A-5 Intermediate 1A-4 (38.2 g), potassium carbonate (36.0 g), tetra(triphenylphosphine)palladium (15.0 g), 3,6-dihydro-2H-pyran-4-boronic acid pinacol (23.7 g), water (80 mL), and dioxane (400 mL) were sequentially added to a reaction flask. After the addition, the atmosphere was purged with nitrogen and the reaction was carried out with stirring at 100 °C. After the reaction was completed, the mixture was filtered and concentrated. Intermediate 1A-5 (24.5 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 334.0.

[0191] Step F: Preparation of Intermediates 1A-6 To a reaction flask, intermediate 1A-5 (24.5 g), 10 wt% palladium hydroxide on carbon (24.5 g), and methanol (100 mL) were added in that order. After the addition, the mixture was stirred at 35°C in a hydrogen atmosphere to react. After the reaction was completed, the mixture was filtered and concentrated to obtain intermediate 1A-6 (22.0 g). MS (ESI, [M+H] + ) m / z: 336.0.

[0192] Step G: Preparation of Intermediate 1A-7 Intermediate 1A-6 (22.0 g) and a 1,4-dioxane solution of hydrochloric acid (164 mL, 4 M) were sequentially added to a reaction flask. After the addition, the mixture was allowed to react at room temperature with stirring. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 10) by adding saturated sodium bicarbonate solution, extracted with dichloromethane, and concentrated to obtain Intermediate 1A-7 (13.0 g). MS (ESI, [M+H] + ) m / z: 236.3.

[0193] Step H: Preparation of Intermediate 1A-8 The compound 5-bromo-2-chloro-3-methylpyridine-4-carboxylic acid (50.0 g), potassium carbonate (54.2 g), iodomethane (14.0 mL), and N,N-dimethylformamide (500 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature. After the reaction was completed, water (1000 mL) was added to the reaction mixture, which was then extracted with ethyl acetate and concentrated to obtain intermediate 1A-8 (41.2 g). MS (ESI, [M+H] + ) m / z: 264.2.

[0194] Step I: Preparation of Intermediates 1A-9 Intermediate 1A-8 (41.2 g), N-bromosuccinimide (42.0 g), dibenzoylmethane peroxide (0.6 g), and 1,2-dichloroethane (500 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at 90°C to react. After the reaction was completed, the reaction mixture was quenched by adding saturated sodium sulfite solution (100 mL), extracted with dichloromethane, washed with saturated brine, dried, and concentrated to obtain Intermediate 1A-9 (54.5 g). 1 H NMR (500MHz, CDCl3) δ 8.51(s,1H), 4.53(s,2H), 4.05(s,3H).

[0195] Step J: Preparation of Intermediates 1A-10 Intermediates 1A-9 (54.5 g), a methanol solution of ammonia (60 mL, 7 M), and methanol (500 mL) were added sequentially to a reaction flask. After the addition, the mixture was reacted at 75°C with stirring. After the reaction was completed, the reaction solution was filtered and dried to obtain Intermediates 1A-10 (29.2 g). 1 H NMR (500MHz, DMSO-d6) δ 9.30 (s, 1H), 8.67 (d,J=2.7Hz, 1H), 4.41 (s, 2H).

[0196] Step K: Preparation of Intermediates 1A-11 Intermediate 1A-10 (29.2 g), N,N-dimethylpyridin-4-amine (1.5 g), di-t-butyl dicarbonate (28.0 g), and dioxane (200 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature while reacting. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain Intermediate 1A-11 (35.3 g). 1 H NMR (500MHz, DMSO-d6) δ 8.75(s,1H), 4.73(s,2H), 1.54(s,9H).

[0197] Step L: Preparation of Intermediate 1A Intermediates 1A-7 (1.2 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (244.6 mg), tris(dibenzylideneacetone)dipalladium (258.3 mg), cesium carbonate (1.8 g), Intermediates 1A-11 (1.1 g), and 1,4-dioxane (100 mL) were sequentially added to a reaction flask, and the atmosphere was replaced with nitrogen. The reaction was carried out with stirring at 100°C. After completion of the reaction, the mixture was filtered and concentrated to obtain the crude product. Intermediate 1A (1.2 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 502.3.

[0198] Intermediate Example 2: Preparation of Intermediate 2A [ka] Step A: Preparation of Intermediate 2A-1 Intermediate 1A-2 (112.2 g), dichloromethane (450 mL), N,N-diisopropylethylamine (162.0 mL), and methanesulfonic anhydride (162.0 g) were sequentially added to a reaction flask. After addition, the mixture was stirred at -15°C while reacting. After the reaction was complete, 3,3-difluoropyrrolidine (118.5 g) was added to the reaction solution in several portions, and the mixture was stirred at room temperature while reacting. After the reaction was complete, the mixture was extracted with dichloromethane, washed with saturated brine, dried, and concentrated. Intermediate 2A-1 (95.0 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 392.3.

[0199] Step B: Preparation of Intermediate 2A-2 Intermediate 2A-1 (30.0 g), potassium carbonate (31.5 g), tetra(triphenylphosphine)palladium (10.5 g), pinacol 2,5-dihydrofuran-3-boronic acid (19.5 g), water (100 mL), and dioxane (500 mL) were sequentially added to a reaction flask. After the addition, the atmosphere was purged with nitrogen and the reaction was carried out with stirring at 100°C. After the reaction was completed, the mixture was filtered and concentrated. Intermediate 2A-2 (23.2 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 382.5.

[0200] Step C: Preparation of Intermediate 2A-3 To a reaction flask, intermediate 2A-2 (15.0 g), 10 wt% palladium hydroxide on carbon (15.0 g), and methanol (225 mL) were sequentially added. After the addition, the mixture was stirred at 35°C in a hydrogen atmosphere to react. After the reaction was completed, the mixture was filtered and concentrated to obtain intermediate 2A-3 (14.5 g). MS (ESI, [M+H] + ) m / z: 384.8.

[0201] Step D: Preparation of Intermediates 2A-4 Intermediate 2A-3 (14.5 g) and a 1,4-dioxane solution of hydrochloric acid (122.4 mL, 4 M) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature while reacting. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 10) by adding saturated sodium bicarbonate solution, extracted with dichloromethane, and concentrated to obtain intermediate 2A-4 (7.5 g). MS (ESI, [M+H] + ) m / z: 284.1.

[0202] Step E: Preparation of Intermediate 2A Intermediate 2A-4 (1.0 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (244.6 mg), tris(dibenzylideneacetone)dipalladium (258.3 mg), cesium carbonate (1.8 g), Intermediate 1A-11 (1.1 g), and 1,4-dioxane (100 mL) were sequentially added to a reaction flask, and the atmosphere was replaced with nitrogen. The reaction was carried out at 100°C with stirring. After completion of the reaction, the mixture was filtered and concentrated to obtain the crude product. Intermediate 2A (1.0 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 550.3.

[0203] Intermediate Example 3: Preparation of Intermediate 3A [ka] Step A: Preparation of Intermediate 3A-1 At -10°C, 7-amino-4-chloroisoindol-1-one (10 g) and 48% hydrogen bromide in methanol (90 mL, w / w) were sequentially added to a reaction flask. After the addition, an aqueous solution of sodium nitrite (7.6 g, 65 mL) was slowly added dropwise to the reaction solution. After the addition, the reaction was allowed to proceed with stirring for 1 hour. A 48% aqueous solution of hydrogen bromide (8.6 g, 90 mL) of cuprous bromide was slowly added dropwise to the reaction solution. After the addition, the reaction was allowed to proceed with stirring at 80°C. After the reaction was completed, the reaction solution was poured into ice water, thoroughly stirred, and filtered. The filter cake was washed and dried to obtain Intermediate 3A-1 (8.5 g). MS (ESI, [M+H]+ ) m / z: 245.9.

[0204] Step B: Preparation of Intermediate 3A-2 Intermediate 3A-1 (8.5 g), tetrahydrofuran (150 mL), 4-dimethylaminopyridine (1.0 g), and di-t-butyl dicarbonate (11.2 g) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was quenched by adding 10% aqueous citric acid solution (200 mL, w / w), extracted with dichloromethane, washed with saturated brine, dried, and concentrated to obtain Intermediate 3A-2 (9.6 g). MS (ESI, [M+H] + ) m / z: 345.9.

[0205] Step C: Preparation of Intermediate 3A-3 Intermediate 3A-2 (2.5 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (612 mg), tris(dibenzylideneacetone)dipalladium (645.3 mg), cesium carbonate (5.8 g), Intermediate 2A-4 (4.6 g), and 1,4-dioxane (100 mL) were sequentially added to a reaction flask, and the atmosphere was replaced with nitrogen. The mixture was stirred at 100°C. After completion of the reaction, the mixture was filtered and concentrated to obtain a crude product. Intermediate 3A-3 (4.2 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 549.3.

[0206] Step D: Preparation of Intermediate 3A Intermediate 3A-3 (2.0 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (573.0 mg), bis(pinacolato)diboron (1.9 g), potassium carbonate (1.0 g), and 1,4-dioxane (60 mL) were sequentially added to a microwave tube, followed by nitrogen substitution and microwave reaction at 90 °C. After completion of the reaction, the mixture was filtered and concentrated. Intermediate 3A (2.4 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 641.5.

[0207] Intermediate Example 4: Preparation of Intermediate 4A [ka] Step A: Preparation of Intermediate 4A-1 Intermediate 1A-4 (25.2 g), potassium carbonate (31.5 g), tetra(triphenylphosphine)palladium (10.5 g), pinacol 2,5-dihydrofuran-3-boronic acid (19.6 g), water (100 mL), and 1,4-dioxane (500 mL) were sequentially added to a reaction flask. After the addition, the atmosphere was purged with nitrogen and the reaction was carried out with stirring at 100 °C. After the reaction was completed, the mixture was filtered and concentrated. Intermediate 4A-1 (20.8 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 320.5.

[0208] Step B: Preparation of Intermediate 4A-2 Intermediate 4A-1 (15.0 g), 10 wt% palladium hydroxide on carbon (15.0 g), and methanol (225 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at 35°C in a hydrogen atmosphere to react. After the reaction was completed, the mixture was filtered and concentrated to obtain Intermediate 4A-2 (14.8 g). MS (ESI, [M+H] + ) m / z: 322.8.

[0209] Step C: Preparation of Intermediate 4A-3 Intermediate 4A-2 (14.8 g) and a 1,4-dioxane solution of hydrochloric acid (122.4 mL, 4 M) were added sequentially to a reaction flask. After the addition, the reaction was allowed to proceed with stirring at room temperature. After the reaction was completed, the mixture was adjusted to an alkaline pH (approximately 10) by adding saturated sodium bicarbonate solution, extracted with dichloromethane, and concentrated to obtain intermediate 4A-3 (8.2 g). MS (ESI, [M+H] + ) m / z: 222.1.

[0210] Step D: Preparation of Intermediate 4A-4 Intermediate 3A-2 (2.5 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (612 mg), tris(dibenzylideneacetone)dipalladium (645.3 mg), cesium carbonate (5.8 g), Intermediate 4A-3 (3.6 g), and 1,4-dioxane (100 mL) were sequentially added to a reaction flask, followed by nitrogen substitution and stirring at 100°C. After completion of the reaction, the mixture was filtered and concentrated to obtain the crude product. Column chromatography (dichloromethane / methanol = 20 / 1) afforded Intermediate 4A-4 (4.0 g). MS (ESI, [M+H] + ) m / z: 487.4.

[0211] Step E: Preparation of Intermediate 4A Intermediate 4A-4 (2.0 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (585.0 mg), bis(pinacolato)diboron (2.1 g), potassium carbonate (1.2 g), and 1,4-dioxane (60 mL) were sequentially added to a microwave tube, purged with nitrogen, and then reacted in a microwave at 90 °C. After completion of the reaction, the mixture was filtered and concentrated. Intermediate 4A (2.6 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 579.5.

[0212] Intermediate Example 5: Preparation of Intermediate 5A [ka] Step A: Preparation of Intermediate 5A-1 Intermediate 3A-2 (2.5 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (612 mg), tris(dibenzylideneacetone)dipalladium (645.3 mg), cesium carbonate (5.8 g), Intermediate 1A-7 (3.8 g), and 1,4-dioxane (100 mL) were sequentially added to a reaction flask, and the atmosphere was replaced with nitrogen. The mixture was stirred at 100°C. After completion of the reaction, the mixture was filtered and concentrated to obtain the crude product. Intermediate 5A-1 (4.4 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 501.3.

[0213] Step B: Preparation of Intermediate 5A Intermediate 5A-1 (2.1 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (585.0 mg), bis(pinacolato)diboron (2.1 g), potassium carbonate (1.2 g), and 1,4-dioxane (60 mL) were sequentially added to a microwave tube, followed by nitrogen substitution and microwave reaction at 90 °C. After completion of the reaction, the mixture was filtered and concentrated. Intermediate 5A (2.8 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 593.3.

[0214] Intermediate Example 6: Preparation of Intermediate 6A [ka] Step A: Preparation of Intermediate 6A-1 The compound 5-chlorofuran[3,2-B]pyridine (9.5 g), toluene (150.0 mL), benzophenone imine (13.5 g), sodium t-butoxide (11.9 g), tris(dibenzylideneacetone) (2.8 g), and 1,1-binaphthyl-2,2-bisdiphenylphosphine (1.9 g) were sequentially added to a reaction flask. After addition, the mixture was stirred at 100 °C to react. After completion of the reaction, the reaction solution was extracted with dichloromethane, and the organic phase was washed with saturated brine, dried, and concentrated. Intermediate 6A-1 (15.2 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 299.12.

[0215] Step B: Preparation of Intermediate 6A-2 Intermediate 6A-1 (15.2 g), dichloromethane (20.0 mL), and a 1,4-dioxane solution of hydrochloric acid (4 M, 191.0 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at 100°C to react. After the reaction was completed, the reaction solution was filtered and concentrated. Intermediate 6A-2 (5.1 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 135.2.

[0216] Step C: Preparation of Intermediate 6A-3 To a reaction flask, intermediate 6A-2 (5.1 g), bromoacetaldehyde diethyl acetal (36.7 g), methanol (10.0 mL), and hydrochloric acid (3 M, 12.2 mL) were sequentially added. After the addition, the mixture was stirred at 35°C to react. After the reaction was completed, the reaction solution was filtered and concentrated, and intermediate 6A-3 (5.3 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 159.1.

[0217] Step D: Preparation of Intermediate 6A Intermediate 6A-3 (5.3 g), dimethyl sulfoxide (30.0 mL), 2,5-dibromo-4,4-dimethylcyclopentane-1,3-dione (3.8 g), and sodium carbonate (2.8 g) were sequentially added to a reaction flask. After the addition, the mixture was protected with nitrogen and stirred at room temperature. After the reaction was completed, the reaction mixture was extracted with water and dichloromethane. The organic phase was separated, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain intermediate 6A-4 (4.3 g). MS (ESI, [M+H] + ) m / z: 237.4.

[0218] Intermediate Example 7: Preparation of Intermediate 7A [ka] Step A: Preparation of Intermediate 7A-1 The compound 4-chlorofuranylpyridine (10 g), acetic acid (130 mL), and zinc powder (10.0 g) were added sequentially to a reaction flask, and the mixture was stirred at 100° C. After the reaction was completed, the reaction mixture was adjusted to alkaline (pH approximately 10) by adding saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was separated, washed, dried, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain intermediate 7A-1 (5.2 g). MS (ESI, [M+H] + ) m / z: 120.0.

[0219] Step B: Preparation of Intermediate 7A-2 Intermediate 7A-1 (5 g), acetonitrile (50.0 mL), and 2,4-dinitrophenylhydroxyamine (8.5 g) were added sequentially to a reaction flask, and the mixture was reacted with stirring at 40° C. After completion of the reaction, the reaction solution was filtered, washed, and the residue was dried to obtain Intermediate 7A-2 (9.8 g), which was used directly in the next reaction.

[0220] Step C: Preparation of Intermediate 7A-3 Intermediate 7A-2 (5 g), potassium carbonate (3 g), ethyl propionate (3.2 g), and N,N-dimethylformamide (60 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give Intermediate 7A-3 (3.4 g). MS (ESI, [M+H] + ) m / z: 231.0.

[0221] Step D: Preparation of Intermediate 7A-4 Intermediate 7A-3 (3.4 g), lithium hydroxide monohydrate (6 g), methanol (60 mL), and water (6 mL) were sequentially added to a reaction flask, and the mixture was stirred at 60° C. After completion of the reaction, the reaction mixture was acidified (pH approximately 5) with 1 M dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain intermediate 7A-4 (2.9 g). MS (ESI, [M+H] + ) m / z: 203.2.

[0222] Step E: Preparation of Intermediate 7A Intermediate 7A-4 (2.9 g), N-bromosuccinimide (2.56 g), sodium bicarbonate (3.6 g), and N,N-dimethylformamide (40 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. After the reaction was completed, the reaction mixture was extracted with water and ethyl acetate, and the organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain Intermediate 7A (3.08 g). MS (ESI, [M+H] + ) m / z: 237.0.

[0223] Intermediate Example 8: Preparation of Intermediate 8A [ka] Step A: Preparation of Intermediate 8A-1 4-Methoxybenzylamine (10.00 g), 3,6-dihydro-2H-pyran-4-boronic acid pinacol (6.60 g), potassium carbonate (20.15 g), chloroacetonitrile (6.05 g), and acetonitrile (100 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at 60°C. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 8A-1 (10.72 g). MS (ESI, [M+H] + ) m / z: 177.1.

[0224] Step B: Preparation of Intermediate 8A-2 Intermediate 8A-1 (10.00 g), a dioxane solution of hydrochloric acid (4 M, 20 mL), and dichloromethane (100 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction solution was filtered and dried to obtain Intermediate 8A-2 (11.53 g). MS (ESI, [M+H] + ) m / z: 177.1.

[0225] Step C: Preparation of Intermediate 8A-3 Intermediate 8A-2 (10.00 g), chlorobenzene (75 mL), and oxalyl chloride (17.90 g) were added sequentially to a flask at 0°C. After the addition, the mixture was allowed to react at room temperature for 0.5 hours. Triethylamine hydrochloride (32.40 g) was then added to the reaction mixture, and the mixture was allowed to react with stirring at room temperature. After the reaction was completed, the reaction mixture was concentrated and extracted with water and dichloromethane. The organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain Intermediate 8A-3 (10.60 g). MS (ESI, [M+H] + ) m / z: 285.2.

[0226] Step D: Preparation of Intermediate 8A-4 Intermediate 8A-3 (8.4 g), cuprous iodide (0.56 g), palladium bistriphenylphosphine dichloride (2.07 g), trimethylsilylacetylene (5.50 g), triethylamine (24 mL), and N,N-dimethylformamide (24 mL) were sequentially added to a reaction flask, and the atmosphere was replaced with nitrogen, followed by stirring at 80° C. After completion of the reaction, the reaction mixture was quenched by adding saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain Intermediate 8A-4 (9.10 g). MS (ESI, [M+H] + ) m / z: 347.1.

[0227] Step E: Preparation of Intermediate 8A-5 Intermediate 8A-4 (9.10 g), dichloromethane (150 mL), silver trifluoromethanesulfonate (0.40 g), and trifluoroacetic acid (9.75 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature while reacting. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain Intermediate 8A-5 (4.26 g). MS (ESI, [M+H] + ) m / z: 227.4.

[0228] Step F: Preparation of Intermediate 8A-6 Intermediate 8A-5 (1.42 g), tetrahydrofuran (25 mL), and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 7.52 mL) were added sequentially to a reaction flask at −78° C. After the addition, the mixture was stirred at −78° C. The reaction was allowed to proceed. After the reaction was completed, the reaction mixture was quenched by adding saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain intermediate 8A-6 (0.89 g). MS (ESI, [M+H] + ) m / z: 155.1.

[0229] Step G: Preparation of Intermediate 8A-7 Intermediate 8A-6 (0.57 g), benzophenone imine (0.80 g), sodium t-butoxide (0.71 g), tris(dibenzylideneacetone)dipalladium (0.17 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.11 g), and 1,4-dioxane (30 mL) were sequentially added to a reaction flask, followed by nitrogen substitution and stirring at 80 °C. After completion of the reaction, the reaction mixture was filtered and concentrated. Intermediate 8A-7 (0.46 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 300.1.

[0230] Step H: Preparation of Intermediate 8A-8 Intermediate 8A-7 (0.46 g), a dioxane solution of hydrochloric acid (4 M, 5.76 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give Intermediate 8A-8 (0.17 g). MS (ESI, [M+H] + ) m / z: 136.0.

[0231] Step I: Preparation of Intermediate 8A-9 Bromoacetaldehyde diethyl acetal (2.47 g), methanol (2 mL), and hydrochloric acid (3 M, 4 mL) were added sequentially to a reaction flask. After the addition, the mixture was allowed to react at 80°C for 1 hour. The pH of the reaction mixture was then adjusted to 8 by adding saturated sodium bicarbonate solution, and then intermediate 8A-8 (0.11 g) was added to the reaction mixture, which was then allowed to react with stirring at room temperature. After the reaction was completed, the reaction mixture was concentrated and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to obtain intermediate 8A-9 (0.12 g). MS (ESI, [M+H] + ) m / z: 160.2.

[0232] Step J: Preparation of Intermediate 8A Dibromobenzene (108 mg), dimethyl sulfoxide (2 mL), sodium carbonate (160 mg), and intermediate 8A-9 (120 mg) were sequentially added to a reaction flask. After the addition, the mixture was stirred at 60°C and reacted. After the reaction was completed, the reaction mixture was extracted with water and dichloromethane, and the organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain intermediate 8A (178 mg). MS (ESI, [M+H] + ) m / z: 238.0.

[0233] Intermediate Example 9: Preparation of Intermediate 9A [ka] Step A: Preparation of Intermediate 9A-1 Pyrazole (10.0 g), 60 wt% sodium hydride (11 g), and N,N-dimethylformamide (120 mL) were added to a reaction flask, and 1,1-bis-bromomethylcyclopropane (10.0 g) was gradually added at 0°C, followed by reaction at room temperature. After completion of the reaction, the reaction mixture was adjusted to neutral (pH approximately 7) with 1 M diluted hydrochloric acid, extracted with ethyl acetate, and the organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain intermediate 9A-1 (8.6 g). MS (ESI, [M+H] + ) m / z: 215.1.

[0234] Step B: Preparation of Intermediate 9A-2 A tetrahydrofuran solution of lithium diisopropylamide (2 M, 41 mL) was slowly added dropwise to a reaction flask containing intermediate 9A-1 (8.6 g) and tetrahydrofuran (100 mL) at -78°C, and the mixture was then allowed to react at room temperature. After completion of the reaction, the reaction was quenched, and ethyl acetate was added for extraction. The organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain intermediate 9A-2 (2.6 g). MS (ESI, [M+H] + ) m / z: 135.1.

[0235] Step C: Preparation of Intermediate 9A In an ice-water bath, intermediate 9A-2 (2.6 g), N-bromosuccinimide (4 g), and dichloromethane (40 mL) were added to a reaction flask, and the mixture was allowed to react at room temperature. After completion of the reaction, the reaction was quenched, and ethyl acetate was added for extraction. The organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain intermediate 9A (2.5 g). MS (ESI, [M+H] + ) m / z: 213.1.

[0236] Example 1: Preparation of Compound I-1 [ka]

[0237] Step A: Preparation of Compound 1a Compound 4-bromo-2-fluoropyridine (23.3 g), acetonitrile (300 mL), N,N-diisopropylethylamine (70 mL), and methylhydrazine sulfate (19 g) were sequentially added to a reaction flask. After the addition, the mixture was stirred at 90°C and reacted. After the reaction was completed, the reaction solution was concentrated, and the residue was dissolved in ethyl acetate, washed with water, dried, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 1a (12.09 g). MS (ESI, [M+H] + ) m / z: 201.8. 1 H NMR (500MHz, CDCl3) δ 7.93(d,J=5.4Hz, 1H), 7.22(d,J=1.4Hz, 1H), 6.72(dd,J=5.4, 1.6Hz, 1H), 3.98(s, 2H), 3.27(s, 3H).

[0238] Step B: Preparation of Compound 1b Compound 1a (6.28 g), cyclopentanone (3.02 mL), and methanol (20 mL) were added sequentially to a reaction flask, and the mixture was reacted with stirring at 60° C. After completion of the reaction, the reaction solution was directly concentrated to obtain compound 1b (6.34 g). MS (ESI, [M+H] + ) m / z: 268.3.

[0239] Step C: Preparation of Compound 1c Compound 1b (3 g) and diethylene glycol (18 mL) were added sequentially to a 35 mL microwave tube and stirred in a microwave at 245° C. for 0.5 hours. After completion of the reaction, the reaction solution was poured into water and filtered to obtain compound 1c (1.5 g). MS (ESI, [M+H] + ) m / z: 251.1. 1 H NMR(500MHz,CDCl3)δ 7.95(d,J=5.2Hz,1H),7.15(d,J=5.2Hz,1H),3.76(s,3H),3.11~3.02(m,2H),2.95~2.84(m,2H),2.49(dt,J=10.2,7.1Hz,2H).

[0240] Step D: Preparation of Compound 1d Compound 1c (0.075 g), intermediate 3A (0.200 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.012 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.020 g), potassium phosphate tripotassium (0.212 g), 1,4-dioxane (5 mL), and water (1 mL) were sequentially added to a microwave tube and reacted at 100 °C for 3 hours. After completion of the reaction, the mixture was filtered and concentrated. Compound 1d (0.082 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 685.45.

[0241] Step E: Preparation of Compound I-1 Compound 1d (0.082 g), dichloromethane (4 mL), and a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M) were sequentially added to a reaction flask and reacted at room temperature with stirring. After completion of the reaction, the reaction mixture was added with 10% aqueous sodium hydroxide (w / w) to adjust the pH to 13, extracted with water and dichloromethane, washed, dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound I-1 (0.035 g). HRMS(ESI, [MH] - ) m / z: 583.26408. 1 H NMR(500MHz,CDCl3)δ 9.84(s,1H),8.86(d,J=8.5Hz,1H),8.22(d,J=4.9Hz,1H),7.57(dd,J=16.2,8.5Hz,2H),6.99(d,J=4 .9Hz,1H),6.83(d,J=8.5Hz,1H),6.38(s,1H),4.38(s,2H),4.08(dt,J=8.3,6.5Hz,2H),3.96~3.80(m ,6H),3.73(ddd,J=22.7,14.5,6.8Hz,2H),3.01(dd,J=13.2,11.5Hz,2H),2.95~2.82(m,4H),2.55(t ,J=6.7Hz,2H), 2.38(ddd,J=12.7,11.7,6.0Hz,3H), 2.32~2.20(m,2H), 1.93(dd,J=12.4,7.5Hz,1H).

[0242] Example 2: Preparation of Compound I-2 [ka] Step A: Preparation of Compound 2a Compound 4-bromo-1H-pyrrole[2,3-B]pyrimidin-2(3H)-one (1 g), diphenyl(vinyl)sulfonium trifluoromethanesulfonate (2 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (2.14 g), and zinc trifluoromethanesulfonate (1.71 g) were sequentially added to a reaction flask. After addition, the reaction was stirred at room temperature. After completion of the reaction, the mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the phases were separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 2a (0.65 g). MS (ESI, [M+H] + ) m / z: 239.0.

[0243] Step B: Preparation of Compound 2b Compound 2a (0.55 g), dichloromethane (40 mL), and diisobutylaluminum hydride (21 mL, 1.5 M) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After the reaction was completed, the mixture was quenched with methanol, filtered, and the filtrate was extracted with dichloromethane, dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 49 / 1) to give compound 2b (0.26 g). MS (ESI, [M+H] + ) m / z: 225.0.

[0244] Step C: Preparation of Compound 2c Compound 2b (0.26 g), bis(triphenylphosphine)dichloropalladium (100 mg), bis(neopentylglycolate)diboron (385 mg), potassium acetate (403 mg), and 1,4-dioxane (10 mL) were sequentially added to a microwave tube, protected with nitrogen, and reacted at 90 °C in a microwave. After completion of the reaction, the mixture was filtered and concentrated. Compound 2c (203 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 191.1.

[0245] Step D: Preparation of Compound 2d To a reaction flask, intermediate 3A-3 (221 mg), compound 2c (102 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (40 mg), potassium phosphate (214 mg), 1,4-dioxane (5 mL), and water (1 mL) were sequentially added. After addition, the mixture was protected with nitrogen and stirred at 80 °C. After completion of the reaction, the mixture was filtered and concentrated. Compound 2d (85 mg) was obtained by column chromatography (dichloromethane / methanol = 19 / 1). MS (ESI, [M+H] + ) m / z: 659.43.

[0246] Step E: Preparation of Compound I-2 Compound 2d (85 mg), dichloromethane (10 mL), and a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M) were sequentially added to a reaction flask and allowed to react at room temperature with stirring. After completion of the reaction, the reaction mixture was adjusted to alkaline by adding saturated sodium bicarbonate solution, extracted with dichloromethane, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound I-2 (22 mg). HRMS (ESI, [M+H] + ) m / z: 559.26292 1 H NMR (500MHz, DMSO-d6)δ 9.75(d,1H), 8.80(m, 1H), 7.52-7.57(m, 1H), 6.91(s, 1H), 6.80(q, 1H), 6.28(t,1H), 4.19(d,2H), 3.84-3. 94(m, 6H), 3.68-3.75(m, 4H), 2.96-3.02(m, 2H), 2.25-2.38(m, 1H), 1.88-1.95(m, 1H), 0.56-1.25(m, 5H).

[0247] Example 3: Preparation of Compound I-3 [ka] Step A: Preparation of Compound 3a Compound 2c (68 mg), Intermediate 2A (185 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (27 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (16 mg), potassium phosphate (142 mg), 1,4-dioxane (5 mL), and water (1 mL) were sequentially added to a reaction flask. After addition, the mixture was protected with nitrogen and subjected to a microwave reaction at 85 °C. After completion of the reaction, the mixture was filtered and concentrated. Compound 3a (98 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 660.44.

[0248] Step E: Preparation of Compound I-3 Compound 3a (98 mg), dichloromethane (10 mL), and a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M) were sequentially added to a reaction flask and reacted at room temperature with stirring. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to approximately 10, and the mixture was extracted with dichloromethane, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound I-3 (50 mg). HRMS (ESI, [M+H] + ) m / z: 560.25881 1 H NMR(500MHz,DMSO-d6)δ 8.25(s,1H),7.56(d,1H),7.38(t,1H),6.80(d,1H),6.36(d,1H),4.27(s,2H),3.63~3.87( m,10H), 2.81~2.94(m,2H),2.18~2.35(m,3H),1.85~1.89(m,1H),1.18(s,3H),0.82(s,2H).

[0249] Example 4: Preparation of Compound I-4 [ka] Step A: Preparation of Compound 4a Compound N-benzyloxycarbonyl-L-proline (20.0 g), iodobenzenediacetic acid (51.7 g), iodine (10.2 g), and dichloromethane (200 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature under nitrogen protection to react. After the reaction was completed, the mixture was concentrated. Compound 4a (14.8 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 20 / 1). MS (ESI, [M+H] + ) m / z: 236.4.

[0250] Step B: Preparation of Compound 4b Compound 4a (14.8 g), dichloromethane (200 mL), N,N-diisopropylethylamine (14.0 mL), and trimethylsilyl trifluoromethanesulfonate (14.8 g) were sequentially added to a reaction flask. After addition, the mixture was protected with nitrogen and stirred at room temperature. After completion of the reaction, the mixture was concentrated. Compound 4b (10.6 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 20 / 1). MS (ESI, [M+H] + ) m / z: 204.1.

[0251] Step C: Preparation of Compound 4c Compound 4b (10.6 g), ether (300 mL), chloroiodomethane (7.86 mL), and diethylzinc (51.2 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and stirred at 0°C. After completion of the reaction, the mixture was concentrated. Compound 4c (5.00 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 10 / 1). MS (ESI, [M+H] + ) m / z: 218.3.

[0252] Step D: Preparation of Compound 4d Compound 4c (5.00 g), ethanol (100 mL), 10 wt% palladium on carbon (2.00 g), and a 1,4-dioxane solution of hydrochloric acid (2.30 mL, 4 M) were added to a reaction flask in this order, and the mixture was stirred at room temperature under hydrogen gas. After completion of the reaction, the mixture was filtered, washed, and concentrated to give compound 4d (2.31 g). MS (ESI, [M+H] + ) m / z: 84.1.

[0253] Step E: Preparation of Compound 4e Compound 4d (2.31 g), tetrahydrofuran (30.0 mL), sodium carbonate (6.64 g), and di-t-butyl dicarbonate (7.61 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated. Compound 4e (3.00 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 10 / 1). MS (ESI, [M+H] + ) m / z: 184.1.

[0254] Step F: Preparation of Compound 4f Compound 4e (2.31 g), ruthenium dioxide (0.300 g), sodium periodate (23.3 g), ethyl acetate (30.0 mL), and water (30.0 mL) were sequentially added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the mixture was concentrated. Compound 4f (1.47 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 198.1.

[0255] Step G: Preparation of Compound 4g Compound 4f (1.47 g), a 1,4-dioxane solution of hydrochloric acid (5.00 mL, 4 M), and dichloromethane (30.0 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature to give compound 4g (1.25 g). MS (ESI, [M+H] + ) m / z: 98.1.

[0256] Step H: Preparation of Compound 4h Compound 4g (2.31 g), dichloromethane (20.0 mL), and trimethyloxonium tetrafluoroboronic acid (3.20 g) were sequentially added to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, the mixture was concentrated. Compound 4h (0.71 g) was obtained by column chromatography (dichloromethane / methanol = 10 / 1). MS (ESI, [M+H] + ) m / z: 112.3.

[0257] Step I: Preparation of compound 4i Compound 4h (0.71 g), n-butanol (20.0 mL), formylhydrazine (0.36 g), and acetic acid (0.18 g) were sequentially added to a microwave tube, and the mixture was stirred at 120 °C under nitrogen protection. After completion of the reaction, the mixture was concentrated. Compound 4i (0.15 g) was obtained by column chromatography (dichloromethane ether / methanol = 2 / 1). MS (ESI, [M+H] + ) m / z: 122.0.

[0258] Step J: Preparation of Compound 4j Compound 4i (0.15 g), N-bromosuccinimide (0.18 g), carbon tetrachloride (5.00 mL), and acetic acid (5.00 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and stirred at 80 °C. After completion of the reaction, the mixture was concentrated. Compound 4j (0.11 g) was obtained by column chromatography (dichloromethane / methanol = 10 / 1). MS (ESI, [M+H] + ) m / z: 200.0.

[0259] Step K: Preparation of Compound 4k Compound 4j (0.15 g), intermediate 3A (0.18 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.02 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.03 g), potassium phosphate (0.09 g), water (2.00 mL), and dioxane (8.00 mL) were sequentially added to a reaction flask. The mixture was protected with nitrogen and stirred at 85 °C. After completion of the reaction, the mixture was concentrated. Compound 4k (0.07 g) was obtained by column chromatography (dichloromethane / methanol = 10 / 1). MS (ESI, [M+H] + ) m / z: 634.4.

[0260] Step L: Preparation of Compound I-4 Compound 4k (0.07 g), dichloromethane (10.0 mL), and a 1,4-dioxane solution of hydrochloric acid (2.00 mL, 4 M) were sequentially added to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to approximately 10, and the mixture was extracted with dichloromethane, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound I-4 (0.036 g). HRMS (ESI, [M+H] + ) m / z: 534.24245. 1H NMR(500MHz,CDCl3)δ 10.05(s,1H),8.93(d,J=8.7Hz,1H),7.92(d,J=8.7Hz,1H),7.57(d,J=8.5Hz,1H),6.84(d,J=8.5Hz,1 H),6.65(s,1H),4.95(d,J=19.1Hz,1H),4.76(d,J=19.1Hz,1H),4.17~3.99(m,3H),3.97~3.80(m,3H), 3.72(dq,J=14.7,7.0Hz,2H),3.27(dd,J=17.3,6.8Hz,1H),3.16~2.96(m,3H),2.86(m,2H),2.34(dtt ,J=43.8,14.4,6.3Hz,4H), 1.93(dq,J=14.8,7.7Hz,1H), 1.42(q,J=6.7Hz,1H), 0.80(d,J=6.2Hz,1H).

[0261] Example 5: Preparation of Compound I-5 [ka] Step A: Preparation of Compound 5a Morpholin-3-one (0.965 g), N,N-dimethylformamide (40 mL), and sodium hydride (0.51 g) were sequentially added to a reaction flask under nitrogen protection at 0°C. After addition, the mixture was stirred at room temperature for 1 hour. 1-Bromo-2-fluoro-3-nitrobenzene (2 g) was added, and the mixture was stirred at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 5a (0.39 g). MS (ESI, [M+H] + ) m / z: 301.0.

[0262] Step B: Preparation of Compound 5b Compound 5a (0.39 g), iron powder (0.36 g), ammonium chloride (0.035 g), ethanol (12 mL), and water (3 mL) were added sequentially to a reaction flask, and the mixture was reacted with stirring at 80° C. After completion of the reaction, the mixture was filtered and concentrated to obtain compound 5b (0.32 g). MS (ESI, [M+H] +) m / z: 271.0.

[0263] Step C: Preparation of Compound 5c Compound 5b (0.32 g) and acetic acid (10 mL) were added to the reaction mixture in that order, and the mixture was reacted with stirring at 110° C. After the reaction was completed, compound 5c (0.11 g) was obtained. MS (ESI, [M+H] + ) m / z: 253.0.

[0264] Step D: Preparation of Compound 5d Compound 5c (0.11 g), Intermediate 5A (0.33 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.041 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.068 g), potassium phosphate tripotassium (0.15 g), 1,4-dioxane (12 mL), and water (3 mL) were sequentially added to a microwave tube and reacted at 85 °C under nitrogen protection. After completion of the reaction, the mixture was filtered and concentrated. Compound 5d (0.20 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1).

[0265] Step E: Preparation of Compound I-5 Compound 5d (0.20 g), dichloromethane (10 mL), and a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M) were sequentially added to a reaction flask and allowed to react at room temperature with stirring. After completion of the reaction, the reaction mixture was adjusted to alkaline with saturated sodium bicarbonate solution, extracted with dichloromethane, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-5 (0.035 g). HRMS (ESI, [M+H] + ) m / z: 539.2762. 1H NMR(500MHz,CDCl3)δ 9.72(s,1H),8.88(d,J=8.5Hz,1H),7.78~7.69(m,1H),7.49(dd,J=22.7,8.5Hz,2H),7.32-7.27(m ,1H),7.13~7.08(m,1H),6.82(d,J=8.4Hz,1H),6.53(s,1H),5.06-4.99(m,2H),4.30(d,J=17.6Hz, 1H),4.12~4.01(m,3H),3.98~3.87(m,2H),3.78~3.71(m,1H),3.64(t,J=11.5Hz,1H),3.56(dd,J= 22.5, 11.8Hz, 3H), 3.44~3.37(m,1H), 3.24~3.15(m,1H), 2.31(d,J=6.3Hz,6H), 1.80~1.67(m,4H).

[0266] Example I-6: Preparation of Compound I-6 [ka] Step A: Preparation of Compound 6a Compound 1c (0.95 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (309 mg), bis(pinacolato)diboron (1.921 g), potassium acetate (743 mg), and 1,4-dioxane (50 mL) were sequentially added to a reaction flask, protected with nitrogen, and reacted at 100 °C with stirring. After completion of the reaction, the mixture was filtered and concentrated. Compound 6a (1.1 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 10 / 1). MS (ESI, [M+H] + ) m / z: 299.19.

[0267] Step B: Preparation of Compound 6b Compound 6a (101 mg), Intermediate 1A (210 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (28 mg), potassium phosphate (216 mg), 1,4-dioxane (15 mL), and water (3 mL) were sequentially added to a reaction flask. After addition, the mixture was protected with nitrogen and stirred at 85 °C. After completion of the reaction, the mixture was filtered and concentrated. Compound 6b (110 mg) was obtained by column chromatography (dichloromethane / methanol = 18 / 1). MS (ESI, [M+H] + ) m / z: 638.45.

[0268] Step C: Preparation of Compound I-6 Compound 6b (0.11 g), dichloromethane (10 mL), and a solution of hydrochloric acid in 1,4-dioxane (2 mL) were added to a reaction flask in this order and allowed to react at room temperature with stirring. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to approximately 10, and the mixture was extracted with dichloromethane, concentrated, and purified by column chromatography (dichloromethane / methanol = 15 / 1) to give compound I-6 (23 mg). HRMS (ESI, [M+H] + ) m / z: 538.2923. 1 H NMR(500MHz,CDCl3)δ 10.23(s,1H),8.22(d,1H),7.58(d,1H),7.31(s,1H),7.11(s,1H),6.88(d,1H),4.53(s,2H),4. 09(dd,2H),3.78~3.82(m,5H),3.57~3.62(m,5H),2.66(t,2H),2.45(s,6H),1.72~1.83(m,4H).

[0269] Example 7: Preparation of Compound I-7 [ka] Step A: Preparation of Compound 7a Compound 2a (488 mg), intermediate 5A (500 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) (103 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (63 mg), potassium phosphate (553 mg), 1,4-dioxane (50 mL), and water (5 mL) were sequentially added to a reaction flask. After addition, the mixture was protected with nitrogen and stirred at 85 °C. After completion of the reaction, the mixture was filtered and concentrated. Compound 7a (156 mg) was obtained by column chromatography (dichloromethane / methanol = 18 / 1). MS (ESI, [M+H] + ) m / z: 625.41.

[0270] Step B: Preparation of Compound I-7 Compound 7a (0.156 g), dichloromethane (10 mL), and a 1,4-dioxane solution of hydrochloric acid (0.65 mL, 4 M) were sequentially added to a reaction flask and allowed to react while stirring at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added to adjust the pH to approximately 10, and the mixture was extracted with dichloromethane, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-7 (30 mg). HRMS (ESI, [M+H] + ) m / z: 525.2609. 1 H NMR (500MHz, DMSO-d6)δ 11.32(s,1H), 9.89(s,1H), 8.73(s,1H), 8.60(d,1H), 8.06(d,1H), 7.64(d,1H), 7.36(d,1H), 6.91(d,1H), 6.85(d,1H), 4.10(s ,2H), 3.94~3.97(m,2H), 3.56(s,2H), 3.40~3.45(m,2H), 3.15~3.21(m,1H), 2.21(s,6H), 1.61~1.71(m,4H), 1.23~1.33(m,4H).

[0271] Example 8: Preparation of Compound I-8 [ka] Step A: Preparation of Compound 8a Compound 1c (0.115 g), intermediate 4A (0.300 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.020 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.033 g), potassium phosphate tripotassium (0.176 g), 1,4-dioxane (5 mL), and water (1 mL) were sequentially added to a microwave tube and reacted at 100 °C for 3 hours. After completion of the reaction, the mixture was filtered and concentrated. Compound 8a (0.125 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 623.41.

[0272] Step B: Preparation of Compound I-8 Compound 8a (0.125 g), dichloromethane (4 mL), and a 1,4-dioxane solution of hydrochloric acid (1 mL, 4 M) were sequentially added to a reaction flask and reacted at room temperature with stirring. After completion of the reaction, the reaction mixture was added with 10% aqueous sodium hydroxide (v / v) to adjust the pH to 13, extracted with water and dichloromethane, washed, dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound I-8 (0.045 g). HRMS (ESI, [M+H] + ) m / z: 523.2814. 1H NMR(500MHz,CDCl3)δ 9.78(s,1H),8.86(d,J=8.5Hz,1H),8.22(d,J=4.9Hz,1H),7.56(t,J=8.8Hz,2H),6.98(d,J=4.9 Hz,1H),6.82(d,J=8.5Hz,1H),6.30(s,1H),4.37(s,2H),4.14~4.04(m,2H),3.97~3.87(m,2H),3 .84(d,J=9.7Hz,3H),3.68(dd,J=13.5,6.4Hz,2H),3.58(d,J=12.3Hz,1H),2.91(t,J=7.1Hz,2H) , 2.54(t,J=6.8Hz,2H), 2.43~2.35(m,3H), 2.32(d,J=16.9Hz,6H), 1.93(dq,J=12.5,7.6Hz,1H).

[0273] Example 9: Preparation of Compound I-9 [ka] Step A: Preparation of Compound 9a Intermediate 4A-4 (0.127 g), 2-methyl-4-pyridineboronic acid (0.300 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.048 g), potassium phosphate tripotassium (0.523 g), 1,4-dioxane (5 mL), and water (1 mL) were sequentially added to a microwave tube and reacted at 100 °C for 3 hours. After completion of the reaction, the mixture was filtered and concentrated. Compound 9a (0.132 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 544.34.

[0274] Step B: Preparation of Compound I-9 Compound 9a (0.132 g), dichloromethane (4 mL), and a solution of hydrochloric acid in 1,4-dioxane (1 mL, 4 mol / L) were added to a reaction flask in this order and allowed to react at room temperature with stirring. After completion of the reaction, the reaction mixture was added with 10% aqueous sodium hydroxide (v / v) to adjust the pH to 13, extracted with water and dichloromethane, washed, dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound I-9 (0.043 g). HRMS (ESI, [M+H] + ) m / z: 444.2396. 1 H NMR(500MHz,CDCl3)δ 9.86(s,1H),8.90(d,J=8.7Hz,1H),8.54(d,J=5.2Hz,1H),7.58(dd,J=24.4,8.6Hz, 2H),7.23(s,1H),7.17(d,J=5.1Hz,1H),6.81(d,J=8.4Hz,1H),6.52(s,1H),4.55(s, 2H),4.08(ddd,J=13.3,12.1,6.4Hz,2H),3.98~3.83(m,2H),3.72~3.64(m,2H),3.5 7(d,J=12.3Hz,1H), 2.61(s,3H), 2.42~2.33(m,1H), 2.30(s,6H), 1.98~1.89(m,1H).

[0275] Example 10: Preparation of Compound I-10 [ka] Step A: Preparation of Compound 10a Intermediate 1A-4 (12 g) and tetrahydrofuran (150 mL) were added to a reaction flask, which was then protected with nitrogen. A solution of n-butyllithium in tetrahydrofuran (55 mL, 2 M) was slowly added dropwise at -78 °C and the reaction was continued with stirring for 2 hours. Tetrahydropyranone (4.73 g) was then slowly added and the reaction was continued with stirring at room temperature. After the reaction was completed, the mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane, washed, dried, filtered, and concentrated to obtain compound 10a (11.75 g). MS (ESI, [M+H]+ ) m / z: 352.21.

[0276] Step B: Preparation of Compound 10b Compound 10a (1 g), dichloromethane (10 mL), and a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M) were sequentially added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH of approximately 10 by adding saturated sodium bicarbonate solution, extracted with dichloromethane, and concentrated to give compound 10b (0.626 g). MS (ESI, [M+H] + ) m / z: 252.22.

[0277] Step C: Preparation of Compound 10c Compound 10b (0.400 g), intermediate 1A-11 (0.553 g), tris(dibenzylideneacetone)dipalladium (0.146 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0.111 g), potassium carbonate (0.660 g), and toluene (10 mL) were sequentially added to a reaction flask and reacted at 100 °C for 3 hours. After completion of the reaction, the mixture was filtered and concentrated. Compound 10c (0.165 g) was obtained by column chromatography (dichloromethane / methanol = 25 / 1). MS (ESI, [M+H] + ) m / z: 518.30.

[0278] Step D: Preparation of Compound 10d Compound 10c (0.165 g), compound 6a (0.114 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.025 g), potassium phosphate tripotassium (0.203 g), 1,4-dioxane (5 mL), and water (1 mL) were sequentially added to a microwave tube and reacted at 100 °C. After completion of the reaction, the mixture was filtered and concentrated. Compound 10d (0.123 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] +) m / z: 654.39.

[0279] Step E: Preparation of Compound I-10 Compound 10d (0.123 g), dichloromethane (4 mL), and a 1,4-dioxane solution of hydrochloric acid (1 mL, 4 mol / L) were sequentially added to a reaction flask and allowed to react at room temperature with stirring. After completion of the reaction, the mixture was adjusted to an alkaline pH (approximately 10) by adding saturated sodium bicarbonate solution, extracted with dichloromethane, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound I-10 (0.023 g). HRMS (ESI, [M+H] + ) m / z: 554.2880. 1 H NMR(500MHz,CDCl3)δ 10.32(s,1H),9.39(s,1H),8.26(d,J=4.9Hz,1H),7.62(d,J=8.6Hz,1H),7.09(d,J=4.9Hz, 1H),6.86(d,J=8.6Hz,1H),6.58(s,1H),4.57(s,2H),4.05(t,J=11.0Hz,2H),3.94(s,2H),3 .86(dd,J=10.9,4.3Hz,2H),3.83(s,3H),2.93(t,J=7.1Hz,2H),2.70(t,J=6.9Hz,2H),2.43 (dd,J=14.0, 7.1Hz, 2H), 2.29(s, 6H), 2.07(td,J=12.8, 4.9Hz, 2H), 1.81(d,J=12.6Hz, 2H).

[0280] Example 11: Preparation of Compound I-11 [ka] Step A: Preparation of Compound 11a To a reaction flask, furan[2,3-c]pyridine (5 g), acetonitrile (50.0 mL), and 2,4-dinitrophenylhydroxyamine (8.5 g) were added in that order, and the mixture was allowed to react with stirring at 40° C. After completion of the reaction, the reaction solution was filtered and washed to obtain compound 11a (9.8 g), which was used directly in the next reaction.

[0281] Step B: Preparation of Compound 11b Compound 11a (5 g), potassium carbonate (3 g), ethyl propionate (3.2 g), and N,N-dimethylformamide (60 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was quenched by adding saturated aqueous sodium chloride solution, extracted with ethyl acetate, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give compound 11b (3.4 g). MS (ESI, [M+H] + ) m / z: 231.0.

[0282] Step C: Preparation of Compound 11c Compound 11b (3.4 g), lithium hydroxide monohydrate (6 g), methanol (60 mL), and water (6 mL) were sequentially added to a reaction flask, and the mixture was stirred at 60° C. After the reaction was completed, dilute hydrochloric acid was added to adjust the mixture to an acidic pH (approximately 5), and ethyl acetate was added to the reaction mixture for extraction. The organic phase was dried, filtered, and concentrated, and compound 11c (2.9 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 3 / 1). MS (ESI, [M+H] + ) m / z: 203.2.

[0283] Step D: Preparation of Compound 11d Compound 11c (2.9 g), N-bromosuccinimide (2.56 g), sodium bicarbonate (3.6 g), and N,N-dimethylformamide (40 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, and the organic phase was dried, filtered, and concentrated. Compound 11d (3.08 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 6 / 1). MS (ESI, [M+H] + ) m / z: 237.0.

[0284] Step E: Preparation of Compound 11e Compound 11d (0.2 g), Intermediate 5A (0.3 g), potassium phosphate (0.1 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.04 g), 1,4-dioxane (10 mL), and water (0.5 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and reacted at 100°C with stirring. The reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain Compound 11e (0.11 g). MS (ESI, [M+H] + ) m / z: 623.1.

[0285] Step F: Preparation of Compound I-11 Compound 11e (0.11 g), a 4 M solution of hydrochloric acid in 1,4-dioxane (1 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 9 / 1) to give compound I-11 (0.01 g). HRMS (ESI, [M+H] + ) m / z: 523.2455. 1 H NMR(500MHz,CD3Cl:CD3OD=10:1)δ 8.83(d,J=8.6Hz,1H),8.36(d,J=7.2Hz,1H),8.00(s,1H),7.81(d,J=8.6Hz,1H),7.69(d,J=2.0Hz,1H),7.52(d,J=8.4Hz,1H),7.04(d,J=7.2Hz, 1H),6.89~6.81(m,2H),4.47(s,2H),4.17~4.03(m,2H),3.69(s,2H),3. 57(td,J=11.6,2.2Hz,2H),3.19(s,1H),2.38(s,6H),1.85~1.67(m,4H).

[0286] Example 12: Preparation of Compound I-12 [ka] Step A: Preparation of Compound 12a 2-Chloro-5-fluoropyridine-6-formaldehyde (5.00 g), potassium carbonate (21.66 g), N,N-dimethylformamide (100 mL), (R)-3-pyrrolidinol (5.46 g), and tetrabutylammonium iodide (2.32 g) were sequentially added to a reaction flask. After addition, the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The organic phase was dried, filtered, and concentrated. Compound 12a (2.56 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 1 / 1). MS (ESI, [M+H] + ) m / z: 227.11.

[0287] Step B: Preparation of Compound 12b Compound 12a (2.54 g), methanol (40 mL), acetic acid (0.34 g), and a tetrahydrofuran solution of dimethylamine (2 M, 8.41 mL) were sequentially added to a reaction flask and reacted at 0°C for 0.5 hours. Sodium cyanoborohydride (1.41 g) was then added to the reaction solution, and the mixture was stirred at room temperature to react. After completion of the reaction, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 12b (1.57 g). MS (ESI, [M+H] + ) m / z: 256.13.

[0288] Step C: Preparation of Compound 12c 4-Chloro-7-nitroisoindolin-1-one (5.00 g), 4-dimethylaminopyridine (3.45 g), di-t-butyl dicarbonate (7.70 g), and tetrahydrofuran (100 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was extracted with ethyl acetate. The organic phase was dried, filtered, and concentrated. Compound 12c (2.57 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+Na] + ) m / z: 335.07.

[0289] Step D: Preparation of Compound 12d Compound 12c (2.00 g), zinc powder (2.09 g), ammonium chloride (2.05 g), ethanol (30 mL), and water (6 mL) were sequentially added to a reaction flask, and the mixture was reacted with stirring at 70° C. After the reaction was completed, the mixture was filtered and concentrated, and then purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 12d (1.77 g). MS (ESI, [M+Na] + ) m / z: 305.09

[0290] Step E: Preparation of Compound 12e Compound 12d (0.27 g), compound 6a (0.30 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.08 g), potassium phosphate tripotassium (0.61 mg), 1,4-dioxane (12.0 mL), and water (2.5 mL) were sequentially added to a reaction flask, and the mixture was stirred at 85 °C under nitrogen protection. After completion of the reaction, the reaction solution was concentrated. Compound 12e (0.37 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 419.32.

[0291] Step F: Preparation of Compound 12f Compound 12e (150 mg), compound 12b (110 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (56 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (43 mg), potassium carbonate (149 mg), and 1,4-dioxane (15 mL) were sequentially added to a reaction flask, protected with nitrogen, and reacted with stirring at 100 °C. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 12f (87 mg). MS (ESI, [M+H] + ) m / z: 638.44.

[0292] Step G: Preparation of Compound I-12 Compound 12f (87 mg), dichloromethane (10 mL), and a 1,4-dioxane solution of hydrochloric acid (4 M, 2 mL) were sequentially added to a reaction flask and allowed to react while stirring at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 10) with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound I-12 (15 mg). HRMS (ESI, [M+H] + ) m / z: 538.2923. 1H NMR(500MHz,CDCl3)δ 9.66(s,1H),8.73(d,J=8.5Hz,1H),8.22(d,J=4.9Hz,1H),7.55(d,J=8.5Hz,1H),7.30(d,J=8.7Hz,1H),6.9 8(d,J=4.9Hz,1H),6.81(d,J=8.6Hz,1H),6.13(s,1H),4.43(t,J=3.8Hz,1H),4.37(s,2H),3.83(s,3H),3.7 4(s,2H),3.43(d,J=7.5Hz,1H),3.28(d,J=9.9Hz,1H),3.20(dd,J=9.9,3.9Hz,1H),3.07(q,J=4.1Hz,1H),2 .91(t,J=7.0Hz, 2H), 2.55(t,J=7.0Hz, 2H), 2.40(q,J=7.0Hz, 2H), 2.33(s, 6H), 2.20(tt,J=8.9, 5.2Hz, 2H).

[0293] Example 13: Preparation of Compound I-13 [ka] Step A: Preparation of Compound 13a 2-Chloro-5-fluoropyridine-6-carboxylic acid (2 g), ethanol (20 mL), and two drops of concentrated sulfuric acid were added to a reaction flask in this order, and the mixture was protected with nitrogen and reacted at 80° C. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain Compound 13a (2.1 g). MS (ESI, [M+H] + ) m / z: 204.6.

[0294] Step B: Preparation of Compound 13b Compound 13a (2.1 g), morpholine (1.72 g), potassium carbonate (4.0 g), and N,N-dimethylformamide (20 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and reacted at 80° C. After completion of the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 9 / 1) to obtain compound 13b (2.2 g). MS (ESI, [M+H] + ) m / z: 271.4.

[0295] Step C: Preparation of Compound 13c Compound 13b (2.2 g), sodium borohydride (400 mg), and methanol (40 mL) were added to a reaction flask in this order at 0° C., and the mixture was then reacted at 70° C. After completion of the reaction, the reaction was quenched by adding saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 13c (1.8 g). MS (ESI, [M+H] + ) m / z: 229.2.

[0296] Step D: Preparation of Compound 13d Compound 13c (1.8 g), methanesulfonic anhydride (2.8 g), N,N-diisopropylethylamine (3.1 g), and dichloromethane (40 mL) were added to a reaction flask in this order in an ice-water bath, and the mixture was allowed to react in an ice-water bath. After the reaction was completed, a tetrahydrofuran solution of dimethylamine (2 M, 30 mL) was added to the reaction mixture, and the mixture was allowed to react at room temperature. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 13d (1.6 g). MS (ESI, [M+H] + ) m / z: 256.2.

[0297] Step E: Preparation of Compound 13e Compound 13d (1.6 g), cyclopropylformamide (1.2 g), cesium carbonate (3.8 g), tris(dibenzylideneindeneacetone)dipalladium (0.2 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0.2 g), and 1,4-dioxane (15 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and reacted at 100°C. The reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 13e (1.3 g). MS (ESI, [M+H] + ) m / z: 277.1.

[0298] Step F: Preparation of Compound 13f Compound 13e (1.3 g), lithium hydroxide monohydrate (1.9 g), methanol (20 mL), and water (2 mL) were added sequentially to a reaction flask in an ice-water bath, and then the mixture was protected with nitrogen and reacted at 60° C. After completion of the reaction, the reaction mixture was adjusted to acidity (pH approximately 6) with 1 M dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 13f (1.1 g). MS (ESI, [M+H] + ) m / z: 237.4.

[0299] Step G: Preparation of Compound 13g Compound 13f (1.1 g), 7-bromo-4-chloro-1-oxa-1,3-dihydro-2-hydro-pyrrolidinyl[3,4-c]pyridine-2-carbamate t-butyl ester (0.8 g), cesium carbonate (2.1 g), tris(dibenzylideneindeneacetone)dipalladium (0.3 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0.3 g), and 1,4-dioxane (20 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and reacted at 100 ° C. After completion of the reaction, the organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain Compound 13f (0.6 g). MS (ESI, [M+H] + ) m / z: 503.1.

[0300] Step H: Preparation of Compound 13h Compound 13g (0.4 g), compound 6a (0.8 g), potassium phosphate (0.3 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.08 g), and 1,4-dioxane (20 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and reacted at 100°C. After completion of the reaction, the organic phase was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 13h (0.12 g). MS (ESI, [M+H] + ) m / z: 639.4.

[0301] Step I: Preparation of Compound I-13 Compound 13h (0.12 g), a 1,4-dioxane solution of hydrochloric acid (4 M, 1 mL), and dichloromethane (10 mL) were added to a reaction flask, and the mixture was allowed to react at room temperature. After the reaction was completed, saturated aqueous sodium bicarbonate was added to adjust the pH to approximately 9, followed by extraction with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 9 / 1) to give compound I-13 (0.042 g). HRMS (ESI, [M+H] + ) m / z: 539.2878. 1 H NMR(500MHz,CDCl3:CD3OD=10:1)δ 10.17(s,1H),8.21(d,J=5.6Hz,1H),7.52(d,J=8.6Hz,1H),7.10(d,J=5.5Hz,1H),6.91(d,J=8.6Hz,1H),4.54(s,2H),3.88 (s,5H),3.82(s,4H),2.95(d,J=14.0Hz,8H),2.79(s,3H),2.68(t,J=6.9Hz,3H),2.45~2.38(m,3H),1.24(d,J=17.1Hz,1H).

[0302] Example 14: Preparation of Compound I-14 [ka]

[0303] Step A: Preparation of Compound 14a To a reaction flask, intermediate 1A-2 (5 g), N,N-diisopropylethylamine (4 g), dichloromethane (30 mL), and methanesulfonic anhydride (7.2 g) were sequentially added. After the addition, the mixture was allowed to react with stirring at -15°C. After the reaction was completed, dimethyl-D6-amine (10 g) was gradually added to the reaction flask, and the mixture was allowed to react with stirring at room temperature. After the reaction was completed, the mixture was extracted with dichloromethane, and the organic phase was washed with saturated aqueous sodium chloride, dried, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to obtain compound 14a (3.8 g). MS (ESI, [M+H] + ) m / z: 336.1.

[0304] Step B: Preparation of Compound 14b Compound 14a (3.8 g), potassium carbonate (3.6 g), tetra(triphenylphosphine)palladium (1.5 g), 3,6-dihydro-2H-pyran-4-boronic acid pinacol (2.3 g), water (8 mL), and 1,4-dioxane (40 mL) were sequentially added to a reaction flask. After the addition, the atmosphere was purged with nitrogen and the reaction was carried out with stirring at 100 °C. After completion of the reaction, the reaction solution was filtered and concentrated, and compound 14b (2.6 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 340.0.

[0305] Step C: Preparation of Compound 14c Compound 14b (2.6 g), 10 wt% palladium hydroxide on carbon (2.6 g), and methanol (12 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered and concentrated to give compound 14c (2.2 g). MS (ESI, [M+H] + ) m / z: 342.0.

[0306] Step D: Preparation of Compound 14d Compound 14c (2.2 g) and a 1,4-dioxane solution of hydrochloric acid (16.4 mL, 4 M) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature while reacting. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 10) by adding saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated to obtain compound 14d (1.4 g). MS (ESI, [M+H] + ) m / z: 242.3.

[0307] Step E: Preparation of Compound 14e Compound 14d (1.4 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (246 mg), tris(dibenzylideneacetone)dipalladium (258 mg), cesium carbonate (1.8 g), intermediate 1A-11 (1.3 g), and 1,4-dioxane (100 mL) were sequentially added to a reaction flask, and the atmosphere was replaced with nitrogen, followed by stirring at 100° C. After completion of the reaction, the reaction solution was filtered and concentrated to obtain a crude product, which was then purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 14e (1.3 g). MS (ESI, [M+H] + ) m / z: 508.3.

[0308] Step F: Preparation of Compound 14f Compound 6a (101 mg), compound 14e (211 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (29 mg), potassium phosphate (219 mg), 1,4-dioxane (15 mL), and water (3 mL) were sequentially added to a reaction flask. After addition, the mixture was protected with nitrogen and stirred at 85 °C. After completion of the reaction, the reaction solution was filtered and concentrated, and compound 14f (101 mg) was obtained by column chromatography (dichloromethane / methanol = 18 / 1). MS (ESI, [M+H] + ) m / z: 644.4.

[0309] Step G: Preparation of Compound I-14 Compound 14f (0.101 g), dichloromethane (10 mL), and a solution of hydrochloric acid in 1,4-dioxane (2 mL) were added to a reaction flask in this order and allowed to react at room temperature with stirring. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH of approximately 10 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 15 / 1) to give compound I-14 (40 mg). HRMS (ESI, [M+H] + ) m / z: 544.3300 1 H NMR (500MHz, CDCl3):δ 10.36(brs, 1H), 9.81(s, 1H), 6.60(s, 1H), 5.20(s, 1H), 4.81(s, 1H), 4.25~4.23(m, 1H), 3.80~3.76(m, 1H), 3.67(s, 2H), 3. 23~3.16(m, 1H), 2.93~2.91(m, 2H), 2.50(s, 3H), 2.5~2.44(m, 1H), 2.13~2.09(m, 1H), 1.94~1.87(m, 4H), 1.13~1.11(m, 6H).

[0310] Example 15: Preparation of Compound I-15 [ka]

[0311] Step A: Preparation of Compound 15a Compound 4-bromo-2-hydrazinopyridine (0.92 g), cyclopentanone (0.412), and methanol (5 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature to react. After completion of the reaction, the reaction solution was concentrated to give compound 15a (1.3 g). MS (ESI, [M+H] + ) m / z: 254.1.

[0312] Step B: Preparation of Compound 15b Compound 15a (1.3 g) and diethylene glycol (10 mL) were added sequentially to a microwave tube, and the mixture was stirred in a microwave at 245° C. After completion of the reaction, the reaction solution was poured into water and filtered. The residue was subjected to column chromatography (dichloromethane / methanol=20 / 1) to obtain compound 15b (0.17 g). MS (ESI, [M+H] + ) m / z: 237.06.

[0313] Step C: Preparation of Compound 15c Compound 15b (0.17 g) and DMF (5 mL) were added to a reaction flask at 0 °C with 60 wt% sodium hydride (0.215 g) and stirred for 0.5 hours. Deuterated iodomethane (1.039 g) was then added dropwise to the reaction flask, and the mixture was then cooled to room temperature and stirred overnight. After completion of the reaction, the reaction was quenched, and ethyl acetate was added to extract the reaction mixture. The organic phase was washed with saturated brine, dried, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 15c (0.12 g). MS (ESI, [M+H] + ) m / z: 254.1.

[0314] Step D: Preparation of Compound 15d 1,1-bis(diphenylphosphine)ferrocenepalladium dichloride (0.039 g), compound 15c (0.12 g), bis(pinacolato)diboron (0.24 g), potassium acetate (0.093 g), and 1,4-dioxane (5 mL) were sequentially added to a reaction flask, and the atmosphere was replaced with nitrogen, followed by stirring at 100° C. After completion of the reaction, the reaction solution was filtered and concentrated, and compound 15d (0.107 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 302.39.

[0315] Step E: Preparation of Compound 15e Compound 14e (0.15 g), compound 15d (0.107 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.023 g), potassium phosphate tripotassium (0.188 g), 1,4-dioxane (5 mL), and water (1 mL) were sequentially added to a reaction flask. The atmosphere was purged with nitrogen and the reaction was carried out at 105 °C with stirring. After completion of the reaction, the reaction mixture was filtered and concentrated to obtain the crude product. Compound 15e (0.103 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 647.51.

[0316] Step F: Preparation of Compound I-15 Compound 15e (0.103 g), dichloromethane (1 mL), and a 4M solution of hydrochloric acid in 1,4-dioxane (0.5 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to approximately 10, followed by extraction with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound I-15 (0.035 g). HRMS (ESI, [M+H] + ) m / z: 547.3490. 1H NMR(500MHz,CDCl3)δ 10.34(s,1H),9.34(s,1H),8.25(d,J=4.9Hz,1H),7.54(d,J=8.3Hz,1H),7.08(d,J=4.9Hz ,1H),6.84(d,J=8.3Hz,1H),6.51(s,1H),4.57(s,2H),4.09(dd,J=11.3,2.9Hz,2H),3.56( t,J=10.7Hz,2H),3.22(d,J=5.9Hz,1H),3.04(d,J=7.0Hz,2H),2.93(t,J=7.0Hz,2H),2.72 (t,J=6.9Hz,2H), 2.42(dd,J=14.0,7.1Hz,2H), 1.78(dd,J=12.5,3.2Hz,2H), 1.37(s,2H).

[0317] Example 16: Preparation of Compound I-16 [ka]

[0318] Step A: Preparation of Compound 16a Intermediate 1A-1 (8.00 g), 3,6-dihydro-2H-pyran-4-boronic acid pinacol (6.60 g), potassium carbonate (10.02 g), tetratriphenylphosphine palladium (5.58 g), 1,4-dioxane (100 mL), and water (15 mL) were sequentially added to a reaction flask under nitrogen protection. After addition, the mixture was stirred at 100 °C to react. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 16a (7.06 g). MS (ESI, [M+H] + ) m / z: 335.11.

[0319] Step B: Preparation of Compound 16b Compound 16a (7.06 g), methanol (50 mL), and 10 wt% palladium hydroxide on carbon (7.41 g) were added to a reaction flask in this order, and the mixture was protected with hydrogen and stirred at room temperature. After completion of the reaction, the reaction mixture was filtered and concentrated to give compound 16b (5.19 g). MS (ESI, [M+H] + ) m / z: 337.12.

[0320] Step C: Preparation of Compound 16c Compound 16b (5.14 g), tetrahydrofuran (100 mL), and lithium aluminum deuteride (1.60 g) were added sequentially to a reaction flask at 0° C. After the addition, the mixture was stirred at room temperature while reacting. After the reaction was completed, the reaction was quenched with water, filtered, and extracted with ethyl acetate. The organic phase was dried, filtered, and concentrated to give compound 16c (2.76 g). MS (ESI, [M+H] + ) m / z: 311.17.

[0321] Step D: Preparation of Compound 16d Compound 16c (2.76 g), dichloromethane (60 mL), triethylamine (1.80 g), and methylsulfonic anhydride (3.10 g) were added sequentially to a reaction flask at -10 °C, followed by stirring at 0 °C. After completion of the reaction, the reaction solution was added dropwise to 40% aqueous dimethylamine solution (20.04 g) at -10 °C, and the mixture was stirred at room temperature. After completion of the reaction, the reaction solution was concentrated, and the crude product was subjected to column chromatography (dichloromethane:methanol = 20:1) to obtain compound 16d (1.17 g). MS (ESI, [M+H] + ) m / z: 336.26.

[0322] Step E: Preparation of Compound 16e Compound 16d (1.17 g), dichloromethane (10 mL), and a 1,4-dioxane solution of hydrochloric acid (4 M, 20 mL) were added to a reaction flask in that order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated, adjusted to an alkaline pH of approximately 10 by adding saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and evaporated to dryness to obtain compound 16e (1.13 g). MS (ESI, [M+H] + ) m / z: 238.25.

[0323] Step F: Preparation of Compound 16f Compound 16e (1.00 g), intermediate 1A-11 (0.86 g), tris(dibenzylideneacetone)dipalladium (0.26 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0.20 g), cesium carbonate (2.82 g), and 1,4-dioxane (30 mL) were added to a reaction flask under nitrogen protection and reacted with stirring at 110 °C. After completion of the reaction, the reaction solution was filtered and concentrated. Compound 16f (0.85 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 503.33.

[0324] Step G: Preparation of Compound 16g Compound 16f (150 mg), compound 6a (107 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (24 mg), potassium phosphate tripotassium (190 mg), 1,4-dioxane (3.0 mL), and water (0.5 mL) were sequentially added to a microwave tube, protected with nitrogen, and stirred at 85 °C in a microwave oven. After completion of the reaction, the reaction mixture was concentrated. Compound 16g (167 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 639.52.

[0325] Step H: Preparation of Compound I-16 Compound 16g (167 mg), dichloromethane (10.00 mL), and a 1,4-dioxane solution of hydrochloric acid (1.00 mL, 4 M) were sequentially added to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to approximately 10, followed by extraction with dichloromethane. The organic phase was dried, filtered, and concentrated. The crude product was purified by column chromatography (dichloromethane ether / methanol = 10 / 1) to obtain compound I-16 (35 mg). HRMS (ESI, [M+H] + ) m / z: 539.3097. 1 H NMR(500MHz,CDCl3)δ 9.77(s,1H),8.86(d,J=8.6Hz,1H),8.23(d,J=4.9Hz,1H),7.57(d,J=8.6Hz,1H),7.51( d,J=8.4Hz,1H),6.98(d,J=5.0Hz,1H),6.83(d,J=8.4Hz,1H),6.08(s,1H),4.37(s,2H) ,4.14~4.06(m,2H),3.83(s,3H),3.58~3.53(m,2H),3.22~3.18(m,1H),2.96~2.87(m,2 H), 2.54 (dd, J=8.1, 5.8Hz, 2H), 2.40 (q, J=7.1Hz, 2H), 2.33 (s, 6H), 1.85~1.70 (m, 4H).

[0326] Example 17: Preparation of Compound I-17 [ka]

[0327] Step A: Preparation of Compound 17a Compound 16e (879 mg), intermediate 1A-11 (500 mg), tris(dibenzylideneacetone)dipalladium (193 mg), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (146 mg), potassium carbonate (873 mg), and toluene (20 mL) were added to a reaction flask under nitrogen protection and reacted at 100 °C with stirring. After completion of the reaction, the reaction solution was filtered and concentrated. Compound 17a (237 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 504.27.

[0328] Step B: Preparation of Compound 17b Compound 17a (150 mg), compound 6a (106 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (23 mg), potassium phosphate tripotassium (190 mg), 1,4-dioxane (8.0 mL), and water (1.5 mL) were sequentially added to a microwave tube, protected with nitrogen, and stirred at 85°C in a microwave oven. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 17b (103 mg). MS (ESI, [M+H] + ) m / z: 640.40.

[0329] Step C: Preparation of Compound I-17 Compound 17b (103 mg), dichloromethane (10.00 mL), and a 1,4-dioxane solution of hydrochloric acid (1.00 mL, 4 M) were added to a reaction flask in that order, and the mixture was stirred at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to approximately 10, followed by extraction with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane ether / methanol = 10 / 1) to give compound I-17 (25 mg). HRMS (ESI, [M+H] + ) m / z: 540.3049. 1 H NMR (500 MHz, CDCl3) δ 10.35(s,1H),9.34(s,1H),8.25(d,J=4.9Hz,1H),7.54(d,J=8.4Hz,1H),7.08( d,J=4.9Hz,1H),6.84(d,J=8.4Hz,1H),6.52(s,1H),4.57(s,2H),4.15~4.05(m ,2H),3.83(s,3H),3.60~3.52(m,2H),3.25~3.19(m,1H),2.93(t,J=7.1Hz,2H) ,2.72(t,J=7.0Hz,2H),2.42(p,J=7.3Hz,2H),2.33(s,6H),1.84~1.71(m,4H).

[0330] Example 18: Preparation of Compound I-18 [ka]

[0331] Step A: Preparation of Compound 18a 2-Chloro-6,7-dihydro-5H-2,3-cyclopentenopyridine (5.5 g) and 85% hydrazine hydrate (10 mL) were added sequentially to a reaction flask, and the mixture was stirred at 120° C. After completion of the reaction, the mixture was extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated to obtain compound 18a (5.2 g). MS (ESI, [M+H] + ) m / z: 150.2

[0332] Step B: Preparation of Compound 18b Compound 18a (5.2 g), N,N-dimethylformamide (25 mL), and imidazole hydrochloride (0.4 g) were sequentially added to a reaction flask, and the mixture was stirred at 170 °C. After completion of the reaction, the reaction solution was concentrated. Compound 18b (4.9 g) was obtained by column chromatography (dichloromethane / methanol = 10 / 1). MS (ESI, [M+H] + ) m / z: 160.0

[0333] Step C: Preparation of Compound 18c Compound 18b (4.9 g), NBS (6.1 g), and carbon tetrachloride (50 mL) were added to a reaction flask in this order, and the mixture was stirred at 60° C. After completion of the reaction, the reaction was quenched, and dichloromethane was added for extraction. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 18c (5.2 g). MS (ESI, [M+H] + ) m / z: 238.4

[0334] Step D: Preparation of Compound 18d Compound 18c (0.18 g), Intermediate 5A (0.17 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.02 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.03 g), potassium phosphate (0.09 g), water (2.00 mL), and 1,4-dioxane (15 mL) were sequentially added to a reaction flask. The mixture was protected with nitrogen and stirred at 85°C. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 18d (0.12 g). MS (ESI, [M+H] + ) m / z: 624.4.

[0335] Step E: Preparation of Compound I-18 Compound 18d (0.12 g), dichloromethane (10 mL), and a 4M solution of hydrochloric acid in 1,4-dioxane (2 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH of approximately 10 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound I-18 (40 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). HRMS (ESI, [M+H] + ) m / z: 524.2768 1H NMR(500MHz,DMSO-d6)δ 10.02(s,1H),8.75(s,1H),8.71(d,J=8.5Hz,1H),7.67(dt,J=8.5,3.1Hz,3H),7.39 (d,J=9.3Hz,1H),6.95(d,J=8.4Hz,1H),4.30(s,2H),3.97(dd,J=10.6,4.1Hz,2H),3 .59(s,2H),3.44(td,J=11.4,2.6Hz,2H),3.25~3.14(m,1H),2.87(t,J=7.4Hz,2H),2 .69(t,J=7.6Hz,2H), 2.23(s,6H), 2.11~1.99(m,2H), 1.66(dt,J=15.5,11.6Hz,4H).

[0336] Example 19: Preparation of Compound I-19 [ka]

[0337] Step A: Preparation of Compound 19a Compound 1H-pyrrolo[2,3-b]pyridine-2-formaldehyde (4 g), cesium carbonate (13.38 g), N,N-dimethylformamide (50.0 mL), and 3-bromopropene (4.30 g) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature. After the reaction was completed, 100 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 17 / 3) to obtain compound 19a (3.4 g). MS (ESI, [M+H] + ) m / z: 187.15.

[0338] Step B: Preparation of Compound 19b To a reaction flask containing methyltriphenylphosphonium bromide (7.3 g) and tetrahydrofuran (100 mL), bis(trimethylsilyl)aminopotassium (5.0 g) was slowly added dropwise under nitrogen protection, followed by stirring at room temperature for 30 minutes. After the reaction was completed, compound 19a (3.4 g) was added and stirred at room temperature. After the reaction was completed, 100 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound 19b (2.85 g). MS (ESI, [M+H] + ) m / z: 185.14.

[0339] Step C: Preparation of Compound 19c Compound 19b (2.35 g), Hoveyda-Grubbs catalyst (1.42 g), and dichloromethane (40 mL) were sequentially added to a reaction flask. After the addition, the reaction mixture was protected with nitrogen and stirred at 40°C. After the reaction was completed, the reaction mixture was filtered and concentrated, and then purified by column chromatography (dichloromethane / methanol = 99 / 1) to give compound 19c (0.56 g). MS (ESI, [M+H] + ) m / z: 157.13.

[0340] Step D: Preparation of Compound 19d Compound 19c (0.56 g), 10 wt% palladium on carbon (0.38 g), ammonium formate (6.6 g), and ethanol (20 mL) were sequentially added to a reaction flask. After the addition, the reaction mixture was protected with nitrogen and stirred at 70 °C. After the reaction was completed, the reaction mixture was filtered and concentrated, and then purified by column chromatography (dichloromethane / methanol = 99 / 1) to give compound 19d (0.392 g). MS (ESI, [M+H] + ) m / z: 159.1.

[0341] Step E: Preparation of Compound 19e Compound 19d (0.392 g), N-bromosuccinimide (0.485 g), and dichloromethane (20 mL) were sequentially added to a reaction flask under ice bath. After the addition, the mixture was protected with nitrogen and stirred. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with dichloromethane. The organic phase was dried, filtered, and concentrated to give compound 19e (0.307 g). MS (ESI, [M+H] + ) m / z: 237.1.

[0342] Step F: Preparation of Compound 19f Compound 19e (0.17 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (16 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (27 mg), potassium phosphate tripotassium (0.143 g), Intermediate 5A (0.25 g), 1,4-dioxane (20 mL), and water (4 mL) were sequentially added to a reaction flask. The atmosphere was purged with nitrogen and the mixture was stirred in a microwave oven at 85 °C. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 3 / 7) to give compound 19f (0.185 g). MS (ESI, [M+H] + ) m / z: 623.44.

[0343] Step F: Preparation of Compound I-19 Compound 19f (0.185 g), dichloromethane (10 mL), and a 4M solution of hydrochloric acid in 1,4-dioxane (1 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, the mixture was adjusted to an alkaline pH of approximately 10 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 3 / 2) to give compound I-19 (50 mg). HRMS (ESI, [M+H] + ) m / z: 523.2818 1H NMR(500MHz,DMSO-d6)δ 9.72(s,1H),8.82(d,J=8.5Hz,1H),8.27(dd,J=4.8,1.5Hz,1H),7.71(dd,J=7.9,1.6Hz,1H),7.5 1(dd,J=16.0,8.4Hz,2H),7.04(dd,J=7.9,4.8Hz,1H),6.83(d,J=8.4Hz,1H),6.33(s,1H),4.36~ 4.26(m,4H),4.09(dd,J=11.1,4.1Hz,2H),3.64(s,2H),3.56(td,J=11.6,2.3Hz,2H),3.20(tt,J =11.8, 4.0Hz, 1H), 3.04(t,J=7.3Hz, 2H), 2.69(p,J=7.2Hz, 2H), 2.34(s, 6H), 1.78~1.71(m, 4H).

[0344] Example 20: Preparation of Compound I-20 [ka]

[0345] Step A: Preparation of Compound 20a Compound 4-hydrazino-6-hydroxypyrimidine (5.0 g), cyclopentanone (3.33 g), and methanol (25 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature to react. After completion of the reaction, the reaction solution was concentrated to give compound 20a (8.3 g). MS (ESI, [M+H] + ) m / z: 193.16.

[0346] Step B: Preparation of Compound 20b Compound 20a (8.3 g) and diethylene glycol (50 mL) were added sequentially to a microwave tube, and the mixture was stirred in a microwave at 245° C. After completion of the reaction, the reaction solution was poured into water and filtered. The residue was subjected to column chromatography (dichloromethane / methanol=20 / 1) to obtain compound 20b (2.3 g). MS (ESI, [M+H] + ) m / z: 176.10.

[0347] Step C: Preparation of Compound 20c Compound 20b (1.0 g), DMF (8 mL), and phosphorus oxybromide (3.48 mL) were added sequentially to a reaction flask, and the mixture was stirred at 80° C. After the reaction was completed, the mixture was adjusted to alkaline (pH approximately 10) by adding saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 25 / 1) to give compound 20c (0.54 g). MS (ESI, [M+H] + ) m / z: 238.0.

[0348] Step D: Preparation of Compound 20d To a reaction flask containing compound 20c (0.50 g) and DMF (5 mL), 60 wt% sodium hydride (0.126 g) was slowly added at 0 °C and stirred for 0.5 hours. Then, iodomethane (0.328 g) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature. After completion of the reaction, the reaction was quenched, extracted with ethyl acetate, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 20d (0.203 g). MS (ESI, [M+H] + ) m / z: 252.02.

[0349] Step E: Preparation of Compound 20e 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.020 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.033 g), potassium phosphate tripotassium (0.179 g), compound 20d (0.117 g), intermediate 5A (0.250 g), 1,4-dioxane (20 mL), and water (4 mL) were sequentially added to a microwave tube. The atmosphere was purged with nitrogen and the mixture was stirred at 85 °C in a microwave oven. After completion of the reaction, the reaction mixture was filtered and concentrated to obtain the crude product. Compound 20e (0.106 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 638.47.

[0350] Step F: Preparation of Compound I-20 Compound 20e (0.106 g), dichloromethane (2 mL), and a 4M solution of hydrochloric acid in 1,4-dioxane (0.5 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to approximately 10, followed by extraction with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound I-20 (40 mg). HRMS (ESI, [M+H] + ) m / z: 538.2919.

[0351] Example 21: Preparation of Compound I-21 [ka]

[0352] Step A: Preparation of Compound 21a Pyrrolidin-2-one (0.85 g), N,N-dimethylformamide (40 mL), and 60 wt% sodium hydride (0.55 g) were sequentially added to a reaction flask at 0°C under nitrogen protection, and the mixture was stirred at 0°C for 1 hour. 1-Bromo-3-fluoro-2-nitrobenzene (2.0 g) was added to the reaction flask, and the mixture was reacted with stirring at 0°C. After the reaction was completed, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 21a (1.0 g). MS (ESI, [M+H] + ) m / z: 285.0

[0353] Step B: Preparation of Compound 21b Compound 21a (1.0 g), reduced iron powder (0.9 g), ammonium chloride (0.9 g), ethanol (12 mL), and water (3 mL) were added sequentially to a reaction flask, and the mixture was reacted with stirring at 80° C. After completion of the reaction, the reaction solution was filtered and concentrated to obtain compound 21b (0.8 g). MS (ESI, [M+H] + ) m / z: 255.0 Step C: Preparation of Compound 21c Compound 21b (0.8 g) and acetic acid (20 mL) were added sequentially to a reaction flask, and the mixture was reacted with stirring at 110° C. After the reaction was completed, the mixture was concentrated, adjusted to pH 8-9 with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated to obtain compound 21c (0.7 g). MS (ESI, [M+H] + ) m / z: 237.1

[0354] Step D: Preparation of Compound 21d Compound 21c (0.4 g), 5,5,5',5'-tetramethyl-2,2'-bis(1,3,2-dioxetane) (0.57 g), [1,1-bis(diphenylphosphoferrocene)palladium dichloride (0.24 g)], potassium acetate (0.33 g), and 1,4-dioxane (15 mL) were sequentially added to a microwave tube, and the mixture was stirred at 125°C in a microwave oven. After completion of the reaction, the reaction mixture was filtered and concentrated to give compound 21d (0.3 g). MS (ESI, [M+H] + ) m / z: 203.2 Step E: Preparation of Compound 21e Intermediate 1A (0.22 g), compound 21d (0.3 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.3 g), potassium phosphate tripotassium (0.28 g), 1,4-dioxane (10 mL), and water (2 mL) were sequentially added to a reaction flask, followed by stirring at 100 °C. After completion of the reaction, the reaction solution was filtered and concentrated. Compound 21e (120 mg) was obtained by column chromatography (dichloromethane / methanol = 40 / 1). MS (ESI, [M+H] + ) m / z: 624.4 Step F: Preparation of Compound I-21 Compound 21e (120 mg), dichloromethane (10 mL), and a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M) were sequentially added to a reaction flask and allowed to react while stirring at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH (approximately 10) by adding saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-21 (8 mg). HRMS (ESI, [M+H] + ) m / z: 524.2767 1 H NMR(500MHz,CDCl3)δ 10.29(d,J=16.1Hz,1H),9.34(d,J=14.7Hz,1H),7.52(s,2H),7.34(s,1H),7.23(s,1H),6.80(s,1H),6.36(d,J=14.1Hz,1H),4.73(d,J=1 6.2Hz,2H),4.12(d,J=46.4Hz,4H),3.59(d,J=42.9Hz,4H),3.22(s,1H),3.07(s,2H),2.74(s,2H),2.29(s,6H),1.25(s,3H),0.84(s,1H).

[0355] Example 22: Preparation of Compound I-22 [ka]

[0356] Step A: Preparation of Compound 22a Compound 2-iodoaniline (25.0 g), dichloromethane (500.0 mL), triethylamine (17.3 g), and trifluoroacetic anhydride (28.8 g) were sequentially added to a reaction flask. After the addition, the mixture was allowed to react at room temperature with stirring. After the reaction was completed, the reaction solution was extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound 22a (34.2 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 316.2.

[0357] Step B: Preparation of Compound 22b Compound 22a (34.2 g), dimethyl sulfoxide (500.0 mL), potassium carbonate (29.8 mL), L-proline (2.4 mL), malononitrile (8.6 mL), and cuprous iodide (2.0 mL) were sequentially added to a reaction flask. After the addition, the atmosphere was replaced with nitrogen, and the reaction was carried out with stirring at 60 °C. After completion of the reaction, the reaction solution was filtered and concentrated. Compound 22b (15.9 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 158.2.

[0358] Step C: Preparation of Compound 22c Compound 22b (15.9 g), triethyl orthoformate (105.0 g), and acetonitrile (150.0 mL) were sequentially added to a reaction flask. After the addition, the mixture was reacted at 95°C with stirring. After the reaction was completed, the reaction solution was filtered and concentrated, and compound 22c (14.4 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 214.2.

[0359] Step D: Preparation of Compound 22d Compound 22c (14.4 g), a methanol solution of ammonia (96.0 mL, 7 M), and methanol (10 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at 105 °C while reacting. After the reaction was completed, the reaction solution was extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 22d (14.4 g). MS (ESI, [M+H] + ) m / z: 185.2.

[0360] Step E: Preparation of Compound 22e Compound 22d (14.4 g), water (500 mL), acetic acid (150 mL), and sodium nitrite (26.9 g) were sequentially added to a reaction flask. After the addition, the mixture was stirred at 60 °C and reacted. After the reaction was completed, the reaction mixture was extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound 22e (12.0 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 186.3.

[0361] Step F: Preparation of Compound 22f Compound 22e (12.0 g) and phosphorus oxychloride (150.0 mL) were sequentially added to a reaction flask. After the addition, the mixture was reacted at 120°C with stirring. After the reaction was completed, the reaction solution was concentrated under reduced pressure, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound 22f (6.8 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 204.2.

[0362] Step G: Preparation of Compound 22g Compound 22f (0.16 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.02 g), potassium phosphate (0.3 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.07 g), Intermediate 5A (0.4 g), water (3.0 mL), and 1,4-dioxane (12.0 mL) were sequentially added to a reaction flask. The mixture was stirred at 85 °C. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain Compound 22g (0.08 g). MS (ESI, [M+H] + ) m / z: 634.4.

[0363] Step H: Preparation of Compound I-22 Compound 22g (0.08 g), dichloromethane (10 mL), and a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M) were sequentially added to a reaction flask and stirred at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 10) with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-22 (0.013 g). HRMS (ESI, [M+H] + ) m / z: 534.2617. 1H NMR(500MHz,CDCl3)δ 9.00~8.85(m,2H),8.04(d,J=8.6Hz,1H),7.85(d,J=8.0Hz,1H),7.61~7.56(m,2H),7 .53(t,J=7.7Hz,1H),7.35(s,2H),7.22(t,J=7.6Hz,1H),6.91(d,J=8.4Hz,1H),4.65( s,2H),4.11(dd,J=11.6,3.9Hz,2H),3.67(s,2H),3.60(d,J=11.6Hz,2H),3.38(s,1H) ,3.26~3.13(m,1H),2.37(s,6H),2.02(t,J=6.6Hz,1H),0.87(dd,J=15.8,8.7Hz,2H).

[0364] Example 23: Preparation of Compound I-23 [ka]

[0365] Step A: Preparation of Compound 23a 3-Azabicyclo[3.1.0]hexane hydrochloride (20 g), triethylamine (30 g), di-t-butyl dicarbonate (52 g), and dichloromethane (300 mL) were added to a reaction flask in that order, and the mixture was allowed to react at room temperature. After the reaction was completed, the mixture was adjusted to an alkaline pH (approximately 9) with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 45 / 1) to give compound 23a (32 g). MS (ESI, [M+H] + ) m / z: 184.3.

[0366] Step B: Preparation of Compound 23b Compound 23a (15 g), ruthenium dioxide (2.5 g), sodium periodate (90 g), ethyl acetate (300 mL), and water (100 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was filtered, the ethyl acetate was extracted, the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 45 / 1) to give compound 23b (12 g). MS (ESI, [M+H] + ) m / z: 198.2.

[0367] Step C: Preparation of Compound 23c Compound 23b (10 g), a 4 M solution of hydrochloric acid in 1,4-dioxane (10 mL), and dichloromethane (100 mL) were added to a reaction flask in that order, and the mixture was allowed to react at room temperature. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added to adjust the pH to approximately 9, and the mixture was extracted with dichloromethane. The organic phase was dried, filtered, and concentrated to give compound 23c (6 g). MS (ESI, [M+H] + ) m / z: 98.3.

[0368] Step D: Preparation of Compound 23d Compound 23c (6 g), trimethyloxonium tetrafluoroboronic acid (12 g), and dichloromethane (80 mL) were added sequentially to a reaction flask in an ice-water bath, and the mixture was stirred at room temperature. After completion of the reaction, water was added to the reaction mixture to quench the reaction, followed by extraction with dichloromethane. The organic phase was dried, filtered, and concentrated to give compound 23d (5.9 g). The concentrated crude product was used directly in the next step.

[0369] Step E: Preparation of Compound 23e Compound 23d (5 g), hydrazine formate (2.7 g), acetic acid (0.6 mL), and n-butanol (25 mL) were added sequentially to a reaction flask, and the mixture was protected with nitrogen and reacted with stirring at 120° C. After completion of the reaction, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 45 / 1) to obtain compound 23e (2.1 g). MS (ESI, [M+H] + ) m / z: 122.3.

[0370] Step F: Preparation of Compound 23f Compound 23e (2 g), N-bromosuccinimide (3.2 g), sodium carbonate (1.8 g), and chloroform (30 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated, extracted with dichloromethane, and the organic phase was dried and filtered to obtain compound 23f (1.2 g). MS (ESI, [M+H] + ) m / z: 200.0.

[0371] Step G: Preparation of Compound 23g Compound 23f (0.5 g), Intermediate 5A (1.2 g), potassium phosphate (0.4 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.22 g), and 1,4-dioxane (20 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and reacted at 100°C with stirring. The reaction solution was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain Compound 23g (0.6 g). MS (ESI, [M+H] + ) m / z: 586.3.

[0372] Step H: Preparation of Compound I-23 Compound 23g (0.6 g), a 4 M solution of hydrochloric acid in 1,4-dioxane (2 mL), and dichloromethane (10 mL) were added to a reaction flask in that order, and the mixture was stirred at room temperature. After the reaction was completed, saturated aqueous sodium bicarbonate was added to adjust the pH to approximately 9, followed by extraction with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 9 / 1) to give compound I-23 (0.24 g). HRMS (ESI, [M+H] + ) m / z: 486.2614. 1 H NMR(500MHz,CDCl3:CD3OD=10:1)δ 8.85(d,J=8.7Hz,1H),7.60(d,J=8.7Hz,1H),7.54(d,J=8.5Hz,1H),6.84(d,J=8.4Hz, 1H),4.85~4.68(m,2H),4.45~4.31(m,2H),4.10(dd,J=11.3,4.0Hz,2H),3.69(s,1H),3 .61~3.54(m,4H),3.29(s,1H),3.21~3.12(m,1H),2.70~2.55(m,2H),2.39(s,6H),1.7 9(dd,J=12.7, 4.3Hz, 2H), 1.75~1.65(m,2H), 1.53~1.43(m,1H), 0.88(d,J=4.8Hz, 1H).

[0373] Example 24: Preparation of Compound I-24 [ka]

[0374] Step A: Preparation of Compound 24a Compound 20b (0.6 g) and phosphorus oxychloride (9.58 mL) were sequentially added to a reaction flask, and the mixture was stirred at 100° C. After completion of the reaction, the reaction solution was concentrated, diluted with dichloromethane to quench the reaction, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and subjected to column chromatography (petroleum ether / ethyl acetate=4 / 1) to give compound 24a (0.623 g). MS (ESI, [M+H] + ) m / z: 194.04.

[0375] Step B: Preparation of Compound 24b Compound 24a (0.2 g), 4-dimethylaminopyridine (0.025 g), DMF (5 mL), and di-t-butyl dicarbonate (0.2 g) were added to a reaction flask in this order and stirred at room temperature. After completion of the reaction, the reaction solution was concentrated. Compound 24b (0.24 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 4 / 1). MS (ESI, [M+H]+ ) m / z: 294.4.

[0376] Step C: Preparation of Compound 24c Compound 24b (0.099 g), Intermediate 5A (0.2 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.016 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.027 g), potassium phosphate tripotassium (0.143 g), 1,4-dioxane (5 mL), and water (1 mL) were sequentially added to a reaction flask, purged with nitrogen, and the reaction was carried out in a microwave oven at 85 °C. After completion of the reaction, the reaction mixture was filtered and concentrated to obtain the crude product. Compound 24c (0.250 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 724.45.

[0377] Step D: Preparation of Compound 24d Compound 24c (0.250 g), dichloromethane (2 mL), and a 1,4-dioxane solution of hydrochloric acid (0.5 mL, 4 M) were added to a reaction flask in that order, and the mixture was stirred at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to approximately 10, and dichloromethane was added for extraction. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 24d (0.020 g). MS (ESI, [M+H] + ) m / z: 524.30.

[0378] Step E: Preparation of Compound I-24 Compound 24d (0.020 g), dichloromethane (5 mL), and a 1,4-dioxane solution of hydrochloric acid (0.4 mL, 0.1 M) were sequentially added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated and purified by trituration with methanol to obtain compound I-24 (0.008 g). HRMS (ESI, [M+H] + ) m / z: 524.2770.

[0379] Example 25: Preparation of Compound I-25 [ka]

[0380] Step A: Preparation of Compound 25a Intermediate 1A (0.5 g), hexamethylditin (0.46 g), bistriphenylphosphinepalladium dichloride (0.07 g), and toluene (30 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and reacted with stirring at 110° C. After completion of the reaction, the mixture was extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 25a (0.32 g). MS (ESI, [M+H] + ) m / z: 632.4.

[0381] Step B: Preparation of Compound 25b Compound 25a (0.20 g), compound 18c (0.10 g), cuprous iodide (0.2 mg), tetra(triphenylphosphine)palladium (0.01 g), and 1,4-dioxane (45 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and stirred at 100° C. After completion of the reaction, the mixture was extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound 25b (0.06 g). MS (ESI, [M+H] + ) m / z: 625.1.

[0382] Step C: Preparation of Compound I-25 Compound 25b (0.06 g), dichloromethane (10 mL), and a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M) were added to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, the mixture was adjusted to an alkaline pH of approximately 10 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-25 (10 mg). HRMS (ESI, [M+H] + ) m / z: 525.2721 1 H NMR (500 MHz, CDCl3) δ 10.31(s,1H),9.46(s,1H),7.68(d,J=9.1Hz,1H),7.56(d,J=8.5Hz,1H),7.30 (d,J=9.2Hz,1H),6.86(d,J=8.4Hz,1H),6.65(s,1H),4.88(s,2H),4.10(dd,J= 10.9,4.4Hz,2H),3.65(s,2H),3.56(td,J=11.7,2.4Hz,2H),3.27(t,J=7.7Hz, 2H), 2.98 (t, J=7.5Hz, 2H), 2.32 (s, 6H), 2.25~2.14 (m, 2H), 1.80~1.69 (m, 5H).

[0383] Example 26: Preparation of Compound I-26 [ka]

[0384] Step A: Preparation of Compound 26a Tetrahydrofuran (40 mL) and 60 wt% sodium hydride (7.13 g) were sequentially added to a reaction flask at room temperature, and a tetrahydrofuran solution (15 mL) of cyclohexanone (6 g) was added dropwise. The mixture was then placed at 0° C., and an ethanol solution of ethyl formate (0.75 mL) was added dropwise. The mixture was then reacted at 0° C. After completion of the reaction, the reaction was quenched, and water and ethyl acetate were added to separate the mixture. The aqueous phase was separated and adjusted to pH 3 with hydrochloric acid. The mixture was extracted with ethyl acetate. The organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 26a (4.1 g). MS(ESI, [MH] - ) m / z: 111.01.

[0385] Step B: Preparation of Compound 26b Compound 26a (1.5 g), ethanol (15 mL), trifluoroacetic acid (0.5 mL), and 4-amino-1,2,4-triazole (1.125 g) were added sequentially to a reaction flask at 0° C., and the mixture was stirred at 0° C. for 1 hour, followed by microwave heating at 100° C. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol=20 / 1) to give compound 26b (1.2 g). MS (ESI, [M+H] + ) m / z: 161.04.

[0386] Step C: Preparation of Compound 26c Compound 26b (0.2 g), dichloromethane (5 mL), and N-bromosuccinimide (0.333 g) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 26c (0.195 g). MS (ESI, [M+H] + ) m / z: 239.0.

[0387] Step D: Preparation of Compound 26d Compound 26c (0.089 g), Intermediate 5A (0.22 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.018 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.029 g), potassium phosphate tripotassium (0.158 g), 1,4-dioxane (20 mL), and water (4 mL) were sequentially added to a reaction flask. The atmosphere was purged with nitrogen and the reaction was stirred at 85 °C in a microwave oven. After completion of the reaction, the reaction mixture was filtered and concentrated to obtain the crude product. Compound 26d (0.106 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 625.39.

[0388] Step E: Preparation of Compound I-26 Compound 26d (0.106 g), dichloromethane (2 mL), and a 1,4-dioxane solution of hydrochloric acid (0.4 mL, 4 M) were sequentially added to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to approximately 10, and dichloromethane was added for extraction. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound I-26 (0.023 g). HRMS (ESI, [M+H] + ) m / z: 525.2725. 1H NMR (500 MHz, DMSO-d6) δ 10.16(s,1H),8.90(s,1H),8.71(dd,J=22.4,8.8Hz,2H),8.10(s,1H),7.66(d,J =8.4Hz,1H),6.94(d,J=8.4Hz,1H),4.70(s,2H),3.96(d,J=10.3Hz,2H),3.59(s, 2H),3.44(dd,J=11.3,9.2Hz,2H),3.20(dd,J=13.2,9.1Hz,1H),3.07(t,J=7.4H z, 2H), 2.99 (t, J=7.1Hz, 2H), 2.24 (s, 6H), 2.20~2.12 (m, 2H), 1.74~1.59 (m, 4H).

[0389] Example 27: Preparation of Compound I-27 [ka]

[0390] Step A: Preparation of Compound 27a Compound 2-chloro-5-chloromethylpyridine (15.0 g), acetone (120.0 mL), and potassium ethylxanthate (14.8 g) were sequentially added to a reaction flask. After the addition, the mixture was allowed to react at room temperature with stirring. After the reaction was completed, the reaction mixture was extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound 27a (23.1 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 248.0.

[0391] Step B: Preparation of Compound 27b Compound 27a (23.1 g), 1,2-dichloroethane (50.0 mL), vinyltrimethylsilane (54.4 mL), and dilauroyl peroxide (16.3 mL) were sequentially added to a reaction flask. After the addition, the atmosphere was replaced with nitrogen, and the reaction was carried out with stirring at 40 °C. After the reaction was completed, the reaction solution was filtered and concentrated. Compound 27b (13.0 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 348.1.

[0392] Step C: Preparation of Compound 27c Compound 27b (13.0 g), dilauroyl peroxide (2.9 g), acetonitrile (80.0 mL), and trifluoroacetic acid (3.1 mL) were sequentially added to a reaction flask. After the addition, the mixture was reacted at 80°C with stirring. After the reaction was completed, the reaction solution was filtered and concentrated, and compound 27c (2.1 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 154.2.

[0393] Step D: Preparation of Compound 27d Compound 27c (2.1 g) and hydrazine hydrate (1.9 mL) were added sequentially to a reaction flask. After the addition, the mixture was reacted at 120°C with stirring. After the reaction was completed, the mixture was extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 27d (1.3 g). MS (ESI, [M+H] + ) m / z: 150.0.

[0394] Step E: Preparation of Compound 27e Compound 27d (1.2 g), imidazole hydrochloride (1.2 g), and N,N-dimethylformamide (50.0 mL) were sequentially added to a reaction flask. After the addition, the mixture was reacted at 160 °C with stirring. After the reaction was completed, the mixture was extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound 27e (0.8 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 160.0.

[0395] Step F: Preparation of Compound 27f Compound 27e (0.8 g), dichloromethane (20.0 mL), and N-bromosuccinimide (0.59 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at 45°C and reacted. After completion of the reaction, the reaction solution was concentrated. Compound 27f (0.09 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 238.1.

[0396] Step G: Preparation of Compound 27g Compound 27f (0.09 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.02 g), potassium phosphate (0.3 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.07 g), Intermediate 5A (0.4 g), water (3.0 mL), and 1,4-dioxane (12.0 mL) were sequentially added to a reaction flask. The mixture was stirred at 85 °C. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain Compound 27g (0.13 g). MS (ESI, [M+H] + ) m / z: 624.3.

[0397] Step H: Preparation of Compound I-27 Compound 27g (0.13 g), dichloromethane (2 mL), and a 1,4-dioxane solution of hydrochloric acid (0.4 mL, 4 M) were sequentially added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH (approximately 10) with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound I-27 (0.03 g). HRMS (ESI, [M+H] + ) m / z: 524.2754. 1H NMR(500MHz,CDCl3)δ 9.95(s,1H),8.99(d,J=8.7Hz,1H),8.15~8.10(m,1H),7.77(d,J=8.6Hz,1H),7.59~ 7.55(m,1H),7.53(d,J=8.5Hz,1H),6.84(d,J=8.4Hz,1H),6.40(s,1H),4.73(s,2H) ,4.09(dd,J=11.1,4.1Hz,2H),3.64(s,2H),3.55(td,J=11.7,2.2Hz,2H),3.21(m,1 H),2.93(td,J=7.3,1.7Hz,2H),2.33(s,6H),2.22~2.13(m,2H),1.76~1.68(m,4H).

[0398] Example 28: Preparation of Compound 28 [ka]

[0399] Step A: Preparation of Compound 28a Intermediate 5A (230 mg), Intermediate 6A (110 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (31 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (19 mg), potassium phosphate tripotassium (165 mg), 1,4-dioxane (3.5 mL), and water (0.5 mL) were sequentially added to a microwave tube and stirred at 85 °C under nitrogen protection. After completion of the reaction, the reaction mixture was filtered and concentrated. Compound 28a (72 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 623.34.

[0400] Step B: Preparation of Compound I-28 Compound 28a (99 mg), dichloromethane (5.00 mL), and methanesulfonic acid (0.1 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to approximately 10, followed by extraction with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane ether / methanol = 10 / 1) to give compound I-28 (20 mg). HRMS (ESI, [M+H] + ) m / z: 523.2457. 1 H NMR(500MHz,CDCl3)δ 9.83(s,1H),8.96(d,J=8.5Hz,1H),7.66(s,1H),7.62~7.51(m,5H),6.86(d,J=8.4Hz,1H),6.34~6.27(m,2H),4. 24(s,2H),4.13~4.06(m,2H),3.64(s,2H),3.58~3.53(m,2H),3.24~3.19(m,1H),2.33(s,6H),1.80~1.69(m,4H).

[0401] Example 29: Preparation of Compound I-29 [ka]

[0402] Step A: Preparation of Compound 29a 2-Chloro-6,7-dihydro-5H-2,3-cyclopentenopyridine (5.0 g), tris(dibenzylideneacetone)dipalladium (0.6 g), benzophenone imine (2.83 g), sodium t-butoxide (6.25 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.4 g), and toluene (80 mL) were sequentially added to a reaction flask, and the mixture was stirred at 80° C. After completion of the reaction, the mixture was extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 29a (4.1 g). MS (ESI, [M+H] + ) m / z: 301.2.

[0403] Step B: Preparation of Compound 29b Compound 29a (4.1 g), dichloromethane (50 mL), and concentrated hydrochloric acid (20 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH of approximately 10 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound 29b (1.6 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 135.3.

[0404] Step C: Preparation of Compound 29c Compound 29b (1.6 g), ethanol (30 mL), and 2-chloroacetaldehyde (10.6 g) were sequentially added to a reaction flask, and the mixture was reacted with stirring at 80° C. After the reaction was completed, the mixture was concentrated, and saturated sodium bicarbonate solution was added to adjust the pH to approximately 10. Dichloromethane was added for extraction, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 29c (1.3 g). MS (ESI, [M+H] + ) m / z: 159.4.

[0405] Step D: Preparation of Compound 29d Compound 29c (1.3 g), CCl4 (30 mL), and NBS (0.4 g) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction was quenched by adding saturated sodium thiosulfate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 29d (1.6 g). MS (ESI, [M+H] + ) m / z: 237.0.

[0406] Step E: Preparation of Compound 29e Compound 29d (0.17 g), Intermediate 5A (0.17 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.02 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.03 g), potassium phosphate (0.09 g), water (2.00 mL), and 1,4-dioxane (15 mL) were sequentially added to a reaction flask. The mixture was then protected with nitrogen and stirred at 85 °C. After completion of the reaction, the reaction mixture was concentrated. Compound 29e (0.11 g) was obtained by column chromatography (dichloromethane / methanol = 10 / 1). MS (ESI, [M+H] + ) m / z: 623.4.

[0407] Step F: Preparation of Compound I-29 Compound 29e (0.11 g), dichloromethane (10 mL), and a 4M solution of hydrochloric acid in 1,4-dioxane (2 mL) were added to a reaction flask in that order and allowed to react at room temperature with stirring. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to approximately 10, and dichloromethane was added for extraction. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-29 (52 mg). HRMS (ESI, [M+H] + ) m / z: 523.2984 1H NMR(500MHz,CDCl3)δ 9.75(s,1H),8.86(d,J=8.5Hz,1H),7.55(s,1H),7.52(dd,J=8.8,4.2Hz,2H),7.4 6(d,J=8.5Hz,1H),7.16(d,J=9.0Hz,1H),6.83(d,J=8.5Hz,1H),6.27(s,1H),4.13 ~4.05(m,2H),3.61(d,J=9.3Hz,2H),3.55(td,J=11.6,2.4Hz,2H),3.20(tt,J=11. 7,3.9Hz,1H),2.88(t,J=7.5Hz,2H),2.31(s,6H),2.05(s,3H),1.83~1.68(m,7H).

[0408] Example 30: Preparation of Compound I-30 [ka]

[0409] Step A: Preparation of Compound 30a Compound cyclopentanone (6.0 g), 60 wt% sodium hydride (7.2 g), and ethyl formate (21.1 g) were sequentially added to a reaction flask. After the addition, the mixture was allowed to react while stirring at 0°C. After the reaction was completed, water was added to the reaction solution to quench the reaction, followed by extraction with dichloromethane. The organic phase was dried, filtered, and concentrated, and then purified by column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 30a (2.0 g). MS (ESI, [M+H] + ) m / z: 113.0.

[0410] Step B: Preparation of Compound 30b Compound 30a (2.0 g), trifluoroacetic acid (1.1 mL), 5-amine-1H-pyrazole (1.2 g), and ethanol (20.0 mL) were sequentially added to a reaction flask at 0°C. After the addition, the mixture was stirred at 0°C while reacting. After the reaction was completed, the reaction solution was filtered and concentrated. Compound 30b (1.6 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H]+ ) m / z: 160.0.

[0411] Step C: Preparation of Compound 30c Compound 30b (1.6 g), N-bromosuccinimide (1.3 g), and acetonitrile (40.0 mL) were added sequentially to a reaction flask at 0° C. After the addition, the mixture was reacted with stirring at 0° C. After the reaction was completed, the reaction solution was filtered and concentrated, and then purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 30c (1.2 g). MS (ESI, [M+H] + ) m / z: 238.0.

[0412] Step D: Preparation of Compound 30d Compound 30c (0.2 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.03 g), potassium phosphate (1.2 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.07 g), Intermediate 5A (0.4 g), water (3.0 mL), and 1,4-dioxane (12.0 mL) were sequentially added to a reaction flask. The atmosphere was then purged with nitrogen and the reaction was carried out at 85 °C with stirring. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 30d (0.2 g). MS (ESI, [M+H] + ) m / z: 624.7.

[0413] Step E: Preparation of Compound I-30 Compound 30d (0.2 g), dichloromethane (10 mL), and a 4M solution of hydrochloric acid in 1,4-dioxane (2 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH of approximately 10 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-30 (0.05 g). HRMS (ESI, [M+H] + ) m / z: 524.2754. 1 H NMR(500MHz,CDCl3)δ 9.75(s,1H),8.80(d,J=8.6Hz,1H),8.45(d,J=1.5Hz,1H),8.12(s,1H),7.96(d,J=8.6H) z,1H),7.49(d,J=8.5Hz,1H),6.83(d,J=8.5Hz,1H),6.41(s,1H),4.62(s,2H),4.14~4.0 3(m,2H),3.66(s,2H),3.56(td,J=11.6,2.3Hz,2H),3.20(td,J=12.0,6.2Hz,1H),3.11 ~2.96(m,4H),2.35(s,6H),2.26(p,J=7.5Hz,2H),1.83~1.75(m,2H),1.74~1.67(m,2H).

[0414] Example 31: Preparation of Compound I-31 [ka]

[0415] Step A: Preparation of Compound 31a Compound 4j (0.15 g), intermediate 5A (0.17 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.02 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.03 g), potassium phosphate (0.09 g), water (2.00 mL), and 1,4-dioxane (15 mL) were sequentially added to a reaction flask. The mixture was then protected with nitrogen and stirred at 85 °C. After completion of the reaction, the reaction mixture was concentrated. Compound 31a (0.11 g) was obtained by column chromatography (dichloromethane / methanol = 10 / 1). MS (ESI, [M+H] + ) m / z: 586.4.

[0416] Step B: Preparation of Compound I-31 Compound 31a (0.11 g), dichloromethane (10 mL), and a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M) were added to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 10) with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound I-31 (36 mg). HRMS (ESI, [M+H] + ) m / z: 486.2615 1 H NMR(500MHz,CDCl3)δ 9.99(s,1H),8.92(d,J=8.7Hz,1H),7.89(d,J=8.7Hz,1H),7.52(d,J=8.4Hz,1H),6.83(d,J=8.4Hz,1H), 6.30(s,1H),4.93(d,J=19.0Hz,1H),4.73(d,J=19.1Hz,1H),4.09(dd,J=10.9,4.4Hz,2H),4.03(td,J=5. 9,2.2Hz,1H),3.69~3.58(m,2H),3.55(td,J=11.6,2.3Hz,2H),3.33~3.16(m,2H),3.10(d,J=17.3Hz,1H) ,2.39(dq,J=12.1,6.2Hz,1H),2.31(s,5H),1.88~1.67(m,4H),1.42(dt,J=8.8,6.1Hz,1H),1.25(s,1H).

[0417] Example 32: Preparation of Compound I-32 [ka]

[0418] Step A: Preparation of Compound 32a 5-Chloro-1H-pyrrolo[3,2-B]pyridine (6 g), cesium carbonate (12.81 g), DMF (120 mL), and iodomethane (5.58 g) were added sequentially to a reaction flask, and the mixture was stirred at 60 °C. After completion of the reaction, the reaction mixture was extracted with water and ethyl acetate, and the organic phase was collected, dried, filtered, and concentrated. Compound 32a (4.4 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS(ESI, [MH] - ) m / z: 167.19.

[0419] Step B: Preparation of Compound 32b Sodium t-butoxide (4.33 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (2.242 g), tris(dibenzylideneacetone)dipalladium (2.473 g), benzophenone imine (4.90 g), compound 32a (3.0 g), and toluene (50 mL) were sequentially added to a reaction flask. The atmosphere was replaced with nitrogen, and the reaction was carried out with stirring at 80 °C. After completion of the reaction, the reaction solution was filtered and concentrated. Compound 32b (2.0 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 1 / 4). MS(ESI, [MH] - ) m / z: 312.36.

[0420] Step C: Preparation of Compound 32c Compound 32b (2.0 g), dichloromethane (20 mL), and a 4M solution of hydrochloric acid in 1,4-dioxane (8 mL) were added to a reaction flask, followed by stirring at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH of approximately 10 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound 32c (0.70 g) was obtained by column chromatography (dichloromethane / methanol = 10 / 1). MS(ESI, [MH] - ) m / z: 148.11.

[0421] Step D: Preparation of Compound 32d Compound 32c (0.7 g), ethanol (20 mL), potassium carbonate (1.315 g), and chloroacetaldehyde (1.12 g) were sequentially added to a reaction flask, and the mixture was stirred at 90°C. After completion of the reaction, the reaction solution was concentrated. Compound 32d (0.68 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS(ESI, [MH] - ) m / z: 172.27.

[0422] Step E: Preparation of Compound 32e Compound 32d (0.25 g), DMSO (5 mL), sodium carbonate (0.310 g), and dibromobenzene (0.209 g) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was extracted with water and ethyl acetate. The organic phase was dried, filtered, and concentrated. The residue was subjected to column chromatography (dichloromethane / methanol = 20 / 1) to give compound 32e (0.223 g). MS (ESI, [M+H] + ) m / z: 250.05.

[0423] Step F: Preparation of Compound 32f Compound 32e (0.106 g), Intermediate 5A (0.25 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.02 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.033 g), potassium phosphate tripotassium (0.179 g), 1,4-dioxane (5 mL), and water (1 mL) were sequentially added to a reaction flask. The atmosphere was purged with nitrogen and the reaction was stirred at 85 °C in a microwave oven. After completion of the reaction, the reaction mixture was filtered and concentrated to obtain the crude product. Compound 32f (0.106 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 636.44.

[0424] Step G: Preparation of Compound I-32 Compound 32f (0.106 g), dichloromethane (2 mL), and a 4M solution of hydrochloric acid in 1,4-dioxane (0.4 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH of approximately 10 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound I-32 (0.025 g) was obtained by column chromatography (dichloromethane / methanol = 10 / 1). HRMS (ESI, [M+H] + ) m / z: 536.2776. 1 H NMR(500MHz,DMSO-d6)δ 9.98(s,1H),8.70(d,J=6.3Hz,2H),7.71~7.54(m,4H),7.34(d,J=9.5Hz,1 H),7.17(d,J=3.0Hz,1H),6.96(d,J=8.4Hz,1H),5.70(d,J=3.0Hz,1H),4. 18(s,2H),4.00~3.92(m,2H),3.84(s,3H),3.61(s,2H),3.44(dd,J=11.4, 9.4Hz, 2H), 3.18 (dd, J=13.3, 9.4Hz, 1H), 2.25 (s, 6H), 1.72~1.59 (m, 4H).

[0425] Example 33: Preparation of Compound I-33 [ka]

[0426] Step A: Preparation of Compound 33a 5-Chlorofuran[3,2-b]pyridine (1.5 g), t-butylhydrazinoformate (1.6 g), cesium carbonate (4.4 g), tris(dibenzylideneacetone)dipalladium (0.92 g), 1,1'-bis(diphenylphosphine)ferrocene (1.10 g), and toluene (20 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and reacted at 100°C with stirring. The reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 6 / 1) to obtain Compound 33a (1.6 g). MS (ESI, [M+H] + ) m / z: 250.2.

[0427] Step B: Preparation of Compound 33b Compound 33a (1.6 g), a 1,4-dioxane solution of hydrochloric acid (4 M, 2 mL), and dichloromethane (10 mL) were added to a reaction flask in that order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 9 / 1) to give compound 33b (1.2 g). MS (ESI, [M+H] + ) m / z: 150.2.

[0428] Step C: Preparation of Compound 33c Compound 33b (1.2 g), imidazole (80 mg), and N,N-dimethylformamide (10 mL) were sequentially added to a reaction flask, and the mixture was then protected with nitrogen and reacted with stirring at 170° C. After completion of the reaction, the reaction mixture was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 33c (0.8 g). MS (ESI, [M+H] + ) m / z: 160.2.

[0429] Step D: Preparation of Compound 33d Compound 33c (0.8 g), N-bromosuccinimide (0.75 g), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was quenched by adding aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 33d (0.7 g). MS (ESI, [M+H] + ) m / z: 238.1.

[0430] Step E: Preparation of Compound 33e Compound 33d (0.7 g), Intermediate 5A (0.9 g), potassium phosphate (0.2 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.15 g), 1,4-dioxane (20 mL), and water (1 mL) were sequentially added to a reaction flask. The mixture was protected with nitrogen and reacted at 100°C with stirring. The reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 15 / 1) to obtain Compound 33e (0.2 g). MS (ESI, [M+H] + ) m / z: 624.5.

[0431] Step F: Preparation of Compound I-33 Compound 33e (0.2 g), a 1,4-dioxane solution of hydrochloric acid (4 M, 1 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 9 / 1) to give compound I-33 (0.11 g). HRMS (ESI, [M+H] + ) m / z: 524.2407. 1H NMR(500MHz,CDCl3:CD3OD=10:1)δ 9.00(s,1H)7.76(d,J=8.6Hz,1H),7.70(d,J=6.3Hz,3H),7.57(d,J=8.5Hz ,1H),6.90(d,J=8.5Hz,1H),6.77(d,J=2.2Hz,1H),4.58(s,2H),4.11(dd, J=11.4,4.0Hz,2H),3.68(s,2H),3.58(t,J=11.5Hz,2H),3.28-3.08(m,1H ),2.36(s,6H),1.80(dd,J=12.6,4.1Hz,2H)1.74(dd,J=12.6,4.1Hz,2H).

[0432] Example 34: Preparation of Compound I-34 [ka]

[0433] Step A: Preparation of Compound 34a To a reaction flask, intermediate 9A (0.7 g), intermediate 5A (0.9 g), potassium phosphate (0.2 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.15 g), 1,4-dioxane (20 mL), and water (1 mL) were sequentially added. The mixture was protected with nitrogen and reacted at 100°C with stirring. The reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 15 / 1) to obtain compound 34a (0.2 g). MS (ESI, [M+H] + ) m / z: 599.5.

[0434] Step B: Preparation of Compound I-34 Compound 34a (0.2 g), a 4 M solution of hydrochloric acid in dioxane (1 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 9 / 1) to give compound I-34 (0.08 g). HRMS (ESI, [M+H] + ) m / z: 499.2818. 1 H NMR(500MHz,CDCl3:CD3OD=10:1)δ 8.72(dd,J=8.6,2.5Hz,1H),7.64(d,J=2.4Hz,1H),7.47(ddd,J=26.6,8.6,2 .4Hz,2H),6.81(dd,J=8.5,2.2Hz,1H),4.51(d,J=2.2Hz,2H),4.16~4.05(m,4 H),3.63(s,2H),3.56(t,J=11.8Hz,2H),3.20(t,J=2.5Hz,2H),3.10(d,J=2.3 Hz,2H), 2.36(s,6H), 1.83~1.74(m,2H), 1.72(s,2H), 0.89(d,J=10.0Hz,4H).

[0435] Example 35: Preparation of Compound I-35 [ka]

[0436] Step A: Preparation of Compound 35a Compound 2, 3-dihydro-furo[3,2-B]pyridin-5-amine (0.7 g), ethanol (20 mL), potassium carbonate (1.766 g), and chloroacetaldehyde (2.018 g) were sequentially added to a reaction flask, and the mixture was stirred at 90°C. After completion of the reaction, the reaction solution was concentrated. Compound 35a (0.60 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 161.23.

[0437] Step B: Preparation of Compound 35b Compound 35a (0.30 g), DMSO (5 mL), sodium carbonate (0.199 g), and dibromobenzene (0.268 g) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was extracted with water and ethyl acetate. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 35b (0.340 g). MS (ESI, [M+H] + ) m / z: 239.21.

[0438] Step C: Preparation of Compound 35c Compound 35b (0.101 g), Intermediate 5A (0.25 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.02 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.033 g), potassium phosphate tripotassium (0.179 g), 1,4-dioxane (5 mL), and water (1 mL) were sequentially added to a reaction flask. The atmosphere was purged with nitrogen and the reaction was stirred at 85 °C in a microwave oven. After completion of the reaction, the reaction mixture was filtered and concentrated to give the crude product. Compound 35c (0.156 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 625.49.

[0439] Step D: Preparation of Compound I-35 Compound 35c (0.106 g), dichloromethane (2 mL), and a 4M solution of hydrochloric acid in 1,4-dioxane (0.4 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH of approximately 10 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound I-35 (0.012 g). HRMS (ESI, [M+H] + ) m / z: 525.2621. 1 H NMR(500MHz,CDCl3)δ 8.81(d,J=8.4Hz,1H),7.54~7.39(m,4H),7.00(d,J=9.6Hz,1H),6.81(d,J=8.3Hz,1H),4.52(t,J=8.7Hz,2H),4.18(s,2H),4.06(d, J=9.3Hz,2H),3.60(s,2H),3.53(t,J=11.2Hz,2H),3.14(t,J=11.5Hz,1H),2.88(s,2H),2.30(s,6H),1.72(dt,J=27.0,11.4Hz,4H).

[0440] Example 36: Preparation of Compound I-36 [ka]

[0441] Step A: Preparation of Compound 36a 4-Chloro-2-methanesulfonylpyrimidine (6 g), THF (120 mL), 3-butyn-1-ol (2.2 g), and 60 wt% sodium hydride (1.246 g) were sequentially added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, water was added to the reaction mixture to quench the reaction, and the mixture was extracted with water and ethyl acetate. The organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 36a (2.0 g). MS (ESI, [M+H] + ) m / z: 183.0.

[0442] Step B: Preparation of Compound 36b Compound 36a (2 g) and diphenyl ether (20 mL) were added sequentially to a reaction flask, and the mixture was stirred in a microwave oven at 240° C. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate=9 / 1) to give compound 36b (1.03 g). MS (ESI, [M+H] + ) m / z: 156.03.

[0443] Step C: Preparation of Compound 36c Compound 36b (0.884 g), di-t-butyl hydrazodicarboxylate (1.2 g), cesium carbonate (2.52 g), tris(dibenzylideneacetone)dipalladium (0.473 g), 1,1'-bis(diphenylphosphine)ferrocene (0.573 g), and toluene (5 mL) were sequentially added to a reaction flask, and the atmosphere was replaced with nitrogen, followed by stirring at 110°C. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 36c (1.4 g). MS (ESI, [M+H] + ) m / z: 352.2.

[0444] Step D: Preparation of Compound 36d Compound 36c (0.5 g), dichloromethane (5 mL), and methanesulfonic acid (0.6 g) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH of approximately 10 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated to give crude compound 36d (1.0 g). MS (ESI, [M+H] + ) m / z: 152.0.

[0445] Step E: Preparation of Compound 36e Compound 36d (1.0 g) and triethyl orthoformate (10 mL) were added sequentially to a reaction flask, and the mixture was reacted with stirring at 80° C. After completion of the reaction, the reaction solution was concentrated to obtain crude compound 36e (1.1 g). MS (ESI, [M+H] + ) m / z: 162.07.

[0446] Step F: Preparation of Compound 36f Compound 36e (1.1 g), DMSO (5 mL), sodium carbonate (2.1 g), and dibromophenone (0.6 g) were added to a reaction flask in this order and stirred at room temperature. After the reaction was completed, the reaction mixture was extracted with water and ethyl acetate. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 36f (0.150 g). MS (ESI, [M+H] + ) m / z: 240.05.

[0447] Step G: Preparation of Compound 36g Compound 36f (0.101 g), Intermediate 5A (0.25 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.02 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.033 g), potassium phosphate tripotassium (0.179 g), 1,4-dioxane (5 mL), and water (1 mL) were sequentially added to a reaction flask. The atmosphere was purged with nitrogen and the reaction was stirred at 85 °C in a microwave oven. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product. Compound 36g (0.106 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 626.62.

[0448] Step D: Preparation of Compound I-36 Compound 36g (0.106 g), dichloromethane (2 mL), and a 4M solution of hydrochloric acid in 1,4-dioxane (0.4 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH of approximately 10 by adding saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound I-36 (0.008 g) was obtained by column chromatography (dichloromethane / methanol = 10 / 1). HRMS (ESI, [M+H] + ) m / z: 526.2566.

[0449] Example 37: Preparation of Compound I-37 [ka]

[0450] Step A: Preparation of Compound 37a 1-Isoindolinone (1 g), trimethyloxonium tetrafluoroboronic acid (2 g), and dichloromethane (30 mL) were added sequentially to a reaction flask in an ice-water bath, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated to give compound 37a (1.1 g). MS (ESI, [M+H] + ) m / z: 148.2.

[0451] Step B: Preparation of Compound 37b Compound 37a (1.1 g), hydrazine formate (0.6 g), acetic acid (0.1 mL), and n-butanol (12 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and reacted with stirring at 120° C. After completion of the reaction, the reaction solution was concentrated and subjected to column chromatography (dichloromethane / methanol = 45 / 1) to obtain compound 37b (0.8 g). MS (ESI, [M+H] + ) m / z: 158.2.

[0452] Step C: Preparation of Compound 37c Compound 37b (0.8 g), N-bromosuccinimide (0.75 g), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was extracted with dichloromethane and water, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 37c (0.6 g). MS (ESI, [M+H] + ) m / z: 236.0.

[0453] Step D: Preparation of Compound 37d Compound 37c (0.5 g), Intermediate 5A (0.7 g), potassium phosphate (0.12 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.08 g), 1,4-dioxane (10 mL), and water (0.5 mL) were sequentially added to a reaction flask, and the mixture was stirred at 100°C under nitrogen protection. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 15 / 1) to obtain Compound 37d (0.11 g). MS (ESI, [M+H] + ) m / z: 622.7.

[0454] Step E: Preparation of Compound I-37 Compound 37d (0.11 g), a 4 M solution of hydrochloric acid in dioxane (0.6 mL), and dichloromethane (10 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH (approximately 9) with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 9 / 1) to give compound I-37 (0.02 g). HRMS (ESI, [M+H] + ) m / z: 522.2616.

[0455] Example 38: Preparation of Compound I-38 [ka]

[0456] Step A: Preparation of Compound 38a To a reaction flask were sequentially added Intermediate 7A (0.4 g), Intermediate 5A (0.6 g), potassium phosphate (0.18 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.06 g), 1,4-dioxane (10 mL), and water (0.5 mL), followed by nitrogen protection and stirring at 100°C. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 15 / 1) to obtain Compound 38a (0.21 g). MS (ESI, [M+H] + ) m / z: 623.4.

[0457] Step B: Preparation of Compound I-38 Compound 38a (0.21 g), a 4 M solution of hydrochloric acid in 1,4-dioxane (0.9 mL), and dichloromethane (10 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH (approximately 9) with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 9 / 1) to give compound I-38 (0.10 g). HRMS (ESI, [M+H] + ) m / z: 523.2455. 1H NMR(500MHz,CDCl3:CD3OD=10:1)δ 8.81(t,J=6.7Hz,1H),8.38(s,1H),7.99(dd,J=6.3,2.2Hz,1H),7.63(t,J=7.3Hz,2H ),7.57~7.49(m,1H),7.32~7.27(m,1H),7.11(s,1H),6.86(s,1H),6.72(d,J=6.1Hz, 1H),4.36(dd,J=6.2,2.2Hz,2H),4.09(p,J=4.8Hz,2H),3.69(d,J=5.9Hz,2H),3.58( tt,J=11.3,4.2Hz,2H), 3.20~3.14(m,1H), 2.39(d,J=6.0Hz,6H), 1.85~1.67(m,4H).

[0458] Example 39: Preparation of Compound I-39 [ka]

[0459] Step A: Preparation of Compound 39a To a reaction flask, 5 g of intermediate 7A-1, 50.0 mL of methanol, and 0.8 g of 10% by weight of wet palladium on carbon were added, and the mixture was then protected with hydrogen and stirred at room temperature. After completion of the reaction, the reaction mixture was filtered and concentrated to give 4.2 g of compound 39a. MS (ESI, [M+H] + ) m / z: 122.2.

[0460] Step B: Preparation of Compound 39b Compound 39a (4.2 g), acetonitrile (50 mL), and 2,4-dinitrophenylhydroxyamine (8 g) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and reacted at 40° C. with stirring. After completion of the reaction, the reaction solution was filtered and washed. Compound 39b (4 g) was obtained and used directly in the next reaction.

[0461] Step C: Preparation of Compound 39c Compound 39b (4 g), potassium carbonate (3 g), ethyl propionate (3.2 g), and DMF (60 mL) were sequentially added to a reaction flask, and the mixture was stirred at room temperature under nitrogen protection. After the reaction was completed, the mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give compound 39c (2 g). MS (ESI, [M+H] + ) m / z: 233.2.

[0462] Step D: Preparation of Compound 39d Compound 39c (2 g), lithium hydroxide monohydrate (4 g), methanol (60 mL), and water (6 mL) were sequentially added to a reaction flask, and the mixture was then protected with nitrogen and stirred at 60° C. After completion of the reaction, the reaction mixture was acidified (pH approximately 5) with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 39d (1.4 g). MS (ESI, [M+H] + ) m / z: 205.2.

[0463] Step E: Preparation of Compound 39e Compound 39d (1.4 g), N-bromosuccinimide (1.2 g), sodium bicarbonate (1.6 g), and N,N-dimethylformamide (40 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give compound 39e (1.0 g). MS (ESI, [M+H] + ) m / z: 239.0.

[0464] Step F: Preparation of Compound 39f Compound 39e (0.4 g), Intermediate 5A (0.6 g), potassium phosphate (0.18 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.06 g), 1,4-dioxane (10 mL), and water (0.5 mL) were sequentially added to a reaction flask, and the mixture was stirred at 100°C under nitrogen protection. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 39f (0.15 g). MS (ESI, [M+H] + ) m / z: 625.8.

[0465] Step G: Preparation of Compound I-39 Compound 39f (0.15 g), a dioxane solution of hydrochloric acid (4 M, 0.9 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 9 / 1) to obtain compound I-39 (0.04 g). HRMS (ESI, [M+H] + ) m / z: 525.2606. 1 H NMR(500MHz,CDCl3:CD3OD=10:1)δ 8.74(dd,J=8.5,3.2Hz,1H),8.29(s,1H),7.88(s,1H),7.55(ddd,J=24.3,8.5,3.1H z,2H),6.90~6.80(m,2H),4.71(td,J=8.2,3.2Hz,2H),4.42(d,J=3.1Hz,2H),4.17~4 .06(m,2H),3.76~3.66(m,2H),3.59(t,J=11.6Hz,2H),3.38(s,1H),3.32(t,J=8.3H z,2H), 3.17(ddq,J=11.7, 7.9, 4.0Hz, 1H), 2.39(d,J=3.1Hz, 6H), 1.85~1.69(m, 4H).

[0466] Example 40: Preparation of Compound I-40 [ka]

[0467] Step A: Preparation of Compound 40a Compound 4-azaspiro[2.4]heptan-5-one (1.0 g), trimethyloxonium tetrafluoroboronic acid (7.2 g), and dichloromethane (20.0 g) were added sequentially to a reaction flask. After the addition, the mixture was stirred at room temperature while reacting. After the reaction was completed, the reaction mixture was extracted with dichloromethane and water. The organic phase was dried, filtered, and concentrated. Compound 40a (1.2 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 126.3.

[0468] Step B: Preparation of Compound 40b Compound 40a (1.2 g), acetic acid (0.3 mL), 5-amine-1H-pyrazole (1.2 g), formylhydrazine (0.5 mL), and n-butanol (20 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at 120 °C and reacted. After the reaction was completed, the reaction solution was filtered and concentrated. Compound 40b (0.3 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 136.1.

[0469] Step C: Preparation of Compound 40c Compound 40b (0.3 g), N-bromosuccinimide (0.3 g), deuterated chloroform (10.0 mL), and sodium carbonate (0.1 g) were added sequentially to a reaction flask at 0° C. After the addition, the mixture was reacted at 0° C. with stirring. After the reaction was completed, the reaction solution was filtered and concentrated, and compound 40c (0.2 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] +) m / z: 214.2.

[0470] Step D: Preparation of Compound 40d Compound 40c (0.2 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.04 g), potassium phosphate (0.3 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.07 g), Intermediate 5A (0.4 g), water (3.0 mL), and 1,4-dioxane (12.0 mL) were sequentially added to a reaction flask. The mixture was stirred at 85 °C. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 40d (0.1 g). MS (ESI, [M+H] + ) m / z: 600.6.

[0471] Step H: Preparation of Compound I-40 Compound 40d (0.1 g), a 4 M solution of hydrochloric acid in dioxane (0.9 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-40 (0.05 g). HRMS (ESI, [M+H] + ) m / z: 500.2767. 1H NMR(500MHz,DMSO-d6)δ 10.00(s,1H),8.78(s,1H),8.63(d,J=8.6Hz,1H),7.66(d,J=8.4Hz,1H),7.45(d,J=8.5 Hz,1H),6.93(d,J=8.4Hz,1H),4.33(s,2H),3.96(dd,J=10.5,3.9Hz,2H),3.58(s,2H),3 .43(td,J=11.4,2.6Hz,2H),3.19(s,1H),3.02(t,J=7.5Hz,2H),2.70(t,J=7.5Hz,2H), 2.22(s,6H),1.66(dt,J=24.1,8.1Hz,4H),1.07(d,J=6.3Hz,2H),0.92(d,J=6.3Hz,2H).

[0472] Example 41: Preparation of Compound I-41 [ka] Step A: Preparation of Compound 41a Compound 5-chlorothiophene[3,2-B]pyridine (2.5 g), toluene (150.0 mL), benzophenone imine (4.5 g), sodium t-butoxide (2.9 g), tris(dibenzylideneacetone) (0.8 g), and 1,1-binaphthyl-2,2-bisdiphenylphosphine (0.9 g) were sequentially added to a reaction flask. After the addition, the mixture was protected with nitrogen and stirred at 110 °C. After the reaction was complete, concentrated hydrochloric acid was added to the reaction mixture, and the mixture was stirred for 1 hour. After the reaction was complete, the reaction mixture was adjusted to an alkaline pH (approximately 9) with saturated aqueous sodium carbonate, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 30 / 1) to obtain compound 41a (1.3 g). MS (ESI, [M+H] + ) m / z: 151.2.

[0473] Step B: Preparation of Compound 41b Compound 41a (1.3 g), potassium carbonate (4.0 g), chloroacetaldehyde (2.9 g), and ethanol (25 mL) were sequentially added to a reaction flask. After the addition, the mixture was reacted at 120°C with stirring. After the reaction was completed, the reaction solution was filtered and concentrated. Compound 41b (1.2 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 175.2.

[0474] Step C: Preparation of Compound 41c Compound 41b (1.2 g), N-bromosuccinimide (1.3 g), and acetonitrile (20.0 mL) were sequentially added to a reaction flask. After the addition, the mixture was allowed to react at room temperature while stirring. After the reaction was completed, the reaction solution was filtered and concentrated, and compound 41c (0.8 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 253.1.

[0475] Step D: Preparation of Compound 41d Compound 41c (0.2 g), compound 25a (0.5 g), tetratriphenylphosphine palladium (0.2 g), cuprous iodide (0.07 g), and toluene (12.0 mL) were sequentially added to a reaction flask. After the addition, the atmosphere was replaced with nitrogen, and the reaction was carried out with stirring at 110 °C. After the reaction was completed, the reaction solution was filtered and concentrated, and compound 41d (0.2 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 640.4.

[0476] Step H: Preparation of Compound I-41 Compound 40d (0.2 g), a 4 M solution of hydrochloric acid in dioxane (0.9 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-41 (0.05 g). HRMS (ESI, [M+H] + ) m / z: 540.2182. 1 H NMR(500MHz,CDCl3)δ 10.36(s,1H),8.08(dd,J=5.7,2.5Hz,1H),7.82(dd,J=9.5,2.5Hz,1H),7.72(dd,J=9.6,2.5 Hz,1H),7.62(ddd,J=16.8,7.1,2.5Hz,2H),7.32(d,J=2.5Hz,2H),6.91(d,J=8.4Hz,1H),4.8 8(d,J=2.4Hz,2H),4.18~4.04(m,2H),3.69(s,2H),3.59(td,J=11.5,5.6Hz,2H),3.39(dd,J= 3.4,1.9Hz,1H), 2.35(d,J=2.4Hz,6H), 1.81(dd,J=12.5,3.6Hz,2H), 1.76(d,J=11.1Hz,2H).

[0477] Example 42: Preparation of Compound I-42 [ka]

[0478] Step A: Preparation of Compound 42a Compound 22e (1.2 g), phosphorus oxybromide (7.7 g), and toluene (50.0 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature while reacting. After the reaction was completed, the reaction mixture was extracted with dichloromethane and water, and the organic phase was dried, filtered, and concentrated. Compound 42a (1.3 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 248.2.

[0479] Step B: Preparation of Compound 42b Compound 42a (1.2 g), tetrahydrofuran (30 mL), N,N-diisopropylethylamine (2 g), di-t-butyl dicarbonate (1.3 g), and 4-dimethylaminopyridine (0.05 g) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature while reacting. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 42b (0.6 g). MS (ESI, [M+H] + ) m / z: 348.2.

[0480] Step C: Preparation of Compound 42c Compound 42b (0.6 g), compound 25a (0.7 g), tetratriphenylphosphine palladium (0.2 g), cuprous iodide (0.07 g), and toluene (12.0 mL) were sequentially added to a reaction flask. After the addition, the mixture was reacted at 110°C with stirring. After the reaction was completed, the reaction solution was filtered and concentrated, and compound 42c (0.3 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 735.7.

[0481] Step H: Preparation of Compound I-42 Compound 42c (0.1 g), a 4 M solution of hydrochloric acid in dioxane (0.9 mL), and dichloromethane (10 mL) were added to a reaction flask in that order, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-42 (0.007 g). HRMS (ESI, [M+H] + ) m / z: 535.2570.

[0482] Example 43: Preparation of Compound I-43 [ka]

[0483] Step A: Preparation of Compound 43a Compound 4h (3.5 g), 2,2-dimethoxyethylamine (4.9 g), and toluene (80 mL) were sequentially added to a reaction flask, and the mixture was reacted with stirring at 120° C. After the reaction was completed, the mixture was extracted with dichloromethane and water, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 43a (3.9 g). MS (ESI, [M+H] + ) m / z: 185.2.

[0484] Step B: Preparation of Compound 43b Compound 43a (3.9 g), concentrated hydrochloric acid (15 mL), and water (10 mL) were sequentially added to a reaction flask, and the mixture was stirred at 100° C. After completion of the reaction, the reaction mixture was adjusted to alkaline (pH approximately 9) by adding saturated sodium carbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 43b (3.3 g). MS (ESI, [M+H] + ) m / z: 121.2.

[0485] Step C: Preparation of Compound 43c Compound 43b (3.3 g), dichloromethane (50 mL), and NCS (9.7 g) were added to a reaction flask in this order, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was quenched by adding saturated sodium thiosulfate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 43c (3.0 g). MS (ESI, [M+H] + ) m / z: 155.0.

[0486] Step D: Preparation of Compound 43d Compound 43c (0.11 g), Intermediate 5A (0.17 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.02 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.03 g), potassium phosphate (0.09 g), water (2.00 mL), and 1,4-dioxane (15 mL) were sequentially added to a reaction flask. The mixture was then protected with nitrogen and stirred at 85 °C. After completion of the reaction, the reaction mixture was concentrated. Compound 43d (0.12 g) was obtained by column chromatography (dichloromethane / methanol = 10 / 1). MS (ESI, [M+H] + ) m / z: 585.4.

[0487] Step E: Preparation of Compound I-43 Compound 43d (0.12 g), dichloromethane (10 mL), and a 1,4-dioxane solution of hydrochloric acid (2 mL, 4 M) were added to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH of approximately 10 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound I-43 (30 mg) was obtained by column chromatography (dichloromethane / methanol = 10 / 1). HRMS (ESI, [M+H] + ) m / z: 485.2662.

[0488] Example 44: Preparation of Compound I-44 [ka]

[0489] Step A: Preparation of Compound 44a Sodium t-butoxide (0.556 g), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.288 g), tris(dibenzylideneacetone)dipalladium (0.318 g), benzophenone imine (0.629 g), compound 36b (0.36 g), and toluene (10 mL) were sequentially added to a reaction flask. The atmosphere was replaced with nitrogen, and the reaction was carried out with stirring at 80 °C. After completion of the reaction, the reaction solution was filtered and concentrated. Compound 44a (0.5 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 1 / 4). MS (ESI, [M+H] + ) m / z: 301.35.

[0490] Step B: Preparation of Compound 44b Compound 44a (0.5 g), dichloromethane (5 mL), and a 4M solution of hydrochloric acid in 1,4-dioxane (2 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH of approximately 8 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound 44b (0.15 g) was obtained by column chromatography (dichloromethane / methanol = 10 / 1). MS (ESI, [M+H] + ) m / z: 137.00.

[0491] Step C: Preparation of Compound 44c Compound 44b (0.15 g), ethanol (5 mL), potassium carbonate (0.305 g), and chloroacetaldehyde (0.324 g) were sequentially added to a reaction flask, and the mixture was stirred at 90 °C. After completion of the reaction, the reaction solution was concentrated. Compound 44c (0.12 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 161.01.

[0492] Step D: Preparation of Compound 44d Compound 44c (0.12 g), DMSO (3 mL), sodium carbonate (0.11 g), and dibromophenone (0.075 g) were added to a reaction flask in this order and stirred at room temperature. After the reaction was completed, the reaction mixture was extracted with water and ethyl acetate. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 20 / 1) to give compound 44d (0.105 g). MS (ESI, [M+H] + ) m / z: 239.07.

[0493] Step E: Preparation of Compound 44e Compound 44d (0.101 g), Intermediate 5A (0.25 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.02 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.033 g), potassium phosphate tripotassium (0.179 g), 1,4-dioxane (5 mL), and water (1 mL) were sequentially added to a reaction flask. The atmosphere was purged with nitrogen and the reaction was stirred at 85 °C in a microwave oven. After completion of the reaction, the reaction mixture was filtered and concentrated to give the crude product. Compound 44e (0.101 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 625.47.

[0494] Step F: Preparation of Compound I-44 Compound 44e (0.101 g), dichloromethane (2 mL), and a 4M solution of hydrochloric acid in 1,4-dioxane (0.4 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH of approximately 10 by adding saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-44 (0.012 g). HRMS (ESI, [M+H] +) m / z: 525.2630. 1 H NMR(500MHz,CDCl3)δ 8.65(d,J=8.4Hz,1H),7.46(d,J=8.5Hz,1H),7.41(dd,J=5.9,2.1Hz,2H),7.26( d,J=2.1Hz,1H),7.16(dd,J=24.5,8.7Hz,2H),6.79(d,J=8.4Hz,1H),4.66(t,J=8 .8Hz,2H),4.22(s,2H),4.02(d,J=8.7Hz,2H),3.59(s,2H),3.50(t,J=11.6Hz,2H ),3.23(t,J=8.8Hz,2H),3.09(t,J=11.4Hz,1H),2.29(s,6H),1.74~1.62(m,4H).

[0495] Example 45: Preparation of Compound I-45 [ka] Step A: Preparation of Compound 45a Intermediate 3A-2 (1.3 g), compound 10b (1.1 g), 1,4-dioxane (50.0 mL), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0.4 g), cesium carbonate (2.2 g), and tris(dibenzylideneacetone) (0.4 g) were sequentially added to a reaction flask. After the addition, the mixture was stirred at 110 °C under nitrogen protection. After completion of the reaction, the reaction solution was filtered and concentrated. Compound 45a (0.7 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 517.3.

[0496] Step B: Preparation of Compound 45b Compound 45a (0.7 g), potassium acetate (0.4 g), bis(pinacolato)diboron (0.6 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.2 g), and 1,4-dioxane (20.0 mL) were sequentially added to a reaction flask. After addition, the atmosphere was purged with nitrogen and the reaction was carried out with stirring at 90 °C. After completion of the reaction, the reaction solution was filtered and concentrated. Compound 45b (0.4 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 609.4.

[0497] Step C: Preparation of Compound 45c Compound 45b (0.4 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.05 g), potassium phosphate (0.3 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.07 g), Intermediate 6A (0.3 g), water (3.0 mL), and 1,4-dioxane (12.0 mL) were sequentially added to a reaction flask. After addition, the atmosphere was purged with nitrogen and the reaction was carried out at 85 °C with stirring. After completion of the reaction, the reaction mixture was filtered and concentrated. Compound 45c (0.2 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 639.4.

[0498] Step D: Preparation of Compound I-45 Compound 45c (0.1 g), dichloromethane (2 mL), and a 4M solution of hydrochloric acid in 1,4-dioxane (0.4 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH of approximately 10 with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound I-45 (0.05 g). HRMS (ESI, [M+H] + ) m / z: 539.2407. 1 H NMR(500MHz,CDCl3)δ 9.90(s,1H),8.90(d,J=8.5Hz,1H),7.67(s,1H),7.62(t,J=8.1Hz,2H),7 .59~7.52(m,3H),6.89(d,J=8.5Hz,1H),6.49(s,1H),6.28(d,J=2.2Hz,1 H),4.91~4.49(m,1H),4.25(s,2H),4.05(t,J=11.5Hz,2H),3.95(s,2H), 3.87(dd,J=11.1,4.7Hz,2H),2.33(s,6H),2.08(td,J=12.7,4.9Hz,3H).

[0499] Example 46: Preparation of Compound I-46 [ka]

[0500] Step A: Preparation of Compound 46a Intermediate 7A (1 g), bis(pinacolato)diboron (1.6 g), potassium carbonate (0.8 g), palladium acetate (0.1 g), tricyclohexylphosphine (0.18 g), diethylene glycol dimethyl ether (15 mL), and water (1 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and reacted with stirring at 100° C. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound 46a (0.8 g). MS (ESI, [M+H] +) m / z: 285.3.

[0501] Step B: Preparation of Compound 46b Compound 46a (0.1 g), intermediate 1A (0.2 g), potassium phosphate (0.2 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.03 g), 1,4-dioxane (10 mL), and water (0.5 mL) were sequentially added to a reaction flask, and the mixture was stirred at 100°C under nitrogen protection. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 46b (0.12 g). MS (ESI, [M+H] + ) m / z: 624.7.

[0502] Step C: Preparation of Compound I-46 Compound 46b (0.12 g), a 1,4-dioxane solution of hydrochloric acid (4 M, 9 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 9 / 1) to give compound I-46 (0.03 g). HRMS (ESI, [M+H] + ) m / z: 524.2407. 1H NMR(500MHz,CDCl3:CD3OD=10:1)δ 8.32(dd,J=11.4,7.2Hz,1H),8.07(d,J=11.1Hz,1H),7.64(d,J=10.1Hz,1H),7.48( s,2H),7.11(dd,J=11.4,7.2Hz,1H),6.83~6.77(m,1H),4.57(d,J=10.8Hz,2H),4.02 (dt,J=11.5,5.6Hz,2H),3.64(d,J=9.9Hz,2H),3.51(q,J=11.1Hz,2H),3.29(d,J=1 0.1Hz, 1H), 3.10 (dd, J=10.2, 5.8Hz, 1H), 2.33 (d, J=10.3Hz, 6H), 1.76~1.61 (m, 4H).

[0503] Example 47: Preparation of Compound I-47 [ka]

[0504] Step A: Preparation of Compound 47a Compound 46a (0.1 g), compound 13g (0.2 g), potassium phosphate (0.2 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.03 g), 1,4-dioxane (10 mL), and water (0.5 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and stirred at 100°C. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 15:1) to obtain compound 47a (0.1 g). MS (ESI, [M+H] + ) m / z: 625.7.

[0505] Step B: Preparation of Compound I-47 Compound 47a (0.1 g), a 1,4-dioxane solution of hydrochloric acid (4 M, 1.9 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. After the reaction was completed, saturated aqueous sodium bicarbonate was added to adjust the pH to approximately 9, followed by extraction with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 9 / 1) to give compound I-47 (0.02 g). HRMS (ESI, [M+H] + ) m / z: 525.2359. 1 H NMR(500MHz,CDCl3:CD3OD=10:1)δ 10.03(s,1H),8.32(d,J=7.3Hz,1H),7.65(s,1H),7.52(s,1H),7.44(d,J=8.6Hz,1H),7.12(d,J=7.3Hz,1H) ,6.82(d,J=8.5Hz,1H),4.58(s,1H),4.40(s,2H),3.88~3.71(m,6H),2.91~2.76(m,4H),2.50~2.33(m,6H).

[0506] Example 48: Preparation of Compound I-48 [ka]

[0507] Step A: Preparation of Compound 48a Intermediate 5A (205 mg), Intermediate 8A (91 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (27 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (17 mg), potassium phosphate tripotassium (147 mg), 1,4-dioxane (3 mL), and water (0.5 mL) were sequentially added to a microwave tube. The mixture was then protected with nitrogen and stirred at 85 °C in a microwave oven. After completion of the reaction, the reaction mixture was filtered and concentrated. Compound 48a (72 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 624.61.

[0508] Step B: Preparation of Compound I-48 Compound 48a (72 mg), a 1,4-dioxane solution of hydrochloric acid (4 M, 1.9 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. After the reaction was completed, saturated aqueous sodium bicarbonate was added to adjust the pH to approximately 9, followed by extraction with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to give compound I-48 (35 mg). HRMS (ESI, [M+H] + ) m / z: 524.2398. 1 H NMR(500MHz,CDCl3)δ 9.86(s,1H),9.01(d,J=8.6Hz,1H),8.83(s,1H),7.87(s,1H),7.65~7.5 9(m,2H),7.55(d,J=8.4Hz,1H),6.86(d,J=8.4Hz,1H),6.47(d,J=2.4Hz, 1H),6.41(s,1H),4.30(s,2H),4.10(dd,J=11.3,4.1Hz,2H),3.63(s,2H ),3.58~3.53(m,2H),3.25~3.19(m,1H),2.32(s,6H),1.84~1.72(m,4H).

[0509] Example 49: Preparation of Compound I-49 [ka]

[0510] Step A: Preparation of Compound 49a Intermediate 1A-1 (6.0 g), 1,4-dioxane (50.0 mL), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (1.6 g), cesium carbonate (11.81 g), tris(dibenzylideneacetone) (1.6 g), and 1-methyl-2-imidazolidinone (2.2 g) were sequentially added to a reaction flask. After the addition, the atmosphere was purged with nitrogen and the reaction was carried out with stirring at 110 °C. After completion of the reaction, the reaction solution was filtered and concentrated. Compound 49a (4.3 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 351.1.

[0511] Step B: Preparation of Compound 49b Compound 49a (4.3 g), tetrahydrofuran (50.0 mL), and lithium borohydride (0.5 g) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature. After the reaction was completed, the reaction mixture was quenched by adding saturated aqueous ammonium chloride solution. Dichloromethane was added for extraction. The organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 49b (2.1 g). MS (ESI, [M+H] + ) m / z: 323.2.

[0512] Step C: Preparation of Compound 49c Compound 49b (2.1 g), dichloromethane (30.0 mL), N,N-diisopropylethylamine (3.45 mL), and methanesulfonic anhydride (4.5 mL) were added to a reaction flask in an ice-water bath in that order, and the mixture was allowed to react in an ice-water bath. After the reaction was completed, a 2 M solution of dimethylamine in tetrahydrofuran (30 mL) was added and the mixture was allowed to react at room temperature. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 49c (1.5 g). MS (ESI, [M+H] + ) m / z: 350.0.

[0513] Step D: Preparation of Compound 49d Compound 49c (1.5 g), dichloromethane (30.0 mL), and a 1,4-dioxane solution of hydrochloric acid (4 M, 11 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature. The reaction mixture was adjusted to an alkaline pH (approximately 10) with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound 49d (1.0 g) was obtained by column chromatography (dichloromethane / methanol = 5 / 1). MS (ESI, [M+H] + ) m / z: 250.0.

[0514] Step E: Preparation of Compound 49e To a reaction flask, intermediate 3A-2 (3.0 g), compound 49d (1.0 g), 1,4-dioxane (50.0 mL), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0.9 g), cesium carbonate (6.6 g), and tris(dibenzylideneacetone) (1.2 g) were sequentially added. After addition, the mixture was stirred at 110 °C and reacted. After completion of the reaction, the reaction solution was filtered and concentrated. Compound 49e (0.7 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 515.0.

[0515] Step F: Preparation of Compound 49f Compound 49e (0.7 g), potassium acetate (0.8 g), bis(pinacolato)diboron (0.5 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.1 g), and 1,4-dioxane (30.0 mL) were sequentially added to a reaction flask. After addition, the atmosphere was purged with nitrogen and the reaction was carried out with stirring at 90 °C. After completion of the reaction, the reaction solution was filtered and concentrated, and compound 49f (0.7 g) was obtained by column chromatography (petroleum ether / ethyl acetate = 5 / 1). MS (ESI, [M+H] + ) m / z: 607.4.

[0516] Step G: Preparation of Compound 49g Compound 49f (0.3 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.07 g), potassium phosphate (0.5 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.1 g), Intermediate 7A (0.4 g), water (3.0 mL), and 1,4-dioxane (12.0 mL) were sequentially added to a reaction flask. The mixture was stirred at 85 °C. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain Compound 49g (0.2 g). MS (ESI, [M+H] + ) m / z: 637.4.

[0517] Step H: Preparation of Compound I-49 Compound 49g (0.2 g), a 1,4-dioxane solution of hydrochloric acid (4 M, 1.9 mL), and dichloromethane (10 mL) were added to a reaction flask in that order, and the mixture was allowed to react at room temperature. After the reaction was completed, saturated aqueous sodium bicarbonate was added to adjust the pH to approximately 9, followed by extraction with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-49 (0.07 g). HRMS (ESI, [M+H] + ) m / z: 537.2365.

[0518] 1H NMR(500MHz,CDCl3)δ 8.85(dd,J=8.6,3.0Hz,1H),8.39(d,J=7.5Hz,1H),8.00(d,J=3.5Hz,1H) ,7.69~7.62(m,2H),7.44(d,J=8.6Hz,1H),7.12(d,J=7.5Hz,1H),6.88(d, J=8.6Hz,1H),6.74(d,J=2.1Hz,1H),4.37(s,2H),3.77(dd,J=9.1,6.7Hz ,2H),3.70(s,2H),3.53(dd,J=9.1,6.7Hz,2H),2.90(s,3H),2.42(s,6H).

[0519] Example 50: Preparation of Compound I-50 [ka]

[0520] Step A: Preparation of Compound 50a Compound 49f (0.3 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.07 g), potassium phosphate (1.4 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.1 g), Intermediate 6A (0.1 g), water (3.0 mL), and 1,4-dioxane (12.0 mL) were sequentially added to a reaction flask. The mixture was stirred at 85 °C. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 50a (0.2 g). MS (ESI, [M+H] + ) m / z: 637.4.

[0521] Step H: Preparation of Compound I-50 Compound 50a (0.1 g), a 4 M solution of hydrochloric acid in 1,4-dioxane (1.9 mL), and dichloromethane (10 mL) were added to a reaction flask, and the mixture was allowed to react at room temperature. After the reaction was completed, saturated aqueous sodium bicarbonate was added to adjust the pH to approximately 9, followed by extraction with dichloromethane. The organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-50 (0.1 g). HRMS (ESI, [M+H] + ) m / z: 537.2365. 1 H NMR(500MHz,CDCl3)δ 9.97(s,1H),8.95(d,J=8.5Hz,1H),7.65(s,1H),7.58(d,J=8.6Hz,1H),7 .54(dd,J=6.6,2.9Hz,3H),7.45(d,J=8.5Hz,1H),6.86(d,J=8.6Hz,1H), 6.64(s,1H),6.29(d,J=2.3Hz,1H),4.22(s,2H),3.77(dd,J=8.9,6.8Hz, 2H), 3.64 (s, 2H), 3.49 (dd, J=8.7, 6.9Hz, 2H), 2.90 (s, 3H), 2.36 (s, 6H).

[0522] Example 51: Preparation of Compound I-51 [ka]

[0523] Step A: Preparation of Compound 51a Intermediate 1A-1 (10.0 g), 1,4-dioxane (150.0 mL), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (2.6 g), cesium carbonate (19.6 g), tris(dibenzylideneacetone) (2.7 g), and 2-pyrrolidone (3.0 g) were sequentially added to a reaction flask. After the addition, the atmosphere was purged with nitrogen and the reaction was carried out with stirring at 110 °C. After completion of the reaction, the reaction solution was filtered and concentrated. Compound 51a (10.5 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H]+ ) m / z: 336.1.

[0524] Step B: Preparation of Compound 51b Compound 51a (10.5 g), tetrahydrofuran (50.0 mL), and lithium borohydride (1.3 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature. After the reaction was completed, water was added to the reaction mixture to quench the reaction, followed by extraction with water and dichloromethane. The organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 51b (5.0 g). MS (ESI, [M+H] + ) m / z: 308.2.

[0525] Step C: Preparation of Compound 51c Compound 51b (5.0 g), dichloromethane (30.0 mL), N,N-diisopropylethylamine (3.45 mL), and methanesulfonic anhydride (4.5 mL) were sequentially added to a reaction flask in an ice-water bath, followed by reaction in an ice-water bath. After completion of the reaction, a tetrahydrofuran solution of dimethylamine (2 M, 30 mL) was added and the reaction was continued at room temperature. After completion of the reaction, the reaction solution was concentrated and subjected to column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 51c (4.0 g). MS (ESI, [M+H] + ) m / z: 335.2.

[0526] Step D: Preparation of Compound 51d Compound 51c (4 g), dichloromethane (30.0 mL), and a 1,4-dioxane solution of hydrochloric acid (4 M, 15 mL) were sequentially added to a reaction flask. After the addition, the mixture was stirred at room temperature. The reaction mixture was adjusted to an alkaline pH (approximately 10) with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated. Compound 51d (1.5 g) was obtained by column chromatography (dichloromethane / methanol = 5 / 1). MS (ESI, [M+H] + ) m / z: 235.0.

[0527] Step E: Preparation of Compound 51e Intermediate 3A-2 (2.9 g), compound 51d (1.4 g), 1,4-dioxane (80.0 mL), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0.9 g), cesium carbonate (6.3 g), and tris(dibenzylideneacetone) (1.1 g) were sequentially added to a reaction flask. After the addition, the atmosphere was purged with nitrogen and the reaction was carried out with stirring at 110 °C. After completion of the reaction, the reaction solution was filtered and concentrated. Compound 51e (1.1 g) was obtained by column chromatography (dichloromethane / methanol = 30 / 1). MS (ESI, [M+H] + ) m / z: 500.0.

[0528] Step F: Preparation of Compound 51f Compound 51e (1.1 g), potassium acetate (0.5 g), bis(pinacolato)diboron (1.2 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.2 g), and 1,4-dioxane (30.0 mL) were sequentially added to a reaction flask. After the addition, the atmosphere was purged with nitrogen and the reaction was carried out with stirring at 90 °C. After completion of the reaction, the reaction solution was filtered and concentrated, and compound 51f (0.7 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 592.4.

[0529] Step G: Preparation of Compound 51g Compound 51f (0.3 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.04 g), potassium phosphate (0.3 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.1 g), Intermediate 7A (0.4 g), water (3.0 mL), and 1,4-dioxane (12.0 mL) were sequentially added to a reaction flask. The mixture was stirred at 85 °C. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain Compound 51g (0.2 g). MS (ESI, [M+H] + ) m / z: 622.1.

[0530] Step H: Preparation of Compound I-51 Compound 51g (0.2 g), a 1,4-dioxane solution of hydrochloric acid (4 M, 1.9 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-51 (0.09 g). HRMS (ESI, [M+H] + ) m / z: 522.2254. 1 H NMR(500MHz,CDCl3)δ 8.87(dd,J=8.7,1.9Hz,1H),8.42~8.35(m,1H),8.00(s,1H),7.69~7.62(m,2H), 7.40(dd,J=8.6,1.9Hz,1H),7.13(d,J=7.6Hz,1H),6.87(d,J=8.6Hz,1H),6.74(d ,J=2.2Hz,1H),4.38(d,J=2.0Hz,2H),3.81(t,J=7.0Hz,2H),3.60(d,J=1.8Hz,2H ),2.58(td,J=8.1,1.9Hz,2H),2.35(d,J=2.0Hz,6H),2.24(p,J=8.0,7.6Hz,2H).

[0531] Example 52: Preparation of Compound I-52 [ka] Step A: Preparation of Compound 52a Compound 51f (0.3 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.04 g), potassium phosphate (0.9 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.1 g), Intermediate 6A (0.1 g), water (3.0 mL), and 1,4-dioxane (12.0 mL) were sequentially added to a reaction flask. The mixture was stirred at 85 °C. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 52a (0.2 g). MS (ESI, [M+H] + ) m / z: 622.4.

[0532] Step H: Preparation of Compound I-52 Compound 52a (0.2 g), a 4 M solution of hydrochloric acid in 1,4-dioxane (1.9 mL), and dichloromethane (10 mL) were added to a reaction flask, and the mixture was allowed to react at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-52 (0.1 g). HRMS (ESI, [M+H] + ) m / z: 522.2254. 1H NMR (500 MHz, CDCl3) δ 8.92(dd,J=8.6,3.7Hz,1H),7.69~7.55(m,4H),7.53(dd,J=9.8,3.9Hz,1H),7 .43(dd,J=8.6,3.8Hz,1H),7.37~7.29(m,1H),6.91(dd,J=8.6,3.8Hz,1H),6.2 9(t,J=3.0Hz,1H),4.24(s,2H),3.88~3.75(m,2H),3.62(d,J=3.9Hz,2H),2.37 (d,J=3.9Hz,6H),2.30~2.19(m,2H),1.56(q,J=5.2Hz,1H),1.32~1.20(m,1H).

[0533] Example 53: Preparation of Compound I-53 [ka] Step A: Preparation of Compound 53a Compound 16f (0.85 g), bis(pinacolato)diboron (0.86 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.27 g), potassium acetate (0.50 g), and 1,4-dioxane (20 mL) were sequentially added to a microwave tube. The mixture was then protected with nitrogen and stirred at 90 °C in a microwave oven. After completion of the reaction, the reaction mixture was filtered and concentrated. Compound 53a (0.54 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 595.43.

[0534] Step B: Preparation of Compound 53b Compound 53a (110 mg), Intermediate 9A (51 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (14 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (9 mg), potassium phosphate tripotassium (79 mg), 1,4-dioxane (3 mL), and water (0.5 mL) were sequentially added to a microwave tube. The mixture was then protected with nitrogen and stirred at 85 °C in a microwave oven. After completion of the reaction, the reaction mixture was filtered and concentrated. Compound 53b (44 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 601.56.

[0535] Step C: Preparation of Compound I-53 Compound 53b (44 mg), a 1,4-dioxane solution of hydrochloric acid (4 M, 1.9 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-53 (10 mg). HRMS (ESI, [M+H] + ) m / z: 501.2944. 1 H NMR(500MHz,CDCl3)δ 9.74(s,1H),8.73(d,J=8.6Hz,1H),7.64(s,1H),7.47(dd,J=24.5,8.6Hz,2H),6.81(d,J=8.5Hz,1H),6.12(s,1H),4.53(s,2H),4.14(s, 2H), 4.08(dd,J=11.2,4.1Hz,2H),3.61~3.50(m,1H),3.23~3.13(m,1H),3.10(s,2H),2.41(s,6H),1.80~1.70(m,2H),0.90~0.87(m,4H).

[0536] Example 54: Preparation of Compound I-54 [ka] Step A: Preparation of Compound 54a Intermediate 4A (205 mg), Intermediate 8A (51 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (28 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (17 mg), potassium phosphate tripotassium (150 mg), 1,4-dioxane (3 mL), and water (0.5 mL) were sequentially added to a microwave tube. The mixture was protected with nitrogen and stirred at 85 °C in a microwave oven. After completion of the reaction, the reaction mixture was filtered and concentrated. Compound 54a (162 mg) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 610.43.

[0537] Step B: Preparation of Compound I-54 Compound 54a (162 mg), a 1,4-dioxane solution of hydrochloric acid (4 M, 1.9 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-54 (70 mg). HRMS (ESI, [M+H] + ) m / z: 510.2242. 1H NMR(500MHz,CDCl3)δ 9.88(s,1H),9.01(d,J=8.6Hz,1H),8.83(s,1H),7.87(s,1H),7.68~7. 58(m,3H),6.86(d,J=8.4Hz,1H),6.47(d,J=2.5Hz,1H),6.33(s,1H),4. 30(s,2H),4.14~4.04(m,2H),3.96~3.86(m,2H),3.73~3.66(m,2H),3.6 0(d,J=12.4Hz,1H),2.42~2.36(m,1H),2.31(s,6H),1.97~1.90(m,1H).

[0538] Example 55: Preparation of Compound I-55 [ka]

[0539] Step A: Preparation of Compound 55a A solution of n-butyllithium in n-hexane (0.8 mL, 2 M) was slowly added dropwise to a reaction flask containing intermediate 9A (0.25 g) and tetrahydrofuran (20 mL) at -78 °C, followed by stirring for 1 hour. Isopropenyl pinacol borate (0.6 g) was then slowly added, and the mixture was warmed to room temperature and stirred. After completion of the reaction, the reaction mixture was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 7 / 3) to obtain compound 55a (0.1 g). MS (ESI, [M+H] + ) m / z: 261.2.

[0540] Step B: Preparation of Compound 55b Compound 55a (0.1 g), intermediate 1A (0.12 g), potassium phosphate (0.2 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.15 g), 1,4-dioxane (20 mL), and water (1 mL) were sequentially added to a reaction flask, and the mixture was stirred at 100°C under nitrogen protection. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol = 15 / 1) to obtain compound 55b (0.1 g). MS (ESI, [M+H] + ) m / z: 600.4.

[0541] Step C: Preparation of Compound I-55 Compound 55b (0.2 g), a 1,4-dioxane solution of hydrochloric acid (4 M, 1.9 mL), and dichloromethane (10 mL) were added to a reaction flask in this order, and the mixture was allowed to react at room temperature. After the reaction was completed, the reaction mixture was adjusted to an alkaline pH (approximately 9) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound I-55 (0.08 g). HRMS (ESI, [M+H] + ) m / z: 500.2768.

[0542] Example 56: Preparation of Compound I-56 [ka]

[0543] Step A: Preparation of Compound 56a Compound 13c (1.98 g), Dess-Martin periodinane (5.5 g), and dichloromethane (20 mL) were added to a reaction flask and allowed to react with stirring at room temperature. After completion of the reaction, the reaction mixture was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to give compound 56a (1.5 g). MS (ESI, [M+H] + ) m / z: 227.6.

[0544] Step B: Preparation of Compound 56b Compound 56a (1.5 g), (R)-t-butylsulfinimide (0.98 g), tetraethyl titanate (5.8 g), and tetrahydrofuran (30 mL) were added to a reaction flask and stirred at room temperature. After completion of the reaction, the reaction mixture was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound 56b (1.82 g). MS (ESI, [M+H] + ) m / z: 330.1.

[0545] Step C: Preparation of Compound 56c Compound 56b (1.8 g) and tetrahydrofuran (30 mL) were added to a reaction flask, and (1,3-dioxane-2-ethyl)magnesium bromide (20 mL, 1 M) was slowly added dropwise at -78 °C, followed by stirring at room temperature. After completion of the reaction, the reaction mixture was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 56c (1.2 g). MS (ESI, [M+H] + ) m / z: 446.2.

[0546] Step D: Preparation of Compound 56d Compound 56c (1.2 g), trifluoroacetic acid (10 mL), and water (0.5 mL) were added to a reaction flask and allowed to react at room temperature with stirring. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH (approximately 8) by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, filtered, and concentrated to give compound 56d (1.82 g), which was used directly in the next reaction.

[0547] Step E: Preparation of Compound 56e Compound 56d (1.82 g) and trifluoroacetic acid (10 mL) were added to a reaction flask, and triethylsilane (2.8 g) was slowly added dropwise in an ice-water bath. The mixture was then stirred at room temperature. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 100 / 1) to give compound 56e (0.8 g). MS (ESI, [M+H] + ) m / z: 268.1.

[0548] Step F: Preparation of Compound 56f Compound 56e (1.2 g), di-t-butyl dicarbonate (3.2 g), 4-dimethylaminopyridine (0.3 g), and dichloromethane (15 mL) were added to a reaction flask and allowed to react at room temperature with stirring. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and water, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give compound 56f (1.1 g). MS (ESI, [M+H] + ) m / z: 368.1.

[0549] Step G: Preparation of Compound 56g 7-amino-4-chloro-1-oxyisoindole-2-t-butylcarbamate (1.2 g), tetrahydroxydiboron (0.95 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.35 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.45 g), potassium phosphate (2.2 g), ethylene glycol (0.8 g), and ethanol (20 mL) were sequentially added to a reaction flask, and the mixture was stirred at 100 °C under nitrogen protection. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 15 / 1) to obtain compound 56 (0.8 g). MS (ESI, [M+H] + ) m / z: 293.2.

[0550] Step H: Preparation of Compound 56h Compound 56g (0.8 g), Intermediate 9A (0.9 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.24 g), potassium phosphate (0.8 g), 1,4-dioxane (15 mL), and water (0.5 mL) were sequentially added to a reaction flask, and the mixture was stirred at 100°C under nitrogen protection. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain compound 56h (0.8 g). MS (ESI, [M+H] + ) m / z: 381.4.

[0551] Step I: Preparation of compound 56i Compound 56f (0.4 g), compound 56h (0.5 g), cesium carbonate (2.1 g), tris(dibenzylideneindeneacetone)dipalladium (0.1 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0.15 g), and 1,4-dioxane (20 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and stirred at 100° C. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 56i (0.24 g). MS (ESI, [M+H] + ) m / z: 712.1.

[0552] Step J: Preparation of Compound I-56 Compound 56i (0.2 g), a 4 M solution of hydrochloric acid in 1,4-dioxane (1.5 mL), and dichloromethane (15 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH (approximately 9) with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 15 / 1) to give compound I-56 (0.10 g). HRMS (ESI, [M+H] + ) m / z: 512.2766. 1 H NMR(500MHz,CDCl3:CD3OD=10:1)δ 9.57(s,1H),7.87(d,J=8.1Hz,1H),7.52~7.44(m,2H),7.34(d,J=8.2Hz,1H),6.78(d,J =8.6Hz,1H),4.36(s,2H),4.05(s,2H),3.81(q,J=9.1,7.4Hz,4H),3.67(s,1H),3.49(s ,1H),3.02(s,2H),2.96~2.89(m,2H),2.69(t,J=7.9Hz,2H),2.63~2.55(m,1H),2.20~2 .13(m,1H), 2.10(s,1H), 1.95(dt,J=14.0,4.6Hz,1H), 1.24~1.14(m,3H), 0.83(s,4H).

[0553] Example 57: Preparation of Compound I-57 [ka]

[0554] Step A: Preparation of Compound 57a Compound 56g (0.8 g), Intermediate 7A (0.9 g), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.24 g), potassium phosphate (0.8 g), 1,4-dioxane (15 mL), and water (0.5 mL) were sequentially added to a reaction flask, and the mixture was stirred at 100°C under nitrogen protection. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain Compound 57a (0.9 g). MS (ESI, [M+H] + ) m / z: 405.4.

[0555] Step B: Preparation of Compound 57b Compound 57a (0.4 g), compound 56f (0.5 g), cesium carbonate (2.1 g), tris(dibenzylideneindeneacetone)dipalladium (0.1 g), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0.1 g), and 1,4-dioxane (20 mL) were sequentially added to a reaction flask, and the mixture was protected with nitrogen and stirred at 100° C. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give 57b (0.32 g). MS (ESI, [M+H] + ) m / z: 736.1.

[0556] Step C: Preparation of Compound I-57 Compound 57b (0.2 g), a 4 M solution of hydrochloric acid in 1,4-dioxane (1.5 mL), and dichloromethane (15 mL) were added to a reaction flask, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was adjusted to an alkaline pH (approximately 9) with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 6 / 1) to give compound I-57 (0.11 g). HRMS (ESI, [M+H] + ) m / z: 536.2407. 1 H NMR(500MHz,CD3Cl:CD3OD=10:1)δ 8.37(d,J=7.5Hz,1H),8.03(d,J=8.0Hz,1H),7.99(s,1H),7.70~7.56(m,3H),7.1 2(d,J=7.4Hz,1H),7.04(d,J=8.2Hz,1H),6.70(s,1H),4.40(s,2H),3.88(q,J=8. 9,7.8Hz,4H),3.74(s,1H),3.53(s,1H),3.01(t,J=7.8Hz,2H),2.78(t,J=8.3Hz, 2H),2.67(s,1H),2.26(s,1H),2.18(s,1H),2.04(s,2H),1.27(d,J=15.2Hz,2H).

[0557] Example 58: Preparation of Compound I-58 [ka]

[0558] Step A: Preparation of Compound 58a To a reaction flask, intermediate 1A-1 (12 g), bis(pinacolato)diboron (13.8 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (2.96 g), potassium acetate (10.67 g), and 1,4-dioxane (200 mL) were sequentially added, and the mixture was heated and stirred at 90°C. After completion of the reaction, the reaction solution was filtered and concentrated, and compound 58a (9.0 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 379.5.

[0559] Step B: Preparation of Compound 58b Compound 4-methoxy-3-pyrrolidin-2-one (10 g), potassium hydroxide (7.44 g), tetrabutylsulfamine sulfate (1.50 g), potassium acetate (10.67 g), tetrahydrofuran (150 mL), and iodomethane (18.82 g) were added to a reaction flask in this order and reacted at room temperature with stirring. After completion of the reaction, the reaction solution was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 40 / 1) to give compound 58b (9.1 g). MS (ESI, [M+H] + ) m / z: 128.0.

[0560] Step C: Preparation of Compound 58c Compound 58b (9.1 g), dichloromethane (10 mL), and trifluoroacetic acid (35 g) were added to a reaction flask in this order, and the mixture was stirred at room temperature to react. After completion of the reaction, the reaction mixture was concentrated to give compound 58c (8.0 g). MS (ESI, [M+H] + ) m / z: 114.0.

[0561] Step D: Preparation of Compound 58d Compound 58c (8.0 g), dichloromethane (100 mL), p-toluenesulfonyl chloride (13.48 g), and N,N-diisopropylethylamine (13.71 g) were sequentially added to a reaction flask and reacted at room temperature with stirring. After completion of the reaction, the reaction mixture was extracted with water and dichloromethane, and the organic phase was separated, dried, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 58d (5.2 g). MS (ESI, [M+H] + ) m / z: 268.3.

[0562] Step E: Preparation of Compound 58e Compound 58a (12.75 g), compound 58d (5.0 g), palladium acetate (0.42 g), tricyclohexylphosphine fluoroborate (1.38 g), potassium phosphate tripotassium (11.92 g), water (38 mL), and 1,4-dioxane (150 mL) were sequentially added to a microwave reaction flask and reacted at 85 °C in a microwave oven. After completion of the reaction, the reaction mixture was filtered and concentrated. Compound 58e (5.0 g) was obtained by column chromatography (dichloromethane / methanol = 20 / 1). MS (ESI, [M+H] + ) m / z: 348.3.

[0563] Step F: Preparation of Compound 58f Compound 58e (5.0 g), methanol (70 mL), and 10 wt% palladium hydroxide on carbon (5.49 g) were sequentially added to a reaction flask under a hydrogen atmosphere, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was filtered and concentrated. Compound 58f (3.1 g) was obtained by column chromatography (dichloromethane / methanol = 40 / 1). MS (ESI, [M+Na] + ) m / z: 372.4.

[0564] Step G: Preparation of Compound 58g Compound 58f (3.1 g), tetrahydrofuran (30 mL), and a 2 M solution of lithium borohydride in tetrahydrofuran (8.87 mL) were added sequentially to a reaction flask at 0° C., and the mixture was allowed to react with stirring at 0° C. After completion of the reaction, the reaction mixture was quenched by adding saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase was separated, dried, filtered, con...

Claims

1. The following formula (II): 【Chemistry 1】 [In the formula, X is selected from N or CH; Y is a bond, —O—, —S—, or —NR ａ -, -C(R ａ ) ２ -, -S(O) ２ -, -S(O) ２ N.R. ａ -, -S(O)-, -S(O)NR ａ -, -C(O)-, -C(O)O-, -C(O)NR ａ -, -C(O)N(R ａ )O-, -OC(O)-, -OC(O)NR ａ -, -N(R ａ )C(O)O-,-N(R ａ )C(O)-, or -N(R ａ ) S (O) ２ Selected from - Ring A is a 3- to 10-membered heterocyclyl, C ５－１０ aryl, or 5-10 membered heteroaryl; R １ are each independently -NH ２ , -NHR ｄ , -N(R ｄ ) ２ , -OH, -OR ｄ , -CN, halogen, -COOR ｄ , -OCOR ｄ , -N(R ｄ ) C(O)(R ｄ ), -CONH(R ｄ ), -CON(R ｄ ) ２ , -NHSO ２ (R ｄ ), -SO ２ NH (R ｄ ), -SO ２ N (R ｄ ) ２ , -PO(R ｄ ) ２ , 【Chemistry 2】 C １－６ Alkyl, C ５－１０ aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein １－６ Alkyl, C ５－１０ An aryl, a 5- to 10-membered heteroaryl, or a 3- to 10-membered heterocyclyl is represented by one or more R ｂ optionally replaced by R ｄ are each independently １－４ Alkyl or C ３－７ cycloalkyl, R ２ is selected from a 5-6 membered monocyclic heteroaryl, or a 9-14 membered saturated, partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 0-6 heteroatoms independently selected from N, O or S; ２ is one or more R ｃ optionally replaced by R ３ Each independently represents a halogen, C １－４ Alkyl or haloC １－４ Selected from alkyl, R ａ are each independently hydrogen or C １－４ Selected from alkyl, R ｂ are each independently deuterium, -NH ２ , -NH(C １－４ Alkyl), -N(C １－４ Alkyl) ２ , —OH, —OC １－４ Alkyl, -CN, halogen, 【Chemistry 3】 C １－４ alkyl, or 3- to 6-membered heterocycloalkyl, wherein the -NH(C １－４ alkyl), -N(C １－４ Alkyl) ２ , -OC １－４ Alkyl, C １－４ Alkyl and 3- to 6-membered heterocycloalkyl may each include one or more deuterium, halogen, or 【Chemistry 4】 is optionally substituted with a substituent; R ｃ are each independently -NH ２ , -NH(C １－４ Alkyl), -N(C １－４ Alkyl) ２ , —OH, —OC １－４ Alkyl, halogen, 【Chemistry 5】 or C optionally substituted with one or more deuterium １－６ Selected from alkyl, n is selected from 1, 2, 3 or 4; m is selected from 0, 1 or 2; Each X, Y, ring A, R １ , R ｄ , R ２ , R ３ , R ａ , R ｂ , or R ｃ are each independently optionally substituted with one or more substituents. A compound of formula (II), a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

2. Y is a bond, —O—, —S— or —NR ａ Selected from - Ring A is C ５－１０ aryl, or 5-10 membered heteroaryl; R １ are each independently -NH ２ , -NHR ｄ , -N(R ｄ ) ２ , -OH, -OR ｄ , -CN, halogen, -COOR ｄ , -OCOR ｄ , -N(R ｄ ) C(O)(R ｄ ), -CONH(R ｄ ), -CON(R ｄ ) ２ , -NHSO ２ (R ｄ ), -SO ２ NH (R ｄ ), -SO ２ N (R ｄ ) ２ , -PO(R ｄ ) ２ , 【Chemistry 6】 C １－６ alkyl, or 3- to 10-membered heterocycloalkyl, wherein １－６ Alkyl, 3- to 10-membered heterocycloalkyl may be one or more R ｂ optionally replaced by R ３ is halogen, C １－４ Alkyl or haloC １－４ Selected from alkyl, R ａ is hydrogen or C １－４ Selected from alkyl 2. A compound of formula (II) according to claim 1, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

3. The following formula (I): 【Chemistry 7】 [In the formula, Y is a bond, —O—, —S— or —NR ａ Selected from - Ring A is C ５－１０ aryl, or 5-10 membered heteroaryl; R １ are each independently -NH ２ , -NH(C １－４ Alkyl), -N(C １－４ Alkyl) ２ , —OH, —OC １－４ Alkyl, -CN, halogen, C １－６ alkyl, or 3- to 10-membered heterocycloalkyl, wherein １－６ Alkyl and 3- to 10-membered heterocycloalkyl are each independently one or more R ｂ optionally replaced by R ｂ are each independently -NH ２ , -NH(C １－４ alkyl), -N(C １－４ Alkyl) ２ , —OH, —OC １－４ Alkyl, -CN, halogen, 【Chemistry 8】 or 3- to 10-membered heterocycloalkyl, wherein said -NH(C １－４ Alkyl), -N(C １－４ Alkyl) ２ , -OC １－４ Alkyl and 3- to 10-membered heterocycloalkyl may each include one or more deuterium, halogen, or 【Chemistry 9】 or a phenyl group or a phenyl group, 3. A compound of formula (II) according to claim 1 or 2, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, wherein X is selected from CH, or X is selected from N, or a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

5. R ａ The compound according to any one of claims 1 to 4, its stereoisomer or a pharma- ceutically acceptable salt thereof, wherein R is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24

6. Y is a bond, —O—, —S— or —NR ａ -, or Y is -NR ａ -, or Y is selected from -NH-, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 5.

7. Ring A is C ５－８ aryl or 5-8 membered heteroaryl; Alternatively, ring A is C ５－６ aryl or 5-6 membered heteroaryl, Alternatively, Ring A is selected from 3-10 membered heterocycloalkyl; Alternatively, Ring A is phenyl or a 5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; Alternatively, Ring A is phenyl or a 6-membered heteroaryl containing 1 or 2 N atoms; Alternatively, Ring A is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, imidazolyl, or oxazolyl; Alternatively, Ring A is phenyl, or pyridyl; Alternatively, Ring A is pyridyl. The compound according to any one of claims 1 to 6, its stereoisomer or a pharma- ceutically acceptable salt thereof.

8. R １ are each independently -NH ２ , -NH(R ｄ ), -N(R ｄ ) ２ , halogen, -N(R ｄ ) C(O)(R ｄ ), -NHSO ２ (R ｄ ), -SO ２ NH (R ｄ ), -PO(R ｄ ) ２ , 【Chemistry 10】 C １－６ alkyl, 5- to 8-membered heteroaryl, or 3- to 10-membered heterocyclyl containing a heteroatom selected from N, O, S, or P, wherein １－６ Alkyl, 5- to 8-membered heteroaryl, or 3- to 10-membered heterocyclyl containing a heteroatom selected from N, O, S, or P may be represented by one or more R ｂ optionally replaced by Or, R １ are each independently -NH ２ , -NHR ｄ , -N(R ｄ ) ２ , halogen, -N(R ｄ ) C(O)(R ｄ ), -NHSO ２ (R ｄ ), -SO ２ NH (R ｄ ), -PO(R ｄ ) ２ , 【Chemistry 11】 C １－６ alkyl, 3- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, or 5- to 10-membered heterocycloalkenyl, wherein １－６ An alkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 6-membered heteroaryl, or a 5- to 10-membered heterocycloalkenyl may be represented by one or more R ｂ optionally replaced by Or, R １ are each independently -NH ２ , -NH(R ｄ ), -N(R ｄ ) ２ , F, Cl, Br, -N(R ｄ ) C(O)(R ｄ ), -NHSO ２ (R ｄ ), -SO ２ NH (R ｄ ), -PO(R ｄ ) ２ , 【Chemistry 12】 C １－４ alkyl, 5- to 10-membered heterocycloalkyl, or 5- to 8-membered heterocycloalkenyl, １－４ The alkyl, 5- to 10-membered heterocycloalkyl, or 5- to 8-membered heterocycloalkenyl may be one or more R ｂ optionally replaced by Or, R １ are each independently -NH ２ , -NH(R ｄ ), -N(R ｄ ) ２ , -N(R ｄ ) C(O)(R ｄ ), -NHSO ２ (R ｄ ), -SO ２ NH (R ｄ ), -PO(R ｄ ) ２ , 【Chemistry 13】 C １－３ alkyl, 5- to 9-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkenyl, wherein １－３ An alkyl, a 5- to 9-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkenyl is represented by one or more R ｂ optionally replaced by Or, R １ are each independently -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperidinyl, piperazinyl, tetrahydroimidazolyl, aza-oxa-bicycloheptyl, aza-oxa-spirononyl, aza-oxa-spiroheptyl, -N(CH ３ )C(O)CH ３ , -NHSO ２ (CH ３ ), -SO ２ NH (CH ３ ), -PO(CH ３ ) ２ , 【Chemistry 14】 oxazolidinyl, phospha-oxa-bicyclohexyl, aza-oxa-bicyclohexyl, phospha-aza-bicyclohexyl, dihydropyridyl, furanyl, or thiazinyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperidinyl, piperazinyl, tetrahydroimidazolyl, aza-oxa-bicycloheptyl, aza-oxa-spirononyl, aza-oxa-spiroheptyl, oxazolidinyl, phospha-oxa-bicyclohexyl, aza-oxa-bicyclohexyl, phospha-aza-bicyclohexyl, dihydropyridyl, furanyl, or thiazinyl is selected from one or more R ｂ optionally replaced by Or, R １ are each independently -NH ２ , F, methyl, ethyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, tetrahydroimidazolyl, -N(CH ３ ) COCH ３ , aza-oxa-bicycloheptyl, aza-oxa-spirononyl, aza-oxa-spiroheptyl, phospha-oxa-bicyclohexyl, aza-oxa-bicyclohexyl, phospha-aza-bicyclohexyl, oxazolidinyl, -NHSO ２ (CH ３ ), -SO ２ NH (CH ３ ), -PO(CH ３ ) ２ , 【Chemistry 15】 wherein said methyl, ethyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, tetrahydroimidazolyl, aza-oxa-bicycloheptyl, aza-oxa-spirononyl, aza-oxa-spiroheptyl, phospha-oxa-bicyclohexyl, aza-oxa-bicyclohexyl, phospha-aza-bicyclohexyl or oxazolidinyl is selected from one, two or three R ｂ optionally replaced by Or, R １ are each independently -NH ２ , F, methyl, ethyl, 【Chemistry 16】 wherein said methyl, ethyl, 【Chemistry 17】 is one, two or three R ｂ is optionally replaced by The compound according to any one of claims 1 to 7, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

9. The compound according to any one of claims 1 to 8, wherein n is selected from 1, 2 or 3, or n is selected from 2, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

10. 3. The compound according to claim 1 or 2, wherein m is selected from 0, 1 or 2, alternatively m is selected from 0 or 1, alternatively m is selected from 0, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

11. R ３ is halogen, C １－３ Alkyl or haloC １－３ Selected from alkyl, Or, R ３ is F, Cl, Br or C １－３ Selected from alkyl, Or, R ３ is selected from F or methyl 3. The compound according to claim 1 or 2, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

12. R ｂ are each independently deuterium, —OH, C １－４ Alkyl, halogen, 【Chemistry 18】 -N(C １－４ Alkyl) ２ or 3- to 6-membered heterocycloalkyl, wherein said —N(C １－４ Alkyl) ２ and 3- to 6-membered heterocycloalkyl may include one or more deuterium, halogen, or 【Chemistry 19】 is optionally substituted with a substituent; Or, R ｂ are each independently deuterium, —OH, C １－３ Alkyl, F, Cl, Br, 【Chemistry 20】 -N(C １－４ Alkyl) ２ or 5-membered heterocycloalkyl, wherein said —N(C １－４ Alkyl) ２ and 5-membered heterocycloalkyl may include one or more deuterium, halogen, or 【Chemistry 21】 is optionally substituted with a substituent; Or, R ｂ are each independently deuterium, —OH, CH ３ , F, 【Chemical 22】 -N(CH ３ ) ２ , -N(CH ３ CH ２ ) ２ , -N(CH ３ CH ２ CH ２ ) ２ , -N(CH ３ ) CH ２ CH ３ , -N(CH ３ ) C(CH ３ ) ２ , tetrahydropyrrolyl, tetrahydrofuranyl, or tetrahydrothienyl, wherein said —N(CH ３ ) ２ , -N(CH ３ CH ２ ) ２ , -N(CH ３ CH ２ CH ２ ) ２ , -N(CH ３ ) CH ２ CH ３ , -N(CH ３ ) C(CH ３ ) ２ , tetrahydropyrrolyl, tetrahydrofuranyl and tetrahydrothienyl are each independently selected from the group consisting of one or more deuterium, halogen, or 【Chemistry 23】 is optionally substituted with a substituent; Or, R ｂ are each independently deuterium, —OH, CH ３ , F, 【Chemistry 24】 -N(CH ３ ) ２ , -N(CH ３ ) CH ２ CH ３ , -N(CH ３ ) C(CH ３ ) ２ or tetrahydropyrrolyl, wherein said -N(CH ３ ) ２ , -N(CH ３ ) CH ２ CH ３ and tetrahydropyrrolyl is a substituted or unsubstituted aryl group, which may be substituted with one or more deuterium, halogen, or 【Chemistry 25】 is optionally substituted with a substituent; Or, R ｂ are each independently deuterium, —OH, CH ３ , F, 【Chemistry 26】 -N(CH ３ ) ２ ,-N(CD ３ ) ２ 、 【Chemistry 27】 Selected from The compound according to any one of claims 1 to 11, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

13. one, two or three of the three rings are aromatic rings; Alternatively, the tricyclic ring of formula (I) 【Chemistry 28】 or of formula (II) 【Chemical 29】 the monocyclic ring attached to the moiety is an aromatic ring; Alternatively, the tricyclic ring of formula (I) 【Chemistry 30】 or of formula (II) 【Chemistry 31】 the monocyclic ring attached to the moiety is an N-atom-containing aromatic ring; or any two adjacent rings of said tricycle are optionally fused, bridged, or spiro; Alternatively, the tricyclic ring of formula (I) 【Chemistry 32】 or of formula (II) 【Chemical 33】 The single ring bound to the moiety and the adjacent ring are fused rings. The compound according to any one of claims 1 to 12, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

14. R ２ is selected from a 6-membered monocyclic heteroaryl, or a 9-14 membered saturated, partially saturated or aromatic tricycle, wherein said tricycle contains 0-6 heteroatoms independently selected from N, O or S; ２ is one or more R ｃ optionally replaced by Or, R ２ is selected from a 6-membered monocyclic heteroaryl containing 1 or 2 N atoms, or a 9-14 membered saturated, partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 1 to 6 heteroatoms independently selected from N, O or S, and said R ２ is one or more R ｃ optionally replaced by Or, R ２ is selected from a 6-membered monocyclic heteroaryl containing 1 or 2 N atoms, or a 9-14 membered saturated, partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 1 to 6 heteroatoms independently selected from N or O, and said R ２ is one or more R ｃ optionally replaced by Or, R ２ is selected from a 6-membered monocyclic heteroaryl containing 1 or 2 N atoms, or a 9-14 membered partially saturated or aromatic tricyclic ring, wherein said tricyclic ring contains 1 to 6 heteroatoms independently selected from N or O, and said R ２ is one or more R ｃ optionally replaced by Or, R ２ teeth, 【Chemical 34】 wherein R ２ is one or more R ｃ optionally replaced by Or, R ２ teeth, 【Chemistry 35】 Selected from The compound according to any one of claims 1 to 13, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

15. R ２ is selected from a 9-14 membered saturated, partially saturated or aromatic tricycle, wherein said tricycle contains 0-6 heteroatoms independently selected from N, O or S; ２ is one or more R ｃ optionally replaced by Or, R ２ is selected from a 9-14 membered saturated, partially saturated or aromatic tricycle, wherein said tricycle contains 1 to 6 heteroatoms independently selected from N, O or S; ２ is one or more R ｃ optionally replaced by Or, R ２ is selected from a 9-14 membered saturated, partially saturated or aromatic tricycle, wherein said tricycle contains 1 to 6 heteroatoms independently selected from N or O, and said R ２ is one or more R ｃ optionally replaced by Or, R ２ is selected from a 9-14 membered partially saturated or aromatic tricycle, wherein said tricycle contains 1-6 heteroatoms independently selected from N or O, and said R ２ is one or more R ｃ is optionally replaced by The compound according to any one of claims 1 to 14, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

16. R ｃ are each independently 【Chemical Formula 36】 or C optionally substituted with one or more deuterium １－６ Selected from alkyl, Or, R ｃ are each independently 【Chemical 37】 or C optionally substituted with one or more deuterium １－４ Selected from alkyl, Or, R ｃ are each independently 【Chemical Formula 38】 or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, optionally substituted with one or more deuterium atoms; Or, R ｃ are each independently 【Chemical 39】 or methyl optionally substituted with one or more deuterium atoms; Or, R ｃ are each independently 【Chemistry 40】 Methyl or -CD ３ Selected from The compound according to any one of claims 1 to 15, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

17. R ｄ are each independently １－４ Alkyl or C ３－６ cycloalkyl, Or, R ｄ are each independently １－２ Alkyl or C ３－４ cycloalkyl, Or, R ｄ are each independently １－２ Selected from alkyl, Or, R ｄ are each independently ３－４ selected from cycloalkyl, The compound according to any one of claims 1 to 16, a stereoisomer thereof or a pharma- ceutically acceptable salt thereof.

18. The compound according to any one of claims 1 to 3, which is selected from the compounds of the following formula (Ia), formula (Ib), formula (Ic), or formula (Id), a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof. 【Chemistry 41】

19. The compound according to any one of claims 1 to 18, which is selected from the following compounds, stereoisomers, or pharma- ceutically acceptable salts thereof: 【Chemistry 42】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

20. 20. Use of the compound according to any one of claims 1 to 19, its stereoisomer or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a disease, wherein the disease is optionally selected from cancer, and the cancer is optionally selected from solid tumors, leukemia, or lymphoma.

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