Compounds as BCR-ABL inhibitors

Abstract

The present invention relates to a compound as a BCR-ABL inhibitor, i.e., a compound of formula (I), or a pharma- ceutically acceptable salt thereof, a process for its preparation, a pharmaceutical composition containing said compound, and its use in the manufacture of a medicament for treating a BCR-ABL-associated disease. TIFF2024519538000298.tif33170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to Chinese invention patent applications bearing application numbers 202110592542.2, 202111094508.9 and 202111661984.4, filed with the China State Intellectual Property Office on May 28, 2021, September 17, 2021 and December 31, 2021, the entire contents of which are hereby incorporated by reference in their entirety into this specification.

[0002] The present application belongs to the field of medicinal chemistry, and relates to compounds as BCR-ABL inhibitors, methods for preparing the same, pharmaceutical compositions containing the compounds, and their use in the manufacture of drugs for treating BCR-ABL-related diseases. [Background technology]

[0003] Chronic myeloid leukemia (CML) is the main type of chronic leukemia in Japan, accounting for approximately 70% of chronic leukemia cases. More than 90% of cases of this disease have chromosomal abnormalities, mainly due to translocation of the long arms of chromosomes 9 and 22, resulting in the formation of the Bcr-Abl fusion gene that expresses the p-210 protein. The tyrosine kinase activity of p-210 is increased by p-150 (normal Since the amount of Abl expression is much greater than the normal c-Abl gene product, this leads to abnormal proliferation and differentiation of hematopoietic stem cells, ultimately resulting in CML.

[0004] Imatinib is the first Bcr-Abl targeted drug on the market and is currently used as a first-line treatment for the treatment of all stages of CML. Nilotinib, dasatinib, and bosutinib (second-generation Bcr-Abl inhibitors) are approved for the treatment of imatinib-resistant or intolerant CML. Second-generation Bcr-Abl inhibitors are generally more effective than imatinib and are effective against almost all types of imatinib-resistant mutations, but the problem of T315I (gatekeeper) mutation resistance has not yet been resolved. In patients resistant to first- and second-generation Bcr-Abl inhibitors, T315I mutation accounts for approximately 20%. The availability of ponatinib (third-generation Bcr-Abl inhibitor) has alleviated the lack of treatment for T315I-resistant mutation patients, and it is the only option for patients who have failed first- and second-generation Bcr-Abl inhibitor treatment.

[0005] ABL001 is a Bcr-Abl allosteric inhibitor developed by Novartis, disclosed in Patent Document 1, and currently in phase III clinical studies. ABL001 is an effective and selective BCR-ABL inhibitor that is active against most mutant types, including T315I (Non-Patent Document 1). [ka]

[0006] Currently, there is still no commercially available BCR-ABL allosteric inhibitor, so there is an urgent need for clinically effective and efficient Bcr-Abl inhibitors with low toxicity for T315I, and there is a need to further develop new BCR-ABL allosteric inhibitors. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. WO2013171639 [Non-patent literature]

[0008] [Non-Patent Document 1] Andrew A. Wylie et al.,(2017) Nature 543,733-737. Summary of the Invention

[0009] In one aspect, the present application provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, Q is selected from N or CH; R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ is replaced by X, Y and Z are each independently selected from CH or N, and at least one of X, Y and Z is selected from CH; Ring A is selected from 5-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O or S atoms; Ring B is selected from a 5- to 10-membered heterocyclyl group containing 1 to 3 heteroatoms selected from N, O, or S atoms, or a 5- to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, or S atoms; R 2 is hydrogen, amino group, C 1~6 Alkyl group, C 1~6 Alkoxy group, amino-C 1~6 alkyl-, a 3- to 10-membered heterocyclyl group, or a 5- or 6-membered heteroaryl group, 1~6 Alkyl group, C 1~6 Alkoxy group, amino-C 1~6The alkyl-, 3- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl group may optionally be one or more R b is replaced by R 3 is selected from -OCF2H, wherein said -OCF2H is optionally substituted by halogen; R a and R a’ are respectively a hydroxy group, an amino group, a cyano group, a halogen atom, [ka] C 1~6 Alkyl groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, 3- to 8-membered cycloalkyl-C 1~6 Alkyl-, 3-8 membered heterocycloalkyl-C 1~6 Alkyl- or C substituted with one or more hydroxy groups or halogens 1~6 independently selected from alkyl groups, R b is a hydroxy group, an amino group, a cyano group, a halogen, [ka] C 1~6 Alkyl group, C 1~6 Alkoxy group, C 1~6 Alkoxy-C 1~6 Alkyl-, C 1~6 Alkyl-C(O)-NH- or C substituted by one or more hydroxy groups or halogens 1~6 It is selected from alkyl groups.

[0010] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is selected from a compound of formula (II), or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ is replaced by X, Y and Z are each independently selected from CH or N, and at least one of X, Y and Z is selected from CH; Ring A is selected from 5-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O or S atoms; Ring B is a 5- to 10-membered heterocyclyl group containing 1 to 3 heteroatoms selected from N, O, or S atoms, or a 5- to 10-membered heterocyclyl group containing 1 to 3 heteroatoms selected from N, O, or S atoms. is selected from 5-8 membered heteroaryl groups containing R 2 is hydrogen, amino group, C 1~6 Alkyl group, C 1~6 Alkoxy group, amino-C 1~6 alkyl-, a 3- to 10-membered heterocyclyl group, or a 5- or 6-membered heteroaryl group, 1~6 Alkyl group, C 1~6 Alkoxy group, amino-C 1~6 The alkyl-, 3- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl group may optionally be one or more R b is replaced by R 3 is selected from -OCF2H, wherein said -OCF2H is optionally substituted by halogen; R a and R a’ are respectively a hydroxy group, an amino group, a cyano group, a halogen atom, [ka] C 1~6Alkyl groups, 3- to 8-membered cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups, 3- to 8-membered cycloalkyl-C 1~6 Alkyl-, 3-8 membered heterocycloalkyl-C 1~6 Alkyl- or C substituted with one or more hydroxy groups or halogens 1~6 independently selected from alkyl groups, R b is a hydroxy group, an amino group, a cyano group, a halogen, [ka] C 1~6 Alkyl group, C 1~6 Alkoxy group, C 1~6 Alkoxy-C 1~6 Alkyl-, C 1~6 Alkyl-C(O)-NH- or C substituted by one or more hydroxy groups or halogens 1~6 It is selected from alkyl groups.

[0011] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ is replaced by X, Y and Z are each independently selected from CH or N, and at least one of X, Y and Z is selected from CH; R 2 is selected from hydrogen or a 3- to 10-membered heterocyclyl group, wherein the 3- to 10-membered heterocyclyl group optionally comprises one or more R b is replaced by R 3is selected from -OCF2H, wherein said -OCF2H is optionally substituted by halogen; R a and R a’ are respectively hydroxyl group, amino group, cyano group, halogen, and C 1~6 an alkyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, or a C substituted with one or more hydroxy groups or halogens; 1~6 independently selected from alkyl groups, R b is a hydroxy group, an amino group, a cyano group, a halogen, [ka] C 1~6 Alkyl group, C 1~6 C substituted by an alkoxy group, one or more hydroxy groups or halogens 1~6 It is selected from alkyl groups.

[0012] In some embodiments, the heterocyclyl or heterocycloalkyl group contains 1, 2, 3, or 4 heteroatoms or heteroatomic groups, respectively, independently selected from -O-, -NH-, -S-, or N, and the other variables are as defined herein. In some embodiments, the heterocyclyl or heterocycloalkyl group contains 1, 2, 3, or 4 heteroatoms or heteroatomic groups, respectively, independently selected from -O-, -NH-, or N, and the other variables are as defined herein. In some embodiments, the heterocyclyl or heterocycloalkyl group contains 1 or 2 heteroatoms or heteroatomic groups, respectively, independently selected from -O-, -NH-, or N, and the other variables are as defined herein.

[0013] In some embodiments, R 2 , R a or R a’The heterocyclyl or heterocycloalkyl groups referred to in the formula (I) each contain 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, or N, and the other variables are as defined herein. 2 , R a or R a’ The heterocyclyl or heterocycloalkyl groups referred to in the formula (I) each contain 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, or N, and the other variables are as defined herein. 2 , R a or R a’ The heterocyclyl or heterocycloalkyl groups referred to in the above formula (I) each contain 1 or 2 heteroatoms or heteroatom groups independently selected from -O-, -NH- or N, and the other variables are as defined herein.

[0014] In some embodiments, Q is selected from N, and other variables are as defined herein. In some embodiments, Q is selected from CH, and other variables are as defined herein.

[0015] In some embodiments, Q is selected from CH; R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ is replaced by R a’ is halogen, [ka] C 1~6R is selected from an alkyl group or a 3- to 6-membered cycloalkyl group. a’ are fluorine, chlorine, [ka] selected from a methyl group, an ethyl group, an isopropyl group, or a cyclopropyl group; R 2 teeth, [ka] wherein said [ka] optionally, one, two or three R b is replaced by R b is a hydroxy group or C 1~4 selected from alkyl groups, R 3 is selected from -OCF2H, wherein said -OCF2H is optionally substituted by halogen.

[0016] In some embodiments, Q is selected from CH; R 1 teeth, [ka] Selected from R 2 teeth, [ka] Selected from R 3 is selected from -OCF2H, wherein said -OCF2H is optionally substituted by chlorine.

[0017] In some embodiments, X, Y, and Z are all selected from CH, and other variables are as defined herein. In some embodiments, one of X, Y, and Z is selected from N, and the other is selected from CH, and other variables are as defined herein. In some embodiments, X is selected from N, Y, and Z are selected from CH, and other variables are as defined herein. In some embodiments, Y is selected from N, X, and Z are selected from CH, and other variables are as defined herein. In some embodiments, Z is selected from N, X, and Y are selected from CH, and other variables are as defined herein. In some embodiments, one of X, Y, and Z is selected from CH, and the other is selected from N, and other variables are as defined herein.

[0018] In some embodiments, Ring A is selected from a 5-membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O, or S atoms, and the other variables are as defined herein.

[0019] In some embodiments, Ring A is selected from a 5-membered heteroaryl group containing 1 or 2 heteroatoms selected from N or O atoms, and the other variables are as defined herein.

[0020] In some embodiments, Ring A is selected from a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, an oxazolyl group, or an isoxazolyl group, and other variables are as defined herein. In some embodiments, Ring A is selected from a pyrrolyl group, a pyrazolyl group, an imidazolyl group, or a furyl group, and other variables are as defined herein.

[0021] In some embodiments, ring B is a 5-8 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N or O atoms, or a 5-8 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N or O atoms. and wherein the aryl group is selected from a 5-8 membered heteroaryl group containing one to three heteroatoms, and the other variables are as defined herein.

[0022] In some embodiments, Ring B is selected from a 5- or 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N or O atoms, or a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from N or O atoms, and the other variables are as defined herein.

[0023] In some embodiments, Ring B is selected from a 5- or 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N or O atoms, or a 5-membered heteroaryl group containing 1 or 2 N atoms, and the other variables are as defined herein.

[0024] In some embodiments, Ring B is selected from a tetrahydropyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an imidazolyl group, or a pyrazolyl group, and other variables are as defined herein. In some embodiments, Ring B is selected from a tetrahydropyrrolidinyl group, a piperidinyl group, a morpholinyl group, or an imidazolyl group, and other variables are as defined herein.

[0025] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ and other variables are as defined herein.

[0026] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ and other variables are as defined herein.

[0027] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ and other variables are as defined herein.

[0028] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ and other variables are as defined herein.

[0029] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ and other variables are as defined herein.

[0030] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ and other variables are as defined herein.

[0031] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ and other variables are as defined herein.

[0032] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ and other variables are as defined herein.

[0033] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ and other variables are as defined herein.

[0034] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ and other variables are as defined herein.

[0035] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ and other variables are as defined herein.

[0036] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ and other variables are as defined herein.

[0037] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ and other variables are as defined herein.

[0038] In some embodiments, R 1 teeth, [ka] wherein said [ka] Optionally, one R a’ and other variables are as defined herein.

[0039] In some embodiments, R 1 teeth, [ka] and other variables are as defined herein.

[0040] In some embodiments, R aand R a’ are halogens, [ka] C 1~6 Alkyl groups, 3- to 6-membered cycloalkyl groups, 3- to 8-membered heterocycloalkyl groups-C 1~6 Alkyl- or C substituted with 1, 2 or 3 hydroxy groups 1~6 alkyl groups, and the other variables are as defined herein.

[0041] In some embodiments, R a and R a’ are halogens, [ka] C 1~4 Alkyl groups, 3- to 6-membered cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups-C 1~4 Alkyl- or C substituted with 1, 2 or 3 hydroxy groups 1~4 alkyl groups, and the other variables are as defined herein.

[0042] In some embodiments, R a and R a’ are respectively hydroxyl group, amino group, cyano group, halogen, and C 1~6 an alkyl group, a 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, or a C substituted with one or more hydroxy groups or halogens; 1~6 alkyl groups, and the other variables are as defined herein.

[0043] In some embodiments, R a and R a’ are halogens, C 1~6 C substituted with an alkyl group, a 3- to 6-membered cycloalkyl group, or one, two, or three hydroxy groups 1~6alkyl groups, and the other variables are as defined herein.

[0044] In some embodiments, R a and R a’ are hydroxyl, amino and silyl groups, respectively. Ano group, halogen, C 1~4 an alkyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, or a C substituted with one or more hydroxy groups or halogens; 1~4 alkyl groups, and the other variables are as defined herein.

[0045] In some embodiments, R a and R a’ are halogens, C 1~4 C substituted with an alkyl group, a 3- to 6-membered cycloalkyl group, or one, two, or three hydroxy groups 1~4 alkyl groups, and the other variables are as defined herein.

[0046] In some embodiments, R a is C 1~4 Alkyl groups, 3- to 6-membered cycloalkyl groups, 3- to 6-membered heterocycloalkyl groups-C 1~4 Alkyl- or C substituted with 1, 2 or 3 hydroxy groups 1~4 The alkyl group is selected from the group consisting of aryl, aryl, aryl and aryl groups, and the other variables are as defined herein.

[0047] In some embodiments, R a is a methyl group, an ethyl group, a cyclopropyl group, a 2-hydroxyethyl group, or [ka] and other variables are as defined herein.

[0048] In some embodiments, R a is C 1~4C substituted with an alkyl group, a 3- to 6-membered cycloalkyl group, or one, two, or three hydroxy groups 1~4 The alkyl group is selected from the group consisting of aryl, aryl, aryl and aryl groups, and the other variables are as defined herein.

[0049] In some embodiments, R a is selected from a methyl group, an ethyl group, a cyclopropyl group, or a 2-hydroxyethyl group, and the other variables are as defined herein.

[0050] In some embodiments, R a is selected from a methyl group, and the other variables are as defined herein.

[0051] In some embodiments, R a’ is a hydroxy group, an amino group, a cyano group, a halogen, [ka] C 1~4 It is selected from an alkyl group or a 3- to 6-membered cycloalkyl group, and the other variables are as defined herein.

[0052] In some embodiments, R a’ is halogen, [ka] C 1~4 alkyl group or 3- to 6-membered cycloalkyl group, and the other variables are defined herein. As stated above.

[0053] In some embodiments, R a’ are fluorine, chlorine, bromine, iodine, [ka] It is selected from a methyl group, an ethyl group, an isopropyl group, or a cyclopropyl group, and the other variables are as defined herein.

[0054] In some embodiments, R a’ are fluorine, chlorine, [ka] It is selected from a methyl group, an ethyl group, or a cyclopropyl group, and the other variables are as defined herein.

[0055] In some embodiments, R a’ is selected from a hydroxy group, an amino group, a cyano group, or a halogen, and the other variables are as defined herein.

[0056] In some embodiments, R a’ is selected from halogen, and the other variables are as defined herein.

[0057] In some embodiments, R a’ is selected from fluorine or chlorine, and the other variables are as defined herein.

[0058] In some embodiments, R 1 teeth, [ka] and other variables are as defined herein.

[0059] In some embodiments, R 1 teeth, [ka] and other variables are as defined herein.

[0060] In some embodiments, R 2 is hydrogen, amino group, C 1~4 Alkoxy group, amino-C 1~4alkyl-, a 3- to 10-membered heterocycloalkyl group, or a 5- or 6-membered heteroaryl group, 1~4 Alkoxy group, amino-C 1~4 The alkyl-, 3- to 10-membered heterocycloalkyl or 5- or 6-membered heterocycloaryl group may optionally be one or more R b and other variables are as defined herein.

[0061] In some embodiments, R 2 is hydrogen, amino group, C 1~4 Alkoxy group, amino-C 1~4 Alkyl-, 4- to 6-membered monoheterocycloalkyl group, 6- to 9-membered bridged heterocycloalkyl group, 7- to 9-membered spiroheterocycloalkyl group, or 5- or 6-membered heteroaryl wherein the amino group, C 1~4 Alkoxy group, amino-C 1~4 The alkyl-, 4- to 6-membered monoheterocycloalkyl group, 6- to 9-membered bridged heterocycloalkyl group, 7- to 9-membered spiroheterocycloalkyl group, or 5- or 6-membered heteroaryl group may optionally be selected from one or more R b and other variables are as defined herein.

[0062] In some embodiments, R 2 is an amino group, C 1~3 Alkoxy group, amino-C 1~3 alkyl-, a 4-, 5- or 6-membered monoheterocycloalkyl group, a 6-, 7- or 8-membered bridged heterocycloalkyl group, a 7-, 8- or 9-membered spiroheterocycloalkyl group, or a 5-membered heteroaryl group, wherein the amino group, C 1~3 Alkoxy group, amino-C 1~3 An alkyl-, 4-, 5-, or 6-membered monoheterocycloalkyl group, a 6-, 7-, or 8-membered bridged heterocycloalkyl group, a 7-, 8-, or 9-membered spiroheterocycloalkyl group, or a 5-membered heteroaryl group may optionally be represented by one or more (e.g., one, two, or three) R band other variables are as defined herein.

[0063] In some embodiments, R 2 is selected from hydrogen or a 3- to 10-membered heterocyclyl group, wherein the 3- to 10-membered heterocyclyl group optionally comprises one or more R b and other variables are as defined herein.

[0064] In some embodiments, R 2 is selected from hydrogen or a 3- to 10-membered heterocycloalkyl group, wherein the 3- to 10-membered heterocycloalkyl group optionally comprises one or more R b and other variables are as defined herein.

[0065] In some embodiments, R 2 is selected from an amino group or a 3- to 10-membered heterocycloalkyl group, wherein the amino group or the 3- to 10-membered heterocycloalkyl group is optionally selected from one or more R b and other variables are as defined herein.

[0066] In some embodiments, the heterocycloalkyl group contains 1, 2, 3, or 4 heteroatoms or heteroatomic groups, each independently selected from -O-, -NH-, -S-, or N, and the other variables are as defined herein. In some embodiments, the heterocycloalkyl group contains 1, 2, 3, or 4 heteroatoms or heteroatomic groups, each independently selected from -O-, -NH-, or N, and the other variables are as defined herein. In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms or heteroatomic groups, each independently selected from -O-, -NH-, or N, and the other variables are as defined herein.

[0067] In some embodiments, R 2 , R a or R a’Each heterocycloalkyl group referred to in the formula (I) contains 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, or N, and the other variables are as defined herein. 2 , R a or R a’ Each heterocycloalkyl group referred to in the formula (I) contains 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, or N, and the other variables are as defined herein. 2 , R a or R a’ Each heterocycloalkyl group referred to in the formula (I) contains one or two heteroatoms or heteroatom groups independently selected from -O-, -NH-, or N, and the other variables are as defined herein. 2 is selected from hydrogen, a 4- to 6-membered monoheterocyclyl group, a 6- to 9-membered bridged heterocyclyl group, or a 7- to 9-membered spiroheterocyclyl group, wherein the 4- to 6-membered monoheterocyclyl group, the 6- to 9-membered bridged heterocyclyl group, or the 7- to 9-membered spiroheterocyclyl group may optionally be selected from one or more R b and other variables are replaced by As defined herein.

[0068] In some embodiments, R 2 is selected from hydrogen, a 4- to 6-membered monoheterocycloalkyl group, a 6- to 9-membered bridged heterocycloalkyl group, or a 7- to 9-membered spiroheterocycloalkyl group, wherein the 4- to 6-membered monoheterocycloalkyl group, the 6- to 9-membered bridged heterocycloalkyl group, or the 7- to 9-membered spiroheterocycloalkyl group may optionally be selected from one or more R b and other variables are as defined herein.

[0069] In some embodiments, R 2 is not hydrogen and the other variables are as defined herein.

[0070] In some embodiments, R 2 is selected from a 4-, 5-, or 6-membered monoheterocycloalkyl group, a 6-, 7-, or 8-membered bridged heterocycloalkyl group, or a 7-, 8-, or 9-membered spiroheterocycloalkyl group, wherein the 4-, 5-, or 6-membered monoheterocycloalkyl group, the 6-, 7-, or 8-membered bridged heterocycloalkyl group, or the 7-, 8-, or 9-membered spiroheterocycloalkyl group optionally comprises one or more (e.g., one, two, or three) R b and other variables are as defined herein.

[0071] In some embodiments, R 2is an amino group, a methoxy group, an ethoxy group, an aminomethyl group, a pyrrolidinyl group, an oxazolidinyl group, an isoxazolidinyl group, a morpholinyl group, a thiomorpholinyl group, a 1,4-dioxane group, an azetidinyl group, a piperazinyl group, a piperidinyl group, a 1,2,3,6-tetrahydropyridinyl group, a tetrahydropyranyl group, a 3,4-dihydropyranyl group, a 3,6-dihydropyranyl group, a 6-oxa-3-azabicyclo[3.1.1]heptyl group, a 3-oxa-6 ... aza-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptyl, pyrazolyl or imidazolyl, wherein said aza-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-oxa-5-azaspiro[3.1.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.4]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptyl, pyrazolyl or imidazolyl, methoxy group, ethoxy group, aminomethyl group, pyrrolidinyl group, oxazolidinyl group, isoxazolidinyl group, morpholinyl group, thiomorpholinyl group, 1,4-dioxane group, azetidinyl group, piperazinyl group, piperidinyl group, 1,2,3,6-tetrahydropyridinyl group, tetrahydropyranyl group, 3,4-dihydropyranyl group, 3,6-dihydropyranyl group, 6-oxa-3-azabicyclo[3.1.1]heptyl group, 3-oxa-6-azabicyclo[3.1 The 2-oxa-6-azaspiro[3.4]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptyl, pyrazolyl or imidazolyl groups may optionally be selected from the group consisting of one or more R b and other variables are as defined herein.

[0072] In some embodiments, R 2is an amino group, a methoxy group, an ethoxy group, an aminomethyl group, a pyrrolidinyl group, a isoxazolidinyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a 1,4-dioxane group, an azetidinyl group, a 6-oxa-3-azabicyclo[3.1.1]heptyl group, a 3-oxa-6-azabicyclo[3.1.1]heptyl group, a 3-oxa-8-azabicyclo[3.2.1]octyl group, a 8-oxa-3-azabicyclo[3.2.1]octyl group, a 2-oxa-5-azabicyclo[2.2.1]heptane group, a 3-azabicyclo[3.1.0]hexyl group, a 2-oxa-6-azaspiro[3.4] octyl group, 2-oxa-7-azaspiro[3.5]nonyl group, 2-oxa-6-azaspiro[3.3]heptyl group, pyrazolyl group or imidazolyl group, wherein the amino group, methoxy group, ethoxy group, aminomethyl group, pyrrolidinyl group, isoxazolidinyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, 1,4-dioxane group, azetidinyl group, 6-oxa-3-azabicyclo[3.1.1]heptyl group, 3-oxa-6-azabicyclo[3. 1.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.4]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptyl, pyrazolyl or imidazolyl group may optionally be selected from the group consisting of one or more R b and other variables are as defined herein.

[0073] In some embodiments, R 2is a pyrrolidinyl group, an isoxazolidinyl group, a morpholinyl group, an azetidinyl group, a piperazinyl group, a piperidinyl group, a 1,2,3,6-tetrahydropyridinyl group, a tetrahydropyranyl group, a 3,4-dihydropyranyl group, a 3,6-dihydropyranyl group, a 6-oxa-3-azabicyclo[3.1.1]heptyl group, a 3-oxa-6-azabicyclo[3.1.1]heptyl group, a 3-oxa-8- azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.4]octyl, 2-oxa-7-azaspiro[3.5]nonyl or 2-oxa-6-azaspiro[3.3]heptyl, wherein the pyrrolic acid is selected from the group consisting of azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.4]octyl, 2-oxa-7-azaspiro[3.5]nonyl or 2-oxa-6-azaspiro[3.3]heptyl. Lysinyl, isoxazolidinyl, morpholinyl, azetidinyl, piperazinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 3-oxa-8-azabicyclo[3.1.1]heptyl, The chloro[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.4]octyl, 2-oxa-7-azaspiro[3.5]nonyl or 2-oxa-6-azaspiro[3.3]heptyl groups may optionally be joined by one or more R b and other variables are as defined herein.

[0074] In some embodiments, R 2is selected from pyrrolidinyl, isoxazolidinyl, morpholinyl, azetidinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.4]octyl, 2-oxa-7-azaspiro[3.5]nonyl, and 2-oxa-6-azaspiro[3.3]heptyl, wherein the pyrrolidinyl, isoxazolidinyl, morpholinyl, azetidinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 3-oxa-6-azabicyclo[3.1.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.4]octyl, 2-oxa-7-azaspiro[3.5]nonyl, and 2-oxa-6-azaspiro[3.3]heptyl groups; The lysinyl, isoxazolidinyl, morpholinyl, azetidinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 3-oxa-6-azabicyclo[3.1.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.4]octyl, 2-oxa-7-azaspiro[3.5]nonyl or 2-oxa-6-azaspiro[3.3]heptyl groups may optionally be joined by one or more R b and other variables are as defined herein.

[0075] In some embodiments, R 2 is an amino group, a methoxy group, an ethoxy group, an aminomethyl group basis, [ka] wherein the amino group, the methoxy group, the ethoxy group, the aminomethyl group, [ka] optionally, one, two or three R b and other variables are as defined herein.

[0076] In some embodiments, R 2 teeth, [ka] wherein said [ka] optionally, one, two or three R b and other variables are as defined herein.

[0077] In some embodiments, R b is a hydroxyl group, a cyano group, a halogen, [ka] C 1~4 Alkyl group, C 1~4 Alkoxy group, C 1~4 Alkoxy-C 1~4 Alkyl-, C 1~4 Alkyl-C(O)-NH- or C substituted by one or more hydroxy groups or halogens 1~4 The alkyl group is selected from the group consisting of aryl, aryl, aryl and aryl groups, and the other variables are as defined herein.

[0078] In some embodiments, R b is a hydroxyl group, a cyano group, a fluorine group, a chlorine group, [ka] The group is selected from a methyl group, a methoxy group, a hydroxymethyl group, a methoxyethyl group, or an acetylamino group, and the other variables are as defined herein.

[0079] In some embodiments, R b is a hydroxy group, an amino group, a cyano group, a halogen, [ka] C 1~6 Alkyl group, C 1~6 C substituted by an alkoxy group, one or more hydroxy groups or halogens 1~6 The alkyl group is selected from the group consisting of aryl, aryl, aryl and aryl groups, and the other variables are as defined herein.

[0080] In some embodiments, R b is a hydroxyl group, a cyano group, a halogen, [ka] C 1~6 Alkyl group, C 1~6 C substituted by an alkoxy group, one or more hydroxy groups or halogens 1~6 The alkyl group is selected from the group consisting of aryl, aryl, aryl and aryl groups, and the other variables are as defined herein.

[0081] In some embodiments, R b is a hydroxyl group, a cyano group, a halogen, [ka] C 1~4 Alkyl group, C 1~4 Alkoxy groups or one, two or three hydroxy groups C substituted by groups 1~3 The alkyl group is selected from the group consisting of aryl, aryl, aryl and aryl groups, and the other variables are as defined herein.

[0082] In some embodiments, R b is a hydroxyl group, a cyano group, a halogen, [ka] C 1~3 Alkyl group, C 1~3 C substituted by an alkoxy group or one hydroxy group 1~3 The alkyl group is selected from the group consisting of aryl, aryl, aryl and aryl groups, and the other variables are as defined herein.

[0083] In some embodiments, R b is a hydroxyl group, a cyano group, a fluorine group, a chlorine group, [ka] The alkyl group is selected from a methyl group, a methoxy group, or a hydroxymethyl group, and the other variables are as defined herein.

[0084] In some embodiments, R 2 is a pyrrolidinyl group, an isoxazolidinyl group, a morpholinyl group, an azetidinyl group, a 6-oxa-3-azabicyclo[3.1.1]heptyl group, a 3-oxa-6-azabicyclo[3.1.1]heptyl group, a 3-oxa-8-azabicyclo[3.2.1]octyl group, a 8-oxa-3-azabicyclo[3.2.1]octyl group, a 2-oxa-5-azabicyclo[2.2.1]heptane, a 3-azabicyclo[3.1.0]hexyl group, a 2-oxa-6-azaspiro[3.4]oct ... and 2-oxa-7-azaspiro[3.5]nonyl or 2-oxa-6-azaspiro[3.3]heptyl, wherein the pyrrolidinyl group is optionally substituted by one or two hydroxy, cyano, fluorine, chlorine or methoxy groups, wherein the azetidinyl group is optionally substituted by one or two hydroxy, cyano, fluorine, methyl or hydroxymethyl groups, and wherein the 2-oxa-6-azaspiro[3.4]octyl group is optionally substituted by one [ka] and other variables are as defined herein.

[0085] In some embodiments, R 2is an amino group, a methoxy group, an ethoxy group, an aminomethyl group, a pyrrolidinyl group, a isoxazolidinyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a 1,4-dioxane group, an azetidinyl group, a 6-oxa-3-azabicyclo[3.1.1]heptyl group, a 3-oxa-6-azabicyclo[3.1.1]heptyl group, a 3-oxa-8-azabicyclo[3.2.1]octyl group, a 8-oxa-3-azabicyclo[3.2.1]octyl group, a 2-oxa-5-azabicyclo[3.2.1]octyl group, a 2-oxa-6-azabicyclo[3.1.1]heptyl group, a 2-oxa-8-azabicyclo[3.2.1]octyl group, a 2-oxa-5 ... cyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexyl, 2-oxa-6-azaspiro[3.4]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptyl, pyrazolyl or imidazolyl, wherein the amino group is optionally substituted by one or two methyl groups, methoxyethyl groups, wherein the ethoxy group is optionally substituted by one methoxy group, wherein The aminomethyl group is optionally substituted by one or two methyl or methoxy groups, wherein the pyrrolidinyl group is optionally substituted by one or two hydroxy groups, cyano groups, fluorine, chlorine, methoxy groups, hydroxymethyl groups or acetylamino groups, wherein the azetidinyl group is optionally substituted by one or two hydroxy groups, cyano groups, fluorine, methyl groups or hydroxymethyl groups, and wherein the 2-oxa-6-azaspiro[3.4]octyl group is optionally substituted by one [ka] and other variables are as defined herein.

[0086] In some embodiments, R 2 is a methoxy group, a methoxyethoxy group, a methylamino group, a dimethylamino group, [ka] and other variables are as defined herein.

[0087] In some embodiments, R 2 teeth, [ka] and other variables are as defined herein.

[0088] In some embodiments, R 2 is a methoxy group, a methoxyethoxy group, a methylamino group, a dimethylamino group, [ka] and other variables are as defined herein.

[0089] In some embodiments, R 2 teeth, [ka] and other variables are as defined herein.

[0090] In some embodiments, R 3 is selected from -OCF2H, wherein said -OCF2H is optionally substituted with halogen, and other variables are as defined herein.

[0091] In some embodiments, R 3 is selected from -OCF2H, where the -OCF2H is optionally substituted by fluorine, chlorine, bromine, iodine, and other variables are as defined herein. For example, R 3 is selected from -OCF2Cl, -OCF2Br, -OCF2I, -OCF3.

[0092] In some embodiments, R 3 is selected from -OCF2Cl, and other variables are as defined herein.

[0093] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ is replaced by Ring A is selected from 5-membered heteroaryl groups containing 1 or 2 heteroatoms selected from N or O atoms; Ring B is selected from a 5- or 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N or O atoms, or a 5-membered heteroaryl group containing 1 or 2 N atoms; R 2 is selected from a 3- to 10-membered heterocycloalkyl group, wherein the 3- to 10-membered heterocycloalkyl group optionally comprises one or more R b wherein the heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from -O-, -NH- or N; R 3 is selected from -OCF2Cl, R a’ teeth, [ka] C 1~6 Alkyl groups, 3-8 membered cycloalkyl groups, or C substituted with one or more hydroxyl groups or halogens 1~6 selected from alkyl groups, R b is a hydroxy group, an amino group, a cyano group, a halogen, [ka] C1~6 Alkyl group, C 1~6 C substituted by alkoxy groups or one or more hydroxy groups or halogens 1~6 It is selected from alkyl groups.

[0094] In some embodiments, R 1 teeth, [ka] wherein said [ka] optionally, one or more R a’ is replaced by X, Y and Z are each independently selected from CH or N, and at least one of X, Y and Z is selected from CH; R 2 is selected from a 3- to 10-membered heterocycloalkyl group, wherein the 3- to 10-membered heterocycloalkyl group optionally comprises one or more R b is replaced by R 3 is selected from -OCF2Cl, R a and R a’ are halogens, C 1~6 C substituted with an alkyl group, a 3- to 6-membered cycloalkyl group, or one, two, or three hydroxy groups 1~6 Alkyl group are independently selected from R b is a hydroxyl group, a cyano group, a halogen, [ka] C 1~6 Alkyl group, C 1~6 C substituted by an alkoxy group, one or more hydroxy groups or halogens 1~6 selected from alkyl groups, The heterocycloalkyl groups contain 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from -O-, -NH- or N, respectively.

[0095] In some embodiments, the "one or more" is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the "one or more" is selected from 1, 2, or 3. In some embodiments, the "one or more" is selected from 1 or 2.

[0096] In addition, some embodiments of the present application are any combination of the above variables.

[0097] In another aspect, the present application provides a compound of formula (III), a compound of formula (IV), or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, R 1 and R 2 The definition is as described above.

[0098] In another aspect, the present application provides a compound of formula (III-A), a compound of formula (III-B), a compound of formula (IV-A), or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, [ka] Optionally, one R a’ is replaced by [ka] Optionally, one or two R a’ is replaced by R2 , R a , R a’ The definitions of X, Y, Z, ring A and ring B are as described above.

[0099] In some embodiments, [ka] The definitions of are the same as those of R above. 1 As defined above.

[0100] In another aspect, the present application provides a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (VIII), a compound of formula (IX), a compound of formula (X), or a pharma- ceutically acceptable salt thereof; [ka] During the ceremony, R 2 , R a , R a’ and ring B is as defined above.

[0101] In another aspect, the present application provides the following compound or a pharma- ceutically acceptable salt thereof: [ka] [ka] [ka] [ka] [ka] [ka]

[0102] In another aspect, the present application provides the following compound or a pharma- ceutically acceptable salt thereof: [ka] [ka] [ka] [ka]

[0103] In another aspect, the present application also provides a pharmaceutical composition comprising the compound of the present application or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further comprises a pharma- ceutically acceptable excipient.

[0104] In another aspect, the present application also provides a method for treating and / or preventing a BCR-ABL associated disease, comprising administering to a mammal (preferably a human) in need of treatment a therapeutically effective amount of the above-mentioned compound of the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0105] In another aspect, the present application also provides the use of the above-mentioned compound of the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for treating and / or preventing a BCR-ABL-associated disease.

[0106] In another aspect, the present application also provides the use of the above-mentioned compound of the present application or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment and / or prevention of a BCR-ABL-associated disease.

[0107] In another aspect, the present application also provides the above-mentioned compound of the present application, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating and / or preventing a BCR-ABL-associated disease.

[0108] In some embodiments, the BCR-ABL associated disease is selected from cancer, for example, chronic myeloid leukemia. Effect of the Invention

[0109] The compounds of the present application have good cell proliferation inhibitory activity (including K562 cells and T315I mutant cells), good in vivo pharmacokinetic properties, low toxicity, very weak inhibitory effect on the hERG potassium channel, and good safety.

[0110] (definition) Unless otherwise specified, the following terms used in this application have the following meanings: Certain terms are to be understood in their ordinary sense in the art, and not as open ended or unclear, unless otherwise defined. When trade names are mentioned in this specification, they refer to the corresponding products or their active ingredients.

[0111] In this application, when a covalent bond is not attached to a specific atom in a particular structural unit or group, it represents that the covalent bond can be attached to any atom of that structural unit or group, provided that valence bond convention is not violated.

[0112] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, provided that the valence of the atom is normal and the compound after substitution is stable. If the substituent is an oxygen substituent (=O), then two hydrogen atoms are replaced. Oxygen substitution does not occur on aryl groups.

[0113] The term "optional" or "optionally" refers to the fact that the subsequently described item or circumstance may or may not occur, including the occurrence of the item or circumstance and the absence of the item or circumstance. "Optionally substituted" refers to substituted or unsubstituted, for example, an ethyl group is "optionally" substituted with a halogen, and the ethyl group may be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (e.g., CF2CF3). As understood by those skilled in the art, a group containing one or more substituents does not allow for substitution or substitution forms that are not spatially possible and / or cannot be synthesized.

[0114] In this specification, C m~n means that the moiety has an integer number of carbon atoms within a specified range of m to n. For example, "C 1~6 " means that the subject group may 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 means that the subject group may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0115] When a particular variable (e.g., R) occurs more than one time in a compound composition or structure, each occurrence is independently defined. Thus, for example, if a subject group is substituted with two R, each R is independently selected.

[0116] When a bond of a substituent is connected across a bond connecting two atoms of a ring, such a substituent can be bonded to any atom of the ring. For example, the structural unit [ka] In the case of the formula (I), it means that the substitution may be performed at any position of the cyclohexyl group or cyclohexadiene.

[0117] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0118] The term "hydroxy" refers to an -OH group.

[0119] The term "amino group" refers to the -NH2 group.

[0120] The term "cyano" refers to the radical -CN.

[0121] The term "alkyl group" refers to a C n H 2n+1 The alkyl group may be linear or branched. For example, the term "C 1~6 The term "alkyl group" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl moiety (i.e., alkyl group) of an alkoxy group, an alkylamino group, a dialkylamino group, an alkylsulfonyl group, and an alkylthio group has the same definition as above. For example, the term "C 1~3 "Alkyl group" refers to an alkyl group containing 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, isopropyl groups).

[0122] The term "alkoxy" refers to an -O-alkyl group.

[0123] The term "cycloalkyl group" refers to a carbocycle that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the carbocycle generally has 3 to 10 members. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantanyl, bicyclo[1.1.1]pent-1-yl, and the like. For example, C 3又は4 The cycloalkyl group includes a cyclopropyl group and a cyclobutyl group.

[0124] The term "heterocyclyl group" refers to a non-aromatic ring that may be fully saturated or partially unsaturated (but not fully unsaturated heteroaryl groups) and may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the heterocyclic ring is generally a 3- to 10-membered, or 4- to 6-membered ring containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuryl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.3]heptyl, 3-azabicyclo[3.1.0]hexyl, and the like.

[0125] The term "heterocycloalkyl group" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise specified, the heterocycle is generally a 3- to 10-membered ring, or a 4- to 6-membered ring, containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thiiranyl, and aziridinyl groups, non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups, and examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, thiazolidin ... Examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, and examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Preferred are monocyclic heterocycloalkyl groups having 4, 5, or 6 ring atoms.

[0126] The term "monoheterocyclyl group" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaryl groups) and exists as only one ring. Unless otherwise specified, the heterocycle is generally a 3- to 10-membered ring, or a 4- to 6-membered ring, containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, and / or nitrogen. Non-limiting examples of monoheterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuryl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, and the like.

[0127] The term "monoheterocycloalkyl group" refers to a fully saturated monoheterocyclyl group.

[0128] The term "bridged heterocyclyl group" refers to a 5-14 membered polycyclic ring that is fully saturated or partially unsaturated and in which two rings share two or more atoms, and which may contain one or more double bonds, but in which none of the rings has a completely conjugated pi-electron system, and in which one or more of the ring atoms is N, O, S(O), n (wherein n is 0, 1 or 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 6 to 10-membered. Depending on the number of constituent rings, it is classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycle, preferably a bicyclic or tricyclic, more preferably a bicyclic. Non-limiting examples of bridged heterocycles are: [ka] etc.

[0129] The term "bridged heterocycloalkyl group" refers to a fully saturated bridged heterocyclyl group.

[0130] The term "spiroheterocyclyl group" refers to a fully saturated or partially unsaturated (but not fully unsaturated) spiro ring in which one or more ring atoms are heteroatoms selected from sulfur, oxygen and / or nitrogen (preferably one or two heteroatoms) and the remaining ring atoms are carbon. It is preferably 6-14 membered, more preferably 6-10 membered. Depending on the number of spiro atoms shared between the rings, the spiro heterocycle is classified as a monospiro heterocycle, a bisspiro heterocycle or a polyspiro heterocycle, preferably a monospiro heterocycle or a bisspiro heterocycle, more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 5-membered heterocycle. Non-limiting examples of spiro heterocycles are: [ka] etc.

[0131] The term "spiroheterocycloalkyl group" refers to a fully saturated spiroheterocyclyl group.

[0132] The term "heteroaryl group" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, and S, the remaining ring atoms being C, and at least one aromatic ring. Preferred heteroaryl groups have one 5-8 membered ring or multiple fused rings containing 6-14, especially 6-10, ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, and the like.

[0133] In this application, [ka] represents a bicyclic structure formed by a covalent bond between ring A and ring B, where the covalent bond may be a single bond or a double bond.

[0134] The term "treatment" refers to the administration of a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with said disease, and (i) arresting the disease or disease state, i.e. arresting its progression; (ii) Alleviating the disease or disease state, i.e., causing the disease or disease state to be eliminated.

[0135] The term "prevention" refers to the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the appearance of a disease or disease state in a mammal, particularly when a mammal susceptible to the disease state has not been diagnosed with the disease state.

[0136] The term "therapeutically effective amount" refers to a dose of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. A "therapeutically effective amount" of a compound of the present application will be determined based on the compound, the condition and its severity, the mode of administration, and the individual to be treated. The amount of treatment will vary depending on the age of the mammal, but can be determined by one of skill in the art based on their knowledge and the present disclosure.

[0137] The term "pharmacologically acceptable" is used to refer to compounds, materials, compositions, and / or dosage forms that are medically determined to be suitable for use in contact with human or animal tissue, not toxic or irritating, and not likely to cause an allergic reaction or other problem or complication, and for which the benefit-to-risk ratio is reasonable.

[0138] Pharmaceutically acceptable salts include, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, and the like.

[0139] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharma- ceutical acceptable excipients, which facilitates administration of the compounds of the present application to a living body.

[0140] The term "pharmaceutical acceptable additive" refers to an additive that does not cause obvious irritation to the living body and does not impair the biological activity and properties of the active compound. Suitable additives, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc., are well known to those skilled in the art.

[0141] The term "comprise" and similar terms, such as the English expressions "comprises" or "comprising", are to be understood in an open and non-exclusive sense, such as "including, but not limited to".

[0142] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. Such 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, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Substituents such as alkyl groups may have additional asymmetric carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention.

[0143] Unless otherwise specified, "(D)" or "(+)" represents dextrorotatory, "(L)" or "(-)" represents levorotatory, and "(DL)" or "(±)" represents racemic.

[0144] Unless otherwise stated, solid wedge bonds ( [ka] ) and the wedge-shaped dashed bond ( [ka] ) represents the absolute configuration of the chiral center, and the linear solid bond ( [ka] ) and linear dashed bond ( [ka] ) indicates the relative configuration of the chiral center, and the wavy line ( [ka] ) with solid wedge-shaped connection ( [ka] ) or wedge-shaped dashed bond ( [ka] ) or a wavy line ( [ka] ) with a straight solid line connection ( [ka] ) and linear dashed bond ( [ka] )

[0145] Optically active (R)- and (S)-isomers, and D- and L-isomers can be prepared by asymmetric synthesis, asymmetric reagents, or other conventional techniques. Enantiomers of certain compounds of the invention may be prepared by asymmetric synthesis or derivatization with asymmetric auxiliaries. The diastereomeric mixture of products is separated and the auxiliary groups are removed to obtain the desired pure enantiomers. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxy) functional group, the diastereomeric salt is formed with an appropriate optically active acid or base, and the diastereomers are then separated and recovered to obtain the pure enantiomers by conventional methods known in the art. Separation of enantiomers and diastereomers is also commonly performed by chromatography, which employs chiral stationary phases, optionally combined with chemical derivatization (e.g., carbamate formation from amines).

[0146] The compounds of the present invention contain one or more atoms that are homogeneous in a non-natural ratio. Isotopes of hydrogen may be included. For example, tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 The compound can be labeled with a radioisotope such as , or C). Alternatively, deuterium can be substituted for hydrogen to produce a deuterated drug, for example, d3-methyl group, which means that all three hydrogen atoms of a methyl group are substituted with deuterium atoms, and the bond formed by deuterium and carbon is stronger than the normal bond formed by hydrogen and carbon, and compared with non-deuterated drugs, deuterated drugs have the advantages of reduced toxicity and side effects, improved drug stability and therapeutic effect, and extended biological half-life of drugs. All isotopic variants of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.

[0147] The present application further includes compounds of the present application that are the same as the compounds described herein, but in which one or more atoms have been replaced by an atom whose atomic mass or mass number is different from the normal atomic mass or mass number occurring in nature, i.e., isotopically labeled. Examples of isotopes that can be attached to the compounds of the present application 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, 123 I, 125 I, 36 Cl, etc.

[0148] Certain isotopically labeled compounds of the present application (e.g., 3 H, 14 C) can be used for tissue distribution analysis of compounds and / or substrates. 3 H), carbon-14 (i.e. 14 C) is particularly preferred because it is easily obtainable and detectable. Positron-emitting isotopes, e.g. 15 O. 13 N, 11 C. 18 F can be used to measure substrate occupancy in positron emission tomography (PET) studies. In general, isotopically labeled compounds of the present application can be prepared by procedures analogous to the techniques and / or examples disclosed below, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0149] Also, isotopes with larger mass numbers (e.g., deuterium (i.e., 2H)) may be preferred in some cases due to the therapeutic benefits that result from greater metabolic stability (e.g., increased in vivo half-life or reduced doses). However, deuterium substitution may be partial or full, with partial deuterium substitution referring to the replacement of at least one hydrogen with at least one deuterium. All such compounds are within the scope of the present application.

[0150] As used herein, singular terms cover plural referents, and vice versa, unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly dictates otherwise.

[0151] Unless otherwise specified, the value of a parameter herein should be understood to be modified by the term "about." When a parameter in the present application is described with the term "about," the term "about" indicates that an error value exists, for example, a variation within a range of ±5%, for example, ±1%, or ±0.1% of a particular value.

[0152] All patents, patent applications, and other previously established publications are expressly incorporated herein by reference for purposes of description and disclosure, and are provided as such because they were made public prior to the filing date of this application. Any statement as to the disclosure date of such documents or representation of their contents is based on the information known to the applicants and does not constitute an admission that the disclosure date of such documents or the contents thereof are correct, nor does the reference to such publications in this specification constitute common general knowledge in the art in any applicable country.

[0153] The compounds of the present application may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are included. Compounds containing asymmetric carbon atoms in the present application can be isolated in optically pure or racemic forms. Optically pure forms may be resolved from racemic mixtures or synthesized using asymmetric starting materials or reagents.

[0154] The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharma- ceutically acceptable excipients, and may be prepared, for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

[0155] Typical routes of administration of the compounds of the present application or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions thereof, include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous.

[0156] The pharmaceutical compositions of the present application may be manufactured by conventional methods well known in the art, for example, by mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, lyophilizing or the like.

[0157] The therapeutic dose of the compound of the present application may be determined, for example, from the specific therapeutic application, the mode of administration of the compound, the health condition of the patient, the judgment of the prescribing physician, and the like. The proportion or concentration of the compound of the present application in the pharmaceutical composition is not necessarily constant, and is determined by various factors, such as the dose, chemical properties (e.g., hydrophobicity), and route of administration. The compound of the present application may be provided for parenteral administration, for example, in phosphate buffered saline containing about 0.1-10% w / v of the compound. Some typical dose ranges are about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg body weight / day. The dose may be determined from variables such as the type of disease or condition and its progression, the general health condition of the particular patient, the relative bioavailability of the selected compound, the excipient formulation, and its route of administration. Effective doses may be obtained by extrapolation to dose-response curves derived from in vitro or animal model test systems.

[0158] The compounds of the present application may be prepared by various synthetic methods familiar to those skilled in the art, including the specific embodiments listed below, embodiments in combination with other chemical synthetic methods, and equivalent alternatives familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present application.

[0159] The chemical reactions of certain embodiments of the present application are carried out in suitable solvents, which must be compatible with the chemical transformations of the present application and the reagents and raw materials used. In order to obtain the compounds of the present application, the skilled artisan may need to modify or select synthetic steps or reaction processes based on existing embodiments.

[0160] In the art, one of the major factors to be considered in planning a synthetic route is the selection of an appropriate protecting group for a reactive functional group (e.g., an amino group in the present application). In this regard, see, for example, "Greene's Protective Groups in Organic Synthesis (4th Ed.)". Hoboken, New Jersey: John Wiley & Sons, 1999. & Sons, Inc.

[0161] The compounds of formula (I) of the present application may be prepared by one skilled in the art of organic synthesis by the following route. [ka] During the ceremony, R 1 , R 2 and R 3 The definition of is as above, and R 2 is not hydrogen.

[0162] The following abbreviations are used in this application: SOCl2 stands for thionyl chloride, TEA stands for triethylamine, DMSO stands for dimethylsulfoxide, and THF stands for tetrahydrofuran. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0163] In the following, the present invention will be described in further detail with reference to examples in order to make the present invention clearer, but the scope of the present application is not limited to these examples. It is obvious to those skilled in the art that various modifications and improvements may be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. All reagents used in the present application are commercially available and can be used without purification.

[0164] Example 1: Preparation of Compound 1 [ka]

[0165] Step A: Preparation of Compound 1-1 Toluene (300mL) and 5-bromo-6-chloronicotinic acid (15.0g) were added in this order to a 500mL three-neck flask, followed by dropwise addition of thionyl chloride (14.79g) to the system at room temperature. Once complete, the temperature was raised to 70-80°C and reacted for 4 hours. The reaction was stopped and concentrated under reduced pressure to obtain a brown oily substance, to which dichloromethane (300mL) was added, stirring was started and 4-(chlorodifluoromethoxy)aniline (12.28g) was added dropwise to the system. Once complete, triethylamine (12.58g) was added dropwise, and once complete, the reaction was allowed to proceed at room temperature for 4 hours. After the reaction was completed, the above reaction solution was added with a saturated aqueous sodium bicarbonate solution (100mL). The mixture was stirred for 10 minutes and then filtered to recover the cake. The mother liquor was separated to obtain an organic phase. A saturated aqueous sodium chloride solution (100 mL) was added and stirred, followed by separation to obtain an organic phase. The cake was added to the organic phase and concentrated together under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 20.44 g of compound 1-1.

[0166] Step B: Preparation of Compound 1-2 In a 50mL sealed tube, isopropanol (10mL), compound 1-1 (1.0g) obtained in step A above, (S)-3-methoxypyrrolidine hydrochloride (0.334g), N,N-diisopropylethylamine (1.004g), and a stirrer were added in this order, sealed, and then the sealed tube was placed in a microwave reactor and reacted at 140°C for 1.5 hours. When the temperature was lowered to room temperature, ethyl acetate (15mL) and saturated aqueous sodium chloride solution (15mL) were added to the reaction solution, stirred and washed, and then separated. The organic phase was collected, dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 0.8g of compound 1-2. MS (ESI, [MH] - ) m / z: 474.0.

[0167] Step C: Preparation of Compounds 1-3 4-Bromopyridin-2(1H)-one (2.0 g) and anhydrous THF (20 mL) were added in this order to a 100 mL three-neck flask, cooled to 0 ° C. in an ice bath, and then 60% sodium hydride (0.919 g) was added in several portions. After replacing with nitrogen three times, the mixture was transferred to room temperature and stirred for 1 hour. Iodomethane (3.26 g) was slowly added to the reaction solution in an ice bath, and the reaction was allowed to proceed overnight at room temperature. Water (10 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (40 mL) was added for extraction. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (20 mL). The organic layers were combined, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain compound 1-3 (1.82 g). MS (ESI, [M + H] + ) m / z: 188.0.

[0168] Step D: Preparation of Compounds 1-4 In a 10 mL waveguide, 1,4-dioxane (5 mL), compound 1-3 (142 mg) obtained in step C above, bis(pinacolato)diboron (160 mg), potassium acetate (124 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (31 mg) were added in this order. Upon completion, the mixture was purged with nitrogen and then heated to 90°C for 4 hours. The reaction was then stopped and cooled to room temperature. The resulting reaction solution was used directly in the next step without separation or purification.

[0169] Step E: Preparation of Compound 1 To the reaction solution obtained in step D above, compound 1-2 (200 mg), potassium carbonate (174 mg), deionized water (1 mL), and tetrakis(triphenylphosphine)palladium(0) (48 mg) were added in this order, and when complete, the air was replaced with nitrogen, the waveguide was sealed, and the reaction was performed in a microwave reactor at 140° C. for 1.5 hours. When the temperature was lowered to room temperature, the reaction solution was filtered, the mother liquor was collected, and the mother liquor was purified by silica gel column chromatography to obtain 123 mg of compound 1. 1H NMR (500MHz, DMSO-d6) δ(ppm) 10.20(s,1H),8.75(d,J=2.3Hz,1H),8.06(d,J=2.3Hz,1H),7.87(d,J=8.9Hz, 2H),7.75(d,J=6.9Hz,1H),7.34(d,J=8.6Hz,2H),6.39(s,1H),6.28(dd,J=7. 0,2.0Hz,1H),3.96(dd,J=5.6,3.0Hz,1H),3.54-3.41(m,5H),3.37-3.34(m,1 H),3.26(d,J=12.0Hz,1H),3.20(s,3H),2.03-1.94(m,1H),1.94-1.85(m,1H). MS (ESI, [M+H] + ) m / z: 505.0.

[0170] Example 2: Preparation of Compound 2 [ka]

[0171] Step A: Preparation of Compound 2-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with (R)-3-methoxypyrrolidine hydrochloride to obtain intermediate compound 2-1. MS (ESI, [M+H] + ) m / z: 476.1.

[0172] Step B: Preparation of Compound 2 Referring to the preparation method in Step E of Example 1, the compound 2-1 prepared in Step A above was added to the reaction solution of the compound 1-4 and reacted to obtain the compound 2. 1H NMR(500MHz,DMSO-d6)δ(ppm)10.20(s,1H),8.75(d,J=2.3Hz,1H),8.06(d,J=2.3Hz ,1H),7.91-7.82(m,2H),7.75(d,J=6.9Hz,1H),7.35(d,J=8.6Hz,2H),6.40(d,J=2.0 Hz,1H),6.28(dd,J=6.9,2.0Hz,1H),4.01-3.93(m,1H),3.54-3.40(m,5H),3.26(d,J =12.0Hz,1H),3.37-3.34(m,1H),3.20(s,3H),2.03-1.95(m,1H),1.95-1.85(m,1H). MS(ESI,[M+H] + ) m / z: 505.1.

[0173] Example 3: Preparation of Compound 3 [ka]

[0174] Step A: Preparation of Compound 3-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with azetidine hydrochloride to obtain intermediate compound 3-1. MS (ESI, [M+H] + ) m / z: 431.9.

[0175] Step B: Preparation of Compound 3 Referring to the preparation method in Step E of Example 1, the compound 3-1 prepared in Step A above was added to the reaction solution of the compound 1-4 and reacted to obtain the compound 3. 1 H NMR(500MHz,DMSO-d6)δ 10.22(s,1H),8.75(d,J=2.0Hz,1H),8.02(d,J=2.0Hz,1H),7.86(d,J=9.0Hz,2H),7.75(d,J=9.0Hz,1H),7 .34(d,J=9.0Hz,2H),6.42(d,J=1.0Hz,1H),6.32(m,1H),3.89(t,J=7.5Hz,4H),3.47(s,3H),2.22(m,2H). HRMS(ESI,[M+H] + ) m / z: 461.12323.

[0176] Example 4: Preparation of Compound 4 [ka]

[0177] Step A: Preparation of Compound 4-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with (S)-3-chloropyrrolidine hydrochloride to obtain intermediate compound 4-1. MS (ESI, [M+H] + ) m / z: 480.00.

[0178] Step B: Preparation of Compound 4 Referring to the preparation method in Step E of Example 1, compound 4-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 4. 1 H NMR(500MHz,DMSO-d6)δ 10.24(s,1H),8.77(d,J=2.5Hz,1H),8.09(d,J=2.5Hz,1H),7.87(m,2H),7.77(d,J=7.0Hz,1H),7.34(d,J=9.0Hz,2H),6.43(s,1H),6.30(dd, J=2.0Hz,7.0Hz,1H),4.80(t,J=2.0Hz,1H),3.84(dd,J=4.5Hz,13.0Hz,1H),3.68(m,1H),3.50(s,3H),3.41(m,2H),2.34(m,1H),2.11(m,1H). HRMS(ESI,[M+H] + ) m / z: 509.10003.

[0179] Example 5: Preparation of Compound 5 [ka]

[0180] Step A: Preparation of Compound 5-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with 2-oxa-6-azaspiro[3.3]heptane hydrochloride to obtain intermediate compound 5-1. MS (ESI, [M+H] + ) m / z: 474.1.

[0181] Step B: Preparation of Compound 5 Referring to the preparation method in Step E of Example 1, compound 5-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 5. 1 H NMR(500MHz,DMSO-d6)δ 10.22(s,1H),8.76(d,J=2.5Hz,1H),8.03(d,J=2.0Hz,1H),7.86(d,J=9.5Hz,2H),7.76(d,J=7.0Hz,1 H),7.35(d,J=9.0Hz,2H),6.42(d,J=1.5Hz,1H),6.30(m,1H),4.64(s,4H),4.07(s,4H),3.49(s,3H). HRMS(ESI,[M+H] + ) m / z: 503.13412.

[0182] Example 6: Preparation of Compound 6 [ka]

[0183] Step A: Preparation of Compound 6-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with 3-fluoroazetidine hydrochloride to obtain intermediate compound 6-1. MS (ESI, [M+H] + ) m / z: 450.0.

[0184] Step B: Preparation of Compound 6 Referring to the preparation method in Step E of Example 1, compound 6-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 6. 1H NMR(500MHz,DMSO-d6)δ 10.27(s,1H),8.78(s,1H),8.09(s,1H),7.86(d,J=9.1Hz,2H),7.79(d,J=6.9Hz,1H),7.35(d,J=9.0Hz,2H),6 .46(s,1H),6.34(d,J=8.9Hz,1H),5.38(d,J=55.1Hz,1H),4.18-4.25(m,2H),3.93-3.98(m,2H),3.48(s,3H). HRMS(ESI,[M+H] + ) m / z: 479.11256.

[0185] Example 7: Preparation of Compound 7 [ka]

[0186] Step A: Preparation of Compound 7-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with morpholine to obtain intermediate compound 7-1. MS (ESI, [M+H] + ) m / z: 462.0.

[0187] Step B: Preparation of Compound 7 Referring to the preparation method in Step E of Example 1, compound 7-1 was added to the reaction solution of compound 1-4 and reacted to obtain compound 7. 1 H NMR(500MHz,DMSO-d6)δ(ppm) 10.37(s,1H),8.80(d,J=2.3Hz,1H),8.17(d,J=2.3Hz,1H),7.91-7.85(m,2H),7.78(d,J=7.0Hz,1H),7.36(d,J=8. 6Hz,2H),6.68(d,J=1.9Hz,1H),6.52(dd,J=7.0,2.0Hz,1H),3.67-3.58(m,4H),3.47(s,3H),3.28(t,J=4.6Hz,4H). MS(ESI,[M+H] + ) m / z: 491.1.

[0188] Example 8: Preparation of Compound 8 [ka]

[0189] Step A: Preparation of Compound 8-1 Referring to the preparation method of Step C of Example 1, 4-bromopyridin-2(1H)-one was reacted with 2-iodoethan-1-ol to obtain intermediate compound 8-1. 1 H NMR(500MHz,DMSO-d6)δ 7.57(d,J=7.2Hz,1H),6.70(d,J=2.1Hz,1H),6.43(d,J=7.2Hz,1H),4.88(t,J=5.4Hz,1H),3.91(t,J=5.4Hz,2H),3.59(q,J=5.4Hz,2H). MS(ESI,[M+H] + ) m / z: 218.03.

[0190] Step B: Preparation of Compound 8-2 Referring to the production method in step D of Example 1, compound 8-1 was reacted with bis(pinacolato)diboron to obtain a reaction solution of intermediate compound 8-2, which was used in the next step reaction without separation and purification.

[0191] Step C: Preparation of Compound 8 Referring to the preparation method in Step E of Example 1, compound 7-1 was added to the reaction solution of compound 8-2 and reacted to obtain compound 8. 1 H NMR(500MHz,DMSO-d6)δ 10.33(s,1H),8.79(d,J=2.2Hz,1H),8.17(d,J=2.2Hz,1H),7.87(d,J=9.0Hz,2H),7.68(d,J=7.0Hz,1H),7.36(d,J=8.8Hz,2H),6.70-6. 61(m,1H),6.55-6.45(m,1H),4.89(t,J=5.3Hz,1H),3.98(t,J=5.4Hz,2H),3.70-3.65(m,2H),3.64-3.60(m,4H),3.28(t,J=4.5Hz,4H). HRMS(ESI,[M+H] + ) m / z: 521.1423.

[0192] Example 9: Preparation of Compound 9 [ka]

[0193] Step A: Preparation of Compound 9-1 4-Bromopyridin-2(1H)-one (500 mg) and anhydrous tetrahydrofuran (10 mL) were added in this order to a 100 mL three-neck flask, cooled to 0 ° C in an ice bath, and then 60% sodium hydride (230 mg) was added in several portions. After replacing with nitrogen three times, the mixture was transferred to room temperature and stirred for 1 hour. Iodoethane (896 mg) was slowly added to the reaction solution in an ice bath, and the temperature was raised to 70 ° C in an oil bath and reacted for 6 hours. Water (10 mL) was added to the reaction solution to quench the reaction, ethyl acetate (15 mL) was added for extraction, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (15 mL × 2). The organic layers were combined, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain compound 9-1 (200 mg). MS (ESI, [M + H] + ) m / z: 202.0.

[0194] Step B: Preparation of Compound 9-2 Referring to the production method in Step D of Example 1, compound 9-1 was reacted with bis(pinacolato)diboron to obtain intermediate compound 9-2, which was used in the next step without separation and purification.

[0195] Step C: Preparation of Compound 9 Referring to the preparation method of Step E of Example 1, compound 7-1 was added to the reaction solution of compound 9-2 and reacted to obtain compound 9. 1H NMR(500MHz,DMSO-d6)δ 10.32(s,1H),8.79(d,J=2.3Hz,1H),8.17(d,J=2.4Hz,1H),7.91-7.84(m,2H),7.78(d,J=7.0Hz,1H),7.36(d,J=8.7Hz,2H),6.66 (d,J=2.1Hz,1H),6.53(dd,J=7.0,2.0Hz,1H),3.99-3.91(m,2H),3.68-3.58(m,4H),3.28(t,J=4.6Hz,4H),1.24(t,J=7.1Hz,3H). MS(ESI,[M+H] + ) m / z: 505.3.

[0196] Example 10: Preparation of Compound 10 [ka]

[0197] Step A: Preparation of Compound 10-1 4-Bromopyridin-2(1H)-one 4-bromo-2-hydroxypyridine (500 mg), cyclopropylboronic acid (494 mg), pyridine (1137 mg), copper acetate (522 mg), cesium carbonate (936 mg), and toluene (10 mL) were added to a 50 mL recovery flask in this order, and the mixture was reacted overnight in air at 95°C in an oil bath. The next day, the reaction solution was diluted with ethyl acetate (10 mL) and suction filtered through diatomaceous earth. The filtrate was washed twice with water, then washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give the compound. Obtained product 10-1 (61 mg). MS (ESI, [M+H] + ) m / z: 214.0.

[0198] Step B: Preparation of Compound 10-2 Referring to the preparation method in step D of Example 1, compound 1-3 was replaced with compound 10-1 prepared in the above step, and reacted to obtain a reaction solution of compound 10-2, which was directly used in the next step of the reaction.

[0199] Step C: Preparation of Compound 10 Referring to the preparation method in Step E of Example 1, compound 7-1 was added to the reaction solution of compound 10-2 and reacted to obtain compound 10. 1 H NMR(500MHz,DMSO-d6)δ 10.33(s,1H),8.78(s,1H),8.16(s,1H),7.86(d,J=8.6Hz,2H),7.61(d,J=7.2Hz,1H),7.36(d,J=8.6Hz,2H),6.65 (s,1H),6.48(d,J=7.3Hz,1H),3.70-3.57(m,4H),3.38(s,1H),3.27(s,4H),1.11-0.95(m,2H),0.93-0.79(m,2H). HRMS(ESI,[M+H] + ) m / z: 517.1451.

[0200] Example 11: Preparation of Compound 11 [ka]

[0201] Step A: Preparation of Compound 11-1 Referring to the preparation method in Step B of Example 1, compound 1-1 was reacted with (R)-pyrrolidin-3-ol hydrochloride to obtain intermediate compound 11-1.

[0202] Step B: Preparation of Compound 11 Referring to the preparation method in Step E of Example 1, compound 11-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 11. 1H NMR (500MHz, DMSO-d6) δ 10.20(s,1H),8.75(s,1H),8.05(d,J=5.0Hz,1H),8.86(d,J=10.0Hz,2H),7.7 5(d,J=5.0Hz,1H),7.34(d,J=10.0Hz,2H),6.38(s,1H),6.28-6.27(m,1H),4. 91(s,1H),4.26(s,1H),3.57-3.56(m,1H),3.47(s,3H),3.44-3.41(m,1H),3. 36-3.35(m,1H),3.06(d,J=10.0Hz,1H)1.92-1.85(m,1H),1.80-1.77(m,1H). HRMS (ESI, [M+H] + ) m / z: 491.1302.

[0203] Example 12: Preparation of Compound 12 [ka]

[0204] Step A: Preparation of Compound 12-1 Referring to the preparation method in Step D of Example 1, 4-bromopyridin-2(1H)-one was reacted with bis(pinacolato)diboron to obtain a reaction solution of intermediate compound 12-1, which was directly used in the next step reaction.

[0205] Step B: Preparation of Compound 12 Referring to the preparation method in Step E of Example 1, compound 11-1 was added to the reaction solution of compound 12-1 and reacted to obtain compound 12. 1H NMR (500MHz, DMSO-d6) δ 11.21(br,1H),10.20(s,1H),8.75(s,1H),8.05(s,1H),7.87-7.86(m,2H), 7.42(d,J=10.0Hz,1H),7.34(d,J=10.0Hz,2H),6.31(s,1H),6.22(d,J=6.6H z,1H),4.92(s,1H),4.26(s,1H),3.60-3.54(m,1H),3.50-3.43(m,1H),3.42 -3.40(m,1H),3.06(d,J=10.0Hz,1H),1.91-1.87(m,1H),1.80-1.78(m,1H). HRMS (ESI, [M+H] + ) m / z: 477.1139.

[0206] Examples 13 and 14: Preparation of Compounds 13 and 14 [ka]

[0207] Step A: Preparation of Compound 13-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with azetidin-2-ylmethanol hydrochloride to obtain compound 13-1. MS (ESI, [MH] - ) m / z: 460.0.

[0208] Step B: Preparation of Compound 13-2 Referring to the preparation method in Step E of Example 1, the compound 13-1 prepared in Step A above was added to the reaction solution of the compound 1-4 and reacted to obtain the compound 13-2.

[0209] Step C: Preparation of Compounds 13 and 14 Compound 13-2 was separated by supercritical fluid chromatography (model: Waters SFC150G), the separation column was a CHIRALART Cellulose-SC column, the mobile phase was 25 vol% ethanol and 75 vol% carbon dioxide, the flow rate was 60 mL / min, and the t R=5.484 points. Compound 13 is obtained. 1 H NMR (500 MHz, DMSO-d6)δ 10.23(s,1H),8.74(d,1H),8.04(d,J=2.2Hz,1H),7.86(d,J=9.1Hz,2H),7.76 (d,J=6.9Hz,1H),7.35(d,J=8.9Hz,2H),6.46(s,1H),6.39(dd,J=6.9,1.7Hz, 1H),4.88(t,J=5.8Hz,1H),4.60-4.43(m,1H),3.86-3.75(m,1H),3.73-3.65( m,1H),3.63-3.54(m,1H),3.48(s,3H),3.44-3.37(m,1H),2.28-2.10(m,2H). HRMS (ESI, [M+H] + )m / z:491.12806.

[0210] and つ, t R =9.467 points. Compound 14 is obtained. 1 H NMR (500 MHz, DMSO-d6)δ 10.23(s,1H),8.74(d,1H),8.04(d,J=2.2Hz,1H),7.86(d,J=9.1Hz,2H),7.76 (d,J=6.9Hz,1H),7.35(d,J=8.9Hz,2H),6.46(s,1H),6.39(dd,J=6.9,1.7Hz, 1H),4.88(t,J=5.8Hz,1H),4.60-4.43(m,1H),3.86-3.75(m,1H),3.73-3.65( m,1H),3.63-3.54(m,1H),3.48(s,3H),3.44-3.37(m,1H),2.28-2.10(m,2H). HRMS (ESI, [M+H] + )m / z:491.12806.

[0211] Example 15: Production of Compound 15

change

[0212] ステップA: Manufacture of compound 15-1 Referring to the preparation method in Step B of Example 1, compound 1-1 was reacted with tetrahydropyrrole to obtain intermediate compound 15-1.

[0213] Step B: Preparation of Compound 15 Referring to the preparation method in Step E of Example 1, compound 15-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 15. 1 H NMR(500MHz,DMSO-d6)δ 10.19(s,1H),8.75(d,J=2.1Hz,1H),8.04(d,J=2.1Hz,1H),7.86(d,J=9.0Hz,2H),7.73(d,J=6.9Hz,1H) ,7.34(d,J=8.8Hz,2H),6.39(d,J=1.3Hz,1H),6.32-6.21(m,1H),3.47(s,3H),3.31(s,4H),1.82(s,4H). HRMS (ESI, [M+H] + ) m / z: 475.13331.

[0214] Example 16: Preparation of Compound 16 [ka]

[0215] Step A: Preparation of compound 16-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with (R)-3-fluoropyrrolidine hydrochloride to obtain compound 16-1. MS (ESI, [M+H] + ) m / z: 464.02.

[0216] Step B: Preparation of Compound 16 Referring to the preparation method in Step E of Example 1, compound 16-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 16. 1H NMR (500MHz, DMSO-d6) δ 10.23(s,1H),8.77(d,J=2.3Hz,1H),8.08(d,J=2.3Hz,1H),7.87(d,J=9.1Hz ,2H),7.76(d,J=6.9Hz,1H),7.35(d,J=8.9Hz,2H),6.43(s,1H),6.29(dt,J= 10.9,5.4Hz,1H),5.35(d,J=53.4Hz,1H),3.76-3.62(m,1H),3.54(tt,J=13. 9,6.9Hz,1H),3.48(s,3H),3.43(dt,J=19.2,6.0Hz,2H),2.22-1.95(m,2H). MS(ESI,[M+H] + ) m / z: 493.29

[0217] Example 17: Preparation of Compound 17 [ka]

[0218] Step A: Preparation of Compound 17-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with (S)-3-fluoropyrrolidine hydrochloride to obtain compound 17-1. MS (ESI, [M+H] + ) m / z: 464.02.

[0219] Step B: Preparation of Compound 17 Referring to the preparation method in Step E of Example 1, compound 17-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 17. 1H NMR (500MHz, DMSO-d6) δ 10.23(s,1H),8.77(d,J=2.3Hz,1H),8.08(d,J=2.3Hz,1H),7.87(d,J=9.1Hz ,2H),7.76(d,J=6.9Hz,1H),7.35(d,J=8.9Hz,2H),6.43(s,1H),6.29(dt,J= 10.9,5.4Hz,1H),5.35(d,J=53.4Hz,1H),3.76-3.62(m,1H),3.54(tt,J=13. 9,6.9Hz,1H),3.48(s,3H),3.43(dt,J=19.2,6.0Hz,2H),2.22-1.95(m,2H). MS(ESI,[M+H] + ) m / z: 493.20.

[0220] Example 18: Preparation of Compound 18 [ka]

[0221] Step A: Preparation of Compound 18-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with (R)-3-chloropyrrolidine hydrochloride to obtain compound 18-1. MS (ESI, [M+H] + ) m / z: 479.98.

[0222] Step B: Preparation of Compound 18 Referring to the preparation method in Step E of Example 1, compound 18-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 18. 1H NMR(500MHz,DMSO-d6)δ 10.24(s,1H),8.81(d,J=2.0Hz,1H),8.13(d,J=2.0Hz,1H),7.92(d,J=9.0Hz,2H), 7.78(d,J=6.9Hz,1H),7.34(d,J=8.7Hz,2H),6.45(s,1H),6.31(d,J=6.7Hz,1H),4. 80(s,1H),3.90(dd,J=12.7,4.3Hz,1H),3.71(dt,J=38.1,19.1Hz,1H),3.51(s,3H) ),3.46(dd,J=22.1,11.0Hz,2H),2.36(dt,J=13.2,11.4Hz,1H),2.15-1.97(m,1H). HRMS(ESI,[M+H] + ) m / z: 509.09537.

[0223] Example 19: Preparation of Compound 19 [ka]

[0224] Step A: Preparation of Compound 19-1 Referring to the method of Step C of Example 1, compound 4-bromo-3-fluoropyridin-2(1H)-one was reacted with iodomethane to obtain compound 19-1. MS (ESI, [M+H] + ) m / z: 208.02.

[0225] Step B: Preparation of compound 19-2 Referring to the preparation method in Step D of Example 1, compound 19-1 was reacted with bis(pinacolato)diboron to obtain a reaction solution of compound 19-2, which was used in the next step without purification.

[0226] Step C: Preparation of Compound 19 Referring to the preparation method in Step E of Example 1, compound 7-1 was added to the reaction solution of compound 19-2 prepared in Step B above, and reacted to obtain compound 19. 1H NMR(500MHz,DMSO-d6)δ 10.31(s,1H),8.83(d,J=2.3Hz,1H),8.10(dd,J=24.6,4.1Hz,2H),7.86(d,J=9.1Hz,2H),7.36(d, J=8.9Hz,2H),6.63(d,J=7.1Hz,1H),3.66-3.54(m,4H),3.44(d,J=8.9Hz,3H),3.39-3.34(m,4H). HRMS(ESI,[M+H] + )m / z:509.12021.

[0227] Example 20: Preparation of Compound 20 [ka]

[0228] Step A: Preparation of Compound 20-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride to obtain compound 20-1. MS (ESI, [M+H] + ) m / z: 474.02.

[0229] Step B: Preparation of Compound 20 Referring to the preparation method in Step E of Example 1, compound 20-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 20. 1 H NMR(500MHz,DMSO-d6)δ 10.27(d,J=25.5Hz,1H),8.79(d,J=2.3Hz,1H),8.05(t,J=5.5Hz,1H),7.90 -7.80(m,2H),7.75(d,J=7.0Hz,1H),7.35(d,J=9.0Hz,2H),6.51(d,J=1.7H z,1H),6.36(dd,J=6.9,1.9Hz,1H),4.19(s,2H),3.97(s,2H),3.64(d,J=10 .1Hz,2H),3.45(s,3H),2.66(dd,J=13.8,6.6Hz,1H),1.73(d,J=8.1Hz,1H). HRMS (ESI, [M+H] +) m / z: 503.12935.

[0230] Example 21: Preparation of Compound 21 [ka]

[0231] Step A: Preparation of Compound 21-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride to obtain compound 21-1. MS (ESI, [M+H] + ) m / z: 474.03.

[0232] Step B: Preparation of Compound 21 Referring to the preparation method in Step E of Example 1, compound 21-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 21. 1 H NMR(500MHz,DMSO-d6)δ 10.25(s,1H),8.75(s,1H),8.07(s,1H),7.86(d,J=8.6Hz,2H),7.73(d,J=6.7Hz,1H),7.35(d,J=8.3Hz,2H),6.51-6.22 (m,2H),4.92(s,1H),4.53(s,1H),3.77(s,2H),3.46(s,3H),3.30(s,1H),2.80(d,J=10.1Hz,1H),1.83(q,J=9.3Hz,2H). HRMS(ESI,[M+H] + ) m / z: 503.12954.

[0233] Example 22: Preparation of Compound 22 [ka]

[0234] Step A: Preparation of Compound 22-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride to obtain compound 22-1. MS (ESI, [M+H] + ) m / z: 474.03.

[0235] Step B: Preparation of Compound 22 Referring to the preparation method in Step E of Example 1, compound 22-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 22. 1 H NMR(500MHz,DMSO-d6)δ 10.25(s,1H),8.75(d,J=2.3Hz,1H),8.07(d,J=2.3Hz,1H),7.87(t,J=9.1 Hz,2H),7.73(d,J=6.9Hz,1H),7.35(d,J=8.9Hz,2H),6.45(s,1H),6.31(d d,J=6.9,1.5Hz,1H),4.92(s,1H),4.53(s,1H),3.77(s,2H),3.47(d,J=9. 4Hz,3H),3.30(d,J=3.4Hz,1H),2.80(d,J=10.2Hz,1H),1.91-1.70(m,2H). HRMS (ESI, [M+H] + ) m / z: 503.12949.

[0236] Example 23: Preparation of Compound 23 [ka]

[0237] Step A: Preparation of compound 23-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with 6-oxa-3-aza-bicyclo[3.1.1]heptane hydrochloride to obtain compound 23-1. MS (ESI ,[M+H] + ) m / z: 474.06.

[0238] Step B: Preparation of Compound 23 Referring to the preparation method in Step E of Example 1, compound 23-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 23. 1 H NMR(500MHz,DMSO-d6)δ 10.26(s,1H),8.79(d,J=2.3Hz,1H),8.08(d,J=2.3Hz,1H),7.96-7.79(m,2 H),7.74(d,J=7.0Hz,1H),7.35(d,J=9.0Hz,2H),6.52(d,J=1.8Hz,1H),6.3 4(dd,J=6.9,2.0Hz,1H),4.57(d,J=6.3Hz,2H),3.80(d,J=12.8Hz,2H),3.6 0(d,J=12.7Hz,2H),3.46(s,3H),3.07-2.93(m,1H),1.79(d,J=8.6Hz,1H). HRMS (ESI, [M+H] + ) m / z: 503.12984.

[0239] Example 24: Preparation of Compound 24 [ka]

[0240] Step A: Preparation of Compound 24-1 Compound 24-1 was prepared using compound 1-1 and 2-oxa-7-azaspiro[3.5]nonane as starting materials according to the preparation method in step B of Example 1. MS (ESI, [M+H] + ) m / z: 502.10.

[0241] Step B: Preparation of Compound 24 Referring to the preparation method in Step E of Example 1, compound 24-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 24. 1H NMR(500MHz,DMSO-d6)δ 10.29(s,1H),8.76(d,J=2.3Hz,1H),8.12(d,J=2.3Hz,1H),7.86(d,J=9.1Hz,2H),7.76(d,J=7.0Hz,1H),7.35(d,J=8.8Hz ,2H),6.65(d,J=1.6Hz,1H),6.45(dd,J=7.0,1.8Hz,1H),4.31(s,4H),3.47(s,3H),3.26-3.17(m,4H),1.84-1.76(m,4H). HRMS(ESI,[M+H] + ) m / z: 531.1332.

[0242] Example 25: Preparation of Compound 25 [ka]

[0243] Step A: Preparation of Compound 25-1 Compound 25-1 was prepared using compound 1-1 and 3-acetonitrilecyclobutylamine as raw materials according to the preparation method in step B of Example 1. MS (ESI, [M+H] + ) m / z: 457.02.

[0244] Step B: Preparation of Compound 25 Referring to the preparation method in Step E of Example 1, compound 25-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 25. 1 H NMR(500MHz,DMSO-d6)δ 10.29(s,1H),8.79(d,J=2.2Hz,1H),8.09(d,J=2.3Hz,1H),7.86(d,J=9.1Hz,2H),7.80(d,J=6.9Hz,1H),7.35(d,J=9.0Hz,2H),6.46(d, J=1.8Hz,1H),6.34(dd,J=6.9,1.9Hz,1H),4.17(t,J=8.9Hz,2H),4.03(dd,J=8.8,5.9Hz,2H),3.77(tt,J=9.0,5.9Hz,1H),3.48(s,3H). HRMS(ESI,[M+H] +) m / z: 486.1140.

[0245] Example 26: Preparation of Compound 26 [ka]

[0246] Step A: Preparation of compound 26-1 Compound 26-1 was prepared using compound 1-1 and 3-methyl-3-acridinol as raw materials according to the preparation method in step B of Example 1. MS (ESI, [M+H] + ) m / z: 462.02.

[0247] Step B: Preparation of Compound 26 Referring to the preparation method in Step E of Example 1, compound 26-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 26. 1 H NMR(500MHz,DMSO-d6)δ 10.22(s,1H),8.76(d,J=2.3Hz,1H),8.04(d,J=2.3Hz,1H),7.90-7.83(m,2H),7.77(d,J=6.9Hz,1H),7.35(d,J=9 .0Hz,2H),6.43(d,J=1.9Hz,1H),6.32(dd,J=6.9,2.0Hz,1H),5.51(s,1H),3.75(s,4H),3.48(s,3H),1.34(s,3H). HRMS(ESI,[M+H] + ) m / z: 491.1298.

[0248] Example 27: Preparation of Compound 27 [ka]

[0249] Step A: Preparation of compound 27-1 Referring to the preparation method in step B of Example 1, compound 1-1 and (3S,4S)-4-fluoropyrrolidin-3-ol hydrochloride were reacted to obtain compound 27-1. MS (ESI, [M+H]+ ) m / z: 480.02.

[0250] Step B: Preparation of Compound 27 Referring to the preparation method in Step E of Example 1, compound 27-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 27. 1 H NMR (500MHz, DMSO-d6) δ 10.23(s,1H),8.83-8.70(m,1H),8.14-8.04(m,1H),7.86(d,J=8.9Hz,2H),7. 77(d,J=6.9Hz,1H),7.34(d,J=8.6Hz,2H),6.43(s,1H),6.28(d,J=6.4Hz,1H), 5.49(d,J=3.1Hz,1H),4.98(d,J=51.4Hz,1H),4.23(s,1H),3.83(dd,J=42.0,1 3.4Hz,1H),3.62(d,J=11.7Hz,1H),3.54-3.39(m,4H),3.18(d,J=12.0Hz,1H). HRMS (ESI, [M+H] + ) m / z: 509.1248.

[0251] Example 28: Preparation of Compound 28 [ka]

[0252] Step A: Preparation of Compound 28-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with 3-azabicyclo[3.1.0]hexane hydrochloride to obtain compound 28-1. MS (ESI, [M+H] + ) m / z: 458.06.

[0253] Step B: Preparation of Compound 28 Referring to the preparation method in Step E of Example 1, compound 28-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 28. 1H NMR (500MHz, DMSO-d6) δ 10.19(s,1H),8.71(d,J=2.3Hz,1H),8.01(d,J=2.3Hz,1H),7.85(d,J=9.1Hz, 2H),7.73(d,J=6.9Hz,1H),7.34(d,J=8.9Hz,2H),6.43(d,J=1.8Hz,1H),6.25 (dd,J=6.9,1.9Hz,1H),3.67(d,J=10.9Hz,2H),3.47(s,3H),3.34(d,J=11.0H z,2H),1.60-1.50(m,2H),0.58(td,J=7.6,4.6Hz,1H),0.05(q,J=4.0Hz,1H). HRMS (ESI, [M+H] + ) m / z: 487.1385.

[0254] Example 29: Preparation of Compound 29 [ka]

[0255] Step A: Preparation of compound 29-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with isoxazolidine hydrochloride to obtain compound 29-1. MS (ESI, [M+H] + ) m / z: 448.03.

[0256] Step B: Preparation of compound 29 To the reaction solution of compound 1-4 obtained in step D of Example 1, compound 29-1 (500 mg) obtained in step A above, potassium phosphate (710 mg), deionized water (3 mL), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium (II) dichloride (73 mg) were added in this order, and after completion, the mixture was replaced with nitrogen and reacted at room temperature for 6 hours. The reaction solution was filtered, the mother liquor was collected, ethyl acetate (30 mL) was added, stirred and washed, and then separated to obtain an organic phase, which was added with a saturated aqueous sodium chloride solution (30 mL), stirred and washed, and then separated. The mixture was purified by silica gel column chromatography to obtain a total of 280 mg of compound 29. 1H NMR(500MHz,DMSO-d6)δ 10.42(s,1H),8.81(d,J=2.2Hz,1H),8.18(d,J=2.2Hz,1H),7.86(d,J=9.1Hz,2H),7.67(d,J=7.0Hz,1H),7.36(d,J=9.0Hz,2H), 6.54(d,J=1.8Hz,1H),6.42(dd,J=7.0,1.9Hz,1H),3.78-3.73(m,2H),3.68(t,J=7.3Hz,2H),3.45(s,3H),2.13(p,J=7.3Hz,2H). HRMS (ESI, [M+H] + ) m / z: 477.1177.

[0257] Example 30: Preparation of Compound 30 [ka]

[0258] Step A: Preparation of Compound 30-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with (S)-pyrrolidine-3-carbonitrile hydrochloride to obtain compound 30-1. MS (ESI, [M+H] + ) m / z: 471.1.

[0259] Step B: Preparation of Compound 30 Referring to the preparation method in Step E of Example 1, compound 30-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 30. 1 H NMR(500MHz,DMSO-d6)δ 10.25(s,1H),8.7 8(d,J=1.9Hz,1H),8.16-8.03(m,1H),7.87(d,J=8.9Hz,2H),7.77(d,J=6.9Hz,1H),7.35(d,J=8.7Hz,2H),6.44(s,1H),6.30(dd,J=6.9,2 .1Hz,1H),3.73-3.64(m,1H),3.59-3.52(m,1H),3.48(s,3H),3.47-3.42(m,2H),3.42-3.36(m,1H),2.27-2.19(m,1H),2.19-2.09(m,1H). HRMS(ESI,[M+H] + ) m / z: 500.1312.

[0260] Example 31: Preparation of Compound 31 [ka]

[0261] Step A: Preparation of compound 31-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with (R)-3-fluoropyrrolidine hydrochloride to obtain compound 31-1. MS (ESI, [M+H] + ) m / z: 471.1.

[0262] Step B: Preparation of Compound 31 Referring to the preparation method in Step E of Example 1, compound 31-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 31. 1H NMR (500MHz, DMSO-d6) δ 10.25(s,1H),8.78(d,J=2.2Hz,1H),8.10(d,J=2.2Hz,1H),7.87(d,J=9.0Hz ,2H),7.77(d,J=6.9Hz,1H),7.35(d,J=8.8Hz,2H),6.44(d,J=1.5Hz,1H),6. 30(dd,J=6.9,1.8Hz,1H),3.71-3.64(m,1H),3.59-3.52(m,1H),3.48(s,3H) ,3.47-3.43(m,2H),3.42-3.36(m,1H),2.29-2.20(m,1H),2.19-2.10(m,1H). HRMS (ESI, [M+H] + ) m / z: 500.1321.

[0263] Example 32: Preparation of Compound 32 [ka]

[0264] Step A: Preparation of Compound 32-1 Dioxane (15 mL), compound 1-1 (1 g), 2-oxa-6-azaspiro[3.4]oct-7-one (0.309 g), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.140 g), tris(dibenzylideneacetone)dipalladium(0) (0.111 g), and tripotassium phosphate (1.030 g) were added in this order to a 35 mL waveguide, and the mixture was placed in a microwave reactor under nitrogen protection, heated to 140 ° C., and reacted for 4 hours. When the temperature was lowered to room temperature, the reaction solution obtained as above was filtered, the mother liquor was collected, and the mixture was transferred to a silica gel column. Purification by column chromatography gave 220 mg of compound 32-1. MS (ESI, [M+H] + ) m / z: 501.99.

[0265] Step B: Preparation of Compound 32 Referring to the preparation method in Step E of Example 1, compound 32-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 32. 1H NMR(500MHz,DMSO-d6)δ 10.62(s,1H),8.99(d,J=2.3Hz,1H),8.38(d,J=2.3Hz,1H),7.88(d,J=9.0Hz,2H),7.69(d,J=7.0Hz,1H),7.39(d,J=8.5Hz,2H),6.5 4(d,J=2.1Hz,1H),6.23(dd,J=7.1,2.1Hz,1H),4.71(d,J=6.1Hz,2H),4.57(d,J=6.1Hz,2H),4.35(s,2H),3.44(s,3H),2.74(s,2H). MS(ESI,[M+H] + ) m / z: 531.12415.

[0266] Example 33: Preparation of Compound 33 [ka]

[0267] Step A: Preparation of compound 33-1 Add purified water (8mL) and 4-bromo-5-chloropyridine-2-amino (500mg) in this order to a 25mL one-neck flask, stir, lower the temperature to 0-5℃, slowly add 98%w / w concentrated sulfuric acid aqueous solution (1mL) to the system, and when complete, add sodium nitrite aqueous solution (1mL, 319mg / mL) to the system after stirring for 5 minutes, keep warm and react for 30 minutes, filter, add purified water to the cake to wash (10mL×2), collect the cake, put it in a vacuum drying oven and dry it at 50℃ until it becomes constant weight, and obtain 420mg of compound 33-1. MS(ESI,[MH] - ) m / z: 205.9.

[0268] Step B: Preparation of compound 33-2 In a 25mL one-neck flask, add N,N-dimethylformamide (5mL), compound 33-1 (200mg) obtained in step A above, and anhydrous potassium carbonate (199mg) in that order, stir, lower the temperature to 0-5℃, slowly add anhydrous N,N-dimethylformamide in iodomethane (1mL, 136mg) solution to the system, keep warm and react for 2 hours, add dichloromethane (20mL) and purified water (10mL) to the system, stir, separate to obtain an organic phase, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 160mg of compound 33-2. MS (ESI, [M+H] + ) m / z: 222.0.

[0269] Step C: Preparation of compound 33-3 A 35 mL waveguide was charged with 1,4-dioxane (10 mL), compound 1-1 (500 mg), bis(pinacolato)diboron (367 mg), potassium acetate (236 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (88 mg ) were added in this order, and when complete, the mixture was replaced with nitrogen, then the temperature was raised to 140°C and reacted for 2 hours, the reaction was stopped, the temperature was lowered to room temperature, and the mixture was used in the next step reaction without separation or purification.

[0270] Step D: Preparation of compound 33-4 Compound 33-2 (282 mg), tripotassium phosphate (639 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (78 mg), and purified water (2 mL) were added in this order to the reaction solution obtained in step C above. When complete, the mixture was substituted with nitrogen and reacted at room temperature for 4 hours. Ethyl acetate (20 mL) was added to the system, stirred and washed, and then separated. The organic phase was collected, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain 300 mg of compound 33-4. MS (ESI, [MH] - ) m / z: 472.0.

[0271] Step E: Preparation of Compound 33 Compound 33-4 (200 mg) obtained in step D above, morpholine (44.1 mg), N,N-diisopropylethylamine (82 mg), and N-methylpyrrolidone (5 mL) were added in this order to a 35 mL waveguide, and the liquid surface was purged with nitrogen for a while, then the liquid was sealed with a cap, and the temperature was raised to 160 ° C. using a microwave reaction apparatus and reacted for 2 hours. After the reaction liquid was cooled, ethyl acetate (10 mL) was added to the system to dilute it, water (10 mL) was added, stirred and washed, and then the liquid was separated. The organic layer was collected, dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain 20 mg of compound 33. 1 H NMR(500MHz,DMSO-d6)δ 10.29(s,1H),8.82(d,J=2.4Hz,1H),8.16(s,1H),8.02(d,J=2.3Hz,1H),7.90-7.81(m,2H ),7.35(d,J=8.7Hz,2H),6.64(s,1H),3.66-3.53(m,4H),3.46-3.36(m,4H),3.48(s,3H). MS(ESI,[MH] - ) m / z: 523.1.

[0272] Example 34: Preparation of Compound 34 [ka]

[0273] Step A: Preparation of Compound 4-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride to obtain intermediate compound 34-1. MS (ESI, [M+H] + ) m / z: 488.04.

[0274] Step B: Preparation of Compound 34 Referring to the preparation method in Step E of Example 1, compound 34-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 34. 1H NMR(500MHz,DMSO-d6)δ 10.31(s,1H),8.77(d,J=2.3Hz,1H),8.10(d,J=2.3Hz,1H),7.86(d,J=9.1Hz,2H),7.80(d,J=7.0Hz,1H) ,7.35(d,J=8.9Hz,2H),6.57(d,J=1.6Hz,1H),6.37(m,J=6.9,1.8Hz,1H),4.29(s,2H),3.48(d,J=10.9Hz ,5H),3.04(d,J=11.4Hz,2H),1.76(m,J=11.0,8.0Hz,4H).HRMS(ESI,[MH] - ) m / z: 517.1452.

[0275] Example 35: Preparation of Compound 35 [ka]

[0276] Step A: Preparation of compound 35-1 Referring to the preparation method in step B of Example 1, compound 1-1 was reacted with 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride to obtain intermediate compound 35-1. MS (ESI, [M+H] + ) m / z: 488.1.

[0277] Step B: Preparation of Compound 35 Referring to the preparation method in Step E of Example 1, compound 35-1 prepared in Step A above was added to the reaction solution of compound 1-4 and reacted to obtain compound 35. 1H NMR(500MHz,DMSO-d6)δ 10.31(s,1H),8.76(d,J=2.2Hz,1H),8.11(d,J=2.2Hz,1H),7.86(d,J=9.0Hz,2H),7.77(d,J=7.0Hz,1H),7.35(d,J=8.8Hz ,2H),6.64(d,J=1.5Hz,1H),6.55-6.41(m,1H),4.19(s,2H),3.66(d,J=10.6Hz,2H),3.55-3.41(m,5H),1.98-1.64(m,4H). HRMS(ESI,[M+H] + ) m / z: 517.1452.

[0278] Example 36: Preparation of Compound 36 [ka]

[0279] Step A: Preparation of compound 36-1 Acetonitrile (80mL), 4-bromo-1H-pyrazole (10g), and cesium carbonate (44.3g) were added in this order to a 250mL three-neck flask, protected with nitrogen, and the reaction system was transferred to an ice-salt bath to cool to 0°C, and (2-bromoethoxy)(tert-butyl)dimethylsilane (19.53g) was dissolved in acetonitrile (40mL) and slowly added dropwise to the above reaction system, and when complete, the reaction system was allowed to naturally rise in temperature and stirred at room temperature overnight. Ethyl acetate (50mL) and water (20mL) were added to the reaction system, and the organic phase was separated and collected, dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 13g of compound 36-1. 1 H NMR(500MHz,DMSO-d6)δ 7.98(s,1H),7.62(s,1H),4.27(t,J=5.0Hz,2H),3.96(t,J=5.0Hz,2H),0.89(s,9H),0.00(s,6H).MS(ESI,[M-(CH3)3C] + ) m / z: 247.

[0280] Step B: Preparation of compound 36-2 Diisopropylamine (3.98 g) and anhydrous tetrahydrofuran (20 mL) were added in this order to a 250 mL three-neck flask and protected with nitrogen. The reaction was transferred to a cryostat at -80°C and 1.6 M n-butyllithium in n-hexane (23 mL) was added dropwise to the reaction, and upon completion, the reaction was stirred at -80°C for 30 minutes. Compound 36-1 (7.5 g) was dissolved in anhydrous tetrahydrofuran (15 mL) and slowly added dropwise to the above reaction, and upon completion, the reaction was stirred at -80°C for 30 minutes. N,N-dimethylformamide (3.23 g) was dissolved in anhydrous tetrahydrofuran (8 mL) and slowly added dropwise to the above reaction, and upon completion, the reaction was stirred at -80°C for 3 hours. Isopropanol (5 mL) was added to the reaction to quench the reaction, and the reaction was transferred to room temperature and stirred. Saturated ammonium chloride solution (40 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the organic phase was separated and collected. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 6 g of compound 36-2. MS (ESI, [M+H] + ) m / z: 333.1.

[0281] Step C: Preparation of compound 36-3 Compound 36-2 (4.8 g), 2-methyltetrahydrofuran (10 mL), water (10 mL), and trifluoroacetic acid (18 mL) were added to a 100 mL one-neck flask in this order and stirred at room temperature for 30 minutes. The pH of the system was adjusted to neutral with saturated aqueous sodium bicarbonate, and a large amount of gas was generated. Dichloromethane (100 mL) was added to the reaction system, and the organic phase was recovered by separation. The organic phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to obtain 3.8 g of compound 36-3. GCMS (EI, [Me] + ) m / z: 218.

[0282] Step D: Preparation of compound 36-4 Dichloromethane (90 mL) and compound 36-3 (3.8 g) were added in this order to a 250 mL three-neck flask, the reaction system was cooled to 0 ° C. in an ice-salt bath, triethylsilane (6.05 g) and trifluoroacetic acid (11.87 g) were added dropwise in this order using a dropping funnel, and the reaction system was stirred at room temperature overnight. The pH of the system was adjusted to neutral with a saturated aqueous solution of sodium bicarbonate. Dichloromethane (100 mL) was added to the reaction system, and the organic phase was recovered by liquid separation. The organic phase was dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 2.4 g of compound 36-4. 1 H NMR(500MHz,DMSO-d6)δ 7.57(s,1H),4.71(s,2H),4.08(m,4H). GCMS(EI,[Me] + ) m / z: 202.

[0283] Step E: Preparation of Compound 36-5 In a 25 mL one-neck flask, add 1,4-dioxane (10 mL), compound 36-4 (165 mg), bis(pinacolato)diboron (247 mg), potassium acetate (159 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (40 mg) in that order. Once complete, replace with nitrogen and then raise the temperature to 90°C for 2 hours. The reaction was stopped and cooled to room temperature. The reaction was used directly in the next step without separation or purification.

[0284] Step F: Preparation of Compound 36 The reaction mixture obtained in step E above was transferred to a 35 mL waveguide, and compound 11- 1 (250 mg), potassium carbonate (224 mg), tetrakis(triphenylphosphine)palladium(0) (62.4 mg), and water (2.5 mL) were added in this order, and when complete, the mixture was protected with nitrogen, sealed, and placed in a microwave reactor, and the microwave reaction conditions were 150° C. and 1 hour. The reaction solution was filtered through diatomaceous earth, and the filtrate was collected. The filtrate was washed with ethyl acetate (50 mL) and saturated saline (25 mL), and then separated. The organic phase was collected and purified by silica gel column chromatography to give 40 mg of compound 36. 1 H NMR(500MHz,DMSO-d6)δ 10.14(s,1H),8.68(s,1H),7.90(m,3H),7.59(s,1H),7.33(s,2H),4.85( s,1H),4.62(m,2H),4.14(m,5H),3.24(s,3H),2.96(s,1H),1.80(m,2H). HRMS(ESI,[M+H] + ) m / z: 506.1413.

[0285] Example 37: Preparation of Compound 37 [ka]

[0286] Step A: Preparation of compound 37-1 Compound 37-1 was prepared by following the procedure of Step B in Example 1 and using compound 1-1 and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride.

[0287] Step B: Preparation of Compound 37 Compound 37 was prepared by following the procedure of Step H in Example 1, using compound 37-1 and compound 36-5. 1H NMR(500MHz,DMSO-d6)δ 10.29(s,1H),8.70(d,J=2.2Hz,1H),7.94(d,J=2.2Hz,1H),7.86(d,J=9.0Hz,2H),7.71(s,1H),7.35(d,J=8.8Hz,2H),4.81(s,2H),4.1 9(t,J=4.9Hz,2H),4.10(dd,J=15.8,9.5Hz,4H),3.62(d,J=10.6Hz,2H),3.43(d,J=10.4Hz,2H),1.88-1.81(m,2H),1.80-1.71(m,2H). HRMS(ESI,[M+H] + ) m / z: 532.15650.

[0288] Example 38: Preparation of Compound 38 [ka]

[0289] Step A: Preparation of compound 38-1 Referring to the method of Step B of Example 1, compound 1-1 and (1R,4R)-2-oxa Compound 38-1 was prepared using -5-azabicyclo[2.2.1]heptane hydrochloride.

[0290] Step B: Preparation of Compound 38 Compound 38 was prepared by following the procedure of Step H in Example 1, using compound 38-1 and compound 36-5. 1H NMR(500MHz,DMSO-d6)δ 10.21(s,1H),8.68(d,J=2.4Hz,1H),7.96(d,J=2.4Hz,1H),7.89-7.84(m,2H),7.61 (s,1H),7.37-7.31(m,2H),4.85(s,1H),4.68-4.62(m,1H),4.60-4.53(m,1H),4.47( d,J=2.3Hz,1H),4.20-4.14(m,2H),4.12-4.05(m,2H),3.83-3.78(m,1H),3.78-3.72 (m,1H),2.93-2.86(m,1H),2.64-2.59(m,1H),1.88-1.82(m,1H),1.81-1.74(m,1H). MS(ESI,[MH] - ) m / z: 516.1 / 518.1.

[0291] Example 39: Preparation of Compound 39 [ka]

[0292] Step A: Preparation of compound 39-1 Compound 39-1 was prepared using compound 1-1 and 6-oxa-3-aza-bicyclo[3.1.1]heptane hydrochloride as raw materials according to the preparation method in step B of Example 1. MS (ESI, [M+H] + ) m / z: 474.04 / 476.06.

[0293] Step B: Preparation of Compound 39 Compound 39 was prepared by following the procedure of Step H in Example 1, using compound 39-1 and compound 36-5. 1H NMR(500MHz,DMSO-d6)δ 10.25(s,1H),8.74(d,J=2.2Hz,1H),7.97(d,J=2.2Hz,1H),7.87(d,J=9 .0Hz,2H),7.63(s,1H),7.34(d,J=8.8Hz,2H),4.69(s,2H),4.53(d,J=6. 2Hz,2H),4.18(t,J=4.8Hz,2H),4.09(t,J=5.0Hz,2H),3.66(d,J=12.8Hz,2H),3.46(d,J=12.8Hz,2H),3.07-2.96(m,1H),1.80(d,J=8.6Hz,1H). HRMS (ESI, [M+H] + ) m / z: 518.1400.

[0294] Example 40: Preparation of Compound 40 [ka]

[0295] Step A: Preparation of compound 40-1 Compound 40-1 was prepared using compound 1-1 and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride as starting materials, following the preparation method of step B in Example 1. MS (ESI, [M+H] + ) m / z: 474.06 / 476.09.

[0296] Step B: Preparation of Compound 40 Compound 40 was prepared by following the procedure of Step H in Example 1, using compound 40-1 and compound 36-5. 1H NMR(500MHz,DMSO-d6)δ 10.21(s,1H),8.69(d,J=2.3Hz,1H),7.96(d,J=2.3Hz,1H),7.86(d,J=9.1Hz,2H),7. 62(s,1H),7.34(d,J=8.9Hz,2H),4.86(s,1H),4.70-4.61(m,1H),4.61-4.53(m,1H), 4.47(s,1H),4.17(t,J=4.9Hz,2H),4.09(t,J=5.5Hz,2H),3.84-3.74(m,2H),2.90(d ,J=9.3Hz,1H),2.61(d,J=10.2Hz,1H),1.85(d,J=9.7Hz,1H),1.79(d,J=9.8Hz,1H). HRMS(ESI,[M+H] + ) m / z: 518.1405.

[0297] Example 41: Preparation of Compound 41 [ka]

[0298] Step A: Preparation of compound 41-1 Following the procedure of Step B in Example 1, compound 41-1 was prepared using compound 1-1 and (R)-3-methoxypyrrolidine hydrochloride.

[0299] Step B: Preparation of Compound 41 Compound 41 was prepared by following the procedure of Step H in Example 1, using compound 41-1 and compound 36-5. 1 H NMR(500MHz,DMSO-d6)δ(ppm) 10.16(s,1H),8.68(d,J=2.4Hz,1H),7.94(d,J=2.4Hz,1H),7.90-7.82(m,2H),7.60(s,1H),7.33(d,J=8.6Hz,2H),4.69-4.5 3(m,2H),4.21-4.15(m,2H),4.11-4.05(m,2H),3.95-3.91(m,1H),3.31-3.24(m,2H),3.22-3.13(m,5H),2.01-1.83(m,2H). MS(ESI,[M+H]+ ) m / z: 520.2.

[0300] Example 42: Preparation of Compound 42 [ka]

[0301] Step A: Preparation of Compound 42 Compound 42 was prepared by following the procedure of Step H in Example 1 using compound 15-1 and compound 36-5. 1 H NMR(500MHz,DMSO-d6)δ(ppm) 10.14(s,1H),8.68(d,J=2.4Hz,1H),7.92(d,J=2.4Hz,1H),7.89-7.82(m,2H),7.58(s,1H),7.33(d,J=8. 6Hz,2H),4.62(s,2H),4.17(t,J=5.1Hz,2H),4.09(t,J=5.3Hz,2H),3.23-3.11(m,4H),1.85-1.71(m,4H). MS(ESI,[M+H] + ) m / z: 490.1.

[0302] Example 43: Preparation of Compound 43 [ka]

[0303] Step A: Preparation of compound 43-1 Referring to the method of Example 1, Step B, compound 1-1 was used to react with morpholine to prepare compound 43-1.

[0304] Step B: Preparation of Compound 43 Compound 43 was prepared by following the procedure of Step H in Example 1 using compound 43-1 and compound 36-5. 1H NMR(500MHz,DMSO-d6)δ 10.31(s,1H),8.73(s,1H),7.97(s,1H),7.87(d,J=10.0Hz,2H),7.80(s,1H),7.36(d,J= 10.0Hz,2H),4.83(s,2H),4.20-4.12(m,4H),3.63(t,J=5.0Hz,4H),3.14(t,J=5.0,4H). HRMS(ESI,[M+H] + ) m / z: 506.1605.

[0305] Example 44: Preparation of Compound 44 [ka]

[0306] Step A: Preparation of compound 44-1 Compound 44-1 was prepared by following the procedure of Step B in Example 1 and using compound 1-1 and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride.

[0307] Step B: Preparation of compound 44 Compound 44 was prepared by following the procedure of Step H in Example 1 using compound 44-1 and compound 36-5. 1 H NMR(500MHz,DMSO-d6)δ 10.28(s,1H),8.71(d,J=2.4Hz,1H),7.92(d,J=2.4Hz,1H),7.88-7.83(m,2H),7.66(s,1H),7.35(d,J=9.0Hz,2H),4.74(s, 2H),4.25(s,2H),4.19(t,J=5.1Hz,2H),4.11(t,J=5.1Hz,2H),3.37(d,J=12.3Hz,2H),2.95(d,J=11.0Hz,2H),1.73(s,4H). HRMS(ESI,[M+H] + ) m / z: 532.15643.

[0308] Example 45: Preparation of Compound 45 [ka] TIFF2024519538000161.tif1456

[0309] Step A: Preparation of compound 45-1 6-Bromopyrimidin-4(3H)-one (2.0 g), N,N-dimethylformamide (20 mL), iodomethane (3.24 g), and potassium carbonate (4.74 g) were added in this order to a 100 mL three-neck flask, and the reaction system was protected with nitrogen and heated to 50 ° C. for 3 hours. Water (10 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (40 mL) was added for extraction. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 mL x 2). The organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1.4 g of compound 45-1. MS (ESI, [M + H] + ) m / z: 189.01.

[0310] Step B: Preparation of compound 45-2 In a 25 mL one-neck flask, 1,4-dioxane (10 mL), compound 45-2 (127 mg), bis(pinacolato)diboron (205 mg), potassium acetate (132 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (33 mg) were added in this order. Upon completion, the mixture was purged with nitrogen and then heated to 90°C for reaction for 2 hours. The reaction was then stopped and cooled to room temperature. The resulting reaction solution was used directly in the next step without separation or purification.

[0311] Step C: Preparation of Compound 45 The reaction solution obtained in step B above was transferred to a 35 mL waveguide, and compound 15-1 (200 mg), cesium carbonate (146 mg), [2'-(amino)[1,1'-biphenyl]-2-yl][[2',6'-bis(1-methylethoxy)[1,1'-biphenyl]-2-yl]dicyclohexylphosphine]palladium chloride (35 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (21 mg), and water (2.5 mL) were added to the waveguide in this order, and when complete, the mixture was sealed after being protected with nitrogen and placed in a microwave reactor, and the microwave reaction conditions were 140 ° C., 2 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was collected. The filtrate was washed with ethyl acetate (50 mL) and saturated saline (25 mL), and then separated. The organic phase was collected and purified by silica gel column chromatography to obtain 15 mg of compound 45. 1 H NMR(500MHz,DMSO-d6)δ 10.21(s,1H),8.77(d,J=2.0Hz,1H),8.53(s,1H),8.17(d,J=2.0Hz,1H),7.86(d,J=9 .5Hz,2H),7.34(d,J=9.0Hz,2H),6.47(s,1H),3.46(s,3H),3.32(s,4H),1.83(m,4H). HRMS(ESI,[M+H] + ) m / z: 476.13469.

[0312] Example 46: Preparation of Compound 46 [ka]

[0313] Step A: Preparation of Compound 46 Referring to the preparation method of Example 45, Step C, compound 11-1 was used to react with compound 45-2 to obtain compound 46. 1H NMR(500MHz,DMSO-d6)δ 10.21(s,1H),8.77(d,J=2.3Hz,1H),8.54(s,1H),8.17(d,J=2.3Hz,1H) ,7.92-7.78(m,2H),7.34(d,J=8.9Hz,2H),6.47(s,1H),4.90(d,J=3.2Hz ,1H),4.28(d,J=1.9Hz,1H),3.66-3.53(m,1H),3.47(s,3H),3.44(d,J=4 .3Hz,1H),3.41-3.34(m,1H),3.08(d,J=11.7Hz,1H),1.98-1.73(m,2H). HRMS (ESI, [M+H] + ) m / z: 492.1247.

[0314] Example 47: Preparation of Compound 47 [ka]

[0315] Step A: Preparation of compound 47-1 In a 50mL one-neck flask, add N-methylpyrrolidone (30mL), 4,5-dibromopyridazin-3-one (4.0g), and cesium carbonate (7.62g) in this order, stir, slowly add benzyl bromide (2.72g) dropwise to the system at room temperature, and when complete, react for 4 hours, filter, and collect the filtrate, add ethyl acetate (30mL) and purified water (20mL) to it, stir and wash, then separate, collect the organic phase, and concentrate under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain 4.7g of compound 47-1. MS (ESI, [M+H] + ) m / z: 342.9.

[0316] Step B: Preparation of compound 47-2 In a 50mL one-neck flask, add anhydrous tetrahydrofuran (30mL) and compound 47-1 (4.7g) obtained in step A above in this order, start stirring, and after cooling to -20℃, slowly add 2M n-butylmagnesium chloride tetrahydrofuran solution (6.9mL) to the system, and when completed, control the temperature and react for 5 minutes, pour the above reaction liquid into saturated ammonium chloride aqueous solution (20mL) to quench the reaction, add ethyl acetate to extract (20mL×2), combine the organic phase, stir and wash with saturated saline, then separate to obtain the organic phase, concentrate under reduced pressure to obtain the residue, and obtain 1.05g of compound 47-2 after purification by silica gel column chromatography. 1 H NMR(500MHz,DMSO-d6)δ 8.14(d,J=2.3Hz,1H),7.48(d,J=2.3Hz,1H),7.37-7.30(m,2H),7.31-7.25(m,3H),5.22(s,2H).MS(ESI,[M+H] + ) m / z: 264.97.

[0317] Step C: Preparation of compound 47-3 Toluene (20mL), compound 47-2 (800mg) obtained in step B above, and aluminum chloride (2028mg) were added in this order to a 50mL one-neck flask, stirring was started, and after replacing with nitrogen, the temperature was raised to 70°C in an oil bath and reacted for 2 hours. Saturated sodium bicarbonate aqueous solution (30mL) was added to the system to quench the reaction, ethyl acetate was added for extraction (30mL x 2), and the organic phase was separated. Saturated sodium chloride aqueous solution (20mL) was added to it, stirred and washed, and then separated to obtain the organic phase. The organic phase was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography to obtain 300mg of compound 47-3. MS (ESI, [MH] - ) m / z: 173.0.

[0318] Step D: Preparation of compound 47-4 In a 50 mL one-neck flask, add N,N-dimethylformamide (10 mL), compound 47-3 (300 mg) obtained in step C above, and cesium carbonate (838 mg) in that order, stir, and slowly add iodomethane (257 mg) diluted with 2 mL of anhydrous N,N-dimethylformamide to the system at room temperature. When complete, react at room temperature for 4 hours, and add purified Water (10 mL) and ethyl acetate (30 mL) were added in this order, stirred and washed, then separated, the organic phase was collected and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain 250 mg of compound 47-4. MS (ESI, [M+H] + ) m / z: 189.0.

[0319] Step E: Preparation of compound 47-5 In a 35 mL waveguide, 1,4-dioxane (15 mL), compound 47-4 (93 mg) obtained in step D above, bis(pinacolato)diboron (136 mg), potassium acetate (110 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (25 mg) were added in this order. Upon completion, the mixture was purged with nitrogen and then heated to 90°C for reaction for 2 hours. The reaction was then stopped and cooled to room temperature. The mixture was used directly in the next step without separation or purification.

[0320] Step F: Preparation of Compound 47 To the reaction solution obtained in step E above, compound 15-1 (200 mg), potassium carbonate (154 mg), deionized water (1 mL), and tetrakis(triphenylphosphine)palladium(0) (30 mg) were added in this order, and when complete, the air was replaced with nitrogen, the waveguide was sealed, and the reaction was performed in a microwave reactor at 140° C. for 1.5 hours. When the temperature was lowered to room temperature, the reaction solution was filtered, and the mother liquor was collected and purified by silica gel column chromatography to obtain 170 mg of compound 47. 1H NMR(500MHz,DMSO-d6)δ 10.17(s,1H),8.78(d,J=2.3Hz,1H),8.13(d,J=2.3Hz,1H),8.02(d,J=2.2Hz,1H),7.89-7.83(m, 2H),7.38-7.31(m,2H),6.90(d,J=2.2Hz,1H),3.70(s,3H),3.30-3.25(m,4H),1.88-1.79(m,4H). MS(ESI,[MH] - ) m / z: 474.09 / 475.99.

[0321] Example 48: Preparation of Compound 48 [ka]

[0322] Step A: Preparation of compound 48-1 In a 35mL sealed tube, isopropanol (10mL), compound 1-1 (1.0g), 3-hydroxyazetidine hydrochloride (0.32g), N,N-diisopropylethylamine (1.004g), and a stirrer were added in this order, sealed, and then the sealed tube was placed in a microwave reactor and reacted at 140°C for 1.5 hours. When the temperature was lowered to room temperature, ethyl acetate (15mL) and saturated aqueous sodium chloride solution (15mL) were added to the reaction solution, stirred and washed, and then separated. The organic phase was collected, dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 0.8g of compound 48-1. MS (ESI, [M+H] + ) m / z: 447.98.

[0323] Step B: Preparation of Compound 48 Compound 45-2, compound 48-1 (500 mg), potassium carbonate (424 mg), and [2'-(amino)[1,1'-biphenyl]-2-yl][[2',6 '-Bis(1-methylethoxy)[1,1'-biphenyl]-2-yl]dicyclohexylphosphine]palladium chloride (80 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (48 mg), and water (2 mL) were added in this order, and when complete, the mixture was placed in a microwave reactor under nitrogen protection, and the microwave reaction conditions were 140°C and 2 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was collected, and the filtrate was washed with ethyl acetate (50 mL) and saturated saline (25 mL), and then separated, and the organic phase was collected and purified by silica gel column chromatography to obtain 100 mg of compound 48. 1 H NMR(500MHz,DMSO-d6)δ 10.26(s,1H),8.78(d,J=2.2Hz,1H),8.56(s,1H),8.20(d,J=2.2Hz,1H),7.86(d,J=9.1Hz,2H),7.34(d,J=8.8Hz,2H), 6.48(s,1H),5.63(d,J=6.4Hz,1H),4.46(h,J=6.5Hz,1H),4.16-4.05(m,2H),3.69(dd,J=9.7,4.2Hz,2H),3.47(s,3H). HRMS(ESI,[M+H] + ) m / z: 478.10934.

[0324] Example 49: Preparation of Compound 49 [ka] Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 35-1 to obtain compound 49. 1H NMR(500MHz,DMSO-d6)δ 10.34(s,1H),8.78(d,J=2.1Hz,1H),8.58(s,1H),8.28(d,J=2.1Hz,1H),7.86(d,J=9.0Hz,2H),7.35(d,J=8.7Hz,2H) ,6.79(s,1H),4.22(s,2H),3.65(d,J=10.7Hz,2H),3.50(d,J=10.5Hz,2H),3.45(s,3H),1.83(dd,J=45.3,5.8Hz,4H). HRMS(ESI,[M+H] + ) m / z: 518.14078.

[0325] Example 50: Preparation of Compound 50 [ka] Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 34-1 to obtain compound 50. 1 H NMR(500MHz,DMSO-d6)δ 10.32(s,1H),8.77(d,J=2.3Hz,1H),8.59(s,1H),8.25(d,J=2.3H) z,1H),7.86(d,J=9.1Hz,2H),7.35(d,J=8.8Hz,2H),6.63(s,1H),4.29(s,2H) ),3.58(d,J=12.6Hz,2H),3.46(s,3H),3.08(d,J=11.6Hz,2H),1.73(s,4H). HRMS(ESI,[M+H] + ) m / z: 518.14054.

[0326] Example 51: Preparation of Compound 51 [ka] Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 21-1 to obtain compound 51. 1H NMR(500MHz,DMSO-d6)δ 10.27(s,1H),8.78(s,1H),8.53(s,1H),8.19(s,1H),7.86-7.87(m,2H),7.34-7.35(m,2H),6.52(s,1H),4. 94(s,1H),4.55(s,1H),3.74-3.79(m,2H),3.45(s,3H),3.36(s,1H),2.80-2.82(m,1H),1.81-1.87(m,2H). HRMS(ESI,[M+H] + ) m / z: 504.12678.

[0327] Example 52: Preparation of Compound 52 [ka] Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 23-1 to obtain compound 52. 1 H NMR(500MHz,DMSO-d6)δ 10.26(s,1H),8.80(d,J=2.3Hz,1H),8.52(s,1H),8.17(d,J=2.4Hz,1H),7.92-7.79(m,2H),7.34(d,J=8.7Hz,2H),6.63(d,J=0.8Hz ,1H),4.57(d,J=6.4Hz,2H),3.81(d,J=12.8Hz,2H),3.64(d,J=12.8Hz,2H),3.45(s,3H),3.08-2.98(m,1H),1.74(d,J=8.6Hz,1H). HRMS(ESI,[M+H] + ) m / z: 504.12424.

[0328] Example 53: Preparation of Compound 53 [ka] Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 16-1 to obtain compound 53. 1H NMR(500MHz,DMSO-d6)δ 10.24(s,1H),8.79(d,J=2.2Hz,1H),8.55(s,1H),8.19(d,J=2.2Hz,1H),7.87(d,J=9.1Hz,2H),7.34(d,J=8.8Hz,2H),6 .54(s,1H),5.54-5.17(m,1H),3.81-3.63(m,1H),3.63-3.48(m,2H),3.47(s,3H),3.45-3.40(m,1H),2.21-1.97(m,2H). HRMS(ESI,[M+H] + ) m / z: 494.1202.

[0329] Example 54: Preparation of Compound 54 [ka] Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 7-1 to obtain compound 54. 1 H NMR(500MHz,DMSO-d6)δ 10.36(s,1H),8.80(d,J=2.3Hz,1H),8.60(s,1H),8.35(d,J=2.3Hz,1H),7.87(d,J=9.0Hz, 2H),7.35(d,J=8.8Hz,2H),6.83(s,1H),3.67-3.59(m,4H),3.46(s,3H),3.40-3.33(m,4H). HRMS(ESI,[M+H] + ) m / z: 492.1249.

[0330] Example 55: Preparation of Compound 55 [ka]

[0331] Step A: Preparation of compound 55-1 Referring to the preparation method of Step A of Example 48, compound 1-1 was reacted with 2-methoxyethan-1-amine to obtain compound 55-1. MS (ESI, [MH] - ) m / z: 448.01.

[0332] Step B: Preparation of Compound 55 Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 55-1 to obtain compound 55. 1 H NMR(500MHz,DMSO-d6)δ 10.19(s,1H),8.89(s,1H),8.75(s,1H),8.64(s,1H),8.44(s,1H),7.94-7.79(m,2H),7.43 -7.29(m,2H),7.01(s,1H),3.76-3.60(m,2H),3.60-3.51(m,2H),3.48(s,3H),3.30(s,3H). HRMS(ESI,[M+H] + ) m / z: 480.12468.

[0333] Example 56: Preparation of Compound 56 [ka]

[0334] Step A: Preparation of compound 56-1 Compound 56-1 was obtained by reacting compound 1-1 with (R)-3-methylmorpholine hydrochloride according to the preparation method of step A in Example 48. MS (ESI, [M+H] + ) m / z: 476.04.

[0335] Step B: Preparation of Compound 56 Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 56-1 to obtain compound 56. 1H NMR(500MHz,DMSO-d6)δ 10.36(s,1H),8.80(d,J=2.4Hz,1H),8.59(s,1H),8.32(d,J=2.4Hz,1H),7.90-7.83(m,2H),7.35(d,J=8.6Hz,2H),6.81(s,1H),4.09(d, J=6.4Hz,1H),3.78(d,J=11.2Hz,1H),3.62-3.55(m,2H),3.50-3.42(m,4H),3.39-3.33(m,1H),3.31-3.24(m,1H),1.14(d,J=6.7Hz,3H). HRMS(ESI,[M+H] + ) m / z: 506.1398.

[0336] Example 57: Preparation of Compound 57 [ka]

[0337] Step A: Preparation of compound 57-1 Compound 57-1 was obtained by reacting compound 1-1 with (S)-3-methylmorpholine hydrochloride according to the preparation method of step A in Example 48. MS (ESI, [M+H] + ) m / z: 476.04.

[0338] Step B: Preparation of Compound 57 Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 57-1 to obtain compound 57. 1 H NMR(500MHz,DMSO-d6)δ 10.36(s,1H),8.80(d,J=2.4Hz,1H),8.59(s,1H),8.32(d,J=2.4Hz,1H),7.87(d,J=9.0Hz,2H),7.35(d,J=8.6Hz,2H),6.81(s,1H) ),4.09(d,J=6.6Hz,1H),3.78(d,J=11.1Hz,1H),3.63-3.53(m,2H),3.52-3.40(m,4H),3.31-3.24(m,2H),1.14(d,J=6.6Hz,3H). HRMS(ESI,[M+H] +) m / z: 506.1404.

[0339] Example 58: Preparation of Compound 58 [ka]

[0340] Step A: Preparation of compound 58-1 Compound 58-1 was prepared by following the procedure of Step A in Example 48 using compound 1-1 and (S)-2-methylazetidine hydrochloride. MS (ESI, [M+H] + ) m / z: 446.02.

[0341] Step B: Preparation of Compound 58 Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 58-1 to obtain compound 58. 1 H NMR(500MHz,CDCl3)δ 8.78(d,J=2.2Hz,1H),8.25-8.09(m,2H),7.97(s,1H),7.69(d,J=8.9Hz,2H),7.23(d,J=8.7Hz,2H),6.53(s,1H),4.66-4.56(m, 1H),4.16-4.02(m,1H),3.57(s,3H),3.45(dd,J=15.3,8.8Hz,1H),2.51-2.39(m,1H),2.01-1.87(m,1H),1.38(d,J=6.2Hz,3H). HRMS(ESI,[M+H] + ) m / z: 476.1314.

[0342] Example 59: Preparation of Compound 59 [ka]

[0343] Step A: Preparation of compound 59-1 Compound 59-1 was obtained by reacting compound 1-1 with tert-butyl (S)-pyrrolidin-3-ylcarbamate according to the preparation method of step A in Example 48. MS (ESI, [M+H]+ ) m / z: 561.09.

[0344] Step B: Preparation of compound 59-2 Compound 59-1 (1 g), dichloromethane (6 mL), and trifluoroacetic acid (4.00 mL) were added to a 50 mL eggplant flask in this order, and the resulting mixture was allowed to react at room temperature. When the reaction was complete, the mixture was concentrated under reduced pressure to remove the solvent. Dichloromethane (10 mL) was added to the residue, and the pH was adjusted to 8 using 1 M aqueous sodium hydroxide solution, and the organic phase was collected by separation. The aqueous phase was extracted twice with ethyl acetate (20 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give 720 mg of compound 59-2. MS (ESI, [M+H] + ) m / z: 461.04.

[0345] Step C: Preparation of compound 59-3 Compound 59-2 (0.7 g), N,N-diisopropylethylamine (0.588 g), and dichloromethane (6 mL) were added in this order to a 50 mL eggplant flask, and acetyl chloride (0.238 g) was added under nitrogen protection, and the resulting mixture was reacted at room temperature overnight. Purification was performed by silica gel column chromatography to obtain 610 mg of compound 59-3. MS (ESI, [M+H] + ) m / z: 503.05.

[0346] Step D: Preparation of Compound 59 Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 59-3 to obtain compound 59. 1 H NMR(500MHz,DMSO-d6)δ 10.22(s,1H),8.79(s,1H),8.54(s,1H),8.19(s,1H),8.07(d,J=6.0Hz,1H),7.87(d,J=8.8Hz,2H),7.34(d ,J=8.5Hz,2H),6.47(s,1H),4.20(s,1H),3.43-3.53(m,6H),3.11-3.13(m,1H),2.05(s,1H),1.78(s,4H). HRMS(ESI,[M+H]+ ) m / z: 533.15133.

[0347] Example 60: Preparation of Compound 60 [ka]

[0348] Step A: Preparation of compound 60-1 In a 50 mL reaction flask, 5-bromopyrimidin-4-one (1 g) was dissolved in tetrahydrofuran (10 mL), cooled to 0° C., and sodium hydride (0.457 g) was added in portions. Upon completion, the atmosphere was flushed with nitrogen three times. The reaction was allowed to proceed for 1 hour. In an ice bath, iodomethane (1.622 g) was added dropwise to the reaction solution using a syringe, and upon completion, the reaction was continued overnight. In an ice bath, the reaction was quenched by adding water (10 mL) dropwise, ethyl acetate (15 mL) was added, the mixture was separated, and the mixture was extracted twice with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give 0.8 g of compound 60-1. MS (ESI, [M+H] + ) m / z: 188.96.

[0349] Step B: Preparation of compound 60-2 Referring to the preparation method in Step B of Example 45, compound 60-1 was reacted with bis(pinacolato)diboron to obtain compound 60-2, which was directly used in the next step without separation and purification.

[0350] Step D: Preparation of Compound 60 Referring to the preparation method of Example 48, Step B, compound 7-1 was used to react with compound 60-2 to obtain compound 60. 1 H NMR(500MHz,DMSO-d6)δ 10.28(s,1H),8.78(s,1H),8.54(s,1H),8.15(s,1H),8.06(s,1H),7.85-7.87 (m,2H),7.34-7.35(m,2H),3.55-3.56(m,4H),3.51(s,3H),3.28-3.29(m,4H). HRMS(ESI,[M+H]+ ) m / z: 492.12730.

[0351] Example 61: Preparation of Compound 61 [ka]

[0352] Step A: Preparation of compound 61-1 Compound 61-1 was prepared by following the procedure of Step A in Example 48 using compound 1-1 and dimethylamine hydrochloride. MS (ESI, [M+H] + ) m / z: 420.00.

[0353] Step B: Preparation of Compound 61 Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 61-1 to obtain compound 61. 1 H NMR(500MHz,DMSO-d6)δ 10.25(s,1H),8.76(d,J=2.3Hz,1H),8.56(s,1H),8.27(d,J=2.3Hz,1H),7.87( d,J=9.0Hz,2H),7.34(d,J=8.8Hz,2H),6.56(s,1H),3.46(s,3H),2.94(s,6H). HRMS(ESI,[M+H] + ) m / z: 450.1141.

[0354] Example 62: Preparation of Compound 62 [ka]

[0355] Step A: Preparation of compound 62-1 Compound 62-1 was prepared by following the procedure of Step A in Example 48 using compound 1-1 and methylamine hydrochloride. MS (ESI, [M+H] + ) m / z: 406.04.

[0356] Step B: Preparation of compound 62-2 In a 15 mL waveguide, 1,4-dioxane (4 mL), compound 62-1 (240 mg), bis(neopentylglycolato)diboron (200 mg), potassium acetate (174 mg), and bis(triphenylphosphine)palladium(II) dichloride (41.5 mg) were added in this order, and upon completion, the reaction was carried out in a microwave reactor at 120° C. for 1 hour under nitrogen protection, and the reaction was stopped and cooled to room temperature. The reaction was used in the next step without separation or purification.

[0357] Step C: Preparation of Compound 62 Compound 45-1 (145 mg), anhydrous potassium carbonate (245 mg), tetrakis(triphenylphosphine)palladium(0) (68 mg), and water (1 mL) were added to the reaction solution obtained in step B above in this order, and when complete, the reaction solution was sealed and placed in a microwave reactor after protecting with nitrogen, and the microwave reaction conditions were 140° C. and 1.5 hours. The filtrate was washed with ethyl acetate (50 mL) and saturated saline (25 mL), and then separated. The organic phase was collected and purified by silica gel column chromatography to obtain 60 mg of compound 62. 1 H NMR(500MHz,DMSO-d6)δ 10.18(s,1H),8.77(d,J=2.2Hz,1H),8.61(s,1H),8.52-8.48(m,1H),8.39(d,J=2.2Hz,1H),7 .86(d,J=9.1Hz,2H),7.35(d,J=8.9Hz,2H),6.96(s,1H),3.48(s,3H),2.99(d,J=4.7Hz,3H). HRMS(ESI,[M+H] + ) m / z: 436.1336.

[0358] Example 63: Preparation of Compound 63 [ka]

[0359] Step A: Preparation of compound 63-1 Compound 63-1 was prepared using compound 2-1 and bis(neopentylglycolato)diboron according to the method of step B of Example 62. The reaction solution was used in the next step without any further treatment.

[0360] Step B: Preparation of Compound 63 Compound 63 was prepared by following the procedure of Step C of Example 62 using compound 63-1 and compound 45-1. 1 H NMR(500MHz,DMSO-d6)δ 10.21(s,1H),8.77(d,J=2.4Hz,1H),8.54(s,1H),8.17(d,J=2.4Hz,1H),7.89-7.83(m,2H),7.38-7.30(m,2H),6.49(d,J=0.9Hz,1 H),4.00-3.94(m,1H),3.55-3.44(m,5H),3.37-3.33(m,1H),3.27(d,J=12.2Hz,1H),3.20(s,3H),1.99(s,1H),1.94-1.86(m,1H). HRMS(ESI,[M+H] + ) m / z: 506.1471.

[0361] Example 64: Preparation of Compound 64 [ka]

[0362] Step A: Preparation of compound 64-1 In a 35 mL waveguide, 1,4-dioxane (15 mL), compound 1-1 (400 mg), bis(pinacolato)diboron (370 mg), potassium acetate (191 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (79 mg) were added in this order, and upon completion, the reaction was carried out in a microwave reactor at 140°C for 1.5 hours under nitrogen protection, and the reaction was stopped and cooled to room temperature. The reaction was used in the next step without separation or purification.

[0363] Step B: Preparation of compound 64-2 Compound 45-1 (150 mg), anhydrous potassium carbonate (90 mg), tetrakis(triphenylphosphine)palladium(0) (57 mg), and water (2 mL) were added to the reaction solution obtained in step A above in that order, and upon completion, the reaction was carried out at 70° C. for 5 hours under nitrogen protection. The reaction solution was washed with ethyl acetate (50 mL) and saturated saline (25 mL), and then separated. The organic phase was collected and purified by silica gel column chromatography to obtain 150 mg of compound 64-2. MS (ESI, [M+H] + ) m / z: 441.02.

[0364] Step C: Preparation of Compound 64 Compound 64-2 (100 mg), 4,4-difluoropiperidine (30 mg), N,N-diisopropylethylamine (64 mg), and N-methylpyrrolidone (10 mL) were added to a 35 mL waveguide in this order, and reacted for 2 hours under microwaves at 180° C. The reaction solution was washed with ethyl acetate (50 mL) and saturated saline (25 mL), and then separated. The organic phase was recovered and purified by silica gel column chromatography to obtain 75 mg of compound 64. 1 H NMR(500MHz,DMSO-d6)δ 10.38(s,1H),8.81(d,J=2.4Hz,1H),8.62(s,1H),8.37(d,J=2.4Hz,1H),7.91-7.84(m,2 H),7.36(d,J=8.7Hz,2H),6.85(s,1H),3.53-3.43(m,7H),2.03(td,J=13.6,6.4Hz,4H). HRMS(ESI,[M+H] + ) m / z: 526.1279.

[0365] Example 65: Preparation of Compound 65 [ka] Compound 65 was prepared using compound 64-2 and R-prolinol according to the method of Example 64, Step C. 1H NMR (500MHz, DMSO-d6) δ 10.26(s,1H),8.77(d,J=2.4Hz,1H),8.55(s,1H),8.27(d,J=2.4Hz,1H),7.91 -7.83(m,2H),7.34(d,J=8.8Hz,2H),6.42(d,J=0.8Hz,1H),4.74(t,J=5.5Hz,1 H),4.47-4.39(m,1H),3.69-3.62(m,1H),3.61-3.51(m,1H),3.30-3.21(m,1H ),2.85-2.74(m,1H),2.03-1.95(m,1H),1.94-1.84(m,2H),1.71-1.55(m,1H). HRMS (ESI, [M+H] + ) m / z: 506.1407.

[0366] Example 66: Preparation of Compound 66 [ka] Compound 64-2 (100 mg), imidazole (30.9 mg), potassium tert-butoxide (76 mg) and dimethyl sulfoxide (4 mL) were added to a 15 mL waveguide. The reaction was carried out under nitrogen protection and microwaves at 120° C. for 15 minutes. The reaction system was washed with ethyl acetate (50 mL) and saturated saline (25 mL), and then separated. The organic phase was collected and purified by silica gel column chromatography to obtain 50 mg of compound 64-2. Item 66 was obtained. 1 H NMR(500MHz,DMSO-d6)δ 10.75(s,1H),9.14(s,1H),8.66(s,1H),8.53(s,1H),7.96(s,1H),7.91(d,J =9.1Hz,2H),7.42(d,J=21.3Hz,3H),7.05(s,1H),6.56(s,1H),3.45(s,3H). HRMS(ESI,[M+H] + ) m / z: 473.09304.

[0367] Example 67: Preparation of Compound 67 [ka] Following the procedure of Step C of Example 64, compound 67 was prepared using compound 64-2 and thiomorpholine. 1 H NMR(500MHz,DMSO-d6)δ 10.37(s,1H),8.80(d,J=2.3Hz,1H),8.61(s,1H),8.34(d,J=2.3Hz,1H),7.87(d,J=9.1Hz, 2H),7.35(d,J=8.9Hz,2H),6.80(s,1H),3.68-3.57(m,4H),3.46(s,3H),2.69-2.59(m,4H). HRMS(ESI,[M+H] + ) m / z: 508.1188.

[0368] Example 68: Preparation of Compound 68 [ka] Compound 64-2 (150 mg), dioxane (10 mL), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (97 mg), anhydrous potassium carbonate (94 mg), tetrakis(triphenylphosphine)palladium(0) (59 mg), and water (1 mL) were added in this order to a 35 mL waveguide. Upon completion, the mixture was protected with nitrogen and then placed in a microwave reactor. The microwave reaction conditions were 140° C. and 1.5 hours. The reaction solution was washed with ethyl acetate (50 mL) and saturated saline (25 mL), then separated, and the organic phase was collected and purified by silica gel column chromatography to obtain 100 mg of compound 68. 1H NMR(500MHz,DMSO-d6)δ10.58(s,1H),9.12(d,J=2.2Hz,1H),8.57(s,1H),8.25(d,J=2.2Hz,1H),7.97(s,1H),7.93-7.86(m,2H),7.60 (s,1H),7.38(d,J=9.0Hz,2H),6.64(s,1H),4.90(t,J=5.2Hz,1H),4.15(t,J=5.6Hz,2H),3.72(q,J=5.5Hz,2H),3.51(d,J=7.6Hz,3H). HRMS(ESI,[M+H] + ) m / z: 517.1368.

[0369] Example 69: Preparation of Compound 69 [ka]

[0370] Step A: Preparation of compound 69-1 Compound 64-2 was reacted with 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinacol ester according to the preparation method of Example 68 to obtain compound 69-1. MS (ESI, [MH] - ) m / z: 555.14.

[0371] Step B: Preparation of Compound 69 Compound 69-1 (330 mg) and dichloromethane (10 mL) were added in this order to a 25 mL eggplant flask, trifluoroacetic acid (3 mL) was slowly added dropwise to the flask, and upon completion, the reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was concentrated to remove the solvent, and dichloromethane (10 mL) was added to redissolve the product, and the product was purified by silica gel column chromatography to obtain 30 mg of compound 69. 1H NMR(500MHz,DMSO-d6)δ 13.05(s,1H),10.68(s,1H),9.19(d,J=2.1Hz,1H),8.52(s,1H),8.36(d,J=2.1Hz,1H),7.9 1(d,J=9.1Hz,2H),7.70(s,1H),7.39(d,J=8.9Hz,2H),6.58(d,J=76.3Hz,2H),3.46(s,3H). HRMS(ESI,[M+H] + ) m / z: 473.09353.

[0372] Example 70: Preparation of Compound 70 [ka]

[0373] Step A: Preparation of compound 70-1 Compound 70-1 was obtained by reacting compound 1-1 with ethylene glycol monomethyl ether according to the preparation method of step A in Example 48. MS (ESI, [M+H] + ) m / z: 450.98.

[0374] Step B: Preparation of Compound 70 Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 70-1 to obtain compound 70. 1 H NMR(500MHz,DMSO-d6)δ 10.59(s,1H),8.96(d,J=2.5Hz,1H),8.85(d,J=2.5Hz,1H),8.61(s,1H),7.89(d,J=9.1Hz,2H),7. 37(d,J=9.0Hz,2H),7.27(s,1H),4.66-4.61(m,2H),3.80-3.73(m,2H),3.46(s,3H),3.34(s,3H). HRMS(ESI,[ M+H] + ) m / z: 481.10819.

[0375] Example 71: Preparation of Compound 71 [ka]

[0376] Step A: Preparation of compound 71-1 Compound 1-1 (0.6 g), potassium hydroxide (245 mg), and methanol (20 mL) were added in this order to a 50 mL reaction flask, and the atmosphere was replaced with nitrogen three times before reacting at 60°C under microwaves for 6 hours. The reaction solution was concentrated, and ethyl acetate (60 mL) was added for extraction. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (40 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and 0.5 g of compound 71-1 was obtained by silica gel column chromatography. MS (ESI, [M+H] + ) m / z: 406.9.

[0377] Step B: Preparation of Compound 71 Referring to the preparation method of Example 48, Step B, compound 1-4 was used to react with compound 25-1 to obtain compound 71. 1 H NMR(500MHz,DMSO-d6)δ 10.60(s,1H),8.93(d,J=2.3Hz,1H),8.88(d,J=2.4Hz,1H),8.61(s,1H),7.90( d,J=9.0Hz,2H),7.38(d,J=8.8Hz,2H),7.17(s,1H),4.09(s,3H),3.46(s,3H). HRMS(ESI,[M+H] + ) m / z: 437.08180.

[0378] Example 72: Preparation of Compound 72 [ka]

[0379] Step A: Preparation of compound 72-1 Referring to the preparation method of Step A of Example 48, compound 1-1 was reacted with 3,3-difluoroazetidine hydrochloride to obtain compound 72-1. MS (ESI, [M+H] + ) m / z: 467.91.

[0380] Step B: Preparation of compound 72-2 Referring to the preparation method of step B of Example 62, compound 72-1 was used to react with bis(neopentylglycolato)diboron to obtain the reaction solution of compound 72-2, which was used in the next step without purification.

[0381] Step C: Preparation of Compound 72 Referring to the preparation method in Step C of Example 62, the reaction mixture of compound 72-2 obtained in Step B above was reacted with compound 45-1 to obtain compound 72. 1 H NMR(500MHz,DMSO-d6)δ 10.36(s,1H),8.84(s,1H),8.57(s,1H),8.28(s,1H),7.87(d,J=8.7Hz,2H ),7.36(d,J=8.4Hz,2H),6.61(s,1H),4.35(t,J=12.4Hz,4H),3.47(s,3H). HRMS(ESI,[M+H] + ) m / z: 498.0951.

[0382] Example 73: Preparation of Compound 73 [ka] Compound 64-2 (330 mg), 1,4-dioxane (20 mL), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (171 mg), potassium carbonate (310 mg), deionized water (2 mL), and bis(triphenylphosphine)palladium(II) dichloride (53 mg) were added in this order to a 50 mL eggplant flask, and the mixture was replaced with nitrogen three times. The reaction solution was placed in an oil bath tank and heated to 100 ° C. for 8 hours. When the temperature dropped to room temperature, the reaction solution was filtered, the mother liquor was collected, and the reaction solution was concentrated under reduced pressure to obtain a brown residue. Ethyl acetate (50 mL) and water (30 mL) were added, stirred and washed, and then separated. The organic phase was obtained, and a saturated aqueous sodium chloride solution (30 mL) was added, stirred and washed, and then separated. The mixture was purified by silica gel column chromatography to obtain a total of 43 mg of compound 73. 1 H NMR(500MHz,DMSO-d6)δ 10.78(s,1H),9.27(d,J=2.1Hz,1H),8.55(d,J=2.1Hz,1H),8.52(s,1H),7.92(d,J=9.0H) z,2H),7.45-7.37(m,3H),6.46(s,1H),6.19(d,J=1.8Hz,1H),3.86(s,3H),3.42(s,3H). HRMS(ESI,[M+H] + ) m / z: 487.10835.

[0383] Example 74: Preparation of Compound 74 [ka] Compound 64-2 (250 mg), N,N-dimethylformamide (10 mL), 1-methyl-5-(tri-n-butyltin)imidazole (275 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (45 mg) were added in this order to a 30 mL sealed tube, and after sealing, the sealed tube was placed in a microwave reactor and reacted at 135°C for 2 hours. When the temperature was lowered to room temperature, the reaction solution was filtered to recover the mother liquor, and the reaction solution was reduced. The mixture was concentrated under reduced pressure to give a brown residue, to which ethyl acetate (50 mL) and water (30 mL) were added, which were stirred and washed, and then separated. The organic phase was added with a saturated aqueous sodium chloride solution (30 mL), which was stirred and washed, and then separated. The organic phase was purified by silica gel column chromatography to give a total of 160 mg of compound 74. 1 H NMR(500MHz,DMSO-d6)δ 10.70(s,1H),9.23(d,J=2.2Hz,1H),8.54(s,1H),8.45(d,J=2.2Hz,1H),7.91(d,J=9.1Hz,2 H),7.79(s,1H),7.39(d,J=8.9Hz,2H),6.84(s,1H),6.54(s,1H),3.79(s,3H),3.45(s,3H). HRMS(ESI,[M+H] + ) m / z: 487.1080.

[0384] Example 75: Preparation of Compound 75 [ka] In a 35 mL waveguide, compound 64-2 (400 mg), cesium carbonate (591 mg), N,N-dimethyl-1-(trifluoro-λ 4 -boranyl)methylamine potassium salt (194 mg), (2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (76 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (85 mg), dioxane (10 mL), and water (1 mL) were added in this order. Upon completion, the reaction was purged with nitrogen for 30 seconds. The reaction was placed in a microwave reactor and the microwave conditions were 120°C, 90 minutes. The reaction was complete. It was filtered through diatomaceous earth and purified by silica gel column chromatography to give 50 mg of compound 75. 1H NMR(500MHz,DMSO-d6)δ 10.68(s,1H),9.09(d,J=2.0Hz,1H),8.61(s,1H),8.42(d,J=2.0Hz,1H),7.90(d,J=9 .0Hz,2H),7.39(d,J=8.8Hz,2H),6.98(s,1H),3.77(s,2H),3.49(s,3H),2.13(s,6H). HRMS(ESI,[M+H] + ) m / z: 464.1294.

[0385] Example 76: Preparation of Compound 76 [ka]

[0386] Step A: Preparation of compound 76-1 Compound 76-1 was prepared by following the procedure of Step A in Example 48 using compound 1-1 and 2-methylazetidine hydrochloride. MS (ESI, [M+H] + ) m / z: 446.02.

[0387] Step B: Preparation of compound 76-2 Referring to the preparation method of Step B of Example 48, compound 45-2 was used to react with compound 76-1 to obtain compound 76-2. MS (ESI, [M+H] + ) m / z: 476.15.

[0388] Step C: Preparation of Compound 76 Compound 76-2 was subjected to chiral resolution using a YMC high pressure preparative chromatograph (CHIRALART Cellulose-SC column, flow rate was 40 mL / min, mobile phase was (ethanol: n-hexane = 2:3)), and finally compound 76 was obtained. 1H NMR(500MHz,DMSO-d6)δ 10.28(s,1H),8.80(d,J=2.3Hz,1H),8.57(s,1H),8.23(d,J=2.3Hz,1H),7.87(d,J=9.1Hz,2H),7.34(d,J=8.9Hz,2H),6.47(s,1H), 4.57-4.44(m,1H),4.01-3.87(m,1H),3.50-3.47(m,1H),3.46(s,3H),2.45-2.36(m,1H),1.93-1.84(m,1H),1.34(d,J=6.2Hz,3H). HRMS(ESI,[M+H] + ) m / z: 476.13008.

[0389] Example 77: Preparation of Compound 77 [ka] Compound 64-2 (150 mg), dimethyl sulfoxide (5 mL), potassium tert-butoxide (114 mg), and pyrazole (35 mg) were added in this order to a 10 mL waveguide. Upon completion, the reaction was carried out in a microwave reactor at 120° C. for 30 minutes under nitrogen protection. The reaction solution was washed with ethyl acetate (50 mL) and saturated saline solution (25 mL), then separated. The organic phase was collected and purified by silica gel column chromatography to obtain 70 mg of compound 77. 1 H NMR(500MHz,DMSO-d6)δ 10.73(s,1H),9.10(d,J=2.2Hz,1H),8.61(d,J=2.2Hz,1H),8.51-8.43(m,2H),7.96-7.88(m,2 H),7.69(d,J=1.0Hz,1H),7.41(d,J=8.9Hz,2H),6.59-6.50(m,1H),6.39(s,1H),3.44(s,3H). HRMS(ESI,[M+H] + ) m / z: 473.09397.

[0390] Example 78: Preparation of Compound 78 [ka]

[0391] Step A: Preparation of compound 78-1 Referring to the preparation method of Step A of Example 45, 6-bromopyrimidin-4(3H)-one was reacted with 4-iodomethyltetrahydropyran to obtain compound 78-1. MS (ESI, [M+H] + ) m / z: 273.04.

[0392] Step B: Preparation of compound 78-2 Referring to the preparation method of step B of Example 62, compound 61-1 was reacted with bis(neopentylglycolato)diboron to obtain the reaction solution of compound 78-2, which was used in the next step without purification.

[0393] Step C: Preparation of Compound 78 Referring to the preparation method in Step C of Example 62, the reaction mixture of compound 78-2 obtained in Step B above was reacted with compound 78-1 obtained in Step A to obtain compound 78. 1 H NMR(500MHz,DMSO-d6)δ 10.27(s,1H),8.81(d,J=30.3Hz,2H),8.31(s,1H),7.87(d,J=8.0Hz,2H),7.35(d,J=7.5Hz,2H),7.11(s,1H),4. 27(d,J=5.5Hz,2H),3.88(d,J=8.6Hz,2H),2.87(s,6H),2.06(s,1H),1.67(d,J=11.7Hz,2H),1.46-1.23(m,2H). HRMS(ESI,[M+H] + ) m / z: 534.17145.

[0394] Example 79: Preparation of Compound 79 [ka] Following the procedure of Step C of Example 64, compound 79 was prepared using compound 64-2 and (3R,4R)-3,4-difluoropyrrolidine hydrochloride. 1 H NMR(500MHz,DMSO-d6)δ 10.29(s,1H),8.81(d,J=2.1Hz,1H),8.57(s,1H),8.22(d,J=2.1Hz,1H),7.87(d,J=9.0Hz,2H),7.35(d,J=8.8Hz,2H),6.63(s ,1H),5.51-5.39(m,1H),5.38-5.27(m,1H),3.96-3.84(m,1H),3.83-3.73(m,1H),3.61(dd,J=26.2,14.1Hz,2H),3.47(s,3H). HRMS(ESI,[M+H] + ) m / z: 512.11122.

[0395] Example 80: Preparation of Compound 80 [ka]

[0396] Step A: Preparation of Compound 80-1 Compound 1-1 and isoxazolidine hydrochloride were prepared by referring to the method of Step A of Example 48. was used to prepare compound 80-1.

[0397] Step B: Preparation of Compound 80 Referring to the preparation method of Example 48, Step B, compound 45-2 was used to react with compound 80-1 to obtain compound 80. 1 H NMR(500MHz,DMSO-d6)δ 10.49(s,1H),8.85(s,1H),8.55(s,1H),8.35(s,1H),7.88(d,J=8.9Hz,2H),7.37(d,J=8.6 Hz,2H),6.67(s,1H),3.80-3.83(m,2H),3.68-3.70(m,2H),3.47(s,3H),2.13-2.18(m,2H). HRMS(ESI,[M+H] + ) m / z: 478.10924.

[0398] Example 81: Preparation of Compound 81 [ka] Compound 64-2 (150 mg), 1,4-dioxane (4 mL), and dimethylhydroxyamine hydrochloride (663 mg) were added in this order to a 10 mL waveguide. After purging the liquid surface with nitrogen for a while, the tube was sealed with a cap and reacted under microwave at 140° C. for 6 hours. Compound 81 was obtained by purging the mixture with a silica gel column. 1 H NMR(500MHz,DMSO-d6)δ 10.45(s,1H),8.85(s,1H),8.55(s,1H),8.16(s,1H),7.87(d,J=9.0Hz,2H) ,7.36(d,J=8.8Hz,2H),6.52(s,1H),3.47(s,3H),3.35(s,3H),3.19(s,3H). HRMS(ESI,[M+H] + ) m / z: 466.1083.

[0399] Example 82: Preparation of Compound 82 [ka]

[0400] Step A: Preparation of Compound 82-1 Add N,N-dimethylformamide (10mL), 5-bromopyrazin-2(1H)-one (500mg), and cesium carbonate (1369mg) in this order to a 50mL one-neck flask, and when complete, start stirring, slowly add iodomethane (419mg / 2mL) diluted with N,N-dimethylformamide to the system at room temperature, and when complete, react at room temperature for 4 hours, add purified water (10mL) and ethyl acetate (30mL) to the system, stir and wash, then separate, then add ethyl acetate (20mL) to the aqueous phase and extract once, combine the organic phase, stir and wash twice with purified water (20mL) and then saturated saline solution (20mL), separate to obtain the organic phase, and concentrate under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography to obtain 120mg of compound 82-1. MS (ESI, [M+H] + ) m / z: 188.97.

[0401] Step B: Preparation of Compound 82-2 Referring to the method of Step D in Example 1, compound 82-1 was reacted with bis(pinacolato)diboron to produce a reaction solution containing compound 82-2, which was cooled to room temperature and used in the subsequent reaction without separation and purification.

[0402] Step C: Preparation of Compound 82 Referring to the method of Example 48, Step B, compound 7-1 was used to react with compound 82-2 to obtain compound 82. 1 H NMR(500MHz,DMSO-d6)δ 10.39(s,1H),8.77(d,J=2.3Hz,1H),8.25(d,J=2.4Hz,1H),8.22(d,J=1.1Hz,1H),8.14(d,J=1.1Hz, 1H),7.92-7.83(m,2H),7.41-7.29(m,2H),3.64(t,J=4.5Hz,4H),3.53(s,3H),3.27(t,J=4.6Hz,4H). HRMS(ESI,[M+H] + ) m / z: 492.12502.

[0403] Example 83: Preparation of Compound 83 [ka] Referring to the method of Example 48, Step B, compound 23-1 was used to react with compound 47-5 to obtain compound 83. 1H NMR(500MHz,DMSO-d6)δ 10.25(s,1H),8.83(d,J=2.3Hz,1H),8.16(d,J=2.4Hz,1H),8.09(d,J=2.1Hz,1H),7.89-7.82(m,2H),7.40-7.30(m,2H),7.05(d,J= 2.2Hz,1H),4.57(d,J=6.3Hz,2H),3.78(d,J=12.7Hz,2H),3.70(s,3H),3.64-3.56(m,2H),3.08-2.99(m,1H),1.78(d,J=8.7Hz,1H). HRMS(ESI,[M+H] + ) m / z: 504.12506.

[0404] Example 84: Preparation of Compound 84 [ka]

[0405] Step A: Preparation of Compound 84-1 Referring to the preparation method of step D of Example 1, 5-bromo-1-methylpyridin-2(1H)-one was reacted with bis(pinacolato)diboron to obtain the reaction solution of compound 84-1, which was directly used in the next step reaction without separation and purification.

[0406] Step B: Preparation of Compound 84 Referring to the preparation method of Step B of Example 48, the reaction solution of compound 84-1 was used to react with compound 7-1 to obtain compound 84. 1 H NMR(500MHz,DMSO-d6)δ 10.36(s,1H),8.75(s,1H),8.06(d,J=14.7Hz,2H),7.88(d,J=8.6Hz,2H),7.79(d,J=8.8Hz ,1H),7.36(d,J=8.4Hz,2H),6.50(d,J=9.4Hz,1H),3.63(s,4H),3.51(s,3H),3.21(s,4H). HRMS(ESI,[M+H] + ) m / z: 491.1295.

[0407] Example 85: Preparation of Compound 85 [ka]

[0408] Step A: Preparation of Compound 85-1 Following the procedure of Step A of Example 82, 6-bromopyridazin-3(2H)-one was used to react with iodomethane to give compound 85-1. MS (ESI, [M+H] + ) m / z: 189.0.

[0409] Step B: Preparation of compound 85-2 Referring to the preparation method in Step D of Example 1, compound 85-1 was reacted with bis(pinacolato)diboron to obtain a reaction solution of compound 85-2, which was used in the next step without separation and purification.

[0410] Step C: Preparation of Compound 85 Referring to the preparation method of Step B of Example 48, the reaction solution of compound 85-2 was reacted with compound 7-1 to obtain compound 85. 1 H NMR(500MHz,DMSO-d6)δ 10.43(s,1H),8.86(d,J=2.4Hz,1H),8.25(d,J=2.4Hz,1H),7.91-7.84(m,3H),7.42-7 .32(m,2H),7.05(d,J=9.6Hz,1H),3.75(s,3H),3.67-3.60(m,4H),3.26-3.20(m,4H). HRMS(ESI,[M+H] + ) m / z: 492.12480.

[0411] Example 86: Preparation of Compound 86 [ka]

[0412] Step A: Preparation of compound 86-1 Refer to the method in Example 1, Step C, using 3-bromopyridin-2(1H)-one and reacted with iodomethane to give compound 86-1. 1 H NMR(500MHz,DMSO-d6)δ 7.90(dd,J=7.3,1.8Hz,1H),7.77(dd,J=6.7,1.8Hz,1H),6.17(t,J=7.0Hz,1H),3.50(s,3H). MS(ESI,[M+H] + ) m / z: 187.99.

[0413] Step B: Preparation of compound 86-2 Referring to the preparation method in Step D of Example 1, compound 86-1 was reacted with bis(pinacolato)diboron to obtain a reaction solution containing compound 86-2, which was used in the preparation of the next step without purification.

[0414] Step C: Preparation of Compound 86 Referring to the preparation method in Step B of Example 48, the reaction solution containing compound 86-2 was reacted with compound 7-1 to obtain compound 86. 1 H NMR(500MHz,DMSO-d6)δ 10.28(s,1H),8.74(d,J=2.2Hz,1H),8.05(d,J=2.2Hz,1H),7.87(d,J=9.0Hz,2H),7.79(dd,J=6.7,1.7Hz,1H),7.63(d d,J=6.9,1.7Hz,1H),7.34(d,J=8.8Hz,2H),6.35(t,J=6.8Hz,1H),3.59-3.54(m,4H),3.53(s,3H),3.29-3.23(m,4H). HRMS(ESI,[M+H] + ) m / z: 491.1307.

[0415] Example 87: Preparation of Compound 87 [ka]

[0416] Step A: Preparation of compound 87-1 Referring to the preparation method in Step A of Example 1, 5-bromonicotinic acid was used to react with 4-(chlorodifluoromethoxy)aniline to obtain compound 87-1. MS (ESI, [M+H] + ) m / z: 377.0.

[0417] Step B: Preparation of compound 87-2 Referring to the preparation method in Step E of Example 1, compound 87-1 was used to react with compound 1-4 to obtain compound 87-2. MS (ESI, [M+H] + ) m / z: 406.17.

[0418] Step C: Preparation of Compound 87 Compound 87-2 (100 mg), benzoyl peroxide (103 mg), trifluoroacetic acid (36 mg), and dioxane (8 mL) were added to the waveguide in this order, and when the reaction was completed, the tube was sealed after being protected with nitrogen and placed in a microwave reactor. The microwave reaction conditions were 100° C. and 2 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was collected, and the filtrate was washed with ethyl acetate (50 mL) and saturated saline solution (25 mL), and then separated. The organic phase was collected and purified by silica gel column chromatography to obtain 26 mg of compound 87. 1 H NMR(500MHz,DMSO-d6)δ 10.69(s,1H),9.16(s,1H),8.70(s,1H),8.26(s,1H),7.90(d,J=8.3Hz,2H),7.81(d,J=6.6Hz,1H),7.36(d,J=8.1Hz,2H),6.20(d,J=6.6H) z,1H),4.60(d,J=9.3Hz,1H),3.97-3.82(m,1H),3.76-3.63(m,1H),3.56-3.53(m,1H),3.50(s,3H),3.47-3.40(m,1H),3.37-3.20(m,2H). HRMS(ESI,[M+H] + ) m / z: 492.11330.

[0419] Example 88: Preparation of Compound 88 [ka]

[0420] Step A: Preparation of compound 88-1 Referring to the preparation method of Step B of Example 64, compound 64-1 was used to react with compound 47-4 to obtain compound 88-1. MS (ESI, [M+H] + ) m / z: 441.05.

[0421] Step B: Preparation of Compound 88 Compound 88 was prepared by following the procedure of Step C of Example 64 using compound 88-1 and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride. 1 H NMR(500MHz,DMSO-d6)δ 10.24(s,1H),8.79(d,J=1.9Hz,1H),8.17(d,J=1.9Hz,1H),8.07-7.99(m,1H),7.86(d,J=9.0Hz,2H),7.35(d,J=8.7Hz,2H),6.98(s,1H),4. 95(s,1H),4.55(s,1H),3.79(s,2H),3.70(s,3H),3.23(d,J=9.6Hz,1H),2.81(d,J=9.9Hz,1H),1.90(d,J=8.8Hz,1H),1.82(d,J=9.8Hz,1H). HRMS(ESI,[M+H] + ) m / z: 504.12449.

[0422] Example 89: Preparation of Compound 89 [ka] Compound 89 was prepared by following the procedure of Step C of Example 64 and using compound 88-1 and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. 1H NMR(500MHz,DMSO-d6)δ 10.32(s,1H),8.81(d,J=2.2Hz,1H),8.20(dd,J=10.7,2.1Hz,2H),7.86(d,J=9.0Hz,2H),7.36(d,J=8.8 Hz,2H),7.18(d,J=2.0Hz,1H),4.15(s,2H),3.69(s,3H),3.66(d,J=10.7Hz,2H),3.50(d,J=10.4Hz,2H), 1.89-1.82(m,2H),1.79(dd,J=13.8,8.8Hz,2H).HRMS(ESI,[M+H] + ) m / z: 518.14261.

[0423] Example 90: Preparation of Compound 90 [ka] Compound 88-1 (200 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (113 mg), potassium carbonate (63 mg), tetrakis(triphenylphosphine)palladium(0) (20 mL), and dioxane (15 mL) were added in this order to a 35 mL waveguide, and when complete, the tube was sealed and placed in a microwave reactor after protection with nitrogen, and the microwave reaction conditions were 140 ° C. and 2 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was collected, and the filtrate was washed with ethyl acetate (50 mL) and saturated saline solution (25 mL), and then separated, and the organic phase was collected and purified by silica gel column chromatography to obtain 100 mg of compound 90. 1 H NMR(500MHz,CDCl3)δ 9.06(s,1H),8.41(s,1H),8.19(s,1H),8.12(s,1H),7.80(s,1H),7.71(d,J=8.7H z,2H),7.40(s,1H),7.26(d,J=6.6Hz,2H),6.58(s,1H),3.88(s,3H),3.57(s,3H). HRMS (ESI, [M+H] + ) m / z: 487.10909.

[0424] Example 91: Preparation of Compound 91 [ka] Compound 91 was prepared by following the procedure of Step C of Example 64 and using compound 88-1 and 8-oxo-3-azabicyclo[3.2.1]octane hydrochloride. 1 H NMR(500MHz,DMSO-d6)δ 10.31(s,1H),8.82(d,J=2.2Hz,1H),8.20(d,J=2.2Hz,1H),8.09(d,J=2.0Hz,1H),7.86(d,J=9.0Hz,2H),7.36(d,J=8. 8Hz,2H),7.11(d,J=2.0Hz,1H),4.30(s,2H),3.71(s,3H),3.45(d,J=12.4Hz,2H),3.08(d,J=11.6Hz,2H),1.74(s,4H). HRMS(ESI,[M+H] + ) m / z: 518.1404.

[0425] Example 92: Preparation of Compound 92 [ka] Referring to the preparation method of Example 48, Step B, compound 20-1 was used to react with compound 36-5 to obtain compound 92. 1 H NMR(500MHz,DMSO-d6)δ 10.26(s,1H),8.72(d,J=2.3Hz,1H),7.95(d,J=2.3Hz,1H),7.90-7.82(m,2H),7.66(s,1H),7.39-7.26(m,2H),4.69(s,2) H),4.21-4.14(m,2H),4.13-4.06(m,2H),4.03-3.85(m,4H),3.61-3.51(m,2H),2.70-2.60(m,1H),1.70(d,J=8.1Hz,1H). HRMS(ESI,[M+H] + ) m / z:518.14062.

[0426] Example 93: Preparation of Compound 93 [ka]

[0427] Step A: Preparation of Compound 93 Referring to the preparation method of Example 48, Step B, compound 56-1 was used to react with compound 36-5 to obtain compound 93. 1 H NMR(500MHz,DMSO-d6)δ 10.35(s,1H),8.74(d,J=2.3Hz,1H),7.97(d,J=2.3Hz,1H),7.87(d,J=9.1Hz,2H),7.79(s, 1H),7.35(d,J=8.9Hz,2H),5.01(d,J=15.1Hz,1H),4.68(d,J=15.1Hz,1H),4.23-4.06(m,4H ),3.77-3.64(m,2H),3.62(dd,J=11.2,2.8Hz,1H),3.58-3.50(m,1H),3.46(dd,J=11.3,3. 4Hz,1H),3.21(ddd,J=12.7,9.6,3.0Hz,1H),3.10(d,J=13.4Hz,1H),0.99(d,J=6.5Hz,3H). HRMS(ESI,[M+H] + ) m / z: 520.15643.

[0428] Example 94: Preparation of Compound 94 [ka]

[0429] Step A: Preparation of Compound 94-1 In a 100 mL one-neck flask, 2-isocyanoethyl acetate (1 g), anhydrous dioxane (10 mL), N-Boc-3-butyn-1-amine (2.24 g), and silver carbonate (0.25 g) were added in this order, and the mixture was protected with nitrogen and heated to 80° C. in an oil bath to react overnight. When the reaction was completed, the reaction solution was washed with ethyl acetate (50 mL) and saturated saline solution (25 mL), and then separated. The organic phase was recovered and purified by silica gel column chromatography to obtain 1 g of compound 94-1. MS (ESI, [M+Na] + ) m / z: 305.14.

[0430] Step B: Preparation of Compound 94-2 Compound 94-1 (1.2 g), methanol (10 mL), and 2M lithium hydroxide aqueous solution (5 mL) were added in this order to a 50 mL one-neck flask, and the mixture was reacted overnight in an oil bath at 50 ° C. When the reaction was complete, the pH was adjusted to 3-4 using 2M dilute hydrochloric acid, and the reaction solution was washed with ethyl acetate (50 mL) and saturated saline solution (25 mL), and then separated. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.6 g of compound 94-2. MS (ESI, [MH] - ) m / z: 253.13.

[0431] Step C: Preparation of compound 94-3 In a 50 mL one-neck flask, compound 94-2 (0.47 g), dichloromethane (10 mL) were added in that order, and thionyl chloride (0.27 g) was slowly added dropwise, and upon completion, the mixture was stirred at room temperature for 2 hours. Upon complete reaction, the pH was adjusted to alkaline using saturated aqueous sodium carbonate solution, and extracted five times with ethyl acetate (100 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.25 g of compound 94-3. MS (ESI, [M+H] + ) m / z: 137.1.

[0432] Step D: Preparation of compound 94-4 Compound 94-3 (0.22 g), dichloromethane (10 mL), triethylamine (0.33 g), di-tert-butyl dicarbonate (0.36 g), and 4-dimethylaminopyridine (10 mg) were added in this order to a 100 mL one-neck flask, and the mixture was stirred at room temperature for 2 hours under nitrogen protection. When the reaction was completed, the reaction solution was washed with ethyl acetate (50 mL) and saturated saline solution (25 mL), and then separated. The organic phase was collected and purified by silica gel column chromatography to obtain 0.13 g of compound 94-4. MS (ESI, [M+HC(CH3)3] + ) m / z: 181.10.

[0433] Step E: Preparation of Compound 94-5 Compound 94-4 (0.1 g), acetonitrile (10 mL), iodomethane (0.1 g), and cesium carbonate (0.28 g) were added in this order to a 50 mL one-neck flask, and the mixture was protected with nitrogen and reacted overnight in an oil bath at 80°C. When the reaction was completed, the reaction solution was washed with ethyl acetate (50 mL) and saturated saline solution (25 mL), and then separated. The organic phase was recovered and purified by silica gel column chromatography to obtain 69 mg of compound 94-5. MS (ESI, [M+HC(CH3)3] + ) m / z: 195.10.

[0434] Step F: Preparation of Compound 94-6 Compound 94-5 (1 g) and 2M hydrochloric acid-dioxane solution (10 mL) were added in this order to a 50 mL one-neck flask, and the mixture was stirred at room temperature for 2 hours under nitrogen protection. When the reaction was completed, triethylamine (5 mL) was added to the reaction system to adjust the pH to alkaline, and the reaction solution was washed with ethyl acetate (50 mL) and saturated saline solution (25 mL), and then separated. The organic phase was recovered and purified by silica gel column chromatography to obtain 0.5 g of compound 94-6. MS (ESI, [M+H] + ) m / z: 151.06.

[0435] Step G: Preparation of Compound 94-7 Compound 94-6 (0.1 g), anhydrous tetrahydrofuran (10 mL), bis(pinacolato)diboron (0.25 g), 3,4,7,8-tetramethyl-1,10-phenanthroline (10 mg), and methoxy(cyclooctadiene)iridium(I) dimer (25 mg) were added in this order to a 50 mL one-neck flask, and the mixture was heated in an oil bath under nitrogen protection. The mixture was heated to 70°C at 40°C and refluxed for 4 hours. When the reaction was completed, the solvent was removed by concentration under reduced pressure. The mixture was used immediately in the next step without purification. MS(ESI, [M+H] + ) m / z: 277.18.

[0436] Step H: Preparation of Compound 94 Compound 11-1 (100 mg), dioxane (10 mL), compound 94-7 (72 mg), anhydrous potassium carbonate (30 mg), tetrakis(triphenylphosphine)palladium(0) (30 mg), and water (1 mL) were added in this order to a 50 mL one-neck flask. After completion, the reaction was carried out overnight at 100° C. in an oil bath after protecting with nitrogen. The reaction solution was washed with ethyl acetate (50 mL) and saturated saline solution (25 mL), then separated, and the organic phase was collected and purified by silica gel column chromatography to obtain 30 mg of compound 94. 1 H NMR(500MHz,DMSO-d6)δ 11.80(d,J=1.6Hz,1H),10.14(s,1H),8.71(d,J=2.4Hz,1H),8.05(d,J=2.4Hz,1H),7.93-7.8 4(m,2H),7.33(d,J=9.0Hz,2H),6.01(d,J=2.0Hz,1H),4.87(d,J=3.4Hz,1H),4.22(d,J=2.4Hz ,1H),3.58-3.49(m,2H),3.49-3.41(m,1H),3.30(dd,J=6.9,4.5Hz,2H),2.99(d,J=11.7Hz,1 H),2.93(s,3H),2.78(t,J=6.9Hz,2H),1.84(ddd,J=12.6,8.6,4.3Hz,1H),1.78-1.70(m,1H). HRMS(ESI,[M+H] + ) m / z: 532.15638.

[0437] Example 95: Preparation of Compound 95 [ka]

[0438] Step A: Preparation of Compound 95-1 Add anhydrous N,N-dimethylformamide (150mL) to a 250mL one-neck flask, start stirring, then add ethyl 4-methyl-5-imidazolecarboxylate (10.0g) to the system, and when the temperature drops to 0℃, add sodium hydride (3.11g, until the content is 60%w / w) in several portions to the system, and when it is complete, keep warm and stir for 30 minutes, then add 2-(trimethylsilyl)ethoxymethyl chloride (12.98g) dropwise to the system, and when it is complete, raise the temperature to room temperature and react for 4 hours. Then add ethyl acetate (100mL) and saturated aqueous ammonium chloride solution (100mL), stir and wash, then separate, then add ethyl acetate (100mL) to the aqueous phase and extract once, combine the organic phase, add saturated aqueous sodium chloride solution (150mL) to it, stir and wash, then separate, concentrate the organic phase under reduced pressure to obtain a residue, and purify it by silica gel column chromatography to obtain 13.18g of compound 95-1. MS (ESI, [M+H] + ) m / z: 285.20.

[0439] Step B: Preparation of Compound 95-2 In a 250 mL one-neck flask, add 1,2-dichloroethane (100 mL), compound 95-1 (4.98 g), N-bromosuccinimide (6.48 g), and azobisisobutyronitrile (0.257 g) in that order. When complete, replace with nitrogen and then raise the temperature to 70-80 °C and react for 6 hours. When cooled to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain 2.20 g of compound 95-2. MS (ESI, [M + Na] + ) m / z: 463.03.

[0440] Step C: Preparation of compound 95-3 Add anhydrous ethanol (50mL), methylamine hydrochloride (1.527g), and N,N-diisopropylethylamine (5.85g) in this order to a 100mL one-neck flask, stir for 30 minutes after completion, then add compound 95-2 (2.0g) obtained in step B above to the system, react overnight at room temperature after completion, concentrate the reaction solution under reduced pressure, and subject the resulting residue to silica gel column chromatography to obtain 570mg of compound 95-3. MS (ESI, [M+H] + ) m / z: 392.05.

[0441] Step D: Preparation of compound 95-4 Methanol (30 mL) was added to a 100 mL single-neck flask, stirring was started, and the system was then charged with compound 95-3 (570 mg) obtained in step C above, lithium hydroxide (0.311 g) and purified water (10 mL) were added in this order, and when complete, the mixture was reacted at room temperature for 3 hours, the system was concentrated under reduced pressure, and ethyl acetate (20 mL) and purified water (10 mL) were added to the obtained residue, followed by dropwise addition of 1M aqueous hydrochloric acid to adjust the pH to 6-7, the system became cloudy and solids precipitated, filtered, the cake was washed with purified water (5 mL) and then ethyl acetate (5 mL), the cake was collected and placed in a vacuum drying oven, and dried under vacuum at 50 °C until constant weight was obtained, obtaining 390 mg of compound 95-4. MS (ESI, [M + H] + ) m / z: 364.2.

[0442] Step E: Preparation of Compound 95-5 Add N,N-dimethylformamide (10 mL) to a 25 mL one-neck flask, start stirring, add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (488 mg) and N,N-diisopropylethylamine (415 mg) in that order to the system, stir for 5 minutes, and then add the N,N-dimethylformamide solution of compound 95-4 (390 mg) obtained in step D above, dissolved in N,N-dimethylformamide (5 mL), to the system. After completion, the mixture was reacted at room temperature for 1 hour, ethyl acetate (30mL) and purified water (10mL) were added to the system, stirred and washed, and then separated. The organic phase was collected, and ethyl acetate (10mL) was added to the aqueous phase for two extractions. The organic phases were combined, and purified water (15mL) and saturated aqueous sodium chloride solution (15mL) were added, stirred and washed twice each, and the organic phase was collected by separation. The mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 200mg of compound 95-5. MS (ESI, [M+H] + ) m / z: 346.1.

[0443] Step F: Preparation of Compound 95-6 Referring to the method of Step B of Example 62, compound 11-1 was used to react with bis(neopentylglycolato)diboron to prepare compound 95-6. The reaction product was used directly in the next step without any further treatment.

[0444] Step G: Preparation of compound 95-7 Referring to the preparation method of step C of Example 62, compound 95-6 was used to react with compound 95-5 to obtain compound 95-7. MS (ESI, [MH] - ) m / z: 647.3.

[0445] Step H: Preparation of Compound 95 Add dichloromethane (10 mL) to a 25 mL one-neck flask, start stirring, and add compound 95-7 (90 mg) obtained in step G above and trifluoroacetic acid (4467 mg) to the system in that order. Upon completion, react for 2 hours at room temperature, concentrate the reaction solution under reduced pressure, add ethyl acetate (15 mL) and saturated aqueous sodium bicarbonate solution (10 mL) to the resulting residue, stir and wash, then separate to obtain an organic phase, then add saturated aqueous sodium chloride solution (10 mL) and stir and wash, then separate, collect the organic phase, concentrate under reduced pressure to obtain a concentrate, and purify by reverse phase chromatography to obtain compound 95 (20 mg). 1 H NMR(500MHz,DMSO-d6)δ 13.09(d,J=115.1Hz,1H),10.23(d,J=8.5Hz,1H),8.98-8.68(m,1H),8.19(d,J=2.5Hz,1H),7.87(d,J=8.7Hz,2H),7.33(d,J=8.6Hz,2H),4.8 9(d,J=3.2Hz,1H),4.33(t,J=49.6Hz,3H),3.50-3.39(m,1H),3.27(s,1H),3.03(d,J=11.5Hz,3H),2.92(d,J=11.8Hz,1H),1.95-1.68(m,2H). HRMS(ESI,[M+H] + ) m / z: 519.13584.

[0446] Example 96: Preparation of Compound 96 [ka]

[0447] Step A: Preparation of Compound 96-1 Following the procedure of Step A of Example 94, compound 96-1 was prepared by reacting ethyl 2-isocyanoacetate with N-Boc-propargylamine. MS (ESI, [M+Na-Boc] + ) m / z: 191.1.

[0448] Step B: Preparation of Compound 96-2 Compound 96-2 was prepared under alkaline conditions using compound 96-1 according to the method of step B of Example 94. MS (ESI, [MH] - ) m / z: 239.214.

[0449] Step C: Preparation of compound 96-3 Compound 96-2 was reacted with thionyl chloride to prepare compound 96-3, following the procedure of step C of Example 94. MS (ESI, [M+H] + ) m / z: 123.06.

[0450] Step D: Preparation of compound 96-4 Following the procedure of Step G of Example 94, compound 96-3 was reacted with bis(pinacolato)diboron to produce compound 96-4. MS (ESI, [M+H] + ) m / z: 249.23.

[0451] Step E: Preparation of Compound 96 Compound 96 was prepared by reacting compound 7-1 with compound 96-4 according to the method of Example 94, Step H. 1 H NMR(500MHz,DMSO-d6)δ 11.99(s,1H),10.35(s,1H),8.72(d,J=1.8Hz,1H),8.22(d,J=1.8Hz,1H),8.06-7.7 4(m,3H),7.36(d,J=8.7Hz,2H),6.52(s,1H),4.15(s,2H),3.65(s,4H),3.17(s,4H). HRMS(ESI,[M+H] + ) m / z: 504.12491.

[0452] Example 97: Preparation of Compound 97 [ka]

[0453] Step A: Preparation of Compound 97-1 Following the procedure of Step G of Example 94, compound 94-3 was reacted with bis(pinacolato)diboron to produce compound 97-1. MS (ESI, [M+H] + )m / z:263.23.

[0454] Step B: Preparation of Compound 97 Compound 97 was prepared by reacting compound 7-1 with compound 97-1 according to the method of Step H of Example 94. 1 H NMR(500MHz,DMSO-d6)δ 11.82(s,1H),10.32(s,1H),8.69(d,J=2.2Hz,1H),8.26(d,J=2.2Hz,1H),7.88(d,J=9.1Hz,2H),7.36(d,J=8.8Hz,2H ),7.21(s,1H),6.44(d,J=1.8Hz,1H),3.90-3.55(m,4H),3.43-3.35(m,2H),3.21-3.13(m,4H),2.71(t,J=6.8Hz,2H). HRMS(ESI,[M+H] + ) m / z:518.14061.

[0455] Example 98: Preparation of Compound 98 [ka]

[0456] Step A: Preparation of Compound 98 Compound 98 was prepared by reacting compound 48-1 with compound 97-1 according to the method of Example 94, Step H. 11H NMR (500 MHz, DMSO-d6) δ 11.82 (s, 1H), 10.17 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 9.1 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.17 (s, 1H), 6.07 (d, J = 1.5 Hz, 1H), 5.55 (d, J = 5.8 Hz, 1H), 4.42 (dd, J = 10.7, 5.1 Hz, 1H), 4.01 - 3.89 (m, 2H), 3.57 (dd, J = 9.6, 4.4 Hz, 2H), 3.39 (dd, J = 6.5, 4.7 Hz, 2H), 2.70 (t, J = 6.7 Hz, 2H). HRMS (ESI, [M+H] + ) m / z: 504.12481.

[0457] Example 99: Preparation of Compound 99

Chemical Structure

[0458] Step A: Preparation of Compound 99 Referring to the method of Step H in Example 94, Compound 11-1 was used to react with Compound 97-1 to prepare Compound 99. 1 1H NMR (500 MHz, DMSO-d6) δ 11.80 (s, 1H), 10.14 (s, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.13 (s, 1H), 6.03 (s, 1H), 4.88 (d, J = 3.2H z, 1H), 4.23 (s, 1H), 3.47 (dd, J = 17.5, 9.7 Hz, 1H), 3.39 (t, J = 5.6 Hz, 2H), 3.31 (d, J = 5.2 Hz, 2H), 2.99 (d, J = 11.6 Hz, 1H), 2.70 (t, J = 6.7 Hz, 2H), 1.89 - 1.79 (m, 1H), 1.76 (d, J = 3.5 Hz, 1H). HRMS (ESI, [M+H] + ) m / z: 518.14020.

[0459] Example 100: Preparation of Compound 100 [ka]

[0460] Step A: Preparation of Compound 100-1 Reaction system A: At -30°C, under nitrogen protection, potassium tert-butoxide (3.50g) was slowly added to a stirred solution of 3-(tert-butoxy)-3-oxopropionic acid (5g) and magnesium chloride (2.97g) in tetrahydrofuran (200mL), the dropwise addition was completed in 30 minutes, and the resulting mixture was reacted at room temperature with stirring for 5 hours. Reaction system B: At -30°C, under nitrogen protection, N,N'-carbonyldiimidazole (4.56g) was added to a stirred solution of (tert-butoxycarbonyl)glycine (4.37g) in tetrahydrofuran (200mL), and after the dropwise addition was completed, the resulting mixture was reacted at room temperature with stirring for 3 hours. At 0°C, reaction system B was added dropwise to reaction system A, and after the dropwise addition was completed, the reaction system was transferred to room temperature and stirred for 2 days. The reaction mixture was extracted with ethyl acetate (500 mL), and the organic phase was washed with 1M hydrochloric acid (200 mL), saturated aqueous sodium bicarbonate (200 mL), and then with water (200 mL). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 8 g of compound 100-1. MS (ESI, [M+Na] + ) m / z: 296.21.

[0461] Step B: Preparation of Compound 100-2 Compound 100-1 (7 g), methanol (6 mL), aqueous ammonia (4.36 g), ammonium acetate (19.74 g), and 2-chloroacetaldehyde (20.10 g) were added in this order to a 50 mL one-neck flask, and the mixture was heated to 50° C. under nitrogen protection and reacted for 3 hours. Stirring was stopped, and the reaction solution was purified by silica gel column chromatography to obtain 6.5 g of compound 100-2. MS (ESI, [M+Na] + ) m / z: 319.25.

[0462] Step C: Preparation of Compound 100-3 At 0°C, under nitrogen protection, sodium tert-butoxide (4.22 g) was slowly added to a stirred solution of compound 100-2 (6.5 g) in tetrahydrofuran (10 mL), and after completion, the resulting mixture was reacted at room temperature with stirring for 1 hour. At 0°C, a solution of 4-p-toluenesulfonyl chloride (5.02 g) in tetrahydrofuran (10 mL) was slowly added dropwise, and the addition was completed in 10 minutes, and the mixture was returned to room temperature and reacted overnight with stirring. Stirring was stopped, and the reaction was quenched by adding saturated ammonium chloride solution (50 mL) to the reaction solution, and acetic acid was added to the reaction solution. The mixture was extracted with ethyl acetate (200 mL) and water (200 mL), the organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed with saturated saline solution (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain 8.5 g of compound 100-3. MS (ESI, [M+Na] + ) m / z: 473.3.

[0463] Step D: Preparation of Compound 100-4 Compound 100-3 (8.5 g) and dichloromethane (10 mL) were added in this order to a 50 mL eggplant flask, and trifluoroacetic acid (10 mL) was added under nitrogen protection, and the mixture was reacted at room temperature overnight. Stirring was stopped, and the solvent was removed from the reaction system by distillation under reduced pressure to obtain 5.6 g of compound 100-4. MS (ESI, [M+H] + ) m / z: 295.11.

[0464] Step E: Preparation of Compound 100-5 In a 50 mL one-neck flask, tetrahydrofuran (5 mL), N,N-diisopropylethylamine (4.61 g), and compound 100-4 (3.5 g) were added in this order, and 1-propylphosphonic anhydride (4.54 g) was added dropwise at 0° C., and the mixture was reacted at room temperature for 3 hours under nitrogen protection. Purification was performed by silica gel column chromatography to obtain 3 g of compound 100-5. MS (ESI, [M+H] + ) m / z: 277.13.

[0465] Step F: Preparation of Compound 100-6 Methanol (5 mL), compound 100-5 (1 g), and potassium carbonate (1.501 g) were added in this order to a 50 mL one-neck flask, and the mixture was reacted at room temperature overnight under nitrogen protection. The mixture was concentrated to dryness under reduced pressure to obtain a white solid crude product, and ethyl acetate (50 mL) was added to dilute the crude product, and water (30 mL) was added to wash the organic phase with saturated sodium chloride to obtain 300 mg of compound 100-6. MS (ESI, [M+H] + ) m / z: 123.04.

[0466] Step G: Preparation of Compound 100-7 In a 25mL one-neck flask, tetrahydrofuran (100mL) and compound 100-6 (200mg) were added in this order, and when complete, the mixture was replaced with nitrogen while stirring, then cooled to -80°C, N-bromosuccinimide (357mg) was added, and stirred for 30 minutes. When the reaction was complete, one drop of water was added to the reaction system, ethanol (5mL) was added, and the reaction system was purified by silica gel column chromatography to obtain 200mg of compound 100-7. MS (ESI, [M+H] + ) m / z: 201.06.

[0467] Step H: Preparation of Compound 100 Referring to the preparation method of Example 62, Step C, compound 95-6 was used to react with compound 100-7 to obtain compound 100. 1 H NMR(500MHz,DMSO-d6)δ11.73(s,1H),10.18(s,1H),8.74(s,1H),8.08(s,1H),7.88(d,J=8.8Hz,2H),7.54(s,1H),7.33(d,J=8 .6Hz,2H),6.17(s,1H),4.87(s,1H),4.23(s,3H),3.46-3.51(m,1H),3.30-3.31(m,2H),3.01-3.04(m,1H),1.76-1.86(m,2H). HRMS(ESI,[M+H] + ) m / z: 504.12477.

[0468] Example 101: Preparation of Compound 101 [ka]

[0469] Step A: Preparation of Compound 101-1 At 0°C, under nitrogen protection, 2-chloroacetaldehyde (24.53g) was slowly added to a stirred solution of 1,3-acetonedicarboxylate diethyl (31.6g) in acetonitrile (80mL), and after completion, the mixture was reacted for 3 hours with stirring at 50°C. Stirring was stopped, and the reaction solution was quenched by adding saturated ammonium chloride solution (50mL), and extracted by adding ethyl acetate (200mL) and water (200mL), the organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (50mL), and the organic phase was combined and washed with saturated saline solution (300mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain 22.6g of compound 101-1. MS (ESI, [M+H] + ) m / z: 227.2.

[0470] Step B: Preparation of Compound 101-2 Acetonitrile (400 mL) and compound 101-1 (22 g) were added in this order to a 50 mL one-neck flask. Upon completion, the system was cooled to 0°C, N-bromosuccinimide (21.19 g) was added, and the mixture was replaced with nitrogen, then the temperature was raised to room temperature and reacted. The mother liquor was collected by filtration and purified by silica gel column chromatography to obtain 25 g of compound 101-2. MS (ESI, [M+H] + ) m / z: 305.1.

[0471] Step C: Preparation of Compound 101-3 Compound 101-2 (24 g) and ethanol (20 mL) were added in this order to a 50 mL one-neck flask, the temperature was lowered to the level of an ice bath, sodium borohydride (8.93 g) was added, and the mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride aqueous solution (100 mL) was added to the reaction system to quench the reaction, ethyl acetate (50 mL) was added to extract, the organic phase was extracted twice with ethyl acetate (50 mL), the organic phases were combined, and purified by silica gel column chromatography to obtain 7 g of compound 101-3. MS (ESI, [M+H] + ) m / z: 263.02.

[0472] Step D: Preparation of Compound 101-4 Compound 101-3 (6.5 g), phthalimide (4.36 g), triphenylphosphine (9.72 g), and tetrahydrofuran (10 mL) were added in this order to a 50 mL three-neck flask, and diisopropyl azodicarboxylate (7.49 g) was added dropwise thereto at 0° C. under nitrogen protection. After the dropwise addition was completed, the mixture was transferred to room temperature and reacted overnight with stirring. Water and ethyl acetate were added to the reaction solution, which was then extracted and separated. The organic phase was washed with water and saturated saline, respectively, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography. Obtained 8.5 g of compound 101-4. MS (ESI, [M+H] + ) m / z: 392.14.

[0473] Step E: Preparation of Compound 101-5 In a 200 mL three-neck flask, compound 101-4 (8 g), ethanol (600 mL) were added in that order, and hydrazine hydrate (2.403 g) was added at 0° C. Upon completion, the mixture was heated to 50° C. and reacted overnight, and purified by silica gel column chromatography to obtain 5 g of compound 101-5. MS (ESI, [M+H] + ) m / z: 262.09.

[0474] Step F: Preparation of Compound 101-6 Compound 101-5 (1 g), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.159 g), and tetrahydrofuran (5 mL) were added in this order to a 50 mL reaction flask, and the resulting mixture was reacted for 30 minutes with stirring at 75° C., and purified by silica gel column chromatography to obtain 600 mg of compound 101-6. MS (ESI, [M+H] + ) m / z: 216.03.

[0475] Step G: Preparation of Compound 101-7 Referring to the preparation method of Step A of Example 60, compound 101-6 was used to react with iodomethane to give compound 101-7. MS (ESI, [M+H] + ) m / z: 230.0.

[0476] Step H: Preparation of Compound 101 Referring to the preparation method of Example 62, Step C, compound 95-6 was used to react with compound 101-7 to give compound 101. 1 H NMR(500MHz,DMSO-d6)δ 11.73(s,1H),10.18(s,1H),8.74(s,1H),8.08(s,1H),7.88(d,J=8.8Hz,2H),7.54(s,1H),7.33(d,J=8.6Hz,2H),6 .17(s,1H),4.87(s,1H),4.23(s,3H),3.46-3.51(m,1H),3.30-3.31(m,2H),3.01-3.04(m,1H),1.76-1.86(m,2H). HRMS(ESI,[M+H] + ) m / z: 533.14074.

[0477] Example 102: Preparation of Compound 102 [ka]

[0478] Step A: Preparation of Compound 102-1 In a 100 mL single-neck flask, add N,N-dimethylformamide (50 mL), 3-bromo-1H-pyrazol-5-amine (3.0 g), cesium carbonate (9.05 g), and bromo Add acetaldehyde diethyl acetal (4.01g), and when complete, protect with nitrogen, raise the temperature to 100 ° C, and react overnight. When cooled to room temperature, add ethyl acetate (50mL) and purified water (50mL) to the system, stir and wash, then separate, collect the organic phase, then add ethyl acetate (50mL) to the aqueous phase and extract twice, combine the organic phase, add purified water (50mL) and saturated aqueous sodium chloride (50mL) and stir and wash twice each, separate, collect the organic phase, concentrate under reduced pressure to obtain the residue, and purify by silica gel column chromatography to obtain 3.15g of compound 102-1. MS (ESI, [M + H] + ) m / z: 278.1.

[0479] Step B: Preparation of Compound 102-2 Add anhydrous ethanol (50mL), compound 102-1 (3.0g), and 1M aqueous sulfuric acid (7.5mL) to a 100mL one-neck flask, and when complete, protect with nitrogen, raise the temperature to 80°C, and react for 4 hours. When cooled to room temperature, concentrate the system under reduced pressure, add dichloromethane (20mL) and saturated sodium bicarbonate solution (10mL) to the resulting residue, stir and wash, then separate, obtain the organic phase, add saturated sodium chloride solution (10mL), stir and wash, then separate, recover the organic phase, concentrate under reduced pressure to obtain the residue, and purify by silica gel column chromatography to obtain 500mg of compound 102-2. MS (ESI, [M+H] + ) m / z: 186.0.

[0480] Step C: Preparation of Compound 102-3 Add dichloromethane (10mL), compound 102-3 (200mg), di-tert-butyl dicarbonate (258mg), N,N-diisopropylethylamine (208mg), and 4-dimethylaminopyridine (15mg) in this order to a 50mL one-neck flask, and when complete, react at room temperature for 2 hours, add 1mol / L hydrochloric acid aqueous solution (10mL) to the system and stir and wash twice, then add saturated sodium chloride aqueous solution and stir and wash once, separate, collect the organic phase, and concentrate under reduced pressure to obtain the residue, which was purified by silica gel column chromatography to obtain 200mg of compound 102-3. MS (ESI, [M+H] + ) m / z: 285.9.

[0481] Step D: Preparation of Compound 102 Referring to the preparation method of Example 62, Step C, compound 95-6 was used to react with compound 102-3 to obtain compound 102. 1 H NMR(500MHz,DMSO-d6)δ 11.09(s,1H),10.16(s,1H),8.72(d,J=2.4Hz,1H),8.08(d,J=2.5Hz,1H) ,7.97-7.81(m,2H),7.53(d,J=2.2Hz,1H),7.32(d,J=8.7Hz,2H),7.18(d ,J=2.2Hz,1H),5.79(s,1H),4.81(d,J=3.3Hz,1H),4.25-4.11(m,1H),3. 56-3.45(m,1H),3.08-2.97(m,1H),1.88-1.77(m,1H),1.77-1.64(m,1H). HRMS (ESI, [M+H] + ) m / z: 489.12628.

[0482] Example 103: Preparation of Compound 103 [ka]

[0483] Step A: Preparation of Compound 103-1 Referring to the preparation method of Example 62, Step B, compound 48-1 was used to react with bis(neopentylglycolato)diboron to give compound 103-1.

[0484] Step B: Preparation of Compound 103 Referring to the preparation method of Step C of Example 62, compound 103-1 was used to react with compound 102-3 to obtain compound 103. 1 H NMR(500MHz,DMSO-d6)δ 11.10(s,1H),10.22(s,1H),8.71(d,J=2.3Hz,1H),8.11(d,J=2.4Hz,1H),7.92-7.84(m,2H),7.56(d,J=1.8Hz,1H),7.36-7.2 9(m,2H),7.20(t,J=2.4Hz,1H),5.82(s,1H),5.48(d,J=5.9Hz,1H),4.41-4.34(m,1H),4.04-3.97(m,2H),3.63-3.55(m,2H). HRMS(ESI,[M+H] + ) m / z: 475.10915.

[0485] Example 104: Preparation of Compound 104 [ka] Referring to the preparation method of Example 94, Step H, compound 48-1 was used to react with compound 96-4 to obtain compound 104. 1 H NMR(500MHz,DMSO-d6)δ 11.94(s,1H),10.21(s,1H),8.73(d,J=1.9Hz,1H),8.08(d,J=1.8Hz,1H),7.87(d,J=9.0Hz,2H),7.82(s,1H),7.34(d,J=8.7 Hz,2H),6.19(s,1H),5.55(d,J=5.7Hz,1H),4.48-4.34(m,1H),4.15(s,2H),4.02-3.88(m,2H),3.57(dd,J=9.4,4.3Hz,2H). HRMS(ESI,[MH] - ) m / z: 488.09439.

[0486] Example 105: Preparation of Compound 105 [ka]

[0487] Step A: Preparation of Compound 105-1 Compound 96-3 (0.1 g), anhydrous tetrahydrofuran (10 mL), bis(pinacolato)diboron (0.25 g), 3,4,7,8-tetramethyl-1,10-phenanthroline (10 mg), and methoxy(cyclooctadiene)iridium(I) dimer (25 mg) were added in this order to a 35 mL waveguide, protected with nitrogen, and the mixture was placed in a microwave reactor. The reaction was completed in a microwave oven at 100° C. for 2 hours. The mixture was concentrated and the solvent was removed. Compound 96-4 and Compound 105-1 were simultaneously produced in the reaction. The mixture was used immediately in the next step without separation and purification.

[0488] Step B: Preparation of Compound 105 Referring to the preparation method of step H of Example 94, compound 48-1 is used to react with the mixture containing compound 105-1 obtained in step A above, and at the same time, a mixture of compound 104 and compound 105 is obtained, and separated using a YMC high pressure preparative chromatograph (Ultimate XB-Phenyl column, flow rate is 40mL / min, mobile phase is pure water:acetonitrile=13:7), and finally compound 105 is obtained. 1 H NMR(500MHz,DMSO-d6)δ 11.89(s,1H),10.20(s,1H),8.66(s,1H),8.01(s,1H),7.94-7.82(m,3H),7.34(d,J=8.1Hz,2H),7.2 5(s,1H),5.50(d,J=5.4Hz,1H),4.39(s,1H),4.09(s,2H),3.97-3.74(m,2H),3.50(d,J=4.7Hz,2H). HRMS(ESI,[MH] - ) m / z: 488.09448.

[0489] Example 106: Preparation of Compound 106 [ka] Referring to the preparation method of Example 94, Step H, compound 11-1 was used to react with compound 96-4 to obtain compound 106. 1 H NMR(500MHz,DMSO-d6)δ 11.90(s,1H),10.17(s,1H),8.74(d,J=2.4Hz,1H),8.08(d,J=2.4Hz,1H),7.90- 7.85(m,2H),7.79(s,1H),7.33(d,J=9.0Hz,2H),6.16(d,J=1.2Hz,1H),4.88(d,J =3.1Hz,1H),4.22(s,1H),4.14(s,2H),3.47(dt,J=9.4,7.3Hz,1H),3.32-3.26(m ,2H),3.05-2.94(m,1H),1.85(ddd,J=12.7,11.9,7.7Hz,1H),1.80-1.71(m,1H). HRMS(ESI,[M+H] + ) m / z: 504.12506.

[0490] Example 107: Preparation of Compound 107 [ka] Referring to the preparation method of Example 94, Step H, compound 48-1 was used to react with compound 94-7 to obtain compound 107. 1 H NMR(500MHz,DMSO-d6)δ 11.82(s,1H),10.18(s,1H),8.69(d,J=2.0Hz,1H),8.07(d,J=1.9Hz,1H),7.87(d,J=9.0Hz,2H),7.34(d,J=8.7Hz ,2H),6.05(s,1H),5.54(d,J=5.5Hz,1H),4.47-4.35(m,1H),4.01-3.90(m,2H),3.62-3.49(m,4H),2.94(s,3H),2.79(t,J=6.8Hz,2H). HRMS(ESI,[M+H] + ) m / z: 518.1399.

[0491] Example 108: Preparation of Compound 108 [ka]

[0492] Step A: Preparation of Compound 108-1 Referring to the preparation method of Step A of Example 105, compound 94-6 was used to react with bis(pinacolato)diboron to prepare a crude product containing compound 108-1, which was directly used in the next step without separation and purification.

[0493] Step B: Preparation of Compound 108 Referring to the preparation method of step H of Example 94, compound 48-1 is used to react with the crude product containing compound 108-1 obtained in step A above, and at the same time, a mixture of compound 107 and compound 108 is obtained, and separated using YMC high pressure preparative chromatograph (Ultimate XB-Phenyl column, flow rate is 40mL / min, mobile phase is pure water:acetonitrile=13:7), and finally compound 108 is obtained. 1 H NMR(500MHz,DMSO-d6)δ 11.80(s,1H),10.17(s,1H),8.73-8.59(m,1H),7.95-7.89(m,1H),7.87(d,J=8.9Hz,2H),7.33(d,J=8.6Hz,2H),7.00(d,J=2.4 Hz,1H),5.49(d,J=5.9Hz,1H),4.37(h,J=6.4Hz,1H),3.97-3.86(m,2H),3.58-3.46(m,4H),2.94(s,3H),2.63(t,J=6.7Hz,2H). HRMS(ESI,[M+H] +) m / z: 518.1408.

[0494] Example 109: Preparation of Compound 109 [ka] Referring to the preparation method of Example 94, Step H, compound 61-1 was used to react with compound 96-4 to obtain compound 109. 1 H NMR(500MHz,DMSO-d6)δ 11.90(s,1H),10.27(s,1H),8.71(d,J=1.9Hz,1H),8.15(d,J=1.9Hz,1H),7.88( d,J=9.0Hz,2H),7.81(s,1H),7.34(d,J=8.7Hz,2H),6.30(s,1H),4.14(s,2H),2. 82(s,6H). HRMS(ESI,[MH] - ) m / z: 460.10014.

[0495] Example 110: Preparation of Compound 110 [ka] Referring to the preparation method of Example 94, Step H, compound 62-1 was used to react with compound 96-4 to obtain compound 110. 1 H NMR(500MHz,DMSO-d6)δ 11.96(s,1H),10.14(s,1H),8.68(s,1H),8.05(s,1H),7.94-7.65(m,3H),7.34(d,J =8.5Hz,2H),6.65(d,J=4.3Hz,1H),6.43(s,1H),4.15(s,2H),2.92(d,J=4.3Hz,3H). HRMS(ESI,[MH] - ) m / z: 446.08408.

[0496] Example 111: Preparation of Compound 111 [ka]

[0497] Step A: Preparation of Compound 111-1 In a 250mL one-neck flask, add N-Boc-propargylamine (10g) and anhydrous N,N-dimethylformamide (150mL) in that order, add sodium hydride (1.5g) in several portions under ice bath, then add iodomethane (8g), and when the reaction is complete, add water slowly to quench the reaction, add ethyl acetate to extract (200mL x 3), combine the organic phases, dry with anhydrous sodium sulfate, and purify by silica gel column chromatography to obtain 9g of compound 111-1. GC-MS (EI, [Me] + ) m / z: 169.0.

[0498] Step B: Preparation of Compound 111-2 Compound 111-2 was prepared by the action of silver carbonate using compound 111-1 according to the method of step A of Example 94. MS (ESI, [M+H] + ) m / z: 283.10.

[0499] Step C: Preparation of Compound 111-3 Following the procedure of Step B of Example 94, compound 111-2 was used to prepare compound 111-3 by hydrolysis with lithium hydroxide. MS (ESI, [MH] - ) m / z: 253.17.

[0500] Step D: Preparation of compound 111-4 Compound 111-4 was prepared by the action of thionyl chloride using compound 111-3 according to the method of step C of Example 94. MS (ESI, [M+H] + ) m / z: 137.0.

[0501] Step E: Preparation of Compound 111-5 Compound 111-4 (0.5 g) and anhydrous tetrahydrofuran (30 mL) were added in this order to a 50 mL one-neck flask, and N-bromosuccinimide (0.6 g) was added in several portions in an ice bath. When the reaction was completed, the mixture was purified by silica gel column chromatography to obtain 0.2 g of compound 111-5. MS (ESI, [M+H] + ) m / z: 215.01.

[0502] Step F: Preparation of Compound 111 Referring to the method of Step G of Example 95, compound 111-5 and compound 95-6 were used in the reaction of tetrakis(triphenylphosphine)palladium(0) and potassium carbonate to prepare compound 111. 1 H NMR(500MHz,DMSO-d6)δ 11.95(s,1H),10.17(s,1H),8.74(s,1H),8.06(s,1H),7.87(d,J=8.5Hz,2H),7.33(d,J=8.5Hz,2H),6.17(s,1H),4.87 (s,1H),4.22(s,3H),3.46(q,J=9.0Hz,1H),3.00(d,J=12.0Hz,4H),1.95-1.66(m,2H),1.45-1.16(m,1H),0.84(s,1H). HRMS(ESI,[MH] - ) m / z: 516.1256.

[0503] Example 112: Preparation of Compound 112 [ka] Referring to the method of Step G of Example 95, compound 103-1 and compound 111-5 were used to prepare compound 112 by the action of tetrakis(triphenylphosphine)palladium(0) and potassium carbonate. 1H NMR(500MHz,DMSO-d6)δ 11.99(d,J=1.8Hz,1H),10.21(s,1H),8.73(d,J=2.3Hz,1H),8.07(d,J=2.4Hz,1H),7.92-7.84(m,2H),7.34(d,J=8.6Hz,2H),6.20(d,J=1. 6Hz,1H),5.54(d,J=5.5Hz,1H),4.41(q,J=5.5Hz,1H),4.23(s,2H),3.95(dd,J=9.6,6.6Hz,2H),3.56(dd,J=9.8,4.5Hz,2H),3.01(s,3H). HRMS(ESI,[MH] - ) m / z: 502.1112.

[0504] Example 113: Preparation of Compound 113 [ka]

[0505] Step A: Preparation of Compound 113-1 In a 100 mL three-neck flask, N-Boc-cyclopropylamine (5 g) was dissolved in tetrahydrofuran (50 mL), flushed with nitrogen three times, added sodium hydride (1.908 g) in portions in an ice bath, flushed with nitrogen once when complete, stirred for 30 minutes, and then added 3-bromopropyne (4.54 g) dropwise. After completion, the reaction was continued for 3 hours to reach completion. The reaction was quenched by adding water (50 mL) dropwise, extracted with ethyl acetate three times (40 mL x 3), and the organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and rotary evaporated to give compound 20-1 (6 g), which was used directly in the next step without further purification.

[0506] Step B: Preparation of Compound 113-2 Compound 113-1 (6 g), dioxane (60 mL), ethyl isocyanate (3.13 g), and silver carbonate (1.695 g) were added to a 250 mL single-neck flask in this order. Upon completion, the mixture was flushed with nitrogen three times. The temperature was raised to 100° C. and the reaction was allowed to proceed overnight until the reaction was complete. The solids were removed by filtration through diatomaceous earth. The filtrate was directly rotary evaporated and purified by silica gel column chromatography to give compound 113-2 (6 g). MS (ESI, [M+Na] + ) m / z: 331.2.

[0507] Step C: Preparation of Compound 113-3 Compound 113-2 (1 g), methanol (8 mL), water (4 mL), and sodium hydroxide (0.259 g) were added in that order to a 50 mL single-neck flask. Upon completion, the temperature was raised to 55 °C and the reaction was allowed to proceed overnight. Upon completion, the reaction was cooled to room temperature, and the pH was adjusted to 6 by dropwise addition of 2 M dilute hydrochloric acid in an ice bath, and then rotary evaporated to give the crude product (1.2 g), which was used directly in the next step without further purification. MS (ESI, [MH] - ) m / z: 279.1.

[0508] Step D: Preparation of compound 113-4 Compound 113-3 (630 mg), dioxane (8 mL), and thionyl chloride (2673 mg) were added in this order to a 50 mL one-neck flask, and the temperature was raised to 60° C. and reacted for 3 hours. When the reaction was complete, it was cooled to room temperature, the solvent was rotary evaporated, and the mixture was redissolved in dichloromethane and N,N-dimethylformamide, and diisopropylethylamine (1452 mg) was added dropwise in an ice bath. When the reaction was complete, the mixture was allowed to react at room temperature for 30 minutes. When the reaction was complete, the solvent was rotary evaporated as it was, and the mixture was subjected to silica gel column chromatography to obtain compound 113-4 (250 mg). MS (ESI, [M+H] + ) m / z: 163.0.

[0509] Step E: Preparation of Compound 113-5 Compound 113-4 (310 mg) and tetrahydrofuran (40 mL) were added in this order to a 100 mL one-neck flask, and the temperature was lowered to -60°C, and a solution of N-bromosuccinimide (306 mg) in tetrahydrofuran (10 mL) was added dropwise. After completion, the mixture was kept warm for 1 hour. The mixture was allowed to naturally warm to room temperature and kept overnight. After the reaction was completed, the mixture was rotatably evaporated at room temperature, dissolved in dichloromethane (2 mL), and subjected to silica gel column chromatography to obtain compound 113-5 (160 mg). MS (ESI, [M+H] + ) m / z: 241.1.

[0510] Step F: Preparation of Compound 113 Referring to the method of Step G of Example 95, compound 113 was prepared by the reaction of compound 113-5 and compound 95-6 with tetrakis(triphenylphosphine)palladium(0) and potassium carbonate. 1 H NMR (500MHz, DMSO-d6) δ 11.94(s,1H),10.18(s,1H),8.74(d,J=2.2Hz,1H),8.04(d,J=2.2Hz,1H),7.87 (d,J=9.0Hz,2H),7.33(d,J=8.8Hz,2H),6.14(s,1H),4.91(s,1H),4.19(d,J=28 .5Hz,3H),3.46(dd,J=17.3,9.8Hz,1H),3.30-3.25(m,1H),2.99(d,J=11.5Hz, 1H),2.86-2.72(m,1H),1.82(ddd,J=39.1,19.5,3.8Hz,2H),0.81-0.68(m,4H). HRMS (ESI, [M+H] + ) m / z: 544.1556.

[0511] Example 114: Preparation of Compound 114 [ka] Referring to the method of Step G of Example 95, compound 114 was prepared by the reaction of compound 113-5 and compound 103-1 with tetrakis(triphenylphosphine)palladium(0) and cesium carbonate. 1 H NMR(500MHz,DMSO-d6)δ 11.99(s,1H),10.22(s,1H),8.72(d,J=1.8Hz,1H),8.05(d,J=1.8Hz,1H),7.87(d,J=8.9Hz,2H),7.34(d,J=8.7Hz,2H),6.17(s,1H),5.55( s,1H),4.40(d,J=4.6Hz,1H),4.16(s,2H),4.04-3.88(m,2H),3.56(dd,J=9.4,4.3Hz,2H),2.80(dd,J=8.6,4.6Hz,1H),0.82-0.68(m,4H). HRMS(ESI,[M+H] + ) m / z: 530.1397.

[0512] Example 115: Preparation of Compound 115 [ka] Compound 7-1 (100 mg), dioxane (10 mL), compound 94-7 (72 mg), anhydrous potassium carbonate (30 mg), tetrakis(triphenylphosphine)palladium(0) (30 mg), and water (1 mL) were added in this order to a 50 mL single-neck flask. After completion, the reaction was carried out overnight at 100° C. in an oil bath after protection with nitrogen. The reaction solution was washed with ethyl acetate (50 mL) and saturated saline (25 mL), then separated, and the organic phase was collected and purified by silica gel column chromatography to obtain 30 mg of compound 115. 1 H NMR(500MHz,CHCl3-d)δ 10.32(s,1H),8.80(s,1H),8.67(s,1H),8.32-7.97(m,1H),7.92-7.53(m,2H),7.29-7.20(m, 2H),6.36(s,1H),4.02-3.67(m,4H),3.66-3.43(m,2H),3.23-2.94(m,7H),2.94-2.69(m,2H). HRMS(ESI,[M+H] + ) m / z: 532.15640.

[0513] Example 116: Preparation of Compound 116 [ka]

[0514] Step A: Preparation of compound 116-1 At room temperature, 4-trifluoromethoxybenzoic acid (0.29 g), anhydrous toluene (20 mL), and thionyl chloride (0.35 g) were added in this order to a 100 mL one-neck flask, protected with nitrogen, and the resulting mixture was heated to 80 ° C in an oil bath and reacted overnight. When the reaction was completed, the mixture was concentrated to remove the solvent, and then dichloromethane (20 mL) was added. 3-bromo-4-fluoroaniline (0.3 g) was added dropwise to the system while stirring, and after completion, diisopropylethylamine (0.3 g) was added dropwise. After the reaction was completed, the reaction solution was washed with ethyl acetate (50 mL) and saturated saline (25 mL), separated, and the organic phase was collected and purified by silica gel column chromatography to obtain 0.5 g of compound 116-1. MS (ESI, [MH] - ) m / z: 392.053 / 394.06.

[0515] Step B: Preparation of Compound 116-2 Compound 116-1 (0.8 g), potassium carbonate (560 mg), and (R)-3-pyrrolidinol (2 g) were added in this order to a 30 mL waveguide, and after replacing the atmosphere with nitrogen three times, the reaction was carried out at 160°C for 2 hours under microwaves. Water (50 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (60 mL) was added for extraction. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. (40 mL x 2). The organic layers were combined, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the compound 116-2 (0.7 g) was obtained by silica gel column chromatography. MS (ESI, [M+H] + ) m / z: 461.1 / 463.0.

[0516] Step C: Preparation of Compound 116 Compound 116-2 (100 mg), ethylene glycol dimethyl ether (10 mL), compound 96-4 (60 mg), anhydrous potassium carbonate (30 mg), tetrakis(triphenylphosphine)palladium(0) (30 mg), and water (0.2 mL) were added in this order to a 50 mL one-neck flask. Upon completion, the reaction was protected with nitrogen and heated to 100° C. in an oil bath overnight. The reaction solution was washed with ethyl acetate (50 mL) and saturated saline (25 mL), then separated, and the organic phase was collected and purified by silica gel column chromatography to obtain 30 mg of compound 116. 1 H NMR(500MHz,DMSO-d6)δ 11.77(s,1H),10.09(s,1H),7.97-7.83(m,4H),7.73(s,1H),7.31(d,J=8.7Hz,2H),6.84(d,J=8.7Hz,1H),6.12(s,1H),4.9 1-4.82(m,1H),4.27-4.18(m,1H),4.13(s,2H),3.30-3.25(m,1H),3.19-3.07(m,2H),2.84-2.74(m,1H),1.94-1.69(m,2H). HRMS(ESI,[M+H] + ) m / z: 503.1295.

[0517] Example 117: Preparation of Compound 117 [ka]

[0518] Step A: Preparation of Compound 117-1 Compound 116-1 (0.8 g), potassium carbonate (560 mg), and azetidin-3-ol (2 g) were added in this order to a 30 mL waveguide, and after replacing with nitrogen three times, the mixture was reacted at 160 °C under microwave for 2 hours. Water (50 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (60 mL) was added for extraction. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (40 mL x 2). The organic layers were combined, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and compound 117-1 (0.7 g) was obtained by silica gel column chromatography. MS (ESI, [M + H] + ) m / z: 447.1 / 449.0.

[0519] Step B: Preparation of Compound 117 Compound 117-1 (100 mg), ethylene glycol dimethyl ether (10 mL), compound 96-4 (60 mg), anhydrous potassium carbonate (30 mg), tetrakis(triphenylphosphine)palladium(0) (30 mg), and water (0.2 mL) were added in this order to a 50 mL single-neck flask. Upon completion, the reaction was protected with nitrogen and heated to 100° C. in an oil bath overnight. The reaction solution was washed with ethyl acetate (50 mL) and saturated saline (25 mL), separated, and the organic phase was collected and purified by silica gel column chromatography to obtain 30 mg of compound 117. 1 H NMR(500MHz,DMSO-d6)δ 11.81(s,1H),10.11(s,1H),7.88(d,J=9.3Hz,4H),7.75(s,1H),7.32(d,J=8.8Hz,2H),6.60(d,J=9.0Hz,1H),6.1 2(s,1H),5.51(s,1H),4.40(q,J=6.0,5.6Hz,1H),4.14(s,2H),3.81(t,J=7.5Hz,2H),3.39(dd,J=8.7,4.8Hz,2H).HRMS(ESI,[M+H] + ) m / z: 489.1143.

[0520] Example 118: Preparation of Compound 118 [ka]

[0521] Step A: Preparation of Compound 118-1 Referring to the method of Example 95, Step F, compound 117-1 was used to react with bis(neopentylglycolato)diboron to give compound 118-1.

[0522] Step B: Preparation of Compound 118 Referring to the method of Step G of Example 95, Compound 118-1 and Compound 111-5 were reacted with tetrakis(triphenylphosphine)palladium(0) and potassium carbonate to give Compound 118. 1 H NMR(500MHz,DMSO-d6)δ 11.85(s,1H),10.11(s,1H),7.97-7.79(m,4H),7.32(d,J=8.6Hz,2H),6.60(d,J=8.5Hz,1H),6.13(s,1H),5.49(d, J=5.8Hz,1H),4.38(p,J=5.6Hz,1H),4.22(s,2H),3.80(t,J=7.5Hz,2H),3.38(dd,J=8.7,4.8Hz,2H),3.01(s,3H). HRMS(ESI,[MH] - ) m / z: 501.1147.

[0523] Example 119: Preparation of Compound 119 [ka]

[0524] Step A: Preparation of Compound 119-1 Referring to the method of Example 95, Step F, compound 116-2 was used to react with bis(neopentylglycolato)diboron to give compound 119-1.

[0525] Step B: Preparation of Compound 119 Referring to the method of Step G of Example 95, compound 119-1 and compound 111-5 were used in the reaction of tetrakis(triphenylphosphine)palladium(0) and potassium carbonate to prepare compound 119. 1 H NMR(500MHz,DMSO-d6)δ 11.81(s,1H),10.09(s,1H),7.88(q,J=4.8,4.4Hz,4H),7.32(d,J=8.6Hz,2H),6.84(d,J=8.9Hz,1H),6.13(s,1H) ,4.86(d,J=3.6Hz,1H),4.21(s,2H),3.30-3.24(m,1H),3.12(ddt,J=21.1 ,8.6,4.0Hz,2H),3.00(s,3H),2.79(d,J=10.7Hz,1H),1.93-1.71(m,2H). HRMS(ESI,[MH] - )515.1302.

[0526] Example 120: Preparation of Compound 120 [ka] Referring to the preparation method of Step G of Example 95, compound 113-5 and compound 118-1 were used in the reaction of tetrakis(triphenylphosphine)palladium(0) and potassium carbonate to prepare compound 120. 1 H NMR(500MHz,DMSO-d6)δ 13.20-12.76(m,1H),10.22(s,1H),7.93-7.85(m,2H),7.83-7.51(m,2H),7.49-7.28(m,3H), 6.54(d,J=18.6Hz,1H),4.68-4.41(m,1H),4.18(s,2H),3.44-3.32(m,4H),2.91-2.69(m,2H). HRMS(ESI,[M+H] + ) m / z: 529.1446.

[0527] Example 121: Preparation of Compound 121 [ka]

[0528] Step A: Preparation of Compound 121-1 Following the procedure of Example 111, Step A, N-Boc-propargylamine was used to react with 2-iodopropane to give compound 121-1.

[0529] Step B: Preparation of Compound 121-2 Compound 121-2 was prepared by the action of silver carbonate using compound 121-1 according to the method of step A of Example 94. MS (ESI, [M+H-Boc] + ) m / z: 211.0.

[0530] Step C: Preparation of Compound 121-3 Following the procedure of Step B of Example 94, compound 121-2 was used to prepare compound 121-3 by hydrolysis with lithium hydroxide. MS (ESI, [MH] - ) m / z: 281.13.

[0531] Step D: Preparation of compound 121-4 Compound 121-4 was prepared by the action of thionyl chloride using compound 121-3 according to the method of step C of Example 94. MS (ESI, [M+H] + ) m / z: 165.11.

[0532] Step E: Preparation of Compound 121-5 Following the procedure of Step E of Example 111, compound 121-4 was reacted with N-bromosuccinimide to give compound 121-5. MS (ESI, [M+H+2] + ) m / z: 245.05.

[0533] Step F: Preparation of Compound 121 Referring to the method of Step G of Example 95, compound 121-5 and compound 77-2 were used in the reaction of tetrakis(triphenylphosphine)palladium(0) and potassium carbonate to prepare compound 121. 1H NMR(500MHz,DMSO-d6)δ 11.94(s,1H),10.18(s,1H),8.73(s,1H),8.07(s,1H),7.87(d,J=8.8Hz,2H),7.33(d,J=8.5Hz,2H),6.19(s,1H),4.29-4.32( m,1H),4.23(s,1H),4.18(s,2H),3.50(s,1H),3.22-3.34(m,3H),3.00-3.02(m,1H),1.77-1.78(m,2H),1.20(d,J=6.6Hz,6H). HRMS(ESI,[M+H] + ) m / z: 546.1715.

[0534] Example 122: Preparation of Compound 122 [ka]

[0535] Step A: Preparation of Compound 122 Referring to the method of Step G of Example 95, compound 119-1 and compound 121-5 were used to prepare compound 122 by the action of tetrakis(triphenylphosphine)palladium(0) and potassium carbonate. 1 H NMR(500MHz,DMSO-d6)δ 11.80(s,1H),10.07(s,1H),7.87-7.89(m,4H),7.31-7.33(m,2H),6.84-6.85(m ,1H),6.14(s,1H),4.87(s,1H),4.33(s,1H),4.28-4.33(m,1H),4.17(s,2H),3.2 8-3.30(m,1H),3.12-3.19(m,2H),2.79-2.81(m,1H),1.78-1.91(m,2H),1.20(d,J=6.7Hz,6H). HRMS (ESI, [MH] - ) m / z: 545.1762.

[0536] Example 123: Preparation of Compound 123 [ka] Referring to the method of Step G of Example 95, compound 121-5 and compound 103-1 were used in the reaction of tetrakis(triphenylphosphine)palladium(0) and potassium carbonate to prepare compound 123. 1 H NMR(500MHz,DMSO-d6)δ 11.97(s,1H),10.20(s,1H),8.73(s,1H),8.06(s,1H),7.87(d,J=9.1Hz,2H),7.34(d,J=8.8Hz,2H),6.21(s,1H),5.54( s,1H),4.40-4.43(m,1H),4.30-4.32(m,1H),4.18(s,2H),3.94-3.98(m,2H),3.55-3.58(m,2H),1.20(d,J=6.8Hz,6H). HRMS(ESI,[MH] - ) m / z: 532.1564.

[0537] Example 124: Preparation of Compound 124 [ka]

[0538] Step A: Preparation of Compound 124 Referring to the method of Step G of Example 95, compound 124 was prepared using compound 118-1 and compound 121-5 in the presence of tetrakis(triphenylphosphine)palladium(0) and potassium carbonate. 1 H NMR(500MHz,DMSO-d6)δ 11.84(s,1H),10.10(s,1H),7.86-7.89(m,4H),7.32(d,J=8.9Hz,2H),6.61(d,J=8.6Hz,1H),6.14(s,1H),5.50(s,1 H),4.38-4.41(m,1H),4.29-4.32(m,1H),4.17(s,2H),3.80-3.83(m,2H),3.38-3.40(m,2H),1.20(d,J=6.8Hz,6H). HRMS(ESI,[MH] - ) m / z: 531.1602.

[0539] Test Example 1: Growth inhibitory effect of compounds on K562 cells K562 cells in exponential growth phase and in good condition were used. The cells were collected in a centrifuge tube and centrifuged at 1000 rpm for 5 minutes in a tabletop low-speed centrifuge. The supernatant was discarded and 5 mL of complete medium (RPMI1640 basal medium + 10% FBS) was added with a pipette to resuspend the cells. The cells were counted using a cell counter and diluted with complete medium to a cell density of 6 × 10 4 pieces / m The same volume of RPMI1640 basal medium was then added to adjust the serum concentration to 5% and the cell density to 3 × 10 4 The cells were inoculated at 100 μL / well using a multichannel pipette into a 96-well plate and incubated in a humidified incubator containing 5% CO2 at 37°C. After 24 hours of incubation, the compounds were added using a nanopipette, and eight concentrations of each compound (1000 nM, 250 nM, 63 nM, 16 nM, 3.9 nM, 0.98 nM, 0.24 nM, 0.061 nM) were prepared. Each concentration was run in parallel in two wells. Cells without the compound were used as negative controls, and inoculated medium without cells was used as blank controls. After 72 hours, CCK-8 was added at 10 μL / well, and its absorbance was detected at 450 nm using an Envision microplate reader after 2 hours to calculate the inhibition rate, which was calculated as follows: inhibition rate (%) = (average of negative control group - average of test group) / (average of negative control group - average of blank group) × 100%, with the logarithm of compound concentration on the horizontal axis and the inhibition rate on the vertical axis, and a dose-response curve was fitted by 4-parameter logistic regression to obtain the IC 50 was calculated and the results are shown in Table 1. [Table 1]

[0540] Test Example 2: Compound potentiation in Ba / F3 cells transfected with BCR-ABL T315I Growth inhibition effect Ba / F3-BCR-ABL1-T315I-C3 cells in exponential growth phase and in good condition were used. The cells were collected in a centrifuge tube and centrifuged at 1000 rpm for 5 minutes in a tabletop low-speed centrifuge, the supernatant was discarded, and 5 mL of complete medium (RPMI1640 basal medium + 10% FBS) was added with a pipette to resuspend the cells. The cells were counted using a cell counter and diluted with complete medium to a cell density of 6 × 10 4 The serum concentration was adjusted to 5% and the cell density to 3 × 10 4 The cells were inoculated at 100 μL / well using a multichannel pipette into a 96-well plate and incubated in a humidified incubator containing 5% CO2 at 37°C. After 24 hours of incubation, the compounds were added using a nanopipette, and eight concentrations of each compound (1000 nM, 250 nM, 63 nM, 16 nM, 3.9 nM, 0.98 nM, 0.24 nM, 0.061 nM) were prepared. Each concentration was run in parallel in two wells. Cells without the compound were used as negative controls, and inoculated medium without cells was used as blank controls. After 72 hours, CCK-8 was added at 10 μL / well. Ba / F3-BCR-ABL1 T315I cells were added with CCK-8 and placed at 37°C. After 1 hour, the absorbance was detected at 450 nm using a microplate reader to calculate the inhibition rate, which was expressed as inhibition rate (%) = (average of negative control group - average of test group) / (average of negative control group - average of blank group) × 100%, with the logarithm of compound concentration on the horizontal axis and the inhibition rate on the vertical axis, and a dose-response curve was fitted by 4-parameter logistic regression to obtain the IC 50 was calculated and the results are shown in Table 2. [Table 2]

[0541] Test Example 3: In vivo pharmacokinetic evaluation in mice The ICR mice (purchased from Shanghai Xipur Bikai Laboratory Animal Co., Ltd.) weighed 18-22g, and were adapted for 3-5 days, then randomly divided into groups, 9 mice per group, and each compound was administered intragastrically at a dose of 10mg / kg. The test animals (ICR mice) were fasted overnight before administration, fed 4 hours after administration, and allowed to drink water freely before, during, and after the test. After intragastric administration, approximately 0.1mL of blood was collected from the orbit at 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 3, 4, 6, 8, 10, and 24 hours (each mouse was collected at three or four time points, and each time point was three mice), and EDTA-K2 was added to anticoagulate, and the blood was transferred to 4℃, 4000rpm, and 10 minutes within 30 minutes to centrifuge the plasma. After all the plasma was collected, it was immediately stored at -20℃ for measurement.

[0542] 30 μL of the plasma sample to be measured and the standard curve sample were aspirated, and 300 μL of acetonitrile solution containing an internal standard (diazepam 20 ng / mL) was added, shaken to mix uniformly for 5 minutes, centrifuged at 13,000 rpm for 10 minutes, 70 μL of the supernatant was recovered, diluted with 70 μL of ultrapure water, mixed uniformly, and 1 μL was aspirated for LC / MS / MS measurement, and the chromatogram was recorded.

[0543] The oral exposure of the compound was evaluated in an in vivo pharmacokinetic study in mice. The software DAS3.2.5 was used to fit the relevant pharmacokinetic parameters, where the absolute bioavailability F abs (%)=(AUC for intragastric administration×dose for intravenous administration) / (AUC for intravenous administration×dose for intragastric administration)×100%, and the results are shown in Table 3. [Table 3]

[0544] Test Example 4: Cardiac Safety Assessment of Compounds The cell line is derived from HEK-293 cells overexpressing hERG potassium ion channel. The cells were cultured in an incubator at 37℃ and 5% CO2. When the cell density reached 80% of the culture dish, first pre-wash with phosphate buffered saline (PBS), then digest the cells with trypsin / EDTA for 2-3 minutes, add cell culture medium to stop the digestion, gently blow off the cells and transfer them into a centrifuge tube, centrifuge at 1000 rpm for 3 minutes, discard the supernatant, add cell culture medium, gently pipette the cells to mix evenly, then transfer them to a culture dish for subculture, or drop the cells onto a circular glass slide and place them in the culture dish, and wait for the cells to attach for testing.

[0545] The composition of the cell culture medium was: DMEM, 15% fetal bovine serum and 1% 100x penicillin-streptomycin.

[0546] Stably transfected cells were seeded on a glass slide, the cell density was less than 50%, and cultured overnight. The test cells were transferred to a water bath of about 1 mL fitted to an inverted microscope platform and perfused with extracellular solution at a perfusion rate of 2.7 mL / min. After 5 minutes of stabilization, the test could be started. The membrane current was recorded using a HEKA EPC-10 patch clamp amplifier and a PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany), and analysis and statistics were performed using the software Origin 8.5 (OriginLab Corporation, Northampton, MA) and Microsoft Excel (results are shown in Table 4). All tests were performed at room temperature (22-24 °C). For the test, the electrode (BF150-110-10) was pulled into a straight shape using a P-97 microelectrode puller (Sutter Instrument Company, One Digital Drive, Novato, CA 94949). The inner diameter of the electrodes was 1 to 1.5 mm, and the underwater resistance after filling with the internal solution was 2 to 4 MΩ.

[0547] The electrophysiological stimulation method of the hERG potassium channel was as follows. First, the membrane voltage was clamped at -80 mV, and a voltage stimulus of +20 mV lasting for 2 seconds was applied to the cell to stimulate the hERG potassium channel. An outward tail current was generated by activating the G potassium channel, followed by repolarization to -50 mV and sustained for 5 seconds, with a stimulation frequency of once every 15 seconds, and the current value was the peak value of the tail current.

[0548] In the test, the channel current was recorded in the whole-cell recording mode. First, extracellular solution was perfused (approximately 2 mL / min) and recorded continuously until the current stabilized (current run-down within 5 minutes was less than 5%), at which point the peak value of the tail current was the control current value. Next, extracellular solution containing the test drug was perfused and recorded continuously until the inhibitory effect of the drug on the hERG current reached a stable state, at which point the peak value of the tail current was the current value after drug addition. The criterion for a stable state was whether the three most recent consecutive current recording lines overlapped. If the hERG current recovered to or was close to the magnitude before drug addition after the stable state was reached and washed out by perfusing the extracellular solution, other concentrations or drugs could be tested by continuing perfusion. Quinidine at 30 μM was used as a positive control in the test to ensure that the response of the cells used was normal. [Table 4]

[0549] Those skilled in the art will appreciate that the scope of the present disclosure is not limited to the various specific embodiments and examples described above, and that various amendments, substitutions, or recombinations may be made without departing from the spirit and concept of the present disclosure, all of which fall within the scope of protection of the present disclosure.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, Q is selected from N or CH; R １ teeth, 【Chemistry 2】 wherein said 【Chemistry 3】 optionally, one or more R ａ’ is replaced by X, Y and Z are each independently selected from CH or N, and at least one of X, Y and Z is selected from CH; Ring A is selected from 5-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O or S atoms; Ring B is a 5-1 heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, or S atoms. a 0-membered heterocyclyl group or a 5-8 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O or S atoms; R ２ is hydrogen, amino group, C １～６ Alkyl group, C １～６ Alkoxy group, amino-C １～６ alkyl-, a 3- to 10-membered heterocyclyl group, or a 5- or 6-membered heteroaryl group, １～６ Alkyl group, C １～６ Alkoxy group, amino-C １～６ The alkyl-, 3- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl group may optionally be one or more R ｂ is replaced by R ３ is -OCF ２ H, wherein said -OCF ２ H is optionally substituted by halogen; R ａ and R ａ’ are respectively a hydroxy group, an amino group, a cyano group, a halogen atom, 【Chemistry 4】 C １～６ Alkyl group, 3- to 8-membered cycloalkyl group, 3- to 8-membered heterocycloalkyl group, 3- to 8-membered cycloalkyl-C １～６ Alkyl-, 3- to 8-membered heterocycloalkyl-C １～６ Alkyl- or C substituted with one or more hydroxy groups or halogens １～６ independently selected from alkyl groups, R ｂ is a hydroxy group, an amino group, a cyano group, a halogen, 【Chemistry 5】 C １～６ Alkyl group, C １～６ Alkoxy group, C １～６ Alkoxy-C １～６ Alkyl-, C １～６ Alkyl-C(O)-NH- or C substituted with one or more hydroxy groups or halogens １～６ A compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: alkyl groups.

2. or a pharma- ceutically acceptable salt thereof, 【Chemistry 6】 During the ceremony, R １ teeth, 【Chemistry 7】 wherein said 【Chemistry 8】 optionally, one or more R ａ’ is replaced by X, Y and Z are each independently selected from CH or N, and at least one of X, Y and Z is selected from CH; Ring A is selected from 5-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O or S atoms; Ring B is selected from a 5- to 10-membered heterocyclyl group containing 1 to 3 heteroatoms selected from N, O or S atoms, or a 5- to 8-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O or S atoms; R ２ is hydrogen, amino group, C １～６ Alkyl group, C １～６ Alkoxy group, amino-C １～６ alkyl-, a 3- to 10-membered heterocyclyl group, or a 5- or 6-membered heteroaryl group, １～６ Alkyl group, C １～６ Alkoxy group, amino-C １～６ The alkyl-, 3- to 10-membered heterocyclyl or 5- or 6-membered heteroaryl group may optionally be one or more R ｂ is replaced by R ３ is -OCF ２ H, wherein said -OCF ２ H is optionally substituted by halogen; R ａ and R ａ’ are respectively a hydroxy group, an amino group, a cyano group, a halogen atom, 【Chemistry 9】 C １～６ Alkyl group, 3- to 8-membered cycloalkyl group, 3- to 8-membered heterocycloalkyl group, 3- to 8-membered cycloalkyl-C １～６ Alkyl-, 3- to 8-membered heterocycloalkyl-C １～６ Alkyl- or C substituted with one or more hydroxy groups or halogens １～６ independently selected from alkyl groups, R ｂ is a hydroxy group, an amino group, a cyano group, a halogen, 【Chemistry 10】 C １～６ Alkyl group, C １～６ Alkoxy group, C １～６ Alkoxy-C １～６ Alkyl-, C １～６ Alkyl-C(O)-NH- or C substituted with one or more hydroxy groups or halogens １～６ 2. The compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein the alkyl group is selected from the group consisting of aryl, ... and aryl.

3. 2. The compound of formula (I) according to claim 1, wherein Q is selected from CH; or a pharma- ceutically acceptable salt thereof.

4. 2. The compound of formula (I) according to claim 1, wherein X, Y and Z are all selected from CH, or one of X, Y and Z is selected from N and the others are selected from CH, or X is selected from N and Y and Z are selected from CH, or Y is selected from N and X and Z are selected from CH, or Z is selected from N and X and Y are selected from CH, or one of X, Y and Z is selected from CH and the others are selected from N.

5. 2. The compound of formula (I) according to claim 1, wherein ring A is selected from a 5-membered heteroaryl group containing one or two heteroatoms selected from N or O atoms, or ring A is selected from a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, an oxazolyl group or an isoxazolyl group, or ring A is selected from a pyrrolyl group, a pyrazolyl group, an imidazolyl group or a furyl group, or a pharma- ceutically acceptable salt thereof.

6. The compound of formula (I) according to claim 1, wherein ring B is selected from a 5-8 membered heterocycloalkyl group containing 1 to 3 heteroatoms selected from N or O atoms, or a 5-8 membered heteroaryl group containing 1 to 3 heteroatoms selected from N or O atoms; or ring B is selected from a 5- or 6-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from N or O atoms, or a 5-membered heteroaryl group containing 1 or 2 N atoms; or ring B is selected from a tetrahydropyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an imidazolyl group, or a pyrazolyl group; or ring B is selected from a tetrahydropyrrolidinyl group, a piperidinyl group, a morpholinyl group, or an imidazolyl group.

7. R １ teeth, 【Chemistry 11】 wherein said 【Chemistry 12】 optionally, one or more R ａ’ or R １ teeth, 【Chemistry 13】 wherein said 【Chemistry 14】 optionally, one or more R ａ’ or R １ teeth, 【Chemistry 15】 wherein said 【Chemistry 16】 optionally, one or more R ａ’ is replaced by Or, R １ teeth, 【Chemistry 17】 wherein said 【Chemistry 18】 optionally, one or more R ａ’ or R １ teeth, 【Chemistry 19】 wherein said 【Chemistry 20】 optionally, one or more R ａ’ or R １ teeth, 【Chemistry 21】 wherein said 【Chemical 22】 optionally, one or more R ａ’ or R １ teeth, 【Chemistry 23】 wherein said 【Chemistry 24】 optionally, one or more R ａ’ 2. The compound of formula (I) according to claim 1 , substituted by: or a pharma- ceutically acceptable salt thereof.

8. R ａ and R ａ’ are halogens, 【Chemistry 25】 C １～６ Alkyl group, 3- to 6-membered cycloalkyl group, 3- to 8-membered heterocycloalkyl-C １～６ Alkyl- or C substituted with 1, 2 or 3 hydroxy groups １～６ alkyl groups, or R ａ and R ａ’ are halogens, 【Chemistry 26】 C １～４ Alkyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocycloalkyl-C １～４ Alkyl- or C substituted with 1, 2 or 3 hydroxy groups １～４ independently selected from alkyl groups, Or, R ａ is C １～４ Alkyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocycloalkyl-C １～４ Substituted by alkyl- or one, two or three hydroxy groups Replaced C １～４ alkyl group or R ａ is a methyl group, an ethyl group, a cyclopropyl group, a 2-hydroxyethyl group, or 【Chemical 27】 Selected from Or, R ａ’ is halogen, 【Chemistry 28】 C １～４ R is selected from an alkyl group or a 3- to 6-membered cycloalkyl group; ａ’ are fluorine, chlorine, 【Chemical 29】 methyl, ethyl, isopropyl or cyclopropyl; or R ａ’ are fluorine, chlorine, 【Chemistry 30】 2. The compound of formula (I) according to claim 1, wherein the aryl group is selected from the group consisting of methyl, ethyl and cyclopropyl, or a pharma- ceutically acceptable salt thereof.

9. R １ teeth, 【Chemistry 31】 wherein said 【Chemistry 32】 optionally, one or more R ａ’ or R １ teeth, 【Chemical 33】 2. The compound of formula (I) according to claim 1, selected from: or a pharma- ceutically acceptable salt thereof.

10. R ２ is hydrogen, amino group, C １～４ Alkoxy group, amino-C １～４ alkyl-, a 3- to 10-membered heterocycloalkyl group, or a 5- or 6-membered heteroaryl group, １～４ Alkoxy group, amino-C １～４ The alkyl-, 3- to 10-membered heterocycloalkyl or 5- or 6-membered heteroaryl group may optionally be one or more R ｂ or R ２ is hydrogen, amino group, C １～４ Alkoxy group, amino-C １～４ alkyl-, a 4- to 6-membered monoheterocycloalkyl group, a 6- to 9-membered bridged heterocycloalkyl group, a 7- to 9-membered spiroheterocycloalkyl group, or a 5- or 6-membered heteroaryl group, wherein the amino group, C １～４ Alkoxy group, amino-C １～４ The alkyl-, 4- to 6-membered monoheterocycloalkyl group, 6- to 9-membered bridged heterocycloalkyl group, 7- to 9-membered spiroheterocycloalkyl group, or 5- or 6-membered heteroaryl group may optionally be selected from one or more R ｂ or R ２ is an amino group, a methoxy group, an ethoxy group, an aminomethyl group, 【Chemical 34】 wherein the amino group, the methoxy group, the ethoxy group, the aminomethyl group, 【Chemistry 35】 optionally one, two or three R ｂ or R ２ is an amino group, a methoxy group, an ethoxy group, an aminomethyl group, a pyrrolidinyl group, an isoxazolidinyl group, a piperidinyl group, a morpholinyl group, a thiomorpholinyl group, a 1,4-dioxane group, an azetidinyl group, a 6-oxa-3-azabicyclo[3.1.1]heptyl group, a 3-oxa-6-azabicyclo[3.1.1]heptyl group, a 3-oxa-8-azabicyclo[3.2.1]heptyl group, octyl group, 8-oxa-3-azabicyclo[3.2.1]octyl group, 2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.1.0]hexyl group, 2-oxa-6-azaspiro[3.4]octyl group, 2-oxa-7-azaspiro[3.5]nonyl group, 2-oxa-6-azaspiro[3.3]heptyl group, pyrazolyl group or imidazolyl group wherein the amino group is optionally substituted by one or two methyl groups, methoxyethyl groups, wherein the ethoxy group is optionally substituted by one methoxy group, wherein the aminomethyl group is optionally substituted by one or two methyl or methoxy groups, wherein the pyrrolidinyl group is optionally substituted by one or two hydroxy groups, cyano groups, fluorine, chlorine, methoxy groups, hydroxymethyl groups or acetylamino groups, wherein the azetidinyl group is optionally substituted by one or two hydroxy groups, cyano groups, fluorine, methyl groups or hydroxymethyl groups, wherein the 2-oxa-6-azaspiro[3.4]octyl group is optionally substituted by one 【Chemical 36】 or R ２ is a methoxy group, a methoxyethoxy group, a methylamino group, a dimethylamino group, 【Chemical 37】 or R ２ is a methoxy group, a methoxyethoxy group, a methylamino group, a dimethylamino group, 【Chemical Formula 38】 2. The compound of formula (I) according to claim 1, selected from: or a pharma- ceutically acceptable salt thereof.

11. R ｂ is a hydroxyl group, a cyano group, a halogen, 【Chemical 39】 C １～４ Alkyl group, C １～４ Alkoxy group, C １～４ Alkoxy-C １～４ Alkyl-, C １～４ Alkyl-C(O)-NH- or C substituted with one or more hydroxy groups or halogens １～４ alkyl group or R ｂ is a hydroxyl group, a cyano group, a fluorine group, a chlorine group, 【Chemistry 40】 2. The compound of formula (I) according to claim 1, wherein the aryl group is selected from the group consisting of a methyl group, a methoxy group, a hydroxymethyl group, a methoxyethyl group and an acetylamino group, or a pharma- ceutically acceptable salt thereof.

12. The compound of formula (I) is a compound of formula (III-A), a compound of formula (III-B), a compound of formula (IV-A), a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (VIII), a compound of formula (IX), or a compound of formula (X); 【Chemistry 41】 【Chemistry 42】 2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof.

13. The compound of formula (I) or a pharma- ceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is the following compound or a pharma- ceutically acceptable salt thereof: 【Chemistry 43-1】 【Chemistry 43-2】 【Chemistry 43-3】 【Chemistry 43-4】 【Chemistry 43-5】 【Chemistry 43-6】 【Chemistry 43-7】 【Chemistry 43-8】 【Chemistry 43-9】 【Chemistry 43-10】

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt thereof.

15. The pharmaceutical composition according to claim 14 for treating and / or preventing a BCR-ABL associated disease.

16. The pharmaceutical composition for treating and / or preventing a BCR-ABL-associated disease described in claim 15, wherein the disease is selected from cancer or the disease is selected from chronic myeloid leukemia.

17. Use of a compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating and / or preventing a BCR-ABL-associated disease.

18. The use described in claim 17, wherein the disease is selected from cancer or the disease is selected from chronic myeloid leukemia.

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