Menin-MLL interaction inhibitor and preparation method therefor, and application

Abstract

Disclosed are a Menin-MLL interaction inhibitor and a preparation method therefor, and an application. The compound is expected to be used for treating Menin-MLL interaction-mediated diseases such as tumors and diabetes.

Description

A Menin-MLL interaction inhibitor and its preparation method and application Technical Field

[0001] The present invention relates to the technical field of chemical medicine, and in particular to a Menin-MLL interaction inhibitor and a preparation method and application thereof, in particular to an application in tumor treatment. Background Art

[0002] Mixed lineage leukemia (MLL) proteins are histone methyltransferases that are crucial for epigenetic regulation of gene transcription. Many acute leukemias, including acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed lineage leukemia (MLL), are characterized by the presence of chimeric MLL fusion proteins, which arise from a chromosomal translocation of the MLL gene located on chromosome 11, band q23 (11q23). Chimeric MLL fusion proteins retain the approximately 1,400 amino acids of the MLL N-terminus but are fused to one of approximately 80 partner proteins (e.g., AF4, AF9, ENL, AF10, ELL, AF6, AF1p, GAS7). MLL fusion proteins lack the original histone methyltransferase activity of the MLL C-terminus and acquire the ability to regulate the transcription of numerous oncogenes, including HOX and MEIS1. This results in increased cell proliferation and decreased cell differentiation, ultimately leading to leukemia.

[0003] Menin is a scaffolding protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene. Mutations in menin cause an inherited autosomal dominant neoplasia syndrome (MEN1 syndrome), resulting in tumors in multiple endocrine organs. Menin binding to the N-terminus of MLL fusion proteins is required for the observed oncogenic activity of MLL fusion proteins. This binding has been shown to constitutively upregulate the expression of HOX and MEIS1 oncogenes and impair hematopoietic cell proliferation and differentiation, leading to leukemia. MLL1 functions as a general transcriptional activator of diverse gene regulatory pathways. In MLL fusion leukemias characterized by distinct chromosomal translocations at 11q23, menin is essential for maintaining MLL-related myeloid transformation. Gene knockdown experiments have shown that knockdown of menin function abolishes the aberrant gene expression program mediated by MLL fusions. Furthermore, other studies have described a crucial role for the interaction between menin and MLL in breast cancer, prostate cancer, synovial sarcoma, and hepatocellular carcinoma. In these indications, the interaction between menin, MLL fusion proteins, and MLL has been described as critically regulating the expression of disease-associated genes. Inhibiting the binding of Menin to MLL has recently emerged as a novel therapeutic strategy. Beneficial therapeutic effects have been demonstrated in models of leukemia, prostate cancer, breast cancer, colon cancer, liver cancer, and synovial sarcoma. Therefore, the interaction between Menin and MLL fusion proteins and MLL represents a potential small molecule therapeutic target.

[0004] The gene encoding nucleophosmin 1 (NPM1) is a multifunctional protein that is primarily localized to the nucleolus. Mutations in the NPM1 gene result in its aberrant cytoplasmic localization (NPM1c). The interaction between MLL and menin in AML with NPM1 mutations shares common HOX gene signatures and dependencies with MLL-menin rearrangements. AML cells with NPM1 mutations rely on the interaction of menin with wild-type MLL to sustain leukemogenesis, and these cells are sensitive to blockade of menin-MLL binding. Both MLL gene rearrangements and NPM1c can be targeted in the same manner because MLL fusion proteins and wild-type MLL share a common amino-terminal domain.

[0005] Mixed lineage leukemia (MLL) gene rearrangements occur in 5-10% of acute leukemias and are particularly common in infantile acute leukemia (up to 70% of cases). The MLL gene-rearranged leukemia subtype is characterized by aggressiveness, resistance to therapy, and a high rate of early relapse, even after an initial complete remission. Leukemia patients, especially infants, with chromosomal translocations of the MLL gene have an extremely poor prognosis, with a 5-year survival rate of less than 40%. Nucleophosmin 1 (NPM1) is the most commonly mutated gene in adult acute myeloid leukemia (AML) (approximately 30%). Novel therapeutic strategies for the treatment of this leukemia are urgently needed. Therefore, small molecule inhibitors that block the Menin-MLL interaction are valuable targets for the treatment of diseases involving MLL fusion proteins and are extremely important for providing new options for cancer treatment.

[0006] Summary of the Invention

[0007] In view of the needs of the prior art, the present invention provides a Menin-MLL interaction inhibitor and a preparation method and application thereof.

[0008] In a first aspect of the present invention, a compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof is provided, wherein the compound has the following structure:

[0009] in,

[0010] Ring A is represents a single bond or a double bond, and ring A is a five- to seven-membered aromatic ring or heterocyclic ring;

[0011] Ring B is a five- to seven-membered nitrogen-containing heterocyclic ring;

[0012] The E ring is a three- to eight-membered saturated or partially saturated aliphatic ring, an aromatic ring, or a four- to twelve-membered saturated or partially saturated heterocyclic ring;

[0013] L1 and L2 are independently selected from: single bond, C1-C 10 Alkylene, -(C0-C 10 Alkylene)-Q-(C0-C 10 Alkylene)-, Q is selected from: -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R La )-、-N(R La )C(O)-、-N(R La )C(O)O-、-N(R La )C(O)N(R La )-、-N(R La )-、-S(O)2-、-S(O)2N(R La )-、-N(R La)S(O)2-、-S(O)-、-S(O)N(R La )-、-N(R La )S(O)-、-C(=NR La )-、-C(=NR La )-NR La -; The H atoms in the alkylene group may be optionally substituted by the following groups: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group, halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, hydroxyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, amino, C1-C 10 Alkylamino; H on the cycloalkyl, aryl, heterocyclic group may be optionally substituted by a group selected from the following: H, halogen, C1-C 10 Alkyl, C1-C 10 Haloalkyl; R La Selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl;

[0014] R1 is one or more independent substituents on the benzene ring, each R1 is independently selected from: H, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, -OR 101 、-C(O)R 101 、-C(O)OR 101 、-NR 102 C(O)OR 101 、-OC(O)R 101 、-NR 102 SO2R 101 、-SO2NR 101 R 102、-NR 102 C(O)R 101 、-C(O)NR 101 R 102 、-NR 101 R 102 、-SR 101 、-S(O)R 101 、-S(O)2R 101 、-SO3H、-NR 102 (CR 103 R 104 ) t OR 101 、-(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), wherein t is an integer from 0 to 5; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0015] Each R 101 to R 104 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0016] R2 is One or more independent substituents on the ring, each R2 is independently selected from: H, =O, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, -OR 201 、-C(O)R 201 、-C(O)OR 201 、-NR 202 C(O)OR 201 、-OC(O)R 201 、-NR 202 SO2R 201、-SO2NR 201 R 202 、-NR 202 C(O)R 201 、-C(O)NR 201 R 202 、-NR 201 R 202 、-SR 201 、-S(O)R 201 、-S(O)2R 201 、-SO3H、-NR 202 (CR 203 R 204 ) j OR 201 、-(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), wherein j is an integer from 0 to 5; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0017] Each R 201 to R 204 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0018] R3 is selected from: H, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, -OR 301 、-C(O)R 301 、-C(O)OR 301 、-NR 302 C(O)OR 301 、-OC(O)R 301 、-NR 302 SO2R 301 、-SO2NR301 R 302 、-NR 302 C(O)R 301 、-C(O)NR 301 R 302 、-NR 301 R 302 、-SR 301 、-S(O)R 301 、-S(O)2R 301 、-SO3H、-NR 302 (CR 303 R 304 ) i OR 301 、-(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), wherein i is an integer from 0 to 5; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0019] Each R 301 to R 304 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0020] Or, R 301 and R 302 Together with the atoms to which they are attached, they form a heterocyclic group, which may be optionally substituted with one or more groups selected from the group consisting of H, ═O, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10Cyanoalkyl, -OR5, -C(O)R5, -C(O)OR5, -NR6C(O)OR5, -OC(O)R5, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -SR5, -S(O)R5, -S(O)2R5, -SO3H, -(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl); wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic radicals may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0021] Each R5, R6 is independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0022] R4 is one or more independent substituents on the E ring, each R4 is independently selected from: H, halogen, =O, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, -OR 401 、-C(O)R 401 、-C(O)OR 401 、-NR 102 C(O)OR 401 、-OC(O)R 401 、-NR 402 SO2R 401 、-SO2NR 401 R 402 、-NR 402 C(O)R 401 、-C(O)NR 401 R 402 、-NR 401 R 402 、-SR 401 、-S(O)R401 、-S(O)2R 401 、-SO3H、-NR 402 (CR 403 R 404 ) m OR 104 、-(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), wherein m is an integer from 0 to 5; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0023] Each R 401 to R 404 Independently selected from: H, C1-C 10 Alkyl, C2-C 10Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0024] Y is selected from: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, three to eight-membered saturated or partially saturated alicyclic group, aryl, four to twelve-membered heterocyclic group, aryl and three to eight-membered alicyclic group, aryl and three to eight-membered heterocyclic group, three to eight-membered alicyclic aryl, three to eight-membered alicyclic and heterocyclic group, three to eight-membered heterocyclic and three to eight-membered alicyclic, three to eight-membered heterocyclic and aryl, three to eight-membered heterocyclic and five to ten-membered heterocyclic group, which may be optionally replaced by one or more R Y Group substitution, R Y Selected from: H, =O, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10Cyanoalkyl, -OR7, -C(O)R7, -C(O)OR7, -NR8C(O)OR7, -OC(O)R7, -NR8SO2R7, -SO2NR7R8, -NR7C(O)R8, -C(O)NR7R8, -NR7R8, -SR7, -S(O)R7, -S(O)2R7, -SO3H, -(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl); wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0025] Each R7, R8 is independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0026] Each R' and R" is independently selected from: H, Cl-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkylalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl.

[0027] In some embodiments of the present invention, ring A is a five-membered or six-membered aromatic ring or a nitrogen-containing heteroaromatic ring, for example,

[0028] In some embodiments of the present invention, Ring B is a five-membered or six-membered nitrogen-containing heterocycle, for example,

[0029] In some embodiments of the present invention, A ring is one of the following structures:

[0030] In some embodiments of the present invention, Part of Wherein, X1 is N or C, X2 is N or C, X6 is N or C, Represents a single bond or a double bond.

[0031] In some embodiments of the present invention, Part of Wherein, X1 is N or C, X2 is N or C, X3 is N or C, and X5 is N or C, for example

[0032] In some embodiments of the present invention, Part of Wherein, X1 is N or C, X2 is N or C, X3 is N or C, and X5 is N or C, for example

[0033] In some embodiments of the present invention, Part of Wherein, X1 is N or C, X2 is N or C, X3 is N or C, X4 is N or C or does not exist (ie, X3 is directly connected to N), X5 is N or C or does not exist (ie, X6 is directly connected to N), X6 is N or C, Represents a single bond or a double bond.

[0034] In some embodiments of the present invention, the compound has the following structure:

[0035] In some embodiments of the present invention, X2 is N.

[0036] In some embodiments of the present invention, X3 is absent.

[0037] In some embodiments of the present invention, X4 is C.

[0038] In some embodiments of the present invention, Part of For example

[0039] In some embodiments of the present invention, Part of For example For example

[0040] In some embodiments of the present invention, Part of For example

[0041] In a preferred embodiment of the present invention, Part of Among them, R 2a 、R 2b 、R 2c R2 has the above definition.

[0042] In a preferred embodiment of the present invention, Part of Among them, R 2a 、R 2d 、R 2c R2 has the above definition.

[0043] In some embodiments of the present invention, Part of Wherein, X1 is N or C, X2 is N or C, X3 is N or C, X4 is N or C or does not exist (ie, X3 is directly connected to N), X5 is N or C or does not exist (ie, X6 is directly connected to N), X6 is N or C, Represents a single bond or a double bond.

[0044] In some embodiments of the present invention, Some are, for example,

[0045] In some embodiments of the present invention, the compound has the following structure:

[0046] In some embodiments of the present invention, the compound has the following structure:

[0047] In other embodiments of the present invention, Ring A is Ring B is an aromatic ring or a five-membered or six-membered nitrogen-containing heteroaromatic ring, for example Some can be In some embodiments of the present invention, the compound has the following structure:

[0048] In other embodiments of the present invention, Ring A is Ring B is an aromatic ring or a five-membered or six-membered nitrogen-containing heteroaromatic ring, for example Some can be In some embodiments of the present invention, the compound has the following structure:

[0049] In some embodiments of the present invention, R2 is selected from: H, C1-C6 alkyl (e.g., -CH3, ), halogen (e.g., F, Cl), cyano, nitro, azido, C1-C6 haloalkyl (e.g., -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3), C1-C6 haloalkoxy (e.g., ), C1-C6 cyanoalkyl (e.g. ),-OR 201 、-C(O)R 201 、-C(O)OR 201 、-NR 202 C(O)OR 201 、-OC(O)R 201 、-NR 202 SO2R 201 、-SO2NR 201 R 202 、-NR 202 C(O)R 201 、-C(O)NR 201 R 202 、-NR 201 R 202 、-SR 201 、-S(O)2R 201 , -SO3H, -(C0-C3 alkylene)-(phenyl), -(C0-C3 alkylene)-(4-10 membered heterocyclyl), -(C0-C3 alkylene)-(C3-C6 cycloalkyl); wherein the phenyl, 4-10 membered heterocyclyl, C3-C 10 The cycloalkyl group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C3 alkyl, and C1-C3 haloalkyl. Specifically, the 4-10 membered heterocycle is a 4-6 membered heterocycle, for example Specifically, the C3-C8 cycloalkyl group is a C3-C6 cycloalkyl group, for example

[0050] In some embodiments of the present invention, R 201 Selected from: H, C1-C6 alkyl.

[0051] In some embodiments of the present invention, R 202 Selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, -(C1-C3 alkylene)-(C3-C6 cycloalkyl) (e.g. ).

[0052] In some embodiments of the present invention, R2 is selected from: H, C1-C6 alkyl, halogen, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, -O(C0-C6 alkyl), -C(O)(C0-C6 alkyl), -(C0-C3 alkylene)-(C3-C6 cycloalkyl).

[0053] In some embodiments of the present invention, R 2a Selected from: H, halogen (eg F, Cl).

[0054] In some embodiments of the present invention, R 2b Selected from: H, C1-C6 alkyl (e.g. methyl), C1-C6 haloalkyl (e.g. -CF3), C1-C6 haloalkoxy (e.g. -OCF3), -(C0-C3 alkylene)-(C3-C6 cycloalkyl) (e.g. ), -C(O)(C0-C6 alkyl)(e.g. ).

[0055] In some embodiments of the present invention, R 2c Selected from: H, halogen (eg F, Cl).

[0056] In some embodiments of the present invention, R 2d Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C3 alkylene)-(C3-C6 cycloalkyl), -C(O)(C0-C6 alkyl), in particular H or C1-C3 alkyl (e.g. methyl).

[0057] In some embodiments of the present invention, Some selected from:

[0058] In some embodiments of the present invention, Part of Among them, R 1a is H or halogen (such as F, Cl), R 1b is one or more independent substituents on the phenyl ring, which have the above definition of R1.

[0059] Specifically, R1 can be selected from: H, halogen, C1-C6 alkyl, halogen, cyano, nitro, azido, C1-C6 haloalkyl, -N(C0-C6 alkyl)C(O)(C0-C6 alkyl), -C(O)N(C0-C6 alkyl)(C0-C6 alkyl).

[0060] In some embodiments of the present invention, R 1a For H.

[0061] In some embodiments of the present invention, R 1a For F.

[0062] In some embodiments of the present invention, R 1a For Cl.

[0063] In some embodiments of the present invention, R 1b For H.

[0064] More specifically, Some can be For example

[0065] In some embodiments of the present invention, the compound has the following structure:

[0066] In some embodiments of the present invention, R3 is -NR 302 C(O)R 301 or -C(O)NR 301 R 302 .

[0067] In some embodiments of the present invention, R 301 、R 302 independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C 10 cycloalkylalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 4-10 membered heterocyclylalkyl; or, R 301 and R 302 Together with the atoms to which they are attached, they form an optionally substituted 4-8 membered saturated or partially saturated heterocyclic ring (especially a saturated heterocyclic ring).

[0068] In some embodiments of the present invention, R 301 、R 302independently selected from: H, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), wherein said C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C( O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl, each R' and R" are independently selected from: H, C1-C6 alkyl.

[0069] In some embodiments of the present invention, R 301 、R 302 Independently selected from: H, C1-C6 alkyl (especially ethyl, isopropyl), C3-C6 cycloalkyl (for example cyclopropyl, cyclobutyl), -(C1-C3 alkylene)-(C3-C6 cycloalkyl), C1-C6 haloalkyl (for example -CHF2, -CF3, -CH2-CHF2, -CH2-CF3), -(C1-C3 alkylene)-O-(C0-C3 alkyl), -(C1-C3 alkylene)-NH-(C0-C3 alkyl).

[0070] In some embodiments of the present invention, R 301 It is isopropyl.

[0071] In some embodiments of the present invention, R 302 Selected from: H, C1-C6 alkyl (e.g. ethyl, isopropyl), C1-C6 haloalkyl (e.g. -CH2-CHF2, -CH2-CF3), C3-C6 cycloalkyl (e.g. cyclopropyl, cyclobutyl), -(C1-C3 alkylene)-O-(C0-C3 alkyl) (e.g. ), -(C1-C3 alkylene)-NH-(C0-C3 alkyl) (e.g. ).

[0072] In some embodiments of the present invention, R3 is

[0073] In some embodiments of the present invention, R3 is selected from:

[0074] In some embodiments of the present invention, R 301 and R302 Together with the atoms to which they are attached, they form a 4-8 membered saturated heterocyclic ring, which may be optionally replaced by one or more R 305 Replacement, R 305 Selected from: H, halogen (such as F), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, hydroxy, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl.

[0075] In some embodiments of the present invention, R3 is Ring J is a 4-8 membered saturated heterocyclic ring, which may be a monocyclic ring, a bicyclic ring (including a condensed ring, a spirocyclic ring), and optionally, may further contain one or more other heteroatoms. 305 is one or more independent substituents on the J ring, which have the above definition of the present invention.

[0076] In some embodiments of the invention, the J loop is

[0077] In some embodiments of the present invention, R3 is selected from:

[0078] In some embodiments of the present invention, R 305 Selected from: H, halogen (e.g. F), C1-C6 alkyl (e.g. methyl), C1-C6 haloalkyl (e.g. -CHF2, -CH2F, -CF3), C3-C6 cycloalkyl (e.g. ), 4-6 membered heterocycloalkyl (e.g. ).

[0079] In some embodiments of the present invention, R 305 Selected from: H, halogen (such as F), C1-C3 alkyl, C1-C3 haloalkyl.

[0080] In some embodiments of the present invention, R 305 Selected from: H, F, -CH3, -CHF2, -CH2F, -CF3.

[0081] In some embodiments of the present invention, R3 is selected from:

[0082] In some embodiments of the present invention, R3 is -(C0-C6 alkylene)-(C6-C 10 aryl) such as phenyl, wherein the aryl (such as phenyl) may be optionally replaced by one or more R306 Replacement, R 306 Selected from: H, halogen (such as F), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, hydroxy, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl.

[0083] In some embodiments of the present invention, R3 is R 306 is one or more independent substituents on the benzene ring, especially

[0084] In some embodiments of the present invention, R 306 Selected from: H, halogen (e.g. F), C1-C6 alkyl (e.g. methyl, ethyl, isopropyl), C1-C6 haloalkyl (e.g. -CHF2, -CH2F, -CF3), C3-C6 cycloalkyl (e.g. ).

[0085] In some embodiments of the present invention, R 306 Selected from: H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl.

[0086] In some embodiments of the present invention, R 306 Selected from:

[0087] In some embodiments of the present invention, R3 is selected from:

[0088] In some embodiments of the present invention, R3 is -(C0-C6 alkylene)-(4-10 membered heterocyclyl), said 4-10 membered heterocyclyl may be optionally replaced by one or more R 307 Replacement, R 307 is selected from the group consisting of: H, halogen (e.g., F), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, hydroxy, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, and 4-10 membered heterocyclic groups. More specifically, the 4-10 membered heterocyclic ring can be

[0089] In some embodiments of the present invention, R3 is selected from the following structures:

[0090] In some embodiments of the present invention, R307 Selected from: H, halogen (e.g. F), C1-C6 alkyl (e.g. methyl, ethyl, isopropyl), C1-C6 haloalkyl (e.g. -CHF2, -CH2F, -CF3), C3-C6 cycloalkyl (e.g. ).

[0091] In some embodiments of the present invention, R 307 Selected from: H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C4 cycloalkyl.

[0092] In some embodiments of the present invention, R 307 Selected from:

[0093] In some embodiments of the present invention, R3 is selected from:

[0094] In some embodiments of the present invention, L1 is a single bond.

[0095] In some embodiments of the present invention, L1 is C1-C6 alkylene, in particular C1-C4 alkylene, such as methylene,

[0096] In some embodiments of the present invention, L1 is -O-, -S-, or -N(R La )-; More specifically, R La It can be selected from: H, C1-C6 alkyl (such as methyl).

[0097] In some embodiments of the present invention, the E ring is a 3-8 membered saturated or partially saturated aliphatic ring, for example

[0098] In some embodiments of the present invention, Part of

[0099] In some embodiments of the present invention, the E ring is a 4-12 membered saturated or partially saturated heterocyclic ring, in particular a 4-10 membered saturated or partially saturated nitrogen-containing heterocyclic ring, for example

[0100] In some embodiments of the present invention, Part (the left end of the structure is connected to L1 and the right end is connected to L2) is in particular Preferably, Part of

[0101] In some embodiments of the present invention, Part of

[0102] In some embodiments of the present invention, Part of in particular

[0103] In some embodiments of the present invention, Part of in particular

[0104] In some embodiments of the present invention, R4 is selected from: H, halogen (e.g., F), =O, cyano, nitro, azido, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 cyanoalkyl.

[0105] In some embodiments of the present invention, R4 is selected from the group consisting of: H, halogen (eg, F), hydroxy, C1-C3 alkyl, and C1-C3 alkoxy.

[0106] In some embodiments of the present invention, R4 is selected from the group consisting of: H, F, and hydroxy.

[0107] In some embodiments of the present invention, The part (the left end of the structure is connected to L1 and the right end is connected to L2) is selected from:

[0108] In some embodiments of the present invention, L2 is a single bond.

[0109] In some embodiments of the present invention, L2 is C1-C6 alkylene or -(C0-C6 alkylene)-C1-(C0-C6 alkylene)-, wherein the H atom in the alkylene group may be optionally substituted by H, C1-C3 alkyl, halogen, cyano, C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C6 alkylamino, C3-C6 cycloalkyl, 3-6 membered heterocyclyl (such as ), C1-C3 alkyl substituted 3-6 membered heterocyclic group (such as ).

[0110] In some embodiments of the present invention, Q is selected from: -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R La )-、-N(R La )C(O)-、-N(R La )C(O)O-、-N(R La )C(O)N(R La )-、-N(R La )-、-S(O)2-、-S(O)2N(R La )-、-N(R La )S(O)2-、-S(O)-、-S(O)N(R La )-、-N(R La )S(O)-、-C(=NR La )-、-C(=NR La )-NR La -; each R La Independently selected from: H, C1-C6 alkyl (eg methyl, ethyl).

[0111] In some embodiments of the present invention, Q is selected from: -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R La )-、-N(R La )C(O)-、-N(R La )C(O)O-、-N(R La )-、-S(O)2-、-S(O)-;wherein each R La Independently selected from: H, C1-C3 alkyl (eg methyl, ethyl).

[0112] In some embodiments of the present invention, Q is selected from: -O-, -C(O)-, -N(C0-C3 alkyl)-, -N(C0-C3 alkyl)C(O)-.

[0113] In some embodiments of the present invention, L2 is selected from the group consisting of: methylene, -O-, -C(O)-, -NHC(O)-,

[0114] In some embodiments of the present invention, R Y R Y0, which is selected from: H, =O, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, azido, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, -OR7, -C(O)R7, -C(O)OR7, -NR8C(O)OR7, -OC(O)R7, -NR8SO2R7, -SO2NR7R8, -NR7C(O)R8, -C(O)NR7R8, -NR7R8, -SR7, -S(O)R7, -S(O)2R7, -SO3H, -(C0-C6 alkylene)-(phenyl), -SO2-(C0-C6 alkylene) - (phenyl), -S-(C0-C6 alkylene) - (phenyl), -O-(C0-C6 alkylene) - (phenyl), -(C0-C6 alkylene) - (4-10 membered heterocyclic group), -SO2-(C0-C6 alkylene) - (4-10 membered heterocyclic group), -S-(C0-C6 alkylene) - (4-10 membered heterocyclic group), -O-(C0-C6 alkylene) - (4-10 membered heterocyclic group), -(C0-C6 alkylene group) - (C3-C6 cycloalkyl), -SO2-(C0-C6 alkylene) - (C3-C6 cycloalkyl), -S-(C0-C6 alkylene) - (C3-C6 cycloalkyl), -O-(C0-C6 alkylene) - (C3-C6 cycloalkyl), the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -NR'C(O)R", -C(O)NR'R", -NR'R", C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl.

[0115] In some embodiments of the present invention, R Y R Y1 , which is selected from: H, -C(O)R7, -C(O)OR7, -NR8SO2R7, -NR8C(O)OR7, -NR8C(O)R7, -C(O)NR7R8, -NR7R8, -S(O)2R7, C1-C6 alkyl, -(C0-C6 alkylene) -(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C6 cycloalkyl); wherein the C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -NR'C(O)R", -C (O)NR'R", -NR'R", C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl; each R7 and R8 are independently selected from: H, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -(C0-C6 alkylene) - (phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); wherein the C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -NR'C(O)R", -C(O)NR'R", -NR'R", C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl.

[0116] In some embodiments of the present invention, R Y R Y2 , which is selected from: H, cyano, C1-C6 alkyl, 4-10 membered heterocyclyl, wherein the C1-C6 alkyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from the following: =O, halogen, cyano, nitro, amino, 4-10 membered heterocyclyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, -(C0-C4 alkylene)-OH, -(C1-C4 alkylene)-O-(C1-C4 alkyl), C1-C4 alkoxy, C1-C4 haloalkoxy, -C(O)O(C0 -C6 alkyl), -C(O)N(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)C(O)(C0-C6 alkyl), -SO2(C0-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2N(C0-C6 alkyl)(C0-C6 alkyl), -SO2NH(phenyl), -NHSO2(C0-C6 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C6 haloalkyl); R Y2In the above, the cycloalkyl group and heterocyclic group may be optionally substituted by a substituent selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl.

[0117] In some embodiments of the present invention, R Y R Y3 , which is selected from: H, =O, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -(C0-C6 alkylene) - (phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); wherein the C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -NR'C(O)R", -C(O)NR'R", -NR'R", C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl.

[0118] Specifically, Y is selected from the groups of Group Y1, Group Y2, Group Y3, Group Y4, and Group Y5.

[0119] In some embodiments of the present invention, Y1 is Wherein, the YⅠ ring is a 3-8 membered saturated or partially saturated aliphatic ring, a benzene ring, or a 4-12 membered saturated or partially saturated heterocyclic ring, and R Y0 is one or more independent substituents on the ring, which have the above definition of the present invention.

[0120] In some embodiments of the present invention, the YI ring is

[0121] In some embodiments of the present invention, Y1 is in particular

[0122] In some embodiments of the present invention, in Y1, R Y0 Selected from: H, halogen (such as F), C1-C3 alkyl (such as methyl), C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy.

[0123] In some embodiments of the present invention, R Y1Selected from: -NR8SO2R7, -NR8C(O)OR7, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2R7, C1-C6 alkyl, -(C0-C3 alkylene)(4-10 membered heterocyclyl), wherein the C1-C6 alkyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkoxy, C1-C6 hydroxy-substituted alkyl, -C(O)N(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)C(O)(C0-C6 alkyl).

[0124] In some embodiments of the present invention, R7 is selected from the group consisting of: H, C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, -(C0-C3 alkylene)-(C3-C6 cycloalkyl) (e.g., ), -(C0-C3 alkylene)-(4-10 membered heterocyclic group) (the 4-10 membered heterocyclic group is for example ), wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxy-substituted alkyl, -C(O)N(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)C(O)(C0-C6 alkyl).

[0125] In some embodiments of the present invention, R7 is selected from: C1-C6 alkyl, C3-C6 cycloalkyl, -(C1-C3 alkylene)-(C3-C6 cycloalkyl), 4-10 membered heterocyclyl, -(C1-C3 alkylene)-(4-10 membered heterocyclyl).

[0126] In some embodiments of the present invention, R8 is selected from the group consisting of: H, C1-C6 alkyl (eg, methyl).

[0127] In some embodiments of the present invention, R8 is H.

[0128] In some embodiments of the present invention, R Y1 -NR8SO2R7, wherein R7 is selected from: H, C1-C6 alkyl (such as methyl, ethyl, n-propyl, isopropyl), C1-C6 haloalkyl, C1-C6 hydroxy substituted alkyl, C3-C6 cycloalkyl (such as ), -(C1-C3 alkylene)-(C3-C6 cycloalkyl) (e.g. ), 4-10 membered heterocyclic group (e.g. ), wherein the 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkoxy, C1-C6 hydroxy-substituted alkyl, -C(O)N(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)C(O)(C0-C6 alkyl); R8 is selected from: H, C1-C6 alkyl (e.g., methyl).

[0129] In some embodiments of the present invention, R Y1 Selected from:

[0130] In some embodiments of the present invention, R Y1 It is -NR8C(O)OR7, wherein R7 is selected from: H, C1-C6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, tert-butyl), and R8 is selected from: H, C1-C6 alkyl (such as methyl).

[0131] In some embodiments of the present invention, R Y1 Selected from:

[0132] In some embodiments of the present invention, R Y1 It is -NR8C(O)R7, wherein R7 is selected from: H, C1-C6 alkyl (such as methyl, ethyl, n-propyl, isopropyl, tert-butyl), C1-C6 haloalkyl, and R8 is selected from: H, C1-C6 alkyl (such as methyl).

[0133] In some embodiments of the present invention, R Y1 Selected from:

[0134] In some embodiments of the present invention, R Y1 -C(O)R7, wherein R7 is selected from: H, C1-C6 alkyl (e.g., methyl, ethyl), -(C0-C3 alkylene)-(C3-C6 cycloalkyl) (e.g. ), -(C0-C3 alkylene)-(4-10 membered heterocyclic group) (the 4-10 membered heterocyclic group is, for example ), wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C6 alkylamino.

[0135] In some embodiments of the present invention, R Y1 Selected from:

[0136] In some embodiments of the present invention, R Y1 It is -C(O)R7, wherein R7 is selected from: H, C1-C6 alkyl (such as methyl, ethyl).

[0137] In some embodiments of the present invention, R Y1 Selected from:

[0138] In some embodiments of the present invention, R Y1 It is -C(O)NR7R8, wherein R7 is selected from: H, C1-C6 alkyl (such as methyl, ethyl), C3-C6 cycloalkyl (such as cyclopropyl), and R8 is selected from: H, C1-C6 alkyl (such as methyl).

[0139] In some embodiments of the present invention, R Y1 Selected from:

[0140] In some embodiments of the present invention, R Y1 It is -S(O)2R7, wherein R7 is selected from: H, C1-C6 alkyl (such as methyl, ethyl), C3-C6 cycloalkyl (such as cyclopropyl).

[0141] In some embodiments of the present invention, R Y1 Selected from:

[0142] In some embodiments of the present invention, R Y1 is -(C0-C3 alkylene)(4-10 membered heterocyclic group), the 4-10 membered heterocyclic group is, for example, The 4-10 membered heterocyclic group may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, amino, and C1-C6 alkylamino.

[0143] In some embodiments of the present invention, R Y1Selected from:

[0144] In some embodiments of the present invention, R Y1 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxyalkyl, -O-(C1-C6 hydroxy-substituted alkyl), -O-(C1-C6 alkoxyalkyl), C1-C6 cyanoalkyl.

[0145] In some embodiments of the present invention, Y1 is selected from the group consisting of:

[0146] In some embodiments of the present invention, L2 is C1-C6 alkylene (e.g., methylene, Especially straight chain alkylene groups such as methylene, ), alkoxy-substituted C1-C6 alkylene (e.g. ) or -N(C0-C3 alkyl)-(C0-C6 alkylene)-(e.g. ), -(C0-C6 alkylene)-O-(e.g. ), Y is Y1.

[0147] In some embodiments of the present invention, Some selected from:

[0148] In some embodiments of the present invention, Y2 is Among them, the YⅡ ring is a benzene ring and a four- to eight-membered aliphatic ring, a benzene ring and a four- to eight-membered heterocyclic ring, or a bicyclic heterocyclic ring, and R Y0 is one or more independent substituents on the ring, which have the above definition of the present invention.

[0149] In some embodiments of the present invention, the YII ring is

[0150] In some embodiments of the present invention, Y2 is

[0151] In some embodiments of the present invention, in Y2, R Y0 Selected from: H, halogen (eg F), C1-C3 alkyl (eg methyl), C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, especially H, methyl.

[0152] In some embodiments of the present invention, R Y2 Selected from: H, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C0-C4 alkylene)-(C3-C6 cycloalkyl), -(C0-C4 alkylene)-(optionally substituted 4-10 membered heterocyclyl); the 4-10 membered heterocyclyl is a 4-6 membered saturated heterocyclyl, for example

[0153] In some embodiments of the present invention, Y2 is selected from:

[0154] In some embodiments of the present invention, L2 is C1-C6 alkylene (e.g., methylene, ), alkoxy-substituted C1-C6 alkylene (e.g. ) or -N(C0-C3 alkyl)-(C0-C6 alkylene)-(e.g. ), Y is Y2.

[0155] In some embodiments of the present invention, Y3 is Among them, the YⅢ ring is a four- to eight-membered monocyclic nitrogen-containing saturated heterocycle, a four- to eight-membered monocyclic nitrogen-containing saturated heterocycle and an acene ring, a four- to eight-membered monocyclic nitrogen-containing saturated heterocycle and a four- to eight-membered aliphatic ring, or a six- to ten-membered bridged nitrogen-containing saturated heterocycle. Y0 is one or more independent substituents on the ring, which have the above definition of the present invention.

[0156] In some embodiments of the present invention, the YIII ring is where p is 1 or 2.

[0157] In some embodiments of the present invention, Y3 is

[0158] In some embodiments of the present invention, in Y3, R Y0 Selected from: H, halogen (eg F), C1-C3 alkyl (eg methyl), C1-C3 haloalkyl, hydroxy, C1-C3 alkoxy, especially H.

[0159] In some embodiments of the present invention, R Y3 Selected from: H, (For example ), halogen (e.g. F), C1-C6 alkyl (e.g. methyl), C1-C6 alkoxy (e.g. methoxy), phenyl, halophenyl (e.g. ).

[0160] In some embodiments of the present invention, Y3 is selected from:

[0161] In some embodiments of the present invention, L2 is C(O) and Y is Y3.

[0162] In some embodiments of the present invention, Some selected from:

[0163] In some embodiments of the present invention, Y4 is in,

[0164] R Y40 Selected from: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, C1-C3 alkyl substituted 3-6 membered heterocyclyl;

[0165] Z' is selected from: C0-C6 alkylene, -(C0-C3 alkylene)-O-(C0-C3 alkylene)-, -(C0-C3 alkylene)-S-(C0-C3 alkylene)-, -(C0-C3 alkylene)-NH-(C0-C3 alkylene)-, -(C0-C3 alkylene)-C(O)NH-(C0-C3 alkylene)-, -(C0-C3 alkylene)-NHC(O)-(C0-C3 alkylene)-, C3-C6 cycloalkylene; wherein the H on the alkylene is optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxyl, amino;

[0166] R Y41 Selected from: H, halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-12 membered heterocyclic group, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 wherein the H in the alkyl, cycloalkyl, aryl, or heterocyclic group is optionally substituted by a group selected from the group consisting of halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-12 membered heterocyclic group, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), -N(C 0-10 alkyl)(4-10 membered heterocyclic group), -N(C 0-10 alkyl)CO(4-10 membered heterocyclic group), -N(C 0-10 alkyl)CON(4-10 membered heterocyclic group), -N(C 0-10 alkyl)SO2(4-10 membered heterocyclyl), -O(4-10 membered heterocyclyl), -S(4-10 membered heterocyclyl), -SO(4-10 membered heterocyclyl), -SO2(4-10 membered heterocyclyl), -SO2N(C 0-10 alkyl) (4-10 membered heterocyclic group), -COO (4-10 membered heterocyclic group), -OCO (4-10 membered heterocyclic group), -CON (C 0-10 alkyl) (4-10 membered heterocyclyl), -CO (4-10 membered heterocyclyl), wherein the H in the alkyl and heterocyclyl groups is optionally substituted by one or more groups selected from the following: halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl).

[0167] In some embodiments of the present invention, R Y40 is a C1-C4 alkyl group or a C1-C4 haloalkyl group, such as In some embodiments of the present invention, R Y40 is a 3-6 membered heterocyclic group optionally substituted by a C1-C3 alkyl group, such as In some embodiments of the present invention, R Y40 It is a C3-C6 cycloalkyl group, such as cyclopropyl and cyclobutyl.

[0168] In some embodiments of the present invention, Z' is a single bond or a C1-C6 alkylene group, in particular a C1-C4 linear alkylene group, wherein the H on the alkylene group is optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxyl. In some embodiments of the present invention, Z' is a C3-C6 cycloalkylene group, for example

[0169] In some embodiments of the present invention, Y4 is in particular

[0170] In some embodiments of the present invention, R Y41 Selected from: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl); wherein the H on the alkyl is optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxyl, C1-C6 alkoxy; more specifically, R Y41 Selected from: -N(C 0-10 Alkyl)(C 0-10 alkyl), -O(C 0-10 Alkyl), -COO(C 0-10 alkyl); wherein the H on the alkyl is optionally substituted by one or more groups selected from the following: hydroxyl, C1-C3 alkoxy. In some embodiments of the present invention, R Y41 Selected from: OH,

[0171] In some embodiments of the present invention, R Y41 is a 4-12 membered heterocyclic group, wherein the H on the heterocyclic group is optionally replaced by one or more R Y42 Replace, each R Y42 independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C3-C6 cycloalkyl, 4-6 membered saturated heterocyclic group, -N(C 0-6 Alkyl)(C 0-6 Alkyl), -N(C 0-6 alkyl)CO(C 0-6 Alkyl), -N(C 0-6 alkyl)CON(C 0-6 Alkyl), -N(C 0-6 alkyl)SO2(C 0-6 alkyl), -O(C 0-6 Alkyl), -S(C 0-6 alkyl), -SO(C 0-6 Alkyl), -SO2(C 0-6 Alkyl), -SO2N(C 0-6 Alkyl)(C 0-6 Alkyl), -COO(C 0-6 alkyl), -OCO(C 0-6 alkyl), -CON(C 0-6 Alkyl)(C 0-6 alkyl), -CO(C 0-6 Alkyl), -N(C 0-6alkyl) (4-6 membered heterocyclic group), -SO2 (4-6 membered heterocyclic group), -COO (4-6 membered heterocyclic group), -OCO (4-6 membered heterocyclic group), -CON (C 0-6 alkyl) (4-6 membered heterocyclyl), -CO (4-6 membered heterocyclyl); wherein the H on the alkyl and heterocyclyl groups is optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C1-C6 cyanoalkyl, -N (C 0-6 Alkyl)(C 0-6 Alkyl), -N(C 0-6 alkyl)CO(C 0-6 Alkyl), -N(C 0-6 alkyl)CON(C 0-6 Alkyl), -N(C 0-6 alkyl)SO2(C 0-6 alkyl), -O(C 0-6 Alkyl), -S(C 0-6 alkyl), -SO(C 0-6 Alkyl), -SO2(C 0-6 alkyl), -SO2N(C 0-6 Alkyl)(C 0-6 Alkyl), -COO(C 0-6 alkyl), -OCO(C 0-6 alkyl), -CON(C 0-6 Alkyl)(C 0-6 alkyl), -CO(C 0-6 alkyl).

[0172] Specifically, in R Y41 In the definition of , the 4-14 membered heterocyclic group is a saturated or partially saturated heterocyclic group, for example, More specifically, R Y41 Can be selected from:

[0173] In some embodiments of the present invention, each R Y42 Independently selected from: H, halogen, CF3, CHF2, CH2F, Hydroxyl, cyano,

[0174] In some embodiments of the present invention, Y4 is in,

[0175] R Y401 Selected from: H, halogen (such as F), C1-C3 alkyl, C1-C3 haloalkyl;

[0176] R Y402 and R Y403 Independently selected from: H, halogen (e.g., F), hydroxyl, amino, C1-C3 alkyl, C1-C3 haloalkyl, -(C0-C3 alkylene)-(C3-C6 cycloalkyl), wherein the alkyl and cycloalkyl groups may be optionally substituted with one or more groups selected from the following: halogen, cyano, hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkylamino; or, R Y402 and R Y403 Together with the attached carbon atoms, they form an aliphatic ring or a heterocyclic ring, wherein the aliphatic ring or the heterocyclic ring may be optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, and C1-C6 haloalkyl;

[0177] R Y404 and R Y405 Independently selected from: H, C1-C6 alkyl, wherein the alkyl may be optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxy, amino, C1-C6 alkoxy, C1-C6 alkylamino; or, R Y404 and R Y405 Together with the nitrogen atom to which it is attached, it forms a heterocyclic ring, or, R Y402 and R Y404 Together with the carbon atom and nitrogen atom connected to it, a heterocyclic ring is formed. Y403 and R Y404 The carbon atom and nitrogen atom to which it is connected together form a heterocyclic ring, wherein the heterocyclic ring may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), -CO(C3-C 10 Cycloalkyl); wherein said C 0-10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C0-C6 alkylene, C3-C 10 The H in the cycloalkyl, phenyl, 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl);

[0178] Z is selected from: C0-C6 alkylene, -(C0-C3 alkylene)-O-(C0-C3 alkylene)-, -(C0-C3 alkylene)-S-(C0-C3 alkylene)-, -(C0-C3 alkylene)-NH-(C0-C3 alkylene)-, -(C0-C3 alkylene)-C(O)NH-(C0-C3 alkylene)-, -(C0-C3 alkylene)-NHC(O)-(C0-C3 alkylene)-;

[0179] a is 0 or 1.

[0180] In some embodiments of the present invention, R Y401 Selected from: H, halogen (eg F).

[0181] In some embodiments of the present invention, R Y401 For H.

[0182] In some embodiments of the present invention, R Y401 For F.

[0183] In some embodiments of the present invention, R Y402 and R Y403 Independently selected from: H, halogen (such as F), hydroxyl, amino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxy-substituted alkyl, C1-C6 alkoxy-substituted alkyl, C1-C3 amino-substituted alkyl, C1-C6 alkylamino-substituted alkyl.

[0184] In some embodiments of the present invention, R Y402 and R Y403 Both are H.

[0185] In some embodiments of the present invention, R Y402 and R Y403 Together with the attached carbon atoms, they form a four- to six-membered saturated aliphatic ring, e.g.

[0186] In some embodiments of the present invention, R Y404 Selected from: H, C1-C6 alkyl (such as methyl).

[0187] In some embodiments of the present invention, R Y404 For H.

[0188] In some embodiments of the present invention, R Y405 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy-substituted alkyl, C1-C6 amino-substituted alkyl, C1-C6 alkylamino-substituted alkyl.

[0189] In some embodiments of the present invention, RY405 Selected from: C1-C6 alkyl (such as methyl), C1-C6 alkoxy substituted alkyl (such as ).

[0190] In some embodiments of the present invention, R Y404 and R Y405 Together with the nitrogen atom to which it is attached, it forms a four- to twelve-membered nitrogen-containing heterocyclic ring, for example The heterocyclic ring is optionally replaced by one or more R Y406 group substitution;

[0191] R Y406 Selected from: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), -CO(C3-C 10 Cycloalkyl); wherein said C 0-10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C0-C6 alkylene, C3-C 10The H in the cycloalkyl, phenyl, 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl).

[0192] In some embodiments of the present invention, R Y406 Selected from: halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkoxyalkyl, C1-C6 alkylamino, C1-C6 alkylaminoalkyl, C3-C6 cycloalkyl, -CO(C 0-6 alkyl), -CO(C3-C6 cycloalkyl), -CO(C 0-6 Halogenated alkyl), -SO2(C 0-10 Alkyl), -SO2(C 0-10 haloalkyl).

[0193] In some embodiments of the present invention, a is 1.

[0194] In some embodiments of the present invention, Z is a single bond, methylene, or O.

[0195] In some embodiments of the present invention, a is 0 and Z is O.

[0196] In some embodiments of the present invention, a is 1 and Z is methylene.

[0197] In some embodiments of the present invention, Y4 is selected from the group consisting of:

[0198] In some embodiments of the present invention, L2 is a single bond and Y is Y4.

[0199] In some embodiments of the present invention, Some selected from:

[0200] In some embodiments of the present invention, Y5 is Among them, R Y501 and R Y502 Independently selected from: H, halogen (e.g., F), hydroxyl, amino, C1-C3 alkyl, C1-C3 haloalkyl, -(C0-C3 alkylene)-(C3-C6 cycloalkyl), wherein the alkyl and cycloalkyl groups may be optionally substituted with one or more groups selected from the following: halogen, cyano, hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkylamino; or, R Y501 and R Y502 Together with the carbon atoms to which it is attached, it forms an aliphatic ring or a heterocyclic ring, wherein the aliphatic ring or the heterocyclic ring may be optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, and C1-C6 haloalkyl;

[0201] R Y503 and R Y504 Independently selected from: H, C1-C6 alkyl, wherein the alkyl may be optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxy, amino, C1-C6 alkoxy, C1-C6 alkylamino; or, R Y503 and R Y504 Together with the nitrogen atom to which it is attached, it forms a heterocyclic ring, wherein the heterocyclic ring may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), -CO(C3-C 10 Cycloalkyl); wherein said C 0-10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C0-C6 alkylene, C3-C 10 The H in the cycloalkyl, phenyl, 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl).

[0202] In some embodiments of the present invention, R Y501 and R Y502 Independently selected from: C1-C3 alkyl, C1-C3 haloalkyl.

[0203] In some embodiments of the present invention, R Y501 and R Y502 Together with the carbon atoms to which it is attached, it forms a C3-C6 cycloalkyl group, which may be optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxy, amino, C1-C3 alkoxy, C1-C3 alkylamino.

[0204] In some embodiments of the present invention, R Y503 For H.

[0205] In some embodiments of the present invention, R Y503 It is a C1-C3 alkyl group.

[0206] In some embodiments of the present invention, R Y503 and R Y504 Together with the nitrogen atom to which it is attached, it forms a four- to twelve-membered nitrogen-containing heterocyclic ring, for example The heterocyclic ring is optionally replaced by one or more R Y505 group substitution;

[0207] R Y505 Selected from: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 Alkyl), -CO(C3-C 10 Cycloalkyl); wherein said C 0-10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C0-C6 alkylene, C3-C 10 The H in the cycloalkyl, phenyl, 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 Alkyl), -S(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 alkyl).

[0208] In some embodiments of the present invention, R Y505 Selected from: halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkoxyalkyl, C1-C6 alkylamino, C1-C6 alkylaminoalkyl, C3-C6 cycloalkyl, -CO(C 0-6 alkyl), -CO(C3-C6 cycloalkyl), -CO(C 0-6 Halogenated alkyl), -SO2(C 0-10Alkyl), -SO2(C 0-10 haloalkyl).

[0209] In some embodiments of the present invention, Y5 is selected from the group consisting of:

[0210] In some embodiments of the present invention, L2 is C(O) and Y is Y5.

[0211] In some embodiments of the present invention, the compound has the following structure:

[0212] In some embodiments of the present invention, the stereoisomer has the following structure:

[0213] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, and a pharmaceutically acceptable excipient.

[0214] Specifically, the pharmaceutically acceptable excipients may be selected from one or more of: disintegrants, binders, lubricants, suspending agents, stabilizers, fillers, absorption enhancers, surfactants, flavoring agents, antioxidants, preservatives, and the like.

[0215] Specifically, in the pharmaceutical composition, the compound of the first aspect or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds can be used alone or in combination with other types of active ingredients.

[0216] Specifically, the pharmaceutical composition can be administered by any suitable route, such as gastrointestinal administration (e.g., oral, sublingual, rectal) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.).

[0217] Specifically, the pharmaceutical composition can be in any suitable dosage form, such as a gastrointestinal dosage form, for example, including but not limited to tablets, pills, powders, granules, capsules, lozenges, syrups, liquids, emulsions, suspensions, etc.; parenteral dosage forms, for example, injectable dosage forms: such as injections (for example, for subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), respiratory tract dosage forms: such as sprays, aerosols, powder mists, etc., skin dosage forms, such as external solutions, lotions, ointments, plasters, pastes, patches, etc., mucosal dosage forms: such as eye drops, eye ointments, nasal drops, gargles, sublingual tablets, etc., cavity dosage forms: such as suppositories, aerosols, effervescent tablets, drops, pills, etc., for rectum, vagina, urethra, nasal cavity, ear canal, etc.

[0218] Specifically, the various dosage forms of the above-mentioned pharmaceutical composition can be prepared according to conventional production methods in the pharmaceutical field, for example, by mixing the active ingredient with one or more pharmaceutically acceptable excipients and then preparing the mixture into the desired dosage form.

[0219] Specifically, in the above-mentioned pharmaceutical composition, the weight percentage of the compound of the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound can be 0.1-99.5%, for example, 0.5%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, and especially 1-30%.

[0220] In a third aspect, the present invention provides use of the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, in the preparation of a medicament for inhibiting the interaction between Menin and MLL.

[0221] In a fourth aspect, the present invention provides use of the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, in the preparation of a medicament for preventing and / or treating diseases mediated by Menin-MLL interaction.

[0222] In some embodiments of the present invention, the disease is a tumor, including, but not limited to, hematological tumors (e.g., leukemia, lymphoma), bladder cancer, brain cancer (e.g., glioma, diffuse intrinsic pontine glioma (DIPG)), breast cancer (e.g., triple-negative breast cancer, estrogen receptor-positive breast cancer (i.e., ER+ breast cancer)), intestinal cancer (e.g., colon cancer, rectal cancer, colorectal cancer), gastrointestinal stromal tumor (GIST), cervical cancer, gastric cancer, genitourinary cancer, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer (e.g., castration-resistant prostate cancer), kidney cancer (e.g., renal cell carcinoma), skin cancer, thyroid cancer (e.g., papillary thyroid cancer), testicular cancer, glioblastoma, sarcoma (e.g., Ewing's sarcoma) and AIDS-related cancers.

[0223] In some embodiments of the present invention, the tumor is a blood tumor, such as leukemia, lymphoma, myeloma, etc.

[0224] In some embodiments of the present invention, the tumor is a solid tumor, such as prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, liver cancer, melanoma, glioblastoma.

[0225] In some embodiments of the invention, the disease includes, but is not limited to, mixed lineage leukemia (MLL), MLL-associated leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL-r), leukemia associated with MLL rearrangement or MLL gene rearrangement, acute leukemia, chronic leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myeloid leukemia, childhood leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia Leukemia (AML), acute myeloid leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), therapy-related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disorders (MPD), myeloproliferative neoplasia (MPN), plasma cell neoplasm, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, lymphoid neoplasm, hairy cell leukemia, leukemic meningitis, multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma (malignant lymphoma).

[0226] In some embodiments of the invention, the disease is diabetes, insulin resistance, hyperglycemia.

[0227] In some embodiments of the invention, the disease is an autoimmune disease.

[0228] In some embodiments of the invention, the disease is non-alcoholic hepatitis.

[0229] In the fifth aspect of the present invention, a method for inhibiting the interaction between Menin and MLL is provided, which comprises the step of administering the compound of the first aspect or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, or the pharmaceutical composition of the second aspect.

[0230] In some embodiments of the invention, the method is performed in vitro.

[0231] In some embodiments of the invention, the method is performed in vivo.

[0232] In the sixth aspect of the present invention, a method for preventing and / or treating diseases mediated by Menin-MLL interaction is provided, comprising the step of administering to a subject in need thereof the compound of the first aspect or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, or the pharmaceutical composition of the second aspect.

[0233] Specifically, the disease has the definition described in the fourth aspect of the present invention.

[0234] Specifically, the subject is a mammal, especially a human. DETAILED DESCRIPTION

[0235] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0236] In the present invention, the term "aliphatic group" refers to a straight or branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a cyclic hydrocarbon group that is fully saturated or contains one or more unsaturated units (also referred to herein as "carbocycle", "aliphatic ring"), which is connected to the rest of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkyl)alkenyl and the like. Typical aliphatic groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms.

[0237] The term "alkyl" refers to a straight or branched hydrocarbon chain radical that does not contain unsaturated bonds and is connected to the rest of the molecule by a single bond. Typical alkyl groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl group is substituted by a cycloalkyl group, it is correspondingly a "cycloalkylalkyl" group, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. Typical cycloalkylalkyl groups are usually C3-C 10 Cycloalkylalkyl, for example -(C1-C3 alkylene)-(C3-C6 cycloalkyl). If the alkyl group is substituted by an aryl group, then the corresponding group is an "aralkyl group", such as benzyl, diphenylmethyl or phenethyl. If the alkyl group is substituted by a heterocyclic group, then the corresponding group is a "heterocyclylalkyl group". In the present invention, C0 alkyl refers to H, i.e., C 0-10 Alkyl groups include H and C 1-10 alkyl.

[0238] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by losing two hydrogen atoms from an alkane molecule, which can be a straight chain or branched chain and is connected to the rest of the molecule by a single bond. In this context, a typical alkylene group has 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In the present invention, a C0 alkylene group refers to a single bond, i.e., C 0-10 Alkylene includes single bonds and C 1-10 Alkylene.

[0239] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 single rings and / or condensed rings, containing 3-18 carbon atoms, preferably 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, etc.

[0240] The term "alkoxy" refers to a substituent formed by replacing the hydrogen of a hydroxy group with an alkyl group, such as an alkoxy group containing 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, and the like.

[0241] The term "alkylamino" refers to a substituent formed when one or both hydrogen atoms in an amino group (-NH2) are replaced by an alkyl group, such as an alkylamino group containing 1 to 10 carbon atoms, for example

[0242] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0243] The term "haloalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with a halogen atom (such as fluorine, chlorine, bromine or iodine), for example, -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0244] The term "aryl" refers to a monocyclic or polycyclic free radical, including a polycyclic free radical containing a monocyclic aromatic group and / or a condensed aromatic group, such as a radical containing 1-3 monocyclic or condensed rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. 12 The aryl group refers to an aryl group containing 6 to 12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc.

[0245] The term "heterocyclyl" refers to a 3- to 18-membered ring radical containing 2- to 17 carbon atoms and 1- to 10 heteroatoms selected from nitrogen, oxygen, or sulfur atoms. A heterocyclyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. Polycyclic ring systems may include fused (two rings share two ring atoms), spiro-connected (two rings share one ring atom), or bridged (two rings share three or more ring atoms) ring systems (excluding linked rings). A heterocyclyl may be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl). Suitable heteroaryl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms and include, for example, coumarin, including 8-coumarin, quinolyl, including 8-quinolyl, isoquinolyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazolyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. Suitable heterocycloalkyl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms, and include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiirane, azepine, oxazepine, diazepine, Heptyl, triazepine, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindole, 2H-pyranyl, 4H-pyranyl, dioxane, 1,3-dioxolane, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinolizinyl. In the present invention, for the optionally substituted heterocyclic group, the substituted position can be any suitable carbon atom or heteroatom, for example, for The substitution position of R can be any suitable carbon atom or nitrogen atom, which can be, for example

[0246] The term "optionally substituted" group may be halogen, -CN, -NO2, -OR', -NR'R", -S(O)t-R', -S(O)t-NR'R", -COR', -C(O)OR', -C(O)NR'R", -C(O)N(R')OR", -OC(O)R', -OC(O)NR'R", -NR'C(O)R", -N(R')C(O)NR'R', -N(R')C(NR')NR'R', -NR'-S(O)t-R', -NR'-S(O)t-NR'R', -N=S(O)R'R", -S(NR')(O)R", -N(R')CN, -P(O)(R')NR'R", -P(O)(R')OR", or -P(O)R'R", C(O) 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkenyl, C 1-6 Alkynyl, C 3-6 Cycloalkyl, C 4-10 Cycloalkylalkyl, C 6-10 Aryl, C 6-10 Arylalkyl, C 3-8 Heterocyclic group, C 3-8 Heterocyclylalkyl; t is 0, 1 or 2; each R' and R" are independently selected from: H, halogen, -CN, -NO2, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl; or, R' and R" attached to the same nitrogen atom together with the nitrogen atom form a heterocycle.

[0247] The term "pharmaceutically acceptable salts" includes acid addition salts and base addition salts.

[0248] The term "acid addition salt" includes, but is not limited to, salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, and phosphonic acids, and salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids, for example, acetate, salicylate, decanoate, stearate, oleate, hexanoate, malate, glycolate, ethanesulfonate, isethionate, and the like. The present invention relates to the preparation of the present invention and the like.Therefore, these salts include but are not limited to sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, tartrate and mesylate, also comprise amino acid whose salt such as arginate, gluconate, galacturonate, aspartate, glutamate etc.Acid addition salts can be prepared by making the free alkali form contact the mode of forming salt with sufficient required acid in a conventional manner.Can regenerate free alkali form by making salt form contact with alkali, and separate this free alkali in a conventional manner.

[0249] The term "base addition salt" refers to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.

[0250] The term "stereoisomer" includes the presence of enantiomers, diastereomers and geometric isomers. Some compounds of the present invention have cyclic hydrocarbon groups that may be substituted on more than one carbon atom, in which case all geometric forms, including cis and trans forms, and mixtures thereof, are within the scope of the present invention.

[0251] The term "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates include solution phases and isolatable solvates. Representative solvates include ethanolates, methanolates, and the like.

[0252] The term "deuterated compound" refers to a compound in which one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by deuterium atoms (D).

[0253] It will be appreciated that, depending on the source of the chemical materials used in the synthesis, some variation in natural isotopic abundance will exist in the synthesized compounds. Therefore, the compounds of the present invention will inherently contain small amounts of deuterated isotopologues. Despite this variation, the concentrations of these naturally abundant stable hydrogen and carbon isotopes are low and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention. See, for example, Wada, E. et al., Seikagaku, 1994, 66:15; Gannes, L.Z. et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0254] In the compounds of the present invention, any atom not designated as deuterium is present at its natural isotopic abundance. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Similarly, unless otherwise indicated, when a position is specifically designated as "D" or "deuterium," the position is understood to have deuterium at an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

[0255] As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.

[0256] In other embodiments, the compounds of the invention have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0257] The term "isotopologue" refers to a substance wherein the chemical structure differs from a specific compound of the present invention only in its isotopic composition.

[0258] The term "prodrug" refers to a form of a compound of Formula I that is suitable for administration to a patient without undue toxicity, irritation, allergic reactions, etc., and is effective for its intended use, including acetal, ester, and zwitterion forms. The prodrug is transformed in vivo, for example, by hydrolysis in the blood, to yield the parent compound.

[0259] The terms "patient" or "subject" and the like are used interchangeably herein to refer to any animal or cell thereof to be treated according to the methods described herein, whether in vitro or in situ. Specifically, the aforementioned animals include mammals, e.g., rats, mice, guinea pigs, rabbits, dogs, monkeys, humans, and particularly humans.

[0260] The term "treating" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, suppressing and / or halting one or more clinical symptoms of a disease after onset of the disease.

[0261] The term "prevent" or "prevent" refers to treating a disease before it occurs to avoid, minimize, or make the onset or development of the disease more difficult.

[0262] The term "tumor" refers to a neoplasm formed by the proliferation of localized tissue cells in response to various tumorigenic factors. Tumors are further categorized into benign and malignant tumors based on their cellular characteristics and the degree of harm they pose to the body. A "malignant tumor" is characterized by the uncontrolled growth and spread of malignant cells, as well as tissue infiltration, and is classified as a malignant tumor as determined by pathological examination according to the "Classification of Diseases and Causes of Death" published by the Ministry of Health.

[0263] In specific embodiments, the compounds of the present invention are used to treat leukemia associated with MLL rearrangement, acute lymphocytic leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute lymphocytic leukemia associated with MLL rearrangement, acute myeloid leukemia associated with MLL rearrangement, acute myeloid leukemia associated with MLL rearrangement, or acute myeloblastic leukemia associated with MLL rearrangement. As used herein, "MLL rearrangement" means a rearrangement of the MLL gene.

[0264] The term "autoimmune disease" refers to diseases caused by the body's immune response to its own antigens, resulting in damage to its own tissues. These diseases can be categorized as organ-specific autoimmune diseases (primarily affecting a single organ) or systemic autoimmune diseases (affecting multiple tissues or organs throughout the body). The American Autoimmune Related Diseases Association provides a comprehensive list of autoimmune diseases, including common ones such as systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, psoriasis, celiac disease, ulcerative colitis, and Crohn's disease.

[0265] Unless otherwise stated, numerical ranges expressed in the format "from x to y" or "xy" should be understood to include x and y. When, for a specific feature, multiple preferred ranges are described in the format "from x to y" or "xy", it should be understood that all ranges combining the different endpoints are also contemplated.

[0266] The disclosures of various publications, patents, and published patent specifications cited herein are incorporated by reference in their entirety.

[0267] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0268] Synthesis Example

[0269] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0270] MS was measured using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid spectrometer / mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0271] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatographs.

[0272] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0273] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0274] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0275] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0276] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0277] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0278] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0279] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0280] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0281] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0282] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0283] The pressure hydrogenation reaction uses a hydrogenator or an autoclave.

[0284] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0285] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0286] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0287] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0288] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: n-hexane / ethyl acetate system, dichloromethane / methanol system, dichloromethane / ethyl acetate system, etc. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0289] Example 1

[0290] 2-(7-{1-[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)methyl]piperidin-3-yl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N,N-diisopropylbenzamide 1

[0291] first step

[0292] 2-Bromobenzoyl chloride 1b

[0293] Dissolve 2-bromobenzoic acid 1a (5.00 g, 24.9 mmol) in dichloromethane (35 mL) and cool to 0°C. Add oxalyl chloride (3.79 g, 29.9 mmol) and N,N-dimethylformamide (0.1 mL) under a nitrogen atmosphere and stir at room temperature for 1.0 hour. This yields a dichloromethane solution of the title product 1b, which is used directly in the next reaction without further treatment.

[0294] Step 2

[0295] 2-Bromo-N,N-diisopropylbenzamide 1c

[0296] A dichloromethane solution of compound 1b prepared in the previous step was cooled to 0°C and added with diisopropylamine (46.1 g, 455 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was adjusted to a pH of 2-3 by adding 2N aqueous hydrochloric acid, diluted with water (10 mL), and extracted with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether as the eluent to obtain the title product 1c (6.32 g, 22.2 mmol, two-step yield: 89.2%).

[0297] MS m / z(ESI):283.9[M+1]

[0298] 1 H NMR(400MHz, DMSO-d6)δ7.65(d,J=8.0Hz,1H),7.43(t,J=7.6Hz,1H),7.34–7.24(m,2H),3.58(dt,J=13.6,6 .8Hz,1H),3.45(dt,J=13.6,6.8Hz,1H),1.46(d,J=6.8Hz,6H),1.17(d,J=6.8Hz,3H),1.03(d,J=6.8Hz,3H).

[0299] Step 3

[0300] N,N-Diisopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide 1d

[0301] Compound 1c (1.50 g, 5.28 mmol), potassium acetate (1.04 g, 10.6 mmol), and pinacol diboronate (2.01 g, 7.92 mmol) were dissolved in dioxane (20 mL). Pd(dppf)Cl2 (386 mg, 527 μmol) was added under a nitrogen atmosphere, and the mixture was stirred at 100°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether as the eluent to obtain the crude title product 1d (790 mg).

[0302] MS m / z(ESI):332.1[M+1]

[0303] 1 H NMR(400MHz,DMSO-d6)δ7.66(d,J=7.6Hz,1H),7.50–7.45(m,1H),7.37–7.32(m,1H),7.1 5(d,J=7.6Hz,1H),3.54(s,2H),1.47(d,J=6.8Hz,6H),1.25(s,12H),1.10–1.05(m,6H).

[0304] Step 4

[0305] 7-Bromo-5-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine 1f

[0306] Dissolve 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine 1e (10.0 g, 46.9 mmol) in N,N-dimethylformamide (500 mL), add N-iodosuccinimide (11.6 g, 51.6 mmol), and stir at room temperature for 12 hours. The reaction mixture is diluted with water (500 mL) and filtered under reduced pressure to obtain a filter cake containing the crude title product 1f (13.7 g, 40.4 mmol, 86.1% yield).

[0307] 1 H NMR (400MHz, DMSO-d6) δ7.97(s,1H),7.08(s,1H).

[0308] Step 5

[0309] 2-{4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazin-5-yl}-N,N-diisopropylbenzamide 1g

[0310] Compound 1f (8.0 g, 23.6 mmol) was dissolved in dimethyl sulfoxide (650 mL), N,N-dimethylformamide (100 mL), and water (70 mL). Sodium carbonate (5.00 g, 47.2 mmol), compound 1d (9.38 g, 28.3 mmol), and tetrakis(triphenylphosphine)palladium (1.36 g, 1.18 mmol) were added, and the mixture was stirred at 60°C under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (500 mL), and then washed with water (500 mL x 3). The aqueous phase was extracted with ethyl acetate (500 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent to obtain the title product 1g (3.32 g, 7.97 mmol, 33.8% yield).

[0311] MS m / z(ESI):416.0[M+1]

[0312] 1 H NMR(400MHz, DMSO-d6)δ8.00(s,1H),7.54–7.43(m,2H),7.39(dd,J=5.6,2.8Hz,1H),7.36–7.27(m,1H),6.75(s, 1H), 3.62–3.46 (m, 1H), 3.31–3.20 (m, 1H), 1.39 (d, J = 6.4Hz, 3H), 0.99 (d, J = 62.0Hz, 6H), 0.27 (d, J = 41.6Hz, 3H).

[0313] Step 6

[0314] tert-Butyl 5-(4-amino-5-{2-[diisopropylcarbamoyl]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate

[0315] Compound 1g (450 mg, 1.08 mmol) and tert-butyl 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (401 mg, 1.30 mmol) were dissolved in dioxane (5.6 mL) and water (1.4 mL). Sodium carbonate (299 mg, 2.16 mmol) and tetrakis(triphenylphosphine)palladium (125 mg, 108 μmol) were added, and the mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent to obtain the title product 1h (294 mg, 567 μmol, 52.4% yield).

[0316] MS m / z(ESI):519.3[M+1]

[0317] 1 H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.49(dd,J=9.2,5.6Hz,2H),7.42–7.27(m,2H),7.01(s,1H),6.65(s,1H ),4.26(s,2H),3.44(d,J=66.8Hz,6H),2.31(s,3H),1.45–1.37(m,12H),1.00(d,J=73.2Hz,7H),0.25(s,2H).

[0318] Step 7

[0319] tert-Butyl 3-(4-amino-5-{2-[diisopropylcarbamoyl]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate 1i

[0320] Compound 1h (294 mg, 567 μmol) was dissolved in acetic acid (4 mL), and PtO2 (51.5 mg, 227 μmol) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent to obtain the title product 1i (207 mg, 398 μmol, 70.1% yield).

[0321] MS m / z(ESI):521.25[M+1]

[0322] Step 8

[0323] tert-Butyl 3-(5-{2-[diisopropylcarbamoyl]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate 1j

[0324] Compound 1i (207 mg, 567 μmol) was dissolved in tetrahydrofuran (5.0 mL), cooled to 0°C, and tert-butyl nitrite (246 mg, 2.39 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent to obtain the title product 1j (36.0 mg, 71.2 μmol, 17.9% yield).

[0325] MS m / z(ESI):506.25[M+1]

[0326] 1H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 8.59 (s, 1H), 7.57 (d, J = 7.6Hz, 1H), 7.52–7.41 (m, 2H), 7. 30(dd,J=7.6,1.2Hz,1H),7.00(d,J=4.4Hz,1H),5.76(s,1H),4.07(dd,J=29.6,6.4Hz,2H),3.1 7(d,J=5.2Hz,3H),2.97–2.82(m,1H),2.08(s,1H),1.83–1.66(m,2H),1.53(d,J=16.0Hz,1H), 1.40(d,J=6.4Hz,12H),1.08(dd,J=16.0,6.4Hz,4H),0.92–0.82(m,3H),0.26(t,J=6.4Hz,3H).

[0327] Step 9

[0328] 2-[7-(Piperidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-N,N-diisopropylbenzamide 1k

[0329] Compound 1j (15.0 mg, 29.7 μmol) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL) at 0°C. The reaction was stirred at room temperature for 3.0 hours. The mixture was concentrated under reduced pressure to afford the crude title product 1k (12.0 mg), which was used directly in the next step without purification.

[0330] MS m / z(ESI):406.1[M+1]

[0331] Step 10

[0332] 2-(7-{1-[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)methyl]piperidin-3-yl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-N,N-diisopropylbenzamide 1

[0333] The crude product of compound 1k (12.0 mg), N,N-diisopropylethylamine (3.82 mg, 29.6 μmol), and 2-oxo-3H-1,3-benzoxazole-5-carbaldehyde 1l (5.79 mg, 35.5 μmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 1.5 hours. The mixture was cooled to 0°C, and sodium triacetoxyborohydride (31.4 mg, 148 μmol) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by thin-layer chromatography using dichloromethane / methanol as the eluent. The crude product was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 45%-50%) to obtain the title product 1 (13.0 mg, 23.5 μmol, yield: 79.5%).

[0334] MS m / z(ESI):553.2[M+1]

[0335] 1 H NMR(400MHz, DMSO-d6)δ9.03(d,J=3.6Hz,1H),8.54(s,1H),7.56(d,J=7.6Hz,1H),7.52–7.38 (m,2H),7.29(d,J=7.2Hz,1H),7.17(s,1H),7.05–6.92(m,3H),3.54(s,1H),3.26–3.21(m,1H) ,3.02(s,1H),2.83(s,1H),2.19–1.97(m,3H),1.70(s,2H),1.48(s,1H),1.39(t,J=5.6Hz,3H ),1.23(s,1H),1.03(dd,J=25.6,6.8Hz,3H),0.91–0.78(m,3H),0.22(dd,J=10.0,6.8Hz,3H).

[0336] Example 2

[0337] N,N-diisopropyl-2-[7-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]benzamide

[0338] first step

[0339] tert-Butyl 3-(4-amino-5-{2-[diisopropylcarbamoyl]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 2a

[0340] Compound 1g (450 mg, 1.08 mmol) and tert-butyl 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (382 mg, 1.30 mmol) were dissolved in dioxane (4.0 mL) and water (1.0 mL). Potassium carbonate (299 mg, 2.16 mmol) and tetrakis(triphenylphosphine)palladium (124 mg, 108 μmol) were added, and the mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent to obtain the title product 2a (334 mg, 661 μmol, yield: 61.2%).

[0341] MS m / z(ESI):505.3[M+1]

[0342] 1 H NMR (400MHz, DMSO-d6) δ8.04(s,1H),7.53–7.44(m,2H),7.39(d,J=7.2Hz,1H),7.33(d,J=8.4Hz,1H),6.86(d,J=6.8Hz,1H),6.6 5(d,J=14.8Hz,1H),4.37(d,J=74.4Hz,4H),3.58(s,1H),3.28(s,1H),1.49–1.33(m,12H),0.99(d,J=62.4Hz,7H),0.23(s,2H).

[0343] Step 2

[0344] Tert-butyl 3-(4-amino-5-{2-[diisopropylcarbamoyl]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)pyrrolidine-1-carboxylate 2b

[0345] Compound 2a (334 mg, 661 μmol) was dissolved in acetic acid (5 mL), and PtO2 (60.1 mg, 264 μmol) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent to obtain the title product 2b (335 mg, 661 μmol, yield: 99.9%).

[0346] MS m / z(ESI):507.3[M+1]

[0347] 1H NMR (400MHz, DMSO-d6) δ7.92(s,1H),7.51–7.41(m,2H),7.36(d,J=6.8Hz,1H),7.30(d,J=6.4Hz,1H),6.53(s,1H),3.82(s,2H),3.44(dd,J=14.0,6. 8Hz,1H),3.39–3.20(m,4H),2.27(dd,J=21.2,16.0Hz,1H),2.07–1.90(m, 1H),1.86(s,2H),1.40(d,J=12.0Hz,12H),1.17–0.76(m,7H),0.24(s,2H).

[0348] Step 3

[0349] Tert-butyl 3-(5-{2-[diisopropylcarbamoyl]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)pyrrolidine-1-carboxylate 2c

[0350] Compound 2b (230 mg, 453 μmol) and 2-hydroxybenzoic acid (6.27 mg, 45.4 μmol) were dissolved in tetrahydrofuran (4.6 mL) and cooled to 0°C. Tert-butyl nitrite (280 mg, 2.72 mmol) was added and stirred at room temperature for 1.0 hour. The mixture was then heated to 60°C and stirred for 1.0 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography using ethyl acetate / petroleum ether as the eluent to obtain the title product 2c (63.0 mg, 128 μmol, 28.2% yield).

[0351] MS m / z(ESI):492.3[M+1]

[0352] Step 4

[0353] N,N-Diisopropyl-2-[7-(pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]benzamide 2d

[0354] Compound 2c (60.0 mg, 122 μmol) was dissolved in dichloromethane (0.75 mL) and trifluoroacetic acid (0.25 mL) at 0°C. The reaction was stirred at room temperature for 2.0 hours. The mixture was concentrated under reduced pressure to afford the crude title product 2d, which was used directly in the next step without purification.

[0355] MS m / z(ESI):392.2[M+1]

[0356] Step 5

[0357] N,N-diisopropyl-2-[7-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]benzamide

[0358] The crude product of compound 2d (50.0 mg) and [(1r,4r)-4-ethanesulfonamidocyclohexyl]methylethane-1-sulfonate 2e (22.5 mg, 72 μmol) were dissolved in N,N-dimethylformamide (1 mL). Potassium carbonate (26.5 mg, 192 μmol) and potassium iodide (7.97 mg, 48.0 μmol) were added, and the mixture was stirred at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent. The crude product was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 35%-45%) to obtain the title product 2 (9.7 mg, 16.3 μmol, yield: 33.9%).

[0359] MS m / z(ESI):595.3[M+1]

[0360] 1 H NMR(400MHz, DMSO-d6)δ9.04(d,J=2.4Hz,1H),8.56(s,1H),7.59(d,J=7.2Hz,1H),7.50–7.42(m,2H) ,7.30(d,J=7.2Hz,1H),7.04(d,J=3.2Hz,1H),7.00(dd,J=7.6,3.2Hz,1H),3.95–3.82(m,1H),3.28( d,J=7.2Hz,2H),3.06–2.89(m,4H),2.66(q,J=8.0Hz,1H),2.40–2.15(m,4H),1.83(d,J=12.4Hz,5H) ,1.41(dd,J=6.4,1.6Hz,3H),1.36–1.07(m,10H),0.87(d,J=6.8Hz,5H),0.25(dd,J=6.8,2.4Hz,3H).

[0361] Example 3

[0362] 2-{7-[4-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)cyclohexyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-N,N-diisopropylbenzamide

[0363] first step

[0364] Tert-butyl N-[4-(4-amino-5-{2-[diisopropylcarbamoyl]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl-3-en-1-yl]carbamate 3a

[0365] Compound 1g (500 mg, 1.20 mmol) and tert-butyl N-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexyl-3-en-1-yl]carbamate (466 mg, 1.44 mmol) were dissolved in dioxane (8.0 mL) and water (2.0 mL). Potassium carbonate (332 mg, 2.40 mmol) and tetrakis(triphenylphosphine)palladium (138.8 mg, 120.1 μmol) were added, and the mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent. The crude product was purified by slurrying with ethyl acetate (20 mL) to obtain the title product 3a (490 mg, 920 μmol, yield: 76.5%).

[0366] MS m / z(ESI):533.3[M+1]

[0367] 1 H NMR (400MHz, DMSO-d6) δ7.93(s,1H),7.51–7.43(m,2H),7.37(d,J=8.0Hz,1H),7.31(d,J=8.4Hz,1H),6.94–6.79(m,2H),6.64(s,1H),3.52(s,2 H),3.26(s,1H),2.64–2.53(m,1H),2.42(s,1H),2.20–2.06(m,1H),1.9 0(d,J=8.4Hz,1H),1.62–1.48(m,1H),1.40(s,13H),1.21–0.10(m,8H).

[0368] Step 2

[0369] tert-Butyl N-[4-(4-amino-5-{2-[b-diisopropylcarbamoyl]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl]carbamate 3b

[0370] Compound 3a (440 mg, 826 μmol) was dissolved in acetic acid (10 mL), and PtO2 (75.0 mg, 330 μmol) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere (1.5 MPa). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent to obtain the title product 3b (433 mg, 810 μmol, yield: 98.0%).

[0371] MS m / z(ESI):535.4[M+1]

[0372] 1 H NMR(400MHz, DMSO-d6)δ7.88(d,J=3.6Hz,1H),7.51–7.39(m,2H),7.38–7.33(m,1H),7.32–7.27(m,1H),6.92–6.75(m,1H),6.65–6.40(m,1H),3.6 4–3.49(m,1.43H),3.31–3.21(m,2H),3.04–2.96(m,0.56H),2.09–1.52( m,7H),1.38(s,12H),1.34–1.29(m,1H),1.19–0.77(m,7H),0.24(s,2H).

[0373] Step 3

[0374] Tert-butyl N-[4-(5-{2-[diisopropylcarbamoyl]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexyl]carbamate 3c

[0375] Compound 3b (353 mg, 660 μmol) and 2-hydroxybenzoic acid (9.12 mg, 66.0 μmol) were dissolved in tetrahydrofuran (10.0 mL), cooled to 0°C, and tert-butyl nitrite (408 mg, 3.96 mmol) was added. The temperature was raised to 70°C and stirred for 1.0 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether as the eluent to obtain the title product 3c (140 mg, 269 μmol, yield: 40.8%). MS m / z (ESI): 520.3 [M+1]

[0376] Step 4

[0377] 2-[7-(4-aminocyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-N,N-diisopropyl)benzamide 3d

[0378] Compound 3c (120 mg, 231 μmol) was dissolved in dichloromethane (4.0 mL) and trifluoroacetic acid (1.0 mL) at 0°C. The reaction was stirred at room temperature for 2.0 hours. The mixture was concentrated under reduced pressure to afford the crude title product 3d, which was used directly in the next step without purification.

[0379] MS m / z(ESI):420.2[M+1]

[0380] Step 5

[0381] 2-{7-[4-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)cyclohexyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-N,N-diisopropylbenzamide

[0382] Compound 3d (49.0 mg, 117 μmol) and 4-(5,6-dimethoxypyridazin-3-yl)benzaldehyde 3e (28.5 mg, 117 μmol) were dissolved in dichloromethane (5 mL) and stirred at 0°C for 0.5 hours. Sodium triacetoxyborohydride (124 mg, 584 μmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent. The crude product was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.05% ammonia), elution gradient: 45%-90%) to give the title product 3 (2.51 mg, 3.87 μmol, yield: 3.31%).

[0383] MS m / z(ESI):648.4[M+1]

[0384] 1 H NMR(400MHz, DMSO-d6)δ9.04(s,1H),8.54(s,1H),8.03(d,J=8.0Hz,2H),7.63–7.55(m, 2H),7.54–7.41(m,4H),7.30(d,J=7.2Hz,1H),7.01(s,1H),4.05(s,3H),3.98(s,3H),3 .78(s,2H),3.41–3.38(m,1H),3.27–3.24(m,1H),2.86(s,1H),2.03–1.57(m,10H),1.4 0(d,J=6.8Hz,3H),1.15(d,J=6.8Hz,3H),0.87(d,J=6.4Hz,3H),0.27(d,J=6.4Hz,3H).

[0385] Example 4

[0386] 2-{6-[4-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)cyclohexyl-1-en-1-yl]pyrrolo[1,2-a]pyrazin-8-yl}-N-ethyl-5-fluoro-N-isopropylbenzamide

[0387] first step

[0388] 2-Bromo-N-ethyl-5-fluoro-N-isopropylbenzamide 4b

[0389] N-Ethylpropan-2-amine (12 g, 137.67 mmol) and triethylamine (27.72 g, 273.96 mmol) were added to a solution of 2-bromo-5-fluoro-benzoic acid 4a (20 g, 91.32 mmol) in dichloromethane (250 mL), followed by the slow addition of HATU (52.08 g, 136.98 mmol). The mixture was stirred at 25°C for 12 hours. The mixture was washed with saturated aqueous sodium carbonate (100 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product, which was purified by silica gel column chromatography (A: petroleum ether, B: ethyl acetate, 0% B to 15% B in A, thin-layer chromatography (petroleum ether:ethyl acetate = 1:1, Rf = 0.35) to afford the title product 4b (24 g, 83.29 mmol, 91.20% yield) as a white solid.

[0390] MS m / z(ESI):289.8[M+1]

[0391] 1 H NMR(400MHz, DMSO-d6)δ7.80–7.61(m,1H),7.38–7.29(m,1H),7.22(dt,J=3.0,8.6Hz,1H),3.57–3.38 (m,2H),3.26(qd,J=7.0,13.8Hz,1H),1.25–1.17(m,6H),1.06(d,J=6.6Hz,2H),0.96(t,J=7.1Hz,1H)

[0392] Step 2

[0393] N-Ethyl-5-fluoro-N-isopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide 4c

[0394] Compound 4b (13 g, 45.11 mmol), potassium acetate (13.3 g, 135.52 mmol), and pinacol diboron (35 g, 137.83 mmol) were dissolved in DMSO (200 mL). Pd(dppf)Cl2.DCM (3.30 g, 4.51 mmol) was added under a nitrogen atmosphere, and the reaction was stirred at 110°C for 12 hours. After cooling to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (150 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (A: petroleum ether, B:ethyl acetate, 0% B to 20% B in A, thin-layer chromatography (petroleum ether:ethyl acetate = 3:1, Rf = 0.2)) to obtain the title product 4c (10 g, 29.83 mmol, yield: 66.12%).

[0395] MS m / z(ESI):336.2[M+1]

[0396] 1 H NMR (400MHz, DMSO-d6) δ7.73 (dd, J=6.5, 8.1Hz, 1H), 7.20 (dt, J=2.4, 8.7Hz, 1H), 7.09 (br dd,J=2.4,9.4Hz,1H),3.54(td,J=6.6,13.2Hz,1H),3.31–3.27(m,2H),1.28–1.20(m,16H),1.16(s,4H)

[0397] Step 3

[0398] 6,8-Dibromopyrrolo[1,2-a]pyrazine 4e

[0399] Pyrrolo[1,2-a]pyrazine 4d (2.0 g, 16.93 mmol) was dissolved in dichloromethane (80 mL), and N-bromosuccinimide (6.03 g, 33.86 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude title product 4e (4.0 g, 14.5 mmol, 85.63% yield). The crude product was used directly in the next step without purification.

[0400] MS m / z(ESI):276.9[M+1].

[0401] Step 4

[0402] tert-Butyl N-(4-{8-bromopyrrolo[1,2-a]pyrazin-6-yl}cyclohexyl-3-en-1-yl)carbamate 4f

[0403] Compound 4e (1.5 g, 5.44 mmol) and tert-butyl N-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexyl-3-en-1-yl]carbamate (1.50 g, 4.64 mmol) were dissolved in dioxane (20 mL) and water (2.0 mL). Sodium carbonate (1.20 g, 11.32 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (225.00 mg, 275.52 μmol) were added, and the mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to give the title product 4f (900 mg, 2.29 mmol, yield: 42.2%).

[0404] MS m / z(ESI):393.9[M+1]

[0405] Step 5

[0406] 4g of tert-butyl N-[4-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}pyrrolo[1,2-a]pyrazin-6-yl)cyclohexyl-3-en-1-yl]carbamate

[0407] Compound 4f (900 mg, 2.29 mmol) and compound 4c (1.15 g, 3.44 mmol) were dissolved in dioxane (15 mL) and water (1.5 mL). Sodium carbonate (730 mg, 6.89 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (150 mg, 230.15 μmol) were added, and the mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 4g (600 mg, 1.15 mmol, 50.23% yield).

[0408] MS m / z(ESI):521.2[M+1]

[0409] Step 6

[0410] 2-[6-(4-aminocyclohexyl-1-en-1-yl)pyrrolo[1,2-a]pyrazin-8-yl]-N-ethyl-5-fluoro-N-isopropylbenzamide 4h

[0411] Compound 4g (170 mg, 326.52 μmol) was dissolved in dichloromethane (4.94 mL) and trifluoroacetic acid (372.3 mg, 3.27 mmol, 0.25 mL) was added. The reaction was stirred at room temperature for 1.0 hour. The mixture was concentrated under reduced pressure to obtain the crude title product 4h (220 mg), which was used directly in the next step without purification.

[0412] Step 7

[0413] 2-{6-[4-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)cyclohexyl-1-en-1-yl]pyrrolo[1,2-a]pyrazin-8-yl}-N-ethyl-5-fluoro-N-isopropylbenzamide

[0414] The crude product of compound 4h (140 mg) was dissolved in dichloromethane (3.0 mL), and triethylamine (265.02 mg, 2.62 mmol) and compound 3e (51.18 mg, 209.52 μmol) were added. The mixture was stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (49.38 mg, 785.72 μmol) was added, and the mixture was stirred at 45°C for 12 hours. The reaction solution was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate (20 mL), and extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 8%-38%) to obtain the title product 4 (79.75 mg, 122.93 μmol, yield: 46.9%).

[0415] MS m / z(ESI):649.2[M+1]

[0416] 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),8.25(d,J=5.2Hz,1H),8.05(d,J=8.4Hz,2H),7.63–7.57(m,2H ),7.55–7.47(m,3H),7.37–7.21(m,2H),6.85–6.80(m,1H),6.07(s,1H),4.05(s,3H),3.99(s,3H), 3.87(s,2H),2.92–2.77(m,2H),2.58(s,1H),2.45–2.22(m,4H),2.12–1.98(m,2H),1.64–1.48(m,1 H),1.26–1.01(m,1H),0.89–0.85(m,2H),0.82–0.74(m,3H),0.73–0.65(m,1H),0.28–0.16(m,3H).

[0417] Example 5

[0418] N-ethyl-2-[1-methyl-6-(4-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)methyl]amino}cyclohexyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-N-isopropylbenzamide 5

[0419] first step

[0420] 2-Bromo-N-ethyl-N-isopropylbenzamide 5a

[0421] Compound 1a (5.00 g, 24.8 mmol), isopropylethylamine (2.60 g, 29.8 mmol, 3.61 mL), HOBt (4.03 g, 29.8 mmol), and diisopropylethylamine (6.43 g, 49.7 mmol, 8.67 mL) were dissolved in dichloromethane (50 mL), cooled to 0°C, and EDCI (5.72 g, 29.8 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether as the eluent to obtain the title product 5a (6.29 g, 23.2 mmol, 93.6% yield).

[0422] MS m / z(ESI):269.9[M+1]

[0423] 1 H NMR (400MHz, DMSO-d6) δ7.69–7.63(m,1H),7.48–7.42(m,1H),7.37–7.29(m,2H),4.57–4.46(m,0.27H),3.55–3.40( m,1.42H),3.32–3.22(m,0.72H),3.19–3.09(m,0.27H),2.98–2.88(m,0.26H),1.28–1.15(m,6H),1.08–0.90(m,3H).

[0424] Step 2

[0425] N-Ethyl-N-isopropyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide 5b

[0426] Compound 5a (3.00 g, 11.1 mmol), potassium acetate (2.18 g, 22.2 mmol), and pinacol diboron (4.23 g, 16.6 mmol) were dissolved in dioxane (40 mL). Pd(dppf)Cl2 (812 mg, 1.11 mmol) was added under a nitrogen atmosphere, and the reaction was stirred at 100°C for 12 hours. The reaction solution was cooled to room temperature, diluted with water (120 mL), and extracted with ethyl acetate (120 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether as the eluent to obtain the crude title product 5b (1.51 g). The crude product was used directly in the next reaction.

[0427] Step 3

[0428] tert-Butyl N-(4-{4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl}cyclohexyl-3-en-1-yl)carbamate 5d

[0429] 4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5c (500 mg, 2.47 mmol) and tert-butyl N-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexyl-3-en-1-yl]carbamate (640 g, 1.98 mmol) were dissolved in dioxane (6.0 mL) and water (1.2 mL). Sodium carbonate (524 mg, 4.95 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (181 mg, 247 μmol) were added, and the mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 5d (360 mg, 0.99 mmol, 40.1% yield).

[0430] 1 H NMR (400MHz, DMSO-d6) δ8.16(s,1H),7.58(s,1H),6.89(d,J=7.2Hz,1H),6.82(s,1H),4.05(s,3H),3.57(s,1H),2.83(d,J=17.6Hz,1 H),2.54(s,1H),2.48–2.45(m,1H),2.16(dd,J=17.2,8.8Hz,1H),1.95(d,J=11.8Hz,1H),1.58(tt,J=10.8,5.2Hz,1H),1.40(s,9H).

[0431] Step 4

[0432] tert-Butyl N-[4-(4-{2-[ethyl(isopropyl)carbamoyl]-phenyl}1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclohexyl-3-en-1-yl]carbamate 5e

[0433] Compound 5d (350 mg, 0.96 mmol) and compound 5b (336 mg, 1.06 mmol) were dissolved in dioxane (6.0 mL) and water (1.2 mL). Sodium carbonate (204 mg, 1.93 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (70.6 mg, 96 μmol) were added, and the mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 5e (380 mg, 0.73 mmol, 75.2% yield).

[0434] MS m / z(ESI):518.3[M+1]

[0435] 1 H NMR(400MHz, DMSO-d6)δ7.98(d,J=8.9Hz,1H),7.68–7.65(m,1H),7.63–7.56(m,2H),7.48–7 .42(m,1H),7.38(d,J=2.8Hz,1H),6.87(d,J=7.8Hz,1H),6.67(s,1H),4.06(d,J=2.4Hz,3H) ,3.55(s,1H),3.36(dd,J=12.8,6.4Hz,3H),2.79(d,J=39.2Hz,2H),2.17(s,1H),1.99–1.93 (m,1H),1.64–1.50(m,1H),1.40(s,9H),0.84(dd,J=6.4,4.0Hz,6H),0.67(d,J=6.8Hz,3H).

[0436] Step 5

[0437] tert-Butyl N-[4-(4-{2-[ethyl(isopropyl)carbamoyl]-phenyl}1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclohexyl]carbamate 5f

[0438] Compound 5e (380 mg, 734 μmol) was dissolved in methanol (5 mL) and Pd / C (10 wt.% 50% water, 8.92 mg, 73.4 μmol) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude title product 5f (300 mg). The crude product was used directly in the next reaction without purification.

[0439] MS m / z(ESI):520.4[M+1]

[0440] 1 H NMR(400MHz, DMSO-d6)δ7.93(d,J=11.6Hz,1H),7.65–7.55(m,3H),7.44(d,J=6.0H z,1H),7.22–7.07(m,1H),6.96–6.76(m,1H),4.05(d,J=3.2Hz,3H),3.40(d,J=17.2 Hz,1H),2.88(dd,J=21.6,7.6Hz,1H),2.77–2.65(m,1H),2.51(s,2H),1.91(s,3H), 1.80–1.55(m,4H),1.39(d,J=1.2Hz,9H),0.86(d,J=6.4Hz,3H),0.79–0.65(m,6H).

[0441] Step 6

[0442] 2-[6-(4-aminocyclohexyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-N-ethyl-N-isopropylbenzamide 5g

[0443] Compound 5f (300 mg, 577 μmol) was dissolved in dichloromethane (6.0 mL) and trifluoroacetic acid (0.5 mL) was added at 0°C. The reaction was stirred at room temperature for 2.0 hours. The mixture was concentrated under reduced pressure to obtain 5 g of crude title product (245 mg), which was used directly in the next step without purification.

[0444] MS m / z(ESI):420.3[M+1]

[0445] Step 7

[0446] N-ethyl-2-[1-methyl-6-(4-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)methyl]amino}cyclohexyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-N-isopropylbenzamide 5

[0447] The crude product of compound 5g (80 mg, 191 μmol) was dissolved in dichloromethane (1.0 mL). Triethylamine was added to adjust the pH of the reaction solution to 9-10. Compound 11 (31.1 mg, 191 μmol) and sodium triacetoxyborohydride (121 mg, 572 μmol) were added at 0°C and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC (mobile phase: acetonitrile, water (0.1% trifluoroacetic acid), elution gradient: 5%-50%) to obtain the title product 5 (62.6 mg, 110 μmol, yield: 58.0%).

[0448] MS m / z(ESI):567.4[M+1]

[0449] 1 H NMR (400MHz, DMSO-d6) δ11.88(d,J=9.2Hz,1H),8.67(d,J=66.0Hz,2H),7.98(d,J=4.8Hz,1H),7.65–7.42(m,4H),7.41 –7.10(m,4H),4.23(d,J=5.2Hz,2H),4.07(d,J=14.8Hz,3H),3.42–2.70(m,5H),2.30–1.49(m,8H),1.09–0.13(m,9H).

[0450] Example 6

[0451] N-ethyl-2-[1-methyl-6-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-N-isopropylbenzamide

[0452] first step

[0453] tert-Butyl 3-{4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl}-2,5-dihydro-1H-pyrrole-1-carboxylate 6a

[0454] 4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5c (200 mg, 989 μmol) was dissolved in dioxane (3.0 mL) and water (0.6 mL). Sodium carbonate (209 mg, 1.98 mmol), tert-butyl 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (233 mg, 791.9 μmol), and Pd(dppf)Cl2 (72.4 mg, 98.9 μmol) were added. The mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to afford the title product 6a (150 mg, 448 μmol, 45.2% yield).

[0455] MS m / z(ESI):279.1[M-55]

[0456] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,1H),7.83(d,J=2.0Hz,1H),6.99(d,J=12.8Hz ,1H),4.54(s,2H),4.32(s,2H),4.06(d,J=1.2Hz,3H),1.46(d,J=8.8Hz,9H).

[0457] Step 2

[0458] tert-Butyl 3-(4-{2-[ethyl(isopropyl)carbamoyl]-phenyl}1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 6b

[0459] Compound 6a (130 mg, 388 μmol) and compound 5b (184 mg, 582 μmol) were dissolved in dioxane (3.0 mL) and water (0.6 mL). Sodium carbonate (204 mg, 1.93 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (70.6 mg, 96 μmol) were added, and the mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 6b (60 mg, 122.5 μmol, 31.5% yield).

[0460] Step 3

[0461] tert-Butyl 3-(4-{2-[ethyl(isopropyl)carbamoyl]-phenyl}1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)pyrrolidine-1-carboxylate 6c

[0462] Compound 6b (60 mg, 122.5 μmol) was dissolved in methanol (2.0 mL), and Pd / C (6.0 mg) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 6c (53.0 mg, 107 μmol, yield: 87.9%).

[0463] MS m / z(ESI):492.3[M+1]

[0464] 1 H NMR(400MHz, DMSO-d6)δ7.98(s,1H),7.61(dd,J=10.4,6.4Hz,3H),7.46(dd,J=12.0,6.4Hz,1H),7.14(s,1H),4.05 (s,3H),3.76–3.36(m,5H),2.89(s,1H),2.25(s,1H),2.20–2.11(m,1H),1.41(d,J=4.8Hz,9H),0.90–0.14(m,9H).

[0465] Step 4

[0466] N-Ethyl-2-[1-methyl-6-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-N-isopropylbenzamide 6d

[0467] Compound 6c (47.0 mg, 95.6 μmol) was dissolved in dichloromethane (4.0 mL) and trifluoroacetic acid (1.0 mL) was added at 0°C. The reaction was stirred at room temperature for 2.0 hours. The mixture was concentrated under reduced pressure to obtain the crude title product 6d (38 mg), which was used directly in the next step without purification.

[0468] MS m / z(ESI):392.3[M+1]

[0469] Step 5

[0470] N-ethyl-2-[1-methyl-6-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-N-isopropylbenzamide

[0471] The crude product of compound 6d (38.0 mg, 97.0 μmol) and [(1r,4r)-4-ethanesulfonamidocyclohexyl]methylethane-1-sulfonate 2e (45.8 mg, 97.0 μmol) were dissolved in N,N-dimethylformamide (2.0 mL). Potassium carbonate (53.6 mg, 388 μmol) and potassium iodide (16.1 mg, 97.0 μmol) were added, and the mixture was stirred at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography. The crude product was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 55%-40%) to obtain the title product 6 (13.0 mg, 21.8 μmol, yield: 22.5%) as a white solid.

[0472] MS m / z(ESI):595.3[M+1]

[0473] 1 H NMR(400MHz, DMSO-d6)δ7.91(s,1H),7.62–7.54(m,3H),7.42(d,J=4.4Hz,1H),7.16(s,1H),4.05(s,3H),3.71–3.60(m,1H),3.42(d,J=6.8Hz, 1H),3.22–2.71(m,9H),2.47(d,J=12.4Hz,1H),2.29(s,2H),2.18–2.07 (m,1H),1.94–1.79(m,4H),1.42(d,J=20.8Hz,1H),1.33–0.06(m,17H).

[0474] Example 8

[0475] 2-{6-[5-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)cyclohexyl-1-en-1-yl]1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl}-N-ethyl-N-isopropylbenzamide 8

[0476] first step

[0477] tert-Butyl N-(3-{4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl}cyclohexyl-3-en-1-yl)carbamate 8a

[0478] 4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5c (300 mg, 1.48 mmol) was dissolved in dioxane (12 mL) and water (2.0 mL). Sodium carbonate (315 mg, 2.97 mmol), tert-butyl N-[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexyl-3-en-1-yl]carbamate (504 mg, 1.56 mmol), and Pd(dppf)Cl2 (109 mg, 149 μmol) were added. The mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to afford the title product 8a (220 mg, 606 μmol, 40.8% yield) as a white solid.

[0479] MS m / z(ESI):363.1[M+1]

[0480] 1 H NMR (400MHz, DMSO-d6) δ8.16(s,1H),7.57(s,1H),6.95(d,J=7.6Hz,1H),6.86(s,1H),4.04(s,3H),3.62( s,1H),2.93(d,J=15.6Hz,1H),2.32(dd,J=16.8,10.4Hz,3H),1.83(d,J=12.4Hz,1H),1.58–1.39(m,10H).

[0481] Step 2

[0482] tert-Butyl N-[3-(4-{2-[ethyl(isopropyl)carbamoyl]phenyl}-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclohexyl-3-en-1-yl]carbamate 8b

[0483] Compound 8a (250 mg, 689 μmol) and sodium carbonate (146 mg, 1.38 mmol) were dissolved in dioxane (6.0 mL) and water (1.0 mL). Compound 5b (437 mg, 689 μmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (50.4 mg, 68.9 μmol) were added, and the mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 8b (227 mg, 439 μmol, yield: 63.7%).

[0484] MS m / z(ESI):518.3[M+1]

[0485] Step 3

[0486] 2-[6-(5-aminocyclohexyl-1-en-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-N-ethyl-N-isopropylbenzamide 8c

[0487] Compound 8b (90.0 mg, 174 μmol) was dissolved in dichloromethane (2.1 mL), and trifluoroacetic acid (0.7 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour and concentrated under reduced pressure to obtain the crude title product 8c (72 mg), which was used directly in the next reaction without purification.

[0488] MS m / z(ESI):418.3[M+1]

[0489] Step 4

[0490] 2-{6-[5-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)cyclohexyl-1-en-1-yl]1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl}-N-ethyl-N-isopropylbenzamide 8

[0491] Dissolve the crude product of compound 8c (72 mg, 172 μmol) in dichloromethane (4.0 mL), and add compound 3e (42 mg, 172 μmol). Cool to 0°C, add sodium triacetoxyborohydride (183 mg, 862 μmol), and stir at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography using dichloromethane / methanol as the eluent. The crude product is then purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia water), elution gradient: 50%-90%) to obtain the title product 8 (20.3 mg, 31.4 μmol, yield: 14.7%).

[0492] MS m / z(ESI):646.3[M+1]

[0493] 1H NMR (400MHz, DMSO-d6) δ8.04(d,J=8.0Hz,2H),7.97(d,J=8.8Hz,1H),7.70–7.64(m,1H),7.63–7.51( m,5H),7.49–7.42(m,1H),7.38(d,J=4.0Hz,1H),6.71(s,1H),4.29–4.19(m,0.23H),4.05(s,6H),3. 98(s,3H),3.92(s,2H),3.40–3.35(m,1H),3.01(dd,J=37.2,16.0Hz,1H),2.89–2.69(m,2H),2.44–2 .18(m,4H),1.97(d,J=11.2Hz,1H),1.41(d,J=6.8Hz,1H),1.08–0.61(m,7H),0.17(d,J=6.4Hz,2H).

[0494] Example 9

[0495] 2-{6-[3-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)piperidin-1-yl]-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl}-N-ethyl-N-isopropylbenzamide 9

[0496] first step

[0497] tert-Butyl N-(1-{4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl}piperidin-3-yl)carbamate 9a

[0498] 4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5c (300 mg, 1.48 mmol) and tert-butyl N-(piperidin-3-yl)carbamate (297 mg, 1.48 mmol) were dissolved in toluene (6 mL). Pd(dba) (85.3 mg, 148 μmol), BINAP (184 mg, 296 μmol), and KCO (410 mg, 2.97 mmol) were added, and the mixture was stirred at 80°C under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to afford the title product 9a (60.0 mg, 164 μmol, 11% yield) as a colorless oil.

[0499] MS m / z(ESI):366.1[M+1]

[0500] Step 2

[0501] tert-Butyl N-[1-(4-{2-[ethyl(isopropyl)carbamoyl]phenyl}-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)piperidin-3-yl]carbamate 9b

[0502] Compound 9a (55.0 mg, 150 μmol) and compound 5b (95.3 mg, 300 μmol) were dissolved in dioxane (4.0 mL) and water (1.0 mL). Xphos-Pd-G2 (11.8 mg, 15.0 μmol), Xphos (14.3 mg, 30.0 μmol), and Cs2CO3 (97.9 mg, 300 μmol) were added, and the mixture was stirred at 80°C under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 9b (64.0 mg, 122 μmol, 81.7% yield).

[0503] MS m / z(ESI):521.3[M+1]

[0504] Step 3

[0505] 2-[6-(3-Aminopiperidin-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-N-ethyl-N-isopropylbenzamide 9c

[0506] Compound 9b (50.0 mg, 96 μmol) was dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (0.5 mL) was added at 0°C. The reaction was stirred at room temperature for 2.0 hours. The mixture was concentrated under reduced pressure to obtain the crude title product 9c (40 mg), which was used directly in the next step without purification.

[0507] MS m / z(ESI):421.2[M+1]

[0508] Step 4

[0509] 2-{6-[3-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)piperidin-1-yl]-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl}-N-ethyl-N-isopropylbenzamide 9

[0510] Crude compound 9c (40 mg, 95.1 μmol) was dissolved in dichloromethane (2.5 mL), and compound 3e (23.2 mg, 95.1 μmol) was added. The mixture was cooled to 0°C, and sodium triacetoxyborohydride (141 mg, 665 μmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using dichloromethane / methanol as the eluent. The crude product was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 5%-50%) to obtain the title product 9 (26.0 mg, 40 μmol, yield: 42.1%) as a white solid.

[0511] MS m / z(ESI):649.3[M+1]

[0512] 1 H NMR (400MHz, DMSO-d6) δ8.05–7.83(m,2H),7.74–7.25(m,8H),6.78–6.63(m,1H),4.50–4.39(m,1H),4.28–4.11(m,2H),4.05(s,3H),3.98( s,3H),3.91(d,J=8.4Hz,2H),3.86(s,3H),3.13–2.62(m,5H),1.98(s ,1H),1.74(s,1H),1.39(s,2H),1.14–0.55(m,7H),0.31–0.14(m,2H).

[0513] Example 11

[0514] N-ethyl-5-fluoro-2-[1-methyl-6-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-N-(isopropyl)benzamide 11

[0515] first step

[0516] tert-Butyl 3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 11a

[0517] Compound 6a (100 mg, 299 μmol) and compound 4c (215 mg, 448 μmol) were dissolved in dioxane (8.0 mL) and water (2.0 mL). Sodium carbonate (63.3 mg, 597 μmol) and Pd(dppf)Cl2 (21.8 mg, 29.8 μmol) were added, and the mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 11a (97.0 mg, 191 μmol, yield: 63.9%) as a white solid.

[0518] MS m / z(ESI):508.2[M+1]

[0519] Step 2

[0520] tert-Butyl 3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)pyrrolidine-1-carboxylate 11b

[0521] Compound 11a (97.0 mg, 191 μmol) was dissolved in methanol (10 mL) and Pd / C (10 mg) was added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product (100 mg) of the title product 11b. The crude product was used directly in the next reaction without purification.

[0522] MS m / z(ESI):510.2[M+1]

[0523] Step 3

[0524] N-Ethyl-5-fluoro-2-[1-methyl-6-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-N-isopropylbenzamide 11c

[0525] Compound 11b (50.0 mg, 98.1 μmol) was dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (0.4 mL) was added at 0°C. The reaction was stirred at room temperature for 2.0 hours. The mixture was concentrated under reduced pressure to obtain the crude title product 11c (40 mg), which was used directly in the next step without purification.

[0526] MS m / z(ESI):410.2[M+1]

[0527] Step 5

[0528] N-ethyl-5-fluoro-2-[1-methyl-6-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-N-(isopropyl)benzamide 11

[0529] The crude product of compound 11c (40 mg) and [(1r,4r)-4-ethanesulfonamidocyclohexyl]methylethane-1-sulfonate 2e (166 mg, 352 μmol) were dissolved in N,N-dimethylformamide (6.0 mL). Potassium carbonate (162 mg, 1.17 mmol) and potassium iodide (48.6 mg, 293 μmol) were added and stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent. The crude product was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 5%-60%) to obtain the title product 11 (70.0 mg, 114 μmol, yield: 38.9%) as a white solid.

[0530] MS m / z(ESI):613.3[M+1]

[0531] 1 H NMR(400MHz, DMSO-d6)δ7.95(s,1H),7.68(dd,J=8.4,5.2Hz,1H),7.48–7.33(m,2H),7.13(s,1H),7.00(d,J=7.6 Hz,1H),4.04(s,3H),3.63–3.56(m,2H),3.08–2.62(m,10H),2.40–2.01(m,4H),1.84(s,4H),1.54–0.06(m,18H).

[0532] Examples 11-1, 11-2

[0533] N-ethyl-5-fluoro-2-{1-methyl-6-[(3R)-1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-N-(isopropyl)benzamide 11-1

[0534] N-ethyl-5-fluoro-2-{1-methyl-6-[(3S)-1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl]-1H-pyrazolo[3,4-b]pyridin-4-yl}-N-(isopropyl)benzamide 11-2

[0535] The racemic compound 11 (68 mg, 111 μmol) was purified by chiral preparative SFC (chiral preparative column: CHIRALCEL AD (250 mm*30 mm, 10 μm); mobile phase: n-hexane / isopropanol / diethylamine = 70 / 30 / 0.1 (V / V / V)). The corresponding fractions were collected and concentrated under reduced pressure. The resulting fractions were purified separately by HPLC (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 10%-35%) to give the title products 11-1 (12 mg, 0.02 mmol, yield: 17.6%) and 11-2 (7.0 mg, 0.01 mmol, yield: 10.2%).

[0536] Single configuration compound 11-1:

[0537] MS m / z(ESI):613.2[M+1]

[0538] Chiral SFC analysis: retention time 2.310 min; column: DAICEL AD-H 4.6 mm I.D.*250 mm L 5 μm; mobile phase: CO2 / IPA [0.1% NH3 (7 M methanol solution)] = 60 / 40.

[0539] 1H NMR(400MHz,DMSO-d6)δ7.95(d,J=2.8Hz,1H),7.67(dt,J=9.2,4.8Hz,1H),7.50–7.33(m ,2H),7.13(s,1H),7.00(d,J=7.6Hz,1H),4.25–4.13(m,0.25H),4.04(d,J=2.0Hz,3H),3 .62–3.49(m,1.78H),3.05–2.56(m,9H),2.36–2.16(m,3H),2.08(s,1H),1.83(t,J=17.2 Hz,4H),1.42–1.28(m,1H),1.27–1.13(m,5H),1.06–0.65(m,9H),0.21(t,J=6.0Hz,2H).

[0540] Single configuration compound 11-2:

[0541] MS m / z(ESI):613.2[M+1]

[0542] Chiral SFC analysis: retention time 2.425 minutes; column: DAICEL AD-H 4.6 mm I.D.*250 mm L 5 μm; mobile phase: CO2 / IPA [0.1% NH3 (7 M methanol solution)] = 60 / 40.

[0543] 1H NMR (400MHz, DMSO-d6) δ7.74(s,1H),7.46(s,1H),7.31–7.10(m,2H),6.92(s,1H),6.80(d,J=6.4Hz,1H),4.03–3.94(m,0 .47H),3.83(s,3H),3.48–3.37(m,1.62H),2.85–2.67(m,5H),2.60–2.38(m,4H),2.19–1.48(m,9H),1.23–0.40(m,16H).

[0544] Example 13

[0545] 2-{6-[4-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)piperidin-1-yl]-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl}-N-ethyl-5-fluoro-N-isopropylbenzamide 13

[0546] first step

[0547] tert-Butyl N-(1-{4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl}piperidin-4-yl)carbamate 13a

[0548] 4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5c (450 mg, 2.23 mmol) and tert-butyl N-(piperidin-4-yl)carbamate (446 mg, 2.23 mmol) were dissolved in toluene (8 mL). Pd(dba) (256 mg, 445 μmol), BINAP (554 mg, 890 μmol), and KCO (615 mg, 4.45 mmol) were added, and the mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using petroleum ether / ethyl acetate as the eluent to afford the title product 13a (78.0 mg, 213 μmol, 9.57% yield) as a yellow solid.

[0549] MS m / z(ESI):366.2[M+1]

[0550] 1H NMR (400MHz, DMSO-d6) δ7.83(s,1H),6.95(s,1H),6.85(d,J=7.6Hz,1H),4.37(d,J=13.2Hz,2H),3.85(s,3H) ,3.53(s,1H),3.02(dd,J=18.4,6.8Hz,2H),1.80(d,J=10.4Hz,2H),1.39(s,9H),1.35(dd,J=7.6,4.4Hz,2H).

[0551] Step 2

[0552] tert-Butyl N-[1-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)piperidin-4-yl]carbamate 13b

[0553] Compound 13a (73.0 mg, 199 μmol) and compound 4c (133 mg, 199 μmol) were dissolved in dioxane (7.3 mL) and water (1.5 mL). Xphos-Pd-G2 (15.7 mg, 19.9 μmol), Xphos (19.0 mg, 39.9 μmol), and Cs2CO3 (130 mg, 399 μmol) were added, and the mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20.0 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using petroleum ether / ethyl acetate as the eluent. The crude product was purified by HPLC (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 55%-65%) to give the title product 13b (20.0 mg, 37.1 μmol, yield: 18.6%).

[0554] MS m / z(ESI):539.3[M+1]

[0555] 1H NMR(400MHz,DMSO-d6)δ7.66(s,2H),7.45–7.31(m,2H),6.88(d,J=7.6Hz,1H) ,6.69(d,J=4.4Hz,1H),4.39–4.21(m,2H),3.87(d,J=2.8Hz,3H),3.52(s,1H) ,3.40–3.34(m,2H),3.01(dd,J=23.6,11.6Hz,2H),2.89(dd,J=13.6,7.2Hz,1 H),1.81(d,J=11.2Hz,2H),1.39(s,11H),0.77(s,7H),0.26(d,J=6.8Hz,2H).

[0556] Step 3

[0557] 2-[6-(4-Aminopiperidin-1-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-N-ethyl-5-fluoro-N-isopropylbenzamide 13c

[0558] Compound 13b (15.0 mg, 27.8 μmol) was dissolved in dichloromethane (0.3 mL), and trifluoroacetic acid (0.1 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The mixture was concentrated under reduced pressure to obtain the crude title product 13c (12 mg), which was used directly in the next reaction without purification.

[0559] MS m / z(ESI):439.2[M+1]

[0560] Step 4

[0561] 2-{6-[4-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)piperidin-1-yl]-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl}-N-ethyl-5-fluoro-N-isopropylbenzamide 13

[0562] The crude product of compound 13c (12.0 mg, 37.3 μmol) was dissolved in dichloromethane (1.5 mL), and compound 3e (6.68 mg, 27.3 μmol) was added. The mixture was stirred at room temperature for 1.5 hours. The mixture was cooled to 0°C, and sodium triacetoxyborohydride (29.0 mg, 136 μmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography using dichloromethane / methanol as the eluent to afford the title product 13 (12.0 mg, 18 μmol, yield: 65.7%) as a white solid.

[0563] MS m / z(ESI):667.3[M+1]

[0564] 1 H NMR (400MHz, DMSO-d6) δ8.03(d,J=8.0Hz,2H),7.66(dd,J=12.4,4.4Hz,2H),7.59(s,1H),7.50(d,J= 8.0Hz,2H),7.38(ddd,J=19.2,10.0,4.0Hz,2H),6.70(d,J=6.0Hz,1H),4.26(s,2H),4.05(s,3H),3. 98(s,3H),3.87(d,J=3.2Hz,3H),3.83(s,2H),3.03(d,J=9.2Hz,2H),2.89(dd,J=13.2,6.8Hz,1H),2 .70(s,1H),1.94(d,J=11.6Hz,2H),1.30(d,J=9.6Hz,2H),1.11–0.63(m,7H),0.26(d,J=6.8Hz,2H).

[0565] Example 14

[0566] N-ethyl-5-fluoro-N-isopropyl-2-[6-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]benzamide 14

[0567] first step

[0568] tert-Butyl 3-{4-chloro-1H-pyrazolo[3,4-b]pyridin-6-yl}-2,5-dihydro-1H-pyrrole-1-carboxylate 14b

[0569] Dissolve 4,6-dichloro-1H-pyrazolo[3,4-b]pyridine 14a (2.0 g, 10.64 mmol) and tert-butyl 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3.14 g, 10.64 mmol) in dioxane (30 mL) and water (5 mL). Add sodium carbonate (3.38 g, 31.9 mmol) and Pd(dppf)Cl2.DCM (779 mg, 1.06 mmol). Stir the reaction at 90°C under a nitrogen atmosphere for 12 hours. Cool the reaction mixture to room temperature, add water (40 mL), and extract with ethyl acetate (50 mL x 3). The combined organic phases are washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to give the title product 14b (600 mg, 1.87 mmol, yield: 17.6%).

[0570] MS m / z(ESI):321.1[M+1]

[0571] 1 H NMR (400MHz, CDCl3) δ8.17(s,1H),7.43–7.28(m,1H),6.94–6.74(m,1H),4.65(br s,2H),4.45(br d,J=12.9Hz,2H),1.54(br s,9H).

[0572] Step 2

[0573] tert-Butyl 3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1H-pyrazolo[3,4-b]pyridin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 14c

[0574] Compound 14b (600 mg, 1.87 mmol) and compound 4c (800 mg, 2.39 mmol) were dissolved in dioxane (8.0 mL) and water (1.5 mL). Cesium carbonate (1.83 g, 1.93 mmol) and Pd(dppf)Cl2.DCM (122 mg, 187.2 μmol) were added, and the reaction was stirred at 90°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, water (15 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 14c (170 mg, 344.4 μmol, yield: 18.4%) as a brown solid.

[0575] MS m / z(ESI):494.2[M+1]

[0576] 1 H NMR (400MHz, DMSO-d6) δ13.92–13.69(m,1H),8.04–7.91(m,1H),7.73(dd,J=5.5,8.5Hz,1H),7.55–7.35(m,3H),6.69(br d,J=12.4Hz,1H),4.61–4.46(m,2H),4.29(br d,J=3.4Hz,2H),3.41–3.32(m,2H),2.79(br dd,J=6.7,13.6Hz,1H),1.46(d,J=7.3Hz,9H),0.93–0.54(m,7H),0.16(br t,J=6.0Hz,2H)

[0577] Step 3

[0578] Tert-butyl 3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1H-pyrazolo[3,4-b]pyridin-6-yl)pyrrolidine-1-carboxylate 14d

[0579] Compound 14c (100 mg, 202.6 μmol) was dissolved in methanol (5.0 mL), and Pd / C (21.6 mg, 202.6 μmol) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 14d (100 mg, 201.8 μmol, yield: 99.6%). The crude product was used directly in the next reaction without purification.

[0580] MS m / z(ESI):496.1[M+1]

[0581] Step 4

[0582] N-Ethyl-5-fluoro-N-isopropyl-2-[6-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]benzamide 14e

[0583] Compound 14d (100 mg, 201.8 μmol) was dissolved in dichloromethane (2.0 mL) and trifluoroacetic acid (0.5 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 14e (100 mg). The crude product was used directly in the next reaction without purification. MS m / z (ESI): 396.3 [M+1]

[0584] Step 5

[0585] tert-Butyl N-[(1r,4r)-4-{[3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1H-pyrazolo[3,4-b]pyridin-6-yl)pyrrolidin-1-yl]methyl}cyclohexyl]carbamate 14f

[0586] Dissolve the crude product of compound 14e (100 mg), tert-butyl N-[(1r,4r)-4-formylcyclohexyl]carbamate (49.07 mg, 215.90 μmol), and triethylamine (59.58 mg, 588.82 μmol) in methanol (2.0 mL) and stir at room temperature for 1.0 hour. Add sodium cyanoborohydride (37.00 mg, 588.82 μmol) and stir at room temperature for 12 hours. Dilute the reaction mixture with saturated aqueous sodium bicarbonate (10 mL) and extract with dichloromethane (20 mL x 3). The combined organic phases are washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by HPLC (mobile phase: acetonitrile, water (0.1% NH 4 HCO 3 ), elution gradient: 40%-70%) to give the title product 14f (70 mg, 115.36 μmol, yield: 58.8%) as a white solid.

[0587] MS m / z(ESI):607.5[M+1]

[0588] 1 H NMR (400MHz, DMSO-d6) δ13.68–13.51(m,1H),7.93(s,1H),7.74–7.63(m,1H),7.51–7.31(m,2H),7.08(s,1H),6.67(br d,J=8.0Hz,1H),3.60–3.46(m,1H),3.22–3.06(m,1H),2.98(br t,J=8.1Hz,1H),2.89–2.72(m,2H),2.56(br d,J=8.3Hz,1H),2.32–2.01(m,4H),1.89–1.67(m,4H),1.36(s,9H),1.17–1.03(m,2H),0.94–0.84(m,4H),0.79–0.61(m,4H),0.19(br dd,J=4.4,6.0Hz,2H)

[0589] Step 6

[0590] N-ethyl-5-fluoro-N-isopropyl-2-[6-(1-{[(1r,4r)-4-aminocyclohexyl]methyl}pyrrolidin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]benzamide 14g

[0591] Compound 14f (60 mg, 98.88 μmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (1.5 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain 14 g (65 mg) of crude title product. The crude product was used directly in the next reaction without purification.

[0592] MS m / z(ESI):507.4[M+1]

[0593] Step 7

[0594] N-ethyl-5-fluoro-N-isopropyl-2-[6-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]benzamide 14

[0595] The crude product (62 mg) of compound 14 was dissolved in dichloromethane (3.0 mL), and ethylsulfonyl chloride (26 mg, 202.2 μmol) and triethylamine (51 mg, 504 μmol) were added. The mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% NH4HCO3), elution gradient: 34%-64%) to obtain the title product 14 (4.86 mg, 8.12 μmol, yield: 8.13%) as a white solid.

[0596] MS m / z(ESI):599.4[M+1]

[0597] 1 H NMR(400MHz,DMSO-d6)δ13.58(s,1H),7.93(s,1H),7.72–7.64(m,1H),7.47–7.33(m,2H ),7.08(s,1H),7.04–6.92(m,1H),3.58–3.47(m,2H),3.03–2.91(m,4H),2.89–2.81(m,1 H),2.78–2.71(m,1H),2.60–2.54(m,1H),2.30–2.16(m,3H),2.13–2.02(m,1H),1.91–1 .72(m,4H),1.43–1.13(m,7H),1.09–0.81(m,6H),0.81–0.59(m,4H),0.25–0.13(m,2H).

[0598] Example 15

[0599] N-ethyl-5-fluoro-2-[1-methyl-6-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)-1H-indazol-4-yl]-N-isopropylbenzamide 15

[0600] first step

[0601] 4-Bromo-6-chloro-1-methyl-1H-indazole 15b

[0602] 4-Bromo-6-chloro-1H-indazole 15a (2.0 g, 8.64 mmol) and cesium carbonate (5.63 g, 17.2 mmol) were dissolved in N,N-dimethylformamide (20 mL), and iodomethane (1.35 g, 9.50 mmol) was added. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure, water (50 mL) was added, and extraction was performed with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to afford the title product 15b (1.30 g, 5.30 mmol, yield: 61.2%) as a white solid.

[0603] MS m / z(ESI):244.95[M+1]

[0604] 1 H NMR (400MHz, DMSO-d6) δ8.04(d,J=0.8Hz,1H),7.95–7.89(m,1H),7.44(d,J=1.6Hz,1H),4.06(s,3H).

[0605] Step 2

[0606] 2-(6-Chloro-1-methyl-1H-indazol-4-yl)-N-ethyl-5-fluoro-N-isopropylbenzamide 15c

[0607] Compound 15b (500 mg, 2.04 mmol) and compound 4c (1.50 g, 2.24 mmol) were dissolved in dioxane (20 mL) and water (4.0 mL). Sodium carbonate (431 mg, 4.07 mmol) and Pd(dppf)Cl2 (149 mg, 203 μmol) were added, and the mixture was stirred at 70°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 15c (519 mg, 1.39 mmol, 68.1% yield) as a white solid.

[0608] MS m / z(ESI):374.1[M+1]

[0609] 1H NMR (400MHz, DMSO-d6) δ7.95–7.87(m,2H),7.66(dd,J=8.4,5.6Hz,1H),7.45–7.32(m,2H),7.07(d,J=1.6Hz,1H),4.18(dd,J= 13.6, 6.8Hz, 0.18H), 4.06 (d, J = 1.6Hz, 3H), 3.37 (s, 2H), 2.81 (dq, J = 13.6, 6.8Hz, 0.89H), 1.07 (s, 7H), 0.17 (d, J = 6.8Hz, 2H).

[0610] Step 3

[0611] tert-Butyl 3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1-methyl-1H-indazol-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 15d

[0612] Compound 15c (886 mg, 1.42 mmol, 60% purity) and tert-butyl 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (419 mg, 1.42 mmol) were dissolved in dioxane (20 mL) and water (4 mL). Sodium carbonate (301 mg, 2.84 mmol) and Pd(dppf)Cl2 (104 mg, 142 μmol) were added. The reaction was stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was added to water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to give the title product 15d (260 mg, 513 μmol, yield: 36.0%) as a white solid.

[0613] MS m / z(ESI):507.2[M+1]

[0614] Step 4

[0615] tert-Butyl 3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1-methyl-1H-indazol-6-yl)pyrrolidine-1-carboxylate 15e

[0616] Compound 15d (260 mg, 513 μmol) was dissolved in methanol (10 mL) and Pd / C (26 mg) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to afford the title product 15e (235 mg, 462 μmol, 90% yield) as a white solid.

[0617] MS m / z(ESI):509.2[M+1]

[0618] Step 5

[0619] N-ethyl-5-fluoro-2-[1-methyl-6-(pyrrolidin-3-yl)-1H-indazol-4-yl]-N-(isopropyl)benzamide 15f

[0620] Compound 15e (30 mg, 58.9 μmol) was dissolved in dichloromethane (0.9 mL) and trifluoroacetic acid (0.3 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 15f (24 mg). The crude product was used directly in the next reaction without purification.

[0621] MS m / z(ESI):409.3[M+1]

[0622] Step 6

[0623] N-ethyl-5-fluoro-2-[1-methyl-6-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)-1H-indazol-4-yl]-N-isopropylbenzamide 15

[0624] Crude compound 15f (24 mg) was dissolved in N,N-dimethylformamide (1.0 mL), and potassium carbonate (24.3 mg, 176 μmol) was added. The mixture was stirred at room temperature for 0.5 hours. Potassium iodide (9.75 mg, 58.7 μmol) and compound 2e (55.5 mg, 117 μmol) were added, and the mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography using dichloromethane / methanol as the eluent to afford the title product 15 (7.0 mg, 11.4 μmol, yield: 19.4%) as a white solid.

[0625] MS m / z(ESI):612.2[M+1]

[0626] 1H NMR (400MHz, DMSO-d6) δ7.79(s,1H),7.57(dt,J=10.0,5.2Hz,1H),7.52(s,1H),7.38(t,J=8.8Hz,1H),7.30(s,1H),7.0 4(d,J=2.0Hz,1H),7.01(d,J=7.6Hz,1H),4.25–4.16(m,0.3H),4.02(d,J=3.2Hz,3H),3.39(d,J=6.8Hz,2H),3.25(d,J= 6.8Hz,1H),2.96(dd,J=7.2,3.2Hz,2H),2.86(ddd,J=20.4,13.6,7.8Hz,3H),2.71–2.59(m,2H),2.45(d,J=8.8Hz,1H), 2.24(d,J=6.8Hz,3H),1.94–1.75(m,5H),1.10(ddd,J=128,66.4,4.4Hz,12H),0.67(t,J=6.8Hz,3H),0.13–0.06(m,2H).

[0627] Example 16

[0628] N-ethyl-5-fluoro-2-[6-(4-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)methyl]amino}cyclohexyl-1-en-1-yl)imidazo[1,5-a]pyridin-8-yl]-N-isopropylbenzamide 16

[0629] first step

[0630] (5-Bromo-3-chloropyridin-2-yl)methanol 16b

[0631] Methyl 5-bromo-3-chloropyridine-2-carboxylate 16a (25 g, 99.8 mmol) was dissolved in methanol (250 mL) and tetrahydrofuran (250 mL), cooled to 0°C, and sodium borohydride (20 g, 528.7 mmol) was added. The reaction was stirred at room temperature for 8.0 hours. The reaction solution was cooled to 0°C, quenched by the addition of water (40 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude title product 16b (18 g, 80.9 mmol, 81.1% yield) as a white solid. The crude product was used directly in the next step without purification.

[0632] MS m / z(ESI):223.8[M+1]

[0633] Step 2

[0634] 2-[(5-Bromo-3-chloropyridin-2-yl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione 16c

[0635] Compound 16b (13 g, 58.4 mmol), 2,3-dihydro-1H-isoindole-1,3-dione (9.5 g, 64.6 mmol), and triphenylphosphine (23 g, 87.69 mmol) were dissolved in tetrahydrofuran (100 mL). Under a nitrogen atmosphere, the mixture was cooled to 0°C, and DIAD (17.7 g, 87.53 mmol) was added. The reaction was stirred at room temperature for 12 hours, during which time a white solid precipitated. The reaction mixture was filtered under reduced pressure, and the filter cake was washed with ethyl acetate and dried under reduced pressure to obtain the crude title product 16c (14 g, 39.8 mmol, yield: 68.1%) as a yellow solid. The crude product was used directly in the next reaction without purification.

[0636] MS m / z(ESI):352.8[M+1]

[0637] Step 3

[0638] (5-Bromo-3-chloropyridin-2-yl)methanamine 16d

[0639] Compound 16c (19.3 g, 54.9 mmol) was dissolved in methylamine in ethanol (170.49 g, 1.65 mol, 189.64 mL, 30% purity). The reaction was stirred at 65°C for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and extracted with water (50 mL) and ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product of title product 16d (30 g, 135 mmol, yield: 247%) was obtained as a blue solid. The crude product was used directly in the next reaction without purification.

[0640] MS m / z(ESI):222.9[M+1]

[0641] Step 4

[0642] N-[(5-Bromo-3-chloropyridin-2-yl)methyl]formamide 16e

[0643] Compound 16d (6.0 g, 27.1 mmol) was dissolved in ethyl formate (60 mL), and triethylamine (4.36 g, 43.1 mmol) was added. The reaction mixture was stirred at 70°C for 12 hours. The reaction mixture was cooled to room temperature under reduced pressure and concentrated under reduced pressure to obtain the crude title product 16e (6.0 g, 24.05 mmol, 88.8% yield). The crude product was used directly in the next step without purification.

[0644] MS m / z(ESI):251.0[M+1]

[0645] Step 5

[0646] 6-Bromo-8-chloroimidazo[1,5-a]pyridine 16f

[0647] Compound 16e (24.0 g, 96.2 mmol) was dissolved in toluene (200 mL), and phosphorus oxychloride (73.75 g, 480.98 mmol) was added. The reaction mixture was stirred at 100°C for 2.0 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (40 mL), and a 3M aqueous sodium hydroxide solution (60 mL) was added. The mixture was extracted with dichloromethane (100 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 16f (4.0 g, 17.28 mmol, yield: 17.96%) as a yellow oil.

[0648] MS m / z(ESI):233.0[M+1]

[0649] Step 6

[0650] 16g of tert-butyl N-(4-{8-chloroimidazo[1,5-a]pyridin-6-yl}cyclohexyl-3-en-1-yl)carbamate

[0651] Compound 16f (760 mg, 3.28 mmol), tert-butyl N-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexyl-3-en-1-yl]carbamate (950 mg, 2.94 mmol), and sodium carbonate (1.04 g, 9.85 mmol) were dissolved in dioxane (15 mL) and water (1.5 mL). Under a nitrogen atmosphere, Pd(dppf)Cl₂.DCM (270 mg, 330 μmol) was added, and the mixture was stirred at 90°C for 8.0 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 16g (750 mg, 2.16 mmol, yield: 65.67%).

[0652] MS m / z(ESI):348.0[M+1]

[0653] Step 7

[0654] tert-Butyl N-[4-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl}cyclohexyl-3-en-1-yl)carbamate 16h

[0655] Compound 16g (750 mg, 2.16 mmol), compound 4c (1.08 g, 3.23 mmol), and cesium carbonate (2.11 g, 6.47 mmol) were dissolved in dioxane (10 mL) and water (1.0 mL). Pd(dppf)Cl2 (140.5 mg, 215.6 μmol) was added under a nitrogen atmosphere, and the reaction was stirred at 100°C for 8.0 hours. The reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 16h (730 mg, 1.40 mmol, yield: 65.0%).

[0656] MS m / z(ESI):521.2[M+1]

[0657] Step 8

[0658] 2-[6-(4-aminocyclohex-1-en-1-yl)imidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-isopropylbenzamide 16i

[0659] Compound 16h (90 mg, 172.9 μmol) was dissolved in dichloromethane (2.0 mL) and trifluoroacetic acid (197.10 mg, 1.73 mmol, 133.18 μL) was added. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 16i (70 mg, 166.46 μmol, 96.29% yield). The crude product was used directly in the next reaction without purification.

[0660] MS m / z(ESI):421.2[M+1]

[0661] Step 9

[0662] N-ethyl-5-fluoro-2-[6-(4-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)methyl]amino}cyclohexyl-1-en-1-yl)imidazo[1,5-a]pyridin-8-yl]-N-isopropylbenzamide 16

[0663] Compound 16i (50 mg, 93.54 μmol, trifluoroacetate) was dissolved in dichloromethane (2.0 mL), and triethylamine (94.65 mg, 935.38 μmol) and compound 11 (30.52 mg, 187.08 μmol) were added. The mixture was stirred at room temperature for 1.0 hour. Sodium cyanoborohydride (25 mg, 397.82 μmol) was added, and the reaction was stirred at room temperature for 12 hours. Aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 8%-38%) to obtain the title product 16 (22.2 mg, 39.1 μmol, yield: 41.8%).

[0664] MS m / z(ESI):568.1[M+1]

[0665] 1 H NMR(400MHz, DMSO-d6)δ8.59–8.24(m,3H),7.73(dd,J=5.2,8.4Hz,1H),7.38–7.31(m,1H),7.29–7.22(m,4H),7.03(s,1H),6.20(s,1H), 4.28–4.14(m,2H),3.61–3.33(m,2H),3.04–2.90(m,1H),2.84–2.23(m,6H),1.93–1.70(m,1H),1.36–0.73(m,7H),0.29(d,J=6.4Hz,2H).

[0666] Examples 18-1, 18-2

[0667] N-ethyl-5-fluoro-N-(isopropyl)-2-{6-[(1s,4s)-4-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)cyclohexyl]imidazo[1,5-a]pyridin-8-yl}benzamide 18-1

[0668] N-ethyl-5-fluoro-N-(isopropyl)-2-{6-[(1r,4r)-4-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)cyclohexyl]imidazo[1,5-a]pyridin-8-yl}benzamide 18-2

[0669] first step

[0670] Tert-butyl N-[4-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)cyclohexyl]carbamate 18a

[0671] Compound 16h (300 mg, 576.2 μmol) was dissolved in methanol (25 mL), and palladium / carbon (250 mg, 2.06 mmol) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (25 mL), and palladium / carbon (250 mg, 2.06 mmol) was added. Stirring was continued at room temperature under a hydrogen atmosphere (15 psi) for another 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 40%-70%) to obtain the title product 18a (170 mg, 325.3 μmol, yield: 56.5%) as a yellow solid.

[0672] MS m / z(ESI):523.2[M+1]

[0673] Step 2

[0674] 2-[6-(4-aminocyclohexyl)imidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-isopropylbenzamide 18b

[0675] Compound 18a (170 mg, 325.3 μmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (370.88 mg, 3.25 mmol, 250.99 μL) was added. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 18b (130 mg, 307.67 μmol, 94.59% yield). The crude product was used directly in the next reaction without purification.

[0676] MS m / z(ESI):423.2[M+1]

[0677] Step 3

[0678] N-ethyl-5-fluoro-N-(isopropyl)-2-{6-[(1s,4s)-4-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)cyclohexyl]imidazo[1,5-a]pyridin-8-yl}benzamide 18-1

[0679] N-ethyl-5-fluoro-N-(isopropyl)-2-{6-[(1r,4r)-4-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)cyclohexyl]imidazo[1,5-a]pyridin-8-yl}benzamide 18-2

[0680] Compound 18b (200 mg, 372.74 μmol, trifluoroacetate salt) was dissolved in dichloromethane (3.0 mL). Triethylamine (113.15 mg, 1.12 mmol) and compound 3e (72.83 mg, 298.20 μmol) were added and stirred at room temperature for 0.5 hours. Sodium cyanoborohydride (70.27 mg, 1.12 mmol) was added and the mixture was stirred at 45°C for 12 hours. Aqueous sodium bicarbonate (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 43%-73%) to give the title products 18-1 (12.46 mg, 19.15 μmol, yield: 5.14%) and 18-2 (19.67 mg, 30.23 μmol, yield: 8.11%).

[0681] Single configuration compound 18-1:

[0682] MS m / z(ESI):651.1[M+1]

[0683] HPLC analysis: retention time 1.307 minutes, 10-80AB_4min.1cm

[0684] SFC analysis: retention time 1.604 minutes; column: Cellulose-2 50×4.6 mm ID, 3 μm; mobile phase: CO2 / [MeOH+ACN (0.05% DEA)]=40 / 60

[0685] 1H NMR (400MHz, DMSO-d6) δ8.32(s,1H),8.17(s,1H),8.03(d,J=8.0Hz,2H),7.67(dd,J=6.0,8.4Hz,1H),7.59(s,1 H),7.49(d,J=7.6Hz,2H),7.40–7.27(m,2H),7.10(s,1H),6.63–6.58(m,1H),4.05(s,3H),3.99(s,3H),3.83(s, 2H),3.47–3.38(m,1H),3.30–3.22(m,1H),3.00–2.83(m,1H),2.47–2.33(m,2H),2.17–1.96(m,3H),1.83(d,J= 12.0Hz,2H),1.47–1.32(m,2H),1.26–1.13(m,2H),1.08–0.84(m,4H),0.80–0.69(m,3H),0.24(d,J=6.4Hz,2H).

[0686] Single configuration compound 18-2:

[0687] MS m / z(ESI):651.2[M+1]

[0688] HPLC analysis: retention time 1.379 minutes, 10-80AB_4min.1cm

[0689] SFC analysis: retention time 0.911 min; column: Cellulose-2 50×4.6 mm ID, 3 μm; mobile phase: CO2 / [MeOH+ACN (0.05% DEA)]=40 / 60

[0690] 1H NMR (400MHz, DMSO-d6) δ8.36(s,1H),8.20(s,1H),8.03(d,J=8.0Hz,2H),7.68(dd,J=5.6,8.4Hz,1H),7. 57(s,1H),7.51(d,J=8.0Hz,2H),7.41–7.27(m,2H),7.10(s,1H),6.69–6.63(m,1H),4.05(s,3H),3.98(s ,3H),3.77(s,2H),3.43(td,J=6.4,13.2Hz,1H),3.30–3.25(m,1H),2.96–2.76(m,2H),2.47–2.37(m,1H) ,2.21–2.07(m,1H),1.95–1.77(m,4H),1.54(d,J=11.6Hz,4H),0.94–0.68(m,7H),0.26(d,J=6.4Hz,2H).

[0691] Example 19

[0692] 2-{6-[4-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)piperidin-1-yl]imidazo[1,5-a]pyridin-8-yl}-N-ethyl-5-fluoro-N-isopropylbenzamide 19

[0693] first step

[0694] tert-Butyl N-(1-{8-chloroimidazo[1,5-a]pyridin-6-yl}piperidin-4-yl)carbamate 19a

[0695] Compound 16f (1.0 g, 4.32 mmol), tert-butyl N-(piperidin-4-yl)carbamate (870 mg, 4.34 mmol), and cesium carbonate (4.22 g, 12.96 mmol) were dissolved in dioxane (15 mL). Ruphos (202 mg, 432.9 μmol) and Pd2(dba)3 (400 mg, 436.38 μmol) were added. The reaction was stirred at 90°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (35 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 19a (315 mg, 897.8 μmol, yield: 20.78%).

[0696] MS m / z(ESI):351.1[M+1]

[0697] Step 2

[0698] Tert-butyl N-[1-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)piperidin-4-yl]carbamate 19b

[0699] Compound 19a (315 mg, 897.8 μmol) and compound 4c (362 mg, 1.08 mmol) were dissolved in dioxane (4 mL) and water (0.8 mL). Potassium phosphate (572 mg, 2.69 mmol) and Pd(dtbpf)Cl2 (59 mg, 90.5 μmol) were added, and the mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, water (15 mL) was added, and extraction was performed with ethyl acetate (25 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 19b (300 mg, 572.9 μmol, yield: 63.8%).

[0700] MS m / z(ESI):524.3[M+1]

[0701] Step 3

[0702] 2-[6-(4-aminopiperidin-1-yl)imidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-isopropylbenzamide 19c

[0703] Compound 19b (300 mg, 572.9 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2.96 g, 25.96 mmol, 2 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The mixture was concentrated under reduced pressure to obtain the crude title product 19c (300 mg), which was used directly in the next step without purification. MS m / z (ESI): 424.2 [M+1]

[0704] Step 4

[0705] 2-{6-[4-({[4-(5,6-dimethoxypyridazin-3-yl)phenyl]methyl}amino)piperidin-1-yl]imidazo[1,5-a]pyridin-8-yl}-N-ethyl-5-fluoro-N-isopropylbenzamide 19

[0706] Crude compound 19c (150 mg, 279 μmol, trifluoroacetate salt), compound 3e (69 mg, 282.5 μmol), and triethylamine (57 mg, 563 μmol) were dissolved in methanol (2.0 mL) and stirred at room temperature for 1.0 hour. Sodium cyanoborohydride (53 mg, 843.4 μmol) was added, and the mixture was stirred at room temperature for 11 hours. Saturated aqueous sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonium bicarbonate), elution gradient: 30%-60%) to afford the title product 19 (13.12 mg, 20.13 μmol, yield: 7.21%) as a white solid.

[0707] MS m / z(ESI):652.5[M+1]

[0708] 1 H NMR(400MHz,DMSO-d6)δ8.25(s,1H),8.10–7.97(m,2H),7.78(s,1H),7.72–7.64(m,1H) ,7.59(s,1H),7.54–7.45(m,2H),7.42–7.27(m,2H),7.08–7.01(m,1H),6.69–6.59(m,1H ),4.05(s,3H),3.99(s,3H),3.85(s,2H),3.50–3.39(m,3H),2.99–2.86(m,1H),2.84–2 .54(m,4H),2.02–1.88(m,2H),1.52–1.37(m,2H),0.96–0.70(m,7H),0.34–0.28(m,2H).

[0709] Example 21

[0710] Tert-butyl N-[(1r,4r)-4-{[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)pyrrolidin-1-yl]methyl}cyclohexyl]carbamate 21

[0711] first step

[0712] tert-Butyl 3-{8-chloroimidazo[1,5-a]pyridin-6-yl}-2,5-dihydro-1H-pyrrole-1-carboxylate 21a

[0713] Compound 16f (2.0 g, 6.91 mmol), tert-butyl 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.8 g, 6.10 mmol), and sodium carbonate (2.18 g, 20.6 mmol) were dissolved in dioxane (30 mL) and water (3 mL). Pd(dppf)Cl₂.DCM (282.24 mg, 345.6 μmol) was added. The reaction was stirred at 95°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 21a (1.2 g, 3.75 mmol, yield: 54.29%).

[0714] MS m / z(ESI):320.1[M+1]

[0715] Step 2

[0716] tert-Butyl 3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 21b

[0717] Compound 21a (1.2 g, 3.75 mmol) and compound 4c (2.62 g, 7.81 mmol) were dissolved in dioxane (24 mL) and water (2.5 mL). Cesium carbonate (3.67 g, 11.26 mmol) and Pd(dtbpf)Cl2 (244.57 mg, 375.2 μmol) were added, and the reaction was stirred at 100°C under a nitrogen atmosphere for 8.0 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 21b (1.43 g, 2.9 mmol, yield: 77.4%).

[0718] MS m / z(ESI):493.2[M+1]

[0719] Step 3

[0720] Tert-butyl 3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)pyrrolidine-1-carboxylate 21c

[0721] Compound 21b (430 mg, 873 μmol) was dissolved in methanol (20 mL) and Pd / C (103.4 mg, 873 μmol) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product of the title product 21c (400 mg, 808.7 μmol, yield: 92.6%). The crude product was used directly in the next reaction without purification.

[0722] MS m / z(ESI):495.3[M+1]

[0723] Step 4

[0724] N-Ethyl-5-fluoro-N-isopropyl-2-[6-(pyrrolidin-3-yl)imidazo[1,5-a]pyridin-8-yl]benzamide 21d

[0725] Compound 21c (400 mg, 808.7 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (922.14 mg, 8.09 mmol, 623.07 μL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 21d (300 mg). The crude product was used directly in the next reaction without purification.

[0726] MS m / z(ESI):395.3[M+1]

[0727] Step 5

[0728] Tert-butyl N-[(1r,4r)-4-{[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)pyrrolidin-1-yl]methyl}cyclohexyl]carbamate 21

[0729] The crude product of compound 21d (300 mg, 590 μmol, trifluoroacetate), tert-butyl N-[(1r,4r)-4-formylcyclohexyl]carbamate (201.15 mg, 884.94 μmol), and triethylamine (298.49 mg, 2.95 mmol) were dissolved in methanol (10 mL) and stirred at room temperature for 0.5 hour. Sodium cyanoborohydride (74.15 mg, 1.18 mmol) was added, and the mixture was stirred at room temperature for 1.0 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 58%-78%) to obtain the title product 21 (142 mg, 234.4 μmol, yield: 39.1%) as a white solid.

[0730] MS m / z(ESI):606.3[M+1]

[0731] 1 H NMR (400MHz, DMSO-d6) δ8.36–8.32(m,1H),8.23–8.19(m,1H),7.69–7.62(m,1H),7.40–7.27(m,2H ),7.10(s,1H),6.71–6.63(m,2H),3.49–3.38(m,1H),3.29–3.06(m,3H),2.99–2.77(m,2H),2.68– 2.54(m,2H),2.47–2.32(m,1H),2.29–2.10(m,3H),1.87–1.65(m,5H),1.39–1.34(m,9H),1.33–1. 25(m,1H),1.18–1.00(m,3H),0.94–0.81(m,5H),0.79–0.71(m,3H),0.28(dd,J=6.8,12.4Hz,2H).

[0732] Example 22

[0733] N-ethyl-5-fluoro-N-isopropyl-2-[6-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-8-yl]benzamide 22

[0734] first step

[0735] N-Ethyl-5-fluoro-N-isopropyl-2-[6-(1-{[(1r,4r)-4-aminocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-8-yl]benzamide 22a

[0736] Compound 21 (100 mg, 165.08 μmol) was dissolved in dichloromethane (5.0 mL) and trifluoroacetic acid (740.00 mg, 6.49 mmol, 0.5 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 22a (80 mg). The crude product was used directly in the next reaction without purification.

[0737] MS m / z(ESI):506.5[M+1]

[0738] Step 2

[0739] N-ethyl-5-fluoro-N-isopropyl-2-[6-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-8-yl]benzamide 22

[0740] The crude product of compound 22a (80 mg) was dissolved in dichloromethane (3.0 mL), and ethylsulfonyl chloride (40.7 mg, 316.4 μmol) and triethylamine (80.04 mg, 791 μmol) were added. The mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with dichloromethane (20 mL), and saturated aqueous sodium carbonate solution (20 mL) was added. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia water), elution gradient: 35%-65%) gave the title product 22 (1.92 mg, 3.21 μmol, yield: 2.03%) as a white solid. MS m / z (ESI): 598.3 [M+1]

[0741] 1 H NMR (400MHz, CD3OD) δ8.57–8.16(m,3H),7.71(dd,J=5.2,8.4Hz,1H),7.35(dt,J=2.8,8.4Hz,1H),7.2 9–7.21(m,2H),6.86–6.80(m,1H),3.56(td,J=6.4,12.0Hz,1H),3.45–3.38(m,2H),3.20–2.91(m,5H) ,2.81–2.58(m,3H),2.43–2.30(m,1H),2.03(d,J=4.8Hz,3H),1.96–1.87(m,2H),1.56(s,1H),1.38–1 .25(m,6H),1.18–1.03(m,3H),1.01–0.88(m,6H),0.82(t,J=7.2Hz,1H),0.32(dd,J=4.4,6.4Hz,2H).

[0742] Examples 22-1, 22-2

[0743] N-ethyl-5-fluoro-N-isopropyl-2-{6-[(3R)-1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl]imidazo[1,5-a]pyridin-8-yl}benzamide 22-1

[0744] N-ethyl-5-fluoro-N-isopropyl-2-{6-[(3S)-1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl]imidazo[1,5-a]pyridin-5-yl}benzamide 22-2

[0745] first step

[0746] (3R)-3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 21c-1

[0747] (3S)-3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 21c-2

[0748] Compound 21c (1.38 g, 2.78 mmol) was separated and purified by chiral preparative SFC (preparative column: DAICEL CHIRALPAK OD (250 mm*30 mm, 10 um), mobile phase: 35% to 35% (v / v) carbon dioxide-ethanol (0.1% ammonia water)) to give the title products 21c-1 (490 mg, 990.7 μmol, yield: 35.5%) and 21c-2 (524 mg, 1.06 mmol, yield: 38.0%).

[0749] Single configuration compound 21c-1:

[0750] MS m / z(ESI):495.6[M+1]

[0751] SFC analysis: retention time 1.42 minutes; chromatographic column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: 5% to 40% (v / v) EtOH (0.05% DEA) / CO2.

[0752] Single configuration compound 21c-2:

[0753] MS m / z(ESI):495.4[M+1]

[0754] SFC analysis: retention time 0.817 min; chromatographic column: Chiralcel OD-3 50×4.6 mm ID, 3 um; mobile phase: 5% to 40% (v / v) EtOH (0.05% DEA) / CO2.

[0755] Steps 2 and 4

[0756] N-ethyl-5-fluoro-N-isopropyl-2-{6-[(3R)-pyrrolidin-3-yl]imidazo[1,5-a]pyridin-8-yl]benzamide 21d-1

[0757] N-ethyl-5-fluoro-N-isopropyl-2-{6-[(3S)-pyrrolidin-3-yl]imidazo[1,5-a]pyridin-8-yl]benzamide 21d-2

[0758] Compound 21c-1 / 21c-2 (220 mg / 150 mg, 244.8 μmol / 303.3 μmol) was dissolved in dichloromethane (4.5 mL / 3.0 mL) and trifluoroacetic acid (1.5 mL / 1.0 mL) was added. The reaction was stirred at room temperature for 1.0 / 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title product 21d-1 / 21d-2 (168 mg / 155 mg). The crude product was used directly in the next reaction without purification.

[0759] Single configuration compound 21d-1:

[0760] MS m / z(ESI):395.3[M+1]

[0761] Single configuration compound 21d-2:

[0762] MS m / z(ESI):395.1[M+1]

[0763] Steps 3 and 5

[0764] N-ethyl-5-fluoro-N-isopropyl-2-{6-[(3R)-1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl]imidazo[1,5-a]pyridin-8-yl}benzamide 22-1

[0765] N-ethyl-5-fluoro-N-isopropyl-2-{6-[(3S)-1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl]imidazo[1,5-a]pyridin-5-yl}benzamide 22-2

[0766] The crude product of compound 21c-1 / 21c-2 (160 mg / 154 mg) was dissolved in DMF (3.0 mL / 3.0 mL). Potassium carbonate (217 mg / 209 mg, 1.57 mmol / 1.52 mmol), TBAI (11.6 mg / 11.2 mg, 31.5 μmol / 30.3 μmol), and compound 35f (142 mg / 228 mg, 378 μmol / 606 μmol) were added and stirred at 90°C for 12.0 / 12.0 hours. Aqueous sodium bicarbonate solution (10 mL / 10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3 / 20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia) / acetonitrile, water (0.1% ammonium bicarbonate), elution gradient: 34%-64% / 24%-54%) to give the title products 22-1 / 22-2 (7.68 mg / 15.58 mg, 12.85 μmol / 26.06 μmol, yield: 4.08% / 8.60%).

[0767] Single configuration compound 22-1:

[0768] MS m / z(ESI):598.2[M+1]

[0769] Chiral HPLC: retention time 1.653 minutes; chromatographic column: Chiralcel OD-3 50X4.6mm ID, 3um; mobile phase: 5% to 40% (v / v) MeOH (0.05% DEA) / CO2.

[0770] 1 H NMR(400MHz,DMSO-d6)δ8.35(s,1H),8.24–8.18(m,1H),7.70–7.62(m,1H),7.41–7.26(m ,2H),7.10(s,1H),7.01–6.96(m,1H),6.72–6.64(m,1H),3.51–3.37(m,1H),3.24–3.18(m ,1H),3.02–2.90(m,4H),2.85–2.76(m,1H),2.64–2.53(m,2H),2.47–2.32(m,1H),2.29– 2.12(m,3H),1.88–1.73(m,5H),1.39–1.13(m,7H),0.97–0.71(m,9H),0.31–0.24(m,2H).

[0771] Single configuration compound 22-2:

[0772] MS m / z(ESI):598.2[M+1]

[0773] Chiral HPLC: retention time 1.717 minutes; chromatographic column: Chiralcel OD-3 50×4.6 mm ID, 3 μm; mobile phase: 5% to 40% (v / v) MeOH (0.05% DEA) / CO 2 .

[0774] 1 H NMR(400MHz,DMSO-d6)δ8.36(br d,J=7.9Hz,1H),8.28–8.18(m,1H),7.74–7.63(m,1H),7.42–7.27(m,2H),7.16–7.08(m,1H),6.68–6.57(m,1H), 8.35(s,1H),8.26–8.16(m,1H),7.74–7.59(m,1H),7.45–7.25(m,2H),7.20–6.82(m,2H),6.73–6.63(m,1H),3.4 8–3.39(m,1H),3.24–3.18(m,1H),3.06–2.87(m,4H),2.86–2.76(m,1H),2.69–2.54(m,2H),2.48–2.36(m,1H),2 .33–2.11(m,3H),1.89–1.73(m,4H),1.64–1.48(m,1H),1.39–1.12(m,7H),0.97–0.72(m,9H),0.32–0.23(m,2H).

[0775] Example 23

[0776] N-ethyl-5-fluoro-2-(6-{1-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]pyrrolidin-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 23

[0777] first step

[0778] (1S,3S,4R)-3-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)pyrrolidine-1-carbonyl]-5-methylene-2-azabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester 23b

[0779] Compound 21d (90.0 mg, 177 μmol, trifluoroacetate), (1S,3S,4R)-2-tert-butyloxycarbonyl-5-methylene-2-azabicyclo[2.2.2]octane-3-carboxylic acid 23a (45.0 mg, 265.5 μmol, prepared according to the method disclosed in Reference Example 13 of WO2020032105A1, page 93), and N,N-diisopropylethylamine (89.6 mg, 693 μmol) were dissolved in dichloromethane (3 mL) and cooled to 0°C. EDCI (50.89 mg, 265.48 μmol) and HOBt (40.66 mg, 265.48 μmol) were added, and the mixture was stirred at room temperature for 12 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by HPLC (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 41%-71%) gave the title product 23b (30 mg, 46.6 μmol, yield: 26.3%) as a white solid.

[0780] MS m / z(ESI):644.3[M+1]

[0781] Step 2

[0782] N-ethyl-5-fluoro-2-(6-{1-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]pyrrolidin-3-yl}imidazo[1,5-a]pyridine-8-

[0783] 1-(2-propyl)-N-(isopropyl)benzamide 23

[0784] Compound 23b (25.0 mg, 38.8 μmol) was dissolved in dichloromethane (4.8 mL) and trifluoroacetic acid (0.2 mL). The reaction was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and the resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 36%-66%) to obtain the title product 23 (8.84 mg, 16.26 μmol, yield: 41.87%).

[0785] MS m / z(ESI):544.4[M+1]

[0786] 1H NMR (400MHz, CD3OD) δ8.40–8.34(m,1H),8.28–8.21(m,1H),7.71(dd,J=5.2,8.4Hz,1H),7.40–7.31(m,1 H),7.29–7.20(m,2H),6.87–6.77(m,1H),5.11–4.95(m,1H),4.14–3.75(m,3H),3.69–3.47(m,3H),3.46 –3.35(m,2H),3.17–3.12(m,1H),3.10–2.94(m,1H),2.77–2.53(m,3H),2.33–1.99(m,2H),1.96–1.70(m ,2H),1.65–1.51(m,2H),1.17–1.05(m,1H),0.97(d,J=5.6Hz,3H),0.93–0.78(m,4H),0.36–0.29(m,2H).

[0787] Example 24

[0788] tert-Butyl N-[4-{[3-(5-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-7-yl}pyrrolidin-1-yl)methyl)cyclohexyl]carbamate 24

[0789] first step

[0790] 4,6-Dichloropyridine-2-carboxylic acid methyl ester 24b

[0791] 4,6-Dichloropyridine-2-carboxylic acid 24a (15 g, 78.13 mmol) was dissolved in methanol (150 mL), cooled to 0°C, and SOCl2 (18.59 g, 156.25 mmol) was slowly added. The reaction was stirred at 65°C for 12 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane (150 mL) was added to dissolve the residue. The organic phase was washed with saturated aqueous sodium bicarbonate (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of the title product 24b (15 g, 72.8 mmol, yield: 93.2%). The crude product was used directly in the next reaction without purification.

[0792] MS m / z(ESI):206.0[M+1]

[0793] 1 H NMR (400MHz, CDCl3) δ8.05 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 4.00 (s, 3H).

[0794] Step 2

[0795] 4-Chloro-6-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}pyridine-2-carboxylic acid methyl ester 24c

[0796] Compound 24b (3.93 g, 19.09 mmol), compound 4c (6.4 g, 19.09 mmol), and sodium carbonate (6.07 g, 57.28 mmol) were dissolved in dioxane (35 mL) and water (5.0 mL). Pd(dppf)Cl2 (1.40 g, 1.91 mmol) was added under a nitrogen atmosphere, and the mixture was stirred at 75°C for 1.0 hour. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 24c (6.0 g, 15.84 mmol, yield: 82.96%).

[0797] MS m / z(ESI):379.1[M+1]

[0798] 1 H NMR (400MHz, DMSO-d6) δ8.08–8.04(m,1H),7.95–7.90(m,1H),7.88–7.81(m,1H),7.46–7.39(m,1H),7.32–7.26(m,1H ),3.90–3.88(m,3H),3.57(td,J=6.6,13.3Hz,1H),3.43–3.36(m,1H),3.21–3.02(m,2H),1.07–0.97(m,6H),0.76(br d,J=6.5Hz,3H).

[0799] Step 3

[0800] 2-[4-chloro-6-(hydroxymethyl)pyridin-2-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 24d

[0801] Compound 24c (6.0 g, 15.84 mmol) was dissolved in tetrahydrofuran (60 mL) and methanol (60 mL). The reaction mixture was cooled to 0°C and NaBH4 (2.5 g, 66.1 mmol) was added. The reaction mixture was stirred at room temperature for 8 hours. Water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product of the title product 24d (4.7 g, 13.4 mmol, yield: 84.6%) was obtained. The crude product was used directly in the next reaction without purification.

[0802] MS m / z(ESI):351.0[M+1]

[0803] Step 4

[0804] 2-{4-chloro-6-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]pyridin-2-yl}-N-ethyl-5-fluoro-N-(isopropyl)benzamide 24e

[0805] Compound 24d (4.7 g, 13.4 mmol), 2,3-dihydro-1H-isoindole-1,3-dione (2.37 g, 16.1 mmol), and triphenylphosphine (4.22 g, 16.1 mmol) were dissolved in tetrahydrofuran (60 mL). Under a nitrogen atmosphere, the mixture was cooled to 0°C, and DIAD (4.06 g, 20.1 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours, and the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 24e (3.5 g, 7.29 mmol, 54.4% yield).

[0806] MS m / z(ESI):480.2[M+1]

[0807] Step 5

[0808] 2-[6-(Aminomethyl)-4-chloropyridin-2-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 24f

[0809] Compound 24e (3.5 g, 7.29 mmol) was dissolved in methylamine in ethanol (45 g, 434.68 mmol, 50.06 mL, 30% purity). The reaction was stirred at 50°C for 1.0 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude title product 24f (3.5 g, 10.0 mmol, yield: 137.2%). The crude product was used directly in the next reaction without purification.

[0810] MS m / z(ESI):350.1[M+1]

[0811] Step 6

[0812] 2-{7-chloroimidazo[1,5-a]pyridin-5-yl}-N-ethyl-5-fluoro-N-(isopropyl)benzamide 24g

[0813] Compound 24f (1.75 g, 5.0 mmol) was dissolved in ethyl formate (20 mL), and triethylamine (3.04 g, 30.1 mmol) was added. The reaction mixture was stirred at 70°C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude product (1.5 g, 5.03 mmol) was dissolved in toluene (15 mL), and phosphorus oxychloride (3.65 g, 23.82 mmol) was added. The reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and adjusted to pH 8 with saturated aqueous sodium bicarbonate. The product was extracted with dichloromethane (35 mL x 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 24g (810 mg, 2.25 mmol, yield: 56.7%).

[0814] MS m / z(ESI):360.0[M+1]

[0815] 1 H NMR (400MHz, DMSO-d6) δ8.29–7.83(m,2H),7.56–7.40(m,4H),6.59–6.43(m,1H),3.79–3.43(m,2H),3.00–2.80(m,1H),1.03–0.63(m,9H).

[0816] Step 7

[0817] tert-Butyl 3-(5-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 24h

[0818] Compound 24g (810 mg, 2.25 mmol), tert-butyl 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (697.71 mg, 2.36 mmol), and potassium phosphate (1.19 g, 5.63 mmol) were dissolved in dioxane (10 mL) and water (1.5 mL). Pd(dppf)Cl2 (150 mg, 230.15 μmol) was added. The reaction mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 24h (780 mg, 1.58 mmol, yield: 70.34%).

[0819] MS m / z(ESI):493.2[M+1]

[0820] 1 H NMR (400MHz, DMSO-d6) δ8.24–7.63(m,2H),7.58–7.39(m,4H),7.00–6.65(m,1H),6.45–6.13(m,1H),4.40(br d,J=3.0Hz,2H),4.29–4.14(m,2H),3.75–3.39(m,2H),3.04–2.73(m,1H),1.45(d,J=8.8Hz,9H),1.03–0.38(m,9H).

[0821] Step 8

[0822] Tert-butyl 3-(5-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-7-yl)pyrrolidine-1-carboxylate 24i

[0823] Compound 24h (320 mg, 649.6 μmol) was dissolved in methanol (10 mL) and Pd / C (200 mg, 1.88 mmol) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude title product 24i (300 mg, 606.55 μmol, 93.4% yield). The crude product was used directly in the next step without purification.

[0824] MS m / z(ESI):495.3[M+1]

[0825] Step 9

[0826] N-Ethyl-5-fluoro-N-isopropyl-2-[7-(pyrrolidin-3-yl)imidazo[1,5-a]pyridin-5-yl]benzamide 24j

[0827] Compound 24i (387 mg, 782.45 μmol) was dissolved in dichloromethane (5.0 mL) and trifluoroacetic acid (3.70 g, 32.45 mmol, 2.5 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 24j (400 mg). The crude product was used directly in the next reaction without purification.

[0828] MS m / z(ESI):395.2[M+1]

[0829] Step 10

[0830] tert-Butyl N-(4-{[3-(5-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-7-yl)pyrrolidin-1-yl]methyl}cyclohexyl)carbamate 24

[0831] The crude product of compound 24j (400 mg, 786.62 μmol, trifluoroacetate), tert-butyl N-[(1r,4r)-4-formylcyclohexyl]carbamate (215 mg, 945.89 μmol), and triethylamine (160 mg, 1.58 mmol) were dissolved in methanol (5.0 mL) and stirred at room temperature for 1.0 hour. Sodium cyanoborohydride (150 mg, 2.39 mmol) was added, and the mixture was stirred at room temperature for 11 hours. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent to obtain the title product 24 (340 mg, 561.26 μmol, yield: 71.35%).

[0832] MS m / z(ESI):606.6[M+1]

[0833] 1 H NMR (400MHz, DMSO-d6) δ8.12–7.64(m,2H),7.50–7.27(m,4H),6.74–6.61(m,1H),6.57–6.45(m,1H),3.64–3.41(m,1H),3.28–3.20(m,1H) ),3.19–3.06(m,1H),2.97–2.73(m,2H),2.67–2.54(m,2H),2.47–2.31(m,1H),2.29–2.09(m,3H),1.97–1.60(m,5H),1.57–0.51(m,24H).

[0834] Examples 25, 26

[0835] N-ethyl-5-fluoro-N-isopropyl-2-[7-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-5-yl]benzamide 25

[0836] N-ethyl-5-fluoro-N-isopropyl-2-[7-(1-{[(1s,4s)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-5-yl]benzamide 26

[0837] first step

[0838] 2-(7-{1-[(4-aminocyclohexyl)methyl]pyrrolidin-3-yl}imidazo[1,5-a]pyridin-5-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 25a

[0839] Compound 24 (340 mg, 561.26 μmol) was dissolved in dichloromethane (5.0 mL), and trifluoroacetic acid (2.96 g, 25.96 mmol, 2 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 25a (350 mg). The crude product was used directly in the next reaction without purification.

[0840] MS m / z(ESI):506.5[M+1]

[0841] Step 2

[0842] N-ethyl-5-fluoro-N-isopropyl-2-[7-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-5-yl]benzamide 25

[0843] N-ethyl-5-fluoro-N-isopropyl-2-[7-(1-{[(1s,4s)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-5-yl]benzamide 26

[0844] The crude product of compound 25a (347 mg) was dissolved in dichloromethane (5.0 mL), and ethylsulfonyl chloride (144.01 mg, 1.12 mmol) and triethylamine (283.33 mg, 2.80 mmol) were added. The mixture was stirred at room temperature for 12 hours. Saturated aqueous sodium carbonate solution (10 mL) was added to the reaction solution. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained mixture (100 mg) was purified by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonium bicarbonate), elution gradient: 50%-80%) and separated and purified by preparative SFC (preparative column: DAICEL CHIRALPAK IF (250 mm*50 mm, 10 um), mobile phase: 25% n-hexane-ethanol (0.1% ammonia water)) to obtain the title products 25 (1.69 mg, 2.83 μmol, yield: 1.69%) and 26 (1.95 mg, 3.26 μmol, yield: 1.95%).

[0845] Compound 25:

[0846] MS m / z(ESI):598.5[M+1]

[0847] SFC analysis: retention time 4.613 minutes; chromatographic column: Chiralpak IF-3 50 x 4.6 mm ID, 3 μm; mobile phase: n-hexane (0.05% isopropylamine) / [ethanol + acetonitrile (0.05% isopropylamine)] = 80 / 20.

[0848] 1 H NMR (400MHz, DMSO-d6) δ8.12–7.62(m,2H),7.52–7.29(m,4H),7.04–6.93(m,1H),6.59–6.43(m,1H),3.30–3.17(m,3H ),3.07–2.76(m,6H),2.74–2.56(m,2H),2.36–2.12(m,3H),1.92–1.67(m,6H),1.28–1.14(m,7H),1.00–0.63(m,9H).

[0849] Compound 26:

[0850] MS m / z(ESI):598.4[M+1]

[0851] SFC analysis: retention time 3.614 minutes; chromatographic column: Chiralpak IF-3 50 x 4.6 mm ID, 3 μm; mobile phase: n-hexane (0.05% isopropylamine) / [ethanol+acetonitrile (0.05% isopropylamine)] = 80 / 20.

[0852] 1 H NMR (400MHz, DMSO-d6) δ8.13–7.58(m,2H),7.51–7.28(m,4H),6.98–6.87(m,1H),6.57–6.44(m,1H),3.28–3.21(m,2H ),3.07–2.72(m,5H),2.71–2.55(m,2H),2.43–2.09(m,4H),1.63–1.33(m,10H),1.29–1.13(m,6H),1.00–0.65(m,7H).

[0853] Examples 25-1, 25-2

[0854] N-ethyl-5-fluoro-N-isopropyl-2-{7-[(3S)-1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl]imidazo[1,5-a]pyridin-5-yl}benzamide 25-1

[0855] N-ethyl-5-fluoro-N-isopropyl-2-{7-[(3R)-1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl]imidazo[1,5-a]pyridin-5-yl}benzamide 25-2

[0856] first step

[0857] (3S)-3-(5-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 24i-1

[0858] (3R)-3-(5-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 24i-2

[0859] Compound 24i (300 mg, 606.6 μmol) was separated and purified by chiral preparative SFC (preparative column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um), mobile phase: 0% to 50% (v / v) carbon dioxide-ethanol (0.1% ammonia water)) to give the title products 24i-1 (100 mg, 202.2 μmol, yield: 33.3%) and 24i-2 (100 mg, 202.2 μmol, yield: 33.3%).

[0860] Single configuration compound 24i-1:

[0861] MS m / z(ESI):495.2[M+1]

[0862] SFC analysis: retention time 1.50 minutes; chromatographic column: Chiralpak IC-3 50x4.6 mm ID, 3 μm; mobile phase: CO 2 / EtOH (0.05% DEA) = 60 / 40.

[0863] Single configuration compound 24i-2:

[0864] MS m / z(ESI):495.2[M+1]

[0865] SFC analysis: retention time 2.0 minutes; chromatographic column: Chiralpak IC-3 50x4.6 mm ID, 3 μm; mobile phase: CO 2 / EtOH (0.05% DEA) = 60 / 40.

[0866] Steps 2 and 6

[0867] N-ethyl-5-fluoro-N-isopropyl-2-{7-[(3S)-pyrrolidin-3-yl]imidazo[1,5-a]pyridin-5-yl]benzamide 24j-1

[0868] N-ethyl-5-fluoro-N-isopropyl-2-{7-[(3R)-pyrrolidin-3-yl]imidazo[1,5-a]pyridin-5-yl]benzamide 24j-2

[0869] Compound 24i-1 / 24i-2 (100 mg / 100 mg, 202.2 μmol / 202.2 μmol) was dissolved in dichloromethane (3.0 mL / 3.0 mL) and trifluoroacetic acid (1.0 mL / 1.0 mL) was added. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product of the title product 24j-1 / 24j-2 (100 mg / 100 mg). The crude product was used directly in the next reaction without purification.

[0870] Single configuration compound 24j-1:

[0871] MS m / z(ESI):395.2[M+1]

[0872] Single configuration compound 24j-2:

[0873] MS m / z(ESI):395.2[M+1]

[0874] Steps 3 and 7

[0875] tert-Butyl N-[(1r,4r)-4-{[(3S)-3-(5-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-7-yl)pyrrolidin-1-yl]methyl}cyclohexyl]carbamate 24-1

[0876] tert-Butyl N-[(1r,4r)-4-{[(3R)-3-(5-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-7-yl)pyrrolidin-1-yl]methyl}cyclohexyl]carbamate 24-2

[0877] The crude product of compound 24j-1 / 24j-2 (100 mg / 100 mg) was dissolved in methanol (2.0 mL / 3.0 mL). Triethylamine (40 mg / 40 mg, 395.3 μmol / 395.3 μmol) and tert-butyl N-[(1r,4r)-4-formylcyclohexyl]carbamate (53.64 mg / 53.75 mg, 235.98 μmol / 236.47 μmol) were added, and the mixture was stirred at room temperature for (1.0 / 1.0) hours. Sodium cyanoborohydride (37.5 mg / 37.5 mg, 596.74 μmol / 596.74 μmol) was added, and the reaction was stirred at room temperature for (11 / 11) hours. Aqueous sodium bicarbonate (10 mL / 10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3 / 20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent to obtain the title product 24-1 / 24-2 (100 mg / 100 mg, 165.08 μmol / 165.08 μmol, yield: 83.94% / 83.94%).

[0878] Single configuration compound 24-1:

[0879] MS m / z(ESI):606.5[M+1]

[0880] SFC analysis: retention time 1.16 minutes; column: Chiralpak IC-3 50×4.6 mm ID, 3 μm; mobile phase: CO2 / [IPA+ACN (0.05% DEA)]=50 / 50.

[0881] Single configuration compound 24-2:

[0882] MS m / z(ESI):606.4[M+1]

[0883] SFC analysis: retention time 0.87 min; column: Chiralpak IC-3 50×4.6 mm ID, 3 μm; mobile phase: CO2 / [IPA+ACN (0.05% DEA)]=50 / 50.

[0884] Steps 4 and 8

[0885] N-ethyl-5-fluoro-N-isopropyl-2-{7-[(3S)-1-{[(1r,4r)-4-aminocyclohexyl]methyl}pyrrolidin-3-yl]imidazo[1,5-a]pyridin-5-yl}benzamide 25a-1

[0886] N-ethyl-5-fluoro-N-isopropyl-2-{7-[(3R)-1-{[(1r,4r)-4-aminocyclohexyl]methyl}pyrrolidin-3-yl]imidazo[1,5-a]pyridin-5-yl}benzamide 25a-2

[0887] Compound 24-1 / 24-2 (100 mg / 100 mg, 165.08 μmol / 165.08 μmol) was dissolved in dichloromethane (2.0 mL / 2.0 mL) and trifluoroacetic acid (1.0 mL / 1.0 mL) was added. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product of the title product 25a-1 / 25a-2 (100 mg / 100 mg). The crude product was used directly in the next reaction without purification.

[0888] Single configuration compound 25a-1:

[0889] MS m / z(ESI):506.2[M+1]

[0890] Single configuration compound 25a-2:

[0891] MS m / z(ESI):506.2[M+1]

[0892] Steps 5 and 9

[0893] N-ethyl-5-fluoro-N-isopropyl-2-{7-[(3S)-1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl]imidazo[1,5-a]pyridin-5-yl}benzamide 25-1

[0894] N-ethyl-5-fluoro-N-isopropyl-2-{7-[(3R)-1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl]imidazo[1,5-a]pyridin-5-yl}benzamide 25-2

[0895] Compound 25a-1 / 25 aThe crude product of -2 (100 mg / 100 mg) was dissolved in dichloromethane (3.0 mL), and ethylsulfonyl chloride (32 mg / 31.82 mg, 248.8 μmol / 247.5 μmol) and triethylamine (85 mg / 83.48, 840 μmol / 825.0 μmol) were added and stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (10 mL) was added. Extraction was performed with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by high performance liquid chromatography (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 0%-30%) gave the title products 25-1 / 25-2 (2.57 mg / 2.99 mg, 4.30 μmol / 5.0 μmol, yield: 2.66% / 3.03%).

[0896] Single configuration compound 25-1:

[0897] MS m / z(ESI):598.4[M+1]

[0898] Chiral HPLC: retention time 5.45 minutes; chromatographic column: Chiralpak IA-3 50 x 4.6 mm ID, 3 um; mobile phase: Hexane (0.05% IPAm) / IPA+ACN (0.05% IPAm) = 85 / 15.

[0899] 1 H NMR(400MHz,DMSO-d6)δ8.20(s,1H),8.09–7.61(m,2H),7.52–7.27(m,4H),6.99(d,J=7.6Hz,1H),6.58–6.43(m,1H) ,3.40–3.20(m,3H),3.12–2.76(m,6H),2.75–2.59(m,2H),2.38–2.11(m,3H),1.92–1.70(m,5H),1.62–0.41(m,17H).

[0900] Single configuration compound 25-2:

[0901] MS m / z(ESI):598.4[M+1]

[0902] Chiral HPLC: retention time 4.85 minutes; chromatographic column: Chiralpak IA-3 50 x 4.6 mm ID, 3 um; mobile phase: Hexane (0.05% IPAm) / IPA+ACN (0.05% IPAm) = 85 / 15.

[0903] 1 H NMR(400MHz, DMSO-d6)δ8.20(s,1H),8.09–7.60(m,2H),7.53–7.28(m,4H),6.99(d,J=7.6Hz,1H),6.58–6.44(m,1H) ,3.46–3.19(m,3H),3.18–2.78(m,6H),2.76–2.61(m,2H),2.40–2.09(m,3H),1.94–1.70(m,5H),1.68–0.31(m,17H)

[0904] Example 27

[0905] N-ethyl-5-fluoro-2-[1-methyl-5-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-N-(isopropyl)benzamide 27

[0906] first step

[0907] 2-{5-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl}-N-ethyl-5-fluoro-N-(isopropyl)benzamide 27b

[0908] 7-Bromo-5-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridine 27a (450 mg, 1.83 mmol) and compound 4c (1.47 g, 2.19 mmol) were dissolved in dioxane (12 mL) and water (2.0 mL). Sodium carbonate (387 mg, 3.65 mmol) and Pd(dppf)Cl2 (66.8 mg, 91.3 μmol) were added, and the mixture was stirred at 70°C under a nitrogen atmosphere for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (C18; mobile phase: acetonitrile, water (0.1% trifluoroacetic acid), elution gradient: 40%-60%) to obtain the title product 27b (425 mg, 1.13 mmol, yield: 62.1%).

[0909] MS m / z(ESI):375.1[M+1]

[0910] 1H NMR(400MHz, DMSO-d6)δ8.28(s,1H),7.69(dd,J=22.4,15.2Hz,1H),7.46(t,J=7.6H z,2H),7.32–7.19(m,1H),3.85–3.51(m,4H),3.27–2.62(m,2H),1.14–0.37(m,9H).

[0911] Step 2

[0912] tert-Butyl 3-(7-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 27c

[0913] Compound 27b (300 mg, 533 μmol) and tert-butyl 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (189 mg, 640 μmol) were dissolved in dioxane (4.0 mL) and water (0.7 mL). Potassium carbonate (221 mg, 1.60 mmol) and Pd(dppf)Cl2 (39.0 mg, 53.4 μmol) were added, and the mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 27c (167 mg, 329 μmol, 61.7% yield).

[0914] MS m / z(ESI):508.25[M+1]

[0915] Step 3

[0916] Tert-butyl 3-(7-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)pyrrolidine-1-carboxylate 27d

[0917] Compound 27c (167 mg, 329 μmol) was dissolved in methanol (3.0 mL) and Pd / C (16.08 mg) was added. The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product of the title product 27d (110 mg, 215 μmol, yield: 65.6%). The crude product was used directly in the next reaction without purification.

[0918] MS m / z(ESI):510.2[M+1]

[0919] Step 4

[0920] N-ethyl-5-fluoro-2-[1-methyl-5-(130yridine130ne-3-yl)-1H-pyrazolo[4,3-b]130yridine-7-yl]-N-(propan-2-yl)benzamide

[0921] N-ethyl-5-fluoro-2-[1-methyl-5-(pyrrolidin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-N-isopropylbenzamide 27e

[0922] Compound 27d (110 mg, 216 μmol) was dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (0.6 mL) was added at 0°C. The reaction was stirred at room temperature for 2.0 hours. The mixture was concentrated under reduced pressure to obtain the crude title product 27e (134 mg), which was used directly in the next step without purification.

[0923] MS m / z(ESI):410.2[M+1]

[0924] Step 5

[0925] N-ethyl-5-fluoro-2-[1-methyl-5-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-N-(isopropyl)benzamide 27

[0926] The crude product of compound 27e (134 mg) and compound 2e (103 mg, 327 μmol) were dissolved in N,N-dimethylacetamide (2.0 mL). Potassium carbonate (135 mg, 0.98 mmol) and potassium iodide (54.3 mg, 327 μmol) were added and stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using dichloromethane / methanol as the eluent. The crude product was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 25%-50%) to obtain the title product 27 (25.3 mg, 41.29 μmol, yield: 19.03%) as a white solid.

[0927] MS m / z(ESI):613.3[M+1]

[0928] 1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),8.11(s,0.49H),7.57(s,1H),7.39(td,J=8.8,2.8Hz,1H ),7.33(d,J=8.8Hz,1H),7.16(s,1H),6.71(d,J=7.6Hz,1H),3.92(s,0.3H),3.73–3.55(m,4.7 H),3.11–2.98(m,6H),2.95(dd,J=14.8,7.2Hz,4H),2.64(s,2H),2.31(s,1H),2.13(s,1H),1 .85(dd,J=30.8,12.0Hz,4H),1.47(s,1H),1.31–1.18(m,5H),1.06–0.72(m,8H),0.56(s,2H).

[0929] Example 29

[0930] tert-Butyl N-[(1r,4r)-4-{[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)pyrrolidin-1-yl]methyl}cyclohexyl]carbamate 29

[0931] first step

[0932] 3-Bromo-5-chloropyridine-2-carboxylic acid methyl ester 29b

[0933] 3-Bromo-5-chloropyridine-2-carboxylic acid 29a (20.0 g, 84.58 mmol) was dissolved in methanol (200 mL), cooled to 0°C, and thionyl chloride (20.13 g, 169.17 mmol) was added. The reaction was stirred at 0°C for 5 minutes, then heated to 65°C and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (60 mL) and washed with saturated aqueous sodium carbonate (40 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude title product 29b (19.5 g, 77.85 mmol, 92.04% yield) as a white solid. The crude product was used directly in the next step without purification.

[0934] MS m / z(ESI):252.0[M+1]

[0935] Step 2

[0936] (3-Bromo-5-chloropyridin-2-yl)methanol 29c

[0937] Compound 29b (19.5 g, 77.85 mmol) was dissolved in methanol (200 mL) and tetrahydrofuran (200 mL), cooled to 0°C, and sodium borohydride (15.0 g, 396.49 mmol) was added. The reaction was stirred at room temperature for 12 hours. The reaction solution was cooled to 0°C, quenched by the addition of water (100 mL), and extracted with ethyl acetate (200 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude title product 29c (16 g, 71.92 mmol, 92.38% yield) as a white solid. The crude product was used directly in the next step without purification.

[0938] MS m / z(ESI):224.0[M+1]

[0939] Step 3

[0940] 2-[5-chloro-2-(hydroxymethyl)pyridin-3-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 29d

[0941] Compound 29c (6 g, 26.97 mmol), compound 4c (8.14 g, 24.27 mmol), and sodium carbonate (8.58 g, 80.91 mmol) were dissolved in dioxane (36 mL) and water (24 mL). Pd(dppf)Cl2 (1.97 g, 2.70 mmol) was added. The reaction was stirred at 95°C under a nitrogen atmosphere for 20 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 29d (4.6 g, 13.11 mmol, yield: 48.62%).

[0942] MS m / z(ESI):351.1[M+1]

[0943] Step 4

[0944] 2-{5-chloro-2-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]pyridin-3-yl}-N-ethyl-5-fluoro-N-(isopropyl)benzamide 29e

[0945] Compound 29d (4.6 g, 13.11 mmol), 2,3-dihydro-1H-isoindole-1,3-dione (2.32 g, 15.73 mmol), and triphenylphosphine (5.16 g, 19.67 mmol) were dissolved in tetrahydrofuran (37 mL). Under a nitrogen atmosphere, the mixture was cooled to 0°C and DIAD (3.98 g, 19.67 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 29e (4 g, 8.33 mmol, yield: 63.6%) as a yellow solid.

[0946] MS m / z(ESI):480.1[M+1]

[0947] Step 5

[0948] 2-[2-(Aminomethyl)-5-chloropyridin-3-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 29f

[0949] Compound 29e (4 g, 8.33 mmol) was dissolved in methylamine (71.92 g, 694.72 mmol, 80.00 mL, 30%) in ethanol. The reaction was stirred at 65°C for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude title product 29f (4.0 g) as a yellow solid. The crude product was used directly in the next reaction without purification.

[0950] MS m / z(ESI):350.3[M+1]

[0951] Step 6

[0952] 2-{6-chloro-3-methylimidazo[1,5-a]pyridin-8-yl}-N-ethyl-5-fluoro-N-(isopropyl)benzamide 29g

[0953] The crude product of compound 29f (4.0 g) was dissolved in acetic anhydride (40 mL), and p-toluenesulfonic acid (1.60 g, 9.29 mmol) was added. The reaction was stirred at 100°C for 2.0 hours. The reaction solution was cooled to room temperature, poured into water (60 mL), and the mixture was made alkaline with 10% aqueous sodium hydroxide solution. The mixture was extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated aqueous sodium carbonate solution (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 29 g (1.5 g, 4.01 mmol, yield: 35.1%).

[0954] MS m / z(ESI):374.1[M+1]

[0955] Step 7

[0956] tert-Butyl 3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 29h

[0957] Compound 29g (1.5g, 4.01mmol), tert-butyl 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.77g, 5.99mmol), and cesium carbonate (4.00g, 12.28mmol) were dissolved in dioxane (15mL) and water (5mL). Pd(dtbpf)Cl2 (261.50mg, 401.23μmol) was added. The reaction was stirred at 95°C under a nitrogen atmosphere for 12 hours. The reaction mixture was cooled to room temperature, water (20mL) was added, and extraction was performed with ethyl acetate (20mL x 3). The combined organic phases were washed with saturated brine (30mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to give the title product 29h (1.8 g, 3.55 mmol, yield: 88.6%).

[0958] MS m / z(ESI):507.3[M+1]

[0959] Step 8

[0960] Tert-butyl 3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)pyrrolidine-1-carboxylate 29i

[0961] Compound 29h (600 mg, 1.18 mmol) was dissolved in methanol (10 mL), and Pd / C (143.8 mg, 1.18 mmol) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 29i (400 mg, 786.4 μmol, yield: 66.4%). The crude product was used directly in the next reaction without purification.

[0962] MS m / z(ESI):509.2[M+1]

[0963] Step 9

[0964] N-ethyl-5-fluoro-2-[3-methyl-6-(pyrrolidin-3-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 29j

[0965] Compound 29i (400 mg, 786.4 μmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2.37 g, 20.77 mmol, 1.60 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 29j (400 mg). The crude product was used directly in the next reaction without purification.

[0966] MS m / z(ESI):409.6[M+1]

[0967] Step 10

[0968] tert-Butyl N-[(1r,4r)-4-{[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)pyrrolidin-1-yl]methyl}cyclohexyl]carbamate 29

[0969] The crude product of compound 29j (70 mg, 134 μmol, trifluoroacetate), tert-butyl N-[(1r,4r)-4-formylcyclohexyl]carbamate (60.90 mg, 267.93 μmol), and triethylamine (67.78 mg, 669.81 μmol) were dissolved in methanol (3.0 mL) and stirred at room temperature for 0.5 hour. Sodium cyanoborohydride (12.63 mg, 200.94 μmol) was added, and the mixture was stirred at room temperature for 2.0 hours. The reaction mixture was diluted with dichloromethane (30 mL), and saturated aqueous sodium carbonate (20 mL) was added. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography using dichloromethane / methanol as the eluent to give the title product 29 (12.1 mg, 19.52 μmol, yield: 14.57%) as a white solid.

[0970] MS m / z(ESI):620.3[M+1]

[0971] 1H NMR(400MHz, DMSO-d6)δ8.09–7.96(m,1H),7.72–7.59(m,1H),7.47–7.22(m,2H),7. 05(s,1H),6.82–6.59(m,2H),3.13–2.80(m,7H),2.65–2.57(m,2H),2.36–2.24(m,1H ),2.17–2.00(m,1H),1.85–1.72(m,3H),1.65–1.48(m,2H),1.37(s,9H),1.27–1.10 (m,7H),1.08–0.97(m,3H),0.92–0.66(m,4H),0.58–0.48(m,1H),0.37–0.17(m,3H).

[0972] Example 30

[0973] N-ethyl-5-fluoro-2-[3-methyl-6-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 30

[0974] first step

[0975] N-ethyl-5-fluoro-2-[3-methyl-6-(1-{[(1r,4r)-4-aminocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 30a

[0976] Compound 29 (150 mg, 242 μmol) was dissolved in dichloromethane (3.0 mL). Trifluoroacetic acid (275.95 mg, 2.42 mmol, 186.45 μL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 30a (150 mg). The crude product was used directly in the next reaction without purification.

[0977] MS m / z(ESI):520.5[M+1]

[0978] Step 2

[0979] N-ethyl-5-fluoro-2-[3-methyl-6-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 30

[0980] The crude product of compound 30a (150 mg) was dissolved in dichloromethane (3.0 mL), cooled to 0°C, and ethylsulfonyl chloride (60.9 mg, 473.40 μmol) and triethylamine (119.76 mg, 1.18 mmol, 164.96 μL) were added. Stir at room temperature for 12 hours. Water (20 mL) was added to the reaction solution. Extraction was performed with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia water), elution gradient: 35%-65%) gave the title product 30 (23.96 mg, 39.16 μmol, yield: 16.55%) as a white solid.

[0981] MS m / z(ESI):612.5[M+1]

[0982] 1 H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.69–7.60(m,1H),7.40–7.26(m,2H), 7.03–6.96(m,2H),6.68–6.61(m,1H),3.44–3.39(m,1H),3.30–3.23(m,2H), 3.10–2.71(m,6H),2.66–2.55(m,5H),2.42–2.32(m,1H),2.29–2.12(m,3H), 1.92–1.68(m,5H),1.38–1.01(m,7H),0.98–0.70(m,7H),0.34–0.25(m,2H).

[0983] Example 31

[0984] 2-(6-{1-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]pyrrolidin-3-yl}-1-methyl-1H-indazol-4-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 31

[0985] first step

[0986] (1R,3S,4S)-3-[3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1-methyl-1H-indazol-6-yl)pyrrolidine-1-carbonyl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 31b

[0987] Compound 15f (31.9 mg, 78.1 μmol), (1R,3S,4S)-2-[(tert-butyloxy)carbonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid 31a (18.8 mg, 78.1 μmol), and N,N-diisopropylethylamine (89.6 mg, 693 μmol) were dissolved in DMF (1 mL) and cooled to 0°C. EDCI (19.4 mg, 101 μmol) and HOBt (12.6 mg, 93.7 μmol) were added, and the mixture was stirred at room temperature for 12 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography using dichloromethane / methanol as the eluent to give the title product 31b (35 mg, 55.4 μmol, yield: 70.8%) as a white solid.

[0988] MS m / z(ESI):632.25[M+1]

[0989] Step 2

[0990] 2-(6-{1-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]pyrrolidin-3-yl}-1-methyl-1H-indazol-4-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 31

[0991] Compound 31b (31.0 mg, 49.0 μmol) was dissolved in dichloromethane (0.9 mL) and trifluoroacetic acid (0.3 mL). The reaction was stirred at room temperature for 1.0 hour. The mixture was concentrated under reduced pressure and the resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 40%-55%) to obtain the title product 31 (10.0 mg, 18.8 μmol, yield: 76.6%) as a white solid.

[0992] MS m / z(ESI):532.3[M+1]

[0993] 1H NMR(400MHz, DMSO-d6)δ7.84(d,J=4.0Hz,1H),7.67–7.56(m,2H),7.44–7.27(m,2H),7.13–7.03(m,1H ),4.29–4.10(m,0.46H),4.05(d,J=2.8Hz,4H),3.93(dt,J=21.2,12.8Hz,1H),3.84–3.54(m,4.61H), 3.33(ddd,J=42.4,12.8,7.6Hz,3H),2.89–2.69(m,2H),2.33(dd,J=19.6,17.6Hz,1H),2.14(dd d,J=27.6,18.8,8.4Hz,1H),1.67–1.32(m,6H),1.09–0.52(m,7H),0.08(dd,J=14.8,6.8Hz,2H).

[0994] Example 33

[0995] 2-(6-{1-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-3-hydroxyazetidin-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 33

[0996] first step

[0997] tert-Butyl 3-{8-chloroimidazo[1,5-a]pyridin-6-yl}-3-hydroxyazetidine-1-carboxylate 33b

[0998] Compound 16f (1.7 g, 7.34 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0°C, and a tetrahydrofuran solution of i-PrMgCl.LiCl (1.3 M, 8.47 mL) was added. The reaction was stirred at 0°C for 10 minutes, followed by the addition of tert-butyl 3-oxoazetidine-1-carboxylate (1.51 g, 8.81 mmol). The reaction was stirred at room temperature for 2.0 hours. The reaction solution was quenched by the addition of saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 33b (950 mg, 2.93 mmol, yield: 39.95%).

[0999] MS m / z(ESI):324.0[M+1]

[1000] 1H NMR (400MHz, DMSO-d6) δ8.52–8.46(m,2H),7.44(s,1H),7.00(d,J=1.0Hz,1H),6.60(s,1H),4.16–3.96(m,4H),1.41(s,9H).

[1001] Step 2

[1002] Tert-butyl 3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)-3-hydroxyazetidine-1-carboxylate 33c

[1003] Compound 33b (300 mg, 926.57 μmol) and compound 4c (465.91 mg, 1.39 mmol) were dissolved in dioxane (5.0 mL) and water (1.0 mL). Potassium phosphate (590.04 mg, 2.78 mmol) and Pd(dtbpf)Cl2 (60.39 mg, 92.66 μmol) were added, and the mixture was stirred at 90°C under a nitrogen atmosphere for 12.0 hours. The reaction mixture was cooled to room temperature, water (15 mL) was added, and extraction was performed with ethyl acetate (25 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 33c (230 mg, 463.18 μmol, yield: 49.99%).

[1004] MS m / z(ESI):497.2[M+1]

[1005] 1 H NMR(400MHz,DMSO-d6)δ8.50(br d,J=3.1Hz,2H),7.70(dd,J=5.6,8.6Hz,1H),7.44–7.28(m,2H),7.15(s,1H),6.82–6.71(m,1 H),6.55(s,1H),4.09–3.91(m,4H),3.48(td,J=6.5,13.2Hz,1H),3.28–3.22(m,1H),2.98(br dd,J=6.9,13.4Hz,1H),1.40(s,9H),0.97–0.74(m,7H),0.33(br d,J=6.4Hz,2H).

[1006] Step 3

[1007] N-ethyl-5-fluoro-2-[6-(3-hydroxyazetidin-3-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 33d

[1008] Compound 33c (110 mg, 221.52 μmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) was added at 0°C. The reaction was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title product 33d (110 mg). The crude product was used directly in the next reaction without purification.

[1009] MS m / z(ESI):397.2[M+1]

[1010] Step 4

[1011] (1R,3S,4S)-3-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)-3-hydroxyazetidine-1-carbonyl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 33e

[1012] Compound 31a (57 mg, 236.24 μmol), N,N-diisopropylethylamine (90 mg, 696.36 μmol), EDCI (62 mg, 323.42 μmol), and HOBt (44 mg, 325.63 μmol) were dissolved in dichloromethane (2 mL). The crude product of compound 33d (110 mg) was added and stirred at room temperature for 12 hours. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 22%-52%) to obtain the title product 33e (100 mg, 161.4 μmol, yield: 75.6%) as a white solid.

[1013] MS m / z(ESI):620.3[M+1]

[1014] Step 5

[1015] 2-(6-{1-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-3-hydroxyazetidin-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 33

[1016] Compound 33e (100 mg, 161.36 μmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (1.0 mL). The reaction was stirred at room temperature for 1.0 hour. The mixture was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonium bicarbonate), elution gradient: 15%-45%) to obtain the title product 33 (32.76 mg, 63.05 μmol, yield: 39.07%).

[1017] MS m / z(ESI):520.0[M+1]

[1018] 1 H NMR (400MHz, DMSO-d6) δ8.54–8.42(m,2H),7.76–7.65(m,1H),7.44–7.28(m,2H),7.21–7.11(m,1H),6.86–6.57(m,2H ),4.64–3.89(m,5H),3.50–3.43(m,1H),3.28–3.16(m,2H),3.10–2.88(m,1H),1.76–0.63(m,14H),0.35–0.25(m,2H).

[1019] Example 34

[1020] 2-(6-{1-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-3-fluoroazetidin-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 34

[1021] first step

[1022] tert-Butyl 3-{8-chloroimidazo[1,5-a]pyridin-6-yl}-3-fluoroazetidine-1-carboxylate 34a

[1023] Compound 33b (300 mg, 926.57 μmol) was dissolved in dichloromethane (5.0 mL), cooled to -60°C, and DAST (298.71 mg, 1.85 mmol, 0.5 mL) was added dropwise. The reaction was stirred at -60°C for 1.0 hour, then slowly warmed to room temperature and stirred at room temperature for 1.0 hour. The reaction solution was quenched by addition of saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 34a (235 mg, 721.4 μmol, yield: 77.9%) as a brown solid.

[1024] MS m / z(ESI):326.0[M+1]

[1025] Step 2

[1026] tert-Butyl 3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)-3-fluoroazetidine-1-carboxylate 34b

[1027] Compound 34a (235 mg, 721.38 μmol) and compound 4c (485 mg, 1.45 mmol) were dissolved in dioxane (3.0 mL) and water (0.5 mL). Potassium phosphate (460 mg, 2.17 mmol) and Pd(dtbpf)Cl2 (48 mg, 73.65 μmol) were added, and the mixture was stirred at 90°C under a nitrogen atmosphere for 12.0 hours. The reaction mixture was cooled to room temperature, water (15 mL) was added, and extraction was performed with ethyl acetate (25 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 34b (240 mg, 481.38 μmol, yield: 66.7%).

[1028] MS m / z(ESI):499.3[M+1]

[1029] 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.46(s,1H),7.70(dd,J=5.5,8.6Hz,1H),7.45–7.31(m,2H),7. 24–7.19(m,1H),6.74–6.67(m,1H),4.41–4.22(m,4H),3.51–3.44(m,1H),3.34–3.26(m,1H),2.91(br dd,J=6.9,13.6Hz,1H),1.40(s,9H),1.00–0.68(m,7H),0.33(br d,J=6.6Hz,2H).

[1030] Step 3

[1031] N-Ethyl-5-fluoro-2-[6-(3-fluoroazetidin-3-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 34c

[1032] Compound 34b (230 mg, 461.33 μmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (2.22 g, 19.47 mmol, 1.5 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 34c (200 mg). The crude product was used directly in the next reaction without purification.

[1033] MS m / z(ESI):399.1[M+1]

[1034] Step 4

[1035] (1R,3S,4S)-3-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)-3-fluoroazetidine-1-carbonyl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 34d

[1036] Compound 31a (57 mg, 236.24 μmol), N,N-diisopropylethylamine (85 mg, 657.69 μmol), EDCI (62 mg, 323.42 μmol), and HOBt (41 mg, 303.43 μmol) were dissolved in dichloromethane (3 mL). The crude product of compound 34c (100 mg) was added and stirred at room temperature for 12 hours. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using dichloromethane / methanol as the eluent to afford the title product 34d (100 mg, 160.85 μmol, yield: 82.43%) as a white solid.

[1037] MS m / z(ESI):622.4[M+1]

[1038] Step 5

[1039] 2-(6-{1-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]-3-fluoroazetidin-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 34

[1040] Compound 34d (100 mg, 160.85 μmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (1.5 mL). The reaction was stirred at room temperature for 1.0 hour. The mixture was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 25%-55%) to obtain the title product 34 (45.77 mg, 87.75 μmol, yield: 54.56%).

[1041] MS m / z(ESI):522.2[M+1]

[1042] 1 H NMR(400MHz, DMSO-d6)δ8.76–8.64(m,1H),8.46(s,1H),7.77–7.65(m,1H),7.46–7.30(m,2H),7.28–7.18(m,1H),6.79–6.70(m,1H),4 .87–4.54(m,2H),4.47–4.16(m,2H),3.51–3.39(m,2H),3.25–3.22(m,1H),3.02–2.62(m,2H),1.57–0.65(m,14H),0.36–0.30(m,2H).

[1043] Example 35

[1044] N-ethyl-5-fluoro-2-[3-methyl-7-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-5-yl]-N-(isopropyl)benzamide 35

[1045] first step

[1046] 2-[4-Chloro-6-(acetamidomethyl)pyridin-2-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 35a

[1047] Compound 24f (4.1 g, 11.72 mmol) and triethylamine (3.56 g, 35.16 mmol) were dissolved in dichloromethane (50 mL), and acetyl chloride (1.38 g, 17.58 mmol, 1.07 mL) was added dropwise. The reaction was stirred at room temperature for 1.0 hour. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (5.4 g) of the title product 35a. The crude product was used directly in the next reaction without purification.

[1048] MS m / z(ESI):392.2[M+1]

[1049] Step 2

[1050] 2-{7-chloro-3-methylimidazo[1,5-a]pyridin-5-yl}-N-ethyl-5-fluoro-N-(isopropyl)benzamide 35b

[1051] The crude product of compound 35a (5.5 g) was dissolved in toluene (40 mL), and phosphorus oxychloride (10.76 g, 70.18 mmol, 8 mL) was added. The reaction was stirred at 100°C for 1.0 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution (100 mL) was added, and the mixture was extracted with dichloromethane (80 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 35b (1.4 g, 3.74 mmol, yield: 26.7%) as a yellow solid.

[1052] MS m / z(ESI):374.1[M+1]

[1053] 1 H NMR(400MHz,DMSO-d6)δ7.77–7.64(m,2H),7.47–7.37(m,2H),7.27(br d,J=2.4Hz,1H),6.44–6.36(m,1H),5.75(s,1H),3.81–3.69(m,1H),3.04–2.9 0(m,1H),1.99–1.92(m,3H),1.13–1.03(m,5H),0.91(d,J=6.8Hz,1H),0.67(br t,J=6.8Hz,3H).

[1054] Step 3

[1055] tert-Butyl 3-(5-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 35c

[1056] Compound 35b (900 mg, 2.41 mmol), tert-butyl 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (852.74 mg, 2.89 mmol), and potassium phosphate (1.28 g, 6.04 mmol) were dissolved in dioxane (15 mL) and water (1.8 mL). Pd(dtbpf)Cl2 (161.61 mg, 247.96 μmol) was added. The reaction was stirred at 80°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, water (30 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 35c (740 mg, 1.46 mmol, 60.7% yield).

[1057] MS m / z(ESI):507.3[M+1]

[1058] 1 H NMR (400MHz, DMSO-d6) δ7.67(br d,J=6.1Hz,1H),7.47–7.28(m,4H),6.75–6.65(m,1H),6.33(br s,1H),4.38(br d,J=4.5Hz,2H),4.18(br d,J=4.4Hz,2H),3.78(br d,J=1.3Hz,1H),3.20(br s,1H),2.99–2.85(m,1H),2.02–1.93(m,3H),1.44(br d,J=9.4Hz,9H),1.11–0.95(m,6H),0.86–0.79(m,1H),0.60(br t,J=6.6Hz,2H).

[1059] Step 4

[1060] Tert-butyl 3-(5-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-7-yl)pyrrolidine-1-carboxylate 35d

[1061] Compound 35c (140 mg, 276.35 μmol) was dissolved in methanol (10 mL) and 10% Pd / C (29.41 mg, 276.35 μmol) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude title product 35d (130 mg, 255.6 μmol, 92.5% yield). The crude product was used directly in the next step without purification.

[1062] MS m / z(ESI):509.2[M+1]

[1063] Step 5

[1064] N-ethyl-5-fluoro-2-[3-methyl-7-(pyrrolidin-3-yl)imidazo[1,5-a]pyridin-5-yl]-N-(isopropyl)benzamide 35e

[1065] Compound 35d (130 mg, 255.6 μmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 35e (110 mg). The crude product was used directly in the next reaction without purification.

[1066] MS m / z(ESI):409.3[M+1]

[1067] Step 6

[1068] N-ethyl-5-fluoro-2-[3-methyl-7-(1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-5-yl]-N-(isopropyl)benzamide 35

[1069] The crude product of compound 35e (50.0 mg, 95.69 μmol, trifluoroacetate) was dissolved in N,N-dimethylformamide (1 mL). [(1r,4r)-4-ethylsulfonamidocyclohexyl]methyl 4-methylbenzene-1-sulfonate 35f (50 mg, 133.15 μmol), potassium carbonate (26.45 mg, 191.38 μmol), and TBAI (3.53 mg, 9.57 μmol) were added, and the mixture was stirred at 90°C for 12 hours. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using dichloromethane / methanol as the eluent to afford the title product 35 (2.88 mg, 4.71 μmol, 4.92% yield).

[1070] MS m / z(ESI):612.3[M+1]

[1071] 1H NMR(400MHz,CD3OD)δ7.70–7.51(m,1H),7.45–7.14(m,4H),6.67–6.34(m,1H ),4.05–3.62(m,1H),3.27–3.21(m,1H),3.15–2.99(m,4H),2.93–2.57(m,3H) ,2.49–2.24(m,3H),2.18–2.07(m,2H),2.05–1.97(m,2H),1.95–1.82(m,3H) ,1.74–1.60(m,1H),1.48–1.25(m,8H),1.22–0.98(m,9H),0.90–0.81(m,2H).

[1072] Example 36

[1073] N-ethyl-5-fluoro-2-{1-methyl-6-[4-({[(1r,4r)-4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]methyl}amino)piperidin-1-yl]-1H-indazol-4-yl}-N-(isopropyl)benzamide 36

[1074] first step

[1075] Tert-butyl N-[1-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1-methyl-1H-indazol-6-yl)piperidin-4-yl]carbamate 36a

[1076] Compound 15c (500 mg, 936 μmol) and tert-butyl N-(piperidin-4-yl)carbamate (187 mg, 936 μmol) were dissolved in toluene (10.5 mL) and tert-butanol (3.5 mL). Pd(Oac)2 (21.0 mg, 93.6 μmol), Xphos (89.3 mg, 187 μmol), and sodium tert-butoxide (89.3 mg, 187 μmol) were added, and the mixture was stirred at 120°C under a nitrogen atmosphere for 8.0 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using petroleum ether / ethyl acetate as the eluent to afford the title product 36a (454 mg, 844.4 μmol, yield: 90.2%) as a white solid. MS m / z (ESI): 538.2 [M+1]

[1077] 1H NMR (400MHz, DMSO-d6) δ7.66 (d, J=5.2Hz, 1H), 7.59 (ddd, J=8.4, 5.6, 2.8Hz, 1H), 7.36 (td, J=8.4, 2.8Hz, 1H),7.28(td,J=9.6,2.8Hz,1H),6.94–6.80(m,3H),3.95(d,J=3.6Hz,3H),3.71(d,J=3.2Hz,2H),3.38(dd ,J=13.2,6.4Hz,2H),3.27(dt,J=13.6,6.8Hz,1H),2.83(dt,J=24.8,9.2Hz,3H),1.83(d,J=11.2Hz,2H),1 .57–1.44(m,2H),1.39(s,9H),0.85(d,J=6.4Hz,3H),0.70(dt,J=33.2,7.2Hz,4H),0.13(d,J=6.4Hz,2H).

[1078] Step 2

[1079] 2-[6-(4-aminopiperidin-1-yl)-1-methyl-1H-indazol-4-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 36b

[1080] Compound 36a (200 mg, 371.98 μmol) was dissolved in dichloromethane (2.0 mL), and trifluoroacetic acid (0.8 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The mixture was concentrated under reduced pressure to obtain the crude title product 36b (430 mg), which was used directly in the next step without purification.

[1081] MS m / z(ESI):438.1[M+1]

[1082] Step 3

[1083] N-ethyl-5-fluoro-2-{1-methyl-6-[4-({[(1r,4r)-4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]methyl}amino)piperidin-1-yl]-1H-indazol-4-yl}-N-(isopropyl)benzamide 36

[1084] The crude product of compound 36b (150 mg) was dissolved in dichloromethane (2.0 mL), and compound 28c (25.2 mg, 128 μmol) was added. The mixture was stirred at 0°C for 0.5 hours. Sodium triacetoxyborohydride (81.3 mg, 383 μmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using dichloromethane / methanol as the eluent. The crude product was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 30%-45%) to obtain the title product 36 (19.5 mg, 31.5 μmol, yield: 45.4%) as a white solid. MS m / z (ESI): 619.25 [M+1]

[1085] 1 H NMR(400MHz,DMSO-d6)δ8.29(s,1H),7.69–7.64(m,1H),7.62–7.56(m,1H),7.37(td,J=8.8,2.8Hz,1H),7.32–7 .24(m,1H),6.92(s,1H),6.87–6.83(m,1H),4.27–4.20(m,2H),3.97–3.94(m,3H),3.73(s,2H),3.51–3.42(m,3 H),3.41–3.34(m,1H),3.28(dd,J=13.6,6.8Hz,1H),2.88–2.70(m,4H),2.55(d,J=6.4Hz,2H),1.92(dd,J=40.0 ,11.6Hz,4H),1.68(d,J=10.4Hz,2H),1.43(dd,J=22.0,12.0Hz,5H),1.09–0.63(m,9H),0.12(d,J=6.8Hz,2H).

[1086] Example 38

[1087] 2-(6-{1-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]pyrrolidin-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 38

[1088] first step

[1089] (1R,3S,4S)-3-[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)pyrrolidine-1-carbonyl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 38a

[1090] Compound 31a (54 mg, 223.80 μmol) and N,N-diisopropylethylamine (80 mg, 619 μmol) were dissolved in dichloromethane (2 mL) and cooled to 0°C. EDCI (58 mg, 302.55 μmol) and HOBt (41 mg, 303.4 μmol) were added. Compound 21d (102 mg, 200.6 μmol, trifluoroacetate) was then added and stirred at room temperature for 12 hours. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by preparative thin-layer chromatography using dichloromethane / methanol as the eluent afforded the title product 38a (80 mg, 129.5 μmol, yield: 64.6%).

[1091] MS m / z(ESI):618.4[M+1]

[1092] Step 2

[1093] 2-(6-{1-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]pyrrolidin-3-yl}imidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 38

[1094] Compound 38a (80 mg, 129.5 μmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (1.0 mL). The reaction was stirred at room temperature for 1.0 hour. The mixture was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 20%-50%) to obtain the title product 38 (17.7 mg, 34.2 μmol, yield: 26.4%).

[1095] MS m / z(ESI):518.3[M+1]

[1096] 1 H NMR (400MHz, DMSO-d6) δ8.45–8.35(m,1H),8.34–8.26(m,1H),7.74–7.64(m,1H),7.44–7.28(m,2H),7.17–7.09(m,1H),6.77–6.62(m,1H) ),4.29–3.55(m,3H),3.54–3.40(m,2H),3.28–3.18(m,3H),3.01–2.66(m,2H),2.42–1.77(m,3H),1.56–0.68(m,14H),0.30–0.22(m,2H).

[1097] Example 39

[1098] N-ethyl-5-fluoro-2-(6-{1-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]piperidin-4-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 39

[1099] first step

[1100] tert-Butyl 4-{8-chloroimidazo[1,5-a]pyridin-6-yl}-1,2,3,6-tetrahydropyridine-1-carboxylate 39a

[1101] Compound 16f (500 mg, 2.16 mmol), tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (560 mg, 1.81 mmol), and sodium carbonate (686.8 mg, 6.48 mmol) were dissolved in dioxane (10 mL) and water (2 mL). Pd(dppf)Cl2 (158 mg, 216 μmol) was added. The reaction was stirred at 90°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 39a (400 mg, 1.20 mmol, 55.5% yield).

[1102] MS m / z(ESI):334.1[M+1]

[1103] Step 2

[1104] tert-Butyl 4-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate 39b

[1105] Compound 39a (400 mg, 1.20 mmol) and compound 4c (600 mg, 1.79 mmol) were dissolved in dioxane (12 mL) and water (4.0 mL). Cesium carbonate (1.17 g, 3.59 mmol) and Pd(dtbpf)Cl2 (78.1 mg, 119.8 μmol) were added, and the mixture was stirred at 95°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 39b (400 mg, 789.6 μmol, yield: 65.9%).

[1106] MS m / z(ESI):507.3[M+1]

[1107] Step 3

[1108] tert-Butyl 4-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)piperidine-1-carboxylate 39c

[1109] Compound 39b (400 mg, 789.6 μmol) was dissolved in methanol (20 mL) and Pd / C (96 mg, 790 μmol) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product (300 mg) of the title product 39c. The crude product was used directly in the next reaction without purification.

[1110] MS m / z(ESI):509.5[M+1]

[1111] Step 4

[1112] N-ethyl-5-fluoro-2-[6-(piperidin-4-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 39d

[1113] Compound 39c (300 mg, 589.8 μmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (134.50 mg, 1.18 mmol, 90.88 μL) was added at 0°C. The reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title product 39d (230 mg, 563.02 μmol, 95.5% yield). The crude product was used directly in the next reaction without purification.

[1114] MS m / z(ESI):409.2[M+1]

[1115] Step 5

[1116] tert-Butyl (1S,3S,4R)-3-[4-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)piperidine-1-carbonyl]-5-methylene-2-azabicyclo[2.2.2]octane-2-carboxylate 39e

[1117] Compound 39d (100.0 mg, 244.8 μmol), (1S,3S,4R)-2-tert-butoxycarbonyl-5-methylene-2-azabicyclo[2.2.2]octane-3-carboxylic acid 23a (40.00 mg, 149.63 μmol), and N,N-diisopropylethylamine (126.55 mg, 979.17 μmol) were dissolved in dichloromethane (4 mL) and cooled to 0°C. EDCI (70.39 mg, 367.19 μmol) and HOBt (56.23 mg, 367.19 μmol) were added, and the mixture was stirred at room temperature for 12 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography using dichloromethane / methanol as the eluent to afford the title product 39e (50 mg, 76.01 μmol, yield: 31.05%) as a white solid.

[1118] MS m / z(ESI):658.4[M+1]

[1119] Step 6

[1120] N-ethyl-5-fluoro-2-(6-{1-[(1S,3S,4R)-5-methylene-2-azabicyclo[2.2.2]octane-3-carbonyl]piperidin-4-yl}imidazo[1,5-a]pyridin-8-yl)-N-(isopropyl)benzamide 39

[1121] Compound 39e (50 mg, 76.01 μmol) was dissolved in dichloromethane (2.0 mL) and trifluoroacetic acid (8.67 mg, 76.01 μmol, 5.86 μL). The reaction was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 32%-62%) to obtain the title product 39 (11.53 mg, 20.67 μmol, yield: 27.2%).

[1122] MS m / z(ESI):558.3[M+1]

[1123] 1H NMR(400MHz,DMSO-d6)δ8.36(br d,J=7.9Hz,1H),8.28–8.18(m,1H),7.74–7.63(m,1H),7.42–7.27(m,2H),7.16–7.08(m,1H),6.68–6.57(m,1H),4.92(br d,J=13.6Hz,1H),4.73(s,1H),4.65–4.53(m,1H),3.94–3.72(m,2H),3.53–3.40(m,2H),3.24–3.00(m,3H),2.73(br d,J=8.3Hz,2H),2.40–2.22(m,2H),2.01–1.74(m,2H),1.72–1.35(m,7H),0.97–0.65(m,7H),0.32–0.13(m,3H).

[1124] Example 40

[1125] 2-(6-{4-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]piperazin-1-yl}imidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 40

[1126] first step

[1127] tert-Butyl 4-{8-chloroimidazo[1,5-a]pyridin-6-yl}-piperazine-1-carboxylate 40a

[1128] Compound 16f (500 mg, 2.16 mmol), tert-butyl piperazine-1-carboxylate (403 mg, 2.16 mmol), Puphos (101 mg, 216.44 μmol), and cesium carbonate (2.11 g, 6.48 mmol) were dissolved in dioxane (10 mL). Pd2(dba)3 (158 mg, 216 μmol) was added. The reaction was stirred at 90°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (35 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 40a (200 mg, 593.80 μmol, yield: 27.5%).

[1129] MS m / z(ESI):337.1[M+1]

[1130] Step 2

[1131] 4-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester 40b

[1132] Compound 40a (150 mg, 445.35 μmol) and compound 4c (300 mg, 894.93 μmol) were dissolved in dioxane (3.0 mL) and water (0.5 mL). Potassium phosphate (284 mg, 1.34 mmol) and Pd(dtbpf)Cl2 (30 mg, 46.03 μmol) were added, and the mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was performed with ethyl acetate (35 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the eluent to obtain the title product 40b (100 mg, 196.23 μmol, yield: 44.1%).

[1133] MS m / z(ESI):510.2[M+1]

[1134] Step 3

[1135] N-Ethyl-5-fluoro-2-[6-(piperazin-1-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 40c

[1136] Compound 40b (100 mg, 196.23 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) was added at 0°C. The reaction was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title product 40c (100 mg). The crude product was used directly in the next reaction without purification.

[1137] MS m / z(ESI):410.1[M+1]

[1138] Step 4

[1139] (1R,3S,4S)-3-[4-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)piperazine-1-carbonyl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 40d

[1140] Compound 31a (52.23 mg, 216.45 μmol) and N,N-diisopropylethylamine (176.42 mg, 1.37 mmol, 237.76 μL) were dissolved in dichloromethane (3 mL), cooled to 0°C, and EDCI (56.45 mg, 294.45 μmol) and HOBt (40.31 mg, 298.35 μmol) were added. The crude product of compound 40c (100 mg) was then added and stirred at room temperature for 12 hours. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by HPLC (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 20%-50%) to give the title product 40d (80 mg, 126.43 μmol, yield: 64.4%).

[1141] MS m / z(ESI):633.4[M+1]

[1142] Step 5

[1143] 2-(6-{4-[(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carbonyl]piperazin-1-yl}imidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 40

[1144] Compound 40d (80 mg, 126.4 μmol) was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL). The reaction was stirred at room temperature for 1.0 hour. The mixture was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia), elution gradient: 25%-55%) to obtain the title product 40 (53.1 mg, 93.3 μmol, yield: 46.2%).

[1145] MS m / z(ESI):533.4[M+1]

[1146] 1 H NMR(400MHz, DMSO-d6)δ8.27(s,1H),7.83(s,1H),7.72–7.63(m,1H),7.44–7.28(m,2H),7.11–7.02(m,1H),6.71–6.62(m,1H), 3.76–3.38(m,8H),3.07–2.86(m,5H),2.42(s,1H),1.54–1.30(m,4H),1.26–0.98(m,3H),0.98–0.67(m,7H),0.34–0.26(m,2H).

[1147] Example 42

[1148] 2-[6-(1-{2-[4-(5,6-dimethoxypyridazin-3-yl)phenyl]ethyl}piperidin-4-yl)imidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 42

[1149] first step

[1150] 2-[4-(5,6-Dimethoxypyridazin-3-yl)phenyl]ethyl-1-ol 42b

[1151] [4-(2-Hydroxyethyl)phenyl]boronic acid 42a (855.65 mg, 5.16 mmol) and 6-chloro-3,4-dimethoxypyridazine 20b (900 mg, 5.16 mmol) were dissolved in dioxane (10 mL) and water (2.0 mL). Sodium carbonate (1.09 g, 10.31 mmol) and tetrakis(triphenylphosphine)palladium (595.70 mg, 515.51 μmol) were added, and the mixture was stirred at 100°C under a nitrogen atmosphere for 3.0 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent to afford the title product 42b (1.23 g, 4.73 mmol, 91.7% yield) as a white solid.

[1152] MS m / z(ESI):261.1[M+1]

[1153] 1 H NMR (400MHz, DMSO-d6) δ7.99(d,J=8.4Hz,2H),7.56(s,1H),7.36(d,J=8.4Hz,1H),4.68(t, J=5.2Hz,1H),4.05(s,2H),3.98(s,2H),3.65(td,J=7.2,5.6Hz,1H),2.79(t,J=6.8Hz,1H).

[1154] Step 2

[1155] 2-[4-(5,6-Dimethoxypyridazin-3-yl)phenyl]acetaldehyde 42c

[1156] Compound 42b (40 mg, 153.68 μmol) was dissolved in dichloromethane (2.0 mL). The mixture was cooled to 0°C and Dess-Martin periodinane (84.73 mg, 199.78 μmol) was added. The reaction was stirred at room temperature for 2.0 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using ethyl acetate / petroleum ether as the eluent to afford the title product 42c (26.27 mg, 101.71 μmol, 66.2% yield) as a yellow solid.

[1157] 1 H NMR(400MHz,DMSO-d6)δ9.74(t,J=1.6Hz,1H),8.07(d,J=8.0Hz,2H),7.61(s ,1H),7.39(d,J=8.0Hz,2H),4.06(s,3H),3.99(s,3H),3.87(d,J=1.6Hz,2H).

[1158] Step 3

[1159] 2-[6-(1-{2-[4-(5,6-dimethoxypyridazin-3-yl)phenyl]ethyl}piperidin-4-yl)imidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 42

[1160] Compound 39d (71.18 mg, 174.23 μmol), triethylamine (58.77 mg, 580.78 μmol, 80.73 μL), and compound 42c (50 mg, 193.59 μmol) were dissolved in methanol (0.9 mL) and stirred at room temperature for 0.5 hour. Sodium cyanoborohydride (24.33 mg, 387.19 μmol) was added, and the mixture was stirred at room temperature for 0.5 hour. Aqueous sodium bicarbonate (5.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by HPLC (mobile phase: acetonitrile, water (0.1% ammonium bicarbonate), elution gradient: 34%-64%) to afford the title product 42 (5.70 mg, 8.76 μmol, yield: 4.52%) as an off-white solid.

[1161] MS m / z(ESI):651.5[M+1]

[1162] 1H NMR (400MHz, CDCl3) δ8.13 (s, 1H), 7.94 (d, J = 8.4Hz, 2H), 7.76 (s, 1H), 7.69–7.60 (m, 1H), 7. 36(d,J=8.0Hz,2H),7.25(s,1H),7.23–7.11(m,3H),6.82–6.78(m,1H),4.24(s,3H),4.02(s, 3H),3.63–3.37(m,2H),3.30–3.17(m,2H),3.02–2.93(m,3H),2.82–2.71(m,2H),2.54–2.44 (m,1H),2.32–2.17(m,2H),2.01–1.83(m,4H),0.79(m,J=9.52Hz,7H),0.24(d,J=6.8Hz,2H).

[1163] Example 48

[1164] N-ethyl-5-fluoro-2-[6-(3-fluoro-1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}azetidin-3-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 48

[1165] first step

[1166] Tert-butyl N-[(1r,4r)-4-{[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}imidazo[1,5-a]pyridin-6-yl)-3-fluoroazetidin-1-yl]methyl}cyclohexyl]carbamate 48a

[1167] Compound 34c (122.99 mg, 240 μmol, trifluoroacetate), tert-butyl N-[(1r,4r)-4-formylcyclohexyl]carbamate (65.46 mg, 288.00 μmol), and triethylamine (72.86 mg, 720.00 μmol) were dissolved in methanol (3.0 mL) and stirred at room temperature for 1.0 hour. Sodium cyanoborohydride (45.70 mg, 727.20 μmol) was added, and the mixture was stirred at room temperature for 11 hours. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using dichloromethane / methanol as the eluent to afford the title product 48a (105 mg, 172.2 μmol, yield: 71.75%) as a white solid.

[1168] MS m / z(ESI):610.4[M+1]

[1169] Step 2

[1170] N-ethyl-5-fluoro-2-[6-(3-fluoro-1-{[(1r,4r)-4-aminocyclohexyl]methyl}azetidin-3-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 48b

[1171] Compound 48a (105 mg, 172.2 μmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 48b (105 mg). The crude product was used directly in the next reaction without purification.

[1172] MS m / z(ESI):510.4[M+1]

[1173] Step 3

[1174] N-ethyl-5-fluoro-2-[6-(3-fluoro-1-{[(1r,4r)-4-ethanesulfonamidocyclohexyl]methyl}azetidin-3-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 48

[1175] Dissolve the crude product of compound 48b (88 mg) in dichloromethane (2.0 mL), add diisopropylethylamine (90.83 mg, 702.77 μmol), cool to 0°C, and slowly add ethylsulfonyl chloride (45.18 mg, 351.38 μmol) dropwise. Stir at room temperature for 12 hours. The reaction solution is diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by preparative thin-layer chromatography using dichloromethane / methanol as the eluent to afford the title product 48 (7.06 mg, 11.73 μmol, yield: 8.35%) as an off-white solid.

[1176] MS m / z(ESI):602.4[M+1]

[1177] 1H NMR(400MHz,DMSO-d6)δ8.63–8.57(m,1H),8.47(s,1H),7.74–7.66(m,1H),7.4 4–7.28(m,2H),7.19(s,1H),7.01–6.96(m,1H),6.86–6.78(m,1H),3.72–3.62(m ,2H),3.49–3.39(m,3H),3.31–3.22(m,1H),3.02–2.87(m,4H),2.39–2.32(m,2 H),1.90–1.67(m,4H),1.23–1.13(m,6H),1.02–0.69(m,9H),0.34–0.28(m,2H).

[1178] Example 50

[1179] tert-Butyl N-(4-{[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)pyrrolidin-1-yl]methyl}-4-hydroxycyclohexyl)carbamate 50

[1180] Compound 29j (200 mg, 382.75 μmol, trifluoroacetate), tert-butyl N-{1-oxaspiro[2.5]octan-6-yl}carbamate 50a (95.70 mg, 421.03 μmol), and triethylamine (193.65 mg, 1.91 mmol) were dissolved in ethanol (1.5 mL) and stirred at 70°C for 12 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 7%-37%) to afford the title product 50 (80 mg, 125.8 μmol, yield: 32.9%) as a yellow solid.

[1181] MS m / z(ESI):636.4[M+1]

[1182] 1H NMR(400MHz,DMSO-d6)δ8.14(s,0.16H),8.03(s,1H),7.70–7.60(m,1H),7.44–7.2 8(m,2H),7.04(s,1H),6.83–6.62(m,2H),5.21–4.53(m,1H),3.67–3.41(m,4H),3. 27–3.08(m,4H),2.96–2.82(m,1H),2.60(s,3H),2.36–2.21(m,1H),2.17–2.01(m, 1H),1.77–1.44(m,7H),1.43–1.29(m,12H),0.99–0.65(m,7H),0.32–0.20(m,2H).

[1183] Examples 51, 52

[1184] N-ethyl-5-fluoro-2-[3-methyl-6-(1-{[(1r,4r)-4-ethanesulfonamido-1-fluorocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 51

[1185] N-ethyl-5-fluoro-2-[3-methyl-6-(1-{[(1s,4s)-4-ethanesulfonamido-1-fluorocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 52

[1186] first step

[1187] tert-Butyl N-[4-fluoro-4-(hydroxymethyl)cyclohexyl]carbamate 51a

[1188] Compound 50a (1.0 g, 4.40 mmol) was dissolved in dichloromethane (15.0 mL) and cooled to -78°C under nitrogen. Hydrogen fluoride in pyridine (622.88 mg, 4.40 mmol, 5 mL, 70% pure hydrogen fluoride) was slowly added dropwise, and the mixture was stirred at -78°C for 2.0 hours. Saturated aqueous sodium bicarbonate (30 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. The crude product was dissolved in methanol (40 mL), and BoC2O (4.80 g, 22.00 mmol, 5.05 mL) and DMAP (53.75 mg, 439.95 μmol) were added. The mixture was stirred at room temperature for 12 hours. The mixture was then extracted with water (30 mL) and dichloromethane (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to give the title product 51a (450 mg, 1.82 mmol, yield: 41.36%) as a white solid.

[1189] MS m / z(ESI):270.1[M+23]

[1190] 1 H NMR (400MHz, CDCl3) δ4.46 (br d, J = 1.3Hz, 1H), 3.69–3.54 (m, 2H), 3.53–3.40 (m, 1H), 2.07–1.88 (m, 4H), 1.49–1.41 (m, 13H).

[1191] Step 2

[1192] tert-Butyl N-(4-fluoro-4-formylcyclohexyl)carbamate 51b

[1193] Dissolve oxalyl chloride (462 mg, 3.64 mmol, 317.53 μL) in dichloromethane (5 mL), cool to -78°C, and add a solution of DMSO (427 mg, 5.47 mmol, 387.83 μL) in dichloromethane (5 mL) dropwise. Stir at -78°C for 10 minutes, then add a solution of compound 51a (450 mg, 1.82 mmol) in dichloromethane (5.0 mL) dropwise. Stir the reaction at -78°C for 0.5 hours, then add triethylamine (1.84 g, 18.20 mmol), warm to room temperature, and continue stirring for 1 hour. Quench the reaction by adding saturated aqueous ammonium chloride (15 mL) and extract with dichloromethane (20 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to give the title product 51b (300 mg, 1.22 mmol, yield: 67.2%) as a white solid.

[1194] MS m / z(ESI):286.1[M+41]

[1195] 1 H NMR (400MHz, CDCl3) δ9.84–9.69(m,1H),4.56(br s,1H),3.60–3.44(m,1H),2.02–1.90(m,4H),1.80–1.67(m,2H),1.45(s,11H).

[1196] Step 3

[1197] tert-Butyl N-(4-{[3-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)pyrrolidin-1-yl]methyl}-4-fluorocyclohexyl)carbamate 51c

[1198] Compound 29j (100 mg, 244.79 μmol), compound 51b (72 mg, 293.53 μmol), and triethylamine (25 mg, 247.06 μmol) were dissolved in methanol (3.0 mL) and stirred at room temperature for 1.0 hour. Sodium cyanoborohydride (47 mg, 747.91 μmol) was added, and the mixture was stirred at room temperature for 11 hours. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using a dichloromethane / methanol system to obtain the title product 51c (105 mg, 164.63 μmol, yield: 67.25%).

[1199] MS m / z(ESI):638.3[M+1]

[1200] Step 4

[1201] 2-(6-{1-[(4-amino-1-fluorocyclohexyl)methyl]pyrrolidin-3-yl}-3-methylimidazo[1,5-a]pyridin-8-yl)-N-ethyl-5-fluoro-N-(isopropyl)benzamide 51d

[1202] Compound 51c (100 mg, 156.79 μmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (740.00 mg, 6.49 mmol, 0.5 mL) was added at 0°C. The reaction was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure to afford the crude title product 51d (100 mg), which was used directly in the next step without purification.

[1203] MS m / z(ESI):538.2[M+1]

[1204] Step 5

[1205] N-ethyl-5-fluoro-2-[3-methyl-6-(1-{[(1r,4r)-4-ethanesulfonamido-1-fluorocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 51

[1206] N-ethyl-5-fluoro-2-[3-methyl-6-(1-{[(1s,4s)-4-ethanesulfonamido-1-fluorocyclohexyl]methyl}pyrrolidin-3-yl)imidazo[1,5-a]pyridin-8-yl]-N-(isopropyl)benzamide 52

[1207] The crude product of compound 51d (100 mg) and triethylamine (77.63 mg, 767.21 μmol) were dissolved in dichloromethane (3.0 mL). Ethylsulfonyl chloride (39.46 mg, 306.89 μmol) was added and stirred at room temperature for 12 hours. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (C18; mobile phase: acetonitrile, water (0.1% ammonium bicarbonate), elution gradient: 33%-63%) to afford the title products 51 (1.21 mg, 1.92 μmol, yield: 1.25%) and 52 (4.01 mg, 6.37 μmol, yield: 4.15%) as white solids.

[1208] Compound 51:

[1209] MS m / z(ESI):630.2[M+1]

[1210] HPLC: retention time 1.101 minutes.

[1211] 1 H NMR(400MHz, DMSO-d6)δ7.93(s,1H),7.70–7.60(m,1H),7.42–7.25(m,2H),7.04–6. 96(m,2H),6.73–6.61(m,1H),3.46–3.42(m,1H),3.28–3.24(m,2H),3.03–2.89(m,4H ),2.78–2.61(m,5H),2.57(s,3H),2.21–2.11(m,1H),1.91–1.62(m,7H),1.51–1.39 (m,2H),1.22–1.13(m,3H),1.09–1.01(m,2H),0.93–0.75(m,6H),0.34–0.25(m,2H).

[1212] Compound 52:

[1213] MS m / z(ESI):630.1[M+1]

[1214] Chiral HPLC: retention time 0.974 minutes.

[1215] 1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.70–7.60(m,1H),7.41–7.26(m,2H),7.12–6.9 6(m,2H),6.73–6.59(m,1H),3.47–3.41(m,1H),3.29–3.22(m,2H),3.16–3.05(m,1H), 3.02–2.84(m,4H),2.78–2.68(m,2H),2.67–2.55(m,5H),2.22–2.07(m,1H),1.98–1.6 4(m,5H),1.59–1.35(m,4H),1.27–1.13(m,3H),1.10–0.70(m,8H),0.33–0.24(m,2H).

[1216] Example 53

[1217] tert-Butyl N-[4-({[1-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azetidin-3-yl]amino}methyl)-4-fluorocyclohexyl]carbamate 53

[1218] first step

[1219] Tert-butyl N-[1-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azetidin-3-yl]carbamate 53a

[1220] Compound 29g (500 mg, 1.34 mmol), tert-butyl N-(azetidin-3-yl)carbamate (276.41 mg, 1.60 mmol), and cesium carbonate (1.31 g, 4.01 mmol) were dissolved in t-AmOH (10 mL). Ruphos (124.82 mg, 267.49 μmol) and Pd2(dba)3 (122.47 mg, 133.74 μmol) were added. The reaction was stirred at 90°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, water (25 mL) was added, and extraction was performed with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent to obtain the title product 53a (420 mg, 824.15 μmol, yield: 61.6%) as a brown solid.

[1221] MS m / z(ESI):510.1[M+1]

[1222] Step 2

[1223] 2-[6-(3-aminoazetidin-1-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 53b

[1224] Compound 53a (200 mg, 392.45 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title product 53b (180 mg). The crude product was used directly in the next reaction without purification.

[1225] MS m / z(ESI):410.1[M+1]

[1226] Step 3

[1227] tert-Butyl N-[4-({[1-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)azetidin-3-yl]amino}methyl)-4-fluorocyclohexyl]carbamate 53

[1228] The crude product of compound 53b (160 mg), compound 51b (110 mg, 448.45 μmol), and triethylamine (119.00 mg, 1.18 mmol) were dissolved in methanol (3.5 mL) and stirred at room temperature for 1.0 hour. Sodium cyanoborohydride (73.90 mg, 1.18 mmol) was added and stirred at room temperature for 11 hours. Saturated aqueous sodium bicarbonate (15 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonia water), elution gradient: 5%-35%) afforded the title product 53 (80 mg, 125.24 μmol, yield: 31.95%) as a yellow solid.

[1229] MS m / z(ESI):639.7[M+1]

[1230] 1H NMR(400MHz,DMSO-d6)δ8.17(br s,1H),7.70–7.61(m,1H),7.38–7.28(m,2H),6.99–6.94(m,2H),6.79–6.72( m,1H),6.28–6.22(m,1H),3.99–3.91(m,3H),3.71–3.63(m,4H),3.36–3.29(m ,4H),2.97–2.90(m,1H),2.71–2.57(m,3H),1.92–1.77(m,3H),1.37(s,14H) ,0.92–0.88(m,3H),0.87–0.82(m,3H),0.78–0.72(m,1H),0.33–0.30(m,2H).

[1231] Examples 54, 55

[1232] tert-Butyl N-[(1s,4s)-4-{[3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1-methyl-1H-indazol-6-yl)pyrrolidin-1-yl]methyl}-4-hydroxycyclohexyl]carbamate 54

[1233] N-ethyl-5-fluoro-2-[1-methyl-6-(1-{[(1s,4s)-4-ethanesulfonamido-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl)-1H-indazol-4-yl]-N-(isopropyl)benzamide 55

[1234] first step

[1235] tert-Butyl N-[(1s,4s)-4-{[3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1-methyl-1H-indazol-6-yl)pyrrolidin-1-yl]methyl}-4-hydroxycyclohexyl]carbamate 54

[1236] Compound 15f (100 mg, 85.7 μmol), tert-butyl N-{1-oxaspiro[2.5]octan-6-yl}carbamate 50a (19.5 mg, 85.7 μmol), and DIPEA (22.2 mg, 171 μmol) were dissolved in ethanol (1.0 mL) and stirred at 60°C for 12 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography using dichloromethane / methanol as the eluent to afford the title product 54 (30 mg, 47.2 μmol, 55.0% yield) as a white solid.

[1237] MS m / z(ESI):636.25[M+1]

[1238] 1 H NMR(400MHz, DMSO-d6)δ7.79(s,1H),7.62–7.50(m,2H),7.42–7.34(m,1H),7.33–7.24(m,1H),7.07(d,J= 16.0Hz,1H),6.69(s,1H),4.26–4.17(m,0.19H),4.03(d,J=3.6Hz,3H),3.83(s,0.85H),3.42–3.36(m,1H ),3.28–3.22(m,1H),3.19–2.96(m,2H),2.89–2.70(m,3H),2.45–2.35(m,3H),2.25–2.14(m,1H),1.91–1 .75(m,1H),1.64–1.43(m,6H),1.37(s,9H),1.33–1.26(m,2H),1.04–0.59(m,7H),0.09(t,J=6.4Hz,2H).

[1239] Step 2

[1240] N-Ethyl-5-fluoro-2-[1-methyl-6-(1-{[(1s,4s)-4-amino-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl)-1H-indazol-4-yl]-N-(isopropyl)benzamide 55a

[1241] Compound 54 (15.0 mg, 23.6 μmol) was dissolved in dichloromethane (0.3 mL), and trifluoroacetic acid (0.1 mL) was added at 0°C. The mixture was stirred at 0°C for 1.0 hour. The mixture was concentrated under reduced pressure to obtain a crude product (30 mg) of the title product 55a, which was used directly in the next reaction without purification.

[1242] MS m / z(ESI):536.25[M+1]

[1243] Step 3

[1244] N-ethyl-5-fluoro-2-[1-methyl-6-(1-{[(1s,4s)-4-ethanesulfonamido-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl)-1H-indazol-4-yl]-N-(isopropyl)benzamide 55

[1245] The crude compound 55a (30 mg) and DIPEA (12.2 mg, 94.1 μmol) were dissolved in DMF (0.5 mL), cooled to 0°C, and ethylsulfonyl chloride (3.02 mg, 23.5 μmol) was added. The mixture was stirred at room temperature for 2.0 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by HPLC (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 10%-35%) to obtain the title product 55 (3.00 mg, 4.78 μmol, yield: 20.3%) as a white solid.

[1246] MS m / z(ESI):628.25[M+1]

[1247] 1 H NMR(400MHz,DMSO-d6)δ7.71(s,1H),7.55–7.41(m,2H),7.35–7.25(m,1H),7.24–7.15( m,1H),6.98(d,J=15.6Hz,1H),6.93–6.82(m,1H),4.18–4.08(m,0.27H),3.94(s,3H),3 .01–2.56(m,9H),2.37–2.24(m,3H),2.19–2.06(m,1H),1.79–1.70(m,1H),1.67–1.40( m,6H),1.32–1.21(m,2H),1.16–1.05(m,3H),0.94–0.48(m,7H),0.08(t,J=6.0Hz,2H).

[1248] Examples 55-1-1, 55-1-2, 55-2-1, 55-2-2

[1249] N-ethyl-5-fluoro-2-[1-methyl-6-[(3R)-1-{[(1s,4s)-4-ethanesulfonamido-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl]-1H-indazol-4-yl]-N-(isopropyl)benzamide 55-1-1

[1250] N-ethyl-5-fluoro-2-[1-methyl-6-[(3R)-1-{[(1r,4r)-4-ethanesulfonamido-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl]-1H-indazol-4-yl]-N-(isopropyl)benzamide 55-1-2

[1251] N-ethyl-5-fluoro-2-[1-methyl-6-[(3S)-1-{[(1s,4s)-4-ethanesulfonamido-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl]-1H-indazol-4-yl]-N-(isopropyl)benzamide 55-2-1

[1252] N-ethyl-5-fluoro-2-[1-methyl-6-[(3S)-1-{[(1r,4r)-4-ethanesulfonamido-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl]-1H-indazol-4-yl]-N-(isopropyl)benzamide 55-2-2

[1253] first step

[1254] (3R)-3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1-methyl-1H-indazol-6-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 15e-1

[1255] (3S)-tert-Butyl 3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1-methyl-1H-indazol-6-yl)pyrrolidine-1-carboxylate 15e-2

[1256] Compound 15e (930 mg, 1.83 mmol) was separated and purified by chiral preparative SFC (preparative column: DAICEL IG (250 mm*30 mm, 10 um), mobile phase 70% (v / v) carbon dioxide-ethanol (0.1% NH3)) to give the title products 15e-1 (378 mg, 743.2 μmol, yield: 40.65%) and 15e-2 (400 mg, 786.4 μmol, yield: 43.01%).

[1257] Single configuration compound 15e-1:

[1258] MS m / z(ESI):509.2[M+1]

[1259] SFC analysis: retention time 5.306 minutes; chromatographic column: DAICEL IG 4.6 mm*250 mm L5 μm; mobile phase: CO 2 / MeOH [0.1% NH 3 (7 M methanol solution)] = 70 / 30.

[1260] 1H NMR (400MHz, DMSO-d6) δ7.82 (s, 1H), 7.59 (q, J = 5.6Hz, 2H), 7.43–7.26 (m, 2H), 7.03 (s,1H),4.21(dd,J=13.6,7.6Hz,0.26H),4.14–3.98(m,3H),3.74(dd,J=10.0,8.0Hz ,1H),3.57–3.34(m,3H),3.31–3.19(m,2H),2.91–2.72(m,1H),2.23(d,J=5.6Hz,1H) ,2.12–1.97(m,1H),1.41(d,J=6.4Hz,9H),1.04–0.60(m,7H),0.07(d,J=5.6Hz,2H).

[1261] Single configuration compound 15e-2:

[1262] MS m / z(ESI):509.2[M+1]

[1263] SFC analysis: retention time 4.702 minutes; chromatographic column: DAICEL IG 4.6 mm*250 mm L5 μm; mobile phase: CO 2 / MeOH [0.1% NH 3 (7 M methanol solution)] = 70 / 30.

[1264] 1 H NMR(400MHz, DMSO-d6)δ7.82(s,1H),7.59(t,J=7.2Hz,2H),7.43–7.26(m,2H),7.02(s,1H),4.27– 3.99(m,4H),3.74(dd,J=10.0,8.0Hz,1H),3.44(dd,J=54.0,7.2Hz,3H),3.31–3.22(m,2H),2.90–2.71(m ,1H),2.22(s,1H),2.03(d,J=6.8Hz,1H),1.41(d,J=6.4Hz,9H),1.05–0.57(m,7H),0.07(d,J=5.6Hz,2H).

[1265] Steps 2 and 6

[1266] N-ethyl-5-fluoro-2-[1-methyl-6-[(3R)-pyrrolidin-3-yl]-1H-indazol-4-yl]-N-(isopropyl)benzamide 15f-1

[1267] N-ethyl-5-fluoro-2-[1-methyl-6-[(3S)-pyrrolidin-3-yl]-1H-indazol-4-yl]-N-(isopropyl)benzamide 15f-2

[1268] Compounds 15e-1 / 15e-2 (110 mg / 116 mg, 202.2 μmol / 294 μmol) were dissolved in dichloromethane (1.0 mL / 4.0 mL) at 0°C, and trifluoroacetic acid (0.3 mL / 1.0 mL) was added. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title products 15f-1 / 15f-2 (200 mg / 166 mg). The crude products were used directly in the next step without purification.

[1269] Single configuration compound 15f-1:

[1270] MS m / z(ESI):409.25[M+1]

[1271] Single configuration compound 15f-1:

[1272] MS m / z(ESI):409.25[M+1]

[1273] Steps 3 and 7

[1274] tert-Butyl N-[(1s,4s)-4-{[(3R)-3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1-methyl-1H-indazol-6-yl)pyrrolidin-1-yl]methyl}-4-hydroxycyclohexyl]carbamate 54-1-1

[1275] tert-Butyl N-[(1r,4r)-4-{[(3R)-3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1-methyl-1H-indazol-6-yl)pyrrolidin-1-yl]methyl}-4-hydroxycyclohexyl]carbamate 54-1-2

[1276] tert-Butyl N-[(1s,4s)-4-{[(3S)-3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1-methyl-1H-indazol-6-yl)pyrrolidin-1-yl]methyl}-4-hydroxycyclohexyl]carbamate 54-2-1

[1277] tert-Butyl N-[(1r,4r)-4-{[(3S)-3-(4-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-1-methyl-1H-indazol-6-yl)pyrrolidin-1-yl]methyl}-4-hydroxycyclohexyl]carbamate 54-2-2

[1278] The crude product of compound 15f-1 / 15f-2 (200 mg / 166 mg) and DIPEA (111 mg / 114 mg, 862 μmol / 884 μmol) were dissolved in ethanol (4.0 mL / 15.0 mL), and compound 50a (49 mg / 67 mg, 215 μmol / 294 μmol) was added. The mixture was stirred at 60°C for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane / methanol as the eluent to obtain the title product 54-1-1 and 54-1-2 mixture / 54-2-1 and 54-2-2 mixture (173 mg / 350 mg).

[1279] Mixture of 54-1-1 and 54-1-2:

[1280] MS m / z(ESI):636.35[M+1]

[1281] Mixture of 54-2-1 and 54-2-2:

[1282] MS m / z(ESI):636.45[M+1]

[1283] Steps 4 and 8

[1284] N-ethyl-5-fluoro-2-{1-methyl-6-[(3R)-1-{[(1s,4s)-4-amino-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl]-1H-indazol-4-yl}-N-(isopropyl)benzamide 55a-1-1

[1285] N-ethyl-5-fluoro-2-{1-methyl-6-[(3R)-1-{[(1r,4r)-4-amino-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl]-1H-indazol-4-yl}-N-(isopropyl)benzamide 55a-1-2

[1286] N-ethyl-5-fluoro-2-{1-methyl-6-[(3S)-1-{[(1s,4s)-4-amino-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl]-1H-indazol-4-yl}-N-(isopropyl)benzamide 55a-2-1

[1287] N-ethyl-5-fluoro-2-{1-methyl-6-[(3S)-1-{[(1r,4r)-4-amino-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl]-1H-indazol-4-yl}-N-(isopropyl)benzamide 55a-2-2

[1288] A mixture of compounds 54-1-1 and 54-1-2 / 54-2-1 and 54-2-2 (293 mg / 187 mg, 322 μmol / 294 μmol) was dissolved in dichloromethane (3.0 mL / 4.0 mL) at 0°C, and trifluoroacetic acid (0.6 mL / 1.0 mL) was added. The reaction was stirred at room temperature for 1.0 hour. The reaction solution was concentrated under reduced pressure to obtain a crude mixture of the title products 55a-1-1 and 55a-1-2 (210 mg); the crude product was used directly in the next reaction without purification. The crude mixture of 55a-2-1 and 55a-2-2 was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% trifluoroacetic acid), elution gradient: 25%-40%) to obtain a mixture of the title products 55a-2-1 and 55a-2-2 (201 mg).

[1289] Mixture of 55a-1-1 and 55a-1-2:

[1290] MS m / z(ESI):536.25[M+1]

[1291] Mixture of 55a-2-1 and 55a-2-2:

[1292] MS m / z(ESI):536.10[M+1]

[1293] Steps 5 and 9

[1294] N-ethyl-5-fluoro-2-[1-methyl-6-[(3R)-1-{[(1s,4s)-4-ethanesulfonamido-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl]-1H-indazol-4-yl]-N-(isopropyl)benzamide 55-1-1

[1295] N-ethyl-5-fluoro-2-[1-methyl-6-[(3R)-1-{[(1r,4r)-4-ethanesulfonamido-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl]-1H-indazol-4-yl]-N-(isopropyl)benzamide 55-1-2

[1296] N-ethyl-5-fluoro-2-[1-methyl-6-[(3S)-1-{[(1s,4s)-4-ethanesulfonamido-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl]-1H-indazol-4-yl]-N-(isopropyl)benzamide 55-2-1

[1297] N-ethyl-5-fluoro-2-[1-methyl-6-[(3S)-1-{[(1r,4r)-4-ethanesulfonamido-1-hydroxycyclohexyl]methyl}pyrrolidin-3-yl]-1H-indazol-4-yl]-N-(isopropyl)benzamide 55-1-2

[1298] The crude product of the mixture of compound 55a-1-1 and 55a-1-2 / 55 a A mixture of 55a-2-1 and 55a-2-2 (200 mg / 160 mg) was dissolved in DMF (2.0 mL / 10 mL), and ethylsulfonyl chloride (39.6 mg / 38.4 mg, 308 μmol / 299 μmol) and DIPEA (159 mg / 193, 1.22 mmol / 1.49 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. Purification by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% formic acid), elution gradient: 25%-40%) afforded a mixture of 55a-1-1 and 55a-1-2 / a mixture of 55a-2-1 and 55a-2-2 (110 mg / 125 mg). The resulting mixture was separated and purified by preparative SFC (chromatographic column: chiralpak-AD-H, mobile phase: CO2-MeOH (0.1% NH3)) to obtain the title products 55-1-1 / 55-1-2 (60.0 mg / 4.0 mg, 95.6 μmol / 6.37 μmol) and the title products 55-2-1 / 55-2-2 (88.5 mg / 7.52 mg, 140 μmol / 11 μmol).

[1299] Single configuration compound 55-1-1:

[1300] MS m / z(ESI):628.2[M+1]

[1301] HPLC: retention time 2.865 minutes; column: Shim-pack Velox C18, 2.7 μm, 3.0 x 50 mm; mobile phase: water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid); elution gradient: 5% to 95%;

[1302] Chiral SFC: retention time 7.233 minutes; chromatographic column: DAICEL AD-H 4.6 mm I.D.*250 mm L 5 μm; mobile phase: CO 2 / MeOH [0.1% NH 3 (7 M methanol solution)] = 60 / 40.

[1303] 1H NMR (400MHz, DMSO-d6) δ7.79(d,J=1.2Hz,1H),7.62–7.50(m,2H),7.40–7.35(m,1H),7.32–7.25(m,1H),7.07(d ,J=16.0Hz,1H),6.98(dd,J=7.6,3.2Hz,1H),4.27–4.17(m,0.21H),4.08–3.96(m,3H),3.89(s,1H),3.42–3.33 (m,2H),3.27–3.21(m,1H),3.05–2.91(m,4H),2.90–2.69(m,4H),2.44–2.36(m,2H),2.27–2.14(m,1H),1.89–1 .77(m,1H),1.68–1.50(m,6H),1.43–1.30(m,2H),1.22–1.14(m,3H),1.05–0.59(m,7H),0.08(t,J=6.0Hz,2H).

[1304] Single configuration compound 25-1-2:

[1305] MS m / z(ESI):628.3[M+1]

[1306] HPLC: retention time 2.483 minutes; column: Shim-pack Velox C18, 2.7 μm, 3.0 x 50 mm; mobile phase: water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid); elution gradient: 5% to 95%;

[1307] 1 H NMR(400MHz,DMSO-d6)δ8.29(s,0.97H),7.79(s,1H),7.62–7.47(m,2H),7.43–7.33(m,1H),7.2 9(t,J=10.4Hz,1H),7.07(d,J=16.0Hz,1H),6.92(d,J=7.2Hz,1H),4.25–4.17(m,0.38H),4.02(s ,3H),3.22(s,3H),3.06–2.91(m,4H),2.89–2.65(m,5H),2.46(s,1H),2.23(s,1H),1.95–1.66( m,5H),1.64–1.21(m,5H),1.17(t,J=7.2Hz,3H),1.02–0.53(m,7H),0.08(dd,J=9.6,6.8Hz,2H).

[1308] Single configuration compound 55-2-1:

[1309] MS m / z(ESI):628.25[M+1]

[1310] HPLC: retention time 2.877 minutes; column: Shim-pack Velox C18, 2.7 μm, 3.0 x 50 mm; mobile phase: water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid); elution gradient: 5% to 95%;

[1311] Chiral SFC: retention time 6.242 minutes; chromatographic column: DAICEL AD-H 4.6 mm I.D.*250 mm L 5 μm; mobile phase: CO 2 / MeOH [0.1% NH 3 (7 M methanol solution)] = 60 / 40.

[1312] 1 H NMR (400MHz, DMSO-d6) δ7.79 (s, 1H), 7.61–7.49 (m, 2H), 7.38 (td, J = 8.4, 2.4Hz, 1H), 7.32–7.25 (m, 1H), 7.11–7. 03(m,1H),6.98(dd,J=7.6,3.6Hz,1H),4.26–4.15(m,0.21H),4.08–3.95(m,3H),3.90(s,1H),3.43–3.33(m,2H) ,3.30–3.20(m,1H),3.07–2.90(m,4H),2.89–2.63(m,4H),2.47–2.35(m,2H),2.28–2.14(m,1H),1.91–1.75(m,1 H),1.68–1.48(m,6H),1.45–1.28(m,2H),1.18(td,J=7.2,2.4Hz,3H),1.06–0.56(m,7H),0.08(t,J=6.0Hz,2H).

[1313] Single configuration compound 55-2-2:

[1314] MS m / z(ESI):628.25[M+1]

[1315] HPLC: retention time 2.874 minutes; column: Shim-pack Velox C18, 2.7 μm, 3.0 x 50 mm; mobile phase: water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid); elution gradient: 5% to 95%;

[1316] Chiral SFC: retention time 1.985 minutes; chromatographic column: DAICEL AD-H 4.6 mm I.D.*250 mmL 5 μm; mobile phase: CO 2 / MeOH [0.1% NH 3 (7 M methanol solution)] = 60 / 40.

[1317] 1 H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.64–7.55(m,2H),7.40(td,J=8.4,2.4Hz,1H),7.36–7.27(m,1H) ,7.13–7.04(m,1H),6.95(d,J=6.8Hz,1H),4.72(brs,1H),4.19(dt,J=14.0,7.2Hz,0.28H),4.11–3.98 (m,3H),3.77–3.34(m,4H),3.30–3.21(m,3H),3.19–2.72(m,6H),2.37–2.29(m,1H),2.14–1.94(m,1H) ,1.88–1.65(m,4H),1.53–1.37(m,4H),1.18(t,J=7.2Hz,3H),1.01–0.57(m,7H),0.08(t,J=6.0Hz,2H).

[1318] Examples 56, 57

[1319] tert-Butyl N-[4-({[1-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)piperidin-4-yl]amino}methyl)-4-fluorocyclohexyl]carbamate 56

[1320] 2-[6-(4-{[(4-ethylsulfonamido-1-fluorocyclohexyl)methyl]amino}piperidin-1-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 57

[1321] first step

[1322] tert-Butyl N-[1-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)piperidin-4-yl]carbamate 56a

[1323] Compound 29g (300 mg, 802.46 μmol), tert-butyl N-(piperidin-4-yl)carbamate (321.43 mg, 1.60 mmol), and cesium carbonate (784.37 mg, 2.41 mmol) were dissolved in t-amyl alcohol (5 mL). Ruphos (74.89 mg, 160.49 μmol) and Pd2(dba)3 (73.48 mg, 80.25 μmol) were added. The reaction mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. The reaction solution was cooled to room temperature, water (15 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane / methanol as the eluent to obtain the title product 56a (400 mg, 743.95 μmol, yield: 92.71%).

[1324] MS m / z(ESI):538.2[M+1]

[1325] Step 2

[1326] 2-[6-(4-aminopiperidin-1-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 56b

[1327] Compound 56a (250.00 mg, 325.48 μmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) was added at 0°C. The reaction was stirred at room temperature for 1.0 hour. The mixture was concentrated under reduced pressure to obtain the crude title product 56b (200 mg), which was used directly in the next step without purification.

[1328] MS m / z(ESI):438.1[M+1]

[1329] Step 3

[1330] tert-Butyl N-[4-({[1-(8-{2-[ethyl(isopropyl)carbamoyl]-4-fluorophenyl}-3-methylimidazo[1,5-a]pyridin-6-yl)piperidin-4-yl]amino}methyl)-4-fluorocyclohexyl]carbamate 56

[1331] The crude product of compound 56b (135 mg, 244.75 μmol, trifluoroacetate salt), compound 51b (68 mg, 277.22 μmol), and triethylamine (74 mg, 731.30 μmol) were dissolved in methanol (3.0 mL) and stirred at room temperature for 1.0 hour. Sodium cyanoborohydride (47 mg, 747.91 μmol) was added, and the mixture was stirred at room temperature for 2.0 hours. Saturated aqueous sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (mobile phase: acetonitrile, water (0.1% ammonium bicarbonate), elution gradient: 41%-71%) to obtain the title product 56 (6.19 mg, 9.28 μmol, yield: 3.79%).

[1332] MS m / z(ESI):667.2[M+1]

[1333] 1 H NMR (400MHz, DMSO-d6) δ7.72–7.63(m,1H),7.41–7.22(m,3H),7.00–6.93(m,1H),6.81–6.70(m,1H),6.64–6.56(m,1H),3.51–3.40(m,3H),3.29 –3.23(m,1H),3.01–2.58(m,6H),2.54(s,3H),1.96–1.83(m,4H),1.72– 1.55(m,3H),1.45–1.32(m,15H),0.98–0.68(m,7H),0.36–0.29(m,2H).

[1334] Step 4

[1335] 2-[6-(4-{[(4-amino-1-fluorocyclohexyl)methyl]amino}piperidin-1-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 57a

[1336] Compound 56 (150.00 mg, 224.94 μmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) was added at 0°C. The reaction was stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure to afford the crude title product 57a (130 mg), which was used directly in the next step without purification.

[1337] MS m / z(ESI):567.2[M+1]

[1338] Step 5

[1339] 2-[6-(4-{[(4-ethylsulfonamido-1-fluorocyclohexyl)methyl]amino}piperidin-1-yl)-3-methylimidazo[1,5-a]pyridin-8-yl]-N-ethyl-5-fluoro-N-(isopropyl)benzamide 57

[1340] The crude product of compound 57a (120 mg, 211.74 μmol, trifluoroacetate) and triethylamine (108 mg, 1.07 mmol) were dissolved in dichloromethane (2.0 mL). Ethylsulfonyl chloride (33 mg, 256.65 μmol) was added and stirred at room temperature for 0.25 hours. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (C18; mobile phase: acetonitrile, water (0.1% ammonium bicarbonate), elution gradient: 26%-56%) to obtain the title product 57 (13.21 mg, 20.05 μmol, yield: 9.47%) as a yellow solid.

[1341] MS m / z(ESI):659.3[M+1]

[1342] 1 H NMR(400MHz,DMSO-d6)δ7.71–7.63(m,1H),7.40–7.22(m,3H),7.08(d,J=8.0Hz,1H),6.99–6 .93(m,1H),6.63–6.56(m,1H),3.50–3.37(m,3H),3.32–3.27(m,1H),3.15–3.04(m,1H),3.0 3–2.87(m,3H),2.86–2.57(m,5H),2.54(s,3H),1.95–1.81(m,4H),1.78–1.67(m,2H),1.58– 1.45(m,4H),1.42–1.31(m,2H),1.19(t,J=7.2Hz,3H),1.11–0.71(m,7H),0.35–...

Claims

1. A compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, wherein the compound has the following structure: in, Ring A is represents a single bond or a double bond, and the A ring is a five- to seven-membered aromatic ring or a heterocyclic ring; Ring B is a five- to seven-membered nitrogen-containing heterocyclic ring; The E ring is a three- to eight-membered saturated or partially saturated aliphatic ring, an aromatic ring, or a four- to twelve-membered saturated or partially saturated heterocyclic ring; L1 and L2 are independently selected from: a single bond, a C1-C 10 Alkylene, -(C0-C 10 Alkylene)-Q-(C0-C 10 Alkylene)-, Q is selected from: -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R La )-、-N(R La )C(O)-、-N(R La )C(O)O-、-N(R La )C(O)N(R La )-、-N(R La )-、-S(O)2-、-S(O)2N(R La )-、-N(R La )S(O)2-、-S(O)-、-S(O)N(R La )-、-N(R La )S(O)-、-C(=NR La )-、-C(=NR La )-NR La -; the H atoms in the alkylene group may be optionally substituted by the following groups: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group, halogen, cyano, nitro, azido, C1-C 10 Haloalkyl, hydroxyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, amino, C1-C 10 Alkylamino; the H on the cycloalkyl, aryl, heterocyclic group may be optionally substituted by a group selected from the following: H, halogen, C1-C 10 Alkyl, C1-C 10 Haloalkyl; R La Selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; R1 is one or more independent substituents on the benzene ring, each R1 is independently selected from: H, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, -OR 101 、-C(O)R 101 、-C(O)OR 101 、-NR 102 C(O)OR 101 、-OC(O)R 101 、-NR 102 S02R 101 、-SO2NR 101 R 102 、-NR 102 C(O)R 101 、-C(O)NR 101 R 102 、-NR 101 R 102 、-SR 101 、-S(O)R 101 、-S(O)2R 101 、-SO3H、-NR 102 (CR 103 R 104 ) t OR 101 、-(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), wherein t is an integer from 0 to 5; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; Each R 101 To R 104 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; R2 is One or more independent substituents on the ring, each R2 is independently selected from: H, =O, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, -OR 201 、-C(O)R 201 、-C(O)OR 201 、-NR 202 C(O)OR 201 、-OC(O)R 201 、-NR 202 S02R 201 、-SO2NR 201 R 202 、-NR 202 C(O)R 201 、-C(O)NR 201 R 202 、-NR 201 R 202 、-SR 201 、-S(O)R 201 、-S(O)2R 201 、-SO3H、-NR 202 (CR 203 R 204 ) j OR 201 、-(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), wherein j is an integer from 0 to 5; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; Each R 201 To R 204 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; R3 is selected from: H, halogen, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, -OR 301 、-C(O)R 301 、-C(O)OR 301 、-NR 302 C(O)OR 301 、-OC(O)R 301 、-NR 302 S02R 301 、-SO2NR 301 R 302 、-NR 302 C(O)R 301 、-C(O)NR 301 R 302 、-NR 301 R 302 、-SR 301 、-S(O)R 301 、-S(O)2R 301 、-SO3H、-NR 302 (CR 303 R 304 ) i OR 301 、-(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), wherein i is an integer from 0 to 5; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; Each R 301 To R 304 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; Or, R 301 and R 302 Together with the atoms to which they are attached, they form a heterocyclic group, which may be optionally substituted by one or more groups selected from the following: H, =O, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, -OR5, -C(O)R5, -C(O)OR5, -NR6C(O)OR5, -OC(O)R5, -NR6SO2R5, -SO2NR5R6, -NR6C(O)R5, -C(O)NR5R6, -NR5R6, -SR5, -S(O)R5, -S(O)2R5, -SO3H, -(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl); wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; Each R5, R6 is independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; R4 is one or more independent substituents on the E ring, each R4 is independently selected from: H, halogen, =O, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, -OR 401 、-C(O)R 401 、-C(O)OR 401 、-NR 102 C(O)OR 401 、-OC(O)R 401 、-NR 402 S02R 401 、-SO2NR 401 R 402 、-NR 402 C(O)R 401 、-C(O)NR 401 R 402 、-NR 401 R 402 、-SR 401 、-S(O)R 401 、-S(O)2R 401 、-SO3H、-NR 402 (CR 403 R 404 ) m OR 104 、-(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), wherein m is an integer from 0 to 5; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; Each R 401 To R 404 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; Y is selected from: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl, a three- to eight-membered saturated or partially saturated alicyclic group, an aryl group, a four- to twelve-membered heterocyclic group, an aryl- and three- to eight-membered alicyclic group, an aryl- and three- to eight-membered heterocyclic group, a three- to eight-membered alicyclic aryl group, a three- to eight-membered alicyclic heterocyclic group, a three- to eight-membered heterocyclic aryl group, a three- to eight-membered heterocyclic heterocyclic group, a three- to eight-membered heterocyclic aryl group, a three- to eight-membered heterocyclic 5- to ten-membered heterocyclic group, which may be optionally substituted with one or more R Y Group substitution, R Y Selected from: H, =O, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, halogen, cyano, nitro, azido, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, -OR7, -C(O)R7, -C(O)OR7, -NR8C(O)OR7, -OC(O)R7, -NR8SO2R7, -SO2NR7R8, -NR7C(O)R8, -C(O)NR7R8, -NR7R8, -SR7, -S(O)R7, -S(O)2R7, -SO3H, -(C0-C6 alkylene)-(C6-C 10 Aryl), -SO2-(C0-C6 alkylene)-(C6-C 10 Aryl), -S-(C0-C6 alkylene)-(C6-C 10 Aryl), -O-(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -S-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -O-(C0-C6 alkylene)-(C3-C 10 Cycloalkyl); wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; Each R7, R8 is independently selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl; wherein the C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, C1-C 10 Cyanoalkyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; Each R' and R" is independently selected from: H, Cl-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkane Alkyl, C6-C 10 Aryl, C7-C 12 Aralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl.

2. The compound according to claim 1, characterized in that Said Part of Wherein, X1 is N or C, X2 is N or C, X6 is N or C, represents a single bond or a double bond; Preferably, The part is selected from the following structures: Preferably, Part of Among them, R 2a Selected from: H, halogen, R 2b Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -(C0-C3 alkylene)-(C3-C6 cycloalkyl), -C(O)(C0-C6 alkyl), R 2c Selected from: H, halogen; Preferably, Part of Among them, R 2a Selected from: H, halogen, R 2d is selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C3 alkylene)-(C3-C6 cycloalkyl), -C(O)(C0-C6 alkyl), R 2c Selected from: H, halogen; More preferably, Some selected from:

3. The compound according to claim 1 or 2, characterized in that Part of Among them, R 1a is H or halogen; R 1b is one or more independent substituents on the benzene ring, each of which is independently selected from: H, halogen, C1-C6 alkyl, halogen, cyano, nitro, azido, C1-C6 haloalkyl, -N(C0-C6 alkyl)C(O)(C0-C6 alkyl), -C(O)N(C0-C6 alkyl)(C0-C6 alkyl); Preferably, R 1a H, F, Cl; More preferably, Part of 4. The compound according to any one of claims 1 to 3, characterized in that R3 is -NR 302 C(O)R 301 or -C(O)NR 301 R 302 , where R 301 , R 302 independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C 10 Cycloalkylalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 4-10 membered heterocyclylalkyl; or, R3 is Among them, the J ring is a 4-8 membered saturated heterocyclic ring, R 305 is one or more independent substituents on the J ring, each of which is independently selected from: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, hydroxyl, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl; or, R3 is -(C0-C6 alkylene)-(C6-C 10 Aryl), preferably Among them, R 306 is one or more independent substituents on the benzene ring, each independently selected from: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, hydroxyl, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl; or, R3 is -(C0-C6 alkylene)-(4-10 membered heterocyclic group), preferably selected from: Among them, R 307 is one or more independent substituents on the ring, each of which is independently selected from: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, hydroxyl, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, and 4-10 membered heterocyclyl.

5. The compound according to claim 4, characterized in that R3 is Preferably, R 302 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; More preferably, R3 is selected from:

6. The compound according to claim 4, characterized in that R3 is selected from: Preferably, R 305 Selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl; More preferably, R3 is selected from:

7. The compound according to claim 4, characterized in that R3 is Preferably, R 306 Selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; More preferably, R3 is selected from:

8. The compound according to claim 4, characterized in that R 307 Selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; Preferably, R3 is selected from:

9. The compound according to any one of claims 1 to 8, characterized in that L1 is a single bond, C1-C6 alkylene, -O-, -S- or -N(R La )-, R La Selected from: H, C1-C6 alkyl, preferably a single bond.

10. The compound according to any one of claims 1 to 9, characterized in that Some selected from: Preferably, R4 is selected from: H, halogen, =O, cyano, nitro, azido, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, more preferably from: H, halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy; More preferably, Some selected from:

11. The compound according to any one of claims 1 to 10, characterized in that L2 is a single bond, C1-C6 alkylene or -(C0-C6 alkylene)-Q-(C0-C6 alkylene)-, Q is selected from: -O-, -C(O)-, -N(C0-C3 alkyl)-, -N(C0-C3 alkyl)C(O)-, wherein the H atom in the alkylene group may be optionally substituted by the following groups: H, C1-C3 alkyl, halogen, cyano, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy, C1-C3 haloalkoxy, amino, C1-C6 alkylamino; Preferably, L2 is selected from: methylene, -O-、-C(O)-、-NHC(O)-、 12. The compound according to any one of claims 1 to 11, characterized in that Y is selected from the group consisting of Group Y1, Group Y2, Group Y3, Group Y4, and Group Y5; Y1 is Wherein, the YⅠ ring is a 3-8 membered saturated or partially saturated aliphatic ring, a benzene ring, or a 4-12 membered saturated or partially saturated heterocyclic ring; Preferably, Y1 is selected from: R Y0 is one or more independent substituents on the ring, R Y1 Selected from: H, -C(O)R7, -C(O)OR7, -NR8SO2R7, -NR8C(O)OR7, -NR8C(O)R7, -C(O)NR7R8, -NR7R8, -S(O)2R7, C1-C6 alkyl, -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -(C0-C6 alkylene)-(C3-C6 cycloalkyl); wherein the C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from the following: halogen , cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -NR'C(O)R", -C(O)NR'R", -NR'R", C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl; each R7, R8 is independently selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -(C0-C6 alkylene) - (phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); wherein the C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -NR'C(O)R", -C(O)NR'R", -NR'R", C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl; Y2 is Among them, the YⅡ ring is a benzene ring and a four- to eight-membered aliphatic ring, a benzene ring and a four- to eight-membered heterocyclic ring, or a bicyclic heterocyclic ring; Preferably, Y2 is selected from: R Y0 is one or more independent substituents on the ring, R Y2 Selected from: H, cyano, C1-C6 alkyl, 4-10 membered heterocyclyl, wherein the C1-C6 alkyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from: =O, halogen, cyano, nitro, amino, 4-10 membered heterocyclyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, -(C0-C4 alkylene)-OH, -(C1-C4 alkylene)-O-(C1-C4 alkyl), C1-C4 alkoxy, C1-C4 haloalkoxy, -C(O)O(C0 -C6 alkyl), -C(O)N(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)C(O)(C0-C6 alkyl), -SO2(C0-C6 alkyl), -SO2(phenyl), -SO2(C1-C6 haloalkyl), -SO2N(C0-C6 alkyl)(C0-C6 alkyl), -SO2NH(phenyl), -NHSO2(C0-C6 alkyl), -NHSO2(phenyl) and -NHSO2(C1-C6 haloalkyl); Y3 is Among them, the YⅢ ring is a four- to eight-membered monocyclic nitrogen-containing saturated heterocyclic ring, a four- to eight-membered monocyclic nitrogen-containing saturated heterocyclic ring and an acene ring, a four- to eight-membered monocyclic nitrogen-containing saturated heterocyclic ring and a four- to eight-membered aliphatic ring, or a six- to ten-membered bridged nitrogen-containing saturated heterocyclic ring; Preferably, Y3 is selected from: R Y3 is one or more independent substituents on the ring, R Y3 Selected from: H, =O, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl); wherein the C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -NR'C(O)R", -C(O)NR'R", -NR'R", C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl; R Y0 Selected from: H, =O, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, cyano, nitro, azido, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, -OR7, -C(O)R7, -C(O)OR7, -NR8C(O)OR7, -OC(O)R7, -NR8SO2R7, -SO2NR7R8, -NR7C(O)R8, -C(O)NR7R8, -NR7R8, -SR7, -S(O)R7, -S(O)2R7, -SO3H, -(C0-C6 alkylene)-(phenyl), -SO2-(C0-C6 alkylene)-(phenyl), -S-(C0-C6 alkylene) - (phenyl), -O-(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclyl), -SO2-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -S-(C0-C6 alkylene)-(4-10 membered heterocyclyl), -O-(C0-C6 alkylene) - (4-10 membered heterocyclic group), -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -SO2-(C0-C6 alkylene)-(C3-C6 cycloalkyl), -S-(C0-C6 alkylene)-(C3-C6 cycloalkyl), -O-(C0-C6 alkylene) - (C3-C6 cycloalkyl), wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -NR'C(O)R", -C(O)NR'R", -NR'R", C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 cyanoalkyl, C3-C6 cycloalkyl, phenyl, 4-10 membered heterocyclyl; Y4 is in, R Y40 Selected from: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group substituted by C1-C3 alkyl; Z' is selected from: C0-C6 alkylene, -(C0-C3 alkylene)-O-(C0-C3 alkylene)-, -(C0-C3 alkylene)-S-(C0-C3 alkylene)-, -(C0-C3 alkylene)-NH-(C0-C3 alkylene)-, -(C0-C3 alkylene)-C(O)NH-(C0-C3 alkylene)-, -(C0-C3 alkylene)-NHC(O)-(C0-C3 wherein the H on the alkylene group is optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxyl, amino; R Y41 Selected from: H, halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 4-12 membered heterocyclic group, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl), -CO(C 0-10 wherein the H in the alkyl, cycloalkyl, aryl, heterocyclic group is optionally substituted by a group selected from the following: halogen, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-12 membered heterocyclic group, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), -N(C 0-10 alkyl)(4-10 membered heterocyclic group), -N(C 0-10 alkyl)CO(4-10 membered heterocyclic group), -N(C 0-10 alkyl)CON(4-10 membered heterocyclic group), -N(C 0-10 alkyl)SO2(4-10 membered heterocyclic group), -O(4-10 membered heterocyclic group), -S(4-10 membered heterocyclic group), -SO(4-10 membered heterocyclic group), -SO2(4-10 membered heterocyclic group), -SO2N(C 0-10 alkyl) (4-10 membered heterocyclic group), -COO (4-10 membered heterocyclic group), -OCO (4-10 membered heterocyclic group), -CON (C 0-10 wherein the H in the alkyl and heterocyclic groups is optionally substituted by one or more groups selected from the following: halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 alkyl); Y5 is Among them, R Y501 and R Y502 R is independently selected from: H, halogen, hydroxyl, amino, C1-C3 alkyl, C1-C3 haloalkyl, -(C0-C3 alkylene)-(C3-C6 cycloalkyl), wherein the alkyl and cycloalkyl groups may be optionally substituted by one or more groups selected from: halogen, cyano, hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkylamino; or, R Y501 and R Y502 Together with the carbon atoms to which it is attached, it forms an aliphatic ring or a heterocyclic ring, wherein the aliphatic ring or the heterocyclic ring may be optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxyl, amino, C1-C6 alkyl, C1-C6 haloalkyl; R Y503 and R Y504 Independently selected from: H, C1-C6 alkyl, wherein the alkyl may be optionally substituted by one or more groups selected from: halogen, cyano, hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkylamino; or, R Y503 and R Y504 Together with the nitrogen atom to which it is attached, it forms a heterocyclic ring, wherein the heterocyclic ring may be optionally substituted by one or more groups selected from the group consisting of halogen, cyano, nitro, azido, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), -CO(C3-C 10 Cycloalkyl); wherein the C 0-10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C0-C6 alkylene, C3-C 10 The H in the cycloalkyl, phenyl, 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 alkyl).

13. The compound according to claim 12, characterized in that R Y1 Selected from: -NR8SO2R7, -NR8C(O)OR7, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2R7, -(CH2) n (4-10 membered heterocyclic group), R7 is selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, -(C0-C3 alkylene)-(C3-C6 cycloalkyl), -(C0-C3 alkylene)-(4-10 membered heterocyclyl), wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-10 membered heterocyclyl may be optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxy-substituted alkyl, -C(O)N(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)C(O)(C0-C6 alkyl), R8 is selected from: H, C1-C6 alkyl; More preferably, R Y1 Selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxyalkyl, -O-(C1-C6 hydroxy-substituted substituted alkyl), -O-(C1-C6 alkoxyalkyl), C1-C6 cyanoalkyl, Preferably, in Y1, R Y0 Selected from: H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy; More preferably, Y1 is selected from: Preferably, L2 is C1-C6 alkylene, alkoxy-substituted C1-C6 alkylene (e.g. ), -N(C0-C3 alkyl)-(C0-C6 alkylene)-, -(C0-C6 alkylene)-O- (e.g. )。 14. The compound according to claim 12, characterized in that R Y2 Selected from: H, -(C1-C4 alkylene)-OH, -(C1-C4 alkylene)-O-(C1-C4 alkyl), -(C0-C4 alkylene)-(C3-C6 cycloalkyl), -(C0-C4 alkylene)-(optionally substituted 4-10 membered heterocyclyl); Preferably, in Y2, R Y0 Selected from: H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy; More preferably, Y2 is selected from: Preferably, L2 is C1-C6 alkylene, alkoxy-substituted C1-C6 alkylene (e.g. ) or -N(C0-C3 alkyl)-(C0-C6 alkylene)-.

15. The compound according to claim 12, characterized in that R Y3 Selected from: H. Halogen, C1-C6 alkyl, C1-C6 alkoxy, phenyl, halogenated phenyl; Preferably, in Y3, R Y0 Selected from: H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, hydroxyl, C1-C3 alkoxy; More preferably, Y3 is selected from: Preferably, L2 is C(O).

16. The compound according to claim 12, characterized in that R Y40 is a C1-C4 alkyl group, a C1-C4 haloalkyl group or a 3-6 membered heterocyclic group optionally substituted by a C1-C3 alkyl group; preferably selected from: Preferably, Z' is a single bond, C1-C6 alkylene or C3-C6 cycloalkylene, wherein the H on the alkylene is optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxyl; Preferably, R Y41 Selected from: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 alkyl); wherein the H on the alkyl is optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxyl, C1-C6 alkoxy; or, R Y41 is a 4-12 membered heterocyclic group, wherein the H on the heterocyclic group is optionally replaced by one or more R Y42 Replace, each R Y42 independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C3-C6 cycloalkyl, 4-6 membered saturated heterocyclic group, -N(C 0-6 Alkyl)(C 0-6 Alkyl), -N(C 0-6 alkyl)CO(C 0-6 Alkyl), -N(C 0-6 alkyl)CON(C 0-6 Alkyl), -N(C 0-6 Alkyl)SO2(C 0-6 Alkyl), -O(C 0-6 Alkyl), -S(C 0-6 Alkyl), -SO(C 0-6 Alkyl), -SO2(C 0-6 Alkyl), -SO2N(C 0-6 Alkyl)(C 0-6 Alkyl), -COO(C 0-6 Alkyl), -OCO(C 0-6 Alkyl), -CON(C 0-6 Alkyl)(C 0-6 Alkyl), -CO(C 0-6 Alkyl), -N(C 0-6 alkyl) (4-6 membered heterocyclic group), -SO2 (4-6 membered heterocyclic group), -COO (4-6 membered heterocyclic group), -OCO (4-6 membered heterocyclic group), -CON (C 0-6 wherein the H on the alkyl and heterocyclic groups is optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C1-C6 cyanoalkyl, -N(C 0-6 Alkyl)(C 0-6 Alkyl), -N(C 0-6 alkyl)CO(C 0-6 Alkyl), -N(C 0-6 alkyl)CON(C 0-6 Alkyl), -N(C 0-6 Alkyl)SO2(C 0-6 Alkyl), -O(C 0-6 Alkyl), -S(C 0-6 Alkyl), -SO(C 0-6 Alkyl), -SO2(C 0-6 Alkyl), -SO2N(C 0-6 Alkyl)(C 0-6 Alkyl), -COO(C 0-6 Alkyl), -OCO(C 0-6 Alkyl), -CON(C 0-6 Alkyl)(C 0-6 Alkyl), -CO(C 0-6 alkyl); More preferably, R Y41 Selected from: -N(C 0-10 Alkyl)(C 0-10 Alkyl), -O(C 0-10 Alkyl), -COO(C 0-10 alkyl); wherein the H on the alkyl is optionally substituted by one or more groups selected from the following: hydroxyl, C1-C3 alkoxy; or, R Y41 Selected from: More preferably, each R Y42 Independently selected from: H, halogen, CHF2、CH2F、 Hydroxyl, Cyano, Preferably, Y4 is selected from: Preferably, L2 is a single bond.

17. The compound according to claim 12, characterized in that R Y501 and R Y502 Independently selected from: C1-C3 alkyl, C1-C3 haloalkyl; or, R Y501 and R Y502 Together with the carbon atoms to which it is attached, it forms a C3-C6 cycloalkyl group, which may be optionally substituted by one or more groups selected from the following: halogen, cyano, hydroxyl, amino, C1-C3 alkoxy, C1-C3 alkylamino; Preferably, R Y503 For H, R Y503 is C1-C3 alkyl; or R Y503 and R Y504 Together with the nitrogen atom to which it is connected, it forms a saturated heterocyclic ring selected from: The heterocyclic ring is optionally replaced by one or more R Y505 Group substitution; R Y505 Selected from: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 Alkyl), -CO(C3-C 10 Cycloalkyl); wherein the C 0-10 Alkyl, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C0-C6 alkylene, C3-C 10 The H in the cycloalkyl, phenyl, 4-10 membered heterocyclic group is optionally substituted by one or more groups selected from the following: halogen, cyano, nitro, azido, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -CO(C 0-10 alkyl); More preferably, Y5 is selected from: Preferably, L2 is C(O).

18. The compound according to claim 1, characterized in that The compound is selected from the following structures: Preferably, the stereoisomer is selected from the following structures:

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, and a pharmaceutically acceptable excipient.

20. Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof in the preparation of a medicament for inhibiting the interaction between Menin and MLL.

21. Use of the compound according to any one of claims 1 to 18 or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound in the preparation of a medicament for preventing and / or treating a disease mediated by Menin-MLL interaction; Preferably, the disease is selected from: tumor, diabetes, insulin resistance, hyperglycemia, autoimmune disease, non-alcoholic hepatitis; More preferably, the tumor is a hematological tumor.

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