Novel PRMT5 inhibitors and their uses

Abstract

The present invention describes novel molecules having protein arginine methyltransferase 5 inhibitory activity, as well as methods for synthesizing and using the compounds. Specifically, the present invention describes a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as well as methods for synthesizing and using the compounds: [Case 1] TIFF2025533677000129.tif105150

Description

[Technical Field]

[0001] The present application is in the field of drug synthesis, and specifically relates to a PRMT5 inhibitor and its use. [Background technology]

[0002] Epigenetic alterations are key mediators that promote and maintain the malignant phenotype of tumors. DNA methylation, histone acetylation and methylation, non-coding RNAs, and post-translational modifications are all epigenetic drivers of cancer development, independent of DNA sequence alterations. Arginine methylation is an important class of post-translational modification that influences cell proliferation and growth, apoptosis, angiogenesis, and metastasis by regulating transcription and post-transcriptional RNA processing. There are three types of methylarginine: ω-NG,N'G-asymmetric dimethylarginine (ADMA) and ω-NG,N'G-symmetric dimethylarginine (SDMA). This modification is catalyzed by the protein arginine methyltransferase (PRMT) family, which transfers methyl from S-adenosylmethionine (AdoMet) to the arginine side chains of histones and non-histones. Nine PRMT genes have been annotated in the human genome and are classified into type I (PRMT1, 2, 3, 4, 6, and 8), type II (PRMT5 and PRMT9), and type III enzymes (PRMT7) based on the type of methylarginine produced. PRMT5 is primarily a type II enzyme and catalyzes the symmetric dimethylation of arginine. PRMT5 was first identified in a two-hybrid assay to detect proteins that interact with Janus tyrosine kinase (Jak2).

[0003] PRMT5 is a general transcriptional repressor that forms complexes with other transcription factors, including BRG1, Hbrm, Blimp1, and Snail. PRMT5 is involved in a variety of different cell biological processes through the methylation of various cytoplasmic and nuclear substrates, including histone H4 residue Arg3 (H4R3) and H3 residue Arg8 (H3R8). While H4R3 methylation is associated with transcriptional repression, H3R8 methylation is involved in both transcriptional activation and repression. In addition to the direct induction of repressive histone marks by PRMT5, the enzyme's role in gene silencing is mediated by the formation of multiple repressive protein complexes, including NuRD components, HDACs, MDB proteins, and DNA methyltransferases. PRMT5 influences its substrate specificity through the interaction of numerous binding proteins. A central component of this protein complex is MEP50, which is required for PRMT5 enzymatic activity. We found that PRMT5 can methylate proteins involved in RNA splicing, such as SmD3, and this could be used to track the chemical activity of PRMT5 in cell biology.

[0004] PRMT5 plays an important role in tumorigenesis. Studies have shown that PRMT5 expression is upregulated in various tumors, including lymphoma, lung cancer, breast cancer, and colorectal cancer. Furthermore, PRMT5 expression was elevated in specimens from mantle cell lymphoma (MCL) patients, and knockdown of PRMT5 suppressed MCL cell proliferation, suggesting that PRMT5 plays an important role in MCL. Overexpression of PRMT5 promotes cell hyperplasia, and knockdown of PRMT5 can suppress the proliferation of these cells in melanoma, breast cancer, and lung cancer cell lines. Therefore, PRMT5 could be a target for cancer therapy.

[0005] Deficiency of methylthioadenosine phosphorylase (MTAP) leads to selective cell dependency on PRMT5 and its binding protein WDR77. MTAP is commonly deficient due to its proximity to the tumor suppressor gene CDKN2A. MTAP-deficient cells exhibit elevated intracellular concentrations of methylthioadenosine (MTA, a metabolite cleaved by MTAP). MTA has a similar structure to S-adenosylmethionine (SAM), and elevated concentrations of MTA essentially act as a selective inhibitor of the binding of SAM to PRMT5, thereby inhibiting the methyltransferase activity of PRMT5.

[0006] A major structural difference between MTAP-deficient and MTAP-wildtype cancer cells is the accumulation of MTA in the PRMT5-MTA complex produced in MTAP-deficient cancer cells. Inhibitors developed against the PRMT5-MTA complex can selectively target MTAP-deficient cancer cells while leaving normal cells largely unaffected, significantly improving their therapeutic index.

[0007] Thus, the identification and development of small molecules that inhibit PRMT5 activity is expected to be used as a therapeutic approach for various PRMT5-associated diseases and conditions, such as cancer. Summary of the Invention

[0008] In order to solve the technical problem of the present invention, the present invention provides a group of compounds with novel structures that have good inhibitory activity against PRMT5.

[0009] Specifically, the present invention provides compounds of formula (I), pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives thereof: [ka] where W is C; In the formula, X3 is N or CR X3 and X4 is N or CR X4and X5 is N or CR X5 and X6 is N or CR X6 and In the formula, X3 is CR X3 If R X3 is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a , -SR a , -P(O)R a R b , -CN, -S(O)2R a , -S(O)R a , -SF5, -NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthiol, hydroxy C1-C6 alkyl, or deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy(C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b C3-C substituted with 0 to 4 substituents selected from the group consisting of 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl; In the formula, X4 is CR X4 If R X4 is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a , -SRa , -P(O)R a R b , -CN, -S(O)2R a , -S(O)R a , -SF5, -NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthiol, hydroxy C1-C6 alkyl, or deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy(C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b C3-C substituted with 0 to 4 substituents selected from the group consisting of 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl; In the formula, X5 is CR X5 If R X5 is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a , -SR a , -P(O)R a R b , -CN, -S(O)2R a , -S(O)R a , -SF5, -NR a R b, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthiol, hydroxy C1-C6 alkyl, or deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy(C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b C3-C substituted with 0 to 4 substituents selected from the group consisting of 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl; In the formula, X6 is CR X6 If R X6 is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a , -SR a , -P(O)R a R b , -CN, -S(O)2R a , -S(O)R a , -SF5, -NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthiol, hydroxy C1-C6 alkyl, or deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy(C1-C6 alkyl), NRa R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b C3-C substituted with 0 to 4 substituents selected from the group consisting of 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl; wherein the A ring may also be optionally fused with a 5- to 6-membered saturated or unsaturated ring which may contain 0 to 3 heteroatoms selected from O, N, and S at the chemical bond between X3 and X4; wherein the A ring may also be optionally fused with a 5- to 6-membered saturated or unsaturated ring which may contain 0 to 3 heteroatoms selected from O, N, and S at the chemical bond between X4 and X5; wherein the A ring may also be optionally fused with a 5- to 6-membered saturated or unsaturated ring which may contain 0 to 3 heteroatoms selected from O, N, and S at the chemical bond between X5 and X6; wherein the A ring can also be deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a , -SR a , -P(O)R a R b , -CN, -S(O)2R a , -S(O)R a , -SF5, -NR a R b, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, or deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy(C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b substituted with 0 to 4 substituents selected from the group consisting of: In the formula, R' is deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic heteromonocyclic ring, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b C1-C6 alkyl, C3-C 10Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl; Preferably, R is -CHR 2 R 3 or -CDR 2 R 3 and In the formula, R 2 , R 3 are independently hydrogen, deuterium, -OR a , halogen, -CN, -C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, -C3-C 10 cycloalkyl, or deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b 4-10 membered heterocycloalkyl substituted by 0-3 optional substituents selected from the group consisting of C-C 10 aryl, 5-10 membered heteroaryl; where M1 is CR a R b , N.R. a , O, S or Se; In the formula, R L , R L’ are each independently hydrogen, deuterium, C1-C6 alkyl, or R L , RL’ form 3-6 membered rings with the atoms to which they are connected; In the formula, n and o each independently represent 0, 1, or 2.

[0010] In the formula, X1 is N or CR X1 and In the formula, X2 is N or CR X2 and In the formula, Y1 is CR Y1 R Y1’ , N.R. Y1 , O, S, Se, In the formula, Y2 is CR Y2 R Y2’ , N.R. Y2 , O, S, Se, In the formula, Y3 is CR Y3 R Y3’ , N.R. Y3 , O, S, Se, In the formula, R X1 , R X2 are each independently hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyC1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a , -SR a , -S(O)2R a , -S(O)R a , -CN, -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , -SF5, In the formula, R Y1 , R Y1’ , R Y2 , R Y2’ , R Y3 , R Y3’are each independently absent, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , -SR a , -S(O)2R a , -S(O)R a , -CN, -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , -SF5, During the ceremony, [ka] is a single or double bond, In the formula, R a , R b are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated (C1-C6 alkyl), or R a , R b and together with the atoms to which they are linked form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

[0011] Additionally, the present invention provides a compound having the structure of formula (II) below, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof: [ka] where W is C; In the formula, X3 is N or CR X3 and X4 is N or CR X4 and X5 is N or CR X5 and X6 is N or CR X6 and In the formula, X3 is CR X3 If R X3 is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a , -SR a , -P(O)R a R b , -CN, -S(O)2R a , -S(O)R a , -SF5, -NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthiol, hydroxy C1-C6 alkyl, or deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy(C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b C3-C substituted with 0 to 4 substituents selected from the group consisting of 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl; In the formula, X4 is CR X4 If R X4 is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a , -SR a , -P(O)R a R b , -CN, -S(O)2R a, -S(O)R a , -SF5, -NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthiol, hydroxy C1-C6 alkyl, or deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy(C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b C3-C substituted with 0 to 4 substituents selected from the group consisting of 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl; In the formula, X5 is CR X5 If R X5 is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a , -SR a , -P(O)R a R b , -CN, -S(O)2R a , -S(O)R a , -SF5, -NR a R b, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthiol, hydroxy C1-C6 alkyl, or deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy(C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b C3-C substituted with 0 to 4 substituents selected from the group consisting of 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl; In the formula, X6 is CR X6 If R X6 is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a , -SR a , -P(O)R a R b , -CN, -S(O)2R a , -S(O)R a , -SF5, -NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthiol, hydroxy C1-C6 alkyl, or deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy(C1-C6 alkyl), NRa R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b C3-C substituted with 0 to 4 substituents selected from the group consisting of 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl; In the formula, R' is deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic heteromonocyclic ring, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl; Preferably, R is -CHR 2 R 3 or -CDR 2 R 3 and In the formula, R 2 , R 3 are independently hydrogen, deuterium, -OR a , halogen, -CN, -C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, -C3-C 10 cycloalkyl, or deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b 4-10 membered heterocycloalkyl substituted by 0-3 optional substituents selected from the group consisting of C-C 10 aryl, 5-10 membered heteroaryl; where M1 is CR a R b , N.R. a , O, S or Se; In the formula, R L , R L’ are each independently hydrogen, deuterium, C1-C6 alkyl, or R L , R L’ form 3-6 membered rings together with the atoms to which they are connected; In the formula, n and o each independently represent 0, 1, or 2.

[0012] In the formula, X1 is N or CR X1 and In the formula, X2 is N or CR X2 and In the formula, Y1 is CR Y1 R Y1’ , N.R. Y1 , O, S, Se, In the formula, Y2 is CR Y2 R Y2’ , N.R. Y2 , O, S, Se, In the formula, Y3 is CR Y3 R Y3’ , N.R. Y3 , O, S, Se, In the formula, R X1 , R X2 are each independently hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyC1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a , -SR a , -S(O)2R a , -S(O)R a , -CN, -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , -SF5, In the formula, R Y1 , R Y1’ , R Y2 , R Y2’ , R Y3 , R Y3’ are each independently absent, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , -SR a , -S(O)2R a , -S(O)R a, -CN, -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , -SF5, During the ceremony, [ka] is a single or double bond, In the formula, R a , R b are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated (C1-C6 alkyl), or R a , R b and together with the atoms to which they are linked form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

[0013] In a preferred aspect of the present invention, [ka] is a double bond.

[0014] In a preferred embodiment of the present invention, X1 is CR X1 or N, where R X1 is hydrogen, deuterium, halogen, —CN, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl.

[0015] In a preferred aspect of the present invention, X1 is CH, CF or N.

[0016] In a preferred aspect of the present invention, X2 is CH or CD.

[0017] In a preferred aspect of the present invention, X2 is CH.

[0018] In a preferred aspect of the present invention, X3 is CH, CD or N.

[0019] In a preferred aspect of the present invention, X3 is CH.

[0020] In a preferred embodiment of the present invention, X4 is CR X4 or N, where R X4 is hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl thiol, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkyl thiol, halogen, SF5, -S(O)2R a , -P(O)R a R b , or cyano, or deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy(C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -S(O)2R a , -SR a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b C3-C substituted with 0 to 4 substituents selected from the group consisting of 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl.

[0021] In a preferred embodiment of the present invention, X4 is CR X4 where R X4 is C1-C6 alkoxy, C1-C6 alkylthiol, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthiol, halogenated C1-C6 alkyl, -SF5.

[0022] In a preferred embodiment of the present invention, X4 is CR X4 where R X4 is a halogenated C1-C6 alkoxy, a halogenated C1-C6 alkyl thiol, a halogenated C1-C6 alkyl, or -SF5.

[0023] In a preferred embodiment of the present invention, X5 is CR X5 or N, where R X5 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, or cyano.

[0024] In a preferred aspect of the present invention, X5 is CH.

[0025] In a preferred aspect of the present invention, X6 is CH, CD or N.

[0026] In a preferred aspect of the present invention, X6 is CH.

[0027] In a preferred technical concept of the present invention, in the formula, the chemical bond between Y1 and Y2 is a double bond.

[0028] In a preferred aspect of the present invention, Y1 is CH, CD or CCH3.

[0029] In a preferred aspect of the present invention, Y2 is N.

[0030] In a preferred aspect of the present invention, Y3 is CH, CD, CCH3 or CCH2OH.

[0031] In a preferred aspect of the present invention, R' is -CHR 2 R 3 or -CDR 2 R 3 where R 2 , R 3 are each independently hydrogen, deuterium, C1-C6 alkyl, or halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b C3-C substituted with 0 to 3 substituents selected from the group consisting of 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl.

[0032] In a preferred aspect of the present invention, R' is -CHR 2 R 3 or -CDR 2 R 3 where R 2 is hydrogen, deuterium, C1-C6 alkyl, and R 3is hydrogen, deuterium, C1-C6 alkyl, or halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR a R b , -NR a COR b or -CONR a R b C3-C substituted with 0 to 3 substituents selected from the group consisting of 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl.

[0033] In a preferred aspect of the present invention, R' is a deuterated group, a halogen group, a C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, -OR a , -CN, NR a R b C3-C substituted by 0 to 3 substituents selected from the group consisting of halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy 10 It is cycloalkyl.

[0034] In a preferred aspect of the present invention, R' is C1-C 6ア alkyl (preferably methyl, ethyl) or deuterated C1-C6 alkyl (preferably deuterated methyl, deuterated ethyl) or C3-C6 cycloalkyl (preferably cyclopropyl).

[0035] In a preferred aspect of the present invention, M1 is O or S.

[0036] In a preferred aspect of the present invention, o is 1 or 2 in the formula.

[0037] In a preferred aspect of the present invention, o is 1.

[0038] In a preferred aspect of the present invention, n is 0 or 1 in the formula.

[0039] In a preferred aspect of the present invention, n is 0 in the formula.

[0040] In a preferred aspect of the present invention, n is 1 in the formula.

[0041] In a preferred aspect of the present invention, L , R L’ are each independently hydrogen or C1-C6 alkyl.

[0042] The present invention specifically provides the following compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Unless otherwise indicated, the compounds of the present invention can be taken to include, in addition to the specific structure of the compound, pharmaceutically acceptable salts, stereoisomers, isotopic isomers (e.g., deuterated compounds), solvates, hydrates, prodrugs, metabolites of the compound, i.e., pharmaceutically acceptable salts, stereoisomers, isotopic isomers, solvates, hydrates, prodrugs, etc. of the compound, and metabolites also fall within the scope of protection of the compound.

[0043] Preferably, the pharmaceutical composition of the present invention may further comprise a second active substance, wherein the second active substance is an anti-tumor drug, and the anti-tumor drug comprises one or more of a chemotherapeutic agent, a targeted anti-cancer agent, or an antibody anti-cancer agent.

[0044] The present invention also provides a method for treating a disease by inhibiting the action of PRMT5 using a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, preferably the disease is a tumor. DETAILED DESCRIPTION OF THE INVENTION

[0045] Definition: Unless otherwise stated, the term “alkyl,” by itself or as part of another substituent, refers to a hydrocarbon radical that is linear (i.e., unbranched), branched, or cyclic, or a combination thereof, which may be saturated, mono- or polyunsaturated, which may contain divalent or polyvalent groups, and which has a specified number of carbon atoms (i.e., C1-C 10 refers to 1 to 10 carbon atoms. ) Examples of saturated hydrocarbon groups include, but are not limited to, radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclohexylmethyl, cyclopropylmethyl (e.g., n-pentyl, n-hexyl, n-heptyl, n-octyl), and other homologs and isomers. Unsaturated alkyls are alkyls with one or more double or triple bonds. Examples of unsaturated alkyls include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkyl limited to hydrocarbon groups is referred to as "homoalkyl." The alkyl is optionally substituted with one or more halogen atoms.

[0046] The term "halogenated alkyl" refers to an alkyl group, as defined above, in which one or more hydrogen atoms have been replaced with a halogen atom.

[0047] The term "alkylene" by itself or as part of another substituent refers to a divalent radical derived from alkyl, including, but not limited to, -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-, and -CH2CH2CH(CH2CH2CH3)CH2-. Alkyl (or alkylene) typically has from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in the present invention. "Lower alkyl" or "lower alkylene" refers to a shorter chain alkyl or alkylene, typically having 8 or fewer carbon atoms. The alkylenes described above are optionally substituted with one or more halogen atoms.

[0048] The term "alkynyl" means a carbon chain containing at least one carbon-carbon triple bond, which may be linear or branched, or a combination thereof. Examples of alkynyl include ethynyl, propynyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like. The alkynyl groups mentioned above are optionally substituted with one or more halogen atoms.

[0049] The term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbocyclic ring, each having 3 to 10 carbon atoms. A "fused analog" of a cycloalkyl is a monocyclic ring fused to an aryl or heteroaryl, where the attachment point is on the non-aromatic portion. Examples of "cycloalkyl" and its fused analogs include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthalene, decahydronaphthalene, dihydroindenyl, and the like. The above cycloalkyls are optionally substituted with one or more halogen atoms. Furthermore, in the present invention, the term "cycloalkyl" includes bridged and spirocyclic rings.

[0050] The term "alkoxy" means a straight or branched chain alkoxy group having the indicated number of carbon atoms. 1-6 Alkoxy includes, for example, methoxy, ethoxy, propoxy, isopropoxy, and the like.

[0051] Unless otherwise indicated, the term "heteroalkyl," by itself or in combination with other terms, means a stable linear or branched chain, or cyclic hydrocarbon group, or combinations thereof, containing at least one carbon atom and at least one heteroatom selected from O, N, P, Si, and S, wherein the nitrogen, phosphorus, or sulfur atom may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any position within the heteroalkyl or at the position at which the alkyl is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive. For example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene," by itself or in combination with other terms, refers to a divalent radical derived from heteroalkyl, including, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. In the case of heteroalkylene, the heteroatoms can be at either or both termini of the chain (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the molecular formula of the linking group is written. For example, the molecular formula -C(O)OR'- denotes -C(O)OR'- and -R'OC(O)-. As noted above, heteroalkyl, as used herein, includes groups attached to the remainder of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -SOR'.When referring to "heteroalkyl" followed by a reference to a specific heteroalkyl, such as -NR'R'', it is understood that the terms heteroalkyl and -NR'R'' are not overlapping and are not mutually exclusive. Instead, reference is made to these specific heteroalkyls for greater clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyls such as -NR'R''.

[0052] The term "cycloalkoxy" means a cycloalkyl, as defined above, attached to an oxygen atom, such as cyclopropoxy.

[0053] The term "halogenated alkoxy" means an alkoxy as defined above in which one or more hydrogen atoms have been halogenated.

[0054] The term "aryl" refers to a monocyclic or bicyclic aromatic group containing only carbon atoms. A "fused analog" of aryl refers to an aryl fused to a monocyclic cycloalkyl or monocyclic heterocycle, where the point of attachment is on the aromatic portion. Examples of aryl and its fused analogs include phenyl, naphthyl, indalyl, indenyl, tetrahydronaphthalene, 2,3-dihydrobenzofuran, dihydrobenzopyran, 1,4-benzodioxane, and the like.

[0055] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic ring containing at least one heteroatom selected from N, O, and S. A "fused analog" of heteroaryl refers to a heteroaryl fused to a monocyclic cycloalkyl or monocyclic heterocycle, where the point of attachment is on the aromatic portion. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thiophene, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuran, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.

[0056] "Substituted or unsubstituted": The defined alkyl, aryl and heteroaryl are unsubstituted or substituted with at least one substituent selected from the group consisting of substituents.The above substituents include a halogen atom, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, halogenated alkyl having 1 to 6 carbon atoms, halogenated alkoxy having 1 to 6 carbon atoms, -CN, alkynyl having 2 to 6 carbon atoms, alkanoyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 cyclo atoms, heteroaryl, aryl, aralkoxy having 7 to 10 carbon atoms, arylcarbonyl, aminocarbonyl, alkenyl having 2 to 5 carbon atoms, alkylthiol having 1 to 6 carbon atoms, aminosulfinyl, aminosulfonyl, hydroxy, -SF5, hydroxyalkyl having 1 to 4 carbon atoms, nitro, amino, carboxyl, alkoxycarbonyl having 2 to 5 carbon atoms, alkoxyalkyl having 1 to 4 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, alkanoylamino having 1 to 4 carbon atoms, alkanoyl(alkyl)amino having 1 to 6 carbon atoms, and alkanoyl and alkyl having 1 to 6 carbon atoms in total. and alkylsulfonamido having 1 to 4 carbon atoms. The alkyl group is selected from the group consisting of alkanoylaminoalkyl having 1 to 6 carbon atoms, alkanoyl and alkanoyl(alkyl)aminoalkyl having a total of 1 to 6 carbon atoms in each alkyl, alkylsulfonylamino having 1 to 4 carbon atoms, monoalkylaminocarbonyl or dialkylaminocarbonyl having 1 to 6 carbon atoms, monoalkylaminosulfinyl or dialkylaminosulfinyl having 1 to 6 carbon atoms, monoalkylaminosulfonyl or dialkylaminosulfonyl having 1 to 6 carbon atoms, aminoalkyl having 1 to 4 carbon atoms, monoalkylamino or dialkylamino having 1 to 6 carbon atoms, monoalkylaminoalkyl or dialkylaminoalkyl having a total of 1 to 6 carbon atoms in each alkyl, aralkyl having 7 to 10 carbon atoms, heteroaralkyl having 1 to 4 carbon atoms in the alkyl, heteroarylalkoxy having 1 to 4 carbon atoms in the alkoxy, and alkylsulfonamido having 1 to 4 carbon atoms.

[0057] As used herein, the terms "heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclo" mean saturated, partially saturated, or unsaturated groups (but not aromatic) having single or fused rings (including bridged and spiro ring systems, having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen), where one or more of the rings in a fused ring system may be cycloalkyl, aryl, or heteroaryl, provided that the connection is through a non-aromatic ring. In one example, the nitrogen and / or sulfur atoms of a heterocyclic group are optionally oxidized to provide N-oxide, sulfinyl, and sulfonyl moieties. Examples of "heterocyclo" and its fused analogs include pyrrolidinyl, piperidine, piperazine, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridine, benzoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydroindolyl, and the like. The term also includes non-aromatic partially unsaturated monocyclic rings such as 2- or 4-pyridones, N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils) linked through a nitrogen atom.

[0058] As used herein, the term "substituted heterocyclic," "substituted heterocycloalkyl," or "substituted heterocyclo" means a heterocyclic group substituted with 1 to 5 (e.g., 1 to 3) substituents, which are the same as those defined for substituted cycloalkyl.

[0059] Unless otherwise stated, the terms "halogenated" or "halogen," by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom. Additionally, the term "halogenated alkyl" is meant to include monohalogenated alkyl and polyhalogenated alkyl. For example, the term "halogenated (C1-C6) alkyl" includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0060] A "prodrug" refers to a substance that is converted into the parent drug in the body. Prodrugs are often used because they are easier to administer than the parent drug for certain conditions. For example, prodrugs are orally bioavailable, whereas the parent drug is not. In pharmaceutical compositions, prodrugs may have higher solubility than the parent drug. Examples of prodrugs include, but are not limited to, any of the compounds of Formula (I) that are administered in ester (prodrug) form to facilitate transport across cell membranes where water solubility is disadvantageous, and then metabolically hydrolyzed to the active carboxylic acid once inside the cell where water solubility is advantageous. Another example of a prodrug is a short peptide (polyamino acid) bonded to an acid group, which is metabolized to release the active moiety.

[0061] Optical Isomers - Diastereomers - Geometric Isomers - Tautomers: The compounds of formula (I) contain one or more asymmetric centers and are therefore available as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers, and the present invention is intended to encompass all such isomeric forms of the compounds of formula (I).

[0062] Some of the compounds described herein contain alkenyl (olefinic) double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

[0063] Some of the compounds of the present invention may comprise one or more ring systems and therefore may exist as cis and trans isomers, and the present invention is intended to encompass all of these cis and trans isomers.

[0064] Some of the compounds described herein may have different bonding sites for hydrogen atoms, known as tautomers. Examples include keto and its enol forms, known as keto-enol tautomers. The individual tautomers and mixtures thereof are included in the compounds of the present invention.

[0065] The compounds of the present invention can be separated into a diastereoisomeric pair of enantiomers by multi-step crystallization from a suitable solvent such as methanol, ethyl acetate, or a mixture thereof. The pair of enantiomers thus obtained can be separated into the individual stereoisomers by conventional methods, such as using optically active amines or acids as resolving agents, or by using a chiral HPLC column.

[0066] Alternatively, any enantiomeric form of a compound of this invention may be obtained by stereosynthesis using optically pure starting materials or reagents of known configuration.

[0067] Stable Isotope Labeled Analogs: One or more protons in the compounds of the invention can be replaced with deuterium atoms, thereby providing deuterium-substituted analogs with improved pharmacological activity.

[0068] Salts and Formulations It should be understood that, as used herein, references to the compounds of the present invention are meant to also include the pharmaceutically acceptable salts.

[0069] use The compounds provided by the present invention can be used to treat diseases associated with PRMT5.

[0070] The compounds of the present invention can be prepared according to the following reaction scheme: Method A: [ka] Method A-SFC [ka] where R L , R L’ , R ’ , A ring, W, n, o, M1, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3, [ka] is as defined in claim 1.

[0071] Method A: Compound AP can be obtained by amino acid condensation reaction of carboxylic acid A-1 with amine A-2, using HATU or PyBrOP as the condensing agent, DIPEA or TEA as the base, and DMF or DMAc as the solvent. If the amine used is racemic, it can be resolved by chiral SFC, and the stereochemistry of the resulting isomers can be randomly assigned to R or S.

[0072] AnalyticalHPLC Instrument: Agilent 1260; Column dimensions: Agilent Poroshell HPH-C18 (3.0 × 50 mm, 2.7 μm); Binary solvent system, mobile phase A: water (0.1% v / v ammonium bicarbonate), mobile phase B: acetonitrile; Flow rate: 1 mL / min; Gradient: 10% B to 90% B; Time: 12 min; Detector: DAD detector; Wavelength: 254 / 220 nm.

[0073] Preparative HPLC-MS HPLC equipment: Waters 2489; column dimensions: Ultimate μ XB-C18 (130A, 5 μm, 30 mm × 150 mm); binary solvent system: mobile phase A: water (0.1% v / v ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60–100 mL / min; gradient: 10% B to 90% B; detector: DAD detector, wavelength: 254 / 220 nm.

[0074] Mass spectrometer: Agilent G6125B.

[0075] The compounds of the present invention can be prepared by methods of chemical synthesis, examples of which are given below, it being understood that the order of the steps described may be varied, particularly mentioned reagents, solvents and reaction conditions may be substituted, and sensitive sites may be protected and deprotected as necessary.

[0076] The following abbreviations have the following meanings: "ACN" refers to acetonitrile; "EA" refers to ethyl acetate; "CDI" refers to N,N'-carbonyldiimidazole; "DBU" refers to 1,8-diazabicyclo[5.4.0]undec-7-ene; "DIBAL-H" refers to diisobutylaluminum hydride; "DIEA" refers to diisopropylethylamine; "DMAP" refers to N,N-dimethyl-4-aminopyridine; "DME" refers to 1,2-dimethoxyethane; "DMF" refers to N,N-dimethylformamide; "DMA" and "DMAc" refer to N,N-dimethylformamide; "DMPE" refers to 1,2-bis(dimethylphosphino)ethane; "DMSO" refers to dimethyl sulfoxide; "DPPB" refers to 1,4-bis(diphenylphosphino)butane; "dppe" refers to 1,2-bis(diphenylphosphino) "dppf" refers to ethane; "dppm" refers to 1,1'-bis(diphenylphosphino)ferrocene; "DIAD" refers to diisopropyl azodicarboxylate; "EDCI" refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; "HATU" refers to 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; "HMPA" refers to hexamethylphosphoric acid triamide; "IPA" refers to isopropanol; "LDA" refers to lithium diisopropylamide; "LHMDS" refers to lithium "LAH" refers to lithium aluminum hydride; "NCS" refers to N-chlorosuccinimide; "NaHMDS" refers to sodium bis(trimethylsilyl)amide; "PyBOP" refers to (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; "PyBrOP" refers to bromotripyrrolidinophosphonium hexafluorophosphate; "TDA-I" refers to tris[2-(2-methoxyethoxy)ethyl]amine; "DCM" refers to dichloromethane; "TEA" refers to triethylamine; "TFA" refers to trifluoroacetic acid; "THF" refers to tetrahydrofuran; "NCS" refers to N-chlorosuccinimide; "NMM" refers to N-methylmorpholine; "NMP" refers to N-methylpyrrolidone; "PPh3" refers to triphenylphosphine; "rt" refers to room temperature; "PMB" refers to p-methoxybenzyl group; "Tosmic" refers to p-toluenesulfonylmethyl isocyanide; "(Boc)2O" refers to di-tert-butyl dicarbonate; "PE" refers to petroleum ether; and "o / n" refers to overnight reaction.

[0077] The following preparations and examples illustrate the present invention but do not limit it in any way.

[0078] The features and advantages of the inventive subject matter will be better understood in light of the detailed description of selected embodiments. As will be understood, the disclosed and claimed subject matter can be modified in various ways without departing from the scope of the claims. Accordingly, the description should be regarded as illustrative rather than limiting in nature. The full scope of the inventive subject matter is set forth in the claims.

[0079] The present invention will be more readily understood by reference to the following examples, which are intended to be merely illustrative of the present invention and are not intended to limit the scope of the present invention.

[0080] Intermediates The following intermediate raw materials were purchased from various suppliers: [Table 1] [Table 2] Intermediate 12: (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine [ka] Step 1: Synthesis of tert-butyl (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (S)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (200 mg, 0.99 mmol) was dissolved in dichloromethane (2 mL), and di-tert-butyl dicarbonate (325 mg, 1.49 mmol) and triethylamine (200 mg, 1.98 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction was monitored using liquid chromatography-mass spectrometry (LC-MS). The residue was purified by flash column chromatography (20 g silica gel column, 20% ethyl acetate / petroleum ether) to give tert-butyl (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (300.0 mg, 99% yield) as a yellow liquid.

[0081] LCMS(ESI)m / z:304[M+H] + Step 2: Synthesis of tert-butyl (S)-methyl (6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate At 0°C, tert-butyl (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (300 mg, 0.99 mmol) was dissolved in DMF (5.00 mL), followed by the addition of sodium hydride (48 mg, 2.00 mmol). The mixture was stirred at 0°C for 1 hour. Iodomethane (211 mg, 1.49 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was monitored using liquid chromatography-mass spectrometry (LC-MS). The residue was purified by flash column chromatography (20 g silica gel column, 15% ethyl acetate / petroleum ether) to give tert-butyl (S)-methyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (200.0 mg, 64% yield) as a yellow liquid.

[0082] LCMS(ESI)m / z:318[M+H] + Step 3: Synthesis of (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine At room temperature, tert-butyl (S)-methyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (200.0 mg, 0.63 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (5.00 mL). The mixture was stirred at room temperature for 0.5 hours. The reaction was monitored using liquid chromatography-mass spectrometry (LC-MS). The mixture was concentrated to give (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (130.0 mg, 95% yield) as a yellow liquid.

[0083] LCMS(ESI)m / z:218[M+H] + The following intermediates were prepared by adopting the method and procedure for preparing Intermediate 12, substituting only the corresponding starting intermediate: [Table 3] [Table 4] Intermediate 22(S)-3-(methylamino)-2,3-dihydrobenzofuran-6-carbonitrile [ka] Step 1: tert-butyl (S)-(6-cyano-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate A mixture of tert-butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (328 mg, 1 mmol), cuprous cyanide (352 mg, 4 mmol), and N-methylpyrrolidone (4 mL) was reacted in a microwave reactor at 135 °C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:petroleum ether = 40:60) to give tert-butyl (S)-(6-cyano-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (66 mg, 23.93% yield) as a colorless oil.

[0084] LCMS(ESI):275[M+H] + Step 2: (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-carbonitrile tert-Butyl (S)-(6-cyano-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (66 mg, 0.24 mmol) was added to a solution of hydrogen chloride in dioxane (3 mL, 4 mol / L), and the mixture was stirred for 2 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure to give crude (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-carbonitrile (40 mg) as a white solid. The crude product was used directly in the next step without purification.

[0085] LCMS(ESI):175[M+H] + Synthesis of intermediate 23(S)-6-methoxy-N-methyl-2,3-dihydrobenzofuran-3-amine [ka] A reaction mixture of tert-butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (328 mg, 1 mmol), CuI (352 mg, 4 mmol), and a methanolic solution of sodium methoxide (180 mg, 40 mmol) in N,N-dimethylformamide (4 mL) was reacted at 120 °C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature and extracted three times with 10 mL portions of ethyl acetate (30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. (S)-6-Methoxy-N-methyl-2,3-dihydrobenzofuran-3-amine (150 mg, 0.8 mmol, 80% yield) was obtained as a colorless oil.

[0086] LCMS(ESI):180[M+H] + Intermediate 24(S)-dimethyl(3-(methylamino)-2,3-dihydrobenzofuran-6-yl)phosphine oxide [ka] Step 1: A reaction mixture consisting of tert-butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (200 mg, 0.61 mmol), dimethylphosphine oxide (57 mg, 0.73 mmol), potassium carbonate (101 mg, 0.73 mmol), palladium acetate (10 mg, 0.06 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg, 0.06 mmol), and 5 mL of dimethylformamide was heated at 150 °C for 20 min in a microwave reactor. After completion of the reaction, the mixture was cooled to room temperature and extracted three times with 10 mL of ethyl acetate (30 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. tert-Butyl (S)-(6-(dimethylphosphinyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (80 mg, 0.245 mmol, 40.35% yield) was obtained as a white solid.

[0087] LCMS(ESI):326[M+H] + Step 2: tert-Butyl (S)-(6-(dimethylphosphinyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (80 mg, 0.25 mmol) was added to a 4 M solution of hydrochloric acid in dioxane (3 mL) and stirred for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to give (S)-dimethyl(3-(methylamino)-2,3-dihydrobenzofuran-6-yl)phosphine oxide (25 mg, 0.11 mmol, 45.14% yield) as a white solid.

[0088] LCMS(ESI):226[M+H] + Intermediate 25(S)-N-methyl-6-(methylsulfonyl)-2,3-dihydrobenzofuran-3-amine [ka] Step 1: A mixture of tert-butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (328 mg, 1 mmol), sodium methanesulfonate (122 mg, 1.2 mmol), L-proline (12 mg, 0.1 mmol), potassium carbonate (166 mg, 1.2 mmol), cuprous iodide (19 mg, 0.1 mmol), and N,N-dimethylformamide (5 mL) was heated in a microwave reactor at 140 °C for 2 h. After completion of the reaction, the mixture was cooled to room temperature and extracted three times with 10 mL portions of ethyl acetate (30 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. tert-Butyl (S)-methyl (6-(methylsulfonyl)-2,3-dihydrobenzofuran-3-yl)carbamate (60 mg, 0.18 mmol, 18.32% yield) was obtained as a colorless oil.

[0089] LCMS(ESI):328[M+H] + Step 2: tert-Butyl (S)-methyl (6-(methylsulfonyl)-2,3-dihydrobenzofuran-3-yl)carbamate (60 mg, 0.24 mmol) was added to a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL) and stirred for 2 hours. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to give (S)-N-methyl-6-(methylsulfonyl)-2,3-dihydrobenzofuran-3-amine (30 mg, 0.13 mmol, 72.03% yield) as a white solid.

[0090] LCMS(ESI):228[M+H] + Intermediate 101: Synthesis of (S)-6-cyclopropylsulfonyl-N-methyl-2,3-dihydrobenzofuran-3-amine [ka] Step 1: Preparation of tert-butyl (S)-(6-(cyclopropylsulfonyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate tert-Butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (300 mg, 0.914 mmol) and cyclopropane sulfinate (118 mg, 0.914 mmol) were dissolved in DMSO (10 mL), and cuprous iodide (35 mg, 0.182 mmol) and (1R,2R)-N1,N2-dimethyl-cyclohexane-1,2-diamine (52 mg, 0.365 mmol) were added, followed by stirring at 25°C for 10 hours. After confirming the completion of the reaction by LCMS, water (10 mL) was added and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (0-10% ethyl acetate / petroleum ether) to give tert-butyl (S)-(6-(cyclopropylsulfonyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (150 mg, yield 46.4%).

[0091] LCMS(ESI)m / z:354.1[M+H] + Step 2: Synthesis of (S)-6-cyclopropylsulfonyl-N-methyl-2,3-dihydrobenzofuran-3-amine The compound tert-butyl (S)-(6-(cyclopropylsulfonyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (150 mg, 0.424 mmol) was dissolved in dichloromethane (3 mL) at room temperature, and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 16 hours and concentrated under reduced pressure to give the crude product S-6-cyclopropylsulfonyl-N-methyl-2,3-dihydrobenzofuran-3-amine (150 mg, crude), which was used directly in the next step without purification.

[0092] LCMS(ESI)m / z:254.1[M+H] + Synthesis of intermediate 26(S)-N-methyl-6-(1-trifluoromethyl)pyrazol-4-yl)-2,3-dihydrobenzofuran-3-amine [ka] Step 1: Synthesis of tert-butyl tert-butyl-(S)-methyl(6-(1-trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)carbamate Under a N2 atmosphere, tert-butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (300 mg, 0.91 mmol) was dissolved in 1,4-dioxane and water (4:1, 10 mL), and the solution was added with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolidin-2-yl)-1-trifluoromethylpyrazole (239.0 mg, 1.37 mmol) and potassium carbonate. The resulting mixture was added with 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (67.0 mg, 0.09 mmol) and reacted at 100 °C for 16 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the anhydrous sodium sulfate, and the filtrate was spin-dried to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give tert-butyl tert-butyl-(S)-methyl(6-(1-trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)carbamate (240.0 mg, 68.8% yield) as a white solid.

[0093] LCMS(ESI)m / z:384.1[M+H] + Step 2: Synthesis of (S)-N-methyl-6-(1-trifluoromethyl)pyrazol-4-yl)-2,3-dihydrobenzofuran-3-amine Tert-butyl tert-butyl-(S)-methyl(6-(1-trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)carbamate (240 mg, 0.626 mmol) was dissolved in 4 M ethyl acetate hydrochloride (3 mL) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to give the crude product (S)-N-methyl-6-(1-trifluoromethyl)pyrazol-4-yl)-2,3-dihydrobenzofuran-3-amine (25.0 mg, crude product).

[0094] LCMS(ESI)m / z:283.1[M+H] + The following intermediates were prepared by employing the method and procedure of Intermediate 26, substituting only the corresponding starting materials: [Table 5] [Table 6] [Table 7] [Table 8] Intermediate 41 6-(trifluoromethyl)benzo[b]thiophen-3(2H)-one [ka] Step 1: Synthesis of 2-fluoro-4-(trifluoromethyl)benzoic acid To a solution of methyl 2-fluoro-4-(trifluoromethyl)benzoate (30.00 g, 135.05 mmol) in tetrahydrofuran:water (300 mL:30 mL) was added lithium hydroxide (9.70 g, 405.15 mmol) at room temperature, and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was poured into water (100 mL), the pH was adjusted to 4 with aqueous formic acid, and then extracted with ethyl acetate (100 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by rapid column chromatography on silica gel (petroleum ether:ethyl acetate = 30%) to give 2-fluoro-4-(trifluoromethyl)benzoic acid (22.00 g, yield: 78%).

[0095] LCMS(ESI)m / z:209.1[M+H] + Step 2: Synthesis of 2-((2-ethoxy-2-oxoethyl)thio)-4-(trifluoromethyl)benzoic acid Sodium bicarbonate (8.46 g, 211.43 mmol) was added to a solution of 2-(ethylsulfanyl)acetic acid (12.70 g, 105.72 mmol) in N,N-dimethylformamide (200.00 mL) at 0 °C, and the mixture was stirred at room temperature for 0.5 h. Next, 2-fluoro-4-(trifluoromethyl)benzoic acid (22.00 g, 105.71 mmol) was added to the solution, and the mixture was stirred at room temperature for 1 h. The reaction mixture was slowly poured into water (100 mL), extracted with ethyl acetate (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by rapid column chromatography on silica gel (petroleum ether:ethyl acetate = 10%) to give 2-((2-ethoxy-2-oxoethyl)thio)-4-(trifluoromethyl)benzoic acid (13.00 g, yield: 40%).

[0096] LCMS(ESI)m / z:309.2[M+H] + Step 3: Synthesis of 2-((carboxymethyl)thio)-4-(trifluoromethyl)benzoic acid A mixture of 2-[(ethoxycarbonyl)methylthio]-4-(trifluoromethyl)benzoic acid (13.00 g, 42.17 mmol) and potassium hydroxide (4.72 g, 84.34 mmol) in methanol (130.00 mL) was stirred at room temperature for 2 hours and then concentrated to give 2-((carboxymethyl)thio)-4-(trifluoromethyl)benzoic acid (7.00 g, crude product).

[0097] LCMS(ESI)m / z:281.2[M+H] + Step 4: Synthesis of 6-(trifluoromethyl)benzo[b]thiophen-3-yl acetate To a solution of 2-(carboxymethylthio)-4-(trifluoromethyl)benzoic acid (7.00 g, 24.98 mmol) in acetic anhydride (70.00 mL) was added sodium acetate trihydrate (10.19 g, 74.94 mmol) at room temperature. The mixture was stirred at 140 °C for 30 minutes. The mixture was poured into water, extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by high-performance column chromatography (petroleum ether:ethyl acetate = 50%) to give 6-(trifluoromethyl)benzo[b]thiophen-3-yl acetate (5.00 g, yield: 77%).

[0098] LCMS(ESI)m / z:261.2[M+H] + Step 5: Synthesis of 6-(trifluoromethyl)benzo[b]thiophen-3(2H)-one Aqueous hydrochloric acid (10.00 mL, 1 mol / L) was added to a solution of 6-(trifluoromethyl)benzo[b]thiophen-3-yl acetate (1.00 g, 3.84 mmol) in 1,4-dioxane (5.00 mL) at room temperature. The mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled and poured into water, and the aqueous layer was extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. Purification by high-performance column chromatography (petroleum ether:ethyl acetate = 70%) afforded 6-(trifluoromethyl)benzo[b]thiophen-3(2H)-one (0.50 g, yield: 59%) as a black solid.

[0099] LCMS(ESI)m / z:219.2[M+H] + Intermediate 42 Synthesis of 1-methyl-7-trifluoromethylisochromen-4-one [ka] Step 1: Synthesis of 2-(1-allyloxy)ethyl)-1-bromo-4-trifluoromethylbenzene 1-(2-Bromo-5-trifluoromethylphenyl)ethan-1-ol (10 g, 37.16 mmol) was dissolved in tetrahydrofuran (100 mL) at room temperature, and potassium hydroxide (4.2 g, 74.33 mmol), tetrabutylammonium hydrogen sulfate (2.6 g, 7.433 mmol), and 3-bromopropene (5.4 g, 44.60 mmol) were added and reacted for 4 hours at 25 ° C. After completion of the reaction, the reaction solution was concentrated under reduced pressure, poured into water (100 mL), and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (12 g, crude product), which was used directly in the next step without purification.

[0100] LCMS(ESI)m / z:309.2[M+H] + Step 2: Synthesis of 1-methyl-4-methylene-7-trifluoromethylisochroman To a solution of 2-(1-allyloxy)ethyl-1-bromo-4-trifluoromethylbenzene (12 g, 38.82 mmol) in DMF (100 mL) was added cesium carbonate (15.5 g, 46.59 mmol), tri(o-tolyl)phosphine (5.1 g, 19.41 mmol), and palladium acetate (0.89 g, 3.882 mmol). The mixture was stirred at 90 °C for 16 h under a N atmosphere. The reaction mixture was poured into 400 mL of water and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give 1-methyl-4-methylene-7-trifluoromethylisochroman (5.5 g, yield: 62.1%).

[0101] LCMS(ESI)m / z:229.1[M+H] + Step 3: Synthesis of 4-hydroxymethyl-1-methyl-7-trifluoromethylisochromen-4-ol 1-Methyl-4-methylene-7-trifluoromethylisochroman (5.5 g, 24.10 mmol) was dissolved in a solvent mixture of acetone (100 mL) and water (20 mL), and N-methylmorpholine-N-oxide (9.2 g, 76.68 mmol) and potassium osmate (0.91 g, 2.410 mmol) were added at room temperature. The reaction was stirred at 25 °C for 16 h under a N2 atmosphere. After the reaction was complete, solid sodium sulfite (5 g) was added to the reaction solution, stirred for 10 min, and concentrated under reduced pressure to remove a certain amount of acetone. The solution was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product 6-fluoro-4-hydroxymethyl-1-methylisochromen-4-ol (6.0 g, yield: 94.9%).

[0102] LCMS(ESI)m / z:263.0[M+H] + Step 4: Synthesis of 1-methyl-7-trifluoromethylisochromen-4-one At room temperature, 4-hydroxymethyl-1-methyl-7-trifluoromethylisochromen-4-ol (6.0 g, 22.88 mmol) was dissolved in a mixed solvent of tetrahydrofuran (100 mL) and water (3.5 mL), and sodium periodate (15.0 g, 68.64 mmol) was added, followed by stirring for 4 hours at 25° C. under a N atmosphere. After completion of the reaction, the reaction solution was diluted with ethyl acetate, filtered, washed, and the filtrate was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product 6-fluoro-1-methylisochromen-4-one (5 g, crude product).

[0103] LCMS(ESI)m / z:230.2[M+H] + The following intermediates were prepared by employing the method and procedure of Intermediate 42, substituting only the corresponding starting materials: [Table 9] The following ketones were purchased from different suppliers: [Table 10] Intermediate 55 N-methyl-6-(trifluoromethyl)isochroman-4-amine hydrochloride [ka] Step 1 Synthesis of 6-(trifluoromethyl)isochroman-4-ol At room temperature, 4-(hydroxymethyl)-6-(trifluoromethyl)isochroman-4-one (1.1 g, 5.09 mmol) was first dissolved in THF (10 mL) in an ice bath, and sodium borohydride (251 mg, 6.62 mmol) was added, followed by two drops of methanol. After the addition, the reaction was left overnight at room temperature. After completion of the reaction, it was quenched with 1 M aqueous hydrogen chloride solution (2 mL) and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over sodium sulfate, and filtered to obtain the crude product, which was purified by column chromatography to obtain 6-(trifluoromethyl)isochroman-4-ol (1.16 g).

[0104] Step 2: Synthesis of tert-butyl (tert-butoxycarbonyl) (6-(trifluoromethyl)isochroman-4-yl)carbamate First, 6-(trifluoromethyl)isochroman-4-ol (100.0 mg, 0.459 mmol) was dissolved in THF (5.0 mL) at room temperature, and bis(tert-butoxycarbonyl)amine (110 mg, 0.505 mmol) and triphenylphosphine (132 mg, 0.505 mmol) were added. The reaction mixture was stirred at 0°C for 5 minutes, and then DIAD (102 mg, 0.505 mmol) was added dropwise. The mixture was stirred in an ice bath for 1 hour, and then returned to room temperature and allowed to react overnight. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (pure petroleum ether) to obtain tert-butyl (tert-butoxycarbonyl) (6-(trifluoromethyl)isochroman-4-yl)carbamate (90.0 mg).

[0105] Step 3: Synthesis of tert-butyl (6-(trifluoromethyl)isochroman-4-yl)carbamate tert-Butyl (tert-butoxycarbonyl) (6-(trifluoromethyl)isochroman-4-yl)carbamate (60.0 mg, 0.14 mmol) was dissolved in acetonitrile (2.0 mL), lithium bromide (37.6 mg, 0.432 mmol) was added, and the reaction system was reacted at 60 ° C for 20 hours. After the reaction was completed, saturated sodium bicarbonate (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl (6-(trifluoromethyl)isochroman-4-yl)carbamate (30 mg).

[0106] Step 4: Synthesis of tert-butyl-N-methyl-(6-(trifluoromethyl)isochroman-4-yl)carbamate tert-Butyl (6-(trifluoromethyl)isochroman-4-yl)carbamate (360.0 mg, 1.14 mmol) was dissolved in 5.0 mL of DMF and stirred in an ice bath for 2 minutes. Sodium hydride (90.8 mg, 2.27 mmol) was added in one portion and stirred at this temperature for 1 hour. Subsequently, iodomethane (487 mg, 3.41 mmol) was added and stirred at room temperature overnight. After completion of the reaction, saturated sodium bicarbonate (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was dried over sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product, tert-butyl-N-methyl-(6-(trifluoromethyl)isochroman-4-yl)carbamate (400.0 mg).

[0107] Step 5: Synthesis of N-methyl-6-(trifluoromethyl)isochroman-4-amine hydrochloride tert-Butyl-N-methyl-(6-(trifluoromethyl)isochroman-4-yl)carbamate (400 mg, 1.21 mmol) was dissolved in dichloromethane (2 mL), 4 M hydrogen chloride dioxane solution (2 mL) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction system was spin-dried to obtain N-methyl-6-(trifluoromethyl)isochroman-4-amine hydrochloride (390 mg).

[0108] The following intermediates were prepared by employing the method and procedure of Intermediate 55, substituting only the corresponding starting materials: [Table 11] Intermediate 60 (R)-N-methyl-7-(trifluoromethyl)pyran-4-amine hydrochloride [ka] Step 1: Synthesis of (S)-7-(trifluoromethyl)pyran-4-ol 7-(Trifluoromethyl)pyran-4-one (500.0 mg, 2.31 mmol) was first dissolved in DCM (10 mL) in an ice bath, and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine(p-isopropylbenzene) chloride (147.0 mg, 0.23 mmol) was added. Formic acid (372.0 mg, 8.10 mmol) was added dropwise, and finally triethylamine (701.0 mg, 6.94 mmol) was added dropwise. The mixture was then left to react overnight at room temperature. After completion of the reaction, saturated aqueous sodium bicarbonate (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over sodium sulfate, and filtered to obtain the crude product. This was then purified by column chromatography (petroleum ether:ethyl acetate = 0-40%) to obtain (S)-7-(trifluoromethyl)pyran-4-ol (370 mg, yield: 73%).

[0109] Step 2: Synthesis of tert-butyl (R)-(tert-butoxycarbonyl)(7-(trifluoromethyl)pyran-4-yl)carbamate Under a nitrogen atmosphere, (S)-7-(trifluoromethyl)pyran-4-ol (370.0 mg, 1.70 mmol) was first dissolved in THF (5.0 mL), and bis(tert-butoxycarbonyl)amine (405 mg, 1.88 mmol) and triphenylphosphine (489 mg, 1.88 mmol) were added. The reaction mixture was stirred at 0 °C for 5 minutes, and then DIAD (377.0 mg, 1.88 mmol) was added dropwise. The reaction mixture was stirred in an ice bath for 1 hour and then at room temperature overnight. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 0 to 5%) to obtain tert-butyl (R)-(tert-butoxycarbonyl)(7-(trifluoromethyl)pyran-4-yl)carbamate (145.0 mg, yield 20%).

[0110] 1H NMR (400 MHz, CDCl3) δ 7.25-7.22(m, 1H), 7.12-7.09(m, 1H), 7.07(d, 1H), 5.59-5.54(m, 1H), 4.46-4.41(m, 1H), 4.18-4.10(m, 1H), 2.67-2.60(m, 1H), 2.16-2.10(m, 1H), 1.46(s, 18H). Step 3: Synthesis of tert-butyl (R)-(7-(trifluoromethyl)pyran-4-yl)carbamate tert-Butyl (R)-(tert-butoxycarbonyl)(7-(trifluoromethyl)pyran-4-yl)carbamate (150.0 mg, 0.36 mmol) was dissolved in acetonitrile (5.0 mL), lithium bromide (94.0 mg, 1.08 mmol) was added, and the reaction system was reacted at 60 ° C. for 20 hours. After the reaction was completed, saturated sodium bicarbonate (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over sodium sulfate, filtered, and evaporated to dryness to obtain crude tert-butyl (R)-(7-(trifluoromethyl)pyran-4-yl)carbamate (83.0 mg, crude product).

[0111] Step 4: Synthesis of tert-butyl (R)-methyl-(7-(trifluoromethyl)pyran-4-yl)carbamate tert-Butyl (R)-(7-(trifluoromethyl)pyran-4-yl)carbamate (83.0 mg, 0.26 mmol) was dissolved in 2.0 mL of DMF and stirred in an ice bath for 2 minutes. Sodium hydride (26.2 mg, 0.66 mmol) was added in one portion and stirred at this temperature for 1 hour. Subsequently, iodomethane (74.4 mg, 0.52 mmol) was added and stirred at room temperature overnight. After completion of the reaction, saturated sodium bicarbonate (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL). The organic phase was dried over sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product, tert-butyl (R)-methyl-(7-(trifluoromethyl)pyran-4-yl)carbamate (100.0 mg, crude product).

[0112] LCMS(ESI)m / z:276.1[M+H] + Step 5: Synthesis of (R)-N-methyl-7-(trifluoromethyl)pyran-4-amine hydrochloride tert-Butyl (R)-methyl-(7-(trifluoromethyl)pyran-4-yl)carbamate (100 mg, 0.3 mmol) was dissolved in dichloromethane (2 mL), 4 M hydrogen chloride in dioxane (2 mL) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction system was spin-dried to obtain the crude product (R)-N-methyl-7-(trifluoromethyl)pyran-4-amine hydrochloride (90 mg, crude product).

[0113] The following intermediates were prepared using the method and procedures used for Intermediate 60: [Table 12] [Table 13] Intermediate 100 N,1,1-trimethyl-7-trifluoromethylisochromen-4-amine [ka] Step 1: Preparation of 1,1-dimethyl-7-trifluoromethylisochromen-4-ol 1,1-Dimethyl-7-trifluoromethylisochromen-4-one (300 mg, 1.229 mmol) was dissolved in MeOH (3 mL), sodium borohydride (70 mg, 1.844 mmol) was added, and the mixture was stirred at 25 °C for 10 hours. After confirming the completion of the reaction by LCMS, aqueous NH4Cl (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (0-10% ethyl acetate / petroleum ether) to give 1,1-dimethyl-7-trifluoromethylisochromen-4-ol (120 mg, yield: 39.4%).

[0114] LCMS(ESI)m / z:247.1[M+H] + Step 2: Preparation of 1,1-dimethyl-7-trifluoromethylisochromene-4-methanesulfonate 1,1-Dimethyl-7-trifluoromethylisochromen-4-ol (120 mg, 0.487 mmol) and methanesulfonyl chloride (112 mg, 0.974 mmol) were dissolved in DCM (10 mL), triethylamine (148 mg, 1.461 mmol) was added, and the mixture was stirred at 25° C. for 10 hours. After confirming the completion of the reaction by LCMS, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, 1,1-dimethyl-7-trifluoromethylisochromen-4-methanesulfonate (130 mg, yield: 13.3%).

[0115] LCMS(ESI)m / z:326.1[M+H] + Step 3: Preparation of N,1,1-trimethyl-7-trifluoromethylisochromene-4-amine. 1,1-Dimethyl-7-trifluoromethylisochromene-4-methanesulfonate (130 mg, 0.398 mmol) was dissolved in DMF (3 mL) at room temperature, and methylamine solution (0.3 mL, 30%) and DIEA (155 mg, 1.194 mmol) were added. The mixture was stirred at room temperature for 16 hours. After confirming completion of the reaction by LCMS, water (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by column chromatography (50-100% ethyl acetate / petroleum ether) to give N,1,1-trimethyl-7-trifluoromethylisochromene-4-amine (52 mg, yield: 50.4%).

[0116] LCMS(ESI)m / z:260.1[M+H] + The following intermediates were prepared by adopting the method and procedure for preparing Intermediate 100, substituting only the corresponding starting intermediates: [Table 14] Intermediate 69 Synthesis of 6-bromo-N-cyclopropyl-2,3-dihydrobenzofuran-3-amine [ka] Step 1: Synthesis of (5-bromo-2-(cyclopropylimino)methyl)phenol To a solution of 4-bromo-2-hydroxybenzaldehyde (2.0 g, 9.95 mmol) in dichloromethane (40 mL) was added cyclopropylamine (1.13 g, 19.9 mmol) and anhydrous magnesium sulfate (4.79 g, 39.8 mmol) at room temperature. The mixture was stirred at 25°C for 20 hours. After the reaction was completed, the reaction mixture was concentrated, ethyl acetate was added, and the mixture was filtered. The filter cake was washed with ethyl acetate. The resulting filtrate was concentrated under reduced pressure to give the crude product (5-bromo-2-(cyclopropylimino)methyl)phenol (1.7 g, crude product) as a yellow solid, which was used directly in the next step without further purification.

[0117] LCMS(ESI)m / z:241.1[M+H] + Step 2: Synthesis of 6-bromo-N-cyclopropyl-2,3-dihydrobenzofuran-3-amine Potassium tert-butoxide (1.99 g, 17.70 mmol) was slowly added to a solution of trimethylsulfoxonium iodide (3.89 g, 17.70 mmol) in THF (5 mL) at room temperature, and the mixture was stirred at room temperature for 0.5 h. Next, (5-bromo-2-(cyclopropylimino)methyl)phenol (1.7 g, 7.08 mmol) was dissolved in THF and slowly added dropwise to the mixture. The resulting suspension was stirred at room temperature for 1 h and then at 50 °C for 3 h. The reaction was cooled to room temperature, and 1 eq of potassium tert-butoxide (0.79 g, 7.08 mmol) was added and stirred at room temperature for 12 h. The reaction mixture was filtered, and the filtrate was diluted with water and extracted with ethyl acetate. After the organic layer was concentrated, the residue was purified by column chromatography with petroleum ether / ethyl acetate (3:1) to give 6-bromo-N-cyclopropyl-2,3-dihydrobenzofuran-3-amine (1.0 g, 3.93 mmol) as a yellow oil.

[0118] LCMS(ESI)m / z:255.1[M+H] + The intermediate amines in the table below can be prepared using the synthetic procedure described for Intermediate 69, substituting only the corresponding starting aldehyde or amine. [Table 15] Intermediate 71 Synthesis of 3-(cyclopropylamino)-2,3-dihydrobenzofuran-6-carbonitrile [ka] 6-Bromo-N-cyclopropyl-2,3-dihydrobenzofuran-3-amine (100 mg, 0.41 mmol) was placed in a 50 mL single-port flask at room temperature. Pd(dba) (18.8 mg, 0.02 mmol), S-Phos (9.8 mg, 0.02 mmol), and zinc cyanide (96.5 mg, 0.82 mmol) were added, followed by N,N-dimethylacetamide (1.0 mL). The mixture was heated to 110 °C in a microwave oven and stirred for 1 h. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the organic phase was spin-dried to obtain the crude product. This was mixed thoroughly and purified by column chromatography using ethyl acetate:petroleum ether (0-50%) to obtain 3-(cyclopropylamino)-2,3-dihydrobenzofuran-6-carbonitrile (55 mg, yield: 67%).

[0119] 1 H NMR (400 MHz, CDCl3) δ 7.44-7.42(dd, 1H), 7.2-7.19(dd, 1H), 7.07(d, 1H), 4.65-4.61(m, 1H), 4.58-4.55(m, 1H), 4.47-4.46(m, 1H), 2.25-2.19(m, 1H), 0.52-0.49(m, 2H), 0.43-0.40(m, 2H). Intermediate 72: (S)-6-(Fluoromethyl)-N-methyl-2,3-dihydrobenzofuran-3-amine [ka] Step 1: Synthesis of tert-butyl (S)-(6-(hydroxymethyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate A mixture of tert-butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (400 mg, 1.22 mmol), 2,2-dibutyl-2-stanoxycyclohexan-1-ol (391 mg, 1.22 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (99 mg, 0.12 mmol) in dioxane (5 mL) was reacted at 100°C for 12 hours. After completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=40:60) to give tert-butyl (S)-(6-(hydroxymethyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (110 mg, yield: 29%).

[0120] LCMS(ESI):280[M+H] + Step 2: Synthesis of tert-butyl (S)-(6-(fluoromethyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate To a mixture of N-[(3S)-6-(hydroxymethyl)(2,3-dihydrobenzo[b]furan-3-yl)](tert-butoxy)-N-methylformamide (100 mg, 0.36 mmol) in dichloromethane (1.00 mL) was added [bis(2-methoxyethyl)amine]sulfur trifluoride (396 mg, 1.79 mmol) at −78° C. The mixture was stirred at −78° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched with ice water (5 mL) and extracted with ethyl acetate (5 mL × 2). The organic layers were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 20:80) to obtain tert-butyl (S)-(6-(fluoromethyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (80 mg, yield: 70).

[0121] LCMS(ESI):282[M+H] + Step 3: Synthesis of (S)-6-(fluoromethyl)-N-methyl-2,3-dihydrobenzofuran-3-amine A mixture of tert-butyl (S)-(6-(fluoromethyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (80 mg, 0.36 mmol) and hydrochloric acid in dioxane (1 mL) was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was spin-dried to give (S)-6-(fluoromethyl)-N-methyl-2,3-dihydrobenzofuran-3-amine (100 mg, crude product).

[0122] LCMS(ESI):182[M+H] + Intermediate 73: Synthesis of (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-formamide [ka] Step 1: Synthesis of (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-carboxylic acid Methyl (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-carboxylate (1 g, 3.25 mmol) was dissolved in a solution of methanol (10.00 mL) and tetrahydrofuran (10.00 mL) at room temperature, and sodium hydroxide (260 mg, 6.5 mmol) was added and stirred for 1 hour. After completion of the reaction, the reaction solution was concentrated to give (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-carboxylic acid (600 mg, crude) as a white solid.

[0123] LCMS(ESI):294[M+H] + Step 2: Synthesis of tert-butyl (S)-(6-carbamoyl-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate To a solution of (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-carboxylic acid (600 mg, 2.04 mmol) in N,N-dimethylformamide (5.00 mL) at room temperature, 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.62 g, 4.38 mmol), N,N-diisopropylethylamine (1.38 g, 10.68 mmol), and ammonium chloride (360 g, 6.78 mmol) were added, and the mixture was reacted at room temperature for 30 minutes. After completion of the reaction, the mixture was diluted with ethyl acetate (30 mL) and water (30 mL), and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether=17%) to give tert-butyl (S)-(6-carbamoyl-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (240 mg, yield: 40%) as a yellow liquid.

[0124] LCMS(ESI):293[M+H] + Step 3: Synthesis of (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-formamide tert-Butyl (S)-(6-carbamoyl-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (240 mg, 0.82 mmol) was dissolved in a solution of dichloromethane (2.00 mL) and trifluoroacetic acid (0.40 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was concentrated to give (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-formamide as a black solid (100 mg, yield: 66.66%).

[0125] Example 74: (S)-N 3 Synthesis of 2,3-methyl-3,6-dihydrobenzofuran-3,6-diamine [ka] Step 1: Synthesis of tert-butyl (S)-(6-((diphenylmethylene)amino)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate tert-Butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (120 mg, 0.35 mmol) was dissolved in 1,4-dioxane (5.00 mL) at room temperature, and benzophenone imide (190 mg, 1.06 mmol), potassium tert-butoxide (80 mg, 0.71 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (40 mg, 0.07 mmol), and palladium acetate (8 mg, 0.03 mmol) were added. The mixture was then reacted at 100 °C for 2 hours. After completion of the reaction, the reaction mixture was poured into water (2 mL) and extracted with ethyl acetate (2 mL × 2). The combined organic layer was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product. Purification by flash column chromatography (petroleum ether:ethyl acetate=10%) afforded tert-butyl (S)-(6-((diphenylmethylene)amino)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (90 mg, yield: 59%) as a white solid.

[0126] LCMS(ESI):429[M+H] + Step 2: (S)-N 3 Synthesis of 2,3-methyl-3,6-dihydrobenzofuran-3,6-diamine tert-Butyl (S)-(6-((diphenylmethylene)amino)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (90 mg, 0.21 mmol) was dissolved in a solution of hydrochloric acid in methanol (5.00 mL) at room temperature, and the mixture was stirred at room temperature for 0.5 hours. After completion of the reaction, the reaction solution was poured into a dichloromethane solution, and the solid precipitated. (S)-N3-methyl-2,3-dihydrobenzofuran-3,6-diamine (60 mg, yield: 90%) was obtained as a white solid.

[0127] LCMS(ESI):165[M+H] + Intermediate 75: Synthesis of (S)-1,1,1-trifluoro-N-(3-(methylamino)-2,3-dihydrobenzofuran-6-yl)methanesulfonamide [ka] Step 1: Synthesis of tert-butyl (S)-methyl (6-(trifluoromethyl)sulfonamido)-2,3-dihydrobenzofuran-3-yl)carbamate tert-Butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (200 mg, 0.61 mmol), trifluoromethylsulfonamide (136 mg, 0.91 mmol), cuprous iodide (1.16 g, 6.09 mmol), and potassium phosphate (259 mg, 1.22 mmol) were dissolved in dimethylformamide (9 mL) and stirred at 90 °C for 2 h. After completion of the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate three times (10 mL each). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and the reaction mixture was concentrated in vacuo to give tert-butyl (S)-methyl(6-(trifluoromethyl)sulfonamido)-2,3-dihydrobenzofuran-3-yl)carbamate (800 mg, 51.85% yield) as a yellow liquid.

[0128] LCMS(ESI):397.2[M+H] + Step 2: Synthesis of (S)-1,1,1-trifluoro-N-(3-(methylamino)-2,3-dihydrobenzofuran-6-yl)methanesulfonamide tert-Butyl (S)-methyl(6-(trifluoromethyl)sulfonamido)-2,3-dihydrobenzofuran-3-yl)carbamate (80 mg, 3.246 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (4.0 M, 5 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the system was cooled to room temperature and the reaction solution was concentrated in vacuo to give (S)-1,1,1-trifluoro-N-(3-(methylamino)-2,3-dihydrobenzofuran-6-yl)methanesulfonamide (60 mg, 1.18 mmol, 82.46% yield).

[0129] Intermediate 76 Methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate [ka] Step 1: Synthesis of imidazo[1,5-a]imidazo[1,5-d]1,4-diazapiperazine-5,10-dione Imidazole-5-carboxylic acid (100 g, 892.14 mmol) was added to dichlorosulfoxide (500 mL) and stirred at 80° C. for 12 hours. The mixture was concentrated, washed with toluene (500 mL × 2), and filtered to obtain a solid product. The residual solvent was removed using an oil pump vacuum to obtain imidazo[1,5-a]imidazo[1,5-d]1,4-diazapiperazine-5,10-dione (70 g, 0.37 mol, 42% yield) as a yellow solid.

[0130] LCMS(ESI)m / z:189[M+H] + Step 2: Synthesis of N-(4-bromo-2-fluorophenyl)imidazol-5-ylformamide To a mixture of 4-bromo-2-fluorophenylamine (60.60 g, 318.91 mmol) in tetrahydrofuran (600 mL), sodium bis(trimethylsilyl)amide (318.91 mL, 637.82 mmol, 2 mol / L) was slowly added dropwise over 1 h at 0 °C. Imidazo[1,5-a]imidazo[1,5-d]1,4-diazapiperazine-5,10-dione (60 g, 318.91 mmol) was then added, and the mixture was stirred at room temperature for 12 h. The mixture was poured into water, filtered, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 40%) to give N-(4-bromo-2-fluorophenyl)imidazol-5-ylformamide (60 g, 0.21 mol, 66% yield) as a white solid. LCMS(ESI)m / z:284.2[M+H] + Step 3: Synthesis of 8-bromo-10-hydroimidazo[1,5-a]quinoxalin-4-ol N-(4-Bromo-2-fluorophenyl)imidazol-5-ylformamide (60 g, 211.20 mmol) and sodium hydride (16.88 g, 422.40 mmol, 60% content) in dimethylacetamide (600 mL) were stirred for 12 hours at 140° C. The mixture was poured into water and filtered to give 8-bromo-10-hydroimidazo[1,5-a]quinoxalin-4-ol (50 g, 90% yield) as a yellow solid.

[0131] LCMS(ESI)m / z:264.2[M+H] + Step 4: Synthesis of 8-bromo-4-chloro-10-hydroimidazo[1,5-a]quinoxaline To a mixture of 8-bromo-10-hydroimidazo[1,5-a]quinoxalin-4-ol (50 g, 189.34 mmol) and N,N-diisopropylethylamine (48.85 g, 378.67 mmol), phosphorus oxychloride (500 mL) was added, and the mixture was stirred at 90°C for 2 hours. After concentrating, the residue was dissolved in acetonitrile and slowly added dropwise to ice water to precipitate a solid. The solid was then filtered to obtain 8-bromo-4-chloro-10-hydroimidazo[1,5-a]quinoxaline (50 g, 93% yield).

[0132] LCMS(ESI)m / z:282.2[M+H] + .

[0133] Step 5: Synthesis of (8-bromo(10-hydroimidazo[1,5-a]quinoxalin-4-yl))[(4-methoxyphenyl)methyl]amine 8-Bromo-4-chloro-10-hydroimidazo[1,5-a]quinoxaline (50 g, 176.98 mmol), 4-methoxybenzylamine (29.13 g, 212.38 mmol) were added to dimethyl sulfoxide (500 mL), followed by N,N-diisopropylethylamine (45.66 g, 353.96 mmol). The mixture was stirred at 80° C. for 2 hours, then poured into water and filtered to give (8-bromo(10-hydroimidazo[1,5-a]quinoxalin-4-yl))[(4-methoxyphenyl)methyl]amine (50 g, 74% yield) as a yellow oil.

[0134] LCMS(ESI)m / z:383.2[M+H] + Step 6: Synthesis of methyl 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (8-Bromo(10-hydroimidazo[1,5-a]quinoxalin-4-yl))[(4-methoxyphenyl)methyl]amine (50 g, 130.47 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10.83 g, 13.05 mmol), and potassium acetate (25.57 g, 260.93 mmol) were added to a solution of dimethylformamide (50 mL) and methanol (250 mL). The mixture was reacted under a carbon monoxide atmosphere (4 MPa) at 100 °C for 12 hours. The mixture was then poured into water, filtered, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80%) to obtain methyl 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (30 g, 63% yield) as a yellow solid.

[0135] LCMS(ESI)m / z:363.2[M+H] + Step 7: Synthesis of 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid Methyl 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (30 g, 82.87 mmol) was added to a mixture of methanol, water, and tetrahydrofuran (1:1:1, 150 mL), potassium hydroxide (92.40 g, 165.0 mmol), and the mixture was reacted at 60 °C for 12 hours. The mixture was then concentrated in vacuo. The organic solvent was removed, the mixture was poured into water, the pH was adjusted to 7-8 with 2 M hydrochloric acid, extracted with ethyl acetate (100 mL x 3), and concentrated in vacuo to give 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (25 g, 86% yield).

[0136] LCMS(ESI)m / z:349.2[M+H] + Step 8: 4-Aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid 4-((4-Methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (100.0 mg, 0.28 mmol) was dissolved in trifluoroacetic acid (2 mL) at room temperature. The mixture was stirred at 100 °C for 2 hours. The reaction was monitored using liquid chromatography-mass spectrometry (LC-MS). The mixture was concentrated to give 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (60.0 mg, yield: 94%) as a white solid.

[0137] LCMS(ESI)m / z:229.2[M+H] + The intermediate carboxylic acids in the table below can be prepared using the synthetic procedure described for Intermediate 76, substituting only the corresponding starting materials. [Table 16] Intermediate 84 4-((4-Methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid [ka] Step 1: Synthesis of methyl 3-(2-methyl-1H-imidazol-1-yl)-4-nitrobenzoate Methyl 3-fluoro-4-nitrobenzoate (20.0 g, 100 mmol) was dissolved in acetonitrile (100 mL), and 2-methyl-1H-imidazole (8.2 g, 100 mmol) and potassium carbonate (27.6 g, 200 mmol) were added. The mixture was stirred at 100 °C for 12 hours. The reaction was monitored by LCMS. The reaction mixture was poured into 300 mL of water and extracted with 200 mL of ethyl acetate three times. The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10%) to give methyl 3-(2-methyl-1H-imidazol-1-yl)-4-nitrobenzoate (25.0 g, 95% yield) as a yellow solid.

[0138] LCMS(ESI)m / z:262[M+H] + Step 2: Synthesis of methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate Methyl 3-(2-methyl-1H-imidazol-1-yl)-4-nitrobenzoate (25 g, 95.8 mmol) was dissolved in methanol (300 mL) at room temperature, and Raney nickel (2 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction was monitored using liquid chromatography-mass spectrometry (LC-MS). The residue was filtered to obtain a filtrate, which was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20%) to obtain methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate (20.5 g, 93% yield) as a yellow solid.

[0139] LCMS(ESI)m / z:232[M+H] + Step 3: Synthesis of methyl 1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate Methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate (2.0 g, 8.7 mmol) was dissolved in o-dichlorobenzene (40 mL) at room temperature, carbonyldiimidazole (2.8 g, 17.4 mmol) was added, and the mixture was stirred at 180 °C for 12 hours. The reaction was monitored by LCMS, and the mixture was filtered to obtain a filter cake, which was pulped with ethyl acetate (5 mL) to obtain methyl 1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate (920.0 mg, yield: 41%) as a black solid.

[0140] LCMS(ESI)m / z:258[M+H] + Step 4: Synthesis of methyl 4-chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate Methyl 1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate (100.0 mg, 0.39 mmol) was dissolved in phosphorus oxychloride (5 mL) at room temperature, and the mixture was stirred at 120° C. for 4 hours. The reaction was monitored by LCMS, and the reaction solution was concentrated under reduced pressure, diluted with a small amount of acetonitrile, poured into water (5 mL), filtered, and the filter cake was washed with water and dried under vacuum to give methyl 4-chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60.0 mg, yield: 56%) as a black solid.

[0141] LCMS(ESI)m / z:276[M+H] + Step 5: Synthesis of methyl 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate Methyl 4-chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60 mg, 0.22 mmol) was dissolved in dimethyl sulfoxide (2 mL) at room temperature, followed by the addition of (4-methoxyphenyl)methylamine (60 mg, 0.44 mmol) and N,N-diisopropylethylamine (67 mg, 0.52 mmol). The mixture was stirred at 100 °C for 1 h. The reaction was monitored by LCMS. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 40%) to give methyl 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60 mg, yield: 73%) as a black solid.

[0142] LCMS(ESI)m / z:377[M+H] + Step 6: Synthesis of 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid Methyl 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60 mg, 0.16 mmol) was dissolved in methanol (1 mL), tetrahydrofuran (1 mL), and water (1 mL) at room temperature, followed by the addition of potassium hydroxide (26 mg, 0.44 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The reaction mixture was poured into water (10 mL), acidified with formic acid, and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to give 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (50 mg, 86% yield) as a white solid.

[0143] LCMS(ESI)m / z:363[M+H] + Step 7: Synthesis of 4-amino-1-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid A solution of 4-{[(4-methoxyphenyl)methyl]amino}-1-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (400 mg, 1.10 mmol) in trifluoroacetic acid (5.00 mL) was stirred for 2 hours at 90° C. The reaction was concentrated in vacuo to give 4-amino-1-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (250 mg, 94% yield).

[0144] LCMS(ESI)m / z:243[M+H] + Intermediate 85: 4-Amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylic acid [ka] Step 1: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylate A solution of methyl 4-amino-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylate (1.20 g, 4.34 mmol), di-tert-butyl dicarbonate (1.89 g, 8.67 mmol), and triethylamine (1.30 g, 13.01 mmol) in dichloromethane (10 mL) was stirred at room temperature for 2 hours. After completion of the reaction, the solution was poured into water (5 mL) and extracted with ethyl acetate (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 70:30) to give methyl 4-((tert-butoxycarbonyl)amino)-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylate (1.00 g, 61% yield) as a white solid.

[0145] LCMS(ESI):376[M+H] + Step 2: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylate A mixture of methyl 4-((tert-butoxycarbonyl)amino)-7-chloroimidazo[1,5-a]quinoxaline-8 carboxylate (0.20 g, 0.53 mmol), potassium iron cyanide (0.05 g, 0.16 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.09 g, 0.21 mmol), (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (0.17 g, 0.21 mmol), and potassium acetate (0.01 g, 0.07 mmol) in dioxane / water (4.00 mL) was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was then concentrated and purified by column chromatography (petroleum ether:ethyl acetate=70:30) to give methyl 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylate (0.10 g, 51%) as a white solid.

[0146] LCMS(ESI):368[M+H]+ Step 3: Synthesis of methyl 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylate To a solution of methyl 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylate (0.20 g, 0.54 mmol) in dichloromethane (0.50 mL) was added trifluoroacetic acid (0.10 mL), and the reaction was stirred at room temperature for 2 hours and then concentrated to give methyl 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylate (0.05 g, crude).

[0147] LCMS(ESI):268[M+H] + Step 4: Synthesis of 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylic acid A mixture of methyl 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylate (0.20 g, 0.75 mmol), potassium hydroxide (0.07 g, 1.50 mmol), and tetrahydrofuran / methanol / water (1 mL / 1 mL / 1 mL) was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated to give the crude product, 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylic acid (210 mg, crude product). The crude product was used directly in the next step without further purification.

[0148] LCMS(ESI):254[M+H] + Intermediate 86 4-Amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid [ka] Step 1: Synthesis of methyl 4-{[(4-methoxyphenyl)methyl]amino}-7-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate A mixture of methyl 7-chloro-4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (200 mg, 0.5 mmol), potassium carbonate (300 mg, 2 mmol), dichloro[1,1'-bis(di-tert-butylphosphine)ferrocene]palladium(II) (0.08 g, 0.1 mmol), trimethylboroxane (0.01 g, 0.10 mmol), and methyl methyl 7-chloro-4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (200 mg, 0.5 mmol) was added. l) in dioxane (2.00 mL) was stirred at 100° C. for 12 hours, then poured into water, extracted with ethyl acetate (5 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (petroleum ether:ethyl acetate=30%) to give methyl 4-{[(4-methoxyphenyl)methyl]amino}-7-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (100 mg, 53%).

[0149] LCMS(ESI):268[M+H] + Step 2: Synthesis of 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid Methyl 4-{[(4-methoxyphenyl)methyl]amino}-7-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (500 mg, 1.86 mmol) was dissolved in methanol:tetrahydrofuran:saturated aqueous potassium hydroxide solution (1 mL:1 mL:1 mL), and the reaction mixture was reacted at 60°C for 12 hours. After the reaction was completed, the mixture was spin-dried, adjusted to pH 3 with formic acid, and filtered to obtain 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (52 mg, 12% yield).

[0150] LCMS(ESI):363[M+H] + Step 3: Synthesis of 4-amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid 4-((4-Methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (500 mg, 1.86 mmol) was dissolved in trifluoroacetic acid solution (5 mL), and the reaction mixture was stirred at 100° C. for 12 hours. After the reaction was completed, 4-amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (520 mg, crude product) was obtained by spin drying.

[0151] LCMS(ESI):363[M+H] + The following intermediate acids were prepared by the method used in Step 3 of Intermediate 86: [Table 17] Intermediate 93 4-Amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid [ka] Step 1: Synthesis of 6-bromo-2-chloro-3-hydrazinoquinoxaline 6-Bromo-2,3-dichloroquinoxaline (278.0 mg, 1.0 mmol) was added to a 25 mL single-port flask at room temperature, and hydrazine hydrate (156 mg, 2.5 mmol, 80% wt) was added. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the mixture was filtered, and the filter cake was washed with water (10 mL x 2) and ethyl acetate (5 mL x 2) to obtain 6-bromo-2-chloro-3-hydrazinoquinoxaline (150 mg).

[0152] LCMS(ESI)m / z:273.0 / 275.0[M+H] + Step 2: Synthesis of 8-bromo-4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline At room temperature, 6-bromo-2-chloro-3-hydrazinoquinoxaline (116.0 mg, 0.5 mmol) was placed in a 25 mL single-port flask, triethyl orthoformate (4.0 mL) was added, and the reaction mixture was heated to 100 °C and allowed to react at this temperature for 1 hour. After confirming the completion of the reaction by LCMS, the mixture was cooled to room temperature and filtered. The filter cake was washed with methanol (3.0 mL x 3) and dried to give 8-bromo-4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline (110 mg).

[0153] 1 H NMR (400 MHz, CDCl3) δ 10.21(s, 1H), 8.84(d, 1H), 7.98(d, 1H), 7.90(dd, 1H). Step 3: Synthesis of 8-bromo-N-(4-methoxybenzyl)-[1,2,4]triazolo[4,3-a]quinoxalin-4-amine 8-Bromo-4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline (1.70 g, 6.00 mmol) was dissolved in DMSO (15.0 mL), p-methoxybenzylamine (1.23 g, 9.00 mmol), and DIEA (2.32 g, 18.00 mmol) were added, and the reaction mixture was heated at 90 °C for 4 hours. After the reaction was completed, water (60 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phase was dried over sodium sulfate, filtered, and evaporated to give crude product 8-bromo-N-(4-methoxybenzyl)-[1,2,4]triazolo[4,3-a]quinoxaline-4-amine (2.20 g).

[0154] LCMS(ESI)m / z:384.1 / 386.1[M+H] + Step 4: Synthesis of methyl 4-((4-methoxybenzyl)amino)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate To a solution of 8-bromo-N-(4-methoxybenzyl)-[1,2,4]triazolo[4,3-a]quinoxaline-4-amine (2.2 g, 5.74 mmol) in MeOH (30 mL) and DMF (30 mL) was added potassium acetate (1.7 g, 17.2 mmol) and Pd(dppf)Cl (420 mg, 0.57 mmol). The mixture was stirred at 100 °C for 12 h under a CO atmosphere. After spinning off the methanol, 100 mL of water was added and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous NaSO, spun dry, and the crude product was pulped with ethyl acetate (20 mL) to give methyl 4-((4-methoxybenzyl)amino)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate (1.1 g, 53% yield).

[0155] LCMS(ESI)m / z:364.2[M+H] + Step 5: Synthesis of methyl 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate.

[0156] The compound 4-((4-methoxybenzyl)amino)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate methyl ester (300.0 mg, 0.78 mmol) was placed in a 25 mL single-port flask, TFA (5.0 mL) was added, and the reaction system was heated to 80 °C and stirred at this temperature for 16 hours. After completion of the reaction, the reaction solution was spin-dried to obtain the crude product 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate methyl ester (190 mg).

[0157] LCMS(ESI)m / z:244.3[M+H] + Step 6: Synthesis of 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid.

[0158] The crude product from the previous step, methyl 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate (190 mg, 0.78 mmol), was added to THF (5.0 mL) and methanol (5.0 mL). The pH was adjusted to 7 with 3 M aqueous potassium hydroxide, and then lithium hydroxide (65.0 mg, 1.56 mmol) was added and stirred at 50 °C for 16 h. After waiting for the reaction to complete, the methanol and THF in the system were spun off, the pH was adjusted to 6.5 with 1 M dilute hydrochloric acid, filtered, the filter cake was washed with water (5.0 mL x 3), the filter cake was dried, and the water was removed to obtain the crude product, 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid (120 mg).

[0159] LCMS(ESI)m / z:230.1[M+H] + Intermediate 94 5-Aminoimidazo[1,5-c]quinazoline-9-carboxylic acid [ka] Step 1: Synthesis of 6-bromo-N-(4-methoxybenzyl)-4-methylquinazolin-2-amine The compound 6-bromo-2-chloro-4-methylquinazoline (0.5 g, 1.942 mmol) was dissolved in DMSO (15 mL), DIEA (768 mg, 5.825 mmol) and 4-methoxybenzylamine (600 mg, 3.883 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by column chromatography (0-10% methanol / dichloromethane) to give 6-bromo-N-(4-methoxybenzyl)-4-methylquinazolin-2-amine (500 mg, yield: 72%).

[0160] LCMS(ESI)m / z:359.2[M+H] + Step 2: Synthesis of 9-bromo-N-(4-methoxybenzyl)imidazo[1,5-c]quinazolin-5-amine The compound 6-bromo-N-(4-methoxybenzyl)-4-methylquinazolin-2-amine (0.5 g, 1.396 mmol) was dissolved in DMSO (20 mL) at room temperature, and glycine (211 mg, 2.792 mmol), tert-butyl hydroperoxide (719 mg, 5.583 mmol), tetrabutylammonium iodide (104 mg, 0.2792 mmol) and acetic acid (251 mg, 4.187 mmol) were added, and the mixture was stirred at 90° C. for 16 hours under nitrogen protection. Water (60 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (0-10% methanol / dichloromethane) to give 9-bromo-N-(4-methoxybenzyl)imidazo[1,5-c]quinazolin-5-amine (300 mg, yield: 56%).

[0161] LCMS(ESI)m / z:384.2[M+H] + Step 3: Synthesis of methyl 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylate To a solution of 9-bromo-N-(4-methoxybenzyl)imidazo[1,5-c]quinazolin-5-amine (300 mg, 0.785 mmol) in MeOH (10 mL) and DMF (10 mL) was added potassium acetate (230 mg, 2.36 mmol) and Pd(dppf)Cl (58 mg, 0.0785 mmol) at room temperature. The mixture was stirred at 100 °C under a CO atmosphere for 12 h. After spinning off the methanol, water (60 mL) was added and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by column chromatography (0-10% methanol / dichloromethane) to give methyl 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylate (200 mg, 56% yield).

[0162] LCMS(ESI)m / z:363.2[M+H] + Step 4: Synthesis of methyl 5-aminoimidazo[1,5-c]quinazoline-9-carboxylate The compound 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylate methyl ester (200 mg, 0.5519 mmol) was placed in a 20 mL round-bottom flask at room temperature, trifluoroacetic acid (2 mL) was added, and the mixture was stirred at 78° C. for 3 hours. After the trifluoroacetic acid was spun off, water (5 mL) was added, filtered, and the filter cake was washed with water to obtain 5-aminoimidazo[1,5-c]quinazoline-9-carboxylate methyl ester (200 mg, crude product).

[0163] LCMS(ESI)m / z:243.2[M+H] + Step 5: Synthesis of 5-aminoimidazo[1,5-c]quinazoline-9-carboxylic acid The compound methyl 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylate (200 mg, 0.8257 mmol) was dissolved in a mixed solvent of methanol / tetrahydrofuran / water (9 mL, 4:4:1) at room temperature, lithium hydroxide (40 mg, 1.651 mmol) was added, and the mixture was stirred at 78°C for 3 hours. After the trifluoroacetic acid was spun off, water (5 mL) was added, filtered, and the filter cake was washed with water to obtain 5-aminoimidazo[1,5-c]quinazoline-9-carboxylic acid (200 mg, crude product).

[0164] LCMS(ESI)m / z:243.2[M+H]+ Intermediate 95 Synthesis of (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)tetrazolo[1,5-a]quinoxaline-8-carboxamide [ka] Step 1: Synthesis of 6-bromo-2-chloro-3-hydrazinoquinoxaline A mixture of 6-bromo-2,3-dichloroquinoxaline (6.00 g, 21.73 mmol) and hydrazine hydrate (1.15 g, 35.98 mmol) in ethanol (50.00 mL) was stirred at 0° C. for 1 hour, followed by room temperature for 2 hours. Filtration and washing with ethanol (100 mL) gave 6-bromo-2-chloro-3-hydrazinoquinoxaline (5.00 g, 18.31 mmol).

[0165] LCMS(ESI):273[M+H] + Step 2: Synthesis of 8-bromo-4-chlorotetrazolo[1,5-a]quinoxaline A mixture of 6-bromo-2-chloro-3-hydrazinoquinoxaline (5.00 g, 18.31 mmol), sodium nitrite (2.52 g, 36.56 mmol), and aqueous hydrochloric acid (0.2 M, 50.00 mL) was stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate (100 mL × 3), concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 70%) to give 8-bromo-4-chlorotetrazolo[1,5-a]quinoxaline (4.00 g, 18.28 mmol).

[0166] LCMS(ESI):284[M+H] + Step 3: Synthesis of 8-bromo-N-(4-methoxybenzyl)tetrazolo[1,5-a]quinoxalin-4-amine A mixture of 8-bromo-4-chlorotetrazolo[1,5-a]quinoxaline (4.00 g, 14.13 mmol), p-methoxybenzylamine (3.87 g, 28.26 mmol), and N,N-diisopropylethylamine (7.30 g, 56.52 mmol) in dichloromethane (50 mL) was stirred at room temperature for 2 h. Extraction with ethyl acetate (100 mL × 3), concentration of the organic phase in vacuo, and silica gel column chromatography (petroleum ether:ethyl acetate = 30%) afforded 8-bromo-N-(4-methoxybenzyl)tetrazolo[1,5-a]quinoxalin-4-amine (3.00 g, 7.81 mmol).

[0167] LCMS(ESI):385[M+H] + Step 4: Synthesis of methyl 4-((4-methoxybenzyl)amino)tetrazolo[1,5-a]quinoxaline-8-carboxylate 8-Bromo-N-(4-methoxybenzyl)tetrazolo[1,5-a]quinoxaline-4-amine (3.00 g, 7.81 mmol), potassium acetate (1.53 g, 15.61 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.63 g, 0.77 mmol) were dissolved in a mixture of N,N-dimethylformamide and methanol (1:1, 30 mL). The mixture was reacted overnight at 100 °C under carbon monoxide (4 mPa) using an autoclave, filtered, and extracted with water (100 mL) and ethyl acetate (100 mL × 3). The organic phase was concentrated in vacuo to give methyl 4-((4-methoxybenzyl)amino)tetrazolo[1,5-a]quinoxaline-8-carboxylate (3.00 g, 8.24 mmol).

[0168] LCMS(ESI):365[M+H] + Step 5: Synthesis of methyl 4-aminotetrazolo[1,5-a]quinoxaline-8-carboxylate Methyl 4-((4-methoxybenzyl)amino)tetrazolo[1,5-a]quinoxaline-8-carboxylate (3.00 g, 8.24 mmol) was dissolved in a solution of hydrochloric acid in dioxane (4 M, 50 mL), stirred at room temperature for 2 hours, extracted with water (100 mL) and ethyl acetate (100 mL × 3), the organic phase was concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 50%) to give methyl 4-aminotetrazolo[1,5-a]quinoxaline-8-carboxylate (2.00 g, 8.16 mmol).

[0169] LCMS(ESI):245[M+H] + Step 6: Synthesis of 4-aminotetrazolo[1,5-a]quinoxaline-8-carboxylic acid Methyl 4-aminotetrazolo[1,5-a]quinoxaline-8-carboxylate (2.00 g, 8.16 mmol) and potassium hydroxide (0.91 g, 16.32 mmol) were dissolved in tetrahydrofuran-water-methanol (10 mL:10 mL:10 mL), stirred at 60°C for 2 hours, extracted with water (50 mL) and ethyl acetate (50 mL x 3), and the organic phase was concentrated in vacuo to give 4-aminotetrazolo[1,5-a]quinoxaline-8-carboxylic acid (1.00 g, 4.34 mmol).

[0170] LCMS(ESI):231[M+H] + Intermediate 96 6-Aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylic acid [ka] Step 1: Synthesis of N-(2,6-dichloropyridin-3-yl)-1H-imidazole-5-carboxamide The compound 2,6-dichloropyridin-3-amine (163 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5.0 mL) and cooled in an ice bath for 5 minutes. NaHMDS (0.1.25 mL, 2.0 M, 2.5 mmol) was added dropwise to the reaction mixture and stirred for 1 hour. 5H,10H-diimidazo[1.5-a:1',5'-d]pyrazine-5,10-dione (188.0 mg, 1.0 mmol) was added and stirred at room temperature overnight. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into water, adjusted to pH 7, and the solid precipitated. The solid was collected, filtered, and dried to give crude N-(2,6-dichloropyridin-3-yl)-1H-imidazole-5-carboxamide (175 mg, crude product).

[0171] LCMS(ESI)m / z:257.0[M+H] + Step 2: Synthesis of 2-chloroimidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one The compound N-(2,6-dichloropyridin-3-yl)-1H-imidazole-5-carboxamide (256.0 mg, 1.0 mmol) was dissolved in N,N-dimethylacetamide (2.0 mL), potassium carbonate (276 mg, 2.0 mmol) was added, the mixture was heated to 140 ° C., and stirred for 2 hours. After confirming the completion of the reaction by LCMS, the reaction mixture was cooled to room temperature, poured into water, and stirred for 30 minutes. A solid was precipitated, filtered, and the solid was collected to obtain the crude product 2-chloroimidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one (153.0 mg, crude product).

[0172] LCMS(ESI)m / z:221.1[M+H] + Step 3: Synthesis of methyl-6-hydroxyimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate To a solution of 2-chloroimidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one (2.0 g, 9.09 mmol) in MeOH (30.00 mL) and DMF (310.00 mL) was added potassium acetate (1.78 g, 18.18 mmol) and Pd(dppf)Cl (660 mg, 0.91 mmol). The mixture was stirred at 100 °C under a CO atmosphere for 12 h. After spinning off the methanol, the reaction solution was added to 100 mL of water to precipitate a solid. The crude product was obtained as a solid by filtration, which was then pulped with ethyl acetate (50 mL × 2) to give the product, methyl 6-hydroxyimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate (1.5 g, 68% yield), as a brown solid.

[0173] LCMS(ESI)m / z:245.2[M+H] + Step 4: Synthesis of methyl 6-chloroimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate Methyl 6-hydroxyimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate (200.0 mg, 0.82 mmol) was added to phosphorus oxychloride (2.0 mL), and N,N-diisopropylethylamine (528 mg, 4.09 mmol) was added dropwise. The mixture was heated to 90°C and reacted for 2.5 hours. After confirming the completion of the reaction by LCMS, phosphorus oxychloride was removed by filtration, and the reaction mixture was added to ice water and stirred for 15 minutes. The mixture was then filtered to obtain a filter cake, which was then dried to obtain methyl 6-chloroimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate (200.0 mg, crude product).

[0174] LCMS(ESI)m / z:263.0[M+H] + Step 5: Synthesis of methyl 6-((4-methoxybenzyl)amino)imidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate Methyl 6-chloroimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate (200.0 mg, 0.76 mmol) was dissolved in DMSO (3.0 mL), p-methoxybenzylamine (125.0 mg, 0.92 mmol) and N,N-diisopropylethylamine (295 mg, 2.29 mmol) were added, and the mixture was heated to 90 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, poured into ice water with stirring, extracted with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 0-5%) to give methyl 6-((4-methoxybenzyl)amino)imidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate (250 mg, yield: 91%).

[0175] LCMS(ESI)m / z:364.2[M+H] + Step 6: Synthesis of methyl 6-aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate The compound 6-((4-methoxybenzyl)amino)imidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate methyl ester (250 mg, 0.69 mmol) was dissolved in TFA (5.0 mL), and the reaction mixture was heated to 80°C and reacted for 16 hours. After waiting for the reaction to be complete, the mixture was cooled, and the TFA in the system was spun off to obtain the crude product 6-aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate methyl ester (160 mg, crude product).

[0176] LCMS(ESI)m / z:244.1[M+H] + Step 7: Synthesis of 6-aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylic acid Methyl 6-aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate (160.0 mg, 0.66 mmol) was dissolved in a THF / MeOH (1.2 mL / 1.2 mL) mixed solvent, and aqueous lithium hydroxide solution (0.66 mL, 2.0 M, 1.32 mmol) was added. The mixture was heated to 50 °C and reacted for 16 hours. After waiting for the reaction to complete, the solvent was spun off and the pH was adjusted to approximately 7 with 1N aqueous hydrochloric acid. After stirring for 15 minutes, the solid was collected by filtration to obtain the product, 6-aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylic acid (83 mg, 55% yield).

[0177] LCMS(ESI)m / z:230.1[M+H] + Intermediate 97 (S)-4-Amino-N,6-dimethyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide [ka] Step 1: Synthesis of N-(4-bromo-2-fluoro-6-methylphenyl)-1H-imidazole-5-carboxamide At room temperature, 4-bromo-2-fluoro-6-methylaniline (15 g, 73.89 mmol) was added to a 500 mL round-bottom flask, and tetrahydrofuran (150 mL) was poured into the flask. Sodium bis(trimethylsilyl)amide (74 mL) was added at 0 °C, and the resulting mixture was stirred at 0 °C for 30 minutes. 5H,10H-diimidazo[1,5-a:1',5'-d]pyrazine-5,10-dione (6.95 g, 36.95 mmol) was then added, and the mixture was allowed to react at room temperature for an additional hour. The reaction mixture was poured into ice water, filtered, and the residue was treated as the product, yielding N-(4-bromo-2-fluoro-6-methylphenyl)-1H-imidazole-5-carboxamide (10 g, yield: 90.9%) as a red solid.

[0178] LCMS(ESI)m / z:298[M+H] + Step 2: Synthesis of 8-bromo-6-methylimidazo[1,5-a]quinoxalin-4-ol N-(4-bromo-2-fluoro-6-methylphenyl)-1H-imidazole-5-carboxamide (10 g, 33.67 mmol) was first added to a 250 mL round-bottom flask at room temperature, followed by N,N-dimethylacetamide (100 mL) and potassium carbonate (13.94 g, 101.01 mmol). The resulting mixture was stirred at 140 °C for 2 hours. The reaction mixture was poured into water to adjust the pH to 3-4, filtered, and the filtrate was used as the product, affording 8-bromo-6-methylimidazo[1,5-a]quinoxalin-4-ol (8 g, 85.74% yield) as a black solid.

[0179] LCMS(ESI)m / z:278[M+H] + Step 3: Synthesis of 8-bromo-4-chloro-6-methylimidazo[1,5-a]quinoxaline At room temperature, 8-bromo-6-methylimidazo[1,5-a]quinoxalin-4-ol (8 g, 28.88 mmol) was first added to a 250 mL round-bottom flask, and then phosphorus oxychloride (100 mL) was poured into the flask. The resulting mixture was stirred at 120° C. for 12 hours. The reaction mixture was concentrated, spin-dried, poured into ice water, and filtered. The residue was used as the product, yielding 8-bromo-4-chloro-6-methylimidazo[1,5-a]quinoxaline (7.5 g, yield: 88.23%) as a black solid.

[0180] LCMS(ESI)m / z:296[M+H] + Step 4: Synthesis of 8-bromo-N-(4-methoxybenzyl)-6-methylimidazo[1,5-a]quinoxalin-4-amine At room temperature, 8-bromo-4-chloro-6-methylimidazo[1,5-a]quinoxaline (7.5 g, 25.42 mmol) was added to a 250 mL round-bottom flask. Then, dimethyl sulfoxide (75 mL) was added to the flask, and (4-methoxyphenyl)methylamine (4.18 g, 30.51 mmol) and N,N-diisopropylethylamine (6.56 g, 50.85 mmol) were added. The resulting mixture was stirred at 90 °C for 2 hours. The reaction mixture was concentrated, spin-dried, poured into ice water, and filtered. The residue was used as the product, yielding 8-bromo-N-(4-methoxybenzyl)-6-methylimidazo[1,5-a]quinoxaline-4-amine (6 g, 60% yield) as a red solid.

[0181] LCMS(ESI)m / z:397[M+H] + Step 5: Synthesis of methyl 4-((4-methoxybenzyl)amino)-6-methylimidazo[1,5-a]quinoxaline-8-carboxylate At room temperature, 8-bromo-N-(4-methoxybenzyl)-6-methylimidazo[1,5-a]quinoxalin-4-amine (6 g, 15.15 mmol) was first added to a 250 mL high-pressure reactor, and then N,N-dimethylformamide (30 mL) and methanol (60 mL) were poured into the reactor. Potassium acetate (2.97 g, 30.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.24 g, 1.52 mmol) were added, carbon monoxide (4 MPa) was charged, and the resulting mixture was stirred and reacted at 100°C for 12 hours. The reaction mixture was concentrated, spin-dried, poured into water, and filtered. The residue was used as the product, methyl 4-((4-methoxybenzyl)amino)-6-methylimidazo[1,5-a]quinoxaline-8-carboxylate (6 g, yield: 60%), as a red solid.

[0182] LCMS(ESI)m / z:377[M+H] + Step 6: Synthesis of 4-((4-methoxybenzyl)amino)-6-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid Methyl 4-((4-methoxybenzyl)amino)-6-methylimidazo[1,5-a]quinoxaline-8-carboxylate (4 g, 10.61 mmol) was first added to a 250 mL round-bottom flask at room temperature. Tetrahydrofuran (40 mL) and methanol (40 mL) were then added to the flask, and potassium hydroxide (1.19 g, 21.22 mmol) was added. The resulting mixture was stirred and reacted at 60 °C for 1 hour. The reaction mixture was concentrated, spin-dried, poured into water, and the pH was adjusted to around 3 with formic acid until solids precipitated. The residue was used as the product, yielding 4-((4-methoxybenzyl)amino)-6-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (2.9 g, 76.31% yield) as a red solid.

[0183] LCMS(ESI)m / z:363[M+H] + Step 7: Synthesis of 4-amino-6-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid At room temperature, 4-((4-methoxybenzyl)amino)-6-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (2.9 g, 7.99 mmol) was first added to a 50 mL round-bottom flask, followed by trifluoroacetic acid (30 mL) and stirring at 100°C for 3 hours. The reaction mixture was concentrated and spin-dried to give 4-amino-6-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (1.5 g, 51.28% yield) as a black solid.

[0184] LCMS(ESI)m / z:243[M+H] + Intermediate 98 Synthesis of 4-amino-1-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxylic acid [ka] Step 1: Synthesis of methyl 3-(2-cyclopropyl-1H-imidazol-1-yl)-4-nitrobenzoate A mixture of methyl 3-(2-bromoimidazolyl)-4-nitrobenzoate (1.00 g, 3.07 mmol), cyclopropylboronic acid (0.26 g, 3.07 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (0.25 g, 0.31 mmol), and potassium carbonate (0.85 g, 6.13 mmol) in dioxane (10 mL) was stirred at 100° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether=10:90) to give methyl 3-(2-cyclopropyl-1H-imidazol-1-yl)-4-nitrobenzoate (0.50 g, yield: 57%).

[0185] LCMS(ESI):288[M+H] + Step 2: Synthesis of methyl 4-amino-3-(2-cyclopropyl-1H-imidazol-1-yl)benzoate A mixture of methyl 3-(2-cyclopropyl-1H-imidazol-1-yl)-4-nitrobenzoate (1.00 g, 3.48 mmol), bis(boronic acid) (0.94 g, 10.44 mmol), and 4,4-bipyridine (0.27 g, 1.74 mmol) in dimethylformamide (10.00 mL) was stirred at room temperature for 2 hours, then concentrated. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered under vacuum. The filtrate was concentrated to give the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 53%) to give methyl 4-amino-3-(2-cyclopropyl-1H-imidazol-1-yl)benzoate (0.60 g, 67% yield).

[0186] LCMS(ESI):257[M+H] + Step 3: Synthesis of methyl 1-cyclopropyl-4-oxo-5,10-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate A mixture of methyl 4-amino-3-(2-cyclopropyl-1H-imidazol-1-yl)benzoate (500 mg, 1.94 mmol) and carbonyldiimidazole (377 mg, 2.33 mmol) in chlorobenzene (5 mL) was stirred at 140 °C for 12 h, concentrated, poured into water (10 mL), extracted with ethyl acetate (10 mL × 2), combined organic layers, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered under suction, and concentrated to give the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 20%) to give methyl 1-cyclopropyl-4-oxo-5,10-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate (500 mg, yield: 91%).

[0187] LCMS(ESI):283[M+H] + Step 4: Synthesis of methyl 4-chloro-1-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxylate A solution of methyl 1-cyclopropyl-4-oxo-5,10-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate (500.00 mg, 1.77 mmol) in phosphorus oxychloride (5.00 mL) was stirred at 120° C. for 12 hours and then concentrated to give methyl 4-chloro-1-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxylate (300 mg, crude product).

[0188] LCMS(ESI):301[M+H] + Step 5: Synthesis of methyl 1-cyclopropyl-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate A solution of methyl 4-chloro-1-cyclopropyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (300 mg, 0.99 mmol), p-methoxybenzylamine (417 mg, 2.98 mmol), and diisopropylethylamine (384 mg, 2.98 mmol) in dimethyl sulfoxide (3 mL, 0.00 mmol) was stirred at 120 °C for 2 h. The reaction mixture was concentrated, poured into water (10 mL), and extracted with ethyl acetate (10 mL × 2). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered under vacuum. The filtrate was concentrated to give the crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 42%) to give methyl 1-cyclopropyl-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (300 mg, yield: 75%).

[0189] LCMS(ESI):402[M+H] + Step 6: Synthesis of 1-cyclopropyl-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid Lithium hydroxide (89.45 mg, 2.24 mmol) was added to a methanol / tetrahydrofuran (5.00 mL / 5 mL) solution of 1-cyclopropyl-4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl mixture (300 mg, 0.75 mmol), and the reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was then concentrated to give 1-cyclopropyl-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (160 mg, yield: 55%).

[0190] LCMS(ESI):388[M+H] + Step 7: Synthesis of 4-amino-1-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxylic acid A mixture of 1-cyclopropyl-4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (200 mg, 0.51 mmol) in trifluoroacetic acid (2.00 mL) was heated at 100° C. for 2 h and concentrated to give 4-amino-1-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxylic acid (100 mg, crude).

[0191] LCMS(ESI):268[M+H] + Example 1 Synthesis of 4-amino-N-(2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide [ka] 4-Aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (50 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (2.50 mL), and 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (125 mg, 0.32 mmol), N,N-diisopropylethylamine (85 mg, 0.65 mmol), and N-methyl-2,3-dihydrobenzofuran-3-amine (33 mg, 0.21 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated, and the crude product was purified by high-performance liquid chromatography (HPLC) (column: XBridge BEH Shield RP18 5 m, 30 mm × 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20% B to 36% B over 8 min; wavelength: 254 nm / 220 nm); 4-amino-N-(2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (2 mg, 0.01 mmol, 3% yield) was obtained as a white solid.

[0192] 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.48-7.41 (m, 5H), 7.30-7.26 (m, 1H), 7.00-6.99 (m, 1H), 6.91-6.89 (M, 1H), 6.35-5.76 (m, 1H), 4.79-4.56 (m, 2H), 2.68 (s, 3H). LCMS(ESI):360.30[M+H] + The examples in the following table can be prepared using the synthetic procedures described in Example 1, substituting only the corresponding starting aldehyde or amine. [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] Example 58 (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)tetrazolo[1,5-a]quinoxaline-8-carboxamide [ka] Step 1: Synthesis of (S)-N-((dimethylamino)((8-(methyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamoyl)tetrazolo[1,5-a]quinoxalin-4-yl)amino)methylidene)-N-methylmethylamine 4-Aminotetrazolo[1,5-a]quinoxaline-8-carboxylic acid (131 mg, 0.56 mmol) was dissolved in N,N-dimethylformamide (4.5 mL) and reacted with 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (325 mg, 0.85 mmol), N,N-diisopropylethylamine (220 mg, 1.71 mmol), and (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (144 mg, 0.660 mmol) at room temperature for 30 min. The mixture was diluted with ethyl acetate (30 mL) and water (30 mL), and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give (S)—N-((dimethylamino)((8-(methyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamoyl)tetrazolo[1,5-a]quinoxalin-4-yl)amino)methylidene)-N-methylmethylamine (100 mg, 0.19 mmol, 33.33% yield) as a white solid.

[0193] LCMS(ESI):528[M+H] + Step 2: Synthesis of (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)tetrazolo[1,5-a]quinoxaline-8-carboxamide (S)—N-((dimethylamino)((8-(methyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamoyl)tetrazolo[1,5-a]quinoxalin-4-yl)amino)methylidene)-N-methylmethylamine (100 mg, 0.19 mmol) was dissolved in tetrahydrofuran (4 mL), and an equal volume of water (4 mL) was added. Lithium hydroxide (27 mg, 1.12 mmol) was then added. The reaction mixture was concentrated, and the crude product was purified by high-performance liquid chromatography (chromatography column: YMC Triart C18 ExRs 5 m, 30 mm * 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 25% B to 50% B in 10 min; wavelength: UV 254 nm / 220 nm; retention time (min): 8.43 / 9.23) to obtain the product (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)tetrazolo[1,5-a]quinoxaline-8-carboxamide (3.58 mg, 0.01 mmol, yield 4.41%) as a white solid.

[0194] 1 H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.01-7.95 (d, 2H), 7.74-7.71 (d, 2H), 7.41-7.39 (d, 1H), 7.33(s,1H), 6.50-5.74(m,1H), 4.91-4.73(m,2H), 3.94(s,3H). LCMS(ESI)m / z:430.10[M+H] + Example 59 Synthesis of 4-amino-N-cyclopropyl-N-(7-(5-(trifluoromethyl)pyridin-3-yl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide [ka] N-Cyclopropyl-7-(5-(trifluoromethyl)pyridin-3-yl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine (45 mg, 0.13 mmol) was dissolved in DMF (3.0 mL), and then 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (33 mg, 0.13 mmol), PyBrop (79 mg, 0.17 mmol), and DIPEA (50.3 mg, 0.39 mmol) were added to the reaction solution. The mixture was stirred at room temperature overnight, and water (10 mL) was added. ethyl acetate (2 mL) was added. The organic phase was washed with water (10 mL × 2), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was purified by column chromatography (methanol / dichloromethane 0-7%) to give the compound 4-amino-N-cyclopropyl-N-(7-(5-(trifluoromethyl)pyridin-3-yl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (18.0 mg, yield: 25%).

[0195] 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 9.18 (s, 1H), 9.02 (s, 1H), 8.63 (d, J = 29.1 Hz, 2H),8.24 (s, 1H), 7.93 (s, 1H), 7.77 (s, 1H), 7.56 (s, 2H), 7.22 (d, J = 11.4 Hz, 1H), 5.39 (s, 1H), 4.46 (d, J= 53.9 Hz, 2H), 3.05 (s, 1H), 2.35 (s, 2H), 0.70 (s, 4H). LCMS(ESI)m / z:564.30[M+H]+ The examples in the following table can be prepared using the synthetic procedure described in Example 59, substituting only the corresponding starting aldehyde or amine. [Table 30] [Table 31] [Table 32] Example 75 Synthesis of (S)-4-amino-N-(methyl-d3)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-2-carboxamide [ka] (S)-N-(methyl-d3)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (0.10 g, 0.45 mmol), 4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylic acid (0.10 g, 0.45 mmol), N,N,N',N'-tetramethylformamidinium chlorohexafluorophosphate (0.19 g, 0.68 mmol), and N-methylimidazole (0.11 g, 1.36 mmol) were stirred in N,N-dimethylformamide (1 mL) for 1 hour. After the reaction was complete, the mixture was cooled to room temperature and extracted three times with 10 mL of ethyl acetate. The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (chromatography column: YMC Triart C18 ExRs 5 m, 30 mm x 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 25% B to 55% B in 8 min; wavelength: 254 nm / 220 nm; retention time (min): 7.22) to give (S)-4-amino-N-(methyl-d3)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide (11.94 mg, yield 6.09%).

[0196] 1H NMR (400 MHz, DMSO-d6) δ 9.31-9.30 (m, 1H), 8.70-8.65 (m, 1H),8.56-8.51 (m, 1H), 7.99 (d, J = 4.0 Hz, 1H), 7.79 - 7.56 (m, 3H),7.36- 7.34 (m, 1H), 7.27-7.25 (m, 1H), 6.44-6.02 (m, 1H), 4.89-4.71 (m, 2H). LCMS(ESI):431.85[M+H] + Using the same method and steps as in Example 75, simply substituting the corresponding starting materials, the following compounds were prepared: [Table 33] Example 77 Synthesis of 4-amino-N-(4S)-6-fluoro-1-methylisochroman-4-yl)-N-methylimidazo[1,5-a]quinoline-8-carboxamide [ka] At room temperature, (4S)-6-fluoro-N,1-dimethylisochromen-4-amine hydrochloride (100 mg, 0.5122 mmol) was dissolved in N,N-dimethylacetamide (4 mL), and 4-amino-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (140 mg, 0.6146 mmol), T3P (489 mg, 0.7683 mmol), and N,N-diisopropylethylamine (338 mg, 3.561 mmol) were added, followed by stirring at 25°C for 2 hours. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the product 4-amino-N-(4S)-6-fluoro-1-methylisochroman-4-yl)-N-methylimidazo[1,5-a]quinoline-8-carboxamide (70 mg, yield: 33.7%).

[0197] 1 H NMR (400 MHz, DMSO-d6) δ 9.27 - 9.11 (m, 1H), 8.38 (d, J = 17.2 Hz, 1H), 7.92 (s, 1H), 7.60 - 6.98 (m, 7H), 5.62 (s, 1H), 4.94 - 4.67 (m, 1H), 4.38 - 3.79 (m, 2H), 2.87 - 2.66 (m, 3H), 1.49 (dd, J = 13.0, 6.2 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -115.37, -115.39. LCMS(ESI)m / z:406[M+H]+ Example 78 (S)-4-Amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide-1-d Example 111 (S)-4-Amino-1-bromo-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide [ka] Step 1: 4-Aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (500 mg, 2.19 mmol) was dissolved in tetrahydrofuran (15 mL). The reaction mixture was cooled to -40 °C, and n-butyllithium (5 mL, 15.34 mmol) was added over 10 min. Bromine (2.5 mL, 21.91 mmol) was then added. The mixture was stirred at -40 °C for 10 min, then transferred to room temperature and stirred for an additional 10 min. After completion of the reaction, the reaction mixture was concentrated in vacuo, dichloromethane was added, and the mixture was filtered to obtain a solid. This solid was purified by silica gel column chromatography (formic acid:acetonitrile = 1:1) to obtain 4-amino-1-bromoimidazo[1,5-a]quinoxaline-8-carboxylic acid (30 mg, yield: 4.46%) as a white solid.

[0198] LCMS(ESI)m / z:307[M+H] + Step 2: 4-Amino-1-bromoimidazo[1,5-a]quinoxaline-8-carboxylic acid (10 mg, 0.03 mmol), 2-(7-azobenzotriazolyl)-tetramethyluronium hexafluorophosphate (19 mg, 0.05 mmol) and N,N-diisopropylethylamine (8 mg, 0.05 mmol) were dissolved in dimethylacetamide (1 ml), (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (7 mg, 0.03 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and the combined organic phases were concentrated in vacuo to obtain Example 111 (S)-4-amino-1-bromo-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (30 mg, 0.03 mmol, yield 80%) as a yellow liquid.

[0199] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.98 (s, 1H), 7.65 - 7.55 (m, 2H), 7.52 (d, J = 7.9 Hz, 3H), 7.32 (d, J = 7.7 Hz, 1H), 7.25 (s, 1H), 6.42(s,1H),4.79 - 4.72 (m, 2H), 2.75 - 2.62 (m, 3H). LCMS(ESI)m / z:506[M+H] + Step 3: (S)-4-Amino-1-bromo-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (20 mg, 0.16 mmol), zinc powder (26 mg, 1.58 mmol), and deuterated formic acid (19 mg, 1.58 mmol) were dissolved in deuterated methanol (1 mL) and deuterium oxide (1 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (column: Kinetex 5 m EVO C18, 30 mm × 150 mm; mobile phase A: water (10 mmol ammonium bicarbonate per liter), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20% B to 47% B in 10 min; wavelength: 254 / 220 nm; retention time (min): 9.35) to obtain (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide-1-d (3.34 mg, 0.16 mmol, 8.45% yield) as a white solid.

[0200] 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H),7.92 (d, J = 7.3 Hz, 1H), 7.64-7.62 (d, J = 7.6 Hz, 1H), 7.49 (s, 4H), 7.33-7.32 (m, 1H), 7.26 (s, 1H),6.48(m,1H),4.73-4.72(m,2H), 2.68 (s, 3H). LCMS(ESI)m / z:428[M+H] + The examples in the following table can be prepared using the synthetic procedures described in Example 78, substituting only the corresponding starting aldehyde or amine.

[0201] [Table 34] Example 109 Synthesis of 4-amino-N-cyclopropyl-N-(4-(trifluoromethoxy)benzyl)imidazo[1,5-a]quinoxaline-8-carboxamide [ka] 4-Amino-3-bromo-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (30 mg, 0.06 mmol), potassium acetate (17 mg, 0.18 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (4 mg, 0.01 mmol) were added to a mixture of N,N-dimethylformamide (5 mL) and ethanol (5 mL). The mixture was stirred overnight at 110 °C in an autoclave filled with carbon monoxide (4 mPa). After completion of the reaction, the mixture was diluted with ethyl acetate (10 mL) and water (5 mL), and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by high-pressure preparative chromatography (Column: Sunfire C18 5 m, 30 mm × 150 mm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 64% B in 10 min; Wavelength: 254 nm / 220 nm; RT1 (min): 5.97) to give ethyl 4-amino-8-(methyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamoyl)imidazo[1,5-a]quinoxaline-3-carboxylate (4.22 mg, 14%).

[0202] 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 9.30-8.61 (m, 1H), 8.46(s,1H), 8.10-7.92(m,1H), 7.70-7.64 (m, 1H), 7.61 - 7.50 (m, 2H), 7.34-7.30 (m, 1H), 7.26 (s, 1H),6.38-5.76(m,1H), 4.84-4.70 (m, 2H), 4.32-4.37 (m, 2H), 2.68-2.66 (m, 3H), 1.37 (t, J = 7.1 Hz, 3H). LCMS(ESI):500.10[M+H] + Example 80: Synthesis of (S)-4-amino-7-fluoro-N-(6-methoxy-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide [ka] Step 1: Synthesis of (S)-6-bromo-N-methyl-2,3-dihydrobenzofuran-3-amine tert-Butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (200 mg, 0.6 mmol) was dissolved in 1,4-dioxane (4 M, 2 mL) of hydrochloric acid and stirred at room temperature. After completion of the reaction, the reaction solution was concentrated to give crude product (S)-6-bromo-N-methyl-2,3-dihydrobenzofuran-3-amine (85 mg, 61% yield).

[0203] LCMS(ESI)m / z:228[M+H] + Step 2: Synthesis of (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 4-Amino-7-fluoroimidazo[1,5-a]quinoxaline-8-oic acid (92 mg, 0.37 mmol) was dissolved in dimethylacetamide (2 mL), and 1-propylphosphoric anhydride (172 mg, 0.74 mmol), N,N-diisopropylethylamine (144 mg, 1.12 mmol), and (S)-6-bromo-N-methyl-2,3-dihydrobenzofuran-3-amine (85 mg, 0.37 mmol) were added and stirred at room temperature overnight. After completion of the reaction, the mixture was extracted three times with 10 mL of ethyl acetate (30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography (dichloromethane:methanol=10%) gave (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (35 mg, yield 20%).

[0204] LCMS(ESI)m / z:456[M+H] + Step 3: Synthesis of (S)-4-amino-7-fluoro-N-(6-methoxy-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (S)-4-Amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (35 mg, 0.08 mmol) was dissolved in dioxane (1 mL) and treated with [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate. The resulting mixture was stirred at room temperature for 10 hours under nitrogen protection with 2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (65 mg, 0.07 mmol), and methanol (86 mg, 2.68 mmol). After completion of the reaction, the mixture was extracted three times with 10 mL of ethyl acetate (30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. High-pressure preparation (column: XBridge BEH Shield RP185 m, 30 mm × 150 mm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient from 28% B to 50% B in 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.88) gave (S)-4-amino-7-fluoro-N-(6-methoxy-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (14.25 mg, 44.60% yield).

[0205] 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H),8.46-8.29 (m, 1H), 7.92 (d, J = 3.6 Hz, 1H), 7.59 (s, 2H), 7.28 - 7.20 (m, 2H), 6.58 - 6.31 (m, 2H),, 5.42- 4.79 (m, 1H), 4.74 - 4.53 (m, 2H), 3.74 (d, J = 10.0 Hz, 3H), 2.70 -2.58(m, 3H). LCMS(ESI)m / z:408.10[M+H] + Example 12 Synthesis of methyl 2(S)-3-(4-amino-N-methylimidazo[1,5-a]quinoxaline-8-carboxamido)-2,3-dihydrobenzofuran-6-carboxylate [ka] Step 1: Synthesis of methyl (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-carboxylate At room temperature, tert-butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (100 mg, 0.31 mmol) was dissolved in methanol (5.00 mL) and N,N-dimethylformamide (10.00 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (56 mg, 0.07 mmol) and potassium acetate (68 mg, 0.69 mmol) were added, and the mixture was stirred overnight at 100 °C with carbon monoxide (4 MPa). After completion of the reaction, the reaction mixture was concentrated, poured into water, filtered, and the filter cake was pulped with petroleum ether to give methyl (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-carboxylate (70 mg, yield: 77.78%) as a red solid. LCMS (ESI): 308 [M+H] + Step 2: Synthesis of methyl (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-carboxylate (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-methyl carboxylate (70 mg, 0.23 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (2 mL, 4 M), and the mixture was reacted at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated to give (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-methyl carboxylate (46 mg, yield: 97%) as a black solid.

[0206] LCMS(ESI):208[M+H] + Step 3: Synthesis of methyl (S)-3-(4-amino-N-methylimidazo[1,5-a]quinoxaline-8-carboxamido)-2,3-dihydrobenzofuran-6-carboxylate 4-Aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (50 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (4.00 mL). 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (128 mg, 0.34 mmol), N,N-diisopropylethylamine (87 mg, 0.67 mmol), and (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-methyl carboxylate (46 mg, 0.22 mmol) were added. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The aqueous layer was extracted with ethyl acetate (2 x 10 mL). The organic layers were combined, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by high-performance liquid chromatography (Sunfire C18 5 m column, 30 mm × 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 30% B in 8 min; wavelength: 254 nm / 221 nm) to give (S)-methyl 3-(4-amino-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide)-2,3-dihydrobenzofuran-6-carboxylate (21 mg, yield: 1%) as a white solid.

[0207] 1 H NMR (400 MHz, DMSO-d6) δ9.21 (s, 1H) , 8.35 (s, 1H), 8.13(s,1H), 8.01-7.92 (s, 1H), 7.62-7.60(m,1H), 7.56-7.54 (m,1H), 7.50-7.49 (m, 2H), 7.40-7.36 (m, 1H), 6.39-5.66 (s, 1H), 4.87-4.68 (m, 2H), 3.85-3.84 (m, 3H),2.67-2.64(m,3H), 0.98-0.79 (m,3H) LCMS(ESI):418.20[M+H] + Example 112 Synthesis of (S)-4-amino-N-(6-(difluoromethyl)-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide [ka] Step 1: Synthesis of (S)-6-bromo-N-methyl-2,3-dihydrobenzofuran-3-amine tert-Butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (100 mg, 0.30 mmol) was dissolved in a 1,4-dioxane solution of hydrogen chloride (4.0 M, 10 mL). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo to give (S)-6-bromo-N-methyl-2,3-dihydrobenzofuran-3-amine (80 mg, 0.30 mmol, 95.46% yield) as a yellow liquid. LCMS (ESI): 228 [M+H] + Step 2: Synthesis of (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 4-Aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (80 mg, 0.35 mmol), 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (200 mg, 0.53 mmol), and N,N-diisopropylethylamine (136 mg, 1.05 mmol) were dissolved in dimethylacetamide (3 mL), followed by the addition of (S)-6-bromo-N-methyl-2,3-dihydrobenzofuran-3-amine (80 mg, 0.35 mmol). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with three 10 mL portions of ethyl acetate. The organic phases were combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and the reaction mixture was spin-dried. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 80:20) to give (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (70 mg, 0.35 mmol, 45.54% yield).

[0208] LCMS(ESI):438[M+H] + Step 3: Synthesis of (S)-4-amino-N-(6-(difluoromethyl)-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide N-((3S)-6-Bromo(2,3-dihydrobenzo[b]furan-3-yl))(4-amino(10-hydroimidazo[1,5-a]quinoxalin-8-yl))-N-methylcarboxamide (30 mg, 0.07 mmol) was dissolved in tetrahydrofuran (2 mL). To this solution, [Ir(dF(CF3)ppy)2(dpy)]PF6 (8 mg, 0.007 mmol), nickel bromide ethylene glycol dimethyl ether complex (1 mg, 0.003 mmol), PPh3(CF2H)2 (17 mg, 0.14 mmol), and diphenyl o-phenanthroline (2 mg, 0.007 mmol) were added in this order. The mixture was reacted at room temperature overnight at 465 nm. After completion of the reaction, the mixture was extracted with three 10 mL portions of ethyl acetate. The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (Kinetex 5 m EVO C18, 30 mm x 150 mm column; mobile phase A: water (10 mmol ammonium bicarbonate per liter), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20% B to 47% B over 10 min; wavelength: 254 / 220 nm; retention time (min): 9.35). (S)-4-amino-N-(6-(difluoromethyl)-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (0.84 mg, 0.07 mmol, 2.96% yield) was obtained as a white solid.

[0209] 1 H NMR (400 MHz, Methanol-d4) δ 9.11 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.57-7.54 (m, 3H), 7.17-7.16 (s, 1H), 7.03 (s, 1H), 4.73-4.62 (s, 2H),4.60-4.52(m,1H), 2.78 (s, 3H). LCMS(ESI):409[M+H] + Example 115 Synthesis of (R)-4-amino-7-fluoro-N-methyl-N-(7-(1-methylpyrazol-5-yl)benzopyran-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide [ka] The compound 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (200 mg, 0.813 mmol) was dissolved in DMAc (3 mL) at room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (187 mg, 0.976 mmol) and 1-hydroxybenzotriazole (133 mg, 0.976 mmol), followed by DIEA (421 mg, 3.264 mmol) were added, and the reaction mixture was stirred at room temperature for 0.5 hours. Next, (R)-N-methyl-7-(1-methylpyrazol-5-yl)benzopyran-4-amine (1.0 g, 4.184 mmol) was added, and the mixture was allowed to react at room temperature for 16 hours. After confirming the completion of the reaction by LCMS, the mixture was poured into water (30 mL) and extracted with ethyl acetate (10 × 3 mL). The organic phase was washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. This was separated and purified by column chromatography (0-5% methanol / dichloromethane) to obtain (R)-4-amino-7-fluoro-N-methyl-N-(7-(1-methylpyrazol-5-yl)benzopyran-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (45.0 mg, yield: 11.75%).

[0210] 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 22.9 Hz, 1H), 8.42 (d, J = 6.6 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 12.8 Hz, 2H), 7.46 (dd, J = 6.2, 1.9 Hz, 1H), 7.27 (td, J = 11.3, 7.6 Hz, 2H), 7.14 (dd, J = 7.9, 1.8 Hz, 1H), 6.98 (dd, J = 27.5, 1.8 Hz, 1H), 6.41 (dd, J = 9.7, 1.9Hz, 1H), 6.10 -5.04 (m, 1H), 4.49 -4.05 (m, 2H), 3.86 (d, J = 15.6 Hz, 3H), 2.82 -2.62 (m, 3H), 2.32 (dd, J = 17.9, 7.3 Hz, 1H), 2.13 (dd, J = 7.1, 3.6 Hz, 1H). LCMS(ESI)m / z:472.1[M+H] + The examples in the following table can be prepared using the synthetic procedures described in Example 115, substituting only the corresponding starting aldehyde or amine. [Table 35] [Table 36] Example 128 Synthesis of (S)-4-amino-3-(hydroxymethyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide [ka] Step 1: (S)-4-Amino-3-bromo-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (60 mg, 0.12 mmol) was dissolved in dimethylformamide (2 mL) with methanol (2 mL). The mixture was then placed in an autoclave with dichloro[1,1'-bis(diphenylphosphino)ferrocene], palladium (3 mL, 0.004 mmol), and potassium acetate (23 mg, 0.24 mmol). The mixture was stirred at 100 °C under a carbon monoxide atmosphere of 4 MPa for 16 hours. After completion of the reaction, the reaction mixture was poured into water and extracted three times with 10 mL of ethyl acetate. The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (alkaline water:acetonitrile = 1:1) to give methyl (S)-4-amino-8-(methyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamoyl)imidazo[1,5-a]quinoxaline-3-carboxylate (40 mg, yield: 69.53%) as a brown solid.

[0211] LCMS(ESI):485.42[M+H] + Step 2: (S)-4-amino-8-(methyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamoyl)imidazo[1,5-a]quinoxaline-3-carboxylate (30 mg, 0.06 mmol) was dissolved in methanol (2 mL) and sodium borohydride (5 mg, 0.12 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and the combined organic phases were concentrated in vacuo. Purification by high-performance liquid chromatography (column: Kinetex 5 m EVO C18, 30 mm × 150 mm; mobile phase A: water (10 mmol ammonium bicarbonate per liter), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20% B to 47% B in 10 min; wavelength: 254 / 220 nm; retention time (min): 9.35) afforded (S)-4-amino-3-(hydroxymethyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (3.17 mg, 11.13% yield) as a white solid.

[0212] 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.31 (s, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.59 (s, 2H), 7.47 (d, J = 5.5 Hz, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.27 - 7.23 (m, 1H), 6.36 (t, J = 5.2 Hz, 1H), 4.85 (d, J = 5.1 Hz, 3H), 4.73 (d, J = 4.6 Hz, 1H), 3.31 (s, 1H),2.67(S,3H). LCMS(ESI):457.41[M+H] + Example 132 Synthesis of 8-{N-[(3S)-6-(trifluoromethyl)(2,3-dihydrobenzo[b]furan-3-yl)]-N-methylcarbamoyl}-4-amino-10-hydroimidazo[1,5-a]quinoxaline-3-carboxamide [ka] A solution of methyl 8-{N-[(3S)-6-(trifluoromethyl)(2,3-dihydrobenzo[b]furan-3-yl)]-N-methylcarbamoyl}-4-amino-10-hydroimidazo[1,5-a]quinoxaline-3-carboxylate (30 mg, 0.06 mmol) in methanol (0.50 mL) / tetrahydrofuran (0.50 mL) / ammonia (0.5 mL) was stirred at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into water (5 mL), extracted with ethyl acetate, and spin-dried to obtain a crude product. This crude product was purified by high-pressure preparative chromatography (column: C18 silica gel; mobile phase: water in acetonitrile, gradient: 10% to 50% in 10 min; detector: UV 254 nm) to obtain 8-{N-[(3S)-6-(trifluoromethyl)(2,3-dihydrobenzo[b]furan-3-yl)]-N-methylcarbamoyl}-4-amino-10-hydroimidazo[1,5-a]quinoxaline-3-carboxamide (1.06 mg, 4%) as a white solid.

[0213] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.32 (s, 1H), 8.42 (s, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 11.1 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.27 (s, 1H), 6.43 (s, 1H), 4.73 (s, 2H), 2.76 - 2.63 (m, 3H). LCMS(ESI):470.80[M+H]+ Example 131 Synthesis of (S)-4-amino-3-(hydroxymethyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide [ka] To a stirred solution of 8-{N-[(3S)-6-(trifluoromethyl)(2,3-dihydrobenzo[b]furan-3-yl)]-N-methylcarbamoyl}-4-amino-10-hydroimidazo[1,5-a]quinoxaline-3-carboxamide (30.00 mg, 0.06 mmol) in dichloromethane (2.00 mL), pyridine (10.09 mg, 0.13 mmol) and trifluoroacetic anhydride (26.79 mg, 0.26 mmol) were added and reacted at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into water (5 mL), and the crude product was spin-dried over ethyl acetate. The crude product was purified by high-pressure preparative chromatography (column: C18 silica; mobile phase: water in acetonitrile; gradient: 10% to 50% over 10 min; detector, UV 254 nm) to give N-[(3S)-6-(trifluoromethyl)(2,3-dihydrobenzo[b]furan-3-yl)](4-amino-3-cyano(10-hydroimidazo[1,5-a]quinoxalin-8-yl))-N-methylformamide (1.61 mg, 5%) as a white solid.

[0214] 1 H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.48 (s, 1H), 7.64 (d, J = 8.7 Hz, 3H), 7.33 (s, 1H), 7.26 (s, 1H), 7.12 (s, 2H),6.40(s,1H), 4.72 (d, J = 10.5 Hz, 1H),4.71(s,1H), 2.67 (d, J = 2.8 Hz, 3H). LCMS(ESI):452.80[M+H] + Examples 81 & 82: Synthesis of Example 81 (R)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide and Example 82 (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide [ka] The compound 4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide (90 mg) was purified by SFC (column: DAICEL CHIRALCEL Purification using an OJ (250 mm × 30 mm, 10 μm) under the conditions of CO₂-i-PrOH (0.1% NH₃-HO), 50% / 50%, flow rate: 80 mL / min gave (R)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide (34.61 mg) and 82(S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide (28.15 mg).

[0215] Example 81 (R)-4-Amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide LCMS(ESI)m / z:465.3[M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.37 (d, J = 1.8 Hz, 1H), 7.91 (s, 1H), 7.59 (dd, J = 8.4, 1.8 Hz, 1H), 7.55 - 7.39 (m, 4H), 7.18 - 7.09 (m, 2H), 5.86 (dd, J = 9.3, 4.1 Hz, 1H), 4.81 (t, J = 9.7 Hz, 1H), 4.65 (dd, J = 10.2, 4.2Hz, 1H), 2.90 (p, J = 3.2 Hz, 1H), 0.45 - 0.26 (m, 2H), 0.24 - 0.03 (m, 2H). Example 82 ( S)-4-Amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide LCMS(ESI)m / z:465.3[M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J = 3.6 Hz, 1H), 8.40 (d, J = 3.5 Hz, 1H), 8.03 (s, 1H), 7.85 (s, 2H), 7.62 (dd, J = 8.4, 3.3 Hz, 1H), 7.47 (dd, J = 8.2, 3.3 Hz, 2H), 7.13 (dd, J = 8.7, 3.3 Hz, 2H), 5.86(dt, J = 8.6, 4.0 Hz, 1H), 4.80 (td, J = 9.7, 3.6 Hz, 1H), 4.65 (dt, J = 9.2, 4.1 Hz, 1H), 2.90 (d, J = 6.7 Hz,1H), 0.44 - 0.26 (m, 2H), 0.13 (ddd, J = 45.3, 10.6, 4.8 Hz, 2H). Using the procedures described in Examples 81 and 82 and the corresponding chiral SFC resolution conditions, the compounds in the following table were obtained: [Table 37] [Table 38] [Table 39] [Table 40] [Table 41] [Table 42] Biochemical evaluation 1. Compound inhibitory activity assay against tumor cell proliferation Experimental Example 1: Inhibitory activity assay of compounds against proliferation of HCT-116 MTAP(- / -)-deficient cells Materials and cells: HCT-116 MTAP(- / -)-deficient cells were purchased from Kang Yuan Bochuang Co., Ltd. (China); RPMI-1640 medium, fetal bovine serum, and penicillin-streptomycin were purchased from Thermo Fisher Scientific (USA); 384-well plates were purchased from PerkinElmer (USA); and Cell-Titer Glo kit was purchased from Promega Scientific (USA).

[0216] Cell culture: HCT116 MTAP(- / -)-deficient cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C and 5% CO2. Cells in the logarithmic growth phase should only be used for experiments.

[0217] Cell proliferation inhibitory activity assay: The growth inhibitory activity of compounds against HCT-116 MTAP(- / -)-deficient cells was detected using the Cell-Titer Glo kit. The cell concentration was adjusted, and 40 μL / well was seeded into a 384-well plate and cultured overnight at 37°C and 5% CO2. 40 nL of compound was added to each well to achieve final concentrations of 0-10,000 nM (starting concentration 10,000 nM, 3-fold dilutions, 10 spots). DMSO content was 0.1%. The cell plate was incubated at 37°C and 5% CO2 for 8 days. Cell activity was measured by adding 40 μL of Cell-Titer Glo reagent. The assay results are shown in Table 1.

[0218] Experimental Example 2: Inhibitory activity assay of compounds against proliferation of HCT-116 wild-type cells Materials and cells: HCT-116 MTAP(- / -) wild-type cells were purchased from Kang Yuan Bochuang Co., Ltd. (China); RPMI-1640 medium, fetal bovine serum, and penicillin-streptomycin were purchased from Thermo Fisher Scientific (USA); 384-well plates were purchased from PerkinElmer (USA); and Cell-Titer Glo kit was purchased from Promega Scientific (USA).

[0219] Cell culture: HCT116 wild-type cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C and 5% CO. Cells in logarithmic growth phase should only be used for experiments.

[0220] Cell proliferation activity assay: The growth inhibitory activity of compounds against HCT-116 wild-type cells was detected using the Cell-Titer Glo kit. The cell concentration was adjusted, and 40 μL / well was seeded into a 384-well plate and cultured overnight at 37°C and 5% CO2. 40 nL of compound was added to each well to achieve final concentrations of 0-10,000 nM (starting concentration 10,000 nM, 2-fold dilution, 10 spots). DMSO content was 0.1%. The cell plate was incubated at 37°C and 5% CO2 for 8 days. Cell activity was measured by adding 40 μL of Cell-Titer Glo reagent. The assay results are shown in Table 1.

[0221] Table 1 below shows the inhibitory activity of the compounds of the examples on the proliferation of HCT116 MTAP(- / -)-deficient cells as well as HCT116 wild-type cells.

[0222] Table 1 [Table 43] [Table 44] [Table 45] [Table 46] 2. Pharmacokinetics Experiments in Mice Test substance The test substance is derived from a specific example compound of the present invention, and the reference compound AMG473 is the compound of embodiment 473 of Amgen's patent WO2022 / 169948A1.

[0223] experimental animals ICR male mice, N=3 / group; Origin: Zhejiang Vital River Laboratory Animal Technologies Co. Ltd. Medication preparation and administration Single oral (PO) administration to ICR mice: Each compound was weighed and dissolved in dimethyl sulfoxide, and a certain amount of polyethylene glycol 400 and water for injection were added. A small amount of 1 mol / L hydrochloric acid solution was added to make a clear solution. Three mice were fasted overnight and then orally administered 10 mg / kg.

[0224] ICR mice were administered a single intravenous (IV) dose: each compound was weighed, dissolved in dimethyl sulfoxide, and a certain amount of polyethylene glycol 400 and water for injection were added, followed by a small amount of 1 mol / L hydrochloric acid solution to prepare a clear solution; after an overnight fast, three mice were injected with 3 mg / kg of IV via their tail vein.

[0225] Sample collection Blood samples were collected from the dorsalis pedis vein at approximately 30 μL per time point, anticoagulated with dipotassium ethylenediaminetetraacetate, placed on ice, and centrifuged within 1 hour to separate plasma (4000 g / min, 5 minutes, 4°C). Blood samples were collected at 0.0833 (intravenous injection), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Samples were stored in a -20°C refrigerator.

[0226] For plasma samples, 30 μL (10 μL sample + 20 μL blank plasma sample) was mixed with 200 μL of ice-cold acetonitrile containing an internal standard, vortexed for 30 seconds, and centrifuged at 4000 g / min for 20 minutes. 100 μL of the supernatant was transferred to a 96-well plate, 200 μL of ultrapure water was added, and the mixture was vortexed for 30 seconds. 5 μL or 10 μL was then injected into an LC-MS / MS for analysis.

[0227] Table 2: Pharmacokinetic data [Table 47] "NA": Not applicable.

[0228] Comparison of pharmacokinetic parameters shows that all examples of the present invention have higher plasma exposure compared to AMG473 at the same dose and administration method, reducing the starting dose of the compound and widening the safety window.

[0229] 3. hERG ion channel inhibition assay Test substance The test substance is derived from a specific example compound of the present invention, and the reference compound AMG473 is the compound of embodiment 473 of Amgen's patent WO2022 / 169948A1.

[0230] Cell lines and cell culture The HEK293 cell line (K1236) stably expressing the hERG ion channel was purchased from Invitrogen. The cell line was cultured in a medium containing 85% DMEM, 10% dialyzed fetal bovine serum, 0.1 mM non-essential amino acid solution, 100 U / mL penicillin-streptomycin solution, 25 mM HEPES, 5 μg / mL blasticidin, and 400 μg / mL Geneticin. When the cell density reached 40-80% of the bottom area of ​​the culture dish, the cells were digested with trypsin and passaged three times a week. Prior to the experiment, the cells were plated at 5 × 10 in a 3.5 cm culture dish. 5 The cells were cultured at a density of 1 μg / mL and induced with 1 μg / mL doxycycline for 48 hours, after which the cells were digested, plated onto slides, and subjected to subsequent manual patch clamp experiments.

[0231] Experimental procedure 1) A small slide containing HEK293 cells in a culture dish was placed in the perfusion chamber on the microscope stage. 2) An appropriate cell tuner was placed in the center of the field of view of an Olympus IX71 or IX73 inverted microscope. Using a 10x objective, the tip of the glass electrode was located and centered. Next, the electrode was moved downward using a micromanipulator while coarsely adjusting the focus so that the electrode slowly approached the cell. 3) Once close to the cell, the objective was switched to 40x and the fine adjustment gear of the micromanipulator was used to gradually move the electrode closer to the cell surface. 4) Negative pressure was applied to form a seal between the electrode tip and the cell membrane with a resistance of 1 GΩ or greater. 5) The instantaneous capacitive current Cfast was compensated for in voltage-clamp mode. Then, repeated short bursts of negative pressure were applied to rupture the membrane, obtaining a whole-cell recording pattern. 6) The membrane potential was clamped at -60 mV to compensate for the slow capacitive current Cslow, cell membrane capacitance (Cm), and input membrane resistance (Ra). 7) After the cells stabilized, the clamp voltage was changed to -90 mV, the sampling frequency was set to 20 kHz, and the filter frequency was set to 10 kHz. Leak currents were detected at a clamp voltage of -80 mV over a 500 ms time window. 8) hERG currents were measured by depolarizing the membrane potential from -80 mV to +30 mV with a depolarizing command voltage for 4.8 s, followed by a repolarizing voltage drop to -50 mV for 5.2 s, deactivating the channel and allowing observation of the hERG tail current. The peak of the tail current represents the magnitude of the hERG current. 9) The hERG current used for test substance detection was continuously recorded for 120 s before administration to assess the stability of the hERG current generated by the test cells. Only stable cells meeting the acceptable criteria were allowed to proceed to subsequent compound assays. 10) Test for hERG current inhibition by test substances: hERG currents measured in an extracellular solution containing 0.1% DMSO were used as the baseline for the assay. After the hERG current had stabilized for at least 5 minutes, solutions containing test substances were perfused around the cells in succession, from low to high concentrations. After each perfusion, we waited approximately 5 minutes for the compounds to reach the cells, and simultaneously recorded the hERG current. After the recorded current had stabilized, the last five hERG current values ​​were recorded and averaged to obtain the final current value at a particular concentration.After compound testing, 450 nM dofetilide was added to the same cells to completely inhibit the current and serve as a positive control for the cells. The positive compound, dofetilide, was also assayed simultaneously with the same membrane clamp system before and after the completion of the test drug experiment to confirm the reliability and sensitivity of the entire assay system. The above test procedure was repeated on two separate test cells (n=2).

[0232] Data analysis Only data that meet the above conditions can be analyzed as follows: Note: Data are exported by PatchMaster software. 1) After perfusion of blank solvent or compound gradient solution, five consecutive current values ​​are stabilized and their average values ​​are calculated as "tail current." ブランク " "Tail current 化合物 The current suppression rate was calculated using the following formula: [ka] 2) Fit the dose-response curve and calculate the IC using Graphpad Prism 8.0 software. 50 3) The range of standard deviations of the three data sets is less than 15 (SD<15); 4) The widely accepted criteria for evaluating the inhibitory potency of hERG channel assay compounds are as follows: 1) Low inhibitory effect: IC 50 >10 μM 2) Moderate inhibitory effect: 1 μM <IC 50 <10 μM 3) High inhibitory effect: IC 50 <1 μM Data Quality Control Standards Subsequent analysis can only be performed if the following criteria are met: 1) initial seal resistance greater than 1 GΩ; 2) series resistance less than 15 MΩ and series resistance voltage error less than 5 mV; 3) leakage current at the detection voltage less than 50% of the current value at that state; 4) tail current greater than the pre-pulse plateau current and initial tail current greater than 250 pA; 5) access resistance Ra less than 15 MΩ; 6) tail current decay rate less than 2.5% per minute.

[0233] hERG IC 50 The data (μM) are shown in Table 3.

[0234] Table 3: hERG IC 50 data [Table 48] hERG IC 50 Comparison of the data above reveals that the examples of the present invention have a lower risk of cardiotoxicity and a wider safety window than AMG473.

[0235] While preferred embodiments have been described above, it will be apparent to those skilled in the art that modifications may be made without departing from the invention, and such changes are to be considered variations that may fall within the scope of the invention.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof. 【Chemical 1】 wherein W is C; In the formula, X ３ is N or CR Ｘ３ and X ４ is N or CR Ｘ４ and X ５ is N or CR Ｘ５ and X ６ is N or CR Ｘ６ and In the formula, X ３ is CR Ｘ３ If R Ｘ３ are hydrogen, deuterium, and C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, halogen, -OR ａ , -SR ａ , -P(O)R ａ R ｂ , -CN, -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -NR ａ R ｂ , halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, halogenated C １ -C ６ Alkylthiol, Hydroxy C １ -C ６ alkyl, or deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy (C １ -C ６ alkyl), NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ C substituted by 0 to 4 substituents selected from the group consisting of ３ -C １０ Cycloalkyl, C ６ -C １０ Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C ６ -C １０ aryl, 5-10 membered heteroaryl; In the formula, X ４ is CR Ｘ４ If R Ｘ４ are hydrogen, deuterium, and C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, halogen, -OR ａ , -SR ａ , -P(O)R ａ R ｂ , -CN, -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -NR ａ R ｂ , halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, halogenated C １ -C ６ Alkylthiol, Hydroxy C １ -C ６ alkyl, or deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy (C １ -C ６ alkyl), NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ C substituted by 0 to 4 substituents selected from the group consisting of ３ -C １０ Cycloalkyl, C ６ -C １０ Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C ６ -C １０ aryl, 5-10 membered heteroaryl; In the formula, X ５ is CR Ｘ５ If R Ｘ５ are hydrogen, deuterium, and C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, halogen, -OR ａ , -SR ａ , -P(O)R ａ R ｂ , -CN, -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -NR ａ R ｂ , halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, halogenated C １ -C ６ Alkylthiol, Hydroxy C １ -C ６ alkyl, or deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy (C １ -C ６ alkyl), NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ C substituted by 0 to 4 substituents selected from the group consisting of ３ -C １０ Cycloalkyl, C ６ -C １０ Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C ６ -C １０ aryl, 5-10 membered heteroaryl; In the formula, X ６ is CR Ｘ６ If R Ｘ６ are hydrogen, deuterium, and C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, halogen, -OR ａ , -SR ａ , -P(O)R ａ R ｂ , -CN, -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -NR ａ R ｂ , halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, halogenated C １ -C ６ Alkylthiol, Hydroxy C １ -C ６ alkyl, or deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy (C １ -C ６ alkyl), NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ C substituted by 0 to 4 substituents selected from the group consisting of ３ -C １０ Cycloalkyl, C ６ -C １０ Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C ６ -C １０ aryl, 5-10 membered heteroaryl; wherein the A ring further comprises X ３ , X ４ In the chemical bond between the rings, a 5- to 6-membered saturated or unsaturated ring may be optionally fused, which may contain 0 to 3 heteroatoms selected from O, N, and S; wherein the A ring further comprises X ４ , X ５ In the chemical bond between the rings, a 5- to 6-membered saturated or unsaturated ring may be optionally fused, which may contain 0 to 3 heteroatoms selected from O, N, and S; wherein the A ring further comprises X ５ , X ６ In the chemical bond between the rings, a 5- to 6-membered saturated or unsaturated ring may be optionally fused, which may contain 0 to 3 heteroatoms selected from O, N, and S; wherein the A ring further contains deuterium, C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, halogen, -OR ａ , -SR ａ , -P(O)R ａ R ｂ , -CN, -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -NR ａ R ｂ , halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, hydroxy C １ -C ６ and optionally substituted with 0, 1, 2, 3 substituents selected from the group consisting of alkyl, deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy (C １ -C ６ alkyl), NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ and optionally substituted with 0 to 4 substituents selected from the group consisting of: In the formula, R' is deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, 3-6 membered saturated or unsaturated aliphatic heteromonocyclic ring, -OR ａ , oxo, hydroxy C １ -C ６ Alkyl, NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ C substituted by 0 to 3 optional substituents selected from the group consisting of １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６ -C １０ aryl, 5-10 membered heteroaryl; Preferably, R' is -CHR ２ R ３ or -CDR ２ R ３ and In the formula, R ２ , R ３ are each independently hydrogen, deuterium, -OR ａ , halogen, -CN, -C １ -C ６ Alkyl, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, hydroxy C １ -C ６ Alkyl, -C ３ -C １０ cycloalkyl or deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy C １ -C ６ Alkyl, NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or CONR ａ R ｂ 4-10 membered heterocycloalkyl substituted by 0 to 3 optional substituents selected from the group consisting of: ６ -C １０ aryl, 5-10 membered heteroaryl; In the formula, M １ is CR ａ R ｂ , N.R. ａ , O, S or Se; In the formula, R Ｌ , R Ｌ’ are independently hydrogen, deuterium, and C １ -C ６ alkyl, or R Ｌ , R Ｌ’ form a 3-6 membered ring together with the atoms to which they are connected, In the formula, n and o each independently represent 0, 1, or 2. In the formula, X １ is N or CR Ｘ１ and In the formula, X ２ is N or CR Ｘ２ and In the formula, Y １ is CR Ｙ１ R Ｙ１’ , N.R. Ｙ１ , O, S, Se, In the formula, Y ２ is CR Ｙ２ R Ｙ２’ , N.R. Ｙ２ , O, S, Se, In the formula, Y ３ is CR Ｙ３ R Ｙ３’ , N.R. Ｙ３ , O, S, Se, In the formula, R Ｘ１ , R Ｘ２ are independently hydrogen, deuterium, and C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, hydroxy C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, -OR ａ , -SR ａ , -S(O) ２ R ａ , -S(O)R ａ , -CN, -OC(O)R ａ , -OCONR ａ R ｂ , halogen, -OSO ３ R ａ , -NR ａ R ｂ , -SF ５ and In the formula, R Ｙ１ , R Ｙ１’ , R Ｙ２ , R Ｙ２’ , R Ｙ３ , R Ｙ３’ do not exist independently, hydrogen, deuterium, C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, hydroxy C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , -SR ａ , -S(O) ２ R ａ , -S(O)R ａ , -CN, -OC(O)R ａ , -OCONR ａ R ｂ , halogen, -OSO ３ R ａ , -NR ａ R ｂ , -SF ５ and During the ceremony, 【Chemistry 2】 is a single bond or a double bond, In the formula, R ａ , R ｂ are each independently hydrogen, deuterium, halogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, halogenated (C １ -C ６ alkyl), or R ａ , R ｂ together with the atoms to which they are attached form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

2. 10. The compound of claim 1, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, having the structure shown in formula (II): 【Chemistry 3】 wherein W is C; In the formula, X ３ is N or CR Ｘ３ and X ４ is N or CR Ｘ４ and X ５ is N or CR Ｘ５ and X ６ is N or CR Ｘ６ and In the formula, X ３ is CR Ｘ３ If R Ｘ３ are hydrogen, deuterium, and C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, halogen, -OR ａ , -SR ａ , -P(O)R ａ R ｂ , -CN, -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -NR ａ R ｂ , halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, halogenated C １ -C ６ Alkylthiol, Hydroxy C １ -C ６ alkyl, or deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy (C １ -C ６ alkyl), NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ C substituted by 0 to 4 substituents selected from the group consisting of ３ -C １０ Cycloalkyl, C ６ -C １０ Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C ６ -C １０ aryl, 5-10 membered heteroaryl; In the formula, X ４ is CR Ｘ４ If R Ｘ４ are hydrogen, deuterium, and C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, halogen, -OR ａ , -SR ａ , -P(O)R ａ R ｂ , -CN, -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -NR ａ R ｂ , halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, halogenated C １ -C ６ Alkylthiol, Hydroxy C １ -C ６ alkyl, or deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy (C １ -C ６ alkyl), NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ C substituted by 0 to 4 substituents selected from the group consisting of ３ -C １０ Cycloalkyl, C ６ -C １０ Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C ６ -C １０ aryl, 5-10 membered heteroaryl; In the formula, X ５ is CR Ｘ５ If R Ｘ５ are hydrogen, deuterium, and C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, halogen, -OR ａ , -SR ａ , -P(O)R ａ R ｂ , -CN, -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -NR ａ R ｂ , halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, halogenated C １ -C ６ Alkylthiol, Hydroxy C １ -C ６ alkyl, or deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy (C １ -C ６ alkyl), NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ C substituted by 0 to 4 substituents selected from the group consisting of ３ -C １０ Cycloalkyl, C ６ -C １０ Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C ６ -C １０ aryl, 5-10 membered heteroaryl; In the formula, X ６ is CR Ｘ６ If R Ｘ６ are hydrogen, deuterium, and C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, halogen, -OR ａ , -SR ａ , -P(O)R ａ R ｂ , -CN, -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -NR ａ R ｂ , halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, halogenated C １ -C ６ Alkylthiol, Hydroxy C １ -C ６ alkyl, or deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy (C １ -C ６ alkyl), NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or CONR ａ R ｂ C substituted by 0 to 4 substituents selected from the group consisting of ３ -C １０ Cycloalkyl, C ６ -C １０ Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C ６ -C １０ aryl, 5-10 membered heteroaryl; In the formula, R' is deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, 3-6 membered saturated or unsaturated aliphatic heteromonocyclic ring, -OR ａ , oxo, hydroxy C １ -C ６ Alkyl, NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ C substituted by 0 to 3 optional substituents selected from the group consisting of １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６ -C １０ aryl, 5-10 membered heteroaryl; Preferably, R' is -CHR ２ R ３ or -CDR ２ R ３ and In the formula, R ２ , R ３ are each independently hydrogen, deuterium, -OR ａ , halogen, -CN, -C １ -C ６ Alkyl, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, hydroxy C １ -C ６ Alkyl, -C ３ -C １０ cycloalkyl or deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy C １ -C ６ Alkyl, NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ 4-10 membered heterocycloalkyl substituted by 0 to 3 optional substituents selected from the group consisting of: ６ -C １０ aryl, 5-10 membered heteroaryl; In the formula, M １ is CR ａ R ｂ , N.R. ａ , O, S or Se; In the formula, R Ｌ , R Ｌ’ are independently hydrogen, deuterium, and C １ -C ６ alkyl, or R Ｌ , R Ｌ’ form a 3-6 membered ring together with the atoms to which they are connected, In the formula, n and o are each independently 0, 1 or 2. In the formula, X １ is N or CR Ｘ１ and In the formula, X ２ is N or CR Ｘ２ and In the formula, Y １ is CR Ｙ１ R Ｙ１’ , N.R. Ｙ１ , O, S, Se, In the formula, Y ２ is CR Ｙ２ R Ｙ２’ , N.R. Ｙ２ , O, S, Se, In the formula, Y ３ is CR Ｙ３ R Ｙ３’ , N.R. Ｙ３ , O, S, Se, In the formula, R Ｘ１ , R Ｘ２ are independently hydrogen, deuterium, and C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, hydroxy C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, -OR ａ , -SR ａ , -S(O) ２ R ａ , -S(O)R ａ , -CN, -OC(O)R ａ , -OCONR ａ R ｂ , halogen, -OSO ３ R ａ , -NR ａ R ｂ , -SF ５ and In the formula, R Ｙ１ , R Ｙ１ ', R Ｙ２ , R Ｙ２ ', R Ｙ３ , R Ｙ３ ' does not exist independently, hydrogen, deuterium, C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, hydroxy C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , -SR ａ , -S(O) ２ R ａ , -S(O)R ａ , -CN, -OC(O)R ａ , -OCONR ａ R ｂ , halogen, -OSO ３ R ａ , -NR ａ R ｂ , -SF ５ and During the ceremony, 【Chemistry 4】 is a single bond or a double bond, In the formula, R ａ , R ｂ are each independently hydrogen, deuterium, halogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, halogenated (C １ -C ６ alkyl), or R ａ , R ｂ together with the atoms to which they are attached form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

3. 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: 【Chemistry 5】 is a double bond.

4. 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein X １ is CR Ｘ１ or N, and R Ｘ１ are hydrogen, deuterium, halogen, -CN, C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogenated C １ -C ６ It is alkyl.

5. 5. The compound of claim 4, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, wherein X １ is CH, CF or N.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein X ２ is CH or CD.

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein X ２ is CH.

8. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein X ３ is CH, CD or N.

9. 9. The compound of claim 8, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, wherein X ３ is CH.

10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein X ４ is CR Ｘ４ or N, where R Ｘ４ are hydrogen, deuterium, and C １ -C ６ Alkyl, deuterated C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthiol, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, halogenated C １ -C ６ Alkylthiol, halogen, SF ５ , -S(O) ２ R ａ , -P(O)R ａ R ｂ , or cyano, or deuterated, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy (C １ -C ６ alkyl), NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -S(O) ２ R ａ , -SR ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ C substituted by 0 to 4 substituents selected from the group consisting of ３ -C １０ Cycloalkyl, C ６ -C １０ Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C ６ -C １０ aryl, 5-10 membered heteroaryl.

11. 11. The compound of claim 10, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, wherein X ４ is CR Ｘ４ where R Ｘ４ is C １ -C ６ Alkoxy, C １ -C ６ Alkylthiol, halogenated C １ -C ６ Alkoxy, halogenated C １ -C ６ Alkylthiol, halogenated C １ -C ６ Alkyl, -SF ５ is.

12. 12. The compound of claim 11, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, wherein X ４ is CR Ｘ４ where R Ｘ４ is halogenated C １ -C ６ Alkoxy, halogenated C １ -C ６ Alkylthiol, halogenated C １ -C ６ Alkyl, -SF ５ is.

13. 13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein X ５ is CR Ｘ５ or N, where R Ｘ５ are hydrogen, deuterium, and C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, halogen, SF ５ Or cyano.

14. 14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein X ５ is CH.

15. 15. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein X ６ is CH, CD or N.

16. 16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein X ６ is CH.

17. 17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein Y １ and Y ２ The chemical bond between is a double bond.

18. 18. The compound of claim 17, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, wherein Y １ is CH, CD or CCH ３ is.

19. 19. A compound according to claim 17 or 18, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein Y ２ is N.

20. 20. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein Y ３ CH, CD, CCH ３ or CCH ２ It's OH.

21. 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, wherein R' is -CHR ２ R ３ or -CDR ２ R ３ where R ２ , R ３ are independently hydrogen, deuterium, and C １ -C ６ alkyl, or halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy C １ -C ６ Alkyl, NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ C substituted with 0 to 3 selected from the group consisting of ３ -C １０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６ -C １０ aryl, 5-10 membered heteroaryl.

22. 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, wherein R' is -CHR ２ R ３ or -CDR ２ R ３ where R ２ are hydrogen, deuterium, and C １ -C ６ alkyl, and R ３ are hydrogen, deuterium, and C １ -C ６ alkyl, or halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, -OR ａ , oxo, hydroxy C １ -C ６ Alkyl, NR ａ R ｂ , -CN, halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ Alkoxy, -SO ３ R ａ , -SR ａ , -S(O) ２ R ａ , -S(O)R ａ , -SF ５ , -C(O)R ａ , -C(O)OR ａ , -OC(O)R ａ , -OC(O)NR ａ R ｂ , -NR ａ COR ｂ or -CONR ａ R ｂ C substituted with 0 to 3 selected from the group consisting of ３ -C １０ Cycloalkyl, 4-10 membered heterocycloalkyl, C ６ -C １０ aryl, 5-10 membered heteroaryl.

23. 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, wherein R' is a deuterated, halogen, C １ -C ６ Alkyl, hydroxy C １ -C ６ Alkyl, -OR ａ , -CN, NR ａ R ｂ , halogenated C １ -C ６ Alkyl, halogenated C １ -C ６ C substituted with 0 to 3 selected from the group consisting of alkoxy ３ -C １０ It is cycloalkyl.

24. 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, wherein R' is C １ -C ６ Alkyl (preferably methyl, ethyl) or deuterated C １ -C ６ Alkyl (preferably deuterated methyl, deuterated ethyl) or C ３ -C ６ It is cycloalkyl (preferably cyclopropyl).

25. 25. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein M １ is O or S.

26. 26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein o is 1 or 2.

27. 27. The compound of claim 26, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, wherein o is 1.

28. 28. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein n is 0 or 1.

29. 29. The compound of claim 28, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, wherein n is 0.

30. 29. The compound of claim 28, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, wherein n is 1.

31. 31. The compound of claim 30, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, wherein R Ｌ , R Ｌ’ are each independently hydrogen or C １ -C ６ It is alkyl.

32. A compound having the structure: or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof. 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】

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