New PRMT5 inhibitors and methods for their use

Abstract

FIELD: pharmaceutical synthesis.SUBSTANCE: compound, the formula of which is indicated below, or pharmaceutically acceptable salt thereof, as well as pharmaceutical composition containing them, are proposed.EFFECT: proposed compound is an inhibitor of PRMT5 activity can be used in the treatment of diseases or conditions associated with PRMT5, in particular cancer.3 cl, 3 tbl, 135 ex

Description

[0001] Field of invention

[0002] The present invention relates to the field of drug synthesis. In particular, the present invention relates to novel PRMT5 inhibitors and methods of using them.

[0003] Background of the invention

[0004] Epigenetic changes play a crucial role in the formation and maintenance of the malignant phenotype of tumors. DNA methylation, histone acetylation and methylation, non-coding RNA, and post-translational modifications are epigenetic factors in cancer development, independent of DNA sequence changes. Arginine methylation is an important post-translational modification that, by regulating transcription and post-transcriptional RNA processing, influences cell growth, proliferation, apoptosis, angiogenesis, and metastasis. Methylated arginines include three types: ω-NG, N'G-asymmetric dimethylarginine (ADMA) and ω-NG, N'G-symmetric dimethylarginine (SDMA). This modification is catalyzed by a family of protein arginine methyltransferases (PRMTs), which transfer methyl groups from S-adenosylmethionine (AdoMet) to arginine side chains in both histone and non-histone proteins.Nine PRMT genes have been annotated in the human genome, classified into type I (PRMT1, 2, 3, 4, 6, and 8), type II (PRMT5 and PRMT9), and type III (PRMT7) enzymes. PRMT5, predominantly a type II enzyme, is responsible for catalyzing the symmetric demethylation of arginine. It was first discovered in a yeast two-hybrid assay screening for proteins interacting with Janus kinase 2 (Jak2).

[0005] PRMT5 acts as a universal transcriptional repressor, forming complexes with various transcription factors, such as BRG1, Hbrm, Blimp1, and Snail. Participating in various cellular processes, PRMT5 methylates substrates in both the cytoplasm and nucleus, including the Arg3 residue of histone H4 (H4R3) and the Arg8 residue of histone H3 (H3R8). H4R3 methylation is associated with transcriptional repression, while H3R8 methylation is associated with both transcriptional activation and repression. In addition to directly inducing repressive histone marks, PRMT5's role in gene silencing includes the formation of multirepressive protein complexes, including NuRD components, HDACs, MDB proteins, and DNA methyltransferases. PRMT5 influences substrate specificity through interactions with binding proteins within these complexes. At the core of this protein complex is MEP50, which is critical for PRMT5 enzymatic activity.Studies have shown the ability of PRMT5 to methylate proteins involved in RNA splicing, such as SmD3, providing insight into the monitoring of PRMT5 chemical activity in cell biology.

[0006] PRMT5 plays a crucial role in tumorigenesis. Studies have shown increased PRMT5 expression in various cancer types, including lymphoma, lung cancer, breast cancer, and colorectal cancer. Furthermore, PRMT5 expression is elevated in samples from patients with mantle cell lymphoma (MCL), and PRMT5 silencing inhibits MCL cell proliferation, highlighting its importance in MCL. Overexpression of PRMT5 promotes cell proliferation, while PRMT5 knockout inhibits proliferation in melanoma, breast cancer, and lung cancer cell lines. Thus, PRMT5 is a potential target for cancer therapy.

[0007] Loss of methylthioadenosine phosphorylase (MTAP) results in selective dependence on PRMT5 and its binding protein WDR77. MTAP is frequently lost due to its proximity to the frequently deleted tumor suppressor gene CDKN2A. Cells lacking MTAP exhibit elevated intracellular concentrations of methylthioadenosine (MTA, a metabolite cleaved by MTAP). Because MTA is structurally similar to S-adenosylmethionine (SAM), a naturally occurring selective inhibitor, elevated MTA concentrations inhibit SAM binding to PRMT5, thereby suppressing PRMT5 methyltransferase activity.

[0008] The structural difference between MTAP-deficient cancer cells and wild-type MTAP-deficient cells primarily occurs in the PRMT5-MTA complex due to MTA accumulation in MTAP-deficient cells. Inhibitors designed to target the PRMT5-MTA complex demonstrate selective efficacy against MTAP-deficient cancer cells, minimizing the impact on normal cells and significantly increasing the therapeutic index.

[0009] Therefore, the identification and development of small molecules that inhibit PRMT5 activity are treatment methods for various PRMT5-related diseases or conditions, especially cancer.

[0010] Brief summary of the invention

[0011] To solve the technical problems of the present invention, a class of compounds with new structures having potent inhibitory activity against PRMT5 is proposed.

[0012] In particular, in one embodiment, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, and isotopic derivative thereof, and wherein

[0013]

[0014] W represents C, and where

[0015] X3 represents N or CR X3 ;

[0016] X4 represents N or CR X4 ;

[0017] X5 represents N or CR X5 ;

[0018] X6 represents N or CR X6 , and where,

[0019] when X3 is CR X3 , R X3 represents 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 , C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6haloalkylthio, hydroxy-(C1-C6alkyl) or C3-C 10cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl, where each ring is C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl optionally substituted with 0-4 deuterium atoms, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy-(C1-C6alkyl), NR a R b , -CN, C1-C6haloalkyl, C1-C6haloalkoxy, -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 , and where,

[0020] when X4 is CR X4 , R X4 represents 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 , C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6haloalkylthio, hydroxy-(C1-C6alkyl) or C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl, where each ring is C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl optionally substituted with 0-4 deuterium atoms, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy-(C1-C6alkyl), NR a R b , -CN, C1-C6haloalkyl, C1-C6haloalkoxy, -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 CORb or -CONR a R b , and where,

[0021] when X5 is CR X5 , R X5 represents 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 , C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6haloalkylthio, hydroxy-(C1-C6alkyl) or C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl, where each ring is C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl optionally substituted with 0-4 deuterium atoms, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy-(C1-C6alkyl), NRa R b , -CN, C1-C6haloalkyl, C1-C6haloalkoxy, -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 , and where

[0022] when X6 is CR X6 , R X6 represents 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 , C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6haloalkylthio, hydroxy-(C1-C6alkyl) or C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl, where each ring is C3-C 10 cycloalkyl, C6-C 10cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl optionally substituted with 0-4 deuterium atoms, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy-(C1-C6alkyl), NR a R b , -CN, C1-C6haloalkyl, C1-C6haloalkoxy, -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 , and where

[0023] ring A may optionally be fused via a chemical bond between X3 and X4 with a 5-6 membered saturated or unsaturated ring which may contain 0-3 heteroatoms selected from O, N, S, and where

[0024] ring A may optionally be fused via a chemical bond between X4 and X5 with a 5-6 membered saturated or unsaturated ring which may contain 0-3 heteroatoms selected from O, N, S, and where

[0025] ring A may optionally be fused via a chemical bond between X5 and X6 with a 5-6 membered saturated or unsaturated ring which may contain 0-3 heteroatoms selected from O, N, S, and where

[0026] Ring A may also be optionally substituted with 0, 1, 2, 3 groups selected from 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 , C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy-(C1-C6) alkyl or substituted groups that are optionally substituted with 0-4 substituents selected from deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a, oxo, hydroxy-(C1-C6alkyl), NR a R b , -CN, C1-C6haloalkyl, C1-C6haloalkoxy, -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 , and where

[0027] R' represents C1-C6 alkyl, C3-C 10 cycloalkyl, 4-10-membered heterocyclyl, C6-C 10 aryl, 5-10-membered heteroaryl, which are independently optionally substituted with 0-3 groups selected from deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6-membered saturated or unsaturated monocyclic heterocyclyl, -OR a , oxo, hydroxy-(C1-C6alkyl), NR a R b , -CN, C1-C6haloalkyl, C1-C6haloalkoxy, -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)NRa R b , -NR a COR b or -CONR a R b ;

[0028] Preferred, R ’ is -CHR²R³ or -CDR²R³, and where

[0029] R 2 and R 3 independently represent hydrogen, deuterium, -OR a , halogen, -CN, -C1-C6alkyl, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy-(C1-C6alkyl), -C3-C 10 cycloalkyl or 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10-membered heteroaryl, where 4-10-membered heterocyclyl, C6-C 10 aryl and 5-10-membered heteroaryl may be optionally substituted with 0-3 groups selected from deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy-(C1-C6alkyl), NR a R b , -CN, C1-C6haloalkyl, C1-C6haloalkoxy, -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 , and where

[0030] M1 is a CR a R b , NR a , O, S or Se, and where

[0031] R L and R L' independently represent hydrogen, deuterium, C1-C6 alkyl, or R L and R L’ can be taken together with the atoms to which they are attached to form a C3-C6 carbocyclyl or heterocyclyl, and where

[0032] n and o are independently equal to 0, 1, or 2, and where

[0033] X1 represents N or CR X1 , and where

[0034] X2 represents N or CR X2 , and where

[0035] Y 1 represents CR Y1 R Y1’ , NR Y1 , O, S, Se, and where

[0036] Y2 represents CR Y2 R Y2’ , NR Y2 , O, S, Se, and where

[0037] Y3 is a CR Y3 R Y3’ , NR Y3 , O, S, Se, and where

[0038] R X1 and R X2 independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy-(C1-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, and where

[0039] R Y1 , R Y1’ , R Y2 , R Y2’ , R Y3 and R Y3’ independently represent absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, 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, and where

[0040] denotes a single or double bond, and where

[0041] R a and R b independently represent hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cyclopropyl, C1-C6 haloalkyl, or R a and R b may be taken together with the atoms to which they are attached to form a 3- to 14-membered saturated or unsaturated ring which may optionally contain 0-2 heteroatoms selected from O, S and N.

[0042] In another embodiment, the invention provides a compound of formula (II), a pharmaceutically acceptable salt, ester, prodrug, stereoisomer, or isotopic derivative thereof, and wherein

[0043]

[0044] W is C, and where

[0045] X3 represents N or CR X3 ;

[0046] X4 represents N or CR X4 ;

[0047] X5 represents N or CR X5 ;

[0048] X6 represents N or CRX6 , and where,

[0049] when X3 is CR X3 , R X3 represents 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 , C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6haloalkylthio, hydroxy-(C1-C6alkyl) or C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl, where each ring is C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl optionally substituted with 0-4 deuterium atoms, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy-(C1-C6alkyl), NR a R b, -CN, C1-C6haloalkyl, C1-C6haloalkoxy, -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 , and where,

[0050] when X4 is CR X4 , R X4 represents 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 , C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6haloalkylthio, hydroxy-(C1-C6alkyl) or C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl, where each ring is C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C10 aryl, 5-10-membered heteroaryl optionally substituted with 0-4 deuterium atoms, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy-(C1-C6alkyl), NR a R b , -CN, C1-C6haloalkyl, C1-C6haloalkoxy, -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 , and where,

[0051] when X5 is CR X5 , R X5 represents 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 , C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6haloalkylthio, hydroxy-(C1-C6alkyl) or C3-C 10 cycloalkyl, C6-C 10cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl, where each ring is C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl optionally substituted with 0-4 deuterium atoms, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy-(C1-C6alkyl), NR a R b , -CN, C1-C6haloalkyl, C1-C6haloalkoxy, -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 , and where,

[0052] when X6 is CR X6 , R X6 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a , -SR a , -P(O)Ra R b , -CN, -S(O)2R a , -S(O)R a , -SF5, -NR a R b , C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6haloalkylthio, hydroxy-(C1-C6alkyl) or C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl, where each ring is C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, 6-10-membered heterocycloalkenyl, C6-C 10 aryl, 5-10-membered heteroaryl optionally substituted with 0-4 deuterium atoms, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy-(C1-C6alkyl), NR a R b , -CN, C1-C6haloalkyl, C1-C6haloalkoxy, -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 -CONRa R b , and where

[0053] R ’ is C1-C6 alkyl, C3-C 10 cycloalkyl, 4-10-membered heterocyclyl, C6-C 10 aryl, 5-10-membered heteroaryl, which are independently optionally substituted with 0-3 groups selected from deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6-membered saturated or unsaturated monocyclic heterocyclyl, -OR a , oxo, hydroxy-(C1-C6alkyl), NR a R b , -CN, C1-C6haloalkyl, C1-C6haloalkoxy, -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 ;

[0054] Preferred, R ’ is -CHR²R³ or -CDR²R³, and where

[0055] R² and R³ independently represent hydrogen, deuterium, -OR a, halogen, -CN, -C1-C6alkyl, C1-C6haloalkyl, C1-C6haloalkoxy, hydroxy-(C1-C6alkyl), -C3-C 10 cycloalkyl or 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10-membered heteroaryl, where 4-10-membered heterocyclyl, C6-C 10 aryl and 5-10-membered heteroaryl may be optionally substituted with 0-3 groups selected from deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy-(C1-C6alkyl), NR a R b , -CN, C1-C6haloalkyl, C1-C6haloalkoxy, -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 , and where

[0056] M1 is a CR a R b , NR a , O, S or Se, and where

[0057] R L and R L’independently represent hydrogen, deuterium, C1-C6 alkyl, or R L and R L’ can be taken together with the atoms to which they are attached to form a 3- to 6-membered carbocyclyl or heterocyclyl, and where

[0058] n and o are independently equal to 0, 1, or 2, and where

[0059] X1 represents N or CR X1 , and where

[0060] X2 represents N or CR X2 , and where

[0061] Y3 is a CR Y1 R Y1’ , NR Y1 , O, S, Se, and where

[0062] Y1 is a CR Y2 R Y2’ , NR Y2 , O, S, Se, and where

[0063] Y2 represents CR Y3 R Y3’ , NR Y3 , O, S, Se, and where

[0064] R X1 and R X2 independently represent hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy-(C1-C6) alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a , -SR a , -S(O)2Ra , -S(O)R a , -CN, -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , -SF5, and where

[0065] R Y1 , R Y1’ , R Y2 , R Y2’ , R Y3 and R Y3’ independently represent absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, 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, and where

[0066] denotes a single or double bond, and where

[0067] R a and R b independently represent hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cyclopropyl, C1-C6 haloalkyl, or R a and R bmay be taken together with the atoms to which they are attached to form a 3- to 14-membered saturated or unsaturated ring which may optionally contain 0-2 heteroatoms selected from O, S and N.

[0068] In a preferred embodiment of the invention, represents a double bond.

[0069] In a preferred embodiment of the invention, X1 is CR X1 or N, where R X1 represents hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl.

[0070] In a preferred embodiment of the invention, X1 is CH, CF or N.

[0071] In a preferred embodiment of the invention, X2 is CH or CD.

[0072] In a preferred embodiment of the invention, X2 is CH.

[0073] In a preferred embodiment of the invention, X3 is CH, CD or N.

[0074] In a preferred embodiment of the invention, X3 is CH.

[0075] In a preferred embodiment of the invention, X4 is CR X4 or N, where R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, halogen, SF5, -S(O)2R a , -P(O)R a R b , CN or C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, C6-C 10 aryl and 5-10-membered heteroaryl, where each ring is C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10-membered heterocyclyl, C6-C 10 aryl and 5-10-membered heteroaryl optionally substituted with 0-4 groups independently selected from deuterium, 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, C1-C6haloalkyl, C1-C6haloalkoxy, -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 .

[0076] In a preferred embodiment of the invention, X4 is CR X4 ; where R X4 represents C1-C6alkoxy, C1-C6alkylthio, C1-C6haloalkoxy, C1-C6haloalkylthio, C1-C6haloalkyl, -SF5.

[0077] In a preferred embodiment of the invention, X4 is CR X4 ; where R X4 represents C1-C6haloalkoxy, C1-C6haloalkylthio, C1-C6haloalkyl, -SF5.

[0078] In a preferred embodiment of the invention, X5 is CR X5 or N, where R X5 represents hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, -SF5, or CN.

[0079] In a preferred embodiment of the invention, X5 is CH.

[0080] In a preferred embodiment of the invention, X6 is CH, CD or N.

[0081] In a preferred embodiment of the invention, X6 is CH.

[0082] In a preferred embodiment of the invention, the chemical bond between Y1 and Y2 is a double bond.

[0083] In a preferred embodiment of the invention, Y1 is CH, CD or CCH3.

[0084] In a preferred embodiment of the invention, Y2 is N.

[0085] In a preferred embodiment of the invention, Y3 is CH, CD, CCH3, or CCH2OH.

[0086] In a preferred embodiment of the invention R ’ is -CHR²R³ or -CDR²R³, where R² and R³ are independently hydrogen, deuterium, C1-C6 alkyl, or C3-C 10 cycloalkyl, 4-10-membered heterocyclyl, C6-C 10aryl, 5-10-membered heteroaryl, where each ring is C3-C 10 cycloalkyl, 4-10-membered heterocyclyl, C6-C 10 aryl, 5-10-membered heteroaryl independently optionally substituted with 0-3 groups selected from 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, C1-C6haloalkyl, C1-C6haloalkoxy, -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 .

[0087] In a preferred embodiment of the invention, R' is -CHR²R³ or -CDR²R³, wherein R² is hydrogen, deuterium, C1-C6 alkyl; R³ is hydrogen, deuterium, C1-C6 alkyl or C3-C 10 cycloalkyl, 4-10-membered heterocyclyl, C6-C 10aryl, 5-10-membered heteroaryl, where each ring is C3-C 10 cycloalkyl, 4-10-membered heterocyclyl, C6-C 10 aryl, 5-10-membered heteroaryl independently optionally substituted with 0-3 groups selected from 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, C1-C6haloalkyl, C1-C6haloalkoxy, -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 .

[0088] In a preferred embodiment of the invention, R' is C3-C 10 cycloalkyl which is optionally substituted with 0-3 groups independently selected from deuterium, halogen, C1-C6 alkyl, hydroxy-(C1-C6) alkyl, -OR a , -CN, NR a R b, C1-C6haloalkyl, C1-C6haloalkoxy.

[0089] In a preferred embodiment of the invention R ’ is C1-C6 alkyl (preferably methyl, ethyl) or deuterated C1-C6 alkyl (preferably deuterated methyl, deuterated ethyl) or C3-C6 cycloalkyl (preferably cyclopropyl).

[0090] In a preferred embodiment of the invention, M1 is O or S.

[0091] In a preferred embodiment of the invention, o is 1 or 2.

[0092] In a preferred embodiment of the invention, o is equal to 1.

[0093] In a preferred embodiment of the invention, n is 0 or 1.

[0094] In a preferred embodiment of the invention, n is equal to 0.

[0095] In a preferred embodiment of the invention, n is equal to 1.

[0096] In a preferred embodiment of the invention R L and R L’independently represent hydrogen or C1-C6 alkyl.

[0097] In particular, in one embodiment, the present invention provides the following compounds:

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104] Unless explicitly stated otherwise, the compounds of this invention, in addition to their specific structures, should be broadly interpreted to include pharmaceutically acceptable salts, stereoisomers, isotopic variants (such as deuterated compounds), solvates, hydrates, prodrugs, and metabolites. Specifically, pharmaceutically acceptable salts, stereoisomers, isotopic variants (such as deuterated compounds), solvates, hydrates, prodrugs, and metabolites of the compound are also included within the scope of protection of the compound.

[0105] Preferably, the pharmaceutical composition of the present invention may further contain a second active substance, wherein the second active substance is an anticancer agent, and the anticancer agent includes chemotherapeutic drugs, drugs for targeted tumor treatment, antibodies for tumor treatment, or a combination thereof.

[0106] Furthermore, the present invention provides a compound of the invention, pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives thereof, as well as methods for treating diseases, preferably tumors, by inhibiting the action of PRMT5.

[0107] Definitions:

[0108] Unless otherwise specified, the term "alkyl," either alone or as part of another substituent, means a hydrocarbon group that may be linear (unbranched) or branched, cyclic, or a combination thereof. It may be saturated, mono- or polyunsaturated, and may include divalent or multivalent moieties with the specified number of carbon atoms (e.g., C1-C 10, denoting from one to ten carbon atoms). Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, 2-propenyl, crotonyl, 2-(buta-1,3-dienyl), 2-isopentenyl, 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and their higher homologues and isomers. Alkyl groups limited to hydrocarbon groups are called "homoalkyl". Alkyl groups may be optionally substituted with one or more halogen atoms.

[0109] The term "haloalkyl" refers to alkyl groups as defined above in which one or more hydrogen atoms are replaced by halogen atoms.

[0110] The term "alkylene" by itself or as part of another substituent refers to a divalent group derived from alkyl, such as, but not limited to, -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-, -CH2CH2CH(CH2CH2CH3)CH2-. Alkyl (or alkylene) groups typically have from 1 to 24 carbon atoms, and the present invention preferably encompasses groups with 10 or fewer carbon atoms. "Lower alkyl" or "lower alkylene" refers to shorter alkyl or alkylene chains, typically with eight or fewer carbon atoms. Alkylene groups may be optionally substituted with one or more halogen atoms.

[0111] The term "alkynyl" denotes a carbon chain containing at least one carbon-carbon triple bond, which may be linear, branched, or a combination of both. Examples of alkynyl include ethynyl, propynyl, 3-methyl-1-pentynyl, 2-heptynyl, etc. Alkynyl groups may be optionally substituted with one or more halogen atoms.

[0112] The term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbon ring, each of which has from 3 to 10 carbon atoms. "Fused analogs" of cycloalkyl groups refer to a monocycle fused with an aryl or heteroaryl, where the point of attachment is at the non-aromatic portion. Examples of cycloalkyl and its fused analogs include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, decahydronaphthyl, dihydroindanyl, etc. Cycloalkyl groups may be optionally substituted with one or more halogen atoms. Furthermore, in the context of the present invention, the term "cycloalkyl" includes bridged and spirocyclic systems.

[0113] The term "alkoxy" refers to linear or branched alkoxy groups with the number of carbon atoms indicated. For example, C 1-6 alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, etc.

[0114] Unless otherwise specified, the term "heteroalkyl," either alone or in combination with other terms, refers to stable linear or branched hydrocarbon groups, or cyclic hydrocarbon groups, or combinations thereof, comprising at least one carbon atom and at least one heteroatom selected from O, N, P, Si, and S. Optional oxidation of the nitrogen, phosphorus, or sulfur atoms and potential quaternization of the nitrogen atoms are permitted. The O, N, P, S, and Si heteroatoms may be located at any position within the heteroalkyl or at the point of attachment of the alkyl to the rest 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 adjacent heteroatoms are permitted. For example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.Similarly, the term "heteroalkylidene," alone or in combination, refers to divalent groups derived from heteroalkyl, including, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. The heteroatoms in a heteroalkylidene may be at either end or both ends of the chain (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Additionally, for alkoxy and heteroalkoxy linking groups, the molecular formula is written without indicating the orientation of the linking group (e.g., -C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-). As noted above, the term "heteroalkyl" encompasses groups attached to the rest of the molecule through heteroatoms, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SO2R'. When "heteroalkyl" is mentioned and then specific heteroalkyls such as -NR'R'' are given, it should be understood that the term "heteroalkyl" and -NR'R'' are distinct and not mutually exclusive.The inclusion of specific heteroalkyls is for clarification and does not exclude others, such as -NR'R''.

[0115] The term "cycloalkyloxy" refers to cyclic alkyl groups as defined above bonded to an oxygen atom, such as cyclopropyloxy.

[0116] The term "haloalkoxy" refers to an alkoxy group, as defined above, in which one or more hydrogen atoms are replaced by halogen.

[0117] The term "aryl" refers to a monocyclic or bicyclic aryl group consisting solely of carbon atoms. "Fused analogs" of aryl are those in which the aryl is fused to a monocyclic cycloalkyl or monocyclic heterocyclyl, with the point of attachment being at the aryl moiety. Examples of aryl and its fused analogs include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, 1,4-benzodioxanyl, etc.

[0118] The term "heteroaryl" refers to a monocyclic or bicyclic aryl group containing at least one heteroatom selected from N, O, and S. "Fused analogs" of heteroaryl are those in which the heteroaryl is combined with a monocyclic cycloalkyl or monocyclic heterocyclyl, the point of attachment being at the heteroaryl moiety. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazine, thiophenyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furan[2,3-b]pyridinyl, quinolinyl, indolyl, isoquinolinyl, etc.

[0119] "Substituted or Unsubstituted": Certain alkyl, aryl, and heteroaryl groups may be unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, alkyl groups with 1 to 6 carbon atoms, alkoxy groups with 1 to 6 carbon atoms, haloalkyl groups with 1 to 6 carbon atoms, halogenated alkoxy groups with 1 to 6 carbon atoms, -CN, alkynyl groups with 2 to 6 carbon atoms, acyl groups with 1 to 6 carbon atoms, cycloalkyl groups with 3 to 7 ring atoms, heteroaryl groups, aryl groups, arylalkoxy groups with 7 to 10 carbon atoms, aryloxycarbonyl groups, aminocarbonyl groups, vinyl groups with 2 to 5 carbon atoms, alkylthio groups with 1 to 6 carbon atoms, aminosulfonyl groups, sulfonylamino groups, hydroxy groups, -SF5, hydroxyalkyl groups with 1-4 carbon atoms, nitro groups, amino groups, carboxyl groups, alkoxycarbonyl groups with 2-5 carbon atoms,alkoxyalkyl groups with 1 to 4 carbon atoms, alkylsulfonyl groups with 1 to 4 carbon atoms, acylamino groups with 1 to 4 carbon atoms, acyl(amino)amino groups with 1 to 6 carbon atoms, acyl(amino)aminoalkyl groups with 1 to 6 carbon atoms in both acyl and alkyl parts, sulfonylamino groups with 1 to 4 carbon atoms, monoalkylamino groups with 1 to 6 carbon atoms or dialkylamino groups with 1 to 6 carbon atoms, monoalkylaminoalkyl groups with 1 to 6 carbon atoms or dialkylaminoalkyl groups with 1 to 6 carbon atoms, aminoalkyl groups with 1 to 4 carbon atoms, monoalkylamino groups with 1 to 6 carbon atoms or dialkylamino groups with 1 to 6 carbon atoms in both alkyl parts, arylalkyl groups with 7 to 10 carbon atoms, heteroarylalkyl groups with 1-4 carbon atoms in the alkyl parts, heteroaryloxyalkyl groups with 1-4 carbon atoms in the alkoxy parts and alkylsulfonylamino groups with 1-4 carbon atoms,

[0120] The term "heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclo" as used herein refers to a saturated, partially saturated, or unsaturated group (but not aromatic) with one ring or fused rings (including bridged and spiro systems) having from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In fused systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided that the points of attachment are through non-aromatic rings. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic groups may be optionally oxidized to form N-oxides, sulfinyl, and sulfonyl moieties. Examples of "heterocyclic" and its fused analogs include pyrrolidinyl, piperidinyl, pyrazinyl, imidazolidinyl, 2,3-dihydrofuran(2,3-b)pyridinyl, quinazolinyl, tetrahydroquinoline, tetrahydroisoquinoline, dihydroindole, etc.The term also encompasses non-aromatic, partially unsaturated monocycles such as 2- or 4-pyridones or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils).

[0121] As used herein, the term "substituted heterocycloalkyl" or "substituted heterocyclo" refers to a heterocycloalkyl group substituted with 1-5 (e.g., 1-3) substituents, wherein the substituents are the same as defined for substituted cycloalkyl.

[0122] Unless otherwise specified, the term "halogenated" or "halo" refers to fluorine, chlorine, bromine, or iodine atoms, either alone or as part of another substituent. Additionally, the term "halogenated alkyl" refers to both mono-halogenated alkyl and poly-halogenated 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, etc.

[0123] "Prodrug" refers to a substance that undergoes conversion into the parent drug upon administration to the body. In certain situations, prodrugs are often used because they may be more easily administered than the parent drug. For example, a prodrug administered orally may have higher bioavailability than the parent drug. In drug combinations, prodrugs may also exhibit higher solubility than the parent drug. Examples of prodrugs include, but are not limited to, any compound of Formula (I) administered in the form of an ester (prodrug) to facilitate transmembrane transport. This helps overcome barriers created by cell membranes, as the water solubility of the prodrug impedes membrane penetration. Once in the favorable aqueous environment of the cell, the ester is metabolized and hydrolyzed to the active carboxylic acid compound.Another example of a prodrug would be a short peptide (polyamino acid) conjugated to an acidic moiety, where the peptide is metabolized to release the active moiety.

[0124] The compound of formula (I) contains one or more asymmetric centers and thus can exist as a racemate and racemic mixtures, single enantiomers, diastereomers and single diastereomers. The present invention encompasses all these stereoisomeric forms of the compound of formula (I).

[0125] Some compounds described herein contain olefinic double bonds, which, unless otherwise noted, refer to both E and Z geometric isomers. Certain compounds of the present invention may contain one or more ring systems, resulting in the formation of cis- and trans-isomers. The invention is intended to encompass all of these cis- and trans-isomers.

[0126] Certain compounds described herein may exist with different hydrogen attachment points, known as tautomerism. An example is keto-enol tautomerism, which involves a keto form and its enol form. Individual tautomers and mixtures thereof are included in the compounds of the present invention.

[0127] The compounds of the present invention can be separated into diastereomeric pairs of enantiomers, for example, by fractional crystallization from suitable solvents such as methanol or ethyl acetate or mixtures thereof. The enantiomeric pairs thus obtained can be separated into individual stereoisomers by conventional methods, including the use of optically active amines or acids as resolving agents or separation on a chiral HPLC column.

[0128] Alternatively, any diastereoisomer of the compounds of the present invention can be stereoselectively synthesized using optically pure starting materials or reagents of known configuration.

[0129] Salt and dosage form

[0130] The compounds mentioned in this document should be understood to include pharmaceutically acceptable salts.

[0131] Application

[0132] These compounds may be used to treat PRMT5-related diseases.

[0133] The compounds of the present invention can be prepared by the following reaction scheme:

[0134] Method A:

[0135]

[0136] Method A-SFC,

[0137]

[0138] where R L , R L' , R ' , ring A, W, n, o, M1, X1, X2, X3, X4, X5, X6, Y1, Y2, Y3and defined in paragraph 1.

[0139] Method A: Compound AP can be prepared by the condensation reaction of carboxylic acid A-1 and amine A-2 using HATU or PyBrOP as the condensing agent and DIPEA or TEA as the base, with DMF or DMAc as the solvent. If the amine used is a racemate, chiral SFC will be used for resolution, and the stereochemistry of the resulting isomer will be arbitrarily designated as R or S.

[0140] Analytical HPLC:

[0141] Instrument: Agilent 1260;

[0142] Column specifications: Agilent Poroshell HPH-C18 (3.0×50 mm, 2.7 μm);

[0143] Dual solvent system, mobile phase A: water (0.1% v / v ammonium bicarbonate), mobile phase B: acetonitrile;

[0144] Flow rate: 1 milliliter / minute;

[0145] Gradient: 10% B to 90% B;

[0146] Duration: 12 minutes;

[0147] Detector: DAD detector;

[0148] Wavelength: 254 / 220 nanometers.

[0149] Preparative HPLC:

[0150] HPLC Equipment: Waters 2489;

[0151] Column Specifications: Ultimate μ XB-C18 (130A, 5μm, 30mm×150mm);

[0152] Dual solvent system, mobile phase A: water (0.1% v / v ammonium bicarbonate), mobile phase B: acetonitrile;

[0153] Flow rate: 60-100 milliliters / minute;

[0154] Gradient: 10% B to 90% B;

[0155] Detector: DAD detector;

[0156] Wavelength: 254 / 220 nanometers;

[0157] Mass spectrometer: Agilent G6125B.

[0158] The compounds of the present invention can be prepared by chemical synthesis, as shown in the following examples. It should be understood that the order of the steps in the process can be changed, the specifically mentioned reagents, solvents, and reaction conditions can be replaced, and reactive sites can be protected or deprotected if necessary.

[0159] The following abbreviations have the following meanings:

[0160] - ACN: Acetonitrile

[0161] - EA: ethyl acetate

[0162] - CDI: N,N'-carbonyldiimidazole

[0163] - DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0164] - DIBAL-H: diisobutylaluminium hydride

[0165] - DIEA: diisopropylethylamine

[0166] - DMAP: N,N-dimethylaminopyridine

[0167] - DME: 1,2-dimethoxyethane

[0168] - DMFA: N,N-dimethylformamide

[0169] - DMA and DMAc: N,N-dimethylacetamide

[0170] - DMPE: 1,2-bis(dimethylphosphino)ethane

[0171] - DMSO: dimethylsulfoxide

[0172] - DPPB: 1,4-bis(diphenylphosphino)butane

[0173] - dppe: 1,2-bis(diphenylphosphino)ethane

[0174] - dppf: 1,1'-bis(diphenylphosphino)ferrocene

[0175] - dppm: 1,1'-bis(diphenylphosphino)methane

[0176] - DIAD: Diisopropylazodicarboxylate

[0177] - EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

[0178] - HATU: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0179] - HMPA: hexamethylphosphoramide

[0180] - IPA: isopropanol

[0181] - LDA: lithium diisopropylamide

[0182] - LHMDS: lithium bis(trimethylsilyl)amide

[0183] - LAH: lithium aluminum hydride

[0184] - NCS: N-chlorosuccinimide

[0185] - NaHMDS: sodium bis(trimethylsilyl)amide

[0186] - PyBOP: benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate

[0187] - PyBrOP: tripyrrolidinophosphonium bromide hexafluorophosphate

[0188] - TDA-I: tri(2-(2-methoxyethoxy)ethyl)amine

[0189] - DCM: dichloromethane (DCM)

[0190] - TEA: triethylamine

[0191] - TFA: trifluoroacetic acid

[0192] - THF: tetrahydrofuran

[0193] - NMM: N-methylmorpholine

[0194] - NMP: N-methyl-2-pyrrolidone

[0195] - PPh3: triphenylphosphine

[0196] - rt: room temperature

[0197] - PMB: para-methoxybenzyl

[0198] - Tosmic: p-toluenesulfonylmethyl isocyanide

[0199] - (Boc)2O: di-tert-butyl dicarbonate

[0200] - PE: petroleum ether

[0201] - o / n: reaction during the night.

[0202] The following preparation and implementation examples illustrate the present invention but do not limit it in any way.

[0203] A more detailed description of selected embodiments will provide a clearer understanding of the features and advantages of the present invention. As one skilled in the art will appreciate, the disclosed and claimed subject matter is subject to modification in various respects, and all such modifications are within the scope of the claims. Therefore, the description should be considered explanatory and not restrictive in nature. The full scope of the present invention is defined by the claims.

[0204] For a better understanding of the present invention, reference may be made to the following examples, which are given for illustration purposes and do not limit the scope of the invention.

[0205] Intermediate compounds

[0206] Intermediate raw materials were purchased from different suppliers:

[0207] Number Structure Name CAS 1 (S)-6-fluoro-2,3-dihydrobenzofuran-3-amine 1228559-33-8 2 (S)-6-chloro-2,3-dihydrobenzofuran-3-amine 1228561-83-8 3 (S)-6-bromo-2,3-dihydrobenzofuran-3-amine 1228568-69-1 4 (S)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine 1272724-36-3 5 (R)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine 1272732-77-0 6 (S)-5-fluoro-2,3-dihydrobenzofuran-3-amine 1228571-72-9 7 (S)-6-(trifluoromethyl)-2,3-dihydrofuro[3,2-c]pyridin-3-amine 8 (R)-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine 9 (S)-N-methyl-6-(trifluoromethoxy)-2,3-dihydrobenzofuran-3-amine 2814522-50-2 10 (1R,4S)-N,1-dimethyl-7-(trifluoromethyl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-amine hydrochloride 11 (5S,8R)-N,8-dimethyl-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine hydrochloride 99 (S)-N-methyl-6-(perfluoroethyl)-2,3-dihydrobenzofuran-3-amine

[0208] Intermediate 12: (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine

[0209]

[0210] Step 1: Synthesis of tert-butyl (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate

[0211] (S)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (200 mg, 0.99 mmol) was dissolved in 2 mL of DCM, then 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 h. The reaction was monitored by LCMS. The residues were purified by flash column chromatography (20 g silica gel column, 20% ethyl acetate / petroleum ether) to give a yellow liquid: tert-butyl (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (300 mg, yield: 99%).

[0212] LCMS (ESI) m / z: 304 [M+H] +

[0213] Step 2: Synthesis of tert-butyl (S)-methyl (6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate

[0214] At 0°C, (S)-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (300 mg, 0.99 mmol) was dissolved in DMF (5.00 mL), then sodium hydride (48 mg, 2.00 mmol) was added. The mixture was stirred at 0°C for 1 hour. Then iodomethane (211 mg, 1.49 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by LCMS. The residue was purified by flash column chromatography (20 g silica gel column, 15% ethyl acetate / petroleum ether) to give a yellow liquid tert-butyl (S)-methyl (6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamate (200.0 mg, 64% yield).

[0215] LCMS (ESI) m / z: 318 [M+H] +

[0216] Step 3: Synthesis of (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine

[0217] (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) at room temperature. The mixture was stirred at room temperature for 0.5 h. The reaction progress was monitored by LCMS. The mixture was concentrated to give a yellow liquid (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (130.0 mg, yield 95%).

[0218] LCMS (ESI) m / z: 218 [M+H] +

[0219] Using the method and steps for preparing intermediate compound 12, with a single replacement of the corresponding starting intermediate compound, the following intermediate compounds were obtained:

[0220] Number Structure Name m / z(IER): (M+H)+ 13 (S)-6-bromo-N-methyl-2,3-dihydrobenzofuran-3-amine 228.1 14 (S)-6-chloro-N-methyl-2,3-dihydrobenzofuran-3-amine 184 15 (S)-6-fluoro-N-methyl-2,3-dihydrobenzofuran-3-amine 168.2 16 (S)-5-fluoro-N-methyl-2,3-dihydrobenzofuran-3-amine 168.2 17 (R)-N-methyl-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine 217.2 18 (S)-N-(methyl-d3)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine 221.2 19 (S)-N-ethyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine 232.2 20 (R)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine 218.2 21 (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrofuro[3,2-c]pyridin-3-amine 219.2

[0221] Intermediate 22:(S)-3-(methylamino)-2,3-dihydrobenzofuran-6-carbonitrile

[0222]

[0223] Step 1: Synthesis of tert-butyl (S)-(6-cyano-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate

[0224] In a microwave reactor, a mixture of tert-butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (328 mg, 1 mmol), copper(I) cyanide (352 mg, 4 mmol), and N-methylpyrrolidone (4 mL) was heated at 135°C for 4 hours. After completion of the reaction, the system was cooled to room temperature, then poured into water and extracted three times with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 40:60) to obtain tert-butyl (S)-(6-cyano-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (66 mg, yield 23.93%), a colorless oily substance.

[0225] LCMS (ESI): 275 [M+H] +

[0226] Step 2: (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-carbonitrile

[0227] 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 1,4-dioxane (3 mL, 4 mol / L). 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), a white solid. The crude product was used directly in the next step without purification.

[0228] LCMS (ESI): 175 [M+H] +

[0229] Intermediate 23: Synthesis of (S)-6-methoxy-N-methyl-2,3-dihydrobenzofuran-3-amine

[0230]

[0231] tert-Butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (328 mg, 1 mmol), CuI (352 mg, 4 mmol) and a solution of sodium methoxide in methanol (180 mg, 40 mmol) in N,N-dimethylformamide (4 mL) were reacted at 120 °C for four hours. After completion of the reaction, the system was cooled to room temperature, and the mixture was extracted three times with ethyl acetate (30 mL each). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, (S)-6-methoxy-N-methyl-2,3-dihydrobenzofuran-3-amine (150 mg, 0.8 mmol, yield 80%), a colorless oily substance, was obtained.

[0232] LCMS (IER):180 [M+H] +

[0233] Intermediate 24:(S)-dimethyl(3-(methylamino)-2,3-dihydrobenzofuran-6-yl)phosphine oxide

[0234]

[0235] Step 1: Synthesis of tert-butyl (S)-(6-(dimethylphosphoryl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate

[0236] tert-Butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (200 mg, 0.61 mmol), dimethyl oxophosphorane (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 were reacted in a microwave reactor at 150 °C for 20 minutes. After completion of the reaction, the system was cooled to room temperature, and the mixture was extracted three times with ethyl acetate (30 mL in total, 10 mL each time). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, tert-butyl (S)-(6-(dimethylphosphoryl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (80 mg, 0.245 mmol, yield 40.35%) was obtained as a white solid.

[0237] LCMS (ESI): 326 [M+H] +

[0238] Step 2: (S)-dimethyl(3-(methylamino)-2,3-dihydrobenzofuran-6-yl)phosphine oxide

[0239] tert-Butyl (S)-(6-(dimethylphosphoryl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (80 mg, 0.25 mmol) was added to a solution of 4 M hydrochloric acid in 1,4-dioxane (3 mL) and stirred for 2 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. This gave (S)-dimethyl (3-(methylamino)-2,3-dihydrobenzofuran-6-yl)phosphine oxide (25 mg, 0.11 mmol, yield 45.14%), a white solid.

[0240] LCMS (ESI): 226 [M+H] +

[0241] Intermediate 25:(S)-N-methyl-6-(methylsulfonyl)-2,3-dihydrobenzofuran-3-amine

[0242]

[0243] Step 1: Synthesis of tert-butyl (S)-methyl (6-(methylsulfonyl)-2,3-dihydrobenzofuran-3-yl)carbamate

[0244] tert-Butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (328 mg, 1 mmol), sodium methanesulfinate (122 mg, 1.2 mmol), L-proline (12 mg, 0.1 mmol), potassium carbonate (166 mg, 1.2 mmol), copper(I) iodide (19 mg, 0.1 mmol) and N,N-dimethylformamide (5 mL) were reacted in a microwave reactor at 140°C for 2 hours. After completion of the reaction, the system was cooled to room temperature, and the mixture was extracted three times with ethyl acetate (30 mL in total, 10 mL each time). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, tert-butyl (S)-methyl (6-(methylsulfonyl)-2,3-dihydrobenzofuran-3-yl)carbamate (60 mg, 0.18 mmol, yield 18.32%) was obtained as a colorless oily substance.

[0245] LCMS (ESI): 328 [M+H] +

[0246] Step 2: Synthesis of (S)-N-methyl-6-(methylsulfonyl)-2,3-dihydrobenzofuran-3-amine

[0247] tert-Butyl (S)-methyl (6-(methylsulfonyl)-2,3-dihydrobenzofuran-3-yl)carbamate (60 mg, 0.24 mmol) was added to a solution of 4 M hydrochloric acid in 1,4-dioxane (3 mL) and stirred for 2 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. This gave (S)-N-methyl-6-(methylsulfonyl)-2,3-dihydrobenzofuran-3-amine (30 mg, 0.13 mmol, yield 72.03%), a white solid.

[0248] LCMS (ESI): 228 [M+H] +

[0249] Intermediate 101: Synthesis of (S)-6-(cyclopropylsulfonyl)-N-methyl-2,3-dihydrobenzofuran-3-amine

[0250]

[0251] Step 1: Synthesis of tert-butyl (S)-(6-(cyclopropylsulfonyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate

[0252] tert-Butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (300 mg, 0.914 mmol) and sodium cyclopropanesulfinate (118 mg, 0.914 mmol) were dissolved in DMSO (10 mL). Copper(I) iodide (35 mg, 0.182 mmol) and (1R,2R)-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (52 mg, 0.365 mmol) was added, and the reaction mixture was stirred at 25°C for 10 h. After LCMS showed the reaction to be complete, water (10 mL) was added, followed by extraction with ethyl acetate (20 mL × 2). The combined organic phases were washed with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (0-10% ethyl acetate / petroleum ether) gave tert-butyl (S)-(6-(cyclopropylsulfonyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (150 mg, 46.4% yield).

[0253] LCMS (ESI) m / z: 354.1 [M+H] +

[0254] Step 2: Synthesis of (S)-6-(cyclopropylsulfonyl)-N-methyl-2,3-dihydrobenzofuran-3-amine

[0255] 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 mixture was stirred at room temperature for 16 hours, and the crude product (S)-6-(cyclopropylsulfonyl)-N-methyl-2,3-dihydrobenzofuran-3-amine (150 mg, crude) was obtained by concentration under reduced pressure without the need for purification and was directly used for the next step.

[0256] LCMS (ESI) m / z: 254.1 [M+H] +

[0257] Intermediate 26: Synthesis of (S)-N-methyl-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-amine

[0258]

[0259] Step 1: Synthesis of tert-butyl (S)-methyl (6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)carbamate

[0260] Under 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 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole (239.0 mg, 1.37 mmol), potassium carbonate (377 mg, 2.73 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (67.0 mg, 0.09 mmol) were added. The reaction was carried out at 100 °C for 16 hours. The mixture was then poured into water (30 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration to remove sodium sulfate, the filtrate was evaporated on a rotary evaporator to obtain the crude product. Purification by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) gave tert-butyl (S)-methyl (6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)carbamate (240.0 mg, yield 68.8%), a white solid.

[0261] LCMS (ESI) m / z: 384.1 [M+H] +

[0262] Step 2: Synthesis of (S)-N-methyl-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-amine

[0263] At room temperature, 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 hydrochloric acid in ethyl acetate (3 mL). After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to obtain a crude product, (S)-N-methyl-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-amine (25.0 mg, crude product).

[0264] LCMS (ESI) m / z: 283.1 [M+H] +

[0265] Using the methods and steps employed for intermediate 26, with only the appropriate starting materials replaced, the following intermediates were synthesized:

[0266] Number Structure Name m / z(IER): (M+H)+ 27 (S)-N-methyl-6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-amine 230.1 28 (S)-N-methyl-6-(2-methylpyrimidin-5-yl)-2,3-dihydrobenzofuran-3-amine 242.1 29 (S)-N-methyl-6-(thiazol-4-yl)-2,3-dihydrobenzofuran-3-amine 202.1 30 (S)-N-methyl-6-(5-(trifluoromethyl)pyridin-3-yl)-2,3-dihydrobenzofuran-3-amine 295.1 31 N-cyclopropyl-6-(2-methylpyrimidin-5-yl)-2,3-dihydrobenzofuran-3-amine 268.1 32 (S)-N-methyl-6-(3-methylisoxazol-5-yl)-2,3-dihydrobenzofuran-3-amine 231.1 33 (S)-N-methyl-6-(1-methyl-1H-pyrazol-5-yl)-2,3-dihydrobenzofuran-3-amine 230.2 34 (4S)-N,1-dimethyl-7-(2-methylpyrimidin-5-yl)isochroman-4-amine 270.2 35 (4S)-N,1-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)isochroman-4-amine 258.2 36 (R)-N-methyl-7-(3-methylisoxazol-5-yl)chroman-4-amine 245.2 37 (R)-N-methyl-7-(1-methyl-1H-pyrazol-5-yl)chroman-4-amine 244.2 38 (R)-N-methyl-7-(1-methyl-1H-pyrazol-4-yl)chroman-4-amine 244.2 39 (R)-N-methyl-7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-amine 298.2 40 N-cyclopropyl-6-morpholino-2,3-dihydrobenzofuran-3-amine 261.2 103 N,1,1-trimethyl-7-(1-methyl-1H-pyrazol-4-yl)isochroman-4-amine 272.17 104 N,1,1-trimethyl-7-(1-methyl-1H-pyrazol-5-yl)isochroman-4-amine 272.17

[0267] Intermediate 41: Synthesis of 6-(trifluoromethyl)benzo[b]thiophene-3(2H)-one

[0268]

[0269] Step 1: Synthesis of 2-fluoro-4-(trifluoromethyl)benzoic acid

[0270] At room temperature, lithium hydroxide (9.70 g, 405.15 mmol) was added to a solution of methyl 2-fluoro-4-(trifluoromethyl)benzoate (30.00 g, 135.05 mmol) in tetrahydrofuran:water (300 mL:30 mL). The mixture was stirred at 50°C for 2 hours. The reaction mixture was poured into water (100 mL), and the pH was adjusted to 4 with formic acid. After extraction with ethyl acetate (100 mL × 3), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was further purified by silica gel flash column chromatography (petroleum ether:ethyl acetate = 30%) to give 2-fluoro-4-(trifluoromethyl)benzoic acid (22.00 g, yield: 78%).

[0271] LCMS (ESI) m / z: 209.1 [M+H] +

[0272] Step 2: Synthesis of 2-((2-ethoxy-2-oxoethyl)thio)-4-(trifluoromethyl)benzoic acid

[0273] At 0°C, sodium hydride (8.46 g, 211.43 mmol) was added to a solution of ethyl 2-mercaptoacetate (12.70 g, 105.72 mmol) in N,N-dimethylformamide (200.00 mL). The mixture was stirred at room temperature for 0.5 hour. Then 2-fluoro-4-(trifluoromethyl)benzoic acid (22.00 g, 105.71 mmol) was added to the solution, and the mixture was stirred for 1 hour at room temperature. 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 flash 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%).

[0274] LCMS (ESI) m / z: 309.2 [M+H] +

[0275] Step 3: Synthesis of 2-((carboxymethyl)thio)-4-(trifluoromethyl)benzoic acid

[0276] A mixture of 2-((2-ethoxy-2-oxoethyl)thio)-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).

[0277] LCMS (ESI) m / z: 281.2 [M+H] +

[0278] Step 4: Synthesis of 6-(trifluoromethyl)benzo[b]thiophen-3-yl acetate

[0279] At room temperature, sodium acetate trihydrate (10.19 g, 74.94 mmol) was added to a solution of 2-((carboxymethyl)thio)-4-(trifluoromethyl)benzoic acid (7.00 g, 24.98 mmol) in acetic anhydride (70.00 mL). The mixture was stirred at 140°C for 30 minutes. After that, the mixture was poured into water, extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (petroleum ether:ethyl acetate = 50%) gave 6-(trifluoromethyl)benzo[b]thiophen-3-yl acetate (5.00 g, yield: 77%).

[0280] LCMS (ESI) m / z: 261.2 [M+H] +

[0281] Step 5: Synthesis of 6-(trifluoromethyl)benzo[b]thiophene-3(2H)-one

[0282] At room temperature, hydrochloric acid solution (10.00 mL, 1 M) 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). The mixture was stirred at 100°C for 2 hours. After cooling, the reaction mixture was 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 obtain a crude product. Purification by flash column chromatography (petroleum ether:ethyl acetate = 70%) gave 6-(trifluoromethyl)benzo[b]thiophen-3(2H)-one (0.50 g, yield: 59%), a black solid.

[0283] LCMS (ESI) m / z: 219.2 [M+H] +

[0284] Intermediate 42: Synthesis of 1-methyl-7-(trifluoromethyl)isochroman-4-one

[0285]

[0286] Step 1: Synthesis of 2-(1-(allyloxy)ethyl)-1-bromo-4-(trifluoromethyl)benzene

[0287] At room temperature, 1-(2-bromo-5-(trifluoromethyl)phenyl)ethan-1-ol (10 g, 37.16 mmol) was dissolved in tetrahydrofuran (100 mL), then 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. The reaction was carried out for 4 hours at 25 °C. After completion, the reaction mixture was concentrated under reduced pressure and poured into water (100 mL). The aqueous layer was extracted with ethyl acetate (3 × 100 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product (12 g, crude). No further purification was required and the product was used directly in the next step.

[0288] LCMS (ESI) m / z: 309.2 [M+H] +

[0289] Step 2: Synthesis of 1-methyl-4-methylene-7-(trifluoromethyl)isochroman

[0290] 2-(1-(allyloxy)ethyl)-1-bromo-4-(trifluoromethyl)benzene (12 g, 38.82 mmol) was dissolved in DMF (100 mL), and 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) were added. The mixture was stirred at 90°C under a nitrogen atmosphere for 16 hours. The reaction mixture was poured into 400 mL of water, extracted with ethyl acetate (3 × 100 mL), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, and further purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 1-methyl-4-methylene-7-(trifluoromethyl)isochroman (5.5 g, yield: 62.1%).

[0291] LCMS (ESI) m / z: 229.1 [M+H] +

[0292] Step 3: Synthesis of 4-(hydroxymethyl)-1-methyl-7-(trifluoromethyl)isochroman-4-ol

[0293] 1-methyl-4-methylene-7-(trifluoromethyl)isochroman (5.5 g, 24.10 mmol) was dissolved in a mixed solvent of acetone (100 ml) and water (20 ml) at room temperature. N-methylmorpholine-N-oxide (9.2 g, 76.68 mmol) and potassium ruthenate (0.91 g, 2.410 mmol) were added thereto. The mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. After completion of the reaction, solid sodium sulfite (5 g) was added to the reaction mixture, and the mixture was stirred for ten minutes. The solution was concentrated under reduced pressure to remove a certain amount of acetone, poured into water (200 mL), extracted with ethyl acetate (3 × 100 mL), the combined organic phases were dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product, and further purified to give 4-(hydroxymethyl)-1-methyl-7-(trifluoromethyl)isochroman-4-ol (6.0 g, yield: 94.9%).

[0294] LCMS (ESI) m / z: 263.0 [M+H] +

[0295] Step 4: Synthesis of 1-methyl-7-(trifluoromethyl)isochroman-4-one

[0296] 4-(hydroxymethyl)-1-methyl-7-(trifluoromethyl)isochroman-4-ol (6.0 g, 22.88 mmol) was dissolved in a mixed solvent of tetrahydrofuran (100 mL) and water (3.5 mL) at room temperature. Sodium periodate (15.0 g, 68.64 mmol) was added under a nitrogen atmosphere, and the mixture was stirred at 25 °C for 4 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, filtered, washed, the combined filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 1-methyl-7-(trifluoromethyl)isochroman-4-one (5 g, crude product).

[0297] LCMS (ESI) m / z: 230.2 [M+H] +

[0298] Using the methods and steps employed for intermediate 42, with only the appropriate starting materials replaced, the following intermediates were synthesized:

[0299] Number Structure Name m / z(IER): (M+H)+ 43 6-(trifluoromethyl)isochroman-4-one 217.2 44 7-fluoro-1-methylisochroman-4-one 180.2 45 7-bromo-1-methylisochroman-4-one 242.1 46 1-methyl-6-(trifluoromethyl)isochroman-4-one 230.2 47 8-methyl-6H-pyrano[3,4-b]pyridin-5(8H)-one 164.2 48 6-fluoro-1-methylisochroman-4-one 181 49 1,1-dimethyl-7-(trifluoromethyl)isochroman-4-one 245.2

[0300] The following ketones were purchased from different suppliers:

[0301] Number Structure Name CAS 50 6-(trifluoromethyl)furo[2,3-b]pyridin-3(2H)-one 1196155-86-8 51 5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one 150969-56-5 52 7-(trifluoromethyl)chroman-4-one 111141-02-7 53 6-bromobenzofuran-3(2H)-one 3260-78-4 54 7-bromo-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one 1624261-71-7 102 7-bromo-1,1-dimethylisochroman-4-one 2763779-54-8

[0302] Intermediate 55: N-methyl-6-(trifluoromethyl)isochroman-4-amine hydrochloride

[0303]

[0304] Step 1: Synthesis of 6-(trifluoromethyl)isochroman-4-ol

[0305] 6-(trifluoromethyl)isochroman-4-one (1.1 grams, 5.09 mmol) was dissolved in THF (10 mL) at room temperature, then sodium borohydride (251 mg, 6.62 mmol) was added in an ice bath, and then 2 drops of methanol were slowly added. After complete addition, the reaction was left at room temperature overnight. After completion, the reaction was quenched with 1 M hydrochloric acid solution (2 mL), extracted with ethyl acetate (10 mL × 2), then the organic phases were combined, dried over sodium sulfate, and then filtered to obtain a crude product, which was further purified by column chromatography to give 6-(trifluoromethyl)isochroman-4-ol (1.16 grams).

[0306] Step 2: Synthesis of tert-butyl (tert-butoxycarbonyl) (6-(trifluoromethyl)isochroman-4-yl)carbamate

[0307] At room temperature, 6-(trifluoromethyl)isochroman-4-ol (100.0 mg, 0.459 mmol) was dissolved in THF (5.0 mL), then di-tert-butyl dicarbonate (110 mg, 0.505 mmol) and triphenylphosphine (132 mg, 0.505 mmol) were added successively. The reaction mixture was stirred at 0 °C for 5 min, then DIAD (102 mg, 0.505 mmol) was added, and the reaction was stirred at room temperature overnight. After completion, water (10 mL) was added. The reaction mixture was extracted with ethyl acetate (10 mL × 3). Then, the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The resulting filtrate was concentrated under reduced pressure to obtain a crude product. Further purification by column chromatography (neat petroleum ether) gave tert-butyl (tert-butoxycarbonyl)(6-(trifluoromethyl)isochroman-4-yl)carbamate (90.0 mg).

[0308] Step 3: Synthesis of tert-butyl (6-(trifluoromethyl)isochroman-4-yl)carbamate

[0309] Tert-butyl (tert-butoxycarbonyl)(6-(trifluoromethyl)isoxazol-4-yl)methylamine (60.0 mg, 0.14 mmol) was dissolved in acetonitrile (2.0 mL), then lithium bromide (37.6 mg, 0.432 mmol) was added. The reaction mixture was heated at 60 °C for 20 hours. After completion, saturated sodium bicarbonate (10 mL) was added and extracted with ethyl acetate (20 mL). Then, the organic phase was dried with sodium sulfate and filtered. The resulting filtrate was concentrated under reduced pressure to obtain (6-(trifluoromethyl)isochroman-4-yl)carbamate (30 mg).

[0310] Step 4: Synthesis of tert-butyl methyl (6-(trifluoromethyl)isochroman-4-yl)carbamate

[0311] (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 min. At this temperature, sodium hydride (90.8 mg, 2.27 mmol) was added and stirred for 1 hour. Then, methyl iodide (487 mg, 3.41 mmol) was added, and the reaction mixture was stirred at room temperature overnight. After completion, saturated sodium bicarbonate solution (15 mL) was added, extracted with ethyl acetate (15 mL × 3), the organic phase was dried with sodium sulfate and then filtered, and the filtrate was concentrated to obtain the crude product tert-butyl methyl (6-(trifluoromethyl)isochroman-4-yl)carbamate (400.0 mg).

[0312] Step 5: Synthesis of N-methyl-6-(trifluoromethyl)isochroman-4-amine hydrochloride

[0313] Tert-butyl methyl (6-(trifluoromethyl)isochroman-4-yl)carbamate (400 mg, 1.21 mmol) was dissolved in 2 ml of dichloromethane at room temperature, and then a solution of 4 M hydrochloric acid in dioxane (2 ml) was added. The reaction was stirred at room temperature overnight. After completion, the reaction mixture was directly evaporated to obtain N-methyl-6-(trifluoromethyl)isochroman-4-amine hydrochloride (390 mg).

[0314] Using the methods and steps employed for intermediate 55, with only the appropriate starting materials replaced, the following intermediates were synthesized:

[0315] Number Structure Name m / z(IER): (M+H)+ 56 N-methyl-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-amine 216.2 57 N-methyl-8-(trifluoromethyl)-1,3,4,5-tetrahydrobenzo[c]oxepin-5-amine 246.2 58 N-methyl-6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-amine 219.2 59 N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzo[b]thiophen-3-amine 234.2

[0316] Intermediate 60: Synthesis of (R)-N-methyl-7-(trifluoromethyl)chroman-4-amine hydrochloride

[0317]

[0318] Step 1: Synthesis of (S)-7-(trifluoromethyl)chroman-4-ol

[0319] 7-(trifluoromethyl)chroman-4-one (500.0 mg, 2.31 mmol) was dissolved in DCM (10 mL) at room temperature, then (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethane-1,2-diamine (147.0 mg, 0.23 mmol) was added thereto under ice bath cooling. Then, formic acid (372.0 mg, 8.10 mmol) was added dropwise, and finally, triethylamine (701.0 mg, 6.94 mmol) was added dropwise. After completion, the reaction mixture was left at room temperature overnight. After completion, saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). After combining the organic phases, drying over sodium sulfate, and filtration, the crude product was obtained. Purification by column chromatography (petroleum ether:ethyl acetate = 0-40%) gave (S)-7-(trifluoromethyl)chroman-4-ol (370 mg, yield: 73%).

[0320] Step 2: Synthesis of tert-butyl (R)-(tert-butoxycarbonyl)(7-(trifluoromethyl)chroman-4-yl)carbamate

[0321] Under a nitrogen atmosphere, (S)-7-(trifluoromethyl)chroman-4-ol (370.0 mg, 1.70 mmol) was first dissolved in THF (5.0 mL), then di-tert-butyl imidodicarbonate (405 mg, 1.88 mmol) and triphenylphosphine (489 mg, 1.88 mmol) were added. The reaction mixture was stirred for 5 min at 0 °C, and DIAD (377.0 mg, 1.88 mmol) was added dropwise. After stirring at room temperature overnight, the reaction was completed. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). After combining the organic phases, drying over anhydrous sodium sulfate, and filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. Further purification by column chromatography (petroleum ether:ethyl acetate = 0-5%) gave tert-butyl (R)-(tert-butoxycarbonyl)(7-(trifluoromethyl)chroman-4-yl)carbamate (145.0 mg, yield: 20%).

[0322] 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).

[0323] Step 3: Synthesis of tert-butyl (R)-(7-(trifluoromethyl)chroman-4-yl)carbamate

[0324] Tert-butyl (R)-(tert-butoxycarbonyl)(7-(trifluoromethyl)chroman-4-yl)carbamate (150.0 mg, 0.36 mmol) was dissolved in acetonitrile (5.0 mL), and lithium bromide (94.0 mg, 1.08 mmol) was added. The reaction mixture was heated at 60°C for 20 hours. After completion of the reaction, saturated sodium bicarbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). After drying the organic phase over sodium sulfate and filtration, the filtrate was concentrated to obtain the crude product, tert-butyl (R)-(7-(trifluoromethyl)chroman-4-yl)carbamate (83.0 mg, crude product).

[0325] Step 4: Synthesis of tert-butyl (R)-methyl(7-(trifluoromethyl)chroman-4-yl)carbamate

[0326] Tert-butyl (R)-(7-(trifluoromethyl)chroman-4-yl)carbamate (83.0 mg, 0.26 mmol) was dissolved in 2.0 mL of DMF. The mixture was stirred in an ice bath for 2 min, and sodium hydride (26.2 mg, 0.66 mmol) was added in one portion. The reaction mixture was stirred at this temperature for 1 h, then iodomethane (74.4 mg, 0.52 mmol) was added; the reaction was continued overnight at room temperature. After completion of the reaction, saturated sodium bicarbonate solution (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 concentrated to give the crude product, tert-butyl (R)-methyl (7-(trifluoromethyl)chroman-4-yl)carbamate (100.0 mg, crude product).

[0327] LCMS (ESI) m / z: 276.1 [M+H] +

[0328] Step 5: Synthesis of (R)-N-methyl-7-(trifluoromethyl)chroman-4-amine hydrochloride

[0329] Tert-butyl (R)-methyl (7-(trifluoromethyl)chroman-4-yl)carbamate (100 mg, 0.3 mmol) was dissolved in 2 mL of dichloromethane, and a solution of 4 M hydrochloric acid in dioxane (2 mL) was added. The reaction was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was directly evaporated to dryness to obtain the crude product, (R)-N-methyl-7-(trifluoromethyl)chroman-4-amine hydrochloride (90 mg, crude product).

[0330] Using the methods and steps employed for intermediate 60, with only the appropriate starting materials replaced, the following intermediates were synthesized:

[0331] Number Structure Name m / z(IER): (M+H)+ 61 (4S)-6-fluoro-N,1-dimethylisochroman-4-amine hydrochloride 196.2 62 (4S)-N,1-dimethyl-7-(trifluoromethyl)isochroman-4-amine hydrochloride 246.2 63 (4S)-7-fluoro-N,1-dimethylisochroman-4-amine hydrochloride 196.2 64 (4S)-7-bromo-N,1-dimethylisochroman-4-amine hydrochloride 256.2 65 (4S)-N,1-dimethyl-6-(trifluoromethyl)isochroman-4-amine hydrochloride 246.2 66 (5S)-N,8-dimethyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-amine hydrochloride 179.2 67 (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzo[b]thiophen-3-amine 234.2 68 (R)-N-methyl-8-(trifluoromethyl)-1,3,4,5-tetrahydrobenzo[c]oxepin-5-amine 246.2

[0332] Intermediate 100: Synthesis of N,1,1-trimethyl-7-(trifluoromethyl)isochroman-4-amine

[0333]

[0334] Step 1: Synthesis of 1,1-dimethyl-7-(trifluoromethyl)isochroman-4-ol

[0335] 1,1-dimethyl-7-(trifluoromethyl)isochroman-4-one (300 mg, 1.229 mmol) was dissolved in MeOH (3 mL), and sodium borohydride (70 mg, 1.844 mmol) was added. The reaction was stirred at 25°C for 10 h. After completion as confirmed by LCMS, NH4Cl solution (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 filtrate was concentrated under reduced pressure. Purification by column chromatography (0-10% ethyl acetate / petroleum ether) gave 1,1-dimethyl-7-(trifluoromethyl)isochroman-4-ol (120 mg, yield: 39.4%).

[0336] LCMS (ESI) m / z: 247.1 [M+H] +

[0337] Step 2: Synthesis of 1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl methanesulfonate

[0338] 1,1-dimethyl-7-(trifluoromethyl)isochroman-4-ol (120 mg, 0.487 mmol) and methanesulfonyl chloride (112 mg, 0.974 mmol) were dissolved in DCM (10 mL), and triethylamine (148 mg, 1.461 mmol) was added. The reaction was stirred at 25°C for 10 h. After completion as confirmed by LCMS, 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 filtrate was concentrated under reduced pressure to obtain crude 1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl methanesulfonate (130 mg, yield: 13.3%).

[0339] LCMS (ESI) m / z: 326.1 [M+H] +

[0340] Step 3: Synthesis of N,1,1-trimethyl-7-(trifluoromethyl)isochroman-4-amine

[0341] At room temperature, 1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl methanesulfonate (130 mg, 0.398 mmol) was dissolved in DMF (3 mL), and a solution of methylamine (0.3 mL, 30%) in MeOH and DIEA (155 mg, 1.194 mmol) were added. The reaction was stirred at room temperature for 16 h. After completion as confirmed by LCMS, 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 filtrate was concentrated under reduced pressure. Purification by column chromatography (50-100% ethyl acetate / petroleum ether) gave N,1,1-trimethyl-7-(trifluoromethyl)isochroman-4-amine (52 mg, yield: 50.4%).

[0342] LCMS (ESI) m / z: 260.1 [M+H] +

[0343] Using the methods and steps employed for intermediate 100, with only the appropriate starting materials replaced, the following intermediates were synthesized:

[0344] Number Structure Name m / z(IER): (M+H)+ 105 7-bromo-N,1,1-trimethylisochroman-4-amine 270.04

[0345] Intermediate 69: Synthesis of 6-bromo-N-cyclopropyl-2,3-dihydrobenzofuran-3-amine

[0346]

[0347] Step 1: Synthesis of 5-bromo-2-((cyclopropylimino)methyl)phenol

[0348] 4-bromo-2-hydroxybenzaldehyde (2.0 g, 9.95 mmol) was dissolved in dichloromethane (40 mL) at room temperature, and cyclopropylamine (1.13 g, 19.9 mmol) and anhydrous magnesium sulfate (4.79 g, 39.8 mmol) were added. The mixture was stirred at 25 °C for 20 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, filtered, and 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) as a yellow solid, used directly in the next step without purification.

[0349] LCMS (ESI) m / z: 241.1 [M+H] +

[0350] Step 2: Synthesis of 6-bromo-N-cyclopropyl-2,3-dihydrobenzofuran-3-amine

[0351] At room temperature, potassium tert-butoxide (1.99 g, 17.70 mmol) was slowly added to a solution of trimethylsilyl iodide (3.89 g, 17.70 mmol) in THF (5 mL). The mixture was stirred at room temperature for 0.5 hour, then 5-bromo-2-((cyclopropylimino)methyl)phenol (1.7 g, 7.08 mmol) dissolved in THF was slowly added to the reaction mixture. The resulting suspension was stirred at room temperature for 1 hour and then at 50 °C for 3 hours. The reaction mixture was cooled to room temperature, and 1 equivalent of potassium tert-butoxide (0.79 g, 7.08 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was diluted with water and extracted with ethyl acetate.After concentration of the organic layer, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give an oily substance, 6-bromo-N-cyclopropyl-2,3-dihydrobenzofuran-3-amine (1.0 g, 3.93 mmol), as a yellow oil.

[0352] LCMS (ESI) m / z: 255.1 [M+H] +

[0353] Using the methods and steps employed for intermediate 69, with only the appropriate starting materials replaced, the following intermediates were synthesized

[0354] Number Structure Name m / z(IER): (M+H)+ 70 N-cyclopropyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine 244.2

[0355] Intermediate 71: Synthesis of 3-(cyclopropylamino)-2,3-dihydrobenzofuran-6-carbonitrile

[0356]

[0357] At room temperature, 6-bromo-N-cyclopropyl-2,3-dihydrobenzofuran-3-amine (100 mg, 0.41 mmol) was placed in a 50 mL single-neck flask, and Pd2(dba)3 (18.8 mg, 0.02 mmol), S-Phos (9.8 mg, 0.02 mmol), zinc cyanide (96.5 mg, 0.82 mmol) were added. Then, N,N-dimethylacetamide (1.0 mL) was added, and the reaction mixture was heated to 110 °C with stirring under microwave irradiation for 1 hour. After adding water (10 mL), the mixture was extracted with ethyl acetate (20 mL × 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain the crude product. After purification by column chromatography using ethyl acetate: petroleum ether (0-50%), the final product 3-(cyclopropylamino)-2,3-dihydrobenzofuran-6-carbonitrile (55 mg, yield: 67%) was obtained.

[0358] 1H 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), 4.5-4.5, (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).

[0359] Intermediate Compound 72:Synthesis of (S)-6-(fluoromethyl)-N-methyl-2,3-dihydrobenzofuran-3-amine

[0360]

[0361] Stage 1: Synthesis of tert-butyl (S)-(6-(hydroxymethyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate

[0362] A mixture of tert-butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (400 mg, 1.22 mmol), (tributylstannyl)methanol (391 mg, 1.22 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) 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), extracted with ethyl acetate (10 mL × 2), and the combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a 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%).

[0363] LCMS (ESI): 280 [M+H] +

[0364] Step 2: Synthesis of tert-butyl (S)-(6-(fluoromethyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate

[0365] At -78°C, [bis(2-methoxyethyl)amino]sulfur trifluoride (396 mg, 1.79 mmol) was added to a mixture of tert-butyl (S)-(6-(hydroxymethyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (100 mg, 0.36 mmol) in dichloromethane (1.00 mL). The mixture was stirred for 1 hour at -78°C. After completion of the reaction, it was quenched with ice water (5 mL), extracted with ethyl acetate (5 mL × 2), and the combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 20:80) to give tert-butyl (S)-(6-(fluoromethyl)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (80 mg, yield: 70%).

[0366] LCMS (ESI): 282 [M+H] +

[0367] Step 3: Synthesis of (S)-6-(fluoromethyl)-N-methyl-2,3-dihydrobenzofuran-3-amine

[0368] 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 completion of the reaction, the reaction mixture was directly evaporated to obtain (S)-6-(fluoromethyl)-N-methyl-2,3-dihydrobenzofuran-3-amine (100 mg, crude product).

[0369] LCMS (ESI): 182 [M+H] +

[0370] Intermediate 73: Synthesis of (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-carboxamide

[0371]

[0372] Step 1: Synthesis of (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-carboxylic acid

[0373] At room temperature, a solution of methyl (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-carboxylate (1 g, 3.25 mmol) in methanol (10.00 mL) and tetrahydrofuran (10.00 mL) was treated with sodium hydroxide (260 mg, 6.5 mmol). The reaction mixture was stirred for 1 hour at room temperature. After completion, the reaction solution was concentrated to obtain white (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-carboxylic acid (600 mg, crude product).

[0374] LCMS (ESI): 294 [M+H] +

[0375] Step 2: Synthesis of tert-butyl (S)-(6-carbamoyl-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate

[0376] (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-carboxylic acid (600 mg, 2.04 mmol) was dissolved in N,N-dimethylformamide (5.00 mL) at room temperature, then N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (1.62 g, 4.38 mmol), N,N-diisopropylethylamine (1.38 g, 10.68 mmol), and ammonium chloride (360 mg, 6.78 mmol) were added. The mixture was allowed to react at room temperature for 30 minutes. After completion, the reaction was diluted with ethyl acetate (30 mL) and water (30 mL). The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to afford the crude product. The crude product was purified by flash chromatography (ethyl acetate / petroleum ether = 17%) to afford tert-butyl (S)-(6-carbamoyl-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (240 mg, 40% yield) as a yellow liquid.

[0377] LCMS (ESI): 293 [M+H] +

[0378] Step 3: Synthesis of (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-carboxamide

[0379] Tert-butyl (S)-(6-carbamoyl-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (240 mg, 0.82 mmol) was dissolved in dichloromethane (2.00 mL) and trifluoroacetic acid (0.40 mL) at room temperature. The mixture was stirred at room temperature for half an hour. After completion, the reaction solution was concentrated to obtain a black solid (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-carboxamide (100 mg, yield: 66.66%).

[0380] Intermediate 74: Synthesis of (S)-N 3 -methyl-2,3-dihydrobenzofuran-3,6-diamine

[0381]

[0382] Step 1: Synthesis of tert-butyl (S)-(6-((diphenylmethylene)amino)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate

[0383] 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. Benzophenone imine (190 mg, 1.06 mmol), potassium tert-butoxide (80 mg, 0.71 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, Xantphos (40 mg, 0.07 mmol), and palladium acetate (8 mg, 0.03 mmol) were added to the solution. The reaction was carried out at 100 °C for 2 hours. After completion, the reaction mixture was poured into water (2 mL), extracted with ethyl acetate (2 mL × 2), and the combined organic layers were washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography (petroleum ether:ethyl acetate = 10%) to obtain a white solid tert-butyl (S)-(6-((diphenylmethylene)amino)-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (90 mg, yield 59%).

[0384] LCMS (ESI): 429 [M+H] +

[0385] Step 2: Synthesis of (S)-N3 -methyl-2,3-dihydrobenzofuran-3,6-diamine

[0386] 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. The mixture was stirred at room temperature for 0.5 hour. After completion, the reaction solution was poured into dichloromethane solution to precipitate a white solid, giving (S)-N 3 -methyl-2,3-dihydrobenzofuran-3,6-diamine (60 mg, yield: 90%).

[0387] LCMS (ESI): 165 [M+H] +

[0388] Intermediate 75: Synthesis of (S)-1,1,1-trifluoro-N-(3-(methylamino)-2,3-dihydrobenzofuran-6-yl)methanesulfonamide

[0389]

[0390] Step 1: Synthesis of tert-butyl (S)-methyl (6-((trifluoromethyl)sulfonamido)-2,3-dihydrobenzofuran-3-yl)carbamate

[0391] Tert-butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (200 mg, 0.61 mmol), trifluoromethanesulfonamide (136 mg, 0.91 mmol), copper(I) iodide (1.16 g, 6.09 mmol) and potassium phosphate (259 mg, 1.22 mmol) were sequentially dissolved in N,N-dimethylformamide (9 mL) solution. The mixture was stirred at 90 °C for 2 hours. After completion, the system was cooled to room temperature and extracted three times with ethyl acetate (10 mL each). The organic phases were combined, washed with saturated brine (10 mL, 3 times), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to obtain tert-butyl (S)-methyl (6-((trifluoromethyl)sulfonamido)-2,3-dihydrobenzofuran-3-yl)carbamate (800 mg, yield: 51.85%) as a yellow liquid.

[0392] LCMS (ESI): 397.2 [M+H] +

[0393] Step 2: Synthesis of (S)-1,1,1-trifluoro-N-(3-(methylamino)-2,3-dihydrobenzofuran-6-yl)methanesulfonamide

[0394] Tert-butyl (S)-methyl (6-((trifluoromethyl)sulfonamido)-2,3-dihydrobenzofuran-3-yl)carbamate (80 mg, 3.246 mmol) was dissolved in a solution of hydrochloric acid in 1,4-dioxane (4.0 M, 5 mL). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the system was cooled to room temperature, and the reaction mixture was concentrated in vacuo to obtain (S)-1,1,1-trifluoro-N-(3-(methylamino)-2,3-dihydrobenzofuran-6-yl)methanesulfonamide (60 mg, 1.18 mmol, yield: 82.46%).

[0395] Intermediate 76: Synthesis of 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0396]

[0397] Step 1: Synthesis of 5H,10H-diimidazo[1,5-a:1',5'-d]pyrazine-5,10-dione

[0398] Imidazo-5-carboxylic acid (100 g, 892.14 mmol) was added to sulfur dichloride (500 mL) and stirred at 80°C for 12 hours. The mixture was concentrated, and the concentrated solution was washed with toluene (500 mL × 2) and filtered to obtain a solid product. After removing the residual solvent under vacuum, 5H,10H-diimidazo[1,5-a:1',5'-d]pyrazine-5,10-dione (70 g, 0.37 mol, yield: 42%) was obtained as a yellow solid.

[0399] LCMS (ESI) m / z: 189 [M+H] +

[0400] Step 2: Synthesis of N-(4-bromo-2-fluorophenyl)-1H-imidazole-5-carboxamide

[0401] At 0°C, a solution of 4-bromo-2-fluorophenylamine (60.60 g, 318.91 mmol) in tetrahydrofuran (600 mL) was slowly added dropwise to a mixture of sodium bis(trimethylsilyl)amide (318.91 mL, 637.82 mmol, 2 mol / L) over 1 hour. Then, 5H,10H-diimidazo[1,5-a:1',5'-d]pyrazine-5,10-dione (60 g, 318.91 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After this, the reaction mixture was poured into water, filtered, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40%) to obtain N-(4-bromo-2-fluorophenyl)-1H-imidazole-5-carboxamide (60 g, 0.21 mol, yield: 66%) as a white solid.

[0402] LCMS (ESI) m / z: 284.2 [M+H] +

[0403] Step 3: Synthesis of 8-bromimidazo[1,5-a]quinoxalin-4-ol

[0404] N-(4-bromo-2-fluorophenyl)-1H-imidazole-5-carboxamide (60 g, 211.20 mmol) and sodium hydride (16.88 g, 422.40 mmol, 60% dispersion) were stirred in dimethylacetamide (600 mL) at 140°C for 12 hours. Then, the mixture was poured into water and filtered to obtain 8-bromimidazo[1,5-a]quinoxalin-4-ol (50 g, yield: 90%) as a yellow solid.

[0405] LCMS (ESI) m / z: 264.2 [M+H] +

[0406] Step 4: Synthesis of 8-bromo-4-chloroimidazo[1,5-a]quinoxaline

[0407] Phosphorus oxychloride (500 mL) was added to a mixture of 8-bromimidazo[1,5-a]quinoxalin-4-ol (50 g, 189.34 mmol) and N,N-diisopropylethylamine (48.85 g, 378.67 mmol). The mixture was stirred at 90°C for 2 hours and then concentrated. The residue was dissolved in acetonitrile and slowly added to ice water, resulting in the formation of a precipitate. 8-bromo-4-chloroimidazo[1,5-a]quinoxaline (50 g, yield: 93%) was obtained by filtration.

[0408] LCMS (ESI) m / z: 282.2 [M+H] + .

[0409] Step 5: Synthesis of 8-bromo-N-(4-methoxybenzyl)imidazo[1,5-a]quinoxalin-4-amine

[0410] N,N-Diisopropylethylamine (45.66 g, 353.96 mmol) was added to a mixture of 8-bromo-4-chloroimidazo[1,5-a]quinoxaline (50 g, 176.98 mmol) and 4-methoxybenzylamine (29.13 g, 212.38 mmol) in dimethyl sulfoxide (500 mL). The mixture was stirred at 80°C for 2 hours and then poured into water. A yellow oily substance, 8-bromo-N-(4-methoxybenzyl)imidazo[1,5-a]quinoxalin-4-amine (50 g, yield: 74%), was obtained by filtration.

[0411] LCMS (ESI) m / z: 383.2 [M+H] +

[0412] Step 6: Synthesis of methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate

[0413] 8-bromo-N-(4-methoxybenzyl)imidazo[1,5-a]quinoxalin-4-amine (50 g, 130.47 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (10.83 g, 13.05 mmol) and potassium acetate (25.57 g, 260.93 mmol) were successively added to a solution of dimethylformamide (50 ml) and methanol (250 ml). The system was maintained under reaction at 100°C under carbon monoxide atmosphere (4 MPa) for 12 hours, then poured into water and filtered. Purification by silica gel chromatography (petroleum ether:ethyl acetate = 80%) gave methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (30 g, yield: 63%) as a yellow solid.

[0414] LCMS (ESI) m / z: 363.2 [M+H] +

[0415] Step 7: Synthesis of 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid

[0416] Methyl 4-((4-methoxybenzyl)amino)imidazo[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) together with potassium hydroxide (92.40 g, 165.0 mmol). The reaction proceeded at 60°C for 12 hours, and after vacuum concentration to remove the organic solvent, the residue was poured into water. The pH was then adjusted to 7-8 with HCl (2 M), followed by extraction with ethyl acetate (100 mL × 3) and vacuum concentration to give 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (25 g, yield: 86%).

[0417] LCMS (ESI) m / z: 349.2 [M+H] +

[0418] LCMS (ESI) m / z: 229.2 [M+H] +

[0419] Step 8: Synthesis of 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0420] 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, and the reaction was monitored by LCMS. The reaction mixture was concentrated to obtain 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (60.0 mg, yield: 94%) as a white solid.

[0421] Using the methods and steps employed for intermediate 76, with only the appropriate starting materials replaced, the following intermediates were synthesized:

[0422] Number Structure Name m / z(IER): (M+H)+ 77 4-aminopyrazolo[1,5-a]quinoxaline-8-carboxylic acid 229.2 78 4-aminoimidazo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxylic acid 230.2 79 4-amino-3-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid 243.2 80 4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylic acid 230.2 81 4-amino-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylic acid 263.2 82 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid 247.2 83 4-amino-7-(trifluoromethyl)imidazo[1,5-a]quinoxaline-8-carboxylic acid 297.2

[0423] Intermediate compound 84: Synthesis of 4-amino-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0424]

[0425] Step 1: Synthesis of methyl 3-(2-methyl-1H-imidazol-1-yl)-4-nitrobenzoate

[0426] Methyl 3-fluoro-4-nitrobenzoate (20.0 g, 100 mmol) was dissolved in acetonitrile (100 mL), then 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, and the reaction progress was monitored by liquid chromatography-mass spectrometry (LCMS). The reaction mixture was poured into 300 mL of water and then extracted with ethyl acetate (200 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated in vacuo, and the residue was further purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10%) to obtain a yellow solid of methyl 3-(2-methyl-1H-imidazol-1-yl)-4-nitrobenzoate (25.0 g, yield: 95%).

[0427] LCMS (ESI) m / z: 262 [M+H] +

[0428] Step 2: Synthesis of methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate

[0429] At room temperature, 3-(2-methyl-1H-imidazol-1-yl)-4-nitrobenzoate (25 g, 95.8 mmol) was dissolved in methanol (300 mL), then Raney nickel (2 g) was added. The mixture was stirred for 12 hours under a hydrogen atmosphere at room temperature. The reaction was monitored by LCMS. The residue was filtered off, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20%) to give a yellow solid methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate (20.5 g, yield: 93%).

[0430] LCMS (ESI) m / z: 232 [M+H] +

[0431] Step 3: Synthesis of methyl 1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate

[0432] At room temperature, methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate (2.0 g, 8.7 mmol) was dissolved in o-dichlorobenzene (40 mL), then carbonyldiimidazole (2.8 g, 17.4 mmol) was added. The mixture was stirred for 12 hours at 180°C. The reaction was monitored by liquid chromatography-mass spectrometry (LCMS). The mixture was filtered to obtain a filter cake, and the filter cake was washed with ethyl acetate (5 mL) to obtain a black solid methyl 1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate (920.0 mg, yield: 41%).

[0433] LCMS (ESI) m / z: 258 [M+H] +

[0434] Step 4: Synthesis of methyl 4-chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate

[0435] At room temperature, 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), and the mixture was stirred for 4 hours at 120°C. The reaction was monitored by liquid chromatography-mass spectrometry (LCMS). The reaction mixture 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. The resulting solid, methyl 4-chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60.0 mg, yield: 56%), was obtained as a black solid.

[0436] LCMS (ESI) m / z: 276 [M+H] +

[0437] Step 5: Synthesis of methyl 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate

[0438] 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, then (4-methoxyphenyl)methanamine (60 mg, 0.44 mmol) and N,N-diisopropylethylamine (67 mg, 0.52 mmol) were added. The mixture was stirred for 1 hour at 100 °C. The reaction was monitored by liquid chromatography-mass spectrometry (LCMS). The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). Then, the combined organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel chromatography (petroleum ether:ethyl acetate = 40%) to obtain a black solid of methyl 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60 mg, yield: 73%).

[0439] LCMS (ESI) m / z: 377 [M+H] +

[0440] Step 6: Synthesis of 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0441] 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, and then potassium hydroxide (26 mg, 0.44 mmol) was added. The mixture was stirred for 1 hour at room temperature. The reaction progress was monitored by liquid chromatography-mass spectrometry (LCMS). The reaction mixture was poured into water (10 mL), then carefully adjusted to acidic pH with formic acid, extracted with ethyl acetate (10 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated to give a white solid of 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (50 mg, yield: 86%).

[0442] LCMS (ESI) m / z: 363 [M+H] +

[0443] LCMS (ESI) m / z: 243 [M+H] +

[0444] Step 7: Synthesis of 4-amino-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0445] A solution of 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (400 mg, 1.10 mmol) in trifluoroacetic acid (5.00 mL) was stirred at 90°C for 2 hours. The reaction solution was then concentrated under vacuum to obtain 4-amino-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (250 mg, yield: 94%).

[0446] Intermediate compound 85: Synthesis of 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0447]

[0448] Step 1: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylate

[0449] 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 mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried over anhydrous sodium sulfate, and filtered. The solution was then concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 70:30) to obtain 4-((tert-butoxycarbonyl)amino)-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylate (1.00 g, yield 61%) as a white solid.

[0450] LCMS (IER): 376 [M+H] +

[0451] Step 2: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylate

[0452] In a nitrogen atmosphere, a mixture of 4-((tert-butoxycarbonyl)amino)-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylate (0.20 g, 0.53 mmol), potassium hexacyanoferrate(III) (0.05 g, 0.16 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.09 g, 0.21 mmol), 2'-(amino)[1,1'-biphenyl]-2-yl][bis(1,1-dimethylethyl)[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonato)palladium acetate (0.17 g, 0.21 mmol) and Potassium hydroxide (0.01 g, 0.07 mmol) in 1,4-dioxane / water (4.00 mL) was stirred at 100°C for 2 h under reflux. Then, the mixture was 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.

[0453] LCMS (IER): 368 [M+H] +

[0454] Step 3: Synthesis of methyl 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylate

[0455] Trifluoroacetic acid (0.10 mL) was added to a solution of 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylate (0.20 g, 0.54 mmol) in dichloromethane (0.50 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to obtain methyl 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylate (0.05 g, crude product).

[0456] LCMS (ESI): 268 [M+H] +

[0457] Step 4: Synthesis of 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0458] 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 completion of the reaction, the system was concentrated to obtain 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 purification.

[0459] LCMS (ESI): 254 [M+H] +

[0460] Intermediate compound 86: Synthesis of 4-amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0461]

[0462] Step 1: Synthesis of methyl 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylate

[0463] A mixture of methyl 7-chloro-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (200 mg, 0.5 mmol), potassium carbonate (300 mg, 2 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.08 g, 0.1 mmol) and trimethylboroxine (0.01 g, 0.10 mmol) in 1,2-dimethoxyethane (2.00 mL) was stirred at 100 °C for 12 hours, then poured into water, extracted with ethyl acetate (5 mL), dried the organic phase with sodium sulfate, filtered and purified by column chromatography (petroleum ether:ethyl acetate = 30%) to obtain Methyl 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylate (100 mg, 53%).

[0464] LCMS (ESI): 268 [M+H] +

[0465] Step 2: Synthesis of 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0466] Methyl 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylate (500 mg, 1.86 mmol) was dissolved in a mixed solvent of methanol / tetrahydrofuran / saturated aqueous potassium hydroxide solution (1 ml / 1 ml / 1 ml). The reaction mixture was heated at 60°C for 12 hours and then evaporated to dryness. The pH was adjusted to 3 with formic acid and filtered to obtain 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (52 mg, yield 12%).

[0467] LCMS (IER): 363 [M+H] +

[0468] Step 3: Synthesis of 4-amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0469] 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (500 mg, 1.86 mmol) was dissolved in trifluoroacetic acid (5 mL). The reaction mixture was stirred at 100°C for 12 hours. After completion, the reaction system was evaporated to dryness to obtain 4-amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (520 mg, crude product).

[0470] LCMS (ESI): 363 [M+H] +

[0471] Using the method described in the third step for intermediate 86, the following intermediate acids were prepared:

[0472] Number Structure Name m / z(IER): (M+H)+ 87 4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylic acid 230.1 88 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid 229.1 89 4-amino-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylic acid 263.1 90 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid 247.1 91 4-amino-7-(trifluoromethyl)imidazo[1,5-a]quinoxaline-8-carboxylic acid 297.1 92 5-aminopyrrolo[1,2-c]quinazoline-9-carboxylic acid 228.1

[0473] Intermediate compound 93: 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid

[0474]

[0475] Step 1: Synthesis of 6-bromo-2-chloro-3-hydrazinylquinoxaline

[0476] At room temperature, 6-bromo-2,3-dichloroquinoxaline (278.0 mg, 1.0 mmol) was first added to a 25 mL single-neck flask. Then, hydrazine hydrate (156 mg, 2.5 mmol, 80% by weight) was added. After completion, the reaction was maintained at room temperature overnight. After completion of the reaction, the mixture was filtered to obtain a precipitate, and the precipitate was washed with water (10 mL × 2), washed with ethyl acetate (5 mL × 2) to obtain 6-bromo-2-chloro-3-hydrazinylquinoxaline (150 mg).

[0477] LCMS (ESI) m / z: 273.0 / 275.0 [M+H] +

[0478] Step 2: Synthesis of 8-bromo-4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline

[0479] 6-bromo-2-chloro-3-hydrazinylquinoxaline (116.0 mg, 0.5 mmol) was added to a 25 mL single-neck flask at room temperature. Then, triethyl orthoformate (4.0 mL) was added. The reaction mixture was then heated to 100 °C and maintained at this temperature for 1 hour. When the reaction was complete as confirmed by LCMS, the reaction mixture was cooled to room temperature and then filtered to obtain a precipitate. The precipitate was washed with methanol (3.0 mL × 3) and then dried to obtain 8-bromo-4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline (110 mg).

[0480] 1 H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 8.84 (d, 1H), 7.98 (d, 1H), 7.90 (dd, 1H).

[0481] Step 3: Synthesis of 8-bromo-N-(4-methoxybenzyl)-[1,2,4]triazolo[4,3-a]quinoxalin-4-amine

[0482] 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), then benzylamine (1.23 g, 9.00 mmol) and DIEA (2.32 g, 18.00 mmol) were added successively. The reaction system was maintained at 90 °C for 4 hours. After completion, water (60 mL) was added, followed by extraction with ethyl acetate (40 mL × 3), dried with sodium sulfate, filtered and concentrated to obtain the crude product, 8-bromo-N-(4-methoxybenzyl)-[1,2,4]triazolo[4,3-a]quinoxalin-4-amine (2.20 g).

[0483] LCMS (ESI) m / z: 384.1 / 386.1 [M+H] +

[0484] Step 4: Methyl 4-((4-methoxybenzyl)amino)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate

[0485] Potassium acetate (1.7 g, 17.2 mmol) and Pd(dppf)Cl2 (420 mg, 0.57 mmol) were successively added to a solution of 8-bromo-N-(4-methoxybenzyl)-[1,2,4]triazolo[4,3-a]quinoxalin-4-amine (2.2 g, 5.74 mmol) in MeOH (30 mL) and DMF (30 mL). Under CO atmosphere, the mixture was stirred at 100°C for 12 h. After removing methanol, 100 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). Then, the organic phases were combined, dried over anhydrous Na2SO4, and concentrated to obtain a crude product. The crude product was washed with ethyl acetate (20 ml) to obtain methyl 4-((4-methoxybenzyl)amino)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate (1.1 g, yield: 53%).

[0486] LCMS (ESI) m / z: 364.2 [M+H] +

[0487] Step 5: Synthesis of methyl 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate

[0488] Methyl 4-((4-methoxybenzyl)amino)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate (300.0 mg, 0.78 mmol) was placed in a 25 mL round-bottomed flask, followed by the addition of TFA (5.0 mL). The reaction system was heated to 80°C and stirred at this temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to obtain the crude product, methyl 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate (190 mg).

[0489] LCMS (ESI) m / z: 244.3 [M+H] +

[0490] Step 6: Synthesis of 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid

[0491] Methyl 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate was dissolved in THF (5 mL) and methanol (5.0 mL). The pH was adjusted to 7 with 3M potassium hydroxide solution, followed by the addition of lithium hydroxide (65.0 mg, 1.56 mmol). The reaction proceeded at 50°C for 16 hours. After completion of the reaction, methanol and THF were evaporated from the system, and the pH was adjusted to 6.5 with 1M hydrochloric acid. The mixture was filtered to obtain a precipitate, and the precipitate was washed with water (5.0 mL × 3), dried to obtain the crude product, 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid (120 mg).

[0492] LCMS (ESI) m / z: 230.1 [M+H] +

[0493] Intermediate compound 94: Synthesis of 5-aminoimidazo[1,5-c]quinazoline-9-carboxylic acid

[0494]

[0495] Step 1: Synthesis of 6-bromo-N-(4-methoxybenzyl)-4-methylquinazolin-2-amine

[0496] 6-bromo-2-chloro-4-methylquinazoline (0.5 g, 1.942 mmol) was dissolved in DMSO (15 mL) at room temperature, followed by the addition of DIEA (768 mg, 5.825 mmol) and 4-methoxybenzylamine (600 mg, 3.883 mmol). The reaction mixture was maintained at room temperature for 16 hours. Then, 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, and filtered. The filtrate was concentrated under reduced pressure, and the residue was further purified by column chromatography (0-10% methanol / dichloromethane) to obtain 6-bromo-N-(4-methoxybenzyl)-4-methylquinazolin-2-amine (500 mg, yield: 72%).

[0497] LCMS (ESI) m / z: 359.2 [M+H] +

[0498] Step 2: Synthesis of 9-bromo-N-(4-methoxybenzyl)imidazo[1,5-c]quinazolin-5-amine

[0499] 6-bromo-N-(4-methoxybenzyl)-4-methylquinazolin-2-amine (0.5 g, 1.396 mmol) was dissolved in DMSO (20 mL) at room temperature. 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 sequentially. The reaction mixture was stirred at 90 °C under nitrogen protection for 16 hours. After completion of the reaction, water (60 mL) was added, followed by extraction 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. The product was purified by column chromatography (0-10% methanol / dichloromethane) to afford 9-bromo-N-(4-methoxybenzyl)imidazo[1,5-c]quinazolin-5-amine (300 mg, yield: 56%).

[0500] LCMS (ESI) m / z: 384.2 [M+H] +

[0501] Step 3 Synthesis of methyl 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylate

[0502] At room temperature, 9-bromo-N-(4-methoxybenzyl)imidazo[1,5-c]quinazolin-5-amine (300 mg, 0.785 mmol) was dissolved in a solution of MeOH (10 mL) and DMF (10 mL). Potassium acetate (230 mg, 2.36 mmol) and Pd(dppf)Cl2 (58 mg, 0.0785 mmol) were added sequentially. The mixture was stirred at 100°C for 12 h under a CO atmosphere. After removing methanol, water (60 mL) was added, and the solution 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. The product was purified by column chromatography (0-10% methanol / dichloromethane) to afford methyl 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylate (200 mg, yield: 56%).

[0503] LCMS (ESI) m / z: 363.2 [M+H] +

[0504] Step 4: Synthesis of methyl 5-aminoimidazo[1,5-c]quinazoline-9-carboxylate

[0505] Methyl 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylate (200 mg, 0.5519 mmol) was placed in a 20 mL round-bottomed flask at room temperature, and trifluoroacetic acid (2 mL) was added. The mixture was stirred at 78°C for 3 hours. After removing trifluoroacetic acid, water (5 mL) was added, and the solution was filtered. The filter cake was washed with water to obtain methyl 5-aminoimidazo[1,5-c]quinazoline-9-carboxylate (200 mg, crude product).

[0506] LCMS (ESI) m / z: 243.2 [M+H] +

[0507] Step 5: Synthesis of 5-aminoimidazo[1,5-c]quinazoline-9-carboxylic acid

[0508] Methyl 5-aminoimidazo[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 to the mixture, and the reaction was stirred at 78°C for 3 hours. After removing trifluoroacetic acid, water (5 mL) was added, and the solution was filtered. The filter cake was washed with water to obtain 5-aminoimidazo[1,5-c]quinazoline-9-carboxylic acid (200 mg, crude product).

[0509] LCMS (ESI) m / z: 243.2 [M+H] +

[0510] Intermediate compound 95: Synthesis of 4-aminotetrazolo[1,5-a]quinoxaline-8-carboxylic acid

[0511]

[0512] Step 1: Synthesis of 6-bromo-2-chloro-3-hydrazinylquinoxaline

[0513] 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 for 1 hour at 0°C and then for 2 hours at room temperature. After filtration and washing with ethanol (100 mL), 6-bromo-2-chloro-3-hydrazinylquinoxaline (5.00 g, 18.31 mmol) was obtained.

[0514] LCMS (ESI): 273 [M+H] +

[0515] Step 2: Synthesis of 8-bromo-4-chlorotetrazolo[1,5-a]quinoxaline

[0516] A mixture of 6-bromo-2-chloro-3-hydrazinylquinoxaline (5.00 g, 18.31 mmol) and sodium nitrite (2.52 g, 36.56 mmol) in hydrochloric acid solution (0.2 M, 50.00 mL) was stirred for 2 hours at room temperature. The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phase was concentrated in vacuo. Further purification by silica gel column chromatography (petroleum ether:ethyl acetate = 70%) gave 8-bromo-4-chlorotetrazolo[1,5-a]quinoxaline (4.00 g, 18.28 mmol).

[0517] LCMS (ESI): 284 [M+H] +

[0518] Step 3: Synthesis of 8-bromo-N-(4-methoxybenzyl)tetrazolo[1,5-a]quinoxalin-4-amine

[0519] A mixture of 8-bromo-4-chlorotetrazolo[1,5-a]quinoxaline (4.00 g, 14.13 mmol) with p-methoxybenzylamine (3.87 g, 28.26 mmol) and N,N-diisopropylethylamine (7.30 g, 56.52 mmol) in dichloromethane (50 mL) was stirred for 2 hours at room temperature. After extraction with ethyl acetate (100 mL × 3), the organic phase was concentrated in vacuo. Further purification by silica gel column chromatography (petroleum ether:ethyl acetate = 30%) gave 8-bromo-N-(4-methoxybenzyl)tetrazolo[1,5-a]quinoxalin-4-amine (3.00 g, 7.81 mmol).

[0520] LCMS (ESI): 385 [M+H] +

[0521] Step 4: Synthesis of methyl 4-((4-methoxybenzyl)amino)tetrazolo[1,5-a]quinoxaline-8-carboxylate

[0522] 8-bromo-N-(4-methoxybenzyl)tetrazolo[1,5-a]quinoxalin-4-amine (3.00 g, 7.81 mmol), potassium acetate (1.53 g, 15.61 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.63 g, 0.77 mmol) were sequentially dissolved in a mixed solvent of N,N-dimethylformamide and methanol (1:1, 30 ml). The reaction was carried out overnight in a high-pressure vessel under a carbon monoxide atmosphere (4 MPa) at 100°C. After filtration, extraction with water (100 mL) and ethyl acetate (100 mL × 3), and vacuum concentration of the organic phase, methyl 4-((4-methoxybenzyl)amino)tetrazolo[1,5-a]quinoxaline-8-carboxylate (3.00 g, 8.24 mmol) was obtained.

[0523] LCMS (ESI): 365 [M+H] +

[0524] Step 5: Synthesis of methyl 4-aminotetrazolo[1,5-a]quinoxaline-8-carboxylate

[0525] Methyl 4-((4-methoxybenzyl)amino)tetrazolo[1,5-a]quinoxaline-8-carboxylate (3.00 g, 8.24 mmol) was dissolved in hydrochloric acid / dioxane solution (4 M, 50 mL). The reaction was stirred at room temperature for 2 hours. After extraction with water (100 mL) and ethyl acetate (100 mL × 3), the organic phase was concentrated under vacuum. Further purification by silica gel column chromatography (petroleum ether:ethyl acetate = 50%) gave methyl 4-aminotetrazolo[1,5-a]quinoxaline-8-carboxylate (2.00 g, 8.16 mmol).

[0526] LCMS (ESI): 245 [M+H] +

[0527] Step 6: Synthesis of 4-aminotetrazolo[1,5-a]quinoxaline-8-carboxylic acid

[0528] 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 successively dissolved in a mixed solvent of tetrahydrofuran (10 mL), water (10 mL), and methanol (10 mL). The reaction was stirred at 60 °C for 2 hours. After extraction with water (50 mL) and ethyl acetate (50 mL × 3), the organic phase was concentrated in vacuo to obtain 4-aminotetrazolo[1,5-a]quinoxaline-8-carboxylic acid (1.00 g, 4.34 mmol).

[0529] LCMS (ESI): 231 [M+H] +

[0530] Intermediate compound 96: Synthesis of 6-aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylic acid

[0531]

[0532] Step 1: Synthesis of N-(2,6-dichloropyridin-3-yl)-1H-imidazol-5-carboxamide

[0533] 2,6-dichloropyridin-3-amine (163 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5.0 mL). After cooling the reaction system in an ice bath for 5 min, NaHMDS (0.125 mL, 2.0 M, 0.25 mmol) was slowly added to the reaction mixture and stirred for 1 h. Then, 5H,10H-diimidazo[1,5-a:1',5'-d]pyrazine-5,10-dione (188.0 mg, 1.0 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction progress was monitored by LCMS. After completion, the reaction mixture was poured into water, and the pH was adjusted to 7, which resulted in the formation of a precipitate. The solid was collected by filtration and dried to give crude N-(2,6-dichloropyridin-3-yl)-1H-imidazole-5-carboxamide (175 mg, crude product).

[0534] LCMS (ESI) m / z: 257.0 [M+H] +

[0535] Step 2: Synthesis of 2-chloroimidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one

[0536] 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, and the reaction was heated to 140 °C and stirred for 2 h. After completion as confirmed by LCMS, the reaction mixture was cooled to room temperature, poured into water, and stirred for 30 min, which resulted in the formation of a precipitate. The solid was collected by filtration to give crude 2-chloroimidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one (153.0 mg, crude product).

[0537] LCMS (ESI) m / z: 221.1 [M+H] +

[0538] Step 3: Synthesis of methyl 6-hydroxyimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate

[0539] 2-chloroimidazo[1,5-a]pyridin[3,2-e]pyrimidin-6(5H)-one (2.0 g, 9.09 mmol) was dissolved in a solution of MeOH (30.00 mL) and DMF (310.00 mL), then potassium acetate (1.78 g, 18.18 mmol) and Pd(dppf)Cl2 (660 mg, 0.91 mmol) were added. Under CO atmosphere, the mixture was stirred at 100°C for 12 h. After removing methanol, the reaction mixture was added to 100 mL of water, which resulted in the formation of a precipitate. The solid was collected by filtration to obtain the crude product. The crude product was washed with ethyl acetate (50 ml × 2) to obtain the product, methyl 6-hydroxyimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate (1.5 g, yield: 68%), as a brown solid.

[0540] LCMS (ESI) m / z: 245.2 [M+H] +

[0541] Step 4: Synthesis of methyl 6-chlorimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate

[0542] 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 reaction was heated to 90°C and held for 2.5 hours. After LCMS showed completion, the mixture was evaporated to remove phosphorus oxychloride. The resulting solution was poured into ice water, stirred for 15 minutes, filtered, and the filter cake was collected and dried to give the crude product methyl 6-chloroimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate (200.0 mg, crude product).

[0543] LCMS (ESI) m / z: 263.0 [M+H] +

[0544] Step 5: Synthesis of methyl 6-((4-methoxybenzyl)amino)imidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate

[0545] 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), and p-methoxybenzylamine (125.0 mg, 0.92 mmol) and N,N-diisopropylethylamine (295 mg, 2.29 mmol) were added sequentially. The reaction was heated to 90°C and stirred for 16 hours. After completion, the reaction mixture was cooled to room temperature, poured into ice water, stirred, and then extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was 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%).

[0546] LCMS (ESI) m / z: 364.2 [M+H] +

[0547] Step 6: Synthesis of methyl 6-aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate

[0548] Methyl 6-((4-methoxybenzyl)amino)imidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate (250 mg, 0.69 mmol) was dissolved in trifluoroacetic acid (TFA) (5.0 mL), and the reaction was heated at 80°C for 16 hours. After the reaction was completed, the mixture was cooled, and TFA was removed by evaporation to give the crude product methyl 6-aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate (160 mg, crude).

[0549] LCMS (ESI) m / z: 244.1 [M+H] +

[0550] Step 7: Synthesis of 6-aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylic acid

[0551] Methyl 6-aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylate (83.0 mg, yield: 55%) was dissolved in THF / MeOH (1.2 mL / 1.2 mL), and lithium hydroxide solution (0.66 mL, 2.0 M, 1.32 mmol) was added. The reaction was heated to 50 °C and stirred for 16 hours. After completion of the reaction, the solvent was evaporated, and the pH of the reaction mixture was adjusted to about 7 with an aqueous 1 N HCl solution. After stirring for 15 minutes, the mixture was filtered, and the solid product was collected to obtain 6-aminoimidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxylic acid (83 mg, yield: 55%)

[0552] LCMS (ESI) m / z: 230.1 [M+H] +

[0553] Intermediate compound 97: Synthesis of 4-amino-6-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0554]

[0555] Step 1: Synthesis of N-(4-bromo-2-fluoro-6-methylphenyl)-1H-imidazole-5-carboxamide

[0556] 4-bromo-2-fluoro-6-methylaniline (15 g, 73.89 mmol) was added to a 500 mL round-bottomed flask at room temperature, followed by the addition of tetrahydrofuran (150 mL). Di(trimethylsilyl)amine (74 mL) was added at 0 °C, and after the resulting mixture was stirred at 0 °C for half an hour, 5H,10H-diimidazo[1,5-a:1',5'-d]pyrazine-5,10-dione (6.95 g, 36.95 mmol) was added. The mixture was stirred for another hour at room temperature. The reaction mixture was then poured into ice water and filtered to obtain a red solid residue as the product, N-(4-bromo-2-fluoro-6-methylphenyl)-1H-imidazole-5-carboxamide (10 g, yield: 90.9%).

[0557] LCMS (ESI) m / z: 298 [M+H] +

[0558] Step 2: Synthesis of 8-bromo-6-methylimidazo[1,5-a]quinoxalin-4-ol

[0559] At room temperature, N-(4-bromo-2-fluoro-6-methylphenyl)-1H-imidazole-5-carboxamide (10 g, 33.67 mmol) was added to a 250 ml round-bottomed flask. Then, N,N-dimethylacetamide (100 ml) was poured into the flask, followed by the addition of potassium carbonate (13.94 g, 101.01 mmol). The resulting mixture was stirred at 140 °C for 2 hours. After completion of the reaction, the reaction mixture was poured into water to adjust pH to 3-4, filtered, and the black solid residue was collected as the product, giving 8-bromo-6-methylimidazo[1,5-a]quinoxalin-4-ol (8 g, yield: 85.74%).

[0560] LCMS (ESI) m / z: 278 [M+H] +

[0561] Step 3: Synthesis of 8-bromo-4-chloro-6-methylimidazo[1,5-a]quinoxaline

[0562] 8-bromo-6-methylimidazo[1,5-a]quinoxalin-4-ol (8 g, 28.88 mmol) was added to a 250 mL round-bottomed flask at room temperature. Then, phosphorus oxychloride (100 mL) was added to the flask, and the resulting mixture was stirred at 120 °C for 12 hours. The reaction solution was concentrated under reduced pressure, poured into ice water, filtered, and the black solid residue was collected as the product, giving 8-bromo-4-chloro-6-methylimidazo[1,5-a]quinoxaline (7.5 g, yield: 88.23%).

[0563] LCMS (ESI) m / z: 296 [M+H] +

[0564] Step 4: Synthesis of 8-bromo-N-(4-methoxybenzyl)-6-methylimidazo[1,5-a]quinoxalin-4-amine

[0565] 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-bottomed flask. Then, dimethyl sulfoxide (75 mL) was poured into the flask, and (4-methoxyphenyl)methanamine (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 solution was concentrated under reduced pressure, poured into ice water, filtered, and the red solid residue was collected as the product to give 8-bromo-N-(4-methoxybenzyl)-6-methylimidazo[1,5-a]quinoxalin-4-amine (6 g, yield: 60%).

[0566] LCMS (ESI) m / z: 397[M+H] +

[0567] Step 5: Synthesis of methyl 4-((4-methoxybenzyl)amino)-6-methylimidazo[1,5-a]quinoxaline-8-carboxylate

[0568] At room temperature, 8-bromo-N-(4-methoxybenzyl)-6-methylimidazo[1,5-a]quinoxalin-4-amine (6 g, 15.15 mmol) was added to a 250 mL high-pressure reaction vessel. Then, N,N-dimethylformamide (30 mL) and methanol (60 mL) were poured into the reaction vessel, and potassium acetate (2.97 g, 30.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.24 g, 1.52 mmol) were added thereto. Carbon monoxide (4 MPa) was introduced, and the resulting mixture was stirred at 100 °C for 12 hours. The reaction solution was concentrated under reduced pressure, poured into water, filtered, and the red solid residue was collected as the product to give methyl 4-((4-methoxybenzyl)amino)-6-methylimidazo[1,5-a]quinoxaline-8-carboxylate (4 g, yield: 70.54%).

[0569] LCMS (ESI) m / z: 377[M+H] +

[0570] Step 6: Synthesis of 4-((4-methoxybenzyl)amino)-6-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0571] Methyl 4-((4-methoxybenzyl)amino)-6-methylimidazo[1,5-a]quinoxaline-8-carboxylate (4 g, 10.61 mmol) was added to a 250 mL round-bottomed flask at room temperature. Then, tetrahydrofuran (40 mL) and methanol (40 mL) were poured into the flask, and potassium hydroxide (1.19 g, 21.22 mmol) was added. The resulting mixture was stirred at 60 °C for 1 hour. The reaction solution was concentrated under reduced pressure, poured into water, and the pH was adjusted to approximately 3 with formic acid, resulting in the formation of a precipitate. The mixture was filtered and the red solid residue was collected as the product to give 4-((4-methoxybenzyl)amino)-6-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (2.9 g, yield: 76.31%).

[0572] LCMS (ESI) m / z: 363[M+H] +

[0573] Step 7: Synthesis of 4-amino-6-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0574] 4-((4-methoxybenzyl)amino)-6-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (2.9 g, 7.99 mmol) was added to a 50 mL round-bottomed flask at room temperature. Then, trifluoroacetic acid (30 mL) was poured into the flask, and the resulting mixture was stirred at 100 °C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a black solid, 4-amino-6-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (1.5 g, yield: 51.28%).

[0575] LCMS (ESI) m / z: 243 [M+H] +

[0576] Intermediate connection 98: Synthesis of 4-amino-1-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0577]

[0578] Step 1: Synthesis of methyl 3-(2-cyclopropyl-1H-imidazol-1-yl)-4-nitrobenzoate

[0579] A mixture of 3 methyl 3-(2-bromo-1H-imidazol-1-yl)-4-nitrobenzoate (1.00 g, 3.07 mmol), cyclopropylboronic acid (0.26 g, 3.07 mmol), Pd(dppf)Cl2 (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), extracted with ethyl acetate (10 mL × 2), and the combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a 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%).

[0580] LCMS (ESI): 288 [M+H] +

[0581] Step 2: Synthesis of methyl 4-amino-3-(2-cyclopropyl-1H-imidazol-1-yl)benzoate

[0582] A mixture of methyl 3-(2-cyclopropyl-1H-imidazol-1-yl)-4-nitrobenzoate (1.00 g, 3.48 mmol), boric acid (0.94 g, 10.44 mmol) and 4,4'-bipyridine (0.27 g, 1.74 mmol) in N,N-dimethylformamide (10.00 mL) was stirred at room temperature for 2 hours. Then, the reaction mixture was concentrated, poured into water (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a 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, yield: 67%).

[0583] LCMS (ESI): 257 [M+H] +

[0584] Step 3: Synthesis of methyl 1-cyclopropyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate

[0585] A mixture of methyl 4-amino-3-(2-cyclopropyl-1H-imidazol-1-yl)benzoate (500 mg, 1.94 mmol) and carbonylimidazole (377 mg, 2.33 mmol) in chlorobenzene (5 mL) was stirred at 140°C for 12 hours. After concentration, the reaction mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate: petroleum ether = 20%) to give methyl 1-cyclopropyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate (500 mg, yield: 91%).

[0586] LCMS (ESI): 283 [M+H] +

[0587] Step 4: Synthesis of methyl 4-chloro-1-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxylate

[0588] A solution of methyl 1-cyclopropyl 4-oxo-4,5-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. After concentration, methyl 4-chloro-1-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxylate (300 mg, crude) was obtained.

[0589] LCMS (IER): 301 [M+H] +

[0590] Step 5: Synthesis of methyl 1-cyclopropyl-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate

[0591] A mixture solution of methyl 4-chloro-1-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxylate (300 mg, 0.99 mmol), p-methoxybenzylamine (417 mg, 2.98 mmol), and diisopropylamine (384 mg, 2.98 mmol) in dimethyl sulfoxide (3 mL) was stirred at 120°C for 2 hours. After concentration, 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, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (ethyl acetate:petroleum ether = 42%) to obtain methyl 1-cyclopropyl-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (300 mg, yield: 75%).

[0592] LCMS (ESI): 402 [M+H] +

[0593] Step 6: Synthesis of 1-cyclopropyl-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid

[0594] Lithium hydroxide (89.45 mg, 2.24 mmol) was added to a solution of methyl 1-cyclopropyl-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (300 mg, 0.75 mmol) in methanol / tetrahydrofuran (5.00 mL / 5.00 mL). The reaction mixture was stirred at 60°C for 2 hours and then concentrated to obtain 1-cyclopropyl-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (160 mg, yield: 55%).

[0595] LCMS (ESI): 388 [M+H] +

[0596] Step 7: Synthesis of 4-amino-1-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0597] A mixture of 1-cyclopropyl-4-((4-methoxybenzyl)amino)imidazo[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 hours and then concentrated to give 4-amino-1-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxylic acid (100 mg, crude).

[0598] LCMS (ESI): 268 [M+H] +

[0599] Example 1

[0600] Synthesis of 4-amino-N-(2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0601]

[0602] 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (50 mg, 0.21 mmol) was dissolved in DMF (2.5 mL), followed by the addition of 2-(7-azabenzotriazol-1-yl)-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) sequentially. The reaction mixture was stirred at room temperature for 0.5 h. After completion of the reaction, the reaction solution was concentrated and further purified by HPLC (Column: Xbridge BEH Shield RP18 5 μm, 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) to obtain 4-amino-N-(2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0603] 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).

[0604] LCMS (ESI): 360.30 [M+H] +

[0605] By using the synthesis methods described in Example 1, with only the corresponding starting materials replaced, the embodiments listed in the table below can be obtained:

[0606] Example Structure Name 1H NMR and 19F NMR and LCMS 2 (S)-4-amino-N-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6): δ m.d. 9.11 (s, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 7.84-7.79 (m, 2H), 7.40-7.36 (m, 4H), 7.31-7.29 (m, 1H), 7.12-7.10 (m, 1H), (7.1H), (7, 02H), 6.21-4.61 (m, 1H), 4.60-4.54 (m, 1H), 3.66 (s, 1H), 2.52 (s, 1H). LCMS (IER) m / z: 440.35 [M+H]+ 3 (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.50-7.45 (m, 4H), 7.38-7.37 (m, 1H), 7.38-7.37 (m, 1H), 7.38-7.37 (s, 1H (m, 1H), 4.80-4.55 (m, 2H), 2.71 (s, 3H). LCMS (IER) m / z: 438.00 [M+H]+ 4 (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.31 (e, J = 7.8 Hz, 1H), 8.67 (e, J = 19.6 Hz, 1H), 8.53 (e, J = 19.7 Hz, 1H), 7.99 (e, J = 3.8 Hz, 1H), 7.89-7.65 (m, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.45-7.19 (m, 2H), 6.51-5.98 (m, 1H), 4.95-4.41 (m, 2H), 2.72 (d, J, 5.2H, 3H). LCMS (IER) m / z: 429.1 [M+H]+ 5 4-amino-N-methyl-N-((4S)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 18.9 Hz, 1H), 8.37 (d, J = 12.5 Hz, 1H), 7.93 (s, 1H), 7.73-7.41 (m, 7H, 5, 7.1 Hz), J 1H), 4.77 (d, J = 40.0 Hz, 2H), 4.42-3.87 (m, 2H), 2.79 (s, 3H), 1.56 (t, J = 7.8 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ -60.92. LCMS (IER) m / z: 456 [M+H]+ 6 (S)-4-amino-N,3-dimethyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.28-8.23 (m, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.47-7.38 (m, 2H), 7.33 (d, J = 7.6, 1H), G (s, 1H), 6.90 (s, 2H), 6.38 (s, 1H), 4.81 (s, 1H), 4.71 (dd, J = 10.3, 4.4 Hz, 1H), 2.67 (s, 3H), 2.63 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -60.80. LCMS (IER) m / z: 442 [M+H]+ 7 4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.33 (s, 1H), 8.13 (d, J = 7.4 Hz, 1H), 7.92 (s, 1H), 7.55-7.42 (m, 5H, 6.9, 1H), 5.01-4.84 (m, 1H), 4.79-4.69 (m, 1H), 2.78 (s, 3H). LCMS (IER) m / z: 429.20 [M+H]+ 8 4-amino-N-methyl-N-(6-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.37 (s, 1H), 7.91 (s, 1H), 7.68-7.66 (m, 2H), 7.51-7.44 (m, 5H), 5.77-7.44 (m, 5H), (m, 1H), 4.76-4.72 (m, 1H), 4.22-4.11 (m, 2H), 2.77 (s, 3H). 9 4-amino-N-((4S)-7-fluoro-1-methylisochroman-4-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.18 (d, 1H), 8.35 (d, 1H), 7.91 (s, 1H), 7.47-7.42 (m, 5H), 7.18-7.13 (m, 2H), 5.5-7.13 (m, 2H), 5.5-6,6H), 4.91-4.61 (m, 2H), 4.34-3.90 (m, 2H), 2.75-2.69 (m, 3H), 1.53-1.33 (m, 3H). LCMS (IER) m / z: 406.3 [M+H]+ 10 (S)-4-amino-N-(6-cyano-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.34-8.32 (m, 1H), 7.91 (s, 1H), 7.63-7.61 (m, 1H), 7.47-7.42 (m, 6.5, 1H), (m, 6.5, 1H), (H 4.81-4.68 (m, 2H), 2.71 (s, 3H). JHMS (IER): 385.05 [M+H]+ 11 (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-2-fluoro-N-methylpyrrolo[1,2-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.45-7.44 (m, 1H), 7.42-7.33 (m, 2H), 7.16 (s, 9.5H), J = 1.6, J Hz, 1H), 4.80-4.61 (m, 3H), 2.65 (s, 3H). LCMS (IER) m / z: 455.20 [M+H]+ 12 (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-7-chloro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.20-9.06 (m, 1H), 8.54-8.68 (m, 1H), 7.93-7.92 (m, 1H), 7.64-7.58 (m, 2H), 7.54-7.58 (m, 1H), 7.54-7.6, (1H), 7.43-7.25 (m, 1H), 7.20 (s, 1H), 7.16-7.12 (m, 1H), 6.88-6.44 (m, 1H), 5.42-5.30 (m, 1H), 4.85-4.62 (m, 1H), 1.95 (s, 1H). JHMS (IER) m / z: 472.15 [M+H]+. 14 (S)-4-amino-7-cyano-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.55-8.44 (m, 1H), 7.97-7.90 (m, 2H), 7.76 (s, 2H), 7.60-7.59 (m, 7.3H), (7.3H), (1H-1H), 7.30-7.26 (m, 1H), 6.53-5.65 (m, 1H), 4.94-4.68 (m, 2H), 2.73-2.62 (m, 3H). JHMS (IER): 452.95 [M+H]+ 15 (S)-4-amino-N,7-dimethyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 7.35-7.32 (m, 2H), 7.22 (s, 17.6-m), 7.15 (m 2H), 6.53-5.71 (m, 1H), 4.89-4.70 (m, 2H), 2.71-2.69 (s, 3H), 2.33 (s, 3H). JHMS (IER): 442.2 [M+H]+ 16 (S)-4-amino-N-(methyl-d3)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.34 (t, J = 1.1 Hz, 1H), 7.91 (s, 1H), 7.65-7.63 (d, J = 7.8 Hz, 1H), 7.4-7.4, (4H), 7.34-7.32 (m, 1H), 7.26 (s, 1H), 6.39-5.78 (m, 1H), 4.84-4.69 (m, 2H). JHMS (IER): 430.95 [M+H]+ 17 4-amino-N-((4S)-7-bromo-1-methylisochroman-4-yl)-N-methylimidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide 1H NMR (400 MHz, CDCl3) δ 9.31-9.28 (m, 1H), 8.67-8.64 (m, 1H), 8.56-8.49 (m, 1H), 7.98 (s, 1H), 7.72-7.66 (m, 2H), 7.56-7.45 (m, 2H), 7.41-7.26 (m, 1H), 5.63-5.62 (m, 0.5H), 5.10-5.09 (m, 0.5H), 4.75-4.64 (m, 1H), 4.24-4.17 (m, 1H), 4.06-4.02 (m, 1H), 3.92-3.88 (m, 1H), 2.85-2.75 (d, 3H), 1.54-1.52 (m, 3H). LCMS (ESI) m / z: 467.1 / 469.1 [M+H]+ 18 (R)-4-amino-N-methyl-N-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 22.0 Hz, 1H), 8.36 (s, 1H), 7.91 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.58-7.29 (m, 5H), 5.83 (d, J = 320.9 Hz, 1H), 3.05 (d, J = 33.9 Hz, 2H), 2.71 (s, 3H), 2.28 (d, J = 69.4 Hz, 2H). 19F NMR (376 MHz, DMSO-d6) δ -60.51 (d, J = 23.8 Hz). LCMS (ESI) m / z: 426.1 [M+H]+ 19 4-amino-N-methyl-N-((4S)-1-methyl-6-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 53.8 Hz, 1H), 8.85-8.31 (m, 1H), 7.92 (d, J = 3.4 Hz, 1H), 7.68 (t, J = 10.1 Hz, 7.7.6 Hz), H (m, 5H), 5.92-5.18 (m, 1H), 5.09-4.73 (m, 1H), 4.46-3.84 (m, 2H), 2.78 (d, J = 21.2 Hz, 3H), 1.77-1.35 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ -60.15--61.37 (m). LCMS (IER) m / z: 456 [M+H]+ 20 (S)-4-amino-N-(6-(dimethylphosphoryl)-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.57-7.55 (m, 1H), 7.47-7.46 (m, 4H), 7.47-7.46 (m, 4H), 7.4-7.39 (m, 1H), 7.33-7.26 (m, 1H), 6.55-5.71 (m, 1H), 4.79-4.65 (m, 2H), 2.71 (s, 3H), 1.71-1.62 (m, 6H). JHMS (IER): 436.20 [M+H]+ 21 4-amino-N-methyl-N-((4S)-1-methyl-7-(2-methylpyrimidin-5-yl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.22-9.20 (m, 1H), 9.06-9.04 (m, 2H), 8.42-8.36 (m, 1H), 7.92 (s, 1H), 7.74-m, 7.67 (m, 7.95), 5H), 5.70-4.90 (m, 1H), 4.71-4.69 (m, 1H), 4.36-4.24 (m, 1H), 4.10-3.94 (m, 1H), 2.82-2.73 (m, 3H), 2.67-2.66 (m, 1.6H), (m, 3H). LCMS (IER) m / z: 480.4 [M+H]+ 22 4-amino-N-methyl-N-((4S)-1-methyl-7-(1-methyl-1H-pyrazol-4-yl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.22-9.19 (m, 1H), 8.40-8.34 (m, 1H), 8.19-8.17 (m, 1H), 7.92-7.89 (m, 2H), 7.48-7.34 (m, 5H), 7.30-7.23 (m, 2H), 5.62-4.78 (m, 1H), 4.74-4.64 (m, 1H), 4.32-4.27 (m, 1H), 4.06-4.00 (m, 1H), 3.86 (s, 3H, 7.7H), 1.51-1.38 (m, 3H). LCMS (IER) m / z: 468.3 [M+H]+ 23 (R)-4-amino-N-methyl-N-(3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.32 (d, J = 6.6 Hz, 1H), 7.93 (d, J = 3.2 Hz, 1H), 7.58 (d, J = 26.7 Hz, 3H), 7.41-7.19 (m, 3H), 6.51-5.61 (m, 1H), 4.96-4.60 (m, 2H), 2.65 (d, J = 31.4 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ -65.97. LCMS (ESI) m / z: 427.5 [M+H]+ 24 (R)-4-amino-N-methyl-N-(3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.30 (d, J = 7.2 Hz, 1H), 8.81-8.49 (m, 3H), 7.99 (d, J = 2.6 Hz, 1H), 7.89 (d, J = 23.8 Hz, 1H), 7.73 (s, 2H), 6.07 (dt, J = 194.2, 8.2 Hz, 1H), 3.19-3.04 (m, 1H), 2.90 (t, J = 8.7 Hz, 1H), 2.79 (d, J = 18.9 Hz, 3H), 2.46-2.35 (m, 1H), 2.22 (dk, J = 13.3, 8.6 Hz, 1H). 19F NMR (376 MHz, DMSO-d6) δ -65.90. LCMS (ESI) m / z: 428.4 [M+H]+ 25 (R)-4-amino-N-methyl-N-(7-(trifluoromethyl)chroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.24-9.13 (m, 1H), 8.37 (s, 1H), 7.92 (s, 1H), 7.53-7.39 (m, 5H), 7.29-7.24 (m, 1.1H), 7.5-m, (1H), 5.99-5.16 (m, 1H), 4.50-4.10 (m, 2H), 2.73 (d, J = 4.4 Hz, 3H), 2.36-2.15 (m, 2H). LCMS (IER) m / z: 442.2 [M+H]+ 26 (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrofuro[3,2-c]pyridin-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.79-8.45 (m, 2H), 8.34 (d, J = 1.7 Hz, 1H), 7.93 (s, 1H), 7.65-7.36 (m, 3H), (6, 3H), 5.05-4.77 (m, 2H), 2.64 (d, J = 82.3 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.36. LCMS (IER) m / z: 429.4 [M+H]+ 27 (S)-4-amino-7-chloro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.20-9.06 (m, 1H), 8.57-7.92 (m, 2H), 7.68-7.47 (m, 4H), 7.37-7.23 (m, 2H), 6.54-50, (1H), 4.91-4.61 (m, 2H), 2.71-2.66 (m, 3H). LCMS (IER) m / z: 462.10 [M+H]+ 28 (S)-4-amino-N-methyl-N-(6-(methylsulfonyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.34 (s, 1H), 7.92 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), J = 7.5, J Hz, 4H), 7.41 (s, 1H), 6.40 (s, 1H), 4.84 (s, 1H), 4.74 (dd, J = 10.2, 4.5 Hz, 1H), 3.24 (s, 3H), 2.69 (s, 3H). JHMS (IER): 438.25 [M+H]+ 29 (S)-4-amino-7-fluoro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.32 (d, J = 6.6 Hz, 1H), 7.93 (d, J = 3.2 Hz, 1H), 7.58 (d, J = 26.7 Hz, 3.1 Hz), 7.1-m, (H), 6.51-5.61 (m, 1H), 4.96-4.60 (m, 2H), 2.65 (d, J = 31.4 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ -60.83 (e, J = 10.8 Hz). LCMS (IER) m / z: 579.2 [M+H]+ 30 (S)-6-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[3,2-e]pyrazine-2-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 24.2 Hz, 1H), 8.04-7.85 (m, 2H), 7.83-7.58 (m, 4H), 7.31 (dd, J = 36.5, 1, 2Hz), 6.48-6.08 (m, 1H), 4.78 (dt, J = 30.4, 9.0 Hz, 2H), 2.86-2.69 (s, 3H). LCMS (IER) m / z: 429.20 [M+H]+ 31 (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrofuro[3,2-c]pyridin-3-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.69-9.21 (m, 1H), 8.86-8.41 (m, 3H), 8.12-7.97 (m, 1H), 7.76 (d, J = 12.4 Hz, 2H, 78-7), (7.3H), 6.47-6.09 (m, 1H), 4.89-4.84 (m, 1H), 3.17 (d, J = 5.2 Hz, 1H), 2.80 (d, J = 55.3 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ -66.33, -66.34. LCMS (IER) m / z: 430.4 [M+H]+ 32 4-amino-N-methyl-N-((1R,4S)-1-methyl-7-(trifluoromethyl)-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.80 (s, 1H), 8.37 (s, 1H), 8.03-7.76 (m, 2H), 7.67-7.27 (m, 4H), 5.76-7.27 (m, 4H), 5.76, (s, 1H), (s, 1H 1H), 4.55-3.99 (m, 2H), 2.82 (s, 3H), 1.59 (d, J = 6.6 Hz, 3H). JHMS (IER): 457.40 [M+H]+ 33 (S)-4-amino-7-fluoro-N-methyl-N-(6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 9.01 (d, J = 7.1 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 6.6 Hz, 1H), J 1H), 7.61 (s, 2H), 7.44-7.19 (m, 4H), 6.48-5.53 (m, 1H), 4.88-4.52 (m, 2H), 2.76-2.57 (m, 3H). LCMS (IER) m / z: 512.2 [M+H]+ 34 (S)-4-amino-7-fluoro-N-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.33 (d, J = 6.6 Hz, 1H), 8.15 (d, J = 7.2 Hz, 1H), 7.98-7.84 (m, 2H), 7.61-7.5, (7.3H), (m, 4H), 6.44-5.47 (m, 1H), 4.86-4.48 (m, 2H), 3.85 (d, J = 5.3 Hz, 3H), 2.75-2.55 (m, 3H). LCMS (IER) m / z: 457.2 [M+H]+ 35 4-amino-N-methyl-N-((5S,8R)-8-methyl-2-(trifluoromethyl)-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.66 (d, J = 6.0 Hz, 1H), 8.55 (d, J = 30.0 Hz, 1H), 8.15 (dd, J = 95.7, 8.1 Hz, 1H), 7.99 (s, 1H), 7.98-7.86 (m, 1H), 7.73 (d, J = 9.9 Hz, 2H), 5.63 (d, J = 169.5 Hz, 1H), 4.80 (dk, J = 40.6, 6.6 Hz, 1H), 4.26 (d, J = 12.3 Hz, 1H), 4.10 (ddd, J = 60.3, 12.6, 4.5 Hz, 1H), 2.86 (d, J = 10.3 Hz, 3H), 1.58 (d, J = 6.6 Hz, 3H). LCMS (ESI) m / z: 458.5 [M+H]+ 36 (S)-4-amino-N-methyl-7-(trifluoromethyl)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J = 73.2 Hz, 1H), 8.46 (d, J = 113.8 Hz, 1H), 8.07-7.80 (m, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.53 (s, 3H), 7.34 (dd, J = 16.4, 7.8 Hz, 1H), 7.21 (d, J = 25.6 Hz, 1H), 6.71-5.28 (m, 1H), 5.09-4.29 (m, 2H), 2.94 (d, J = 178.2 Hz, 3H). LCMS (ESI) m / z: 496.4 [M+H]+ 37 (S)-4-amino-N,6-dimethyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.17 (d, J = 2.2 Hz, 1H), 7.91 (s, 1H), 7.65-7.63 (d, J = 7.8 Hz, 1H, 43, 7.3 H), 1H), 7.35-7.33 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 6.53-5.75 (m, 1H), 4.82-4.69 (m, 2H), 2.67 (s, 3H), 2.53 (s, 3H). LCMS (IER) m / z: 442.10 [M+H]+ 38 (S)-4-amino-7-fluoro-N-methyl-N-(6-(methylsulfonyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.32-8.31 (m, 1H), 7.93-7.92 (m, 1H), 7.65-7.61 (m, 2H), 7.59-7.57 (m, 2H), 7.59-7.57 (m, 7.97 H), 1H), 7.28-7.23 (m, 1H), 6.55-6.47 (m, 1H), 4.94-4.85 (m, 1H), 4.69-4.62 (m, 2H), 3.24-3.21 (m, 3H), 2.70-2.53 (m, 3H). JHMS (IER): 456.10 [M+H]+ 39 (S)-4-amino-N,1-dimethyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 8.15-8.10 (m, 1H), 7.83 (s, 1H), 7.65-7.61 (m, 1H), 7.55-7.45 (m, 2H), 7.38-7.32 (m, 2H), 7.38-7.32 (d, J = 33). 8.0 Hz, 1H), 7.25-7.21 (m, 1H), 6.29-5.95 (m, 1H), 4.86-4.71 (m, 2H), 2.99 (s, 3H), 2.68 (s, 3H). LCMS (IER) m / z: 442.20 [M+H]+ 40 (S)-4-amino-7-fluoro-N-methyl-N-(6-(2-methylpyrimidin-5-yl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.15 (e, J = 5.3 Hz, 1H), 9.02 (e, J = 9.9 Hz, 2H), 8.34 (e, J = 6.6 Hz, 1H), 7.94 (e, J = 6.6 Hz, 1H), 7.94 (e, J = 3.5 Hz, 7.6 Hz), 2H), 7.52-7.13 (m, 4H), 6.56-5.56 (m, 1H), 4.93-4.52 (m, 2H), 2.83-2.57 (m, 6H). LCMS (IER) m / z: 470.1 [M+H]+ 41 (S)-4-amino-7-fluoro-N-(methyl-d3)-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.34 (d, J = 6.5 Hz, 1H), 7.96 (d, J = 2.3 Hz, 1H), 7.71 (s, 2H), 7.56 (d, 7.8), G 7.42-7.15 (m, 3H), 6.53-5.58 (m, 1H), 4.88 (t, J = 9.8 Hz, 1H), 4.68 (dd, J = 10.3, 4.3 Hz, 1H) LCMS (IER) m / z: 449.4 [H++] 42 (S)-4-amino-2-fluoro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)pyrrolo[1,2-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.64-7.63 (d, J = 7.8 Hz, 1H), 7.49-7.38 (m, 7.4), H 7.25-7.24 (m, 1H), 7.18 (s, 2H), 6.97-6.95 (m, 1H), 6.46-5.62 (m, 1H), 4.82-4.54 (m, 2H), 2.67 (s, 3H). JHMS (IER):444.80 [M+H]+ 43 4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzo[b]thiophene-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.36 (t, J = 1.2 Hz, 1H), 7.92 (s, 1H), 7.79-7.66 (m, 1H), 7.61-7.37 (m, 1H), (d, 6,6H), (d 299.0 Hz, 1H), 3.69 (d, J = 49.5 Hz, 2H), 2.82 (s, 3H). JHMS (IER): 442.2 [M+H]+ 44 4-amino-N-methyl-N-(8-(trifluoromethyl)-1,3,4,5-tetrahydrobenzo[c]oxepin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.30 (d, J = 69.6 Hz, 1H), 7.94 (s, 1H), 7.70 (s, 2H), 7.62-7.41 (m, 400 MHz, 7.2 Hz), J 1H), 5.97 (d, J = 10.7 Hz, 1H), 4.83 (k, J = 14.1 Hz, 2H), 4.11 (d, J = 57.7 Hz, 2H), 3.02 (s, 3H), 2.23 (dd, J = 48.7 Hz, 2H). JHMS (IER): 455.2 [M+H]+ 45 4-amino-N-methyl-N-(6-(pentafluoro-λ6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.33 (s, 1H), 7.98 (s, 1H), 7.65-7.63 (m, 1H), 7.52-7.42 (m, 6H), 6.5-7.42 (m, 6H), 6.5-5,1 (1H), 4.84-4.69 (m, 2H), 2.70 (s, 3H). JHMS (IER): 486.1 [M+H]+ 46 (S)-4-amino-7-fluoro-N-methyl-N-(6-(thiazol-4-yl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.41-8.97 (m, 2H), 8.63-8.03 (m, 2H), 7.93 (d, J = 4.4 Hz, 1H), 7.77-7.47 (m, 3H), 7.42-7.06 (m, 3H), 6.71-5.34 (m, 1H), 5.00-4.49 (m, 2H), 2.66 (d, J = 41.7 Hz, 3H). LCMS (ESI) m / z: 461.20 [M+H]+ 47 (S)-4-amino-N-methyl-N-(6-(5-(trifluoromethyl)pyridin-3-yl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, CDCl3) δ 9.20 (d, J = 9.1 Hz, 2H), 8.97 (d, J = 1.9 Hz, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 7.92 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.46 (dd, J = 19.2, 6.8 Hz, 6H), 6.73-5.58 (m, 1H), 4.75 (d, J = 41.0 Hz, 2H), 2.70 (s, 3H). LCMS (ESI) m / z: 505.30 [M+H]+ 48 (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.37 (t, J = 1.2 Hz, 1H), 7.88 (s, 2H), 7.68-7.56 (m, 3H), 7.34 (d, J = 7.8 Hz, 1H), 7.27 (s, 1H), 6.09 (d, J = 257.8 Hz, 1H), 5.20-4.40 (m, 2H), 2.69 (s, 3H). LCMS (ESI) m / z: 429.2 [M+H]+ 49 (S)-5-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-c]quinazoline-9-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.99 (s, 1H), 7.81 (s, 2H), 7.66 (d, J = 7.8 Hz, 1H, 3, 7.8), J 2.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 6.39 (s, 1H), 4.90-4.60 (m, 2H), 2.68 (s, 3H). LCMS (IER) m / z: 428.2 [M+H]+ 50 4-amino-N-methyl-N-((4S)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.34-9.25 (m, 1H), 8.70-8.62 (m, 1H), 8.62-8.47 (m, 1H), 7.99 (d, J = 2.0 Hz, 1H, 7.5), 7.5, (H 5.92-5.18 (m, 1H), 4.88 (ddc, J = 74.5, 37.9, 6.4 Hz, 1H), 4.34-4.19 (m, 1H), 4.13-3.88 (m, 1H), 2.83-2.68 (m, 3.1H), 3H). 19F NMR (376 MHz, DMSO) δ -60.91. LCMS: LCMS (IER) m / z: 457 [M+H]+ 51 (R)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) 9.19 (s, 1H), 8.35 (s, 1H), 7.93 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 8.6 Hz, 4, 7.8 Hz, 7.0 H), (22H), 6.08 (d, J = 254.7 Hz, 1H), 5.00-4.65 (m, 2H), 2.69 (s, 3H). LCMS (IER) m / z: 428.1 [M+H]+ 52 (S)-4-amino-N-(6-(fluoromethyl)-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.26 (s, 1H), 7.94 (s, 1H), 7.58-7.55 (m, 1H), 7.54-7.52 (m, 1H), 7.4-7.52 (m, 1H), 7.4-7.30 (m, 1H), 7.05-7.01 (m, 1H), 6.93-6.88 (m, 1H), 6.48-5.75 (m, 1H), 5.44-5.38 (m, 1H), 5.28 (s, 1H), 4.69-4.63 (m, 1H, 1H), 3.5.5 (m, 1H), 2.80-2.69 (m, 3H). JHMS (IER): 392.10 [M+H]+ 53 (S)-4-amino-N-(6-carbamoyl-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.33 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.50-7.47 (m, 4H), 7.43 (2H), 7.38 (m, 3.38) 2H), 6.42-5.71 (m, 1H), 4.89-4.64 (m, 2H), 2.66-2.65 (m, 3H). JHMS (IER): 403.10 [M+H]+ 54 (S)-4-amino-N-(6-amino-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.28 (s, 1H), 7.91 (s, 1H), 7.47-7.42 (m, 4H), 7.00 (d, J = 8.0 Hz, 1H, 1H, 0.8 Hz), J 1H), 6.05 (s, 1H), 5.40-5.23 (d, 2H), 4.61-4.48 (s, 2H), 2.77 (s, 1H), 2.61 (s, 3H). JHMS (IER): 375.10 [M+H]+ 55 (S)-4-amino-N-ethyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.28 (d, J = 1.7 Hz, 1H), 7.91 (d, J = 0.7 Hz, 1H), 7.66 (d, J = 7.8 Hz, 14,7.7 Hz), (7.4H), (7.4H), 7.33-7.29 (m, 1H), 7.23 (d, J = 1.5 Hz, 1H), 5.85 (s, 1H), 4.79-4.68 (m, 2H), 3.23-3.20 (m, 2H), 0.93 (s, 3H). LCMS (IER) m / z: 442.15 [M+H]+ 56 (S)-4-amino-N-methyl-N-(6-(trifluoromethoxy)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.31 (d, J = 6.6 Hz, 1H), 7.93 (d, J = 3.1 Hz, 1H), 7.86-7.03 (m, 5H), 6, 94, (d, J = 42). 9.1, 4.0 Hz, 1H), 4.92-4.55 (m, 2H), 3.06-2.56 (m, 3H). JHMS (IER): 443.75 [M+H]+ 57 (S)-4-amino-7-fluoro-N-methyl-N-(6-(trifluoromethoxy)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.34 (s, 1H), 8.0-7.82 (m, 1H), 7.66-7.39 (m, 1H), 7.36-7.30 (m, 1H), 6.26 (s), (m, 1H), 4.71 (d, J = 4.2 Hz, 2H), 2.67 (s, 3H). JHMS (IER): 461.75 [M+H]+ 107 (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.33 (t, J = 1.1 Hz, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 15, 7.4 H), (7.4H), (41H), 7.33 (d, J = 7.8 Hz, 1H), 7.25 (s, 1H), 6.37 (s, 1H), 5.86 (s, 1H), 4.81 (s, 1H), 4.72 (dd, J = 10.3, 4.4 Hz, 1H, 2, 6H), (2 , 3H). LCMS (IER) m / z: 428.2 [M+H]+ 108 4-amino-N-methyl-N-((5S)-8-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.26-9.12 (m, 1H), 8.52 (d, J = 18.6 Hz, 1H), 8.43-8.32 (m, 1H), 7.92 (s, 1H), 7.79 (dd, J = 7.8 Hz, 7.8 Hz 1H), 7.61-7.32 (m, 5H), 5.79 (d, J = 49.5 Hz, 1H), 5.09-4.53 (m, 2H), 4.43-3.89 (m, 2H), 2.77 (d, J = 31.5 Hz, 3.6 Hz, 37 (H), 13.3H). LCMS (IER) m / z: 389.4 [M+H]+ 124 (S)-4-amino-N-ethyl-7-fluoro-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.10-9.04 (m, 1H), 8.42-8.21 (m, 1H), 7.86 (s, 1H), 7.53-7.49 (m, 3H), 7.26-7.24 (m, 1H), 7.26-7.24 (m, 7.15), 2H), 5.94-5.53 (s, 1H), 4.87-4.82 (t, J = 9.7 Hz, 1H), 4.60-4.57 (m, 3H), 0.98-0.79 (m, 3H). LCMS (IER) m / z: 460.20 [M+H]+ 110 4-amino-7-fluoro-N-methyl-N-(7-(trifluoromethyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 52.0 Hz, 1H), 8.69-8.49 (m, 1H), 8.31 (dd, J = 21.8, 6.5 Hz, 1H), 7.91 (d, 16.2 Hz, 7.2 Hz), G (dd, J = 23.9, 2.0 Hz, 1H), 7.54 (d, J = 16.2 Hz, 2H), 7.22 (dd, J = 11.0, 7.9 Hz, 1H), 6.03-5.01 (m, 1H), 4.64-4.17 (m, J, 2.71), J 2.0 Hz, 3H), 2.46-2.20 (m, 2H). LCMS (IER) m / z: 461.20 [M+H]+ 125 4-amino-N-(2,3-dihydro-1H-inden-1-yl)-N-methylimidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.43-9.23 (m, 1H), 8.79-8.61 (m, 1H), 8.51 (d, J = 3.7 Hz, 1H), 8.03-7.94 (m, 1H, 7.8), 7.5, (2H), 7.37-7.21 (m, 4H), 6.30-5.52 (m, 1H), 3.06-2.84 (m, 2H), 2.72-2.55 (m, 3H), 2.46-2.27 (m, 1H), 2.16-2.01 (m, 1H). LCMS (IER) m / z: 359.15 [M+H]+ 117 (S)-4-amino-7-fluoro-N-methyl-N-(6-(1-methyl-1H-pyrazol-5-yl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.36 (d, J = 6.6 Hz, 1H), 7.95 (d, J = 3.6 Hz, 1H), 7.64 (s, 2H), 7.46 (dt, 2.7, Hz, 2.7 Hz), 7.36-6.98 (m, 3H), 6.53-5.46 (m, 2H), 4.92-4.52 (m, 2H), 3.86 (d, J = 14.2 Hz, 3H), 2.69 (d, J = 41.8 Hz, 3H). LCMS (IER) m / z: 458.1 [M+H]+ 119 (S)-4-amino-7-fluoro-N-methyl-N-(6-(3-methylisoxazol-5-yl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.34 (d, J = 6.6 Hz, 1H), 7.94 (d, J = 3.6 Hz, 1H), 7.62 (s, 2H), 7.48 (d, 3,2H), 7.48 (d, 2H), G 7.41-7.20 (m, 2H), 6.93 (d, J = 6.6 Hz, 1H), 6.52-5.60 (m, 1H), 4.93-4.58 (m, 2H), 2.67 (d, J = 37.4 Hz, 3H), 2.2.9 (d, J = 36.6 Hz). LCMS (IER) m / z: 459.1 [M+H]+ 116 (R)-4-amino-7-fluoro-N-methyl-N-(7-(3-methylisoxazol-5-yl)chroman-4-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.27-9.07 (m, 1H), 8.42 (e, J = 6.6 Hz, 1H), 7.94 (e, J = 10.1 Hz, 1H), 7.62 (d, J = 14.7 Hz, 1H), 7.62 (d, J = 14.7 Hz, J 8.1, 1.8 Hz, 1H), 7.33-7.11 (m, 3H), 7.03-6.82 (m, 1H), 6.04 (dd, J = 10.6, 6.3 Hz, 1H), 4.52-4.03 (m, 2H), 2.17 (J, 3.4), = Hz 2.42-2.06 (m, 5H). LCMS (IER) m / z: 473.1 [M+H]+ 130 (S)-4-amino-N-methyl-N-(6-(perfluoroethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.34 (e, J = 1.2 Hz, 1H), 7.92 (s, 1H), 7.68 (e, J = 7.8 Hz, 1H), 7.52-7.40 (m, J = 7.2 Hz, 1H), 7.9 Hz, 1H), 7.21 (s, 1H), 6.54-5.59 (m, 1H), 5.09-4.48 (m, 2H), 2.69 (s, 3H). LCMS (IER) m / z: 478.3 [M+H]+ 129 4-amino-7-fluoro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzo[b]thiophene-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 17.1 Hz, 1H), 8.51-8.23 (m, 1H), 7.93 (d, J = 3.1 Hz, 1H), 7.83-7.67 (m, J = 3.1 Hz, 1H), 7.83-7.67 (d, 17, 17 Hz), (d, J = 1,17 Hz, 2H), 7.52 (t, J = 9.4 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.26 (dd, J = 11.0, 1.7 Hz, 1H), 6.62-5.58 (m, 1H), 3.9-38 (d, 2.29), J = 41.5 Hz, 3H). LCMS (IER) m / z: 462.2 [M+H]+

[0607] Example 58: (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)tetrazolo[1,5-a]quinoxaline-8-carboxamide

[0608]

[0609] Step 1: Synthesis of N-((dimethylamino)((8-(methyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamoyl)tetrazolo[1,5-a]quinoxalin-4-yl)amino)methylene)-N-methylmethanaminium

[0610] 4-Aminotetrazolo[1,5-a]quinoxaline-8-carboxylic acid (131 mg, 0.56 mmol) was dissolved in DMF (4.5 mL), then 2-(7-azabenzotriazol-1-yl)-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) were added. The reaction was carried out at room temperature for 0.5 h. The reaction mixture was diluted with ethyl acetate (30 mL) and water (30 mL), the aqueous layer was extracted with ethyl acetate (2×20 mL). The organic phase was combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to give (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)tetrazolo[1,5-a]quinoxaline-8-carboxamide (100 mg, 0.19 mmol, yield: 33.33%) as a white solid.

[0611] LCMS (IER): 528 [M+H] +

[0612] Step 2: Synthesis of (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)tetrazolo[1,5-a]quinoxaline-8-carboxamide

[0613] (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)tetrazolo[1,5-a]quinoxaline-8-carboxamide (100 mg, 0.19 mmol) was dissolved in THF (4 mL), then water (4 mL) and LiOH (27 mg, 1.12 mmol) were added. After completion of the reaction, the reaction mixture was concentrated and purified by HPLC (column: YMC Triart C18 ExRs 5 μm, 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 over 10 minutes; Wavelength: 254 nm / 220 nm; Retention time: 8.43 / 9.23 minutes) to give (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.

[0614] 1H 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), 6.5-m, (1H), 4.91-4.73 (m, 2H), 3.94 (s, 3H).

[0615] LCMS (IER) m / z: 430.10 [M+H] +

[0616] Example 59:Synthesis 4-amino-N-cyclopropyl-7-fluoro-N-(7-(5-(trifluoromethyl)pyridin-3-yl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)imidazo[1,5-a]quinoxalin-8-carboxamide

[0617]

[0618] 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 mL), 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. The reaction was stirred at room temperature overnight. Then, water (10 mL) was added and extracted with ethyl acetate (20 mL). The combined organic phase was washed with water (2×10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (MeOH / DCM = 0-7%) to give 4-amino-N-cyclopropyl-7-fluoro-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 mg, yield: 25%).

[0619] 1H 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).

[0620] LCMS (ESI) m / z: 564.30 [M+H] +

[0621] By using the synthetic procedures described in Example 59 and replacing the appropriate starting materials, the embodiments listed in the table below can be obtained:

[0622] Example Structure Name 1H NMR and 19F NMR and LCMS 60 (R)-4-amino-7-fluoro-N-methyl-N-(7-(trifluoromethyl)chroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J = 28.3 Hz, 1H), 8.40 (d, J = 6.6 Hz, 1H), 8.02-7.84 (m, 1H), 7.59 (d, J = 14.5 Hz), 7.7.7Hz (m, 2H), 7.14 (d, J = 27.6 Hz, 1H), 5.56 (ddd, J = 387.9, 10.8, 6.3 Hz, 1H), 4.69-3.91 (m, 2H), 2.94-2.59 (m, 3H, 26.2H), 2.09 (2H). LCMS (IER) m / z: 460.20 [M+H]+ 61 4-amino-7-chloro-N-((4S)-7-fluoro-1-methylisochroman-4-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.26-9.13 (m, 1H), 8.41-8.34 (m, 1H), 7.93-7.91 (m, 1H), 7.59-7.58 (m, 2H), 7.56-7.47 (m, 1H), ( 7.47-7.37 (m, 1H), 7.23-7.08 (m, 2H), 5.68-4.93 (m, 1H), 4.85-4.61 (m, 1H), 4.27-3.88 (m, 2H), 2.78-2.51 (m, 3.5H), 3H). LCMS (IER) m / z: 440.2 [M+H]+ 62 4-amino-N-((4S)-7-fluoro-1-methylisochroman-4-yl)-N-methylimidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.31-9.27 (m, 1H), 8.67-8.65 (m, 1H), 8.55-8.48 (m, 1H), 7.98 (d, 1H), 7.72-m, 7.70 (m, 7.49), 7.49 (m, H 1H), 7.21-7.10 (m, 2H), 5.64-5.08 (m, 1H), 4.86-4.62 (m, 1H), 4.25-3.87 (m, 2H), 2.78-2.69 (m, 3H), 1.54-1.37 (m, 3H). LCMS (IER) m / z: 407.2 [M+H]+ 63 (S)-4-amino-7-chloro-N-(5-fluoro-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.45-8.21 (m, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.46 (s, 1H), 7.31 (2, 7.6) (m, 1H), 2H), 6.90-6.86 (m, 1H), 6.42-5.39 (m, 1H), 4.78-4.54 (m, 2H), 2.72-2.48 (m, 3H). LCMS (IER) m / z: 412.1 [M+H]+ 64 (S)-4-amino-N-(5-fluoro-2,3-dihydrobenzofuran-3-yl)-N,3-dimethylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.25 (s, 1H), 7.44-7.40 (m, 2H), 7.30-7.28 (m, 1H), 7.11-7.09 (m, 1.7H), 6.08-m, (H 4.72-4.62 (m, 2H), 4.62-4.60 (m, 1H), 2.67 (s, 3H), 2.63 (s, 3H). LCMS (IER) m / z: 392.2 [M+H]+ 65 4-amino-N-(6-cyano-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.38 (s, 1H), 7.92 (s, 1H), 7.73 (d, 1H), 7.62 (m, 1H), 7.47-7.41 (m, 7, 3H), (3, 3H), ( 5.95-5.91 (m, 1H), 4.89-4.84 (m, 1H), 4.70-4.67 (m, 1H), 3.0 (m, 1H), 0.46-0.09 (m, 4H). LCMS (IER) m / z: 411.30 [M+H]+. 66 (S)-4-amino-N-(5-fluoro-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.32 (s, 1H), 7.91 (s, 1H), 7.46 (d, 4H), 7.31-7.28 (m, 1H), 7.13-7 (d, 08.8), 6.81-H (m, 1H), 4.81-4.65 (m, 2H), 4.63-4.60 (m, 1H), 2.67 (s, 3H). LCMS (IER) m / z: 378.1 [M+H]+ 67 4-amino-N-cyclopropyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.65 (d, J = 1.9 Hz, 1H), 8.44 (s, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.72 (s, 2H), J = 6.7, J Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.21 (s, 1H), 5.97 (s, 1H), 4.87 (d, J = 10.3 Hz, 1H), 4.78-4.68 (m, 1H), 2.95 (s, 0.3H), (27H), 0.22 (s, 1H), 0.11 (s, 1H). LCMS (IER) m / z: 455 [M+H]+ 68 (S)-4-amino-N-(6-fluoro-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.33 (d, J = 1.2 Hz, 1H), 7.95 (s, 1H), 7.58 (s, 2H), 7.48 (s, 2H), 7.42 (dd, J = 7.8, 5.8 Hz, 1H), 6.80 (t, J = 9.1 Hz, 2H), 6.29 (s, 1H), 4.90-4.57 (m, 2H), 2.65 (s, 3H). LCMS (ESI) m / z: 378 [M+H]+ 69 4-amino-N-cyclopropyl-3-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.32 (d, J = 1.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.60-7.52 (m, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.20 (s, 1H), 6.91 (s, 2H), 5.94 (dd, J = 9.7, 4.5 Hz, 1H), 4.87 (t, J = 9.8 Hz, 1H), 4.70 (dd, J = 10.3, 4.6 Hz, 1H), 3.01-2.94 (m, 1H), 2.63 (s, 3H), 0.49-0.38 (m, 1H), 0.34 (g, J = 5.0 Hz, 1H), 0.20 (dk, J = 12.7, 6.4 Hz, 1H), 0.10 (dt, J = 10.6, 5.2 Hz, 1H). LCMS (ESI) m / z: 468 [M+H]+ 70 (S)-4-amino-N-(6-chloro-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.32 (d, J = 1.4 Hz, 1H), 7.94 (s, 1H), 7.54 (g, J = 4.9, 4.4 Hz, 1H, 48), 7.4 (d, J = 4.4 Hz, 1H 8.4 Hz, 1H), 7.09-6.97 (m, 2H), 4.86-4.59 (m, 2H), 2.66 (s, 3H). LCMS (IER) m / z: 395 [M+H]+ 72 4-amino-N-cyclopropyl-N-(6-(2-methylpyrimidin-5-yl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 9.04 (s, 2H), 8.42 (d, J = 1.8 Hz, 1H), 7.98 (s, 1H), 7.81~7.55 (m, 4Hz, 7, 46 Hz), J 1H), 7.41~7.22 (m, 2H), 5.96 (dd, J = 9.2, 4.2 Hz, 1H), 4.83 (t, J = 9.7 Hz, 1H), 4.68 (m, 1H), 2.95 (s, 1H), 2.67 (s, 0, J, 38), J 20.6, 5.9, 6.1 Hz, 2H), 0.26~0.08 (m, 2H). LCMS (IER) m / z: 478.2 [M+H]+ 73 4-amino-N-cyclopropyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.39 (d, J = 1.9 Hz, 1H), 7.92 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.61 (dd, 8.8 Hz, 19 Hz), H 7.51~7.38 (m, 3H), 7.31 (d, J = 7.8 Hz, 1H), 7.21 (s, 1H), 5.95 (dd, J = 9.8, 4.5 Hz, 1H), 4.87 (t, J = 9.8 Hz, 1H, 1H, 14, 6.1, J Hz, 1H), 2.98 (dt, J = 11.3, 5.1 Hz, 1H), 0.38 (ddt, J = 36.4, 10.8, 5.7 Hz, 2H), 0.26~0.04 (m, 2H). LCMS (IER) m / z: 454.3 [M+H]+ 74 4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.37 (d, J = 1.9 Hz, 1H), 7.92 (s, 1H), 7.59 (dd, J = 8.4, 1.8 Hz, 1H), 7.5-7.7, (m, 1H), 7.24-7.03 (m, 2H), 5.86 (dd, J = 9.3, 4.2 Hz, 1H), 4.81 (t, J = 9.7 Hz, 1H), 4.65 (dd, J = 10.2, 4.2 Hz, 1H), 2.92 (d, J = 1, 1H), 0.50-0.27 (m, 2H), 0.27-0.04 (m, 2H). LCMS (IER) m / z: 465.3 [M+H]+ 126 4-amino-N-cyclopropyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[2,3-e]pyrazine-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.84 (d, 1H), 8.75 (d, 1H), 8.5-8.5 (m, 2H), 8.10 (s, 1H), 7.74 (d, 3H), (7, 1H), (7, 21H), (s, 1H), 5.99-5.95 (m, 1H), 4.91-4.86 (m, 1H), 4.73-4.70 (m, 1H), 3.63-3.59 (m, 1H), 0.51-0.13 (m, 4H). LCMS (IER) m / z: 455.3 [M+H]+ 121 4-amino-N-cyclopropyl-7-fluoro-N-(6-morpholino-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.30 (d, J = 6.6 Hz, 1H), 7.92 (s, 1H), 7.58 (s, 2H), 7.21 (t, J = 9.3 Hz, 2.6, 6.8H), 2H), 5.97 (s, 1H), 4.71 (s, 1H), 4.54 (dd, J = 10.5, 3.5 Hz, 1H), 3.72 (t, J = 4.7 Hz, 4H), 3.10 (t, J = 4.8 Hz, 4H, 2H), 0.22 (d, J = 76.8 Hz, 4H). JHMS (IER) m / z: 489.1 [M+H]+

[0623] 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-8-carboxamide

[0624]

[0625] (S)-N-(methyl-d3)-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (0.1 g, 0.45 mmol), 4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylic acid (0.1 g, 0.45 mmol), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (0.19 g, 0.68 mmol) and 1-methylimidazole (0.11 g, 1.36 mmol) were added to DMF (1 mL), and the reaction mixture was stirred for 1 hour. After completion of the reaction, the reaction system was cooled to room temperature. Then, the reaction mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was further purified by HPLC (column: YMC Triart C18 ExRs 5 μm, 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 55% B over 8 min; Wavelength: 254 nm / 220 nm.Retention time (minimum value): 7.22 minutes) 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%).

[0626] 1 H 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).

[0627] LCMS (ESI): 431.85 [M+H] +

[0628] By using the synthetic procedures described in Example 75 and substituting the appropriate starting materials, the embodiments listed in the table below can be obtained:

[0629] Example Structure Name 1H NMR and 19F NMR and LCMS 76 (S)-4-amino-N-methyl-N-(6-((trifluoromethyl)sulfonamido)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.30 (s, 1H), 7.91 (s, 1H), 7.80-7.16 (m, 4H), 7.08 (s, 1H), 6.52-6.46, (5.3.3H), (m, 1H), 4.62-4.49 (m, 2H), 2.98-2.50 (m, 3H). JHMS (IER): 507.1 [M+H]+ 118 (S)-4-amino-1-cyclopropyl-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.79 (s, 1H), 7.62-7.60 (m, 1H), 7.54-7.45 (m, 2H), 7.32-7.31 (m, 3H), (7, 2H), (, 1H 6.34-6.11 (m, 1H), 4.84-4.70 (m, 2H), 2.67 (d, J = 3.0 Hz, 3H), 2.58-2.51 (m, 1H), 1.30-0.95 (m, 4H). JHMS (IER): 467.75 [M+H]+

[0630] Example 77: Synthesis of 4-amino-N-((4S)-6-fluoro-1-methylisochroman-4-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0631]

[0632] (4S)-6-fluoro-N,1-dimethylisochroman-4-amine hydrochloride (100 mg, 0.5122 mmol) was dissolved in DMA (4 mL), then 4-aminoimidazo[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. After stirring the reaction mixture for 2 hours, the reaction solution was poured into water (40 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the crude product and further purified by silica gel column chromatography (DCM:MeOH=10:1) to obtain 4-amino-N-((4S)-6-fluoro-1-methylisochroman-4-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (70 mg, yield: 33.7%).

[0633] 1H 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, 14.94-m), 1H), 4.38-3.79 (m, 2H), 2.87-2.66 (m, 3H), 1.49 (dd, J = 13.0, 6.2 Hz, 3H).

[0634] 19 F NMR (376 MHz, DMSO-d6) δ -115.37, -115.39.

[0635] JHMS (IER) m / z: 406 [M+H] +

[0636] Example 78: (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide-1-d

[0637] Example 111:(S)-4-amino-1-bromo-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0638]

[0639] Stage 1: Synthesis of 4-amino-1-bromoimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0640] 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (500 mg, 2.19 mmol) was dissolved in THF (15 mL). Then, the reaction system was cooled to -40°C, and n-butyl lithium (5 mL, 15.34 mmol) was added dropwise while maintaining the temperature at -40°C. The mixture was reacted for 10 minutes at 40°C, then reacted for 10 minutes at room temperature. After completion of the reaction, the reaction mixture was concentrated to dryness under vacuum. After adding DCM, the mixture was filtered and then further purified by silica gel column chromatography (formic acid:acetonitrile=1:1) to obtain 4-amino-1-bromimidazo[1,5-a]quinoxaline-8-carboxylic acid (30 mg, yield: 4.46%) as a white solid.

[0641] LCMS (ESI) m / z: 307 [M+H] +

[0642] Step 2: Synthesis of Example 111 (S)-4-amino-1-bromo-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0643] 4-amino-1-bromimidazo[1,5-a]quinoxaline-8-carboxylic acid (10 mg, 0.03 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19 mg, 0.05 mmol), N,N-diisopropylethylamine (8 mg, 0.05 mmol) and (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (7 mg, 0.03 mmol) were dissolved in DMF (1 mL) sequentially. After completion, the reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to give 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.

[0644] 1H 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 = 7.9 Hz, 3H), 7.32 (d, J = 7.7 Hz, 1H), (1H), 6.42 (s, 1H), 4.79-4.72 (m, 2H), 2.75-2.62 (m, 3H).

[0645] JHMS (IER)m / z: 506 [M+H] +

[0646] Stage 3 Synthesis of Example 78 (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide-1-d

[0647] (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 a solution of deuterated methanol (1 mL) and D2O (1 mL). The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified by HPLC (column: Kinetex 5 μm EVO C18, 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 47% B over 10 min; Wavelength: 254 nm / 220 nm.Retention time: 9.35 minutes) to give Example 78 (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, yield: 8.45%) as a white solid.

[0648] 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).

[0649] LCMS (ESI) m / z: 428 [M+H] +

[0650] By using the synthetic procedures described in Example 78 and replacing the appropriate starting materials, the embodiments listed in the table below can be obtained:

[0651] Example Structure Name 1H NMR and 19F NMR and LCMS 79 (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide-3-d 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.33 (t, J = 1.1 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.52-7.37 (m, 4H), 7.33 (d, J = 7.9 Hz, 1H), 7.26 (s, 1H), 6.52 (s, 1H), 4.72 (dd, J = 10.1, 4.5 Hz, 2H), 2.67 (d, J = 2.8 Hz, 3H). LCMS (ESI) m / z: 428 [M+H]+ 127 (S)-4-amino-3-bromo-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.33 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.56-7.47 (m, 2H), 7.34-7.32 (m, 1H), 7.26 (s, 1H), 7.05 (s, 2H), 6.52-5.65 (m, 1H), 4.89-4.65 (m, 2H), 2.67 (s, 3H). LCMS (ESI): 506 [M+H]+

[0652] Example 109: Synthesis of ethyl 4-amino-8-(methyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamoyl)imidazo[1,5-a]quinoxaline-3-carboxylate

[0653]

[0654] 4-amino-3-bromo-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (30 mg, 0.006 mmol), potassium acetate (17 mg, 0.18 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (4 mg, 0.01 mmol) were added to a mixed solvent of DMF (5 mL) and EtOH (5 mL). The reaction was carried out overnight in a pressure vessel under carbon monoxide pressure (4 MPa) at 110°C. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product.The crude product was purified by HPLC (Column: Sunfire C18 5 μm, 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 over 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%).

[0655] 1 H 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).

[0656] LCMS (ESI): 500.10 [M+H] +

[0657] 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

[0658]

[0659] Step 1: Synthesis of (S)-6-bromo-N-methyl-2,3-dihydrobenzofuran-3-amine

[0660] tert-Butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (200 mg, 0.6 mmol) was dissolved in a solution of hydrochloric acid in 1,4-dioxane and stirred at room temperature. After completion of the reaction, the reaction solution was concentrated to obtain the crude product (S)-6-bromo-N-methyl-2,3-dihydrobenzofuran-3-amine (85 mg, yield 61%)

[0661] LCMS (ESI) m / z: 228 [M+H] +

[0662] 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

[0663] 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid was dissolved in DMA (2 mL), then propylphosphonic 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 sequentially. The reaction system was then stirred overnight at room temperature. After completion of the reaction, the solution was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then purified by silica gel column chromatography (DCM: MeOH = 10%) to give (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (35 mg, 20%).

[0664] LCMS (ESI) m / z: 456 [M+H] +

[0665] 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

[0666] (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), then [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (65 mg, 0.07 mmol), MeOH (86 mg, 2.68 mmol) were added under N2 atmosphere. After completion, the reaction system was stirred for 10 hours at room temperature. After completion of the reaction, the solution was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated.The residue was further purified by preparative HPLC Column: XBridge BEH Shield RP18 5 μm, 30 mm × 150 mm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 50% B over 8 min; Wavelength: 254 nm / 220 nm; RT1(min): 7.88) to afford (S)-4-amino-7-fluoro-N-(6-methoxy-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (14.25 mg, yield: 44.6%).

[0667] 1 H 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).

[0668] LCMS (ESI) m / z: 408.10 [M+H] +

[0669] Example 122: Synthesis of methyl (S)-3-(4-amino-N-methylimidazo[1,5-a]quinoxaline-8-carboxamido)-2,3-dihydrobenzofuran-6-carboxylate

[0670]

[0671] Step 1: Synthesis of methyl (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-carboxylate

[0672] Tert-butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate (100 mg, 0.31 mmol) was dissolved in a solution of MeOH (5 mL) and DMF (10 mL) at room temperature. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (56 mg, 0.07 mmol) and potassium acetate (68 mg, 0.69 mmol) were added sequentially. The reaction system was carried out overnight at 100°C under a CO atmosphere (4 MPa). After completion of the reaction, the solution was concentrated, poured into water, and filtered. The filter cake was suspended in petroleum ether to give methyl (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-carboxylate (70 mg, yield 77.78%), a red solid.

[0673] LCMS (ESI): 308 [M+H] +

[0674] Step 2: Synthesis of methyl (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-carboxylate

[0675] (S)-3-((tert-butoxycarbonyl)(methyl)amino)-2,3-dihydrobenzofuran-6-carboxylate (70 mg, 0.23 mmol) was dissolved in a solution of HCl in 1,4-dioxane (2 mL, 4 M). The reaction mixture was carried out for 0.5 h at room temperature. After completion of the reaction, the solution was concentrated to obtain methyl (S)-3-(methylamino)-2,3-dihydrobenzofuran-6-carboxylate (46 mg, yield 97%), a black solid.

[0676] LCMS (ESI): 208 [M+H] +

[0677] Step 3 Synthesis of methyl (S)-3-(4-amino-N-methylimidazo[1,5-a]quinoxaline-8-carboxamido)-2,3-dihydrobenzofuran-6-carboxylate

[0678] 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid was dissolved in DMF (4 mL), then 2-(7-azabenzotriazol-1-yl)-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-carboxylate (46 mg, 0.22 mmol) were added sequentially. The reaction mixture was stirred for 3 hours at room temperature. After completion of the reaction, the mixture was diluted with ethyl acetate (10 mL) and water (5 mL). Then, the aqueous phase was separated and extracted with ethyl acetate (2×10 mL). The combined organic phase 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 further purified by HPLC (column: Sunfire C18 5 μm, 30 mm×150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient from 5% B to 30% B over 8 min; wavelength: 254 nm / 220 nm) to give methyl (S)-3-(4-amino-N-methylimidazo[1,5-a]quinoxaline-8-carboxamido)-2,3-dihydrobenzofuran-6-carboxylate (21 mg, yield: 1%) as a white solid.

[0679] 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (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)

[0680] LCMS (ESI): 418.20 [M+H] +

[0681] Example 112: Synthesis of (S)-4-amino-N-(6-(difluoromethyl)-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0682]

[0683] Step 1: Synthesis of (S)-6-bromo-N-methyl-2,3-dihydrobenzofuran-3-amine

[0684] tert-Butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)(methyl)carbamate was dissolved in a solution of HCl in 1,4-dioxane (4.0 M, 10 mL). Then, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solution was concentrated under vacuum to obtain (S)-6-bromo-N-methyl-2,3-dihydrobenzofuran-3-amine (80 mg, 0.30 mmol, yield: 95.46%) as a yellow liquid.

[0685] LCMS (ESI): 228 [M+H] +

[0686] Step 2: Synthesis of (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0687] 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (80 mg, 0.35 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (200 mg, 0.53 mmol) and N,N-diisopropylethylamine (136 mg, 1.05 mmol) were dissolved in DMA (3 mL), followed by the addition of (S)-6-bromo-N-methyl-2,3-dihydrobenzofuran-3-amine (80 mg, 0.35 mmol). The reaction mixture was stirred for 2 h at room temperature. After completion of the reaction, the solution was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was further purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:20) to obtain (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (70 mg, 0.35 mmol, yield: 45.54%).

[0688] LCMS (ESI): 438 [M+H] +

[0689] Step 3: Synthesis of (S)-4-amino-N-(6-(difluoromethyl)-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0690] (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (30 mg, 0.07 mmol) was dissolved in THF (2 mL), followed by the addition of [Ir(dF(CF3)ppy)2(dpy)]PF6 (8 mg, 0.007 mmol), nickel(II) bromide complex with ethylene glycol dimethyl ether (1 mg, 0.003 mmol), PPh3(CF2H)2 (17 mg, 0.14 mmol), diphenylphenanthroline (2 mg, 0.007 mmol). The reaction was carried out overnight at room temperature at a wavelength of 465 nm. After completion of the reaction, the solution was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product.The crude product was further purified by HPLC (column: Kinetex 5 μm EVO C18, 30 mm × 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient from 20% B to 47% B in 10 min; wavelength: 254 / 220 nm; retention time (minimum value): 9.35) to afford (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, yield: 2.96%).

[0691] 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).

[0692] LCMS (IER): 409 [M+H] +

[0693] Example 115: Synthesis of (R)-4-amino-7-fluoro-N-methyl-N-(7-(1-methyl-1H-pyrazol-5-yl)chroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0694]

[0695] 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, then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (187 mg, 0.976 mmol) and 1-hydroxybenzotriazole (133 mg, 0.976 mmol) were added, followed by DIEA (421 mg, 3.264 mmol). The reaction system was carried out at room temperature for 0.5 h. Then (R)-N-methyl-7-(1-methyl-1H-pyrazol-5-yl)chroman-4-amine (1 g, 4.184 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, as confirmed by LCMS, water (30 mL) was added and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product.The crude product was further purified by silica gel column chromatography (0-5% MeOH / DCM) to obtain (R)-4-amino-7-fluoro-N-methyl-N-(7-(1-methyl-1H-pyrazol-5-yl)chroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (45 mg, yield: 11.75%).

[0696] 1 H 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, 1.9 Hz, 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).

[0697] LCMS (ESI) m / z: 472.1 [M+H] +

[0698] By using the synthetic procedures described in Example 115 and substituting the appropriate starting materials, the embodiments listed in the table below can be obtained:

[0699] Example Structure Name 1H NMR and 19F NMR and LCMS 13 4-amino-N-(1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.81 (s, 1H), 8.34 (d, J = 6.6 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 16.4 Hz, 2H), 7.60 (s, 2H), 7.24 (d, J = 11.2 Hz, 1H), 4.90 (s, 2H), 2.81 (s, 1H), 0.53 (d, J = 12.7 Hz, 4H). LCMS (ESI) m / z: 488.2 [M+H]+ 113 (R)-4-amino-7-fluoro-N-methyl-N-(7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J = 22.8 Hz, 1H), 8.98 (d, J = 3.8 Hz, 1H), 8.44 (dd, J = 20.3, 7.1 Hz, 2H), 7.93 (d, J = 9.8 Hz, 1H), 7.58 (t, J = 13.0 Hz, 2H), 7.39-7.13 (m, 4H), 5.52 (ddd, J = 405.6, 10.5, 6.5 Hz, 1H), 4.49-3.96 (m, 2H), 2.81-2.58 (m, 3H), 2.28 (cd, J = 12.2, 10.9, 6.8 Hz, 1H), 2.19-2.02 (m, 1H). LCMS (ESI) m / z: 472.1 [M+H]+ 114 (R)-4-amino-7-fluoro-N-methyl-N-(7-(1-methyl-1H-pyrazol-4-yl)chroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.19-9.13 (m, 1H), 8.43-8.19 (m, 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.60-7.53 (m, 2H), 7.29-6.96 (m, 4H), 5.48 (ddd, J = 409.0, 10.4, 6.4 Hz, 1H), 4.43-3.98 (m, 2H), 3.85 (d, J = 6.1 Hz, 3H), 2.82-2.59 (m, 3H), 2.36-2.19 (m, 1H), 2.08 (t, J = 5.9 Hz, 1H). LCMS (ESI) m / z: 472.1 [M+H]+ 120 (R)-4-amino-7-fluoro-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.44-8.24 (m, 1H), 7.93 (e, J = 3.1 Hz, 1H), 7.58 (d, J = 28.1 Hz, 3H, 3H), 7.5, (3H), 6.53-5.60 (m, 1H), 4.96-4.58 (m, 2H), 2.65 (d, J = 31.4 Hz, 3H). LCMS (IER) m / z: 446.1 [M+H]+ 133 (S)-4-amino-N-(6-(cyclopropylsulfonyl)-2,3-dihydrobenzo[b]thiophen-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.34 (s, 1H), 7.92 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.60-7.29 (m, 6H), 5.5, (m, 1H), 4.97-4.58 (m, 2H), 2.98-2.84 (m, 1H), 2.70 (s, 3H), 1.19-0.94 (m, 4H). LCMS (IER) m / z: 464.2 [M+H]+ 136 4-amino-N-(1,1-dimethyl-7-(1-methyl-1H-pyrazol-5-yl)isochroman-4-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide LCMS (IER) m / z: 500.2 [M+H]+ 137 4-amino-N-(1,1-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)isochroman-4-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide LCMS (IER) m / z: 500.2 [M+H]+

[0700] 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

[0701]

[0702] Step 1: Synthesis of methyl (S)-4-amino-8-(methyl(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)carbamoyl)imidazo[1,5-a]quinoxaline-3-carboxylate

[0703] (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 a mixture of DMF (2 mL) and MeOH (2 mL), then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3 mL, 0.04 mmol) and potassium acetate (23 mg, 0.24 mmol) were added. The reaction was carried out for 16 h at 100°C under a CO atmosphere (4 MPa) in a pressure vessel. After completion of the reaction, the solution was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate and concentrated in vacuo, then further purified by silica gel column chromatography (basic water: acetonitrile = 1:1) to obtain 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.

[0704] LCMS (ESI): 485.42 [M+H] +

[0705] Step 2: Synthesis of (S)-4-amino-3-(hydroxymethyl)-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0706] Methyl (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 then sodium borohydride (5 mg, 0.12 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction, the solution was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product.The crude product was purified by HPLC (column: Kinetex 5 μm EVO C18, 30 mm × 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient from 20% B to 47% B over 10 min; wavelength: 254 / 220 nm; retention time (minimum): 9.35) to afford (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, yield: 11.13%) as a white solid.

[0707] 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).

[0708] LCMS (ESI): 457.41 [M+H] +

[0709] Example 132: Synthesis of (S)-4-amino-N 8 -methyl-N 8-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-3,8-dicarboxamide

[0710]

[0711] Methyl (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 MeOH (0.5 mL) / THF (0.50 mL) / ammonia solution (0.5 mL) and stirred at 60 °C for 2 hours. After completion of the reaction, the reaction solution was poured into water (5 mL), extracted with ethyl acetate, and concentrated to obtain a crude product. The crude product was further purified by preparative high-pressure HPLC to obtain (S)-4-amino-N 8 -methyl-N 8 -(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-3,8-dicarboxamide (1.06 mg, 4%) as a white solid.

[0712] 1H 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).

[0713] LCMS (ESI): 470.80 [M+H] +

[0714] Example 131: Synthesis of (S)-4-amino-3-cyano-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0715]

[0716] To a stirred solution of (S)-4-amino-N 8 -methyl-N 8-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-3,8-dicarboxamide in DCM (2 ml) was added pyridine (10.09 mg, 0.13 mmol), trifluoroacetic anhydride (26.79 mg, 0.26 mmol). The reaction was carried out at room temperature for 12 h. After completion of the reaction, the solution was poured into water (5 ml) and extracted with ethyl acetate. The combined organic phase was concentrated to obtain the crude product, which was then further purified by preparative high-pressure HPLC (Column: C18; mobile phase A: water, mobile phase B: acetonitrile; gradient from 10% to 50% over 10 min) to afford (S)-4-amino-3-cyano-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (1.61 mg, yield: 5%) as a white solid.

[0717] 1H 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), (4, 4H), 4.72 (d, J = 10.5 Hz, 1H), 4.71 (s, 1H), 2.67 (d, J = 2.8 Hz, 3H).

[0718] JHMS (IER): 452.80 [M+H] +

[0719] Examples 81 and 82 :

[0720] Example 81:(R)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide

[0721] Example 82:(S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide

[0722]

[0723] 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 OJ (250 mm × 30 mm, 10 μm); Condition: CO2-i-PrOH (0.1% NH3⋅H2O), 50% / 50%, Flow rate: 80 mL / min) to obtain (R)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide (34.61 mg) and (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide (28.15 mg)

[0724] Example 81: (R)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide

[0725] LCMS (ESI) m / z: 465.3 [M+H] +

[0726] 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, 4.2 Hz, 1H), 2.90 (p, J = 3.2 Hz, 1H), 0.45-0.26 (m, 2H), 0.24-0.03 (m, 2H).

[0727] Example 82: (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide

[0728] LCMS (ESI) m / z: 465.3 [M+H] +

[0729] 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).

[0730] By carrying out the procedures described in Examples 81 and 82, together with the appropriate conditions for the chiral separation of SFC, the embodiments listed in the table below can be obtained:

[0731] Example Structure Name SFC conditions 83 (R)-4-amino-N-cyclopropyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide Peak 1: SFC (column: DAICEL CHIRALCEL OJ (250×30 mm, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 40% / 40%, flow rate: 80 ml / min) 84 (S)-4-amino-N-cyclopropyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide Peak 2: SFC (column: DAICEL CHIRALCEL OJ (250×30 mm, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 40% / 40%, flow rate: 80 ml / min) 85 (R)-4-amino-N-cyclopropyl-3-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide Peak 1: SFC (column: Phenomenex-Cellulose-2, (250 mm × 30 mm, 10 μm), conditions: A for CO2 and B for EtOH (0.1% NH₃H₂O), 45% / 45%, flow rate: 80 mL / min) 86 (S)-4-amino-N-cyclopropyl-3-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide Peak 2: SFC (column: Phenomenex-Cellulose-2, (250 mm × 30 mm, 10 μm), conditions: A for CO2 and B for EtOH (0.1% NH3H2O), 45% / 45%, flow rate: 80 mL / min) 87 (R)-4-amino-N-cyclopropyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide Peak 1: SFC (column: DAICEL CHIRALCEL OJ, (250 mm × 30 mm, 10 μm), conditions: A for CO2 and B for EtOH (0.1% NH3H2O), 35% / 35%, flow rate: 80 mL / min) 88 (S)-4-amino-N-cyclopropyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide Peak 2: SFC (column: DAICEL CHIRALCEL OJ, (250 mm × 30 mm, 10 μm), conditions: A for CO2 and B for EtOH (0.1% NH3H2O), 35% / 35%, flow rate: 80 mL / min) 89 (R)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide Peak 1: SFC (column: DAICEL CHIRALCEL AD, (250 mm × 30 mm, 10 μm), conditions: A for CO2 and B for EtOH (0.1% NH3H2O), 45% / 45%, flow rate: 150 mL / min) 90 (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide Peak 2: SFC (column: DAICEL CHIRALCEL AD, (250 mm × 30 mm, 10 μm), conditions: A for CO2 and B for EtOH (0.1% NH3H2O), 45% / 45%, flow rate: 150 mL / min) 91 (R)-4-amino-N-(6-cyano-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide Peak 1: SFC (column: DAICEL CHIRALPAK AS, (250 mm × 30 mm, 10 μm), conditions: A for CO2 and B for EtOH (0.1% NH3H2O), 45% / 45%, flow rate: 100 mL / min) 92 (S)-4-amino-N-(6-cyano-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylimidazo[1,5-a]quinoxaline-8-carboxamide Peak 2: SFC (column: DAICEL CHIRALPAK AS, (250 mm × 30 mm, 10 μm), conditions: A for CO2 and B for EtOH (0.1% NH3H2O), 45% / 45%, flow rate: 100 mL / min) 93 (R)-4-amino-N-methyl-N-(6-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide Peak 1: CFH (column: ChiralCel OJ, (250 × 40 mm ID, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 40% / 40%, flow rate: 120 mL / min) 94 (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide Peak 2: CFH (column: ChiralCel OJ, (250 × 40 mm ID, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 40% / 40%, flow rate: 120 mL / min) 95 4-amino-N-((1S,4S)-7-fluoro-1-methylisochroman-4-yl)-N-methylimidazo[1,5-a]quinoxalin-8-carboxamide Peak 1: CFH (column: ChiralCel OJ, (250 × 40 mm ID, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 40% / 40%, flow rate: 120 mL / min) 96 4-amino-N-((1R,4S)-7-fluoro-1-methylisochroman-4-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide Peak 2: CFH (column: ChiralCel OJ, (250 × 40 mm ID, 10 μm), conditions: for CO2 and B for MeOH (0.1% NH3H2O), 40% / 40%, flow rate: 120 mL / min) 97 4-amino-N-methyl-N-((1S,4S)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide Peak 1: CFH (column: ChiralCel OJ, (250 × 40 mm ID, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 50% / 50%, flow rate: 120 mL / min) 98 4-amino-N-methyl-N-((1R,4S)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide Peak 2: CFH (column: ChiralCel OJ, (250 × 40 mm ID, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 50% / 50%, flow rate: 120 mL / min) 99 4-amino-N-((1S,4S)-6-fluoro-1-methylisochroman-4-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide Peak 1: CFH (column: ChiralCel OJ, (250 × 40 mm ID, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 40% / 40%, flow rate: 120 mL / min) 100 4-amino-N-((1R,4S)-6-fluoro-1-methylisochroman-4-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide Peak 2: CFH (column: ChiralCel OJ, (250 × 40 mm ID, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 40% / 40%, flow rate: 120 mL / min) 101 (R)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzo[b]thiophen-3-yl)imidazo[1,5-a]quinoxalin-8-carboxamide Peak 1: SFC (column: ChiralPak IJ, (250 × 40 mm ID, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 45% / 45%, flow rate: 130 mL / min) 102 (S)-4-amino-N-methyl-N-(6-(trifluoromethyl)-2,3-dihydrobenzo[b]thiophen-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide Peak 2: SFC (column: ChiralPak IJ, (250 × 40 mm ID, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 45% / 45%, flow rate: 130 mL / min) 103 (R)-4-amino-N-methyl-N-(6-(pentafluoro-λ6-sulfanyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide Peak 1: SFC (column: Daicel ChiralPak IG, (250 × 40 mm ID, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 50% / 50%, flow rate: 140 mL / min) 104 (S)-4-amino-N-methyl-N-(6-(pentafluoro-4.80-4.61-sulfanyl)-2,3-dihydrobenzofuran-3-yl)imidazo[1,5-a]quinoxaline-8-carboxamide Peak 2: SFC (column: Daicel ChiralPak IG, (250 × 40 mm ID, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 50% / 50%, flow rate: 140 mL / min) 105 4-amino-N-methyl-N-((1S,4S)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide Peak 1: SFC (column: ChiralCel OJ, (250 × 40 mm ID, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 50% / 50%, flow rate: 120 mL / min) 106 4-amino-N-methyl-N-((1R,4S)-1-methyl-7-(trifluoromethyl)isochroman-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide Peak 2: SFC (column: ChiralCel OJ, (250 × 40 mm ID, 10 μm), conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 50% / 50%, flow rate: 120 mL / min) 134 (R)-4-amino-N-(1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide Peak 1: SFC (Column: ChiralPak IC, (40 mm ID × 250 mm, 10 μm), Conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 50% / 50%, Flow Rate: 140 mL / min) 135 (S)-4-amino-N-(1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl)-7-fluoro-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide Peak 2: SFC (Column: ChiralPak IC, (40 mm ID × 250 mm, 10 μm), Conditions: A for CO2 and B for MeOH (0.1% NH3H2O), 50% / 50%, Flow Rate: 140 mL / min)

[0732] Biological activity testing

[0733] I. Tumor cell growth inhibition assay

[0734] Test 1: Inhibitory activity of the compound on HCT-116 MTAP cell proliferation( - / - ).

[0735] Materials and cells: HCT-116 MTAP cells( - / -) were obtained from Kyinno Bio (China); RPMI-1640 medium, fetal bovine serum and penicillin-streptomycin were purchased from Thermo Fisher Scientific (America); 384-well plates from PerkinElmer (America); Cell-Titer Glo assay kit from Promega (America).

[0736] Cell Culture: HCT116 MTAP Cells( - / - ) were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C, 5% CO2. Only cells in the logarithmic growth phase were used for the experiments.

[0737] Cell proliferation inhibition assay: Inhibitory activity of the compound on HCT-116 MTAP( cells - / -) was assessed using the Cell-Titer Glo assay kit. By adjusting the cell concentration, 40 μl were added to a 384-well plate and cultured overnight at 37°C, 5% CO2. 40 nl of compound were added to each well, achieving concentrations from 0 to 10,000 nM (starting concentration 10,000 nM, 3-fold dilution, 10 points), with 0.1% DMSO. The cell plate was incubated for 8 days at 37°C, 5% CO2. To measure cell viability, 40 μl of Cell-Titer Glo reagent were added. The results are presented in Table 1.

[0738] Test 2: Inhibitory activity of the compound on the proliferation of wild-type HCT-116 cells by MTAP.

[0739] Materials and cells: MTAP wild-type HCT-116 cells were purchased from Kyinno Bio (China); RPMI-1640 medium, fetal bovine serum and penicillin-streptomycin were purchased from Thermo Fisher Scientific (America); 384-well plates were purchased from PerkinElmer (America); Cell-Titer Glo assay kit was purchased from Promega (America).

[0740] Cell culture: MTAP wild-type HCT116 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C, 5% CO2. Only logarithmic-phase cells were used for experiments.

[0741] Cell proliferation inhibition assay: The inhibitory activity of the compound on wild-type HCT-116 cells by MTAP was evaluated using the Cell-Titer Glo assay kit. By adjusting the cell concentration, 40 μL was added to a 384-well plate and cultured overnight at 37°C, 5% CO2. 40 nL of the compound were added to each well, achieving concentrations from 0 to 10,000 nM (starting concentration 10,000 nM, 3-fold dilution, 10 points), with 0.1% DMSO. The cell plate was incubated for 8 days at 37°C, 5% CO2. To measure cell viability, 40 μL of Cell-Titer Glo reagent was added. The results are shown in Table 1.

[0742] The following Table 1 shows the inhibitory activity of various embodiments of the compounds on the proliferation of HCT116 MTAP( cells - / - ) and wild-type HCT116 cells.

[0743] Table 1

[0744] Example IC50 (nM) MTAP(- / -)-deficient HCT-116 cells Wild-type HCT-116 1 2306 >10000 2 61 6667,6 3 23,4 2251 4 9,9 1711 5 4 280 6 10,6 993 7 141 >10000 8 106 6478,3 9 41,1 2144,5 10 31,2 3111,3 11 1767,4 6410 12 6,1 1112,4 13 15,7 2511,8 14 14,7 1283,1 15 3,5 282,3 16 5,6 1081 17 4,2 243 18 14,5 4327,5 19 23,2 2233,8 20 >3000 >10000 21 14,8 2129,6 22 5,1 1688,6 23 119,5 >10000 24 147,5 >10000 25 176,9 >10000 26 67,7 >10000 27 4,4 842,1 28 321,2 >10000 29 7,1 934,8 30 2086,4 >10000 31 296,6 >10000 32 25,7 1411,8 33 15,1 2665 34 29,6 6572,3 35 23,2 2233,8 36 36 5126,7 37 >3000 >10000 38 30 4063 39 15,9 2041,3 40 32,1 9203,5 41 11 1144 42 659,7 5456,9 43 22,4 2988 44 310 >10000 45 10,3 947,4 46 52,2 >10000 47 17,7 4096 48 >3000 >3000 49 588,7 >10000 50 4,2 196 51 212,6 5864 52 123,4 >10000 53 >3000 >10000 54 2495 >10000 55 11,8 1221,7 56 15,9 1532,1 57 10,5 1869,6 58 >3000 >10000 59 710,6 >10000 60 66,8 7074,5 61 7,7 882,4 62 19,7 3705,7 63 46,8 3256,4 64 278,2 >20000 65 95,3 5946,3 66 2257 >20000 67 35,6 3639,1 68 381,5 8570 69 87,1 5019,1 70 54 3889 72 117,2 >20000 73 55,5 4622,8 74 148,1 5991,4 75 7,3 1167,4 76 >3000 >10000 77 101,4 4260,8 78 7,1 2071,4 79 5,6 1302,6 80 39,3 9168,6 81 1791,2 2359 82 52,9 1920,5 83 2635,5 4704 84 21,9 1470,1 85 790,6 780,7 86 61,1 1329,3 87 9029,4 10755 88 24,1 1846,5 89 >3000 >10000 90 36,4 >10000 91 2179,2 >20000 92 46,6 4753,5 93 >3000 >10000 94 80,8 5169,3 95 211,4 >10000 96 6,6 1255,1 97 29,8 1547,7 98 1,4 114 99 927,7 7131 100 68,3 3581 101 2187,6 >10000 102 7,9 1993 103 930,6 6256,4 104 4,6 591,2 105 66,1 2193,5 106 3,5 145,2 107 7,4 1727,2 108 120,8 >10000 109 >3000 9086 110 >3000 >10000 111 500 >10000 112 338,1 >10000 113 88,1 >10000 114 146,4 >10000 115 84,3 >10000 116 109,1 >10000 117 6,6 617,3 118 2933 >10000 119 13,5 1307,8 120 900 >10000 121 73,7 >10000 122 50,6 >10000 123 428,7 >10000 124 6,5 634,4 125 2447,2 >10000 126 592,1 >20000 127 100,1 9905 128 26 >10000 129 14,5 2676,6 130 5,8 1291,6 131 >3000 >10000 132 >3000 >10000 133 71,4 >10000 134 623 5891 135 9,3 1959

[0745] II. Pharmacokinetic study in mice

[0746] 1. Tested connections

[0747] The compounds used in this experiment are specific embodiments of the present invention, and the compound AMG473 from Amgen patent WO 2022 / 169948A1, identified as example 473, was used for comparison.

[0748] 2. Experimental animals

[0749] Male ICR mice, N=3 / group; obtained from Zhejiang Vital River Laboratory Animal Technology Co., Ltd.

[0750] 3. Preparation and administration of the drug

[0751] Single oral (PO) administration to ICR mice: Compounds were dissolved in dimethyl sulfoxide, polyethylene glycol 400 and sterile water were added, and then the solution was made clear with a small amount of 1 mol / L hydrochloric acid. After an overnight fast, mice were orally administered a dose of 10 mg / kg.

[0752] Single intravenous (IV) administration to ICR mice: Compounds were dissolved in dimethyl sulfoxide, polyethylene glycol 400 and sterile water were added, and then the solution was made clear with a small amount of 1 mol / L hydrochloric acid. After an overnight fast, mice were administered a dose of 3 mg / kg via the tail vein.

[0753] 4. Sample collection

[0754] Approximately 30 μL of blood was collected at each time point via the tail vein. Potassium ethylenediaminetetraacetate was used as an anticoagulant, and samples were centrifuged at 4000 g / min for 5 minutes at 4°C for 1 hour. Blood collection time points were: 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Samples were stored in a freezer at -20°C.

[0755] Plasma samples (30 μL, 10 μL sample + 20 μL clean plasma) were mixed with 200 μL of chilled acetonitrile containing internal standards. After vortexing for 30 seconds, the samples were centrifuged at 4000 g / min for 20 minutes. One hundred microliters of supernatant were transferred to a 96-well plate, then 200 μL of ultrapure water was added. After vortexing for 30 seconds, 5 μL or 10 μL were injected into the LC-MS / MS for analysis.

[0756] Table 2: Pharmacokinetic data

[0757] Example Route of administration (Dosage) AUClast (h*ng / ml) T1 / 2 (h) Bioavailability F (%) 4 IV (3 mg / kg) 8094 4,06 NA PO (10 mg / kg) 21020 2,67 77 29 IV (3 mg / kg) 12925 4,38 NA PO (10 mg / kg) 43906 4,16 102 16 IV (3 mg / kg) 9710 3,65 NA PO (10 mg / kg) 42546 3,31 131 107 IV (3 mg / kg) 11237 4,53 NA PO (10 mg / kg) 44065 4,56 119 104 IV (3 mg / kg) 10548 6,1 NA PO (10 mg / kg) 26536 5,02 74 130 IV (3 mg / kg) 10782 4,5 NA PO (10 mg / kg) 28276 3,34 77,5 41 IV (3 mg / kg) 5421 4,3 NA PO (10 mg / kg) 46322 4,12 257 AMG473 PO (10 mg / kg) 16174 4,2 NA

[0758] "NA": not available.

[0759] Comparing pharmacokinetic parameters, it can be observed that, compared to AMG473, at equivalent doses and the same route of administration, embodiments of the present invention consistently exhibit higher plasma exposure. This may reduce the effective dose of the compound, expanding the safety margin.

[0760] III. Experiment on inhibition of the hERG ion channel

[0761] 1. Tested connections

[0762] The compounds used in this experiment are specific embodiments of the present invention, and the compound AMG473 from Amgen patent WO 2022 / 169948A1, identified as example 473, was used for comparison.

[0763] 2. Cell line and cell culture

[0764] The HEK293 cell line stably expressing the hERG ion channel (Catalog: K1236) was purchased from Invitrogen. This cell line was cultured in a medium containing 85% DMEM, 10% dialyzed fetal bovine serum, 0.1 mM 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 culture vessel area, trypsin digestion was performed, and the cells were passaged three times a week. Before the experiment, the cells were cultured at a density of 5 × 10 5 Cells were cultured in 3.5 cm diameter culture dishes and induced with 1 μg / ml doxycycline for 48 hours. The cells were then trypsinized and plated on glass slides for subsequent experiments using a manual patch clamp.

[0765] 3. Experimental procedure

[0766] 1) Place the slides with HEK293 cells into the perfusion chamber of the micromanipulation system.

[0767] 2) Using an Olympus IX71 or IX73 inverted microscope, position suitable cells in the central field of view using a ×10 objective. Position the tip of the glass electrode in the central field. Use a micromanipulator to lower the electrode, adjusting the coarse focusing spiral to slowly approach the cell.

[0768] 3) When rapidly approaching the cell, switch to the ×40 objective for observation. Fine-tune the electrode's approach using the micromanipulator to gradually reach the cell surface.

[0769] 4) Apply negative pressure to establish 1GΩ contact between the electrode tip and the cell membrane.

[0770] 5) Compensate for the transient capacitive current Cfast in voltage clamp mode. Then, briefly apply negative pressure to rupture the membrane, eventually achieving whole-cell recording mode.

[0771] 6) When fixing the voltage at -60mV, compensate for the slow capacitive current Cslow, the cell membrane capacitance (Cm) and the membrane input resistance (Ra).

[0772] 7) After the cell stabilizes, change the clamp voltage to -90 mV, set the sampling frequency to 20 kHz, and the filter frequency to 10 kHz. The leakage current detection conditions include changing the clamp voltage to -80 mV for 500 ms.

[0773] 8) The hERG current testing method is as follows: Apply a 4.8-second depolarization voltage to depolarize the membrane potential from -80 mV to +30 mV, then immediately apply a 5.2-second repolarization voltage to reduce the membrane potential to -50 mV to release channel inactivation, allowing the hERG tail current to be observed. The peak tail current represents the magnitude of the hERG current.

[0774] 9) The hERG current induced by the test compound is continuously recorded for 120 seconds prior to drug administration to assess the stability of the test cells in producing hERG currents. Only stable cells within the acceptable range are suitable for subsequent compound testing.

[0775] 10) Testing the inhibitory effect of the test compound on hERG current: First, determine the baseline hERG current obtained in extracellular fluid containing 0.1% DMSO. After maintaining a stable hERG current for at least 5 minutes, perfuse the cells sequentially with a solution containing the test compound from low to high concentrations. After each perfusion, wait approximately 5 minutes for the compound to act on the cells, and simultaneously record the hERG currents. Record the last 5 hERG current values ​​after the recorded current has stabilized, and take their average value as the final current value at a given concentration. After testing the compound, add 450 nM dofetilide to the same cell to completely inhibit its current, which serves as a positive control for this cell.Meanwhile, the positive compound dofetilide is synchronously detected before and after the end of the experiment with the test drug using the same patch-clamp system to ensure the reliability and sensitivity of the entire detection system. The above testing steps will be repeated on two separate test cells (n=2).

[0776] 4. Data Analysis

[0777] Data that meets the above criteria will be analyzed in the following steps. Note: The data is output by PatchMaster software.

[0778] 1) After perfusion of the carrier solution or the compound gradient solution, 5 consecutive stable current values ​​are obtained, the average value is calculated and used as "Carrier Tail Current" and "Compound Tail Current" respectively.

[0779] The current inhibition percentage is calculated by the following formula:

[0780] Tail current inhibition percentage = (1-(junction tail current - positive control tail current) / (carrier tail current - positive control tail current)) × 100%

[0781] 2) Dose-response curves were plotted and IC values 50 were calculated using GraphPad Prism 8.0 software. 3) The standard deviation for the three data sets is less than 15 (SD < 15); 4) Widely accepted criteria for assessing the inhibitory capacity of compounds in determining the hERG channel are as follows:

[0782] 1) Low inhibitory capacity: IC 50 > 10 μM

[0783] 2) Moderate inhibitory capacity: 1 μM < IC 50 < 10 μM

[0784] 3) High inhibitory capacity: IC 50 < 1 μM

[0785] Data Quality Control Standards

[0786] Only the data that meets the following criteria are subject to further analysis: 1) The initial resistance of the gigaohm seal is greater than 1 GΩ; 2) The series resistance is less than 15 MΩ and the voltage error of the series resistance is less than 5 mV; 3) The leakage current at the detection voltage is less than 50% of the current value under these conditions; 4) The tail current is greater than the size of the plateau current before the pre-pulse, with the initial value of the tail current greater than 250 pA; 5) The burst resistance Ra is less than 15 MΩ; 6) The decay rate of the tail current per minute is less than 2.5%.

[0787] 5. IC data 50 hERG (μM) are presented in Table 3:

[0788] Table 3: IC Data 50 hERG

[0789] Example hERG IC50 (μM) 4 5,29 29 11,4 16 2,3 107 4,5 104 1,51 130 1,36 41 8,16 AMG473 <0,37

[0790] Comparing IC data 50hERG, compared to AMG473, embodiments of the present invention exhibit a lower risk of cardiotoxicity, indicating a greater safety margin.

[0791] While preferred embodiments have been described above, it is evident that those skilled in the art can make modifications without departing from the scope of the invention. Such modifications are considered as possible variations within the scope of the present invention.

Claims

1. A compound, its pharmaceutically acceptable salt.

2. A pharmaceutical composition for inhibiting PRMT5, comprising a compound, a pharmaceutically acceptable salt thereof according to claim 1 and a second active substance, wherein the second active substance is an anticancer agent.

3. The composition of claim 2, wherein the anticancer agent comprises one or more chemotherapeutic agents, drugs for targeted tumor treatment, and antibodies for tumor treatment.

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