Novel PRMT5 inhibitor and application thereof

Abstract

A compound having protein arginine methyltransferase 5 inhibitory activity of formula (I), and methods of synthesis and use of the compound. # imgabs0 #

Description

Novel PRMT5 inhibitors and their applications

[0001] This application claims priority to the following Chinese patent applications: 1) Chinese patent application No. 202211173943.5, filed with the State Intellectual Property Office of China on September 26, 2022, entitled “Novel PRMT5 inhibitors and their applications”; 2) Chinese patent application No. 202211473887.7, filed with the State Intellectual Property Office of China on November 22, 2022, entitled “Novel PRMT5 inhibitors and their applications”; 3) Chinese patent application No. 202310080068.4, filed with the State Intellectual Property Office of China on January 17, 2023, entitled “Novel PRMT5 inhibitors and their applications”; and 4) Chinese patent application No. 202310402301.6, filed with the State Intellectual Property Office of China on April 14, 2023, entitled “Novel PRMT5 inhibitors and their applications”. The entire contents of the above Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present application relates to the field of drug synthesis, and specifically to a PRMT5 inhibitor and its application. Background Art

[0003] Epigenetic alterations are key mediators driving and maintaining the malignant phenotype of tumors. Changes in DNA methylation, histone acetylation and methylation, noncoding RNAs, and post-translational modifications are all epigenetic drivers of cancer development, independent of DNA sequence changes. Arginine methylation is an important post-translational modification that influences cell growth and proliferation, apoptosis, angiogenesis, and metastasis by regulating transcription and post-transcriptional RNA processing. Three types of methylarginine exist: ω-NG, N'G-asymmetric dimethylarginine (ADMA) and ω-NG, N'G-symmetric dimethylarginine (SDMA). This modification is catalyzed by the protein arginine methyltransferase (PRMT) family, transferring a methyl group from S-adenosylmethionine (AdoMet) to arginine side chains on histones and non-histone proteins. Nine PRMT genes have been annotated in the human genome and are categorized as type I (PRMT1, 2, 3, 4, 6, and 8), type II (PRMT5 and PRMT9), and type III enzymes (PRMT7) based on the type of methylarginine produced. PRMT5 is primarily a type II enzyme that catalyzes the symmetric dimethylation of arginine. PRMT5 was first discovered in a two-hybrid assay to detect proteins that interact with Janus tyrosine kinase (Jak2).

[0004] PRMT5 is a universal transcriptional repressor that forms a complex with other transcription factors, including BRG1 and Hbrm, Blimp1, and Snail. PRMT5 participates in diverse cellular processes by methylating a variety of cytoplasmic and nuclear substrates, including histone H4 residue Arg3 (H4R3) and H3 residue Arg8 (H3R8). H4R3 methylation is associated with transcriptional repression, while H3R8 methylation is considered to be involved in both transcriptional activation and repression. In addition to directly inducing repressive histone marks, PRMT5's role in gene silencing is mediated by the formation of a multi-repressor protein complex, including NuRD components, HDACs, MDB proteins, and DNA methyltransferases. PRMT5 influences its substrate specificity through interactions with several binding proteins. A core component of this protein complex is MEP50, which is essential for the enzymatic activity of PRMT5. Studies have found that PRMT5 can methylate proteins involved in RNA splicing, such as SmD3, which can be used to track the chemical activity of PRMT5 in cell biology.

[0005] PRMT5 plays a crucial role in tumorigenesis. Studies have found that PRMT5 expression is upregulated in a variety of tumors, 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 knockout inhibits MCL cell proliferation, suggesting a key role for PRMT5 in MCL. PRMT5 overexpression promotes cell proliferation, while PRMT5 knockout inhibits cell proliferation in melanoma, breast cancer, and lung cancer cell lines. Therefore, PRMT5 is a potential target for cancer therapy.

[0006] Loss of methylthioadenosine phosphorylase (MTAP) confers a selective reliance on PRMT5 and its binding protein, WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene CDKN2A. Cells harboring MTAP deletion have increased levels of intracellular methylthioadenosine (MTA), a metabolite cleaved by MTAP. MTA shares a similar structure to S-adenosylmethionine (SAM). As concentrations increase, MTA acts as an intrinsic, selective inhibitor, inhibiting the binding of SAM to PRMT5 and, consequently, the methyltransferase activity of PRMT5.

[0007] The most significant structural difference between MTAP-deficient and MTAP-wild-type cancer cells lies in the accumulation of MTA in MTAP-deficient cancer cells, which results in the formation of a PRMT5-MTA complex. Inhibitors developed against the PRMT5-MTA complex can selectively target MTAP-deficient cancer cells while minimizing the effect on normal cells, significantly improving the therapeutic index.

[0008] Therefore, identifying and developing small molecules that inhibit PRMT5 activity will be useful as therapeutic approaches for treating various PRMT5-associated diseases or disorders, such as cancer.

[0009] Summary of the Invention

[0010] To solve the technical problem of the present invention, the present invention provides a class of compounds with novel structures that have excellent inhibitory activity against PRMT5.

[0011] In addition, the present invention provides a compound, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, which has the following structure:

[0012] Where W represents N or CR W ;

[0013] Where X3 represents N or CR X3 ; X4 represents N or CR X4 ; X5 represents N or CR X5 ; X6 represents N or CR X6 ;

[0014] Among them, when X3 represents CR X3 When R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a Rb 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0015] Among them, when X4 represents CR X4 When R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0016] Among them, when X5 represents CR X5 When R X5represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0017] Among them, when X6 represents CR X6 When R X6 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0018] Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X3 and X4, and the ring may contain 0-3 heteroatoms selected from O, N, and S;

[0019] Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X4 and X5, and the ring may contain 0-3 heteroatoms selected from O, N, and S;

[0020] Wherein, the ring A may also be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X5 and X6, and the ring may contain 0-3 heteroatoms selected from O, N, and S;

[0021] Where W represents CR W When R W Selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, halogenated C1-C6 alkoxy;

[0022] Where X1 represents N or CR X1 ;

[0023] Where X2 represents N or CR X2 ;

[0024] Among them, Y1 represents CR Y1 R Y1’ NR Y1 , O, S, Se;

[0025] Among them, Y2 represents CR Y2 R Y2’ NR Y2 , O, S, Se;

[0026] Among them, Y3 represents CR Y3 R Y3’ NR Y3 , O, S, Se;

[0027] Among them, R X1 、R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5;

[0028] Among them, R Y1 、R Y1’ 、R Y2 、R Y2’ 、R Y3 、R Y3’ Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONRa R b , halogen, -SO3R a 、-NR a R b , -SF5;

[0029] Among them, M 2 Indicates CR M1 R M2 ,S,O,NR M1 ;

[0030] Among them, R M1 、R M2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, or R M1 、R M2 Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N;

[0031] Among them, R 4 represents hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl or halogen;

[0032] in, Indicates a single bond or a double bond;

[0033] Wherein, s represents an integer from 0 to 3;

[0034] Among them, R a 、R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a 、R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

[0035] In addition, the present invention provides a compound, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, which has the following structure:

[0036] Where W represents N or CR W ;

[0037] Where X3 represents N or CR X3 ; X4 represents N or CR X4 ; X5 represents N or CR X5 ; X6 represents N or CR X6 ;

[0038] Among them, when X3 represents CRX3 When R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0039] Among them, when X4 represents CR X4 When R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0040] Among them, when X5 represents CR X5 When R X5 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)Ra 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0041] Among them, when X6 represents CR X6 When R X6 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0042] Where W represents CR W When RW Selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, halogenated C1-C6 alkoxy;

[0043] Where X1 represents N or CR X1 ;

[0044] Where X2 represents N or CR X2 ;

[0045] Among them, Y1 represents CR Y1 R Y1’ NR Y1 , O, S, Se;

[0046] Among them, Y2 represents CR Y2 R Y2’ NR Y2 , O, S, Se;

[0047] Among them, Y3 represents CR Y3 R Y3’ NR Y3 , O, S, Se;

[0048] Among them, R X1 、R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5;

[0049] Among them, R Y1 、R Y1’ 、R Y2 、R Y2’ 、R Y3 、R Y3’Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5;

[0050] Among them, M 2 Indicates CR M1 R M2 ,S,O,NR M1 ;

[0051] Among them, R M1 、R M2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, or R M1 、R M2 Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N;

[0052] Among them, R 4 represents hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl or halogen;

[0053] in, Indicates a single bond or a double bond;

[0054] Wherein, s represents an integer from 0 to 3;

[0055] Among them, R a 、R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a 、R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

[0056] In the preferred technical solution of formula I-3 or I-3', wherein X 1 Indicates CR X1 or N, where R X1represents hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, or halogenated C1-C6 alkyl.

[0057] In the preferred technical solution of formula I or II, X2 represents CH or CD.

[0058] In the preferred technical solution of formula I or II, X3 represents CH, CD or N.

[0059] In the preferred technical solution of formula I or II, wherein X4 represents CR X4 or N where R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, -SO3R a 、-SR a 、-P(O)R a R b , or cyano or is selected from 0-4 of the following substituents: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

[0060] In the preferred technical solution of formula I or II, wherein X5 represents CR X5 or N where R X5 represents hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, or cyano.

[0061] In the preferred technical solution of formula I or II, X6 represents CH, CD or N.

[0062] In the preferred technical solution of Formula I or II, the chemical bond between Y1 and Y2 is a double bond.

[0063] In the preferred technical solution of formula I or II, wherein Y1 represents CR Y1 , where R Y1 It represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, -S(O)2CH3 or cyano.

[0064] In the preferred technical solution of formula I or II, wherein Y 2 Indicates N.

[0065] In the preferred technical solution of formula I or II, wherein Y 3 Indicates CH or CD.

[0066] In the preferred technical solution of formula I or II, wherein R 4 represents hydrogen or C1-C6 alkyl or deuterated C1-C6 alkyl.

[0067] In the preferred technical solution of formula I or II, wherein M 2 Represents O, NH, and S.

[0068] In the preferred technical solution of formula I or II, wherein M 2 Indicates CR M1 R M2 ; Among them, R M1 、R M2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, or R M1 、R M2 Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring.

[0069] Specifically, the present invention provides the following compounds:

[0070] In the above preferred technical solution of the present invention, at least one or more hydrogen atoms in the isotope derivative are deuterium atoms.

[0071] In addition, the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises any one of the above-mentioned compounds of the present invention, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative and a pharmaceutically acceptable carrier.

[0072] Unless otherwise indicated, the compounds of the present invention may be interpreted to include, in addition to the specific structures of the compounds, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotope isomers (e.g., deuterated compounds), solvates, hydrates, prodrugs, and metabolites. In other words, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotope isomers, solvates, hydrates, prodrugs, and metabolites also fall within the scope of protection of the compounds.

[0073] Preferably, the pharmaceutical composition of the present invention may further include a second active substance, wherein the second active substance is an anti-tumor drug, and the anti-tumor drug includes one or more of a chemotherapy drug, a targeted tumor treatment drug or a tumor treatment antibody drug.

[0074] In addition, the present invention also provides a compound of the present invention, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative thereof, for treating a disease by inhibiting the action of PRMT5, preferably the disease is a tumor. Definition:

[0075] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a straight chain (i.e., unbranched) or branched chain, or cyclic hydrocarbon radical, or combinations thereof, which may be saturated, mono- or polyunsaturated, and may include divalent or polyvalent groups, having the specified number of carbon atoms (i.e., C1-C 10 Refers to one to ten carbon atoms). Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclohexylmethyl, cyclopropylmethyl, and homologs and isomers such as n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated alkyl groups are alkyl groups having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkyl groups that are limited to hydrocarbon groups are referred to as "homoalkyl". The alkyl group is optionally substituted with one or more halogen atoms.

[0076] The term "haloalkyl" refers to an alkyl group as defined above wherein one or more hydrogen atoms are replaced by a halogen atom.

[0077] The term "alkylene" by itself or as part of another substituent refers to a divalent radical derived from an alkyl group, for example, but not limited to, -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-, -CH2CH2CH(CH2CH2CH3)CH2-. Alkyl (or alkylene) groups typically have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred. "Lower alkyl" or "lower alkylene" refers to shorter chain alkyl or alkylene groups, typically having eight or fewer carbon atoms. The alkylene group is optionally substituted with one or more halogen atoms.

[0078] The term "alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which may be linear or branched, or a combination thereof. Examples of alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like. The alkynyl group may be optionally substituted with one or more halogen atoms.

[0079] The term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbocyclic ring, each having 3 to 10 carbon atoms. A "fused analog" of a cycloalkyl refers to a monocyclic ring fused to an aryl or heteroaryl group, wherein the point of attachment is on the non-aromatic portion. Examples of cycloalkyls and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, decahydronaphthyl, and dihydroindanyl. The cycloalkyl group is optionally substituted with one or more halogen atoms. Furthermore, the term "cycloalkyl" as used herein includes bridged ring systems and spirocyclic ring systems.

[0080] The term "alkoxy" refers to a straight or branched chain alkoxy group having the indicated number of carbon atoms. 1-6 The alkoxy group includes, for example, methoxy, ethoxy, propoxy, isopropoxy and the like.

[0081] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched chain, or cyclic hydrocarbon radical consisting of at least one carbon atom and at least one heteroatom selected from O, N, P, Si, S, or combinations thereof, wherein the nitrogen, phosphorus, or sulfur atom may be optionally oxidized and the nitrogen atom may be optionally quaternized. The heteroatoms O, N, P, S, and Si may be placed at any position within the heteroalkyl radical or at the position at which the alkyl radical is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive. For example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene," by itself or in combination with other terms, refers to a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene, the heteroatom can be at either or both ends of the chain (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Additionally, for alkylene and heteroalkylene linking groups, the direction in which the linking group formula is written does not indicate the orientation of the linking group. For example, the formula -C(O)OR'- refers to both -C(O)OR'- and -R'OC(O)-. As described above, heteroalkyl groups as used herein include those groups that are attached to the rest of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -S02R'. Where "heteroalkyl" is mentioned followed by a specific heteroalkyl group such as -NR'R", it is understood that the terms heteroalkyl and -NR'R" are not redundant and are not mutually exclusive. Rather, these specific heteroalkyl groups are cited for clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups such as -NR'R".

[0082] The term "cycloalkoxy" refers to a cycloalkyl group as defined above bound to an oxygen atom, such as cyclopropyloxy.

[0083] The term "haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms are replaced by a halo.

[0084] The term "aryl" refers to a monocyclic or bicyclic aromatic group containing only carbon atoms. A "fused analog" of an aryl group refers to an aryl group fused to a monocyclic cycloalkyl group or a monocyclic heterocyclic group, wherein the point of attachment is on the aryl portion. Examples of aryl groups and fused ring analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrochromenyl, 1,4-benzodioxanyl, and the like.

[0085] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic group containing at least one heteroatom selected from N, O, and S. A "fused analog" of a heteroaryl group refers to a heteroaryl group fused to a monocyclic cycloalkyl group or a monocyclic heterocyclyl group, wherein the point of attachment is located on the aromatic portion. Examples of heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, furo(2,3-b)pyridinyl, quinolinyl, indolyl, isoquinolinyl, and the like.

[0086] "Substituted or unsubstituted": the alkyl, aryl and heteroaryl groups are defined as being unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, haloalkyl groups having 1 to 6 carbon atoms, haloalkoxy groups having 1 to 6 carbon atoms, -CN, alkynyl groups having 2 to 6 carbon atoms, alkanoyl groups having 1 to 6 carbon atoms, cycloalkyl groups having 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkyloxy groups having 7-10 carbon atoms, arylcarbonyl groups, aminocarbonyl groups, alkyl groups having 2 to 6 carbon atoms, alkynyl groups having 1 to 6 carbon atoms, alkanoyl groups having 1 to 6 carbon atoms, cycloalkyl groups having 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkyloxy groups having 7-10 carbon atoms, arylcarbonyl groups, aminocarbonyl groups, alkyl groups having 2 to 6 carbon atoms, alkyl groups having 1 to 6 carbon atoms, alkyl groups having 1 to 6 carbon atoms, alkyl groups having 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkyloxy groups having 7-10 carbon atoms, arylcarbonyl groups, aralkyloxy groups having 7-10 carbon atoms, aralkyl groups having 1 to ... an alkenyl group having 1 to 5 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an aminosulfinyl group, an aminosulfonyl group, a hydroxyl group, -SF5, a hydroxyalkyl group having 1 to 4 carbon atoms, a nitro group, an amino group, a carboxyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxyalkyl group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1-4 carbon atoms, an alkanoylamino group having 1 to 4 carbon atoms, an alkanoyl(alkyl)amino group having 1 to 6 carbon atoms, an alkanoylaminoalkyl group having 1 to 6 carbon atoms in both the alkanoyl and alkyl moieties, an alkanoyl(alkyl)aminoalkyl group having 1 to 6 carbon atoms in both the alkanoyl and alkyl moieties, an alkylsulfonylamino group having 1 to 4 carbon atoms, a monoalkylaminocarbonyl group or a dialkylaminocarbonyl group having 1 to 6 carbon atoms, a monoalkylaminosulfinyl group or a dialkylaminosulfinyl group having 1 to 6 carbon atoms, a monoalkylaminosulfonyl group or a dialkylaminosulfonyl group having 1 to 6 carbon atoms dialkylaminosulfonyl, aminoalkyl having 1 to 4 carbon atoms, mono- or dialkylamino having 1 to 6 carbon atoms, mono- or dialkylaminoalkyl having 1 to 6 carbon atoms in each alkyl moiety, aralkyl having 7 to 10 carbon atoms, heteroaralkyl having 1 to 4 carbon atoms in the alkyl moiety, heteroarylalkoxy having from 1 to 4 carbon atoms in the alkoxy moiety, and alkylsulfonamide having 1 to 4 carbon atoms.

[0087] As used herein, the term "heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated, partially saturated or unsaturated group (but not aromatic) having a single ring or a fused ring (including bridged ring systems and spiro ring systems) with 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the ring. In a fused ring system, one or more rings can be cycloalkyl, aryl or heteroaryl, as long as the point of attachment is through the non-aromatic ring. In one embodiment, the nitrogen atom and / or sulfur atom of the heterocyclic group is optionally oxidized. , to provide N-oxide, sulfinyl and sulfonyl moieties. Examples of "heterocyclyl" and its fused analogs include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuryl (2,3-b) pyridinyl, benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolinyl, etc. The term also includes non-aromatic partially unsaturated monocyclic rings, such as 2- or 4-pyridones or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils) attached through a nitrogen atom.

[0088] As used herein, the term "substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclic group substituted with 1 to 5 (e.g., 1 to 3) substituents, the substituents being the same as those defined for substituted cycloalkyl.

[0089] Unless otherwise indicated, the term "halogenated" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. Additionally, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C6)alkyl" includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0090] "Prodrug" refers to a substance that is converted into the parent drug in vivo. In some cases, prodrugs are often used because they are easier to administer than the parent drug. For example, a prodrug may be bioavailable orally while the parent drug cannot. In a pharmaceutical composition, a prodrug may also have a higher solubility than the parent drug. Examples of prodrugs, but not limited to, may be any of the compounds of Formula I administered in the form of an ester (prodrug) to facilitate transcellular transport, where water solubility in the cell membrane is detrimental to migration, and once in the cell where water solubility is beneficial, the ester is subsequently metabolically hydrolyzed to the active substance, carboxylic acid. Another example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group, wherein the peptide is metabolized to release the active portion.

[0091] Optical isomers - diastereomers - geometric isomers - tautomers:

[0092] The compounds of formula (I) contain one or more asymmetric centers and can occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is intended to encompass all such isomeric forms of the compounds of formula (I).

[0093] Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are intended to include both E and Z geometric isomers.

[0094] Some of the compounds of the present invention may contain one or more than one ring system and may therefore exist as cis- and trans-isomers. The present invention is intended to include all such cis- and trans-isomers.

[0095] Some compounds described herein may have different sites of attachment to hydrogen atoms, known as tautomers. Examples of such are the ketone and its enol form, known as keto-enol tautomers. Individual tautomers as well as mixtures thereof are encompassed within the compounds of the present invention.

[0096] The compounds of the present invention can be separated into diastereomeric pairs of enantiomers, for example by fractional crystallization from a suitable solvent such as methanol or ethyl acetate or a mixture thereof. A pair of enantiomers thus obtained can be separated into individual stereoisomers by conventional methods, for example using an optically active amine or acid as a resolving agent or in a chiral HPLC column.

[0097] Alternatively, any enantiomer of a compound of the invention may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

[0098] Stable isotope-labeled analogs: One or more protons in the compounds of the present invention may be replaced with deuterium atoms to provide deuterated analogs with improved pharmacological activity.

[0099] Salt and dosage form

[0100] It will be understood that, as used herein, references to the compounds of the present invention also include the pharmaceutically acceptable salts.

[0101] application

[0102] The compounds of the present invention can be used to treat PRMT5-related diseases.

[0103] The compounds of the present invention can be prepared by the following reaction formula:

[0104] Method A:

[0105] Method A-SFC

[0106] Method B:

[0107] Method B-SFC

[0108] Method C:

[0109] Method C-SFC:

[0110] Among them, R 4 , A ring, W, M 2 , s, X1, X2, X3, X4, X5, X6, Y1, Y2, and Y3 are as defined in claim 1, and PG is a protecting group.

[0111] Method A: Compound AP can be prepared by the amino acid condensation reaction of carboxylic acid A-1 and amine A-2. The condensing agent can be HATU or PyBrOP, the base can be DIPEA or TEA, and the solvent can be DMF or DMAc. If the amine used is a racemic form, chiral SFC will be used for resolution, and the stereochemistry of the resulting isomers will be randomly assigned to R or S.

[0112] Method B: Compound BP can be obtained by reacting acid chloride B-1 with amine B-2. The base used can be Et3N, DIPEA, or pyridine, and the solvent can be THF, 1,4-dioxane, DCM, or DCE. A catalyst such as DMPK can also be added to promote the reaction. Similarly, if the amine used is a racemate, the product can be resolved by chiral SFC, and the stereochemistry of the resulting isomers will be randomly assigned to R or S.

[0113] Method C: Compound CP can be obtained via an amino acid condensation reaction between carboxylic acid C-1 and amine C-2, followed by a one-step deprotection reaction. The condensation agent used in the condensation reaction can be HATU or PyBrOP, the base used can be DIPEA or TEA, and the solvent used can be DMF or DMAc. The protecting group selected is PMB or Boc. The reagent used for PMB deprotection is TFA or 5% methanesulfonic acid + TFA. The reagent used for Boc deprotection is TFA or HCl / EA, HCl / 1,4-dioxane, or TMSOTf + 2,6-lutidine. Similarly, if the amine used is a racemate, the product will be resolved by chiral SFC, and the stereochemistry of the resulting isomers will be randomly assigned to R or S.

[0114] Analytical HPLC

[0115] Equipment: Agilent 1260; Column dimensions: Agilent Poroshell HPH-C18 (3.0 × 50 mm, 2.7 μm); Binary solvent system: Mobile phase A: Water (0.1% v / v ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 1 mL / min; Gradient: 10% B to 90% B; Flow duration: 12 min; Detector: DAD; Wavelength: 254 / 220 nm;

[0116] Preparative HPLC-MS

[0117] HPLC equipment: Waters 2489; Column specifications: Ultimate μXB-C18 (130A, 5 μm, 30 mm × 150 mm); Binary solvent system: Mobile phase A: Water (0.1% v / v ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60–100 mL / min; Gradient: 10% B to 90% B; Detector: DAD; Wavelength: 254 / 220 nm;

[0118] Mass spectrometer: Agilent G6125B.

[0119] The compounds of the present invention can be prepared by chemical synthesis, examples of which are shown below. It should be understood that the order of the steps in the process can be changed, those specifically mentioned reagents, solvents and reaction conditions can be replaced, and if necessary, reactive sites can be protected and deprotected.

[0120] The following abbreviations have the following meanings: ACN means acetonitrile; EA means ethyl acetate; CDI means N,N'-carbonyldiimidazole; DBU means 1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL-H means diisobutylaluminum hydride; DIEA means diisopropylethylamine; DMAP means N,N-dimethylaminopyridine; DME means 1,2-dimethoxyethane; DMF means N,N-dimethylformamide; DMA and DMAc mean N,N-dimethylformamide; DMPE means 1,2-bis(dimethylformamide) phosphino)ethane; DMSO denotes dimethyl sulfoxide; DPPB refers to 1,4-bis(diphenylphosphino)butane; dppe denotes 1,2-bis(diphenylphosphino)ethane; dppf denotes 1,1'-bis(diphenylphosphino)ferrocene; dppm denotes 1,1'-bis(diphenylphosphino)methane; DIAD denotes diisopropyl azodicarboxylate; EDCI denotes 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; HATU denotes 2-(7-aza-1H-benzotriazol-1-yl)-1,1, 3,3-Tetramethyluronium hexafluorophosphate; HMPA is hexamethylphosphoramide; IPA is isopropyl alcohol; LDA is lithium diisopropylamide; LHMDS is lithium bis(trimethylsilyl)amide; LAH is lithium aluminum hydride; NCS is N-chlorosuccinimide; NaHMDS is sodium bis(trimethylsilyl)amide; PyBOP is benzotriazol-1-yl-oxytripyrrolidinylphosphonium benzotriazole hexafluorophosphate; PyBrOP is tripyrrolidinylphosphonium bromide hexafluorophosphate; TDA-I is tris(trimethylsilyl)phosphonium benzotriazole hexafluorophosphate. (2-(2-methoxyethoxy)ethyl)amine; DCM refers to dichloromethane; TEA refers to triethylamine, TFA refers to trifluoroacetic acid; THF refers to tetrahydrofuran; NCS refers to N-chlorosuccinimide; NMM refers to N-methylmorpholine; NMP refers to N-methylpyrrolidone; PPh3 refers to triphenylphosphine, rt refers to room temperature; PMB refers to p-methoxybenzyl; Tosmic refers to p-toluenesulfonylmethyl isocyanide; (Boc)2O refers to di-tert-butyl dicarbonate; PE refers to petroleum ether; o / n refers to overnight reaction.

[0121] The following preparations and examples illustrate the present invention but do not limit it in any way.

[0122] The features and advantages of the subject matter of the present invention will become more apparent from the detailed description of selected embodiments. As will be appreciated, the disclosed and claimed subject matter is capable of modification in various respects, all without departing from the scope of the claims. Therefore, the description is to be regarded as illustrative in nature, not restrictive. The full scope of the subject matter of the present invention is set forth in the claims.

[0123] The present invention can be more easily understood by referring to the following examples, which are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0124] intermediates

[0125] Intermediate 1: 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0126] Step 1: Synthesis of imidazo[1,5-a]imidazo[1,5-d]1,4-diazapiperazine-5,10-dione

[0127] Imidazole-5-carboxylic acid (100 g, 892.14 mmol) was added to thionyl chloride (500 ml) and stirred at 80°C for 12 h. The mixture was concentrated to give imidazo[1,5-a]imidazo[1,5-d]1,4-diazapiperazine-5,10-dione (70 g, 0.37 mol, 42% yield) as a yellow solid.

[0128] LCMS (ESI) m / z: 189 [M+H] +

[0129] Step 2: Synthesis of N-(4-bromo-2-fluorophenyl)imidazol-5-ylcarboxamide

[0130] To a mixture of 4-bromo-2-fluorophenylamine (60.60 g, 318.91 mmol) in tetrahydrofuran (600 ml) was slowly added dropwise sodium bistrimethylsilylamide (318.91 ml, 637.82 mmol, 2 mol / L) at 0°C over a period of 1 hour. Imidazo[1,5-a]imidazo[1,5-d]1,4-diazapiperazine-5,10-dione (60 g, 318.91 mmol) was then added. The mixture was stirred at room temperature for 12 hours, poured into water, filtered, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 40%) to give N-(4-bromo-2-fluorophenyl)imidazol-5-ylformamide (60 g, 0.21 mol, 66% yield) as a white solid.

[0131] LCMS (ESI) m / z: 284 [M+H] +

[0132] Step 3: Synthesis of 8-bromo-10-hydroimidazo[1,5-a]quinoxaline-4-ol

[0133] N-(4-Bromo-2-fluorophenyl)imidazol-5-ylformamide (60 g, 211.20 mmol) and sodium hydride (16.88 g, 422.40 mmol, 60% content) were stirred in dimethylacetamide (600 ml) at 140° C. for 12 hours. The mixture was poured into water and filtered to give 8-bromo-10-hydroimidazo[1,5-a]quinoxaline-4-ol (50 g, 90% yield) as a yellow solid.

[0134] LCMS (ESI) m / z: 264 [M+H] +

[0135] Step 4: Synthesis of 8-bromo-4-chloro-10-hydroimidazo[1,5-a]quinoxaline

[0136] Phosphorus oxychloride (500 ml) was added to a mixture of 8-bromo-10-hydroimidazo[1,5-a]quinoxaline-4-ol (50 g, 189.34 mmol) and N,N-diisopropylethylamine (48.85 g, 378.67 mmol), and the mixture was stirred at 90° C. for 2 hours, followed by concentration. The residue was dissolved in acetonitrile and slowly added dropwise to ice water to precipitate a solid, which was filtered to give 8-bromo-4-chloro-10-hydroimidazo[1,5-a]quinoxaline (50 g, yield 93%).

[0137] LCMS (ESI) m / z: 282 [M+H] + .

[0138] Step 5: Synthesis of (8-bromo(10-hydroimidazo[1,5-a]quinoxalin-4-yl))[(4-methoxyphenyl)methyl]amine

[0139] 8-Bromo-4-chloro-10-hydroimidazo[1,5-a]quinoxaline (50 g, 176.98 mmol) and 4-methoxybenzylamine (29.13 g, 212.38 mmol) were added to dimethyl sulfoxide (500 ml), and N,N-diisopropylethylamine (45.66 g, 353.96 mmol) was added. The mixture was stirred at 80 degrees for 2 hours, then poured into water and filtered to give (8-bromo(10-hydroimidazo[1,5-a]quinoxaline-4-yl))[(4-methoxyphenyl)methyl]amine (50 g, yield 74%) as a yellow oil.

[0140] LCMS (ESI) m / z: 384 [M+H] +

[0141] Step 6: Synthesis of methyl 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate

[0142] (8-Bromo(10-hydroimidazo[1,5-a]quinoxaline-4-yl))[(4-methoxyphenyl)methyl]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 added to a solution of dimethylformamide (50 ml) and methanol (250 ml). The system was reacted at 100° C. under a carbon monoxide atmosphere (4 MPa) for 12 hours, then poured into water and filtered. The mixture was purified by silica gel chromatography (petroleum ether:ethyl acetate = 80%) to give methyl 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (30 g, 63% yield) as a yellow solid.

[0143] LCMS (ESI) m / z: 363 [M+H] +

[0144] Step 7: Synthesis of 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0145] 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (30 g, 82.87 mmol) was added to a mixed solution of methanol, water, and tetrahydrofuran (1:1:1, 150 ml), and potassium hydroxide (92.40 g, 165.0 mmol) was added. The mixture was reacted at 60°C for 12 hours. The organic solvent was removed by vacuum concentration and then poured into water. The mixture was extracted with ethyl acetate (100 ml × 3) and concentrated in vacuo to give 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (25 g, yield 86%).

[0146] LCMS (ESI) m / z: 349 [M+H] +

[0147] The following intermediate carboxylic acids can be prepared by using the synthetic steps described in the method of Intermediate 1, replacing only the corresponding starting materials:

[0148] Intermediate 9 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid

[0149] Step 1: Synthesis of methyl 1-(5-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylate

[0150] At room temperature, methyl 3-amino-4-nitrobenzoate (5 g, 25.12 mmol) and methyl 1H-pyrrole-2-carboxylate (4.711 g, 37.68 mmol) were added to a 250 ml round-bottom flask. Then, N,N-dimethylformamide (100 ml) was poured into the flask, and cesium carbonate (24.5 g, 75.37 mmol) was added. The resulting mixture was stirred at 70°C for 6 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain methyl 1-(5-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylate (3.0 g, yield: 39.2%) as a yellow solid.

[0151] LCMS (ESI) m / z: 305.2 [M+H] +

[0152] Step 2: Synthesis of methyl 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-8-carboxylate

[0153] At room temperature, 1-(5-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylic acid methyl ester (3.0 g, 22.94 mmol) was first dissolved in acetic acid (60 ml), and then iron powder (7.7 g, 137.64 mmol) was added to the system. The resulting reaction system was stirred at 110°C for 4 hours. After the reaction was completed, the reaction solution was poured into water (100 ml) and filtered. The filter cake was washed with water and dried to obtain a gray solid 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-8-carboxylic acid methyl ester (1.8 g, yield: 32.4%).

[0154] LCMS (ESI) m / z: 243.1 [M+H] +

[0155] Step 3: Synthesis of methyl 4-chloropyrrolo[1,2-a]quinoxaline-8-carboxylate

[0156] At room temperature, 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-8-carboxylic acid methyl ester (1.8 g, 7.43 mmol) was first dissolved in phosphorus oxychloride (20 ml). The mixture was then heated to 90°C and maintained at this temperature for 3 hours. After the reaction was completed, the system was poured into water (50 ml) and filtered. The filter cake was washed with water and dried to obtain a brown solid 4-chloropyrrolo[1,2-a]quinoxaline-8-carboxylic acid methyl ester (1.3 g, yield: 67.2%).

[0157] LCMS (ESI) m / z: 261.2 [M+H] +

[0158] Step 4: Synthesis of methyl 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylate

[0159] Methyl 4-chloropyrrolo[1,2-a]quinoxaline-8-carboxylate (1.3 g, 5.000 mmol) was dissolved in DMSO (25 mL) at room temperature. 4-Methoxybenzylamine (1.027 g, 7.500 mmol) and DIEA (1.935 g, 15.00 mmol) were then added sequentially to the reaction system. The resulting mixture was reacted at 90°C for 8 hours. Upon completion, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate, volume ratio 1:1) to obtain methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (1.4 g, yield: 77.7%) as a yellow solid.

[0160] LCMS (ESI) m / z: 361.1 [M+H] +

[0161] Step 5: Synthesis of 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid

[0162] At room temperature, methyl 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylate (130 mg, 0.3601 mmol) was dissolved in a mixture of tetrahydrofuran, methanol and water (4 ml, volume ratio of 2:2:1), and then lithium hydroxide monohydrate (25.9 mg, 1.080 mmol) was added. The resulting mixture was reacted at 25°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 6 with 4M hydrochloric acid and then concentrated under reduced pressure to obtain a crude product 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid (100 mg, crude product), which was used directly in the next reaction without purification.

[0163] LCMS (ESI) m / z: 348.1 [M+H] +

[0164] The following intermediate carboxylic acids can be prepared by using the synthetic steps described for intermediate 9, replacing only the corresponding starting materials:

[0165] Intermediate 16 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0166] Step 1: Synthesis of methyl 3-(2-methyl-1H-imidazol-1-yl)-4-nitrobenzoate

[0167] Methyl 3-fluoro-4-nitrobenzoate (20.0 g, 100 mmol) was dissolved in acetonitrile (100 ml), followed by the addition of 2-methyl-1H-imidazole (8.2 g, 100 mmol) and potassium carbonate (27.6 g, 200 mmol). The mixture was stirred at 100° C. for 12 hours. The reaction was monitored by LCMS. The reaction solution was poured into water (300 ml), extracted with ethyl acetate (200 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and chromatographed on silica gel (petroleum ether:ethyl acetate=10%) to give methyl 3-(2-methyl-1H-imidazole-1-yl)-4-nitrobenzoate (25.0 g, 95% yield) as a yellow solid.

[0168] LCMS (ESI) m / z: 262 [M+H] +

[0169] Step 2: Synthesis of methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate

[0170] At room temperature, methyl 3-(2-methyl-1H-imidazol-1-yl)-4-nitrobenzoate (25 g, 95.8 mmol) was dissolved in methanol (300 ml), and then Raney nickel (2 g) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction was monitored by LCMS. The residue was filtered to obtain a filtrate, which was concentrated and purified by silica gel chromatography (petroleum ether:ethyl acetate=20%) to give methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate (20.5 g, 93% yield) as a yellow solid.

[0171] LCMS (ESI) m / z: 232 [M+H] +

[0172] Step 3: Synthesis of 1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester

[0173] Methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate (2.0 g, 8.7 mmol) was dissolved in o-dichlorobenzene (40 ml) at room temperature, and carbonyldiimidazole (2.8 g, 17.4 mmol) was then added. The mixture was stirred at 180°C for 12 hours. The reaction was monitored by liquid chromatography-mass spectrometry. The mixture was filtered to obtain a filter cake, which was then slurried with ethyl acetate (5 ml) to afford methyl 1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate (920.0 mg, 41% yield) as a black solid.

[0174] LCMS (ESI) m / z: 258 [M+H] +

[0175] Step 4: Synthesis of methyl 4-chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate

[0176] Methyl 1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate (100.0 mg, 0.39 mmol) was dissolved in phosphorus oxychloride (5 ml) at room temperature, and the mixture was stirred at 120°C for 4 hours. The reaction was monitored by liquid chromatography-mass spectrometry. The reaction solution was concentrated under reduced pressure, diluted with a small amount of acetonitrile, poured into water (5 ml), filtered, and the filter cake was washed with water and dried in vacuo to give methyl 4-chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60.0 mg, 56% yield) as a black solid.

[0177] LCMS (ESI) m / z: 276 [M+H] +

[0178] Step 5: Synthesis of methyl 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate

[0179] Methyl 4-chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60 mg, 0.22 mmol) was dissolved in dimethyl sulfoxide (2 ml) at room temperature, followed by the addition of (4-methoxyphenyl)methanamine (60 mg, 0.44 mmol) and N,N-diisopropylethylamine (67 mg, 0.52 mmol). The mixture was stirred at 100°C for 1 hour. The reaction was monitored by liquid chromatography-mass spectrometry. The reaction solution was poured into 10 ml of water and extracted with ethyl acetate (10 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether:ethyl acetate = 40%) to give methyl 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60 mg, 73% yield) as a black solid.

[0180] LCMS (ESI) m / z: 377 [M+H] +

[0181] Step 6: Synthesis of 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0182] Methyl 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60 mg, 0.16 mmol) was dissolved in methanol (1 ml), tetrahydrofuran (1 ml), and water (1 ml) at room temperature, followed by the addition of potassium hydroxide (26 mg, 0.44 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was monitored by liquid chromatography-mass spectrometry. The reaction solution was poured into 10 ml of water, acidified by the addition of formic acid, and extracted with ethyl acetate (10 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (50 mg, 86% yield) as a white solid.

[0183] LCMS (ESI) m / z: 363 [M+H] +

[0184] The following intermediate carboxylic acids can be prepared by using the synthetic steps described for intermediate 16, replacing only the corresponding starting materials:

[0185] Intermediate 18: 4-amino-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylic acid

[0186] Step 1: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylate

[0187] 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) and extracted with ethyl acetate (5 ml). The organic layer was dried over anhydrous sodium sulfate and filtered, then concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to give methyl 4-((tert-butoxycarbonyl)amino)-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylate (1.00 g, 61% yield) as a white solid.

[0188] LCMS(ESI):376[M+H] +

[0189] Step 2: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylate

[0190] Under nitrogen atmosphere, 4-((tert-butyloxycarbonyl)amino)-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylate)carbonylamino]-7-chloro-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (0.20 g, 0.53 mmol), potassium ferricyanide (0.05 g, 0.16 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.09 g, 0.21 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl A mixture of 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (0.10 g, 51%) was stirred at 100° C. for 2 hours with 1,1′-biphenylyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (0.17 g, 0.21 mmol) and potassium acetate (0.01 g, 0.07 mmol) in dioxane / water (4.00 ml) and stirred at 100° C. for 2 hours, then concentrated and purified by column chromatography (petroleum ether:ethyl acetate=70:30) to give methyl 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylate (0.10 g, 51%) as a white solid.

[0191] LCMS(ESI):368[M+H] +

[0192] Step 3: Synthesis of methyl 4-amino-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylate

[0193] Trifluoroacetic acid (0.10 ml) was added to a solution of methyl 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylate (0.20 g, 0.54 mmol) in dichloromethane (0.50 ml), and the reaction was stirred at room temperature for 2 hours and then concentrated to give methyl 4-amino-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylate (0.05 g, crude product).

[0194] LCMS(ESI):268[M+H] +

[0195] Step 4: Synthesis of 4-amino-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylic acid

[0196] 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), tetrahydrofuran / methanol / water (1 ml / 1 ml / 1 ml) was stirred at room temperature for 2 hours. After the reaction was completed, the system was concentrated to give a crude product of 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.

[0197] LCMS(ESI):254[M+H] +

[0198] Intermediate 19 4-amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0199] Step 1: Synthesis of methyl 4-{[(4-methoxyphenyl)methyl]amino}-7-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate

[0200] A mixture of methyl 7-chloro-4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (200 mg, 0.5 mmol), potassium carbonate (300 mg, 2 mmol), dichloro[1,1'-bis(tert-butylphosphino)ferrocenepalladium(II)] (0.08 g, 0.1 mmol), and trimethylboroxane (0.01 g, 0.10 mmol) was stirred in dioxane (2.00 ml) at 100° C. for 12 hours, then poured into water, extracted with ethyl acetate (5 ml), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (petroleum ether:ethyl acetate=30%) to give methyl 4-{[(4-methoxyphenyl)methyl]amino}-7-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (100 mg, 53%).

[0201] LCMS(ESI):268[M+H] +

[0202] Step 2: Synthesis of 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0203] Methyl 4-{[(4-methoxyphenyl)methyl]amino}-7-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (500 mg, 1.86 mmol) was dissolved in methanol:tetrahydrofuran:saturated potassium hydroxide aqueous solution (1 ml:1 ml:1 ml). The reaction solution was reacted at 60° C. for 12 hours. After completion, the reaction solution was spin-dried and the pH was adjusted to 3 with formic acid. The solution was filtered to give 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (52 mg, 12% yield).

[0204] LCMS(ESI):363[M+H] +

[0205] Step 3: Synthesis of 4-amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0206] 4-((4-Methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (500 mg, 1.86 mmol) was dissolved in trifluoroacetic acid solution (5 ml), and the reaction solution was stirred at 100° C. for 12 hours. After completion, the solution was dried to give 4-amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (52 mg, 0.23 mmol).

[0207] LCMS(ESI):363[M+H] +

[0208] The following intermediate acid was prepared using the method used in the third step of intermediate 19:

[0209] Example 1 Synthesis of (R)-(4-aminopyrrolo[1,2-a]quinoxaline-8-yl)(2-(4-fluorophenyl)piperidin-1-yl)methanone

[0210] Step 1: Synthesis of (R)-(4-aminopyrrolo[1,2-a]quinoxaline-8-yl)(2-(4-fluorophenyl)piperidin-1-yl)methanone

[0211] 4-((4-Methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid (40 mg, 0.12 mmol) and (R)-2-(4-fluorophenyl)piperidine (20 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1 ml). 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (130 mg, 0.34 mmol) and N,N-diisopropylethylamine (44 mg, 0.34 mmol) were then added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (10 ml x 3). The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=10:90) to give (R)-(4-aminopyrrolo[1,2-a]quinoxalin-8-yl)(2-(4-fluorophenyl)piperidin-1-yl)methanone (20 mg, 34.15% yield) as a white solid.

[0212] LCMS (ESI) m / z: 509 [M+H] +

[0213] Step 2: Synthesis of (R)-(4-aminopyrrolo[1,2-a]quinoxaline-8-yl)(2-(4-fluorophenyl)piperidin-1-yl)methanone

[0214] (R)-(4-aminopyrrolo[1,2-a]quinoxaline-8-yl)(2-(4-fluorophenyl)piperidin-1-yl)methanone (20 mg, 0.039 mmol) was dissolved in trifluoroacetic acid (1 ml) and reacted at 60°C for 4 hours. After the reaction, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution (30 ml) and extracted with ethyl acetate (30 ml × 3). The organic phases were combined and washed with saturated brine (30 ml) and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated. The crude product was purified by preparative liquid chromatography (chromatographic column: XBridge Prep OBD C 18 , 30×150mm 5μm, mobile phase A: 10 mmol / L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile, flow rate: 60 ml / min, elution gradient: mobile phase B from 15% to 60% in 8 minutes, detection wavelength: 220 nm, retention time: 8.38 minutes) to obtain (R)-(4-aminopyrrolo[1,2-a]quinoxaline-8-yl)(2-(4-fluorophenyl)piperidin-1-yl)methanone (0.35 mg, yield 2.29%) as a white solid.

[0215] 1 H NMR (400MHz, DMSO-d6): δppm 8.21(br,1H),8.06(s,1H),7.36-7.31(m,3H),7.24(d,J=7.6Hz,1H),7.19-7.14(m,2H),7.00(d,J=4.8Hz,3H),6.69-6.67(m,1H),3 .12-3.09(m,1H),2.34(br,2H),1.92-1.85(m,1H),1.62-1.56(m,1H),1.48(br,2H),1.38-1.29(m,1H).LCMS(ESI)m / z:388.85[M+H] +

[0216] Example 2

[0217] Synthesis of 4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0218] Step 1: Synthesis of (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[0219] At room temperature, 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (200 mg, 0.5741 mmol) was first dissolved in N,N-dimethylacetamide (5 ml), and then 3-(4-(trifluoromethyl)phenyl)morpholine (159 mg, 0.6889 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (541 mg, 1.148 mmol) and N,N-diisopropylethylamine (227 mg, 1.722 mmol) were added to the system in sequence. The resulting mixture was The reaction was carried out at 50°C for 3 hours. After completion of the reaction, the reaction solution was poured into water (20 ml) and extracted with ethyl acetate (10 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether and ethyl acetate, volume ratio of 1:1) to obtain a yellow solid (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (100 mg, yield: 75%).

[0220] LCMS (ESI) m / z: 561.3 [M+H] +

[0221] Step 2: Synthesis of 4-{[(4-methoxyphenyl)methyl]amino}(10-hydroimidazo[1,5-a]quinoxalin-8-yl)3-[4-(trifluoromethyl)phenyl]morpholin-4-ylketone

[0222] At room temperature, (4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (200 mg, 0.3561 mmol) was dissolved in TFA (5 ml). The resulting reactants were reacted at 50°C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and poured into water (10 ml). The pH was adjusted to 8 with saturated sodium bicarbonate solution and the mixture was heated to 40°C with acetic acid. The reaction mixture was extracted with ethyl acetate (10 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was then purified by column chromatography (dichloromethane:methanol, volume ratio 20:1) to give 4-{[(4-methoxyphenyl)methyl]amino}(10-hydroimidazo[1,5-a]quinoxalin-8-yl)3-[4-(trifluoromethyl)phenyl]morpholin-4-yl ketone (71.0 mg, 45.2% yield) as a white solid.

[0223] LCMS (ESI) m / z: 441.3 [M+H] +

[0224] 1H NMR(400MHz, DMSO-d6)δ9.17(s,1H),8.30(d,J=1.7Hz,1H),7.91(s,1H),7.78(d,J=7.9Hz,2H),7.71(s,2H),7.52–7.37(m,4H) ,5.57(s,1H),4.49(d,J=12.4Hz,1H),3.94(d,J=12.3Hz,1H),3.80(s,1H),3.70–3.56(m,1H),3.23(s,2H),0.88–0.79(m,1H).

[0225] Example 2A (R) -4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide and Example 2B (S) -4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0226] Example 2A

[0227] (R)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0228] Column: CHIRALPAK IF-3, 4.6×50mm, 3μm; Mobile Phase A:Hex (0.1% D ethyl acetate): (EtOH:DCM=1:1)=65:35; Flow rate: 1mL / min; Injection Volume: 5μl

[0229] 1 H NMR (400MHz, DMSO-d6) δ9.17(s,1H),8.30(d,J=1.7Hz,1H),7.91(s,1H),7.78(d,J=8.0Hz,2H),7.70(s,2H) ,7.43(d,J=8.9Hz,4H),4.49(d,J=12.2Hz,1H),3.94(d,J=12.5Hz,1H),3.80(s,1H),3.62(t,J=11.3Hz,1H).

[0230] LCMS (ESI) m / z: 442.30 [M+H] +

[0231] Example 2B

[0232] (S)-4-amino-N-(6-bromo-2,3-dihydrobenzofuran-3-yl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0233] Column: CHIRALPAK IF-3, 4.6×50mm, 3μm; Mobile Phase A:Hex (0.1% D ethyl acetate): (EtOH:DCM=1:1)=65:35; Flow rate: 1mL / min; Injection Volume: 5μl

[0234] 1 H NMR (400MHz, DMSO-d6) δ9.17(s,1H),8.29(d,J=1.8Hz,1H),7.91(s,1H),7.78(d,J=8.0Hz,2H),7.70(s,2H),7.43( d,J=9.3Hz,4H),5.61(s,1H),4.49(d,J=12.4Hz,1H),3.94(d,J=12.1Hz,1H),3.80(s,1H),3.62(t,J=11.5Hz,1H).

[0235] LCMS (ESI) m / z: 442.35 [M+H] +

[0236] Example 3:

[0237] Synthesis of (4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[0238] Step 1: Synthesis of N-cyclopropyl-4-((4-methoxybenzyl)amino)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide

[0239] At room temperature, 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid (100 mg, 0.288 mmol) was first dissolved in N,N-dimethylacetamide (3 ml), and then 3-(4-(trifluoromethyl)phenyl)morpholine (95.04 mg, 0.432 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (135.1 mg, 0.5762 mmol) and N,N-diisopropylethylamine (112.23 mg, 0.864 mmol) were added to the system in sequence. The resulting mixture The reaction was carried out at 50°C for 3 hours. After completion of the reaction, the reaction solution was poured into water (15 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether: ethyl acetate, volume ratio of 1:1) to obtain a yellow solid N-cyclopropyl-4-((4-methoxybenzyl)amino)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide (90 mg, yield: 57%).

[0240] LCMS (ESI) m / z: 546.3 [M+H] +

[0241] Step 2: Synthesis of (4-aminopyrrolo[1,2-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[0242] (4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (90 mg, 0.1830 mmol) was dissolved in TFA (2 mL) at room temperature. The resulting reaction mixture was reacted at 50°C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and poured into water (10 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by reverse phase column chromatography (water:acetonitrile, volume ratio 5:95) to obtain (4-aminopyrrolo[1,2-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (10.3 mg, 14.0% yield) as a white solid.

[0243] 1H NMR (400MHz, DMSO-d6): δ8.28(s,1H),8.14(d,J=1.8Hz,1H),7.78(d,J=8.0Hz,2H),7. 71(s,2H),7.42(d,J=8.2Hz,1H),7.33(dd,J=8.3,1.7Hz,1H),7.12(s,2H),7.08(dd,J= 3.9,1.3Hz,1H),6.75(dd,J=3.9,2.8Hz,1H),5.57(s,1H),4.49(d,J=12.3Hz,1H),3.95 (dd,J=12.3,3.5Hz,1H),3.86–3.74(m,1H),3.63(td,J=11.5,2.8Hz,1H),3.22(s,2H).

[0244] LCMS (ESI) m / z: 441.4 [M+H] +

[0245] Example 4:

[0246] Synthesis of (4-amino-7-chloroimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[0247] Step 1: Synthesis of (7-chloro-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[0248] At room temperature, 7-chloro-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (200 mg, 0.5225 mmol) was dissolved in N,N-dimethylacetamide (5 ml), and then 3-(4-(trifluoromethyl)phenyl)morpholine (145 mg, 0.6270 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (369 mg, 0.7837 mmol) and N,N-diisopropylethylamine (207 mg, 1.567 mmol) were added to the bottle in sequence, and the mixture was stirred at 50 °C for 2 h. The reaction was continued at 40 °C for 3 hours. After completion of the reaction, the reaction solution was poured into water (40 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH=10:1) to give 7-chloro-N-cyclopropyl-4-((4-methoxybenzyl)amino)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (160 mg, yield: 51.4%) as a yellow solid.

[0249] LCMS (ESI) m / z: 597 [M+H] +

[0250] Step 9: Synthesis of (4-amino-7-chloroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone

[0251] (7-Chloro-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (160 mg, 0.252 mmol) was dissolved in TFA (5 mL) at room temperature and the reaction was carried out at 50°C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and poured into water (10 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (DCM:MeOH = 20:1) to give (4-amino-7-chloroimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (75 mg, yield: 62.6%) as a white solid.

[0252] LCMS (ESI) m / z: 476 [M+H] +

[0253] 1 H NMR (400MHz, DMSO-d6) δ9.24–9.15(m,1H),8.40–8.22(m,1H),7.95(s,1H),7.82(s,3H),7.71(t,J=8.4Hz,1H),7.61(s,2H),7.54–7 .46(m,1H),5.78(d,J=15.8Hz,1H),4.65–4.53(m,1H),3.98–3.87(m,1H),3.81–3.68(m,1H),3.67–3.55(m,1H),3.27–3.16(m,2H).

[0254] Example 4A Synthesis of (3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl-4-amino-7-chloro(10-hydroimidazo[1,5-a]quinoxalin-8-yl)ketone and Example 4B (3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl-4-amino-7-chloro(10-hydroimidazo[1,5-a]quinoxalin-8-yl)ketone

[0255] 4-Amino-7-chloro(10-hydroimidazo[1,5-a]quinoxalin-8-yl)3-[4-(trifluoromethyl)phenyl]morpholin-4-yl ketone (70 mg, 0.15 mmol) was separated by chiral HPLC (column: CHIRALPAK I 2×25 cm; mobile phase A: methyl tert-butyl ether (0.5% 2 mol / L ammonia-methanol solution), mobile phase B: methanol; flow rate: 20 ml / min; gradient: isocratic; wavelength: 254 / 220 nm; retention time of the front peak: 5.647 min; retention time of the back peak: 11.537 min; injection volume: 2.7 ml; number of runs: 10) to give the front peak (3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl ketone. [1,5-a]quinoxalin-8-yl)one (8.44 mg, 12%) as a white solid and (3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl-4-amino-7-chloro(10-hydroimidazo[1,5-a]quinoxalin-8-yl)one (7.54 mg, 11%) as a white solid.

[0256] Pre-peak Example 4A (3R)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl 4-amino-7-chloro(10-hydroimidazo[1,5-a]quinoxalin-8-yl)ketone

[0257] LCMS (ESI) m / z: 476.05 [M+H] +

[0258] 1 H NMR(400MHz,DMSO-d6)δ9.20-8.95(m,1H),8.39-8.23(m,1H),7.93-7.87(m,1H),7.83-7.39(m,7H ),5.79-4.94(m,1H),4.59-4.41(m,1H),4.29-3.77(m,2H),3.69-3.55(m,1H),3.25-3.03(m,2H).

[0259] Later peak Example 4B (3S)-3-[4-(trifluoromethyl)phenyl]morpholin-4-yl 4-amino-7-chloro(10-hydroimidazo[1,5-a]quinoxalin-8-yl)ketone

[0260] LCMS (ESI) m / z: 476.05 [M+H] +

[0261] 1H NMR(400MHz,DMSO-d6)δ9.20-8.95(m,1H),8.39-8.23(m,1H),7.93-7.40(m,8H),5.79-4.93(m,1H ),4.59-4.11(m,2H),3.91-3.88(m,1H),3.74-3.69(m,1H),3.60-3.58(m,1H),3.25-3.03(m,1H).

[0262] Example 5:

[0263] Synthesis of (4-amino-7-chloroimidazo[1,5-a]quinoxalin-8-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone

[0264] Step 1: Synthesis of (7-chloro-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxalin-8-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone

[0265] At room temperature, 7-chloro-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (200 mg, 0.522 mmol) was dissolved in N,N-dimethylacetamide (5 ml), and then 2-(4-fluorophenyl)pyrrolidine (104 mg, 0.627 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (369 mg, 0.7837 mmol) and N,N-diisopropylethylamine (207 mg, 1.567 mmol) were added to the bottle in sequence, and the mixture was reacted at 50°C. The reaction was completed after 3 hours. The reaction solution was poured into water (40 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH=10:1) to give 7-chloro-N-cyclopropyl-4-((4-methoxybenzyl)amino)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (150 mg, yield: 54.2%) as a yellow solid.

[0266] LCMS (ESI) m / z: 531 [M+H] +

[0267] Step 2: Synthesis of (4-amino-7-chloroimidazo[1,5-a]quinoxaline-8-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone

[0268] (7-Chloro-4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxalin-8-yl)(2-(4-fluorophenyl)pyrrolidin-1-yl)methanone (150 mg, 0.2830 mmol) was dissolved in TFA (5 mL) at room temperature and reacted at 50°C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and poured into water (10 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (DCM:MeOH = 20:1) to give (4-amino-7-chloroimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)morpholino)methanone (70 mg, yield: 60.4%) as a white solid.

[0269] LCMS (ESI) m / z: 410 [M+H] +

[0270] 1 H NMR (400MHz, DMSO-d6) δ9.14(d,J=7.5Hz,1H),8.31(d,J=6.6Hz,1H),7.93(d,J=7.2Hz,1H),7. 58(d,J=8.3Hz,2H),7.48(d,J=12.9Hz,1H),7.44–7.38(m,1H),7.34–7.27(m,1H),7.22–7.15(m ,1H),7.14–7.07(m,1H),4.10–3.73(m,1H),3.67–3.55(m,1H),3.49–3.40(m,1H),3.38(dd,J= 8.7,4.9Hz,1H),3.23(t,J=9.8Hz,1H),2.42–2.22(m,1H),2.00(ddq,J=21.3,11.8,9.1Hz,1H).

[0271] Example 6:

[0272] Synthesis of (2R)-2-(4-fluorophenyl)piperidinyl-4-amino-7-chloro-10-hydroimidazo[1,5-a]quinoxalin-8-yl)ketone

[0273] Step 1: 7-Chloro-4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (0.10 g, 0.26 mmol) was dissolved in trifluoroacetic acid (1 mL). The reaction was stirred at 60°C for 4 hours. After completion, the reaction was concentrated under reduced pressure and diluted with ethyl acetate (5 mL) and saturated sodium bicarbonate solution (5 mL). The aqueous layer was separated and extracted with ethyl acetate (10 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 4-amino-7-chloro-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (0.05 g, 0.26 mmol, 73% yield) as a brown solid.

[0274] LCMS(ESI):262[M+H] +

[0275] Step 2: A mixture of 4-amino-7-chloro-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (20.0 mg, 0.08 mmol), (2R)-2-(4-fluorophenyl)piperidine (15.01 mg, 0.08 mmol), N,N,N′N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (43.43 mg, 0.11 mmol), and N,N-diisopropylethylamine (29.52 mg, 0.23 mmol) in dimethylformamide (1.00 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (5 mL) and saturated sodium bicarbonate solution (5 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (10×3 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by PREP_HPLC (column: XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 20% B to 55% B, 55% B in 10 minutes; wavelength: 220 nm; RT1 (min): 8.48; number of runs: 0) to give (2R)-2-(4-fluorophenyl)piperidinyl 4-amino-7-chloro(10-hydroimidazo[1,5-a]quinoxalin-8-yl)one (14.12 mg, 0.076 mmol, 44% yield) as a white solid.

[0276] 1HNMR(400MHz,DMSO-d6)δ9.25-8.98(m,1H),8.37-8.28(m,1H),7.94-7.87(m, 1H),7.59-7.57(m,2H),7.55-7.48(m,2H),7.41-7.17(m,3H),5.93-4.55(m,1 H),3.27-3.24(m,1H),3.00-2.90(m,1H),2.71-2.54(m,1H),2.40-2.25(m,1H ),2.15-1.88(m,1H),1.73-1.62(m,1H),1.54-1.42(m,1H),1.39-1.35(m,1H).

[0277] LCMS (ESI) m / z: 424.00 [M+H] +

[0278] Example 7

[0279] Synthesis of (R)-(4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)(2-(4-fluorophenyl)piperidin-1-yl)methanone

[0280] To a solution of 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (100 mg, 0.41 mmol) in dimethylacetamide (4 ml) were added 1-hydroxybenzotriazole (60.37 mg, 0.45 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide (85.65 mg, 0.45 mmol), diisopropylethylamine (209.98 mg, 1.62 mmol), and (S)-N-methyl-6-(trifluoromethyl)-2,3-dihydrobenzofuran-3-amine (73 mg, 0.41 mmol). The reaction was allowed to proceed 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 x 3), dried over anhydrous sodium sulfate, and the filtrate was concentrated with suction. The crude product was purified by column chromatography: Kinetex 5m EVO C18, 30 mm × 150 mm; mobile phase A: water (10 mmol / L NH4HCO5), mobile phase B: acetonitrile; flow rate: 60 ml / min ml / min; gradient: 20% B to 49% B in 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.77, to give (R) - (4-amino-7-fluoroimidazo [1, 5-a] quinoxaline -8-yl) (2- (4-fluorophenyl) piperidin-1-yl)methanone (23.74 ml, 13.92%) as a white solid.

[0281] LCMS (ESI) m / z: 408.15 [M+H] +

[0282] 1 H NMR(400MHz, Methanol-d4)δ9.18(s,1H),8.35(s,1H),7.92(m,1H),7.57-7.56(m,2H),7.40-7.25(m,5H),5.93–4.53(m ,1H),3.44-3.41(m,1H),2.97-2.67(m,1H),2.36-2.32(m,1H),2.06-1.87(m,1H),1.66-1.63(m,1H),1.49-1.23(m,3H).

[0283] Example 8

[0284] Synthesis of (4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)(3-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-1-yl)methanone

[0285] The first step is the preparation of (4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(3-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-1-yl)methanone

[0286] At room temperature, 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (200 mg, 0.80 mmol), 2-(pyrrolidin-3-yl)-5-(trifluoromethyl)pyridine hydrochloride (238 mg, 0.80 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (456 mg, 1.20 mmol), and DIEA (515 mg, 4.0 mmol) were placed in a bottle. N,N-dimethylacetamide (5.0 ml) was added and the reaction was stirred at 25°C for 16 hours. After the reaction was completed, aqueous sodium bicarbonate solution (10 mL) was added and extracted with ethyl acetate (20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to obtain the target compound (4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(3-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-1-yl)methanone (90.0 mg, yield: 25%).

[0287] LCMS (ESI) m / z: 445.2 [M+H] +

[0288] 1H NMR(400MHz, DMSO-d6)δ9.14(d,J=3.3Hz,1H),9.00–8.84(m,1H),8.33(dd,J=6.7, 3.5Hz, 1H), 8.17 (ddd, J=27.5, 8.3, 2.5Hz, 1H), 7.92 (dd, J=5.6, 0.7Hz, 1H), 7.63 (dd, J=35.8, 7. 1Hz, 3H), 7.23 (dd, J=11.2, 8.6Hz, 1H), 4.10–3.70 (m, 3H), 3.66–3.47 (m, 2H), 2.34–2.08 (m, 2H).

[0289] Example 9

[0290] Synthesis of (4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)(3-(5-(trifluoromethyl)phenyl)pyrrolidin-1-yl)methanone

[0291] The first step was the preparation of (4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)(3-(5-(trifluoromethyl)phenyl)pyrrolidin-1-yl)methanone.

[0292] At room temperature, 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (200 mg, 0.8124 mmol), 2-(pyrrolidin-3-yl)-5-(trifluoromethyl)phenyl hydrochloride (159 mg, 0.7385 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (344 mg, 0.8862 mmol), and DIEA (292 mg, 2.216 mmol) were placed in a bottle. N,N-dimethylacetamide (3 ml) was added and the reaction was stirred at 50°C for 16 hours. After the reaction was completed, water (30 mL) was added and the mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by column chromatography (dichloromethane:methanol=10:1) to give the target compound 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(3-(5-(trifluoromethyl)phenylcyclo-2-yl)pyrrolidin-1-yl)methanone (42 mg, yield: 12.9%).

[0293] LCMS (ESI) m / z: 444.4 [M+H] +

[0294] 1H NMR (400MHz, DMSO-d6) δ9.14(d,J=7.8Hz,1H),8.34(dd,J=6.6,3.0Hz,1H),7.93(d,J=7 .1Hz,1H),7.73(d,J=8.0Hz,1H),7.65(d,J=8.2Hz,1H),7.63–7.55(m,3H),7.51(d,J=8 .1Hz,1H),7.23(dd,J=14.8,11.2Hz,1H),3.86–3.73(m,1H),3.68–3.58(m,1H),3.52(t d, J=8.7, 3.3Hz, 2H), 3.44 (q, J=10.4, 9.7Hz, 1H), 2.46–2.26 (m, 1H), 2.18–1.91 (m, 1H).

[0295] Example 10

[0296] Synthesis of (4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)3-(5-(trifluoromethyl)pyridin-2-yl)azetidin-1-yl)methanone

[0297] Step 1: Preparation of 2-azetidin-3-yl-5-trifluoromethylpyridine

[0298] Tert-butyl 3-(5-(trifluoromethyl)pyridin-2-yl)azetidine-1-carboxylate (200 mg, 0.6623 mmol) was dissolved in dichloromethane (5 mL) at room temperature. Trifluoroacetic acid (2 mL) was added and the mixture was stirred at room temperature for 2 hours. LCMS monitored the reaction completion, and the reaction solution was concentrated under reduced pressure to afford crude 2-azetidin-3-yl-5-trifluoromethylpyridine (150 mg, crude), which was used directly in the next step without purification.

[0299] LCMS (ESI) m / z: 203.1 [M+H] +

[0300] Step 2: Preparation of (4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)3-(5-(trifluoromethyl)pyridin-2-yl)azetidin-1-yl)methanone.

[0301] At room temperature, the compound 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (200 mg, 0.8124 mmol) was placed in a bottle with 2-azetidin-3-yl-5-trifluoromethylpyridine (181 mg, 0.8936 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (378 mg, 0.9748 mmol) and DIEA (321 mg, 2.437 mmol). N,N-dimethylacetamide (3 ml) was added and the reaction was stirred at 50°C for 16 hours. After the reaction was completed, water (30 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by column chromatography (dichloromethane:methanol=10:1) to give the target compound 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(3-(5-(trifluoromethyl)phenylcyclo-2-yl)pyrrolidin-1-yl)methanone (20 mg, yield: 6%).

[0302] LCMS (ESI) m / z: 431.4 [M+H] +

[0303] 1 H NMR (400MHz, DMSO-d6) δ9.25–9.17(m,1H),9.07–8.93(m,1H),8.63–8.36(m,1H),8.19(dt,J=8.5,2.6Hz,1H),8.00–7 .89(m,1H),7.71–7.58(m,2H),7.45–7.33(m,1H),7.22(dd,J=11.6,2.5Hz,1H),4.59–4.36(m,2H),4.35–4.20(m,2H).

[0304] Example 11

[0305] (S)-(4-Amin-7-fluoroimidazo[1,5,a]quinoxalin-8-yl)(3-(4-trifluoromethoxy)phenyl)morpholine)methanone

[0306] At room temperature, compound (S) 3-(4-trifluoromethoxy)phenyl)morpholine (200 mg, 0.80 mmol), 2-(pyrrolidin-3-yl)-5-(trifluoromethyl)pyridine hydrochloride (238 mg, 0.80 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (456 mg, 1.20 mmol), and DIEA (515 mg, 4.0 mmol) were placed in a bottle, and N,N-dimethylacetamide (5.0 ml) was added. The reaction was stirred at 25°C for 16 hours. After the reaction was completed, aqueous sodium bicarbonate solution (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to obtain the target compound (S)-(4-amino-7-fluoroimidazo[1,5,a]quinoxaline-8-yl)(3-(4-trifluoromethoxy)phenyl)morpholine)methanone (90.0 mg, yield: 21%).

[0307] LCMS (ESI) m / z: 460.2 [M+H] +

[0308] Example 12

[0309] (4-Amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholinyl)methanone

[0310] 4-Amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (100.0 mg, 0.41 mmol) and (3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholine (150.0 mg, 0.61 mmol) were dissolved in DMF (3.0 mL). Triethylamine (124 mg, 1.23 mmol) and CMPI (156 mg, 0.61 mmol) were added, and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through Celite. The filtrate was washed with water (10 mL x 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The title compound was purified by column chromatography (0-5% methanol / dichloromethane) to obtain the title compound (21.0 mg, 11% yield).

[0311] LCMS (ESI) m / z: 474.20 [M+H] +

[0312] 1H NMR(400MHz, DMSO-d6)δ9.16(d,J=11.1Hz,1H),8.34(d,J=9.1Hz,1H),7.92(s,1H),7.79(d,J=14.7Hz,4H),7 .59(s,2H),7.26(d,J=10.8Hz,1H),4.76(s,1H),3.75(d,J=47.5Hz,4H),2.68(s,1H),1.24(d,J=5.9Hz,3H).

[0313] Example 13

[0314] (4-Amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

[0315] Compound 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (210.0 mg, 0.85 mmol) and 3-(4-(trifluoromethyl)phenyl)piperidine (226.0 mg, 0.85 mmol) were dissolved in DMF (8.0 ml), and HATU (496.0 mg, 1.28 mmol) and DIEA (337.0 mg, 2.56 mmol) were added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with water (20 mL x 3) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain a crude product. This was then separated and purified by column chromatography (0-5% methanol / dichloromethane solution) to afford (4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (130.0 mg, 33% yield). LCMS (ESI) m / z: 458.2 [M+H] +

[0316] 1 H NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.31(d,J=6.5Hz,1H),7.92(d,J=10.2Hz,1H),7.73(d,J=8.1Hz,1H),7.66–7.49(m,4H),7.40(d ,J=7.9Hz,1H),7.22(dd,J=23.0,11.0Hz,1H),4.62(t,J=15.0Hz,1H),3.55(t,J=16.0Hz,1H),3.22–2.76(m,3H),2.09–1.47(m,4H).

[0317] Example 13A Synthesis of (R)-4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone and Example 13B (S)-4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

[0318] (4-Amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (55 mg, 0.15 mmol) was separated by chiral HPLC (column: ChiralPak IG, 100×40 mm ID, 10 μm; mobile phase: A for CO2 and B for MeOH (0.1% NH3H2O, 50% / 50%, flow rate: 140 ml / min) gave the leading peak (R)-4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (19 mg, 35%) as a white solid and the trailing peak (S)-4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(3-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (22 mg, 40%) as a white solid.

[0319] Pre-peak Example 13A (R)-4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

[0320] LCMS (ESI) m / z: 458.2 [M+H] +

[0321] 1 H NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.30(s,1H),7.91(d,J=10.2Hz,1H),7.73(d,J=8.1Hz,1H),7.58(t,J=11.4Hz,4H),7.40(d,J=8.0Hz,1 H),7.24(d,J=10.9Hz,1H),4.61(t,J=14.3Hz,1H),3.54(t,J=16.5Hz,1H),3.17(d,J=5.3Hz,1H),2.87(d,J=11.9Hz,2H),1.99–1.42(m,4H).

[0322] Later Peak Example 13B (S)-4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)(3-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

[0323] LCMS (ESI) m / z: 458.2 [M+H] +

[0324] 1 H NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.30(s,1H),7.91(d,J=10.2Hz,1H),7.73(d,J=8.1Hz,1H),7.58(t,J=11.4Hz,4H),7.40(d,J=8.0Hz,1 H),7.24(d,J=10.9Hz,1H),4.61(t,J=14.3Hz,1H),3.54(t,J=16.5Hz,1H),3.17(d,J=5.3Hz,1H),2.87(d,J=11.9Hz,2H),1.99–1.42(m,4H).

[0325] Example 14

[0326] (R)-(4-Aminoimidazo[1,5-a]quinoxalin-8-yl)(2-(4-fluorophenyl)piperidin-1-yl)methanone

[0327] 4-Amino-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (10 mg, 0.04 mmol), (2R)-2-(4-fluorophenyl)piperidine (8 mg, 0.05 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (25 mg, 0.07 mmol), and N,N-diisopropylethylamine (17 mg, 0.13 mmol) were stirred in dimethylformamide (1.00 ml) at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (5 ml) and saturated sodium bicarbonate solution (5 ml). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3×5 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the crude product concentrated in vacuo was purified by HPLC (column: XBridge Shield RP18 OBD, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L sodium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 20% B to 55% B, 55% B in 10 minutes; wavelength: 220 nm; RT1 (min): 8.48; number of runs: 0) to give (R)-(4-aminoimidazo[1,5-a]quinoxaline-8-yl)(2-(4-fluorophenyl)piperidin-1-yl)methanone (0.95 mg, 6% yield) as a white solid.

[0328] LCMS (ESI) m / z: 390.30 [M+H]+

[0329] 1 H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.30(s,1H),7.91(s,1H),7.46-7.38(m,5H),7.26-7.21(m,2H),3.23-3 .22(m,1H),2.44-2.41(m,2H),2.07(s,2H),1.67-1.64(m,1H),1.56-1.55(m,2H),1.23(s,1H),0.85(s,1H).

[0330] Example 15 Synthesis of (S)-(4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(2-(4-(trifluoromethyl)phenyl)morpholinyl)methanone

[0331] At room temperature, the compound 4-amino-7-fluoro-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (387 mg, 1.563 mmol) was dissolved in DMF (3 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 1.563 mmol) and 1-hydroxybenzotriazole (71 mg, 0.521 mmol) were added, followed by the addition of DIEA (671 mg, 5.208 mmol), and the reaction was stirred at room temperature for 0.5 hour. S-2-(4-trifluoromethylphenyl)morpholine (300.0 mg, 1.302 mmol) was then added, and the mixture was reacted at room temperature for 16 hours. When LCMS showed the reaction was complete, water (40 mL) was poured into the mixture, and the mixture was extracted with ethyl acetate (40 x 3 mL). The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by column chromatography (0-5% methanol / dichloromethane) to give (S)-(4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)(2-(4-(trifluoromethyl)phenyl)morpholinyl)methanone (280 mg, yield: 46.9%).

[0332] LCMS (ESI) m / z: 460.2 [M+H] +

[0333] 1H NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.33(d,J=6.5Hz,1H),7.94(d,J=4.6Hz,1H),7.84–7.58(m,5H),7.51(d,J=8 .0Hz,1H),7.24(t,J=12.0Hz,1H),4.65(d,J=9.5Hz,1H),4.62–3.93(m,2H),3.81–3.47(m,2H),3.29–2.85(m,2H).

[0334] Example 16 Synthesis of (R)-(4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(2-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)methanone

[0335] 4-Amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (97.70 mg, 0.40 mmol) and (R)-2-(4-(trifluoromethyl)phenyl)pyrrolidine hydrochloride (100.0 mg, 0.40 mmol) were dissolved in DMF (8.0 mL), and HATU (228 mg, 0.60 mmol) and DIEA (155 mg, 1.20 mmol) were added. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, water (20 ml) was added, and the mixture was extracted with ethyl acetate (30 ml × 2). The organic phases were combined, washed with water (20 ml × 3), washed with saturated brine (20 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give a crude product, which was separated and purified by column chromatography (0-5% methanol / dichloromethane solution) to give (R)-4-amino-7-fluoro-N,1-dimethyl-N-(7-(trifluoromethyl)pyran-4-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (130.0 mg, yield: 73%).

[0336] LCMS (ESI) m / z: 444.2 [M+H]+

[0337] 1 H NMR (400MHz, CDCl3) δ8.97(d,J=163.2Hz,1H),8.43–7.83(m,2H),7.73(d,J=8.1Hz,2H),7.62–7.45(m,3H),7.40–7.2 0(m,1H),7.17–6.81(m,1H),5.09(dt,J=129.5,6.7Hz,1H),3.94–3.62(m,1H),3.58–3.31(m,1H),2.07–1.69(m,2H).

[0338] Example 17 (S)-(4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)(2-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)methanone

[0339] At room temperature, the compound 4-amino-7-fluoro-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (137 g, 0.558 mmol) was dissolved in DMF (3 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg, 0.558 mmol) and 1-hydroxybenzotriazole (76 mg, 0.558 mmol) were added, followed by DIEA (240 mg, 1.860 mmol). The reaction was stirred at room temperature for 0.5 hour. (S)-2-(4-trifluoromethylphenyl)pyrrolidine (100.0 mg, 0.465 mmol) was then added, and the mixture was reacted at room temperature for 16 hours. When LCMS showed the reaction was complete, water (20 mL) was poured into the mixture, and the mixture was extracted with ethyl acetate (20×3 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by column chromatography (0-5% methanol / dichloromethane) to give (S)-(4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)(2-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)methanone (15 mg, yield: 7.28%).

[0340] LCMS (ESI) m / z: 444.2 [M+H] +

[0341] 1 H NMR (400MHz, DMSO-d6) δ8.99(d,J=163.3Hz,1H),8.33(d,J=6.6Hz,1H),7.97-7.81(m,1H),7.74(d,J=8.1Hz,1H),7.66-7.37( m,4H),7.26(d,J=11.2Hz,1H),7.22-6.87(m,1H),5.10(ddd,J=128.8,7.9,5.4Hz,1H),3.91-3.44(m,2H),2.50-1.70(m,4H).

[0342] Example 18

[0343] Synthesis of 2-(1,5-naphthyridin-3-yl)piperidin-1-yl)(4-aminoimidazo[1,5-a]quinoxaline-8-yl)methanone

[0344] Step 1: Synthesis of 2-(1,5-naphthyridin-3-yl)piperidin-1-yl)(4-aminoimidazo[1,5-a]quinoxaline-8-yl)methanone

[0345] 3-(2-Piperidinyl)-1,5-naphthyridine (50 mg, 0.2344 mmol) was dissolved in DMAC (4 ml) at room temperature, and 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (54 mg, 0.2344 mmol), HATU (182 mg, 0.4689 mmol) and N,N-diisopropylethylamine (93 mg, 0.7033 mmol) were added, and the mixture was stirred at 25°C for 2 hours. After 3 hours, the reaction solution was poured into water (20 ml) and extracted with ethyl acetate (15 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the product 2-(1,5-naphthyridin-3-yl)piperidin-1-yl)(4-aminoimidazo[1,5-a]quinoxaline-8-yl)methanone (4 mg, yield: 4%).

[0346] LCMS (ESI) m / z: 424.5 [M+H] +

[0347] 1 H NMR(400MHz, DMSO-d6)δ9.23(s,1H),9.04(dd,J=4.4,1.7Hz,2H),8.46(d,J=8.4Hz,1H),8.40(s,1H),8.33(s,1H),7.91(s,1H),7.80(dd,J=8.5 ,4.2Hz,1H),7.45(d,J=14.2Hz,4H),5.91(s,1H),3.96(s,1H),3.01(s, 1H), 2.65 (d, J=15.0Hz, 1H), 2.10 (t, J=12.2Hz, 1H), 1.78–1.42 (m, 5H).

[0348] Example 19

[0349] Synthesis of (4-aminoimidazo[1,5-a]quinoxalin-8-yl)(2-(4-fluorophenoxy)phenyl)piperidin-1-yl)methanone

[0350] Step 1: Synthesis of (4-aminoimidazo[1,5-a]quinoxalin-8-yl)(2-(4-fluorophenoxy)phenyl)piperidin-1-yl)methanone

[0351] 2-(4-(4-Fluorophenoxy)phenyl)piperidine (100 mg, 0.3685 mmol) was dissolved in DMAC (5 ml) at room temperature, and 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (84 mg, 0.3685 mmol), HATU (286 mg, 0.7371 mmol) and N,N-diisopropylethylamine (146 mg, 1.106 mmol) were added, and the mixture was stirred at 25°C for 2 hours. The reaction solution was poured into water (20 ml), extracted with ethyl acetate (15 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give the product (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(2-(4-fluorophenoxy)phenyl)piperidin-1-yl)methanone (50 mg, yield: 28%) as a white solid.

[0352] 1 H NMR (400MHz, DMSO-d6) δ9.16 (s, 1H), 8.28 (d, J = 1.8Hz, 1H), 7.92 (s, 1H), 7. 43(d,J=8.3Hz,4H),7.25(t,J=8.8Hz,2H),7.18(dd,J=8.3,1.8Hz,1H),7.16 –7.08(m,3H),6.95–6.84(m,2H),5.60(s,1H),3.85(s,1H),2.86(s,1H),2.4 0(d,J=13.9Hz,1H),1.92(t,J=14.2Hz,1H),1.74–1.48(m,3H),1.39(s,1H).

[0353] LCMS (ESI) m / z: 482.5 [M+H] +

[0354] Example 20

[0355] Synthesis of (4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)2-(1-methylpyrazolo[3,4-b]pyridin-5-yl)piperidine-1-methanone (AP-APRN-2102-32-732)

[0356] Step 1: Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)2-(1-methylpyrazolo[3,4-b]pyridin-5-yl)piperidine-1-methanone

[0357] At room temperature, 1-methyl-5-piperidin-2-yl-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.461 mmol) was dissolved in DMAC (4 ml), and 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (136 mg, 0.552 mmol), HATU (212 mg, 0.552 mmol) and N,N-diisopropylethylamine (238 mg, 1.844 mmol) were added, and the mixture was stirred at 50°C for 16 hours. The reaction solution was poured into water (40 ml) and extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give the product (4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)2-(1-methylpyrazolo[3,4-b]pyridin-5-yl)piperidine-1-methanone (30 mg, yield: 14.8%) as a white solid.

[0358] LCMS (ESI) m / z: 441.2 [M+H] +

[0359] 1 H NMR (400MHz, DMSO-d6) δ9.20(s,1H),8.77–8.39(m,2H),8.19(d,J=22.1Hz,2H),7.94(s,1H),7.59(s,2H),7.28(d,J=10.9Hz ,1H),6.14(s,1H),4.08(d,J=6.9Hz,3H),3.46(s,1H),3.03(s,1H),2.60(d,J=14.1Hz,1H),1.98(m,1H),1.75–1.46(m,4H).

[0360] Example 21

[0361] Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)2-(5-(trifluoromethyl)pyridin-2-yl)piperidin-1-yl)methanone

[0362] Step 1: Synthesis of tert-butyl 5'-trifluoromethyl-5,6-dihydro-[2,2'-bipyridine]-1(4H)-carboxylate

[0363] Under N2 atmosphere, tert-butyl 6-((trifluoromethylsulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (300 mg, 0.906 mmol) was dissolved in toluene (10 ml), and 2-tributylstannyl-5-trifluoromethylpyridine (400 mg, 0.906 mmol), lithium chloride (115 mg, 2.72 mmol), and bistriphenylphosphine palladium dichloride (64.0 mg, 0.09 mmol) were added. The reaction was carried out at 100°C for 16 hours. The system was poured into water (50 ml) and extracted with ethyl acetate (40 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to give tert-butyl 5'-trifluoromethyl-5,6-dihydro-[2,2'-bipyridine]-1(4H)-carboxylate (70 mg, 23.6% yield) as a brown solid.

[0364] LCMS (ESI) m / z: 329.2 [M+H] +

[0365] Step 2: Synthesis of tert-butyl 2-(5-(trifluoromethyl)pyridin-2-yl)piperidine-1-carboxylate

[0366] Under H2 atmosphere, tert-butyl 5'-trifluoromethyl-5,6-dihydro-[2,2'-bipyridine]-1(4H)-carboxylate (70 mg, 0.213 mmol) was dissolved in ethanol (3 ml), and Pd / C (400 mg, 0.426 mmol) and ammonium formate (269 mg, 4.26 mmol) were added. The atmosphere was replaced with a hydrogen balloon three times, and then stirred at 40°C for 8 hours. When LCMS showed that the reaction was complete, it was filtered and the filtrate was concentrated under reduced pressure to give crude tert-butyl 2-(5-(trifluoromethyl)pyridin-2-yl)piperidine-1-carboxylate (60 mg, crude product).

[0367] LCMS (ESI) m / z: 331.2 [M+H] +

[0368] Step 3: Synthesis of 2-(piperidin-2-yl)-5-trifluoromethylpyridine

[0369] Tert-butyl 2-(5-(trifluoromethyl)pyridin-2-yl)piperidine-1-carboxylate (190 mg, 0.759 mmol) was dissolved in hydrochloric acid / ethyl acetate (5 ml) at room temperature. The reaction was stirred at room temperature for 3 hours and concentrated under reduced pressure to give a crude product, 2-(piperidin-2-yl)-5-trifluoromethylpyridine (50 mg, crude product), which was used directly in the next step without purification.

[0370] LCMS (ESI) m / z: 231.2 [M+H] +

[0371] Step 4: Synthesis of 4-aminoimidazo[1,5-a]quinoxaline-8-yl)2-(5-(trifluoromethyl)pyridin-2-yl)piperidin-1-yl)methanone

[0372] At room temperature, 2-(piperidin-2-yl)-5-trifluoromethylpyridine (50 mg, 0.552 mmol) was dissolved in DMAC (4 ml), and 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (53 mg, 0.230 mmol), HATU (106 mg, 0.276 mmol) and N,N-diisopropylethylamine (119 mg, 0.922 mmol) were added. The mixture was stirred at 50°C for 16 hours and the reaction was completed. The reaction solution was poured into water (20 ml) and extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give the product 4-aminoimidazo[1,5-a]quinoxaline-8-yl)2-(5-(trifluoromethyl)pyridin-2-yl)piperidin-1-yl)methanone (8 mg, yield 7.91%) as a light yellow solid.

[0373] LCMS (ESI) m / z: 441.2 [M+H] +

[0374] 1 H NMR(400MHz, DMSO-d6)δ9.19(s,1H),9.04(d,J=2.4Hz,1H),8.38–8.19(m,2H),7.92(s,1H),7.69(d,J=8.3Hz,1H ),7.44(s,4H),5.92(s,1H),3.73(s,1H),2.64(s,1H),2.06–1.85(m,1H),1.76–1.42(m,3H),1.40–1.24(m,2H).

[0375] Example 22 Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)2-(4-(trifluoromethoxy)phenyl)piperidin-1-ylmethanone

[0376] At room temperature, 2-(4-(trifluoromethoxy)phenyl)piperidine (100 mg, 0.4078 mmol) was dissolved in DMAC (5 ml), and 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (93 mg, 0.4078 mmol), HATU (316 mg, 0.8155 mmol) and N,N-diisopropylethylamine (161 mg, 1.223 mmol) were added. After stirring at 50° C. for 2 hours, The reaction solution was poured into water (20 ml), extracted with ethyl acetate (15 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to give the product (4-aminoimidazo[1,5-a]quinoxaline-8-yl) 2-(4-(trifluoromethoxy)phenyl)piperidin-1-ylmethanone (30 mg, yield: 16.2%) as a white solid.

[0377] LCMS (ESI) m / z: 455.5 [M+H] +

[0378] 1 H NMR(400MHz, DMSO-d6)δ9.19(s,1H),8.32(d,J=1.7Hz,1H),7.92(s,1H),7.54–7.38(m,9H),5.63(d,J=4.5Hz,1H),3.0 6–2.79(m,2H),2.45(d,J=14.4Hz,1H),1.98(ddd,J=13.8,9.5,4.8Hz,1H),1.70–1.55(m,3H),1.39(d,J=13.0Hz,1H).

[0379] Example 23

[0380] Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)2-(1-methylpyrazolo[3,4-b]pyridin-5-yl)piperidine-1-methanone

[0381] Step 1: Synthesis of tert-butyl 6-((trifluoromethylsulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate

[0382] Under N2 atmosphere, lithium bis(trimethylsilyl)amide (60 ml, 1.0 M, 50.25 mmol) was slowly added dropwise to a solution of tert-butyl 2-oxopiperidine-1-carboxylate (10 g, 50.25 mmol) in tetrahydrofuran (160 ml) at -78°C, and the reaction was stirred at -78°C for 1.5 hours. Then, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (29.5 g, 75.37 mmol) was slowly added at this temperature. The reaction was stirred at 4°C for 4 hours. After completion of the reaction, the reaction solution was quenched with ammonium chloride solution, poured into water (400 mL), and extracted with ethyl acetate (300 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to give tert-butyl 6-((trifluoromethylsulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (8.1 g, 48.7% yield) as a yellow oily liquid.

[0383] LCMS (ESI) m / z: 332.1 [M+H] +

[0384] Step 2: Synthesis of tert-butyl 6-(1-methylpyrazolo[3,4-b]pyridin-5-yl)-3,4-dihydropyridine-1(2H)carboxylate

[0385] Under N2 atmosphere, tert-butyl 6-((trifluoromethylsulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (300 mg, 0.906 mmol) was dissolved in 1,4-dioxane and water (4:1, 6 ml), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazolo[3,4-b]pyridine (282 mg, The mixture was reacted at 100°C for 16 hours with potassium carbonate (376 mg, 2.72 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (67.0 mg, 0.09 mmol). The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the anhydrous sodium sulfate, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain tert-butyl 6-(1-methylpyrazolo[3,4-b]pyridin-5-yl)-3,4-dihydropyridine-1(2H)carboxylate (250 mg, 88.0% yield) as a brown solid.

[0386] LCMS (ESI) m / z: 315.2 [M+H] +

[0387] Step 3: Synthesis of tert-butyl 2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)piperidine-1-carboxylate

[0388] Under an H₂ atmosphere, tert-butyl 6-(1-methylpyrazolo[3,4-b]pyridin-5-yl)-3,4-dihydropyridine-1(2H)carboxylate (250 mg, 0.796 mmol) was dissolved in MeOH (5 mL), and Pd / C (850 mg, 1.592 mmol) was added. The mixture was purged with a hydrogen balloon three times, and the reaction was stirred at 25°C for 16 hours. When LCMS indicated the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude tert-butyl 2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)piperidine-1-carboxylate (240 mg, crude), which was used directly in the next step without purification.

[0389] LCMS (ESI) m / z: 317.2 [M+H] +

[0390] Step 4: Synthesis of 1-methyl-5-piperidin-2-yl-1H-pyrazolo[3,4-b]pyridine

[0391] At room temperature, the compound 2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (240 mg, 0.759 mmol) was dissolved in hydrochloric acid / ethyl acetate (5 ml) and stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to give a crude product of 1-methyl-5-piperidin-2-yl-1H-pyrazolo[3,4-b]pyridine (280 mg, crude product), which was used directly in the next step without purification.

[0392] LCMS (ESI) m / z: 217.2 [M+H] +

[0393] Step 5: Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)2-(1-methylpyrazolo[3,4-b]pyridin-5-yl)piperidine-1-methanone

[0394] At room temperature, 1-methyl-5-piperidin-2-yl-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.461 mmol) was dissolved in DMAC (4 ml), and 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (127 mg, 0.552 mmol), HATU (212 mg, 0.552 mmol) and N,N-diisopropylethylamine (238 mg, 1.844 mmol) were added, and the mixture was stirred at 50° C. for 16 hours. After completion, the reaction solution was poured into water (20 ml) and extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give the product (4-aminoimidazo[1,5-a]quinoxaline-8-yl)2-(1-methylpyrazolo[3,4-b]pyridin-5-yl)piperidine-1-methanone (40 mg, yield: 15.2%) as a white solid.

[0395] LCMS (ESI) m / z: 427.2 [M+H] +

[0396] 1 H NMR(400MHz, DMSO-d6)δ9.22(s,1H),8.58(d,J=2.1Hz,1H),8.37(s,1H),8.31–8.21(m,1H),8.15(s,1H),7.94(s,1H),7.4 9(d,J=21.2Hz,4H),5.80(s,1H),4.08(s,3H),2.74-2.55(m,2H),2.11–1.94(m,1H),1.80–1.43(m,4H),1.36–1.21(m,1H).

[0397] Example 24 Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)2-(quinolin-2-yl)piperidin-1-yl)methanone

[0398] Step 1: Synthesis of 2-(tributyltinyl)quinoline

[0399] Under N2 atmosphere, 2-bromoquinoline (1 g, 4.81 mmol) was dissolved in tetrahydrofuran (20 ml), and n-butyllithium (3.6 ml, 1.6 mol / L, 5.76 mmol) was slowly added dropwise to the system at -78°C, and the reaction was stirred at -78°C for 0.5 hour. Then, tributyltin chloride (29.5 g, 75.37 mmol) was slowly added at this temperature, and the reaction was stirred at -78°C for 2 hours. After the reaction was completed, the reaction solution was quenched with ammonium chloride solution, poured into water (400 ml), and extracted with ethyl acetate (300 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product 2-(tributyltinyl)quinoline (1.3 g, crude product), which was used directly in the next step without purification.

[0400] LCMS (ESI) m / z: 419.1 [M+H] +

[0401] Step 2: Synthesis of tert-butyl 6-(quinolin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0402] Under N2 atmosphere, tert-butyl 6-((trifluoromethylsulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (300 mg, 0.906 mmol) was dissolved in toluene (10 ml), and 2-(tributyltinyl)quinoline (600 mg, crude), lithium chloride (115 mg, 2.72 mmol), and bistriphenylphosphine palladium dichloride (64.0 mg, 0.09 mmol) were added. The reaction was carried out at 100°C for 16 hours. The system was poured into water (50 ml) and extracted with ethyl acetate (40 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give tert-butyl 6-(quinolin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (200 mg, 71.2% yield) as a brown solid.

[0403] LCMS (ESI) m / z: 311.2 [M+H] +

[0404] Step 3: Synthesis of tert-butyl 2-(quinolin-2-yl)piperidine-1-carboxylate

[0405] Under H2 atmosphere, tert-butyl 6-(quinolin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (200 mg, 0.645 mmol) was dissolved in MeOH (5 mL), and Pd / C (720 mg, 1.290 mmol) was added, and the reaction was stirred at 40°C for 8 hours. When LCMS showed the reaction was complete, the reaction was filtered, and the filtrate was concentrated under reduced pressure to give crude tert-butyl 2-(quinolin-2-yl)piperidine-1-carboxylate (190 mg, crude product).

[0406] LCMS (ESI) m / z: 313.2 [M+H] +

[0407] Step 4: Synthesis of 2-(piperidin-2-yl)quinoline

[0408] tert-Butyl 2-(quinolin-2-yl)piperidine-1-carboxylate (190 mg, 0.759 mmol) was dissolved in hydrochloric acid / ethyl acetate (5 mL) at room temperature and stirred for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to afford crude 2-(piperidin-2-yl)quinoline (240 mg, crude product), which was used directly in the next step without purification.

[0409] LCMS (ESI) m / z: 213.2 [M+H] +

[0410] Step 5: Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)2-(quinolin-2-yl)piperidin-1-yl)methanone

[0411] At room temperature, 2-(piperidin-2-yl)quinoline (120 mg, 0.552 mmol) was dissolved in DMAC (4 ml), and 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (106 mg, 0.461 mmol), HATU (212 mg, 0.552 mmol) and N,N-diisopropylethylamine (238 mg, 1.844 mmol) were added. The mixture was stirred at 50°C for 16 hours and the reaction was completed. After completion, the reaction solution was poured into water (20 ml) and extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain the product (4-aminoimidazo[1,5-a]quinoxaline-8-yl)2-(quinolin-2-yl)piperidin-1-yl)methanone (10 mg, yield 5.14%) as a white solid.

[0412] LCMS (ESI) m / z: 423.2 [M+H] +

[0413] 1H NMR(400MHz, DMSO-d6)δ9.22(s,1H),8.62–8.31(m,2H),8.26–7.93(m,3H),7.90–7.21(m,7H),6.05(s,1H),2.10–1.91(m,1H),1.80–1.26(m,6H).

[0414] Example 25 Synthesis of (4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)2-(quinolin-2-yl)piperidin-1-yl)methanone

[0415] Synthesis of (4-amino-7-fluoroimidazo[1,5-a]quinoxalin-8-yl)2-(quinolin-2-yl)piperidin-1-yl)methanone

[0416] At room temperature, 2-(piperidin-2-yl)quinoline (120 mg, 0.552 mmol) was dissolved in DMAC (4 ml), and 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (114 mg, 0.461 mmol), HATU (212 mg, 0.552 mmol) and N,N-diisopropylethylamine (238 mg, 1.844 mmol) were added. The mixture was stirred at 50°C for 16 hours and the reaction was completed. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give the product (4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)2-(quinolin-2-yl)piperidin-1-yl)methanone (8 mg, 3.94% yield) as a white solid.

[0417] LCMS (ESI) m / z: 441.2 [M+H] +

[0418] 1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.49-8.28(m,2H),8.12-7.93(m,2H),7.85-7.71(m,1H),7.69-7.48(m,4H),7.37-7 .23(m,1H),6.12(s,1H),5.19-4.60(m,1H),3.73-3.48(m,1H),2.89(dd,J=14.0Hz,1H),2.69(s,1H),2.09-1.42(m,5H).

[0419] Example 26 Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(2-(benzothiazol-5-yl)piperidin-1-yl)methanone

[0420] Step 1: Synthesis of tert-butyl 6-(benzothiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0421] Under N2 atmosphere, tert-butyl 6-((trifluoromethylsulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (300 mg, 0.906 mmol) was dissolved in 1,4-dioxane and water (4:1, 6 ml), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiazole (284 mg, 1.09 mmol), potassium carbonate (376 mg, 2.72 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (67.0 mg, 0.09 mmol) were added. The reaction was carried out at 100°C for 16 hours. The system was poured into water (30 ml) and extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to give tert-butyl 6-(benzothiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate (200 mg, 69.8% yield) as a brown solid.

[0422] LCMS (ESI) m / z: 317.2 [M+H] +

[0423] Step 2: Synthesis of 5-(3,4,5,6-tetrahydropyridin-2-yl)benzothiazole

[0424] At room temperature, tert-butyl 6-(benzothiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate (200 mg, 0.632 mmol) was dissolved in dichloromethane (2.5 ml), and trifluoroacetic acid (0.5 ml) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water and adjusted to pH = 8 by adding a certain amount of saturated sodium bicarbonate aqueous solution. The solution was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 5-(3,4,5,6-tetrahydropyridin-2-yl)benzothiazole (150 mg, crude product), which was used directly in the next step without purification.

[0425] LCMS (ESI) m / z: 217.2 [M+H] +

[0426] Step 3: Synthesis of 5-(piperidin-2-yl)benzothiazole

[0427] 5-(3,4,5,6-tetrahydropyridin-2-yl)benzothiazole (150 mg, 0.694 mmol) was dissolved in methanol at room temperature, and sodium triacetylborohydride (284 mg, 1.314 mmol) was added. The reaction was stirred at 50°C for 10 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, poured into water, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 5-(piperidin-2-yl)benzothiazole (100 mg, crude product), which was used directly in the next step without purification.

[0428] LCMS (ESI) m / z: 219.2 [M+H] +

[0429] Step 4: Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(2-(benzothiazol-5-yl)piperidin-1-yl)methanone

[0430] At room temperature, 5-(piperidin-2-yl)benzothiazole (100 mg, 0.460 mmol) was dissolved in DMAC (4 ml), and 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (127 mg, 0.552 mmol), 2-chloro-1-methylpyridinium iodide (141 mg, 0.552 mmol) and N,N-diisopropylethylamine (238 mg, 1.844 mmol) were added, and the mixture was stirred at 50°C for 16 hours. After completion of the reaction, the reaction solution was poured into water (20 ml) and extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give the product (4-aminoimidazo[1,5-a]quinoxaline-8-yl)(2-(benzothiazol-5-yl)piperidin-1-yl)methanone (3 mg, yield 1.53%) as a light yellow solid.

[0431] LCMS (ESI) m / z: 429.2 [M+H] +

[0432] 1 H NMR (400MHz, DMSO-d6) δ9.43(s,1H),9.21(s,1H),8.37(d,J=1.6Hz,1H),8.22(d,J=8.4Hz,1H),8.05(s,1H) ,7.92(s,1H),7.59-7.35(m,5H),5.78(s,1H),2.94(s,1H),2.60(s,1H),2.10-96(m,1H),1.80-1.41(m,5H)

[0433] Example 27 Synthesis of (4-aminoimidazo[1,5-a]quinoxaline-8-yl)2-(7-fluoroquinolin-2-yl)piperidine-1-methanone

[0434] Step 1: Synthesis of 7-fluoroquinoline-2-boronic acid

[0435] 2-Bromo-7-fluoroquinoline (1 g, 4.424 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) at room temperature. At -78°C, n-butyl lithium (3.5 ml, 8.848 mmol) was slowly added dropwise to the system. After stirring for 10 minutes, isopropyl pinacol borate (1.6 g, 8.848 mmol) was added and the reaction was stirred at -78°C for 2 hours. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (1 ml), and the mixture was concentrated under reduced pressure to obtain a crude product, which was washed with ethyl acetate and filtered. The filter cake was washed twice with ethyl acetate to obtain a white solid (0.5 g, crude product).

[0436] LCMS (ESI) m / z: 192.0 [M+H] +

[0437] Step 2: tert-Butyl 6-(7-fluoroquinolin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0438] At room temperature, 7-fluoroquinoline-2-boronic acid (346 mg, 1.811 mmol) and tert-butyl 6-((trifluoromethylsulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (300 mg, 0.906 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (10 ml, 4:1), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (68 mg, 0.091 mmol) and potassium carbonate (383 mg, 2.72 mmol) were added. The nitrogen atmosphere was replaced three times, and the reaction was carried out at 100°C for 14 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give tert-butyl 6-(7-fluoroquinolin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (150 mg, 50% yield).

[0439] LCMS (ESI) m / z: 329.2 [M+H] +

[0440] Step 3: Synthesis of 7-fluoro-2-(1,4,5,6-tetrahydropyridin-2-yl)quinoline

[0441] At room temperature, tert-butyl 6-(7-fluoroquinolin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (150 mg, 0.457 mmol) was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (0.5 ml) was added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water and adjusted to pH = 8 by adding a certain amount of saturated sodium bicarbonate aqueous solution. The solution was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (100 mg, crude product), which was used directly in the next step without purification.

[0442] LCMS (ESI) m / z: 229 [M+H] +

[0443] Step 4: Synthesis of 7-fluoro-2-(piperidin-2-yl)quinoline

[0444] 7-Fluoro-2-(1,4,5,6-tetrahydropyridin-2-yl)quinoline (100 mg, 0.438 mmol) was dissolved in methanol at room temperature, and sodium triacetylborohydride (284 mg, 1.314 mmol) was added. The reaction was stirred at 50°C for 10 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, poured into water, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (100 mg, crude product), which was used directly in the next step without purification.

[0445] LCMS (ESI) m / z: 231.1 [M+H] +

[0446] Step 5: (4-aminoimidazo[1,5-a]quinoxaline-8-yl)2-(7-fluoroquinolin-2-yl)piperidine-1-methanone

[0447] 7-Fluoro-2-(piperidin-2-yl)quinoline (100 mg, 0.369 mmol) was dissolved in DMAC (5 mL) at room temperature, and 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (84 mg, 0.369 mmol), HATU (286 mg, 0.737 mmol), and N,N-diisopropylethylamine (146 mg, 1.11 mmol) were added. After stirring at 25°C for 2 hours, the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give (4-aminoimidazo[1,5-a]quinoxalin-8-yl)(2-(4-fluorophenoxy)phenyl)piperidin-1-yl)methanone (50 mg, 28% yield).

[0448] LCMS (ESI) m / z: 441.2 [M+H] +

[0449] Example 28 Synthesis of (4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)2-(quinoxaline-6-yl)piperidine-1-methanone

[0450] Step 1: Synthesis of tert-butyl 6-(quinoxaline-6-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0451] Under N2 atmosphere, tert-butyl 6-((trifluoromethylsulfonyl)oxy)-3,4-dihydropyridine-1(2H)-carboxylate (300 mg, 0.906 mmol) was dissolved in 1,4-dioxane and water (4:1, 6 ml), and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (280 mg, 1.09 mmol), potassium carbonate (376 mg, 2.72 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (67.0 mg, 0.09 mmol) were added. The reaction was carried out at 100°C for 16 hours. The system was poured into water (30 ml) and extracted with ethyl acetate (20 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give tert-butyl 6-(quinoxaline-6-yl)-3,4-dihydropyridine-1(2H)-carboxylate (200 mg, 70.9% yield) as a brown solid.

[0452] LCMS (ESI) m / z: 312.2 [M+H] +

[0453] Step 2: Synthesis of 6-(3,4,5,6-tetrahydropyridin-2-yl)quinoxaline

[0454] At room temperature, tert-butyl 6-(quinoxalin-6-yl)-3,4-dihydropyridine-1(2H)-carboxylate (200 mg, 0.643 mmol) was dissolved in dichloromethane (2.5 mL). Trifluoroacetic acid (0.5 mL) was added and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured into water and adjusted to pH 8 with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford crude 6-(3,4,5,6-tetrahydropyridin-2-yl)quinoxaline (150 mg, crude product), which was used directly in the next step without purification.

[0455] LCMS (ESI) m / z: 212.2 [M+H] +

[0456] Step 3: Synthesis of 6-(piperidin-2-yl)quinoxaline

[0457] 6-(3,4,5,6-tetrahydropyridin-2-yl)quinoxaline (150 mg, 0.710 mmol) was dissolved in methanol at room temperature, and sodium triacetylborohydride (307 mg, 1.314 mmol) was added. The reaction was stirred at 50°C for 10 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, poured into water, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude 6-(piperidin-2-yl)quinoxaline (100 mg, crude product), which was used directly in the next step without purification.

[0458] LCMS (ESI) m / z: 214.2 [M+H] +

[0459] Step 4: Synthesis of (4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)2-(quinoxaline-6-yl)piperidine-1-methanone

[0460] At room temperature, 6-(piperidin-2-yl)quinoxaline (100 mg, 0.469 mmol) was dissolved in DMAC (4 ml), and 4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (136 mg, 0.552 mmol), 2-chloro-1-methylpyridinium iodide (141 mg, 0.552 mmol) and N,N-diisopropylethylamine (238 mg, 1.844 mmol) were added, and the mixture was stirred at 50°C. After 16 hours, the reaction was completed and the reaction solution was poured into water (20 ml), extracted with ethyl acetate (20 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the product (4-amino-7-fluoroimidazo[1,5-a]quinoxaline-8-yl)2-(quinoxaline-6-yl)piperidin-1-methanone (3 mg, yield 1.53%).

[0461] 1 H NMR (400MHz, DMSO-d6) δ9.23 (s, 1H), 8.99 (d, J = 7.1Hz, 2H), 8.44 (d, J = 6.5Hz, 1H), 8.22–8.09 (m, 1H), 8.02–7.75 (m, 2H), 7.66–7. 21(m,3H),4.92(d,J=225.1Hz,1H),3.56(d,J=13.7Hz,1H),3.12(s,1H),2.71(d,J=14.6Hz,1H),2.03(s,1H),1.83–1.38(m,4H).

[0462] LCMS (ESI) m / z: 424.2 [M+H] +

[0463] Biochemical evaluation

[0464] 1. Experimental study on the inhibitory activity of compounds on tumor cell proliferation

[0465] Test Example 1: Inhibitory activity of compounds on HCT-116 MTAP(- / -) deficient cell proliferation

[0466] Materials and cells: HCT-116 MTAP(- / -)-deficient cells were purchased from Kangyuan Bochuang (China); RPMI-1640 medium, fetal bovine serum, and penicillin-streptomycin were purchased from Thermo Fisher Scientific (USA); 384-well plates were purchased from PerkinElmer (USA); and the Cell-Titer Glo kit was purchased from Promega (USA).

[0467] Cell culture: HCT116 MTAP(- / -)-deficient cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C and 5% CO2. Cells in the logarithmic growth phase were used for experiments.

[0468] Cell proliferation inhibitory activity assay: The Cell-Titer Glo kit was used to detect the inhibitory activity of the compound on HCT-116MTAP(- / -) deficient cells. The cell concentration was adjusted, and 40 μL was inoculated into each well of a 384-well plate and cultured overnight at 37°C and 5% CO2. 40 nL of compound was added to each well to a final concentration of 0-10,000 nM (starting concentration 10,000 nM, 3-fold dilution, 10 points) with a DMSO content of 0.1%. The cell plates were incubated at 37°C and 5% CO2 for 8 days. 40 μL of Cell-Titer Glo reagent was added to detect cell activity. The test results are shown in Table 1.

[0469] Test Example 2: Experimental study on the inhibitory activity of compounds on HCT-116 wild-type cell proliferation

[0470] Materials and cells: HCT-116 wild-type cells were purchased from Kangyuan Bochuang (China); RPMI-1640 medium, fetal bovine serum, and penicillin-streptomycin were purchased from Thermo Fisher Scientific (USA); 384-well plates were purchased from PerkinElmer (USA); and the Cell-Titer Glo kit was purchased from Promega (USA).

[0471] Cell culture: HCT-116 wild-type cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C and 5% CO2. Cells in the logarithmic growth phase were used in experiments.

[0472] Cell proliferation activity assay: The Cell-Titer Glo kit was used to detect the inhibitory activity of the compound on HCT-116 wild-type cells. The cell concentration was adjusted, and 40 μL was inoculated into each well of a 384-well plate and cultured overnight at 37°C and 5% CO2. 40 nL of compound was added to each well to a final concentration of 0-10,000 nM (starting concentration 10,000 nM, 2-fold dilution, 10 points) with a DMSO content of 0.1%. The cell plates were incubated at 37°C and 5% CO2 for 8 days. 40 μL of Cell-Titer Glo reagent was added to detect cell activity. The test results are shown in Table 1.

[0473] Table 1 shows the inhibitory activity of the compounds in the examples on the proliferation of HCT116 MTAP(- / -) deficient cells and HCT116 wild-type cells.

[0474] Table 1

[0475] Although the preferred embodiment has been described above, it will be apparent to those skilled in the art that modifications may be made without departing from the invention. Such modifications are considered to be possible variations within the scope of the invention.

Claims

1. The compound according to claim 1, or its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, which has the following formula (I): in, W stands for N or CR W ; Where X3 represents N or CR X3 ; X4 represents N or CR X4 ; X5 represents N or CR X5 ; X6 represents N or CR X6 ; Among them, when X3 represents CR X3 When R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X4 represents CR X4 When R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X5 represents CR X5 When R X5 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X6 represents CR X6 When R X6 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X3 and X4, and the ring may contain 0-3 heteroatoms selected from O, N, and S; Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X4 and X5, and the ring may contain 0-3 heteroatoms selected from O, N, and S; Wherein, the ring A may also be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X5 and X6, and the ring may contain 0-3 heteroatoms selected from O, N, and S; Where W represents CR W When R W Selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, halogenated C1-C6 alkoxy; Where X1 represents N or CR X1 ; Where X2 represents N or CR X2 ; Among them, Y1 represents CR Y1 R Y1’ NR Y1 , O, S, Se; Among them, Y2 represents CR Y2 R Y2’ NR Y2 , O, S, Se; Among them, Y3 represents CR Y3 R Y3’ NR Y3 , O, S, Se; Among them, R X1 、R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5; Among them, R Y1 、R Y1’ 、R Y2 、R Y2’ 、R Y3 、R Y3’ Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5; Among them, M 2 Indicates CR M1 R M2 ,S,O,NR M1 ; Among them, R M1 、R M2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, or R M1 、R M2 Together with The connected atoms together form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N; Among them, R 4 represents hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl or halogen; in, Indicates a single bond or a double bond; Wherein, s represents an integer from 0 to 3; Among them, R a 、R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a 、R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

2. The compound according to claim 1, or its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, which has the following formula (II): in, W stands for N or CR W ; Where X3 represents N or CR X3 ; X4 represents N or CR X4 ; X5 represents N or CR X5 ; X6 represents N or CR X6 ; Among them, when X3 represents CR X3 When R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X4 represents CR X4 When R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b 、-CN、 Halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X5 represents CR X5 When R X5 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X6 represents CR X6 When R X6 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Where W represents CR W When R W Selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, halogenated C1-C6 alkoxy; Where X1 represents N or CR X1 ; Where X2 represents N or CR X2 ; Among them, Y1 represents CR Y1 R Y1’ NR Y1 , O, S, Se; Among them, Y2 represents CR Y2 R Y2’ NR Y2 , O, S, Se; Among them, Y3 represents CR Y3 R Y3’ NR Y3 , O, S, Se; Among them, R X1 、R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5; Among them, R Y1 、R Y1’ 、R Y2 、R Y2’ 、R Y3 、R Y3’ Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5; Among them, M 2 Indicates CR M1 R M2 ,S,O,NR M1 ; Among them, R M1 、R M2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, or R M1 、R M2 Together with The connected atoms together form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N; Among them, R 4 represents hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl or halogen; in, Indicates a single bond or a double bond; Wherein, s represents an integer from 0 to 3; Among them, R a 、R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a 、R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X1 represents CR X1 or N, where R X1 represents hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, or halogenated C1-C6 alkyl.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X2 represents CH and CD.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X3 represents CH, CD or N.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X4 means CR X4 or N where R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, -SO3R a 、-SR a 、-P(O)R a R b , or cyano or is selected from 0-4 of the following substituents: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X5 means CR X5 or N where R X5 represents hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, or cyano.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X6 represents CH, CD or N.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: The chemical bond between Y1 and Y2 is a double bond.

10. The compound according to claim 9, or its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein: Y1 represents CR Y1 , where R Y1 It represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, -S(O)2CH3 or cyano.

11. The compound according to claim 8 or 9, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Y2 represents N.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Y3 represents CH or CD.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R 4 represents hydrogen or C1-C6 alkyl or deuterated C1-C6 alkyl.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: M 2 Represents O, NH, and S.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: M 2 Indicates CR M1 R M2 ; Among them, R M1 、R M2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, or R M1 、R M2 Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring.

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, characterized in that Selected from any of the following compound structures:

17. The isotopic derivative of the compound according to any one of claims 1 to 16, characterized in that: At least one or more hydrogen atoms in the isotope derivative are deuterium atoms.

18. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to any one of claims 1 to 17, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative thereof, and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition according to claim 18, characterized in that A second active substance may also be included, wherein the second active substance is an anti-tumor drug, and the anti-tumor drug includes one or more of a chemotherapy drug, a targeted tumor treatment drug or a tumor treatment antibody drug.

20. A method for treating a disease by inhibiting the action of PRMT5 using a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof.

21. The method according to claim 20, wherein the disease is a tumor.

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