Triheterocyclic derivatives, pharmaceutical compositions and uses thereof

Abstract

The present invention relates to a triheterocyclic derivative, its pharmaceutical composition, and its use. The triheterocyclic derivative (I), its stereoisomer, or a pharmaceutically acceptable salt thereof has the following structure: The triheterocyclic derivative has an excellent effect of inhibiting ATR level in vivo and in vitro, and can also effectively treat diseases caused by abnormal ATR level, such as cancer. [Formula 1] TIFF2023545196000051.tif63170

Description

Detailed Description of the Invention

[0001] This application claims priority to Chinese patent application CN202011107416.5, filed on October 16, 2020, Chinese patent application CN202110097827.9, filed on January 25, 2021, and Chinese patent application CN202110929213.2, filed on August 13, 2021. This application cites the above Chinese patent applications in their entirety.

[0002] [Technical field] The present invention relates to triheterocyclic derivatives, pharmaceutical compositions thereof, and their use as therapeutic agents, particularly as therapeutic agents for cancer.

[0003] [Background technology] Human cells incur thousands of DNA damage every day. The causes of DNA damage include normal cellular function (e.g., oxidative metabolites), DNA metabolic products (e.g., spontaneous DNA errors during transcription and replication), and environmental factors (e.g., ultraviolet light, ionizing radiation, genotoxins, etc.). If these damages are not properly repaired, cells and organisms lose their vitality. The accumulation of DNA damage also affects genome stability and integrity, potentially promoting cancer formation. DNA damage can occur through oxidation or alkylation of DNA bases, DNA base mismatches and dimers, DNA backbone breaks and discontinuities, intrastrand / interstrand DNA crosslinks, and general changes in DNA structure. To ensure the stability and integrity of the cellular genome, cells have a complex set of DNA damage response (DDR) mechanisms that recognize and process these specific types of DNA damage during specific parts of the cell cycle, maintaining genome integrity and cell viability. Research has shown that healthy cells have multiple DDR mechanisms, and these repair mechanisms can compensate for each other during the DNA repair process. (Jackson SP, Nature, 2009, 461(7267), 1071-1078) However, many cancer cells exhibit defects in multiple DNA repair pathways, resulting in a greater reliance on intact DNA repair pathways.

[0004] Ataxia telangiectasia mutated and Rad3-related kinase (ATR, also known as FRAP-Related Protein 1, FRP1, MEC1, SCK1, and SECKL1) is a member of the phosphatidylinositol-3 kinase-related kinase (PIKK) protein family. It is a key kinase that activates cellular responses after DNA damage, leading to cell cycle arrest, stabilizing replication forks, repairing DNA, and thereby preventing apoptosis (Cimprich KA, Nature Rev. Mol. Cell Biol., 2008, 9:616-627). ATR acts by stabilizing stalled replication forks and regulating cell cycle checkpoint activation and DNA damage repair. Upon activation, ATR activates three signaling pathways by regulating its downstream regulators (mainly including Chk1, WRN, and FANCI) to halt cell cycle progression, promote DNA repair, and stabilize replication forks. Although the presence of RPA-coated single-stranded DNA is a common feature of ATR activation, in some cases ATR can be activated in the absence of DNA helicase and polymerase uncoupling, for example, by UV irradiation, platinum chemotherapy, or alkylating agents.

[0005] DNA repair in tumor cells may be defective due to the presence of multiple mutations, thus showing greater reliance on intact DNA repair pathways. Therefore, the theory of synthetic lethality can be used to kill specific tumor cells while sparing healthy cells. Current cancer treatments, including chemotherapy and ionizing radiation, can induce DNA damage and stalled replication forks, thereby activating cell cycle checkpoints and leading to cell cycle arrest. This response mechanism is important for helping cancer cells survive treatment. Broken double-stranded DNA or replication stress can rapidly activate ATR, which in turn can activate a series of downstream targets, including Chk1 (ATR substrate), p53, and DNA topoisomerase 2-binding protein (TopBP1), resulting in DNA repair and cell cycle arrest. Because the ATR gene is rarely mutated, it is easily activated during cancer chemotherapy. Inhibiting ATR can also result in several synthetic lethal interactions, particularly with the ATM / p53 pathway. p53 is the most common tumor suppressor gene mutation, and DNA repair in cells with ATM / p53 gene deficiency or mutation is more dependent on ATR activation (Reaper, PM, Nat. Chem. Biol., 2011, 7, 428-430).

[0006] Studies have shown that loss of certain DNA repair proteins, such as X-ray damage repair cross-complementing gene 1 (XRCC1) and excision repair cross-complementing gene 1 (ERCC1), also makes tumor cells more sensitive to ATR inhibition (Sultana R, PLoS One, 2013, 8(2): e57098). Furthermore, hypoxic tumor cells can induce replication stress, making them more sensitive to ATR inhibition. Inhibiting ATR selectively enhances tumor cell sensitivity to ionizing radiation and chemotherapy, increasing tumor cell sensitivity to replication stress by several times over normal cells (Lecona E, Exp Cell Res, 2014, 329(1): 26-34). Furthermore, because ATR is essential for maintaining telomere homologous recombination, tumor cells that rely on alternative telomere elongation pathways for DNA damage repair are also more sensitive to ATR inhibition.

[0007] As a DNA damage response mechanism, the ATR pathway plays an important role in tumor cell survival. Inhibition of ATR, a key factor in this pathway, can induce the death of malignant tumor cells dependent on the ATR pathway. This has minimal impact on normal cells, making it an ideal target for the development of low-toxicity, highly effective targeted drugs. Currently, two small molecule entities, VX970 and AZD6738, have entered Phase II clinical trials. Many patents, including WO2015 / 084384, WO2017 / 180723, WO2016 / 061097, WO2014 / 140644, WO2007 / 015632, WO2017 / 123588, and WO2007 / 046426, have disclosed the ATR pathway, but no corresponding drugs have yet been launched. The triheterocyclic derivatives of the present invention provide a new concept for the development of ATR inhibitors.

[0008] [Summary of the Invention] The technical problem to be solved by the present invention is to provide a novel tri-heterocyclic derivative, its pharmaceutical composition and use. The tri-heterocyclic derivative of the present invention has a good ATR inhibitory effect and can effectively treat and / or alleviate various ATR-mediated related diseases, such as malignant tumors.

[0009] The present invention provides a compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,

[0010] [ka]

[0011] where: X is CR3 or NR5, and X1 is CR 3a , C.R. 3a R 4a or NR 5a and X2 is CR 3b , C.R. 3b R 4b or NR 5b and X3 is a connecting bond, CR 3c , C.R. 3c R 4c or NR 5c and U is N or CH; U1 and U2 are each independently N or C, and U1 and U2 are not both N; V is NR6 or CR7, and V1 is N, NR 6a or CR 7a and V2 is N, NR 6b or CR 7b and V3 is a ligation bond, N, NR 6c or CR 7c and R1 is hydrogen or C 1-6 is alkyl, R2 is methyl; R3, R 3a , R 3b and R 3c are each independently hydrogen, halogen, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 6-10 Aryl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 6-10 Aryl C 1-6 Alkyl, C3-8 Cycloalkyl C 1-6 Alkyl, 3-8 membered heterocycloalkylC 1-6 Alkyl, 5-6 membered heteroarylC 1-6 Alkyl, -SR a , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -C(O)N(R b ) OR a , -C(O)NR b S(O)2R a , -C(=NH)R a , -NR a R b , -NR b C(O)R a , -N(R b )C(O)OR a , -N(R b )C(O)NR a R b , -NR b S(O)2R a , -NR b C(=NH)R a , -NR b C(=NH)NR b R a , -S(O) 1-2 R a , -S(O)NR a R b , -S(O)(=NCN)R a , -S(O)(=NR b )R a or -NR b S(O)NR a R b where C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 6-10 Aryl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C6-10 Aryl C 1-6 Alkyl, C 3-8 Cycloalkyl C 1-6 Alkyl, 3-8 membered heterocycloalkylC 1-6 Alkyl or 5-6 membered heteroaryl C 1-6 Alkyl is unsubstituted or optionally substituted with halogen, cyano, nitro, -SR a , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -C(O)NR b S(O)2R a , -NR a R b , -NR b C(O)R a , -N(R b )C(O)OR a , -N(R b )C(O)NR a R b , -NR b C(=NH)R a , -NR b C(=NH)NR a R b , -NR b S(O)2R a , -NR b S(O)NR a R b , -S(O) 1-2 R a , -S(O)NR a R b , -S(O)(=NCN)R a and -S(O)(=NR b )R a and substituted at any position with 1 to 3 substituents selected from R 4a , R 4b and R 4c are independently hydrogen, halogen, or C 1-6 Alkyl, C 1-6Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 is an alkoxy, R5, R 5a , R 5b and R 5c Each independently represents hydrogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 6-10 Aryl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 6-10 Aryl C 1-6 Alkyl, C 3-8 Cycloalkyl C 1-6 Alkyl, 3-8 membered heterocycloalkylC 1-6 Alkyl, 5-6 membered heteroarylC 1-6 Alkyl, -SR a , -OR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -C(O)N(R b ) OR a , -C(O)NR b S(O)2R a , -C(=NH)R a , -S(O) 1-2 R a , -S(O)NR a R b , -S(O)(=NCN)R a or-S(O)(=NR b )R a where C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 6-10 Aryl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 6-10 Aryl C 1-6 Alkyl, C 3-8 Cycloalkyl C 1-6 Alkyl, 3-8 membered heterocycloalkylC 1-6Alkyl or 5-6 membered heteroaryl C 1-6 Alkyl is unsubstituted or optionally substituted with halogen, cyano, nitro, -SR a , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -C(O)NR b S(O)2R a , -NR a R b , -NR b C(O)R a , -N(R b )C(O)OR a , -N(R b )C(O)NR a R b , -NR b C(=NH)R a , -NR b C(=NH)NR a R b , -NR b S(O)2R a , -NR b S(O)NR a R b , -S(O) 1-2 R a , -S(O)NR a R b , -S(O)(=NCN)R a and -S(O)(=NR b )R a and substituted at any position with 1 to 3 substituents selected from R6, R 6a , R 6b and R 6c are independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl C 1-6 Alkyl or 3-8 membered heterocycloalkylC 1-6 alkyl, wherein said C 6-10 The aryl or 5- to 10-membered heteroaryl is unsubstituted or optionally substituted with halogen, cyano, -R c , -OR c , -NR c R d , -N(CN)R c , -N(OR d )R c , -S(O) 0-2 R c , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(NH)NR c R d , -NR d C(O)R c , -NR d C(O)NR c R d , -NR d S(O)2R c and -OC(O)R c and substituted at any position with 1 to 3 substituents selected from R7, R 7a , R 7b and R 7c are independently hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl C 1-6 Alkyl or 3-8 membered heterocycloalkylC 1-6 alkyl, wherein said C 6-10 The aryl or 5- to 10-membered heteroaryl is unsubstituted or optionally substituted with halogen, cyano, -R c , -ORc , -NR c R d , -N(CN)R c , -N(OR d )R c , -S(O) 0-2 R c , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(NH)NR c R d , -NR d C(O)R c , -NR d C(O)NR c R d , -NR d S(O)2R c and -OC(O)R c and substituted at any position with 1 to 3 substituents selected from Each R a , R b , R c and R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl C 1-6 Alkyl, 3-8 membered heterocycloalkylC 1-6 Alkyl, Phenyl C 1-6 Alkyl or 5-6 membered heteroaryl C 1-6 alkyl, and the R a , R b , R c and R d is unsubstituted or optionally substituted with halogen, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl and C2-6 It is substituted at any position with 1 to 3 substituents selected from alkynyl.

[0012] All embodiments of formula (I) described below, and any combination of embodiments, are included within the scope of the structural formula of formula (I) of the present invention. In some embodiments, R1 is hydrogen or methyl.

[0013] In some embodiments, R2 is hydrogen or methyl. In some embodiments, R1 is hydrogen and R2 is methyl. In some embodiments, each R a , R b , R c and R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl C 1-6 Alkyl, 3-8 membered heterocycloalkylC 1-6 Alkyl, Phenyl C 1-6 Alkyl or 5-6 membered heteroaryl C 1-6 alkyl, and the R a , R b , R c and R d is unsubstituted or optionally substituted with halogen, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl and C 2-6 alkynyl, substituted at any position with one or more substituents selected from:

[0014] In some embodiments, Ra and R b together with the N atom to which they are commonly attached form a 3- to 8-membered heterocycloalkyl. In some embodiments, R c and R d together with the N atom to which they are commonly attached form a 3- to 8-membered heterocycloalkyl.

[0015] In some embodiments, each R a are independently hydrogen, C 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl, a is unsubstituted or optionally substituted with halogen, hydroxyl, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkyl and halogenated C 1-6 It is substituted at any position with 1 to 3 substituents selected from alkoxy.

[0016] In some embodiments, each R a are independently hydrogen or C 1-6 alkyl, 1-6 The alkyl is unsubstituted or optionally substituted with halogen, hydroxyl, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkyl and halogenated C 1-6 It is substituted at any position with 1 to 3 substituents selected from alkoxy.

[0017] In some embodiments, each R b are independently hydrogen or C 1-6 It is alkyl. In some embodiments, each R c are independently hydrogen or C 1-6 alkyl, 1-6 The alkyl is unsubstituted or optionally substituted with halogen, hydroxyl, amino, C 1-6 Alkoxy, C 1-6Alkylamino, halogenated C 1-6 Alkyl and halogenated C 1-6 It is substituted at any position with 1 to 3 substituents selected from alkoxy.

[0018] In some embodiments, each R d are independently hydrogen or C 1-6 It is alkyl. In some embodiments, R3 is C 1-6 Alkyl, phenyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl C 1-6 Alkyl, 3-8 membered heterocycloalkylC 1-6 Alkyl, 5-6 membered heteroarylC 1-6 Alkyl, -NR b S(O)2R a , -S(O) 1-2 R a , -S(O)NR a R b , -S(O)(=NCN)R a or -S(O)(=NR b )R a where C 1-6 Alkyl, phenyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl C 1-6 Alkyl or 3-8 membered heterocycloalkylC 1-6 Alkyl is unsubstituted or optionally halogen, -CN, -SR a , -OR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a R b , -NR b C(O)R a , -NR b S(O)2R a , -S(O) 1-2 R a , -S(O)NRa R b , -S(O)(=NCN)R a and -S(O)(=NR b )R a It is substituted at any position with 1 to 3 substituents selected from:

[0019] In some embodiments, R 3a , R 3b and R 3c are independently hydrogen, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl or halogenated C 1-6 It is an alkoxy. In some embodiments, R 3a , R 3b and R 3c are each independently hydrogen.

[0020] In some embodiments, R 4a , R 4b and R 4c are each independently hydrogen or C 1-6 It is alkyl. In some embodiments, R 4a , R 4b and R 4c are each independently hydrogen.

[0021] In some embodiments, R5 is C 1-6 Alkyl, phenyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl C 1-6 Alkyl, 3-8 membered heterocycloalkylC 1-6 Alkyl, 5-6 membered heteroarylC 1-6 Alkyl, -S(O) 1-2 R a , -S(O)NR a R b , -S(O)(=NCN)R a or -S(O)(=NR b )R a where C 1-6Alkyl, phenyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl C 1-6 Alkyl or 3-8 membered heterocycloalkylC 1-6 Alkyl is unsubstituted or optionally halogen, -CN, -SR a , -OR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a R b , -NR b C(O)R a , -NR b S(O)2R a , -S(O) 1-2 R e , -S(O)NR a R b , -S(O)(=NCN)R a and -S(O)(=NR b )R a It is substituted at any position with 1 to 3 substituents selected from:

[0022] In some embodiments, R 5a , R 5b and R 5c are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 3-8 It is cycloalkyl. In some embodiments, R 5a , R 5b and R 5c are each independently hydrogen.

[0023] In some embodiments, R6 and R7 are each independently a 5- to 6-membered heteroaryl, and the 5- to 6-membered heteroaryl is unsubstituted or optionally substituted with halogen, cyano, -R c , -OR c , -NR c R d , -N(CN)R c, -N(OR d )R c , -S(O) 0-2 R c , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(NH)NR c R d , -NR d C(O)R c , -NR d C(O)NR c R d , -NR d S(O)2R c and -OC(O)R c It is substituted at any position with 1 to 3 substituents selected from:

[0024] In some embodiments, R and R are each independently pyrrolyl, pyrazolyl, or isoxazolyl, and the pyrrolyl, pyrazolyl, or isoxazolyl is unsubstituted or optionally selected from halogen, cyano, -R c , -OR c , -NR c R d , -N(CN)R c , -N(OR d )R c , -S(O) 0-2 R c , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(NH)NR c R d , -NR d C(O)R c , -NR d C(O)NR c R d , -NR d S(O)2R c and -OC(O)R c It is substituted at any position with 1 to 3 substituents selected from:

[0025] In some embodiments, R6 and R7 are each independently pyrrolyl, pyrazolyl, or isoxazolyl. In some embodiments, R6 and R7 are each independently pyrazolyl.

[0026] In some embodiments, R 6a , R 6b and R 6c are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 It is alkyl. In some embodiments, R 6a , R 6b and R 6c are each independently hydrogen.

[0027] In some embodiments, R 7a , R 7b and R 7c are independently hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 It is an alkoxy.

[0028] In some embodiments, R 7a , R 7b and R 7c are each independently hydrogen. In some embodiments, X is CR, N, O, S, SO, S(O)(NH), CR, R, or NR; and X is CR. 3a , N, O, S, SO2, S(O)(NH), CR 3a R 4a or NR 5a and X2 is CR 3b , N, O, S, SO2, S(O)(NH), CR 3b R 4b or NR 5b and X3 is a connecting bond, CR 3c , N, O, S, SO2, S(O)(NH), CR 3c R 4c or NR 5cand R4 is hydrogen, halogen, or C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 It is an alkoxy.

[0029] In some embodiments, X is CR, N, O, S, CR, R, or NR; and X is CR. 3a ,N,O,S,CR 3a R 4a or NR 5a and X2 is CR 3b ,N,O,S,CR 3b R 4b or NR 5b and X3 is a connecting bond, CR 3c ,N,O,S,CR 3c R 4c or NR 5c and R4 is hydrogen, halogen, or C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 It is an alkoxy.

[0030] In some embodiments, X is NR5 and X1 is CR 3a , C.R. 3a R 4a or NR 5a and X2 is CR 3b , C.R. 3b R 4b or NR 5b and X3 is a connecting bond. In some embodiments, V is N, NR6, or CR7, and V is N, NR 6a or CR 7a and V2 is N, NR 6b or CR 7b and V3 is a ligation bond, N, NR 6c or CR 7c is.

[0031] In some embodiments, V is NR6 or CR7 and V is N or CR 7a and V2 is N or CR7b and V3 is a connecting bond, N or CR 7c is. In some embodiments, U is N.

[0032] In some embodiments, U1 and U2 are C. In some embodiments, the definitions of certain groups in the compound of formula (I), its stereoisomer, or pharmaceutically acceptable salt may be as described below, and groups not described may be as described in any of the above forms: Here, the base

[0033] [ka] is one of the following structures:

[0034] [ka]

[0035] In some embodiments, the compound represented by Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a compound represented by Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0036] [ka]

[0037] where U1 and U2 are each C, V is NR6, and V1 is N or CR 7a and V2 is N or CR 7b and Or, U1 is C, U2 is N, V ​​is CR7, and V1 is N or CR 7a and V2 is N or CR 7b and Or, U1 is N, U2 is C, V is CR7, and V1 is N or CR 7a and V2 is N or CR 7band R1, R2, U, X, X1, X2, R6, R7, R 7a and R 7b The definitions are as described above.

[0038] In some embodiments, U1 and U2 are each C, V is NR6, and V1 is N or CR 7a and V2 is N or CR 7b and U is N and R6 is pyrrolyl, pyrazolyl or isoxazolyl, wherein said pyrrolyl, pyrazolyl or isoxazolyl is unsubstituted or optionally substituted with halogen, cyano, -R c , -OR c , -NR c R d , -N(CN)R c , -N(OR d )R c , -S(O) 0-2 R c , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(NH)NR c R d , -NR d C(O)R c , -NR d C(O)NR c R d , -NR d S(O)2R c and -OC(O)R c and substituted at any position with 1 to 3 substituents selected from R 7a and R 7b are each independently hydrogen, R c and R d are each independently hydrogen or C 1-6 It is alkyl.

[0039] In some embodiments, the compound represented by Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a compound represented by Formula (IIA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0040] [ka]

[0041] where:

[0042] [ka] is a double bond or a single bond,

[0043] The definitions of X1, X2, V1, V2 and R5 are as described above. In some embodiments, X 1 and X 2 are each independently N or CH. In some embodiments, X1 and X2 are each independently CH2.

[0044] In some embodiments, V1 and V2 are each independently N or CH. In some embodiments, R5 is C 1-6 Alkyl, phenyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl C 1-6 Alkyl, 3-8 membered heterocycloalkylC 1-6 Alkyl, 5-6 membered heteroarylC 1-6 Alkyl, -S(O) 1-2 R a , -S(O)NR a R b , -S(O)(=NCN)R a or -S(O)(=NR b )R a where C 1-6 Alkyl, phenyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl C 1-6 Alkyl or 3-8 membered heterocycloalkylC 1-6Alkyl is unsubstituted or optionally halogen, -CN, -SR a , -OR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a R b , -NR b C(O)R a , -NR b S(O)2R a , -S(O) 1-2 R a , -S(O)NR a R b , -S(O)(=NCN)R a and -S(O)(=NR b )R a and substituted at any position with 1 to 3 substituents selected from Each R a are independently hydrogen or C 1-6 alkyl, 1-6 The alkyl is unsubstituted or optionally substituted with halogen, hydroxyl, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkyl and halogenated C 1-6 substituted at any position with 1 to 3 substituents selected from alkoxy; Each R b are independently hydrogen or C 1-6 It is alkyl.

[0045] In some embodiments, the compound represented by Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a compound represented by Formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0046] [ka]

[0047] wherein U1 and U2 are each independently C, V is CR7, and V1 is N or CR 7aand V2 is N or CR 7b and V3 is N or CR 7c and R1, R2, U, X, X1, X2, R7, R 7a , R 7b and R 7c The definitions are as described above.

[0048] In some embodiments, U is N and R7 is pyrrolyl, pyrazolyl, or isoxazolyl, wherein said pyrrolyl, pyrazolyl, or isoxazolyl is unsubstituted or optionally substituted with halogen, cyano, -R c , -OR c , -NR c R d , -N(CN)R c , -N(OR d )R c , -S(O) 0-2 R c , -C(O)R c , -C(O)OR c , -C(O)NR c R d , -C(NH)NR c R d , -NR d C(O)R c , -NR d C(O)NR c R d , -NR d S(O)2R c and -OC(O)R c and substituted at any position with 1 to 3 substituents selected from R 7a , R 7b and R 7c are each independently hydrogen, R c and R d are each independently hydrogen or C 1-6 It is alkyl.

[0049] In some embodiments, the compound represented by Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a compound represented by Formula (IIIA), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0050] [ka]

[0051] where:

[0052] [ka] is a double bond or a single bond,

[0053] The definitions of X1, X2, V1, V2, V3 and R5 are as described above. In some embodiments, X 1 and X 2 are each independently N or CH. In some embodiments, X1 and X2 are each independently CH2.

[0054] In some embodiments, V1, V2, and V3 are each independently N or CH. In some embodiments, V1 is N, and V2 and V3 are each independently CH. In some embodiments, R5 is C 1-6 Alkyl, phenyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl C 1-6 Alkyl, 3-8 membered heterocycloalkylC 1-6 Alkyl, 5-6 membered heteroarylC 1-6 Alkyl, -S(O) 1-2 R a , -S(O)NR a R b , -S(O)(=NCN)R a or -S(O)(=NR b )R a where C 1-6 Alkyl, phenyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-8 Cycloalkyl C 1-6Alkyl or 3-8 membered heterocycloalkylC 1-6 Alkyl is unsubstituted or optionally halogen, -CN, -SR a , -OR a , -C(O)OR a , -C(O)R a , -C(O)NR a R b , -NR a R b , -NR b C(O)R a , -NR b S(O)2R a , -S(O) 1-2 R a , -S(O)NR a R b , -S(O)(=NCN)R a and -S(O)(=NR b )R a and substituted at any position with 1 to 3 substituents selected from Each R a are independently hydrogen or C 1-6 alkyl, 1-6 The alkyl is unsubstituted or optionally substituted with halogen, hydroxyl, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkyl and halogenated C 1-6 substituted at any position with 1 to 3 substituents selected from alkoxy; Each R b are independently hydrogen or C 1-6 It is alkyl.

[0055] In some embodiments, the compound of Formula (I), a stereoisomer, or a pharmaceutically acceptable salt thereof is optionally selected from the following compounds:

[0056] [ka] TIFF0007774621000011.tif152170, or a pharmaceutically acceptable salt thereof.

[0057] The present invention also provides a method for producing a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is any one of the following methods: Method 1:

[0058] [ka]

[0059] In Method 1, the definitions of X, X1, X2, X3, R2, and R6 are as described above. Step 1: In a solvent (e.g., N,N-dimethylformamide), IV-1 is reacted with phosphorus oxychloride to obtain IV-2, or IV-1 is reacted with urotropine / trifluoroacetic acid to obtain IV-2. Step 2: In a solvent (e.g., ethanol), IV-2 is reacted with an appropriate organic hydrazine (e.g., heteroaryl hydrazine) to obtain IV-3. Step 3: In a solvent (e.g., N-methylpyrrolidone), IV-3 is ring-closed under high temperature conditions to obtain a compound represented by formula IV.

[0060] Method 2:

[0061] [ka]

[0062] In Method 2, Lev is a leaving group, preferably a halogen, more preferably chlorine or bromine. X, X1, X2, X3, V1, V2, V3, R2, and R7 are defined as above. In a solvent (e.g., 1,4-dioxane / water) under basic conditions (e.g., potassium carbonate, sodium carbonate, or cesium carbonate) in the presence of a catalyst (e.g., 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium), V-1 undergoes a coupling reaction to give a compound represented by Formula V.

[0063] Method 3:

[0064] [ka]

[0065] In Method 3, the definitions of X1, X2, V, V1, V2, V3, U, U1, U2, R2 and R5 are as described above. 1) R5 is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl C 1-6 Alkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkylC 1-6 Alkyl, substituted or unsubstituted 5-6 membered heteroaryl C 1-6 Alkyl, -S(O) 1-2 R a or -S(O)NR a R b When R5-D is a halogen atom, preferably chlorine, bromine, or iodine, VI-1 and R5-D undergo a nucleophilic substitution reaction under basic conditions to give a structure represented by formula VI.

[0066] 2) When R5 is substituted or unsubstituted phenyl or substituted or unsubstituted 5- to 6-membered heteroaryl, D is halogen (preferably chlorine or bromine). Under basic conditions (e.g., potassium carbonate or cesium carbonate) in the presence of a catalyst (e.g., methanesulfonic acid (2-dicyclohexylphosphino-2',6')-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl) palladium (II), VI-1 and R5-D undergo a coupling reaction to give a compound represented by formula VI.

[0067] 3) R5 is substituted or unsubstituted C 3-8 When D is cycloalkyl or a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, D is a boronic acid group or a boronic ester group. Under basic conditions (e.g., sodium carbonate or potassium carbonate) in the presence of a catalyst (e.g., copper acetate), VI-1 and R5-D undergo a coupling reaction to give a compound of formula VI.

[0068] In the above methods 1, 2, or 3, if an amino, hydroxyl, or carboxyl group is present in X, X1, X2, X3, V, V1, V2, V3, -R5, -R6, or -R7, the amino, hydroxyl, or carboxyl group can be protected with a protecting group to avoid any side reactions. If the amino-protecting group, hydroxyl-protecting group, or carboxyl-protecting group is present, a subsequent deprotection step is required to obtain a compound represented by formula IV, V, or VI. Any suitable amino-protecting group, such as tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz), can be used to protect the amino group. When Boc is used as the protecting group, the subsequent deprotection reaction can be carried out under standard conditions, such as p-toluenesulfonic acid / methanol, dichloromethane / trifluoroacetic acid, hydrogen chloride in an organic solution (organic solutions include, but are not limited to, ether, 1,4-dioxane, methanol, ethanol, and isopropanol), or trimethylsilyl trifluoromethanesulfonate / 2,6-dimethylpyridine / dichloromethane. The Cbz protecting group can be deprotected using a palladium-carbon / hydrogen system. Any suitable hydroxyl protecting group can be used for hydroxyl protection, for example, benzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP), (trimethylsilyl)ethoxymethyl (SEM), or organosilicon groups (including, but not limited to, tert-butyldimethylsilyl and trimethylsilyl). The subsequent deprotection reaction can be carried out under standard conditions, for example, benzyl can be deprotected using a palladium carbon / hydrogen system, MOM protecting groups can be deprotected using an organic solution system of hydrogen chloride (organic solutions include, but are not limited to, ether solution, 1,4-dioxane solution, methanol solution, ethanol solution, and isopropanol solution), THP protecting groups and SEM protecting groups can be deprotected using a trifluoroacetic acid / dichloromethane system, and organosilicon groups can be deprotected using a tetrabutylammonium fluoride / tetrahydrofuran system.The carboxyl group can be protected by forming any suitable carboxyl protecting group, such as a carboxylate group (e.g., methyl carboxylate, ethyl carboxylate), followed by deprotection under standard conditions, such as sodium hydroxide, potassium hydroxide, or lithium hydroxide in tetrahydrofuran, water, and / or methanol solvent. The deprotection is preferably carried out as the last step.

[0069] The pharmaceutically acceptable salts of the triheterocyclic derivative (I) can be synthesized by conventional chemical methods. Generally, salts can be prepared by reacting the free base or acid with a chemical equivalent or excess of an acid (inorganic or organic) or base (inorganic or organic) in a suitable solvent or solvent composition.

[0070] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises one or more of the triheterocyclic derivative (I), its stereoisomers or pharmaceutically acceptable salts.

[0071] In the pharmaceutical composition, the active ingredient may further comprise other therapeutic agents for diseases associated with abnormalities in ATR levels. In the pharmaceutical composition, the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent and / or excipient.

[0072] Depending on the purpose of treatment, the pharmaceutical composition can be in various dosage unit forms such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions), preferably liquids, suspensions, emulsions, suppositories, and injections (solutions and suspensions).

[0073] For shaping the pharmaceutical composition into the form of a tablet, any excipient known and widely used in the art can be used. Examples of suitable carriers include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; adhesives such as water, ethanol, propanol, plain syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants such as dry starch, sodium alginate, agar powder, and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene dehydrosorbitol, dodecyl Na2SO4, stearic acid monoglyceride, starch, and lactose; anti-disintegrants such as sucrose, stearic acid triglyceride, coconut oil, and hydrogenated oil; adsorption promoters such as quaternary ammonium bases and dodecyl Na2SO4; wetting agents such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as pure talc, stearates, boric acid powder, and polyethylene glycol. If necessary, conventional coating materials may be used to form sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, and multi-layered tablets.

[0074] In order to shape the pharmaceutical composition into a pill form, any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin, and talc; binders such as gum arabic powder, tragacanth gum powder, gelatin, and ethanol; and disintegrants such as agar and kelp powder.

[0075] In order to form the pharmaceutical composition into a suppository, any excipient known and widely used in the art, such as polyethylene glycol, nut oil, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides, can be used.

[0076] To prepare a pharmaceutical composition in the form of an injection, the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose, glycerin, etc.) and then made into an injection that is isotonic with blood. When preparing an injection, any carrier commonly used in the art can be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan. In addition, conventional solubilizers, buffers, analgesics, etc. can also be added.

[0077] In the present invention, the content of the composition in the pharmaceutical composition is not particularly limited and can be selected from a wide range, and is usually 5 to 95% by mass, preferably 30 to 80% by mass. In the present invention, the method of administration of the pharmaceutical composition is not particularly limited. Various dosage forms can be selected and administered depending on the patient's age, sex, other conditions and symptoms. For example, tablets, pills, solutions, suspensions, emulsions, granules, or capsules are administered orally; injections can be administered alone or mixed with an injection delivery liquid (such as a glucose solution or an amino acid solution) and then injected intravenously; and suppositories can be administered rectally.

[0078] The present invention further provides use of the triheterocyclic derivative (I), its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the manufacture of an ATR inhibitor, which can inhibit the activity or expression of ATR (including abnormal activity or overexpression of ATR).

[0079] The triheterocyclic derivative (I), its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition provided by the present invention has the effect of resisting tumor cell proliferation, promoting tumor cell apoptosis, and / or resisting tumor cell invasion. The effect of promoting tumor cell apoptosis is achieved by inhibiting ATR activity.

[0080] The present invention further provides the use of the triheterocyclic derivative (I), its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the manufacture of a medicament for treating, alleviating and / or preventing an ATR-mediated related disease.

[0081] The present invention further provides the use of said triheterocyclic derivative (I), its stereoisomer or pharmaceutically acceptable salt, or said pharmaceutical composition in the manufacture of a medicament for treating and / or alleviating cancer. The present invention further provides the use of said triheterocyclic derivative (I), its stereoisomer or pharmaceutically acceptable salt, or said pharmaceutical composition in the manufacture of a drug having an anti-proliferative effect in a mammalian body.

[0082] The present invention further provides use of the triheterocyclic derivative (I), its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the manufacture of a medicament having the effect of promoting apoptosis in a mammalian body.

[0083] The present invention also provides use of the triheterocyclic derivative (I), its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the manufacture of a drug having the effect of resisting cancer cell invasion in a mammalian body.

[0084] The present invention further provides the use of the triheterocyclic derivative (I), its stereoisomer or pharmaceutically acceptable salt, or said pharmaceutical composition in the treatment and / or alleviation of cancer, which comprises administering to a mammal a therapeutically effective amount of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt, or said pharmaceutical composition comprising the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt.

[0085] The present invention further provides a combination of said triheterocyclic derivative (I), its stereoisomer or pharmaceutically acceptable salt, or said pharmaceutical composition with one or more other types of therapeutic agents and / or methods in the treatment, alleviation and / or prevention of related diseases mediated by ATR.

[0086] In the present invention, the ATR-mediated related disease is a related disease caused by abnormalities in ATR levels, preferably a proliferative disease, more preferably cancer. In the present invention, the other therapeutic agent for the ATR-mediated related disease is preferably a therapeutic agent for treating other types of cancer.

[0087] In the present invention, the therapeutic agent for treating the other types of cancer may be in a single-dose therapeutic dosage form together with the triheterocyclic derivative (I), or may be in a sequentially administered therapeutic dosage form. In the present invention, the therapeutic agents for treating the other types of cancer include, but are not limited to, one or more of alkylating agents, topoisomerase I / II inhibitors, mitotic inhibitors, antimetabolites, hormones and hormone analogs, antitumor antibiotics, small molecule kinase inhibitors, small molecule immunomodulators, interferons, aromatase inhibitors, PARP inhibitors, antitumor vaccines, cytokines, chimeric antigen receptor T cells (CAR-T), monoclonal antibodies, and radiation therapy.

[0088] In the present invention, the alkylating agent may be selected from one or more of, but is not limited to, cisplatin, carboplatin, oxaliplatin, nedaplatin, nitrogen mustard, N-oxide-nitrogen mustard hydrochloride, cyclobutyric acid nitrogen mustard, uracil nitrogen mustard, cyclophosphamide, isocyclophosphamide, thiotepa, carboquone, triaziquone, improsulfan tosylate, mannosulfan, treosulfan, busulfan, nimustine hydrochloride, dibromomannitol, melphalan, dacarbazine, ranimustine, carmustine, lomustine, streptozotocin, temozolomide, procarbazine, ethyleneimine derivatives, methanesulfonic acid esters, nitrosoureas, and triazenes.

[0089] In the present invention, the topoisomerase I / II inhibitor may be selected from one or more of doxorubicin, daunorubicin, epirubicin, edarubicin, irinotecan, topotecan, rubitecan, belotecan, etoposide, tiniposide, adriamycin, dexrazoxane, and camptothecin, but is not limited thereto.

[0090] In the present invention, the mitotic inhibitors include, but are not limited to, one or more of paclitaxel, docetaxel, paclitaxel poliglumex, leuroxydine, vincristine, vinblastine, vindesine, vinzolidine, etoposide, teniposide, ixabepilone, larotaxel, ortataxel, tesetaxel, tocosar, and ispinesib.

[0091] In the present invention, the antimetabolite may be selected from one or more of, but is not limited to, folate antagonists, pyrimidine analogs, purine analogs, adenosine deaminase inhibitors, such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0092] In the present invention, the hormone therapy agent may be selected from one or more of, but is not limited to, fosfestrol, diethylstilbestrol, chlorothricin, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, allylestrenol, gestrinone, nomegestrol, tadenane, mepartricin, raloxifene, ormeloxifene, levormeloxifene, aminoglutethimide, testolactone, antiestrogens, LH-RH derivatives, aromatase inhibitors, antiandrogens, adrenal corticosteroids, androgen synthesis inhibitors, retinoic acid, and drugs that slow retinoic acid metabolism.

[0093] In the present invention, the antitumor antibiotics include, but are not limited to, one or more of actinomycin D, doxorubicin, daunorubicin, bleomycin, peromycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin, sirolimus, and valrubicin.

[0094] In the present invention, the small molecule kinase inhibitors include erlotinib, imatinib, apatinib, nilotinib, crizotinib, dasatinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, afatinib, axitinib, dabrafenib, dacomitinib, nintedanib, lenvatinib, masitinib, midostaurin, neratinib, These include, but are not limited to, one or more of ponatinib, radotinib, trametinib, brivanib alaninate, cediranib, cabozantinib malate, ibrutinib, icotinib, sipatinib, cobimetinib, idelalisib, ponatinib, alisertib, dinaciclib, lincitinib, orantinib, rigosertib, tipifarnib, tivozanib, pimasertib, bupalisib, and fedratinib.

[0095] In the present invention, the anti-tumor vaccine includes, but is not limited to, synthetic peptides, DNA vaccines, and recombinant viruses. In the present invention, the cytokine therapy includes, but is not limited to, IL2 and GM-CSF.

[0096] In the present invention, the monoclonal antibody includes, but is not limited to, one or more of alemtuzumab, brentuximab, cetuximab, rituximab, denosumab, ipilimumab, ofatumumab, monoclonal, panitumumab, tositumomab, trastuzumab, bevacizumab, pertuzumab, catumab, elotuzumab, epratuzumab, necituzumab, nimotuzumab, tocilizumab, matuzumab, zalutumumab, atezolizumab, ramucirumab, nivolumab, mogamulizumab, ocaratuzumab, oregovomab, dalotuzumab, and onartuzumab.

[0097] In the present invention, the small molecule immunomodulator includes, but is not limited to, one or more of a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, an IDO inhibitor, a CD73 inhibitor, a STING inhibitor, and an A2AR antagonist.

[0098] In the present invention, the interferon for cancer treatment includes, but is not limited to, interferon α, interferon α-2a, interferon α-2b, interferon β, interferon γ-1a, or interferon γ-n1.

[0099] In the present invention, the aromatase inhibitors include, but are not limited to, one or more of anastrozole, aminoglutethimide, exemestane, fadrozole, and letrozole.

[0100] In the present invention, the PARP inhibitors include, but are not limited to, one or more of olaparib, niraparib, rucaparib, veliparib, and SC10914. In the present invention, the cancer includes metastatic and non-metastatic cancers, and also includes familial and sporadic cancers, and may further include solid tumors and non-solid tumors.

[0101] In the present invention, specific examples of the solid tumor may include, but are not limited to, tumors of the eye, bone, lung, stomach, pancreas, breast, prostate, brain (including glioblastoma and medulloblastoma), ovary (including stromal cells, germ cells, and stromal cells derived from epithelial cells), bladder, testis, spinal cord, kidney (including adenocarcinoma and Wilms' tumor), mouth, lip, throat, oral cavity (including squamous cell carcinoma), nasal cavity, small intestine, colon, rectum, parathyroid gland, gallbladder, bile duct, cervix, heart, hypopharyngeal gland, bronchus, liver, ureter, vagina, anus, laryngeal gland, thyroid gland (including thyroid cancer and medullary carcinoma), esophagus, nasopharyngeal pituitary gland, salivary gland, adrenal gland, head and neck intraepithelial neoplasia (including Bowen's disease and Paget's disease), sarcoma (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma), skin (including melanoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma), and other related tumors.

[0102] In the present invention, the solid tumor is preferably one or more of human eye cancer, bone cancer, stomach cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including, but not limited to, malignant glioma and medulloblastoma), ovarian cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer (including, but not limited to, adenocarcinoma and Wilms' carcinoma), oral cancer (including squamous cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal cancer, head and neck cancer, colon cancer, small intestine cancer, rectal cancer, parathyroid cancer, thyroid cancer, esophageal cancer, gallbladder cancer, bile duct cancer, cervical cancer, liver cancer, lung cancer (including, but not limited to, small cell lung cancer and non-small cell lung cancer), choriocarcinoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, and skin cancer.

[0103] In the present invention, specific examples of the non-solid tumor (including blood tumor) may include, but are not limited to, one or more of lymphocytic leukemia (including lymphoblastic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia (T-cell chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia), Hodgkin's lymphoma, and non-Hodgkin's lymphoma), myeloid-related leukemia (including acute myeloid leukemia and chronic myeloid leukemia), and AIDS-associated leukemia.

[0104] In the present invention, the cancer is preferably one or more of non-small cell lung cancer, small cell lung cancer, gastric cancer, esophageal cancer, melanoma, colon cancer, pancreatic cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, brain cancer, bladder cancer, kidney cancer, myeloma, liver cancer, acute myeloid leukemia, chronic myeloid leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, and lymphoma.

[0105] In the present invention, the mammal is preferably a human. In the present invention, the terms "tumor" and "cancer" have the same meaning. In the present invention, unless otherwise specified, the term "substituted at any position with one or more groups" means that any one or more hydrogen atoms of one or more atoms specified on the group are replaced with the specified group, provided that the normal valence of the specified atom is not exceeded, and that all such substitutions are reasonable substitutions common in the art. For example, R a is selectively substituted with 1 to 3 groups at any position means that R a can be reasonably substituted at any position with 1, 2 or 3 identical or different substituents.

[0106] In the present invention, any combination of variables is permissible only if such combination results in a stable compound. For example, V is NR6 or CR7. V1 is N, NR 6a or CR 7a V2 is N, NR 6b or CR 7b V3 is a bond, N, NR 6c or CR 7c When V, V1, V2, and V3 include any stable combination of the following: 1) V is NR6, and V1 is N or CR 7a , V2 is N or CR 7b 2) V is CR7, V is N or CR 7a , V2 is N or CR 7b , V3 is a connecting bond. 3) V is CR7, V1 is N or CR 7a , V2 is N or CR 7b , V3 is N or CR7c 4) V is CR7, V1 is N or CR 7a , V2 is NR 6b and V3 is a linking bond; or 5) V is CR7 and V1 is NR 6a , V2 is N or CR 7b , V3 is a connecting bond.

[0107] In the present invention, when any variable occurs more than one time in any composition or structure of a compound, its definition is independent at each occurrence. In the present invention, unless otherwise specified, the cyclic group is

[0108] [ka] " means that the cyclic group is an aromatic ring or a non-aromatic ring.

[0109] [ka] " means that the cyclic group is an aromatic ring. For example, the group

[0110] [ka] is a 5- to 6-membered aromatic ring or a 5- to 6-membered non-aromatic ring, and the definitions of X, X1, X2, and X3 are as described above.

[0111] [ka] is a 5- to 6-membered aromatic ring, and the definitions of X, X1, X2, and X3 are as described above.

[0112] Unless otherwise stated, the following terms appearing in the specification and claims have the following meanings: The term "alkyl" means a saturated straight-chain or branched-chain hydrocarbon group containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Representative examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, octyl, nonyl, decyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, and the like. Examples of alkyl esters include, but are not limited to, propyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 4,4-dimethylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and the various isomers thereof.

[0113] The term "cycloalkyl" refers to a saturated or partially unsaturated (containing one or two double bonds) monocyclic or fused ring group containing 3 to 20 carbon atoms. "Monocyclic cycloalkyl" is preferably a 3- to 10-membered monocyclic alkyl, more preferably a 3- to 8- or 3- to 6-membered monocyclic alkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl, 2,3-dihydro-1-H-indene, decahydronaphthalene, etc. The cycloalkyl may be attached to the parent molecule via any carbon atom on the ring.

[0114] The term "heterocycloalkyl" refers to a saturated or partially unsaturated (containing one or two double bonds) 3- to 20-membered non-aromatic cyclic group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, and sulfur. This cyclic group may be a monocyclic or fused ring group. In the present invention, the number of heteroatoms in a heterocycloalkyl is preferably 1, 2, 3, or 4, and the nitrogen, carbon, or sulfur atom of the heterocycloalkyl may be optionally oxidized. The nitrogen atom may be optionally further substituted with another group to form a tertiary amine or a quaternary ammonium salt. The heterocycloalkyl is preferably a 3- to 10-membered monocyclic heterocycloalkyl, more preferably a 3- to 6-membered monocyclic heterocycloalkyl. Examples of the heterocycloalkyl include, but are not limited to, aziridinyl, tetrahydrofuran-2-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholin-S-oxid-4-yl, piperidin-1-yl, N-alkylpiperidin-4-yl, pyrrolidin-1-yl, N-alkylpyrrolidin-2-yl, piperazin-1-yl, 4-alkylpiperazin-1-yl, etc. The heterocycloalkyl may be bonded to the parent molecule via any ring atom on the ring. The ring atom specifically refers to the carbon atom and / or nitrogen atom constituting the ring skeleton.

[0115] The term "non-aromatic group" or "non-aromatic ring" refers to "cycloalkyl" and / or "heterocycloalkyl", which includes the definitions of cycloalkyl and / or heterocycloalkyl above. The term "cycloalkylalkyl" means that the cycloalkyl is bonded to the core structure via an alkyl. Thus, "cycloalkylalkyl" includes the definitions of alkyl and cycloalkyl above.

[0116] The term "heterocycloalkylalkyl" means that the heterocycloalkyl is bonded to the core structure via an alkyl. Thus, "heterocycloalkylalkyl" includes the definitions of alkyl and heterocycloalkyl above.

[0117] The term "alkoxy" means a cyclic or non-cyclic alkyl having the stated number of carbon atoms attached through an oxo bridge, including alkyloxy, cycloalkyloxy, and heterocycloalkyloxy. Thus, "alkoxy" includes the definitions of alkyl, heterocycloalkyl, and cycloalkyl above.

[0118] The term "alkenyl" refers to a straight-chain, branched-chain, or cyclic non-aromatic hydrocarbon group containing at least one carbon-carbon double bond. There may be 1 to 3 carbon-carbon double bonds, and preferably 1 carbon-carbon double bond. 2-4 The term "alkenyl" means an alkenyl group having 2 to 4 carbon atoms, and "C 2-6 The term "alkenyl" refers to alkenyl groups having from 2 to 6 carbon atoms, including vinyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl.

[0119] The term "alkynyl" refers to a straight, branched, or cyclic hydrocarbon group containing at least one carbon-carbon triple bond. There may be 1 to 3 carbon-carbon triple bonds, preferably 1 carbon-carbon triple bond. 2-6 The term "alkynyl" refers to alkynyl groups having from 2 to 6 carbon atoms, including ethynyl, propynyl, butynyl, and 3-methylbutynyl.

[0120] The term "aryl" refers to any stable 6- to 10-membered monocyclic or fused aromatic group, wherein at least one ring of the fused aromatic group is a benzene ring, and the remaining rings may be benzene rings, monocyclic cycloalkyl, or monocyclic heterocycloalkyl. The aryl includes, but is not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, benzo[d][1,3]dioxolyl, indolinyl, isoindolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[b]thienyl, benzopyranyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, 2,2-dioxo-1,3-dihydrobenzo[c]isothiazolyl, 1,1-dioxodihydrobenzothiopyranyl, 1,1-dioxo-2,3-dihydrobenzo[b]thiophenyl, 1-imino-1-oxo-2,3-dihydrobenzo[b]thienyl, and 2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl.

[0121] The term "heteroaryl" refers to an aromatic ring group formed by replacing at least one ring carbon atom with a heteroatom selected from nitrogen, oxygen, or sulfur, and may be a 5- to 7-membered monocyclic ring or a 7- to 12-membered fused ring structure, in which at least one ring of the fused ring structure is heteroaryl, and the remaining rings are optionally aromatic, heteroaromatic, cycloalkyl, or heterocycloalkyl. In the present invention, the number of heteroatoms is preferably 1, 2, 3, or 4, and the nitrogen atom in the heteroaryl group may be optionally oxidized. The heteroaryl is preferably a 5- to 10-membered heteroaryl, and examples thereof include pyridyl, pyrimidinyl, pyrazinyl, pyridazine-3(2H)-keto, furyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 1H-tetrazolyl, 1H-indazolyl, 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[3,4-c]pyridyl, and 1H-pyrazolo[4,3-c]pyridyl. ]pyridyl, 1H-indolyl, 1H-benzimidazolyl, 1H-benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, 1H-pyrrolo[3,2-c]pyridyl, 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridyl, 7H-pyrrolo[2,3-d]pyrimidinyl or 7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridyl.

[0122] The term "aromatic group" or "aromatic ring" refers to "aryl" and / or "heteroaryl", which include the definitions of aryl and / or heteroaryl above. The term "arylalkyl" means that the aryl is bonded to the core structure via an alkyl. Thus, "arylalkyl" includes the definitions of alkyl and aryl above.

[0123] The term "heteroarylalkyl" means that a heterocycloalkyl is bonded to a core structure via an alkyl. Thus, "heteroarylalkyl" includes the definitions of alkyl and heteroaryl above.

[0124] The term "halogen" means fluorine, chlorine, bromine or iodine. The term "haloalkyl" means an alkyl optionally substituted with a halogen. Thus, "haloalkyl" includes the definitions of halogen and alkyl above.

[0125] The term "haloalkoxy" means an alkoxy optionally substituted with a halogen. Thus, "haloalkoxy" includes the definitions of halogen and alkoxy above. The term "amino" means -NH2, and the term "alkylamino" means that at least one hydrogen atom on an amino group is replaced by alkyl, including, but not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, and -N(CH3)(CH2CH3). Thus, "alkylamino" includes the definitions of alkyl and amino above.

[0126] The term "nitro" means -NO2. The term "cyano" means -CN. The term "carboxyl" means --C(O)OH.

[0127] The symbol "=" indicates a double bond. "Room temperature" as used in the present invention means 15 to 30°C. The "pharmaceutically acceptable salts" described in the present invention are discussed in Berge, et al., "Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and it is obvious to medicinal chemists that the salts described are essentially non-toxic and can provide desired pharmacokinetic properties, palatability, absorption, distribution, metabolism, excretion, etc. The compounds described in the present invention may have an acidic group, a basic group, or an amphoteric group, and typical pharmaceutically acceptable salts include salts prepared by reacting the compounds of the present invention with an acid, such as hydrochloride, hydrobromide, sulfate, pyrosulfate, hydrogensulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, nitrate, acetate, propionate, caprate, caprylate, formate, acrylate, isobutyrate, hexaphosphate, etc. The pharmaceutically acceptable salts include acetic acid salts, heptanoic acid salts, oxalic acid salts, malonate salts, succinic acid salts, suberate salts, benzoic acid salts, methylbenzoic acid salts, phthalic acid salts, maleic acid salts, mesylate salts, p-toluenesulfonic acid salts, (D,L)-tartaric acid salts, citric acid salts, maleic acid salts, (D,L)-malic acid salts, fumaric acid salts, succinic acid salts, lactate salts, triflate salts, naphthalene-1-sulfonic acid salts, mandelate salts, pyruvate salts, stearate salts, ascorbate salts, and salicylate salts. When the compounds of the present invention contain an acidic group, pharmaceutically acceptable salts thereof may further include, but are not limited to, alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts, and organic base salts such as salts formed with ammonia, alkylammonium salts, hydroxyalkylammonium salts, amino acids (lysine, arginine), N-methylglucamine, and the like.

[0128] The term "isomer" as used herein means that the compound of formula (I) of the present invention may have asymmetric centers, racemates, racemic mixtures, and individual diastereomers. All of these isomers, including stereoisomers, geometric isomers, and atropisomers, are included in the present invention. When the compound of formula (I) or a salt thereof exists in stereoisomeric forms (e.g., containing one or more asymmetric carbon atoms), the individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the present invention. The present invention further includes mixtures of individual isomers of the compound or salt of formula (I) and isomers in which one or more chiral centers are inverted. The scope of the present invention includes mixtures of stereoisomers, as well as pure enantiomers or enantiomer- / diastereomer-enriched mixtures. The present invention includes mixtures of stereoisomers in all possible different combinations of all enantiomers and diastereomers. The present invention includes all combinations and subsets of stereoisomers of all specific groups defined above. The present invention further includes geometric isomers of the compounds of formula (I) or salts thereof, and said geometric isomers include cis-trans isomers.

[0129] The above-mentioned preferred conditions can be arbitrarily combined to obtain each preferred embodiment of the present invention, provided that this does not violate the common knowledge of the art. The reagents and raw materials used in the present invention are commercially available. [Brief explanation of the drawings]

[0130] [Figure 1] 1 shows the tumor volume change curves of Compound 2 (5 mg / kg, 10 mg / kg, 20 mg / Kg, po) and the positive control AZD6738 (20 mg / kg, po) in an OCI-LY19 human B-cell lymphoma mouse subcutaneous tumor model. DETAILED DESCRIPTION OF THE INVENTION

[0131] [Specific embodiment] The present invention will be further described through the following examples, but the present invention is not limited to the scope of the examples. In the following examples, experimental methods for which specific conditions are not described are selected according to conventional methods and conditions or product instructions.

[0132] The meanings of the abbreviations used in the examples of the present invention are as follows: The structures of all compounds of the present invention can be determined by nuclear magnetic resonance ( 1 The identity can be determined by 1 H NMR and / or mass spectrometry (MS).

[0133] 1 H NMR chemical shifts (δ) are in ppm (10 -6 ) NMR was performed on a Bruker AVANCE-400 spectrometer. Suitable solvents were deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and deuterated dimethyl sulfoxide (DMSO-d6), with tetramethylsilane (TMS) as the internal standard.

[0134] Low-resolution mass spectra (MS) were measured using a Utimate 3000 HPLC-MSQ Plus MS mass spectrometer with a Kinetex 2.6u C18 100A (50 × 4.6 mm) LCMS-02-001 ESI source. The gradient elution conditions were 95% solvent A and 5% solvent B (less than 1.5 min or more than 3 min), followed by 5% solvent A and 95% solvent B (1.5–3 min), where percentages are the volume percentages of the specified solvent relative to the total solvent volume. Solvent A: 10 mM NH4HCO3 (aq), Solvent B: acetonitrile.

[0135] The compounds and intermediates of the present invention can be purified using conventional preparative silica gel plates or quick separators, and the elution system can be EtOAc / PE or DCM / MeOH. They can also be separated using preparative HPLC.

[0136] High-performance liquid chromatography (prep-HPLC) was performed using a SHIMADZU LC-20 column with a Waters xBridge Pre C18 column, 10 μm, 19 × 260 mm. The elution gradient was alkaline: Mobile Phase B: 15–70% (v / v%), elution time: 20 min, Mobile Phase A: 10 mM NH₄HCO₃ (aq), Mobile Phase B: acetonitrile. The elution gradient was acidic: Mobile Phase B: 15–55% (v / v%), elution time: 20 min, Mobile Phase A: 0.1% trifluoroacetic acid aqueous solution, Mobile Phase B: acetonitrile. Detection wavelength: 214 nm, 254 nm, and 262 nm, Flow rate: 10.0 mL / min.

[0137] The microwave reactions described in the examples of the present invention use a microwave reactor of the Biotage® Initiator+Microwave System EU (356006) type. Unless otherwise specified in the present invention, the reactions in all examples are carried out under a nitrogen or argon atmosphere.

[0138] Thin layer silica gel plates (prep-TLC) were Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates. Quick Separator (Flash Column Chromatography) (Flash System / Cheetah TM ) was performed using an Agela Technologies MP200, and the corresponding separation column was Flash column Silica-CS (80 g), Cat No. CS140080-0.

[0139] The hydrogen atmosphere of the present invention can be achieved by: 1) connecting the reaction system to a hydrogen balloon with a capacity of approximately 1 L; 2) directly and continuously introducing hydrogen into the reaction system under normal pressure; and 3) replacing the atmosphere with hydrogen in a closed tube and then sealing it.

[0140] Unless otherwise specified in the present invention, the reactions in all examples are carried out under the protection of nitrogen or argon. Example 1: Synthesis of (R)-3-methyl-4-(1-(methylsulfonyl)-6-(1H-pyrazol-3-yl)-1,6-dihydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridin-4-yl)morpholine trifluoroacetate (Compound 1)

[0141] [ka]

[0142] Step 1: To a solution of 2,6-difluoro-4-iodopyridine (1.0 g, 4.15 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium diisopropylamide (2.0 M, 2.2 mL, 4.46 mmol) in tetrahydrofuran at -70 °C. The reaction mixture was stirred at this temperature for 30 min. Methyl formate (412 mg, 5.58 mmol) was added to the reaction mixture and stirred for 1 h. Water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate. The organic phase was separated and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 4) to give compound 1.1 (300 mg, 27% yield) as a yellow solid.

[0143] Step 2: To a solution of compound 1.1 (250 mg, 0.93 mmol) in ethanol (95%, 5 mL) was added 3-hydrazino-1H-pyrazole (91 mg, 0.93 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by slowly adding saturated aqueous sodium bicarbonate solution in an ice-water bath. The aqueous phase was extracted with ethyl acetate, and the organic phase was separated and concentrated under reduced pressure to give compound 1.2 (130 mg, 40% yield) as a yellow solid.

[0144] Step 3: A solution of compound 1.2 (130 mg, 0.37 mmol) in N-methylpyrrolidone (2 mL) was microwaved at 200 °C for 15 minutes. The reaction mixture was poured directly into water and filtered. The filter cake was dried under vacuum to give compound 1.3 (150 mg, crude product) as a yellow solid. m / z: [M+H] + 330.0.

[0145] Step 4: To a solution of compound 1.3 (80 mg, 0.24 mmol) in dimethyl sulfoxide (3 mL), (R)-3-methylmorpholine (48 mg, 0.48 mmol) was added, and the reaction mixture was stirred at 145 °C for 1 hour. The reaction mixture was then poured into water and filtered. After drying the filter cake, compound 1.4 (70 mg, 71% yield) was obtained as a yellow solid. m / z: [M+H] + 411.0.

[0146] Step 5: To a solution of compound 1.4 (130 mg, 0.32 mmol) in tetrahydrofuran (3 mL) under ice bath conditions, sodium hydride (60%, 14 mg, 0.35 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (73 mg, 0.44 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was quenched with water, and the aqueous phase was extracted with ethyl acetate. The organic phase was separated and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 3) to give compound 1.5 (90 mg, 52% yield) as a yellow oil. m / z: [M+H] + 541.3.

[0147] Step 6: To a solution of compound 1.5 (26 mg, 0.05 mmol) in 1,4-dioxane (3 mL), aminoacetaldehyde dimethyl acetal (26 mg, 0.25 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol), S-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (6 mg, 0.01 mmol), and cesium carbonate (32.5 mg, 0.1 mmol) were added sequentially. The reaction mixture was purged with nitrogen and stirred at 120 °C under a nitrogen atmosphere for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 1) to give compound 1.6 (40 mg, 78% yield) as a yellow oil. m / z: [M+H] + 518.2.

[0148] Step 7: Under ice bath conditions, boron trifluoride ethyl etherate (62 mg, 0.44 mmol) was added to a solution of compound 1.6 (150 mg, 0.29 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at 0 °C for 30 minutes. The reaction was then quenched with saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane, and the combined organic phases were concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give compound 1.7 (17 mg, 13% yield) as a yellow oil. m / z: [M+H] + 454.2.

[0149] Step 8: Under ice bath conditions, sodium hydride (60%, 2.4 mg, 0.06 mmol) was added to a solution of compound 1.7 (17 mg, 0.04 mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred at 0° C. for 30 minutes. Methanesulfonyl chloride (6.8 mg, 0.06 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure to give compound 1.8 (20 mg, crude product) as a yellow oil. m / z: [M+H] + 532.2.

[0150] Step 9: To a solution of compound 1.8 (20 mg, crude product) in dichloromethane (0.7 mL) under ice bath conditions, triethylsilane (33 mg, 0.29 mmol) and trifluoroacetic acid (0.5 mL) were added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by prep-HPLC (acidic conditions) to give compound 1 (1.16 mg, 6% yield over two steps) as a gray solid. m / z: [M+H] + 402.1; 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 7.86 (d, J = 2.4Hz, 1H), 7.56 (d, J = 3.6Hz, 1H), 7.12 (d, J = 4.0Hz, 1H), 6.86 (d, J = 2.4Hz, 1H), 4.56-4.54 (m, 1H), 3.98- 3.95 (m, 2H), 3.81-3.53 (m, 7H), 1.26 (d, J = 6.8Hz, 3H).

[0151] Example 2: Synthesis of (R)-3-methyl-4-(1-(methylsulfonyl)-6-(1H-pyrazol-3-yl)-1,2,3,6-tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridin-4-yl)morpholine trifluoroacetate (Compound 2)

[0152] [ka]

[0153] Step 1: A solution of 2,6-difluoro-4-iodopyridine (4.0 g, 16.6 mmol) and (R)-3-methylmorpholine (1.68 g, 16.6 mmol) in dimethyl sulfoxide (30 mL) was stirred at 100 °C for 5 h. After cooling to room temperature, the reaction was quenched by adding water. The aqueous phase was extracted with ethyl acetate. The combined organic phase was washed successively with water and saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 3 / 2) to give compound 2.1 (4.4 g, 82% yield) as a colorless oil. m / z: [M+H] + 323.0.

[0154] Step 2: A mixture of compound 2.1 (4.4 g, 13.6 mmol), aminoacetaldehyde dimethyl acetal (7.2 g, 68.0 mmol), tris(dibenzylideneacetone)dipalladium (576 mg, 0.68 mmol), S-(+)-1,1'-binaphthyl-2,2'-diphenylphosphine (396 mg, 0.63 mmol), cesium carbonate (5.9 g, 18.2 mmol), and 1,4-dioxane (30 mL) was purged with nitrogen three times and stirred at 100 °C under a nitrogen atmosphere for 5 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 1) to give compound 2.2 (3.0 g, 74% yield) as a yellow oil. m / z: [M+H] + 300.2.

[0155] Step 3: At -10 °C, a solution of compound 2.2 (3.0 g, 10.0 mmol) in dichloromethane (10 mL) was added to a suspension of aluminum trichloride (5.3 g, 40.0 mmol) in dichloromethane (40 mL) and stirred at -10 °C for 20 min. Water was added to quench the reaction, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 3) to give compound 2.3 (1.56 g, 66% yield) as a yellow solid. m / z: [M+H] + 236.2.

[0156] Step 4: To a solution of compound 2.3 (2.8 g, 11.8 mmol) in acetic acid (25 mL) was added sodium cyanoborohydride (1.49 g, 23.7 mmol). The resulting mixture was stirred at room temperature for 9 hours. The reaction mixture was slowly poured into saturated aqueous sodium bicarbonate, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 4) to give compound 2.4 (1.65 g, 59% yield) as a yellow oil. m / z: [M+H] +238.2.

[0157] Step 5: To a solution of compound 2.4 (1.6 g, 6.72 mmol) in pyridine (5.0 mL) was added methanesulfonyl chloride (1.0 mL) under ice bath conditions, and the reaction mixture was stirred at 0 °C for 1 h. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 2) to give compound 2.5 (1.7 g, 80% yield) as a yellow oil. m / z: [M+H] + 316.2.

[0158] Step 6: To a solution of compound 2.5 (1.86 g, 5.9 mmol) in trifluoroacetic acid (20 mL), urotropine (3.3 g, 23.5 mmol) was added, and the mixture was stirred at 70 °C for 1 h. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 2) to give compound 2.6 (0.24 g, 12% yield) as a yellow solid. m / z: [M+H] + 344.2.

[0159] Step 7: To a solution of compound 2.6 (0.24 g, 0.7 mmol) in ethanol (95%, 5 mL) was added 3-hydrazino-1H-pyrazole (0.34 g, 3.49 mmol), and the reaction mixture was stirred at room temperature for 20 minutes. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 2.7 (0.3 g, crude product) as a yellow solid. m / z: [M+H] + 424.2.

[0160] Step 8: A solution of compound 2.7 (0.3 g, crude product) in N-methylpyrrolidone (4 mL) was microwave-activated at 180 °C for 20 minutes. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (acidic conditions) to give compound 2 (136 mg, 38% yield over two steps) as a yellow solid. m / z: [M+H] + 404.2; 1 H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H), 7.84 (d, J = 4.0Hz, 1H), 6.83 (d, J = 4.0Hz, 1H), 4.20-4.02 (m, 3H), 3.94-3.88 (m, 1H), 3.76-3.66 (m, 3H), 3.41-3.28 (m, 2H), 3.24-3.10 (m, 5H), 1.18 (d, J = 8.0Hz, 3H).

[0161] Example 3: Synthesis of (R)—N,N-dimethyl-4-(3-methylmorpholine)-6-(1H-pyrazol-3-yl)pyrazolo[3,4-b]pyrrolo[2,3-d]pyridine-1(6H)-sulfonamide trifluoroacetate (Compound 3)

[0162] [ka]

[0163] Using the synthesis method for compound 1, and substituting dimethylaminosulfonyl chloride for methanesulfonyl chloride in step 8, compound 3 was obtained as an off-white solid. m / z: [M+H] + 431.2; 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 7.81 (s, 1H), 7.60-7.56 (m, 1H), 7.04-7.02(m, 2H), 4.65 (m, 1H), 4.05-4.03 (m, 2H), 3.95-3.91 (m, 1H), 3.81-3.78 (m, 4H), 2.89 (s, 6H), 1.41 (d, J = 6.4Hz, 3H).

[0164] Example 4: Synthesis of (R)—N,N-dimethyl-4-(3-methylmorpholine)-6-(1H-pyrazol-3-yl)-2,3-dihydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridine-1(6H)-sulfonamide trifluoroacetate (Compound 4)

[0165] [ka]

[0166] Step 1: Sodium hydride (136 mg, 3.4 mmol) was added to a solution of compound 2.3 (0.4 g, 1.7 mmol) in tetrahydrofuran (2 mL) under ice-bath conditions, and the reaction mixture was stirred at 0 °C for 1 h. Next, dimethylaminosulfonyl chloride (0.4 g, 3.4 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 1) to give compound 4.1 (0.45 g, 77% yield) as a yellow oil. m / z: [M+H] + 343.2.

[0167] Step 2: Compound 4.1 (0.45 g, 1.3 mmol) was added to borane-tetrahydrofuran complex (5 mL, 5.0 mmol), and the mixture was stirred at 80 °C for 1 h. After cooling to room temperature, methanol (5 mL) was added, and the reaction mixture was then refluxed and stirred for 48 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 2 / 1) to give compound 4.2 (0.1 g, 22% yield) as a yellow solid. m / z: [M+H] + 345.2.

[0168] Step 3: Under ice bath conditions, phosphorus oxychloride (0.5 mL) was slowly added dropwise to N,N-dimethylformamide (2.0 mL), and the reaction mixture was stirred for 30 minutes. Compound 4.2 (80 mg, 0.23 mmol) was then added to the reaction mixture, and the reaction mixture was stirred at 80 °C for 2 hours. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 4.3 (39 mg, 44% yield) as a yellow solid. m / z: [M+H] + 373.2.

[0169] Step 4: To a solution of compound 4.3 (38 mg, 0.1 mmol) in ethanol (95%, 3 mL) was added 3-hydrazino-1H-pyrazole (50 mg, 0.51 mmol), and the reaction mixture was stirred at room temperature for 20 minutes. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 4.4 (38 mg, crude product) as a yellow solid. m / z: [M+H] + 453.2.

[0170] Step 5: A solution of compound 4.4 (38 mg, crude product) in N-methylpyrrolidone (2 mL) was microwave-activated at 180° C. for 20 minutes. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (acidic conditions) to give compound 4 (5.2 mg, 9% yield over two steps) as a pale yellow solid. m / z: [M+H] + 433.2; 1 H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.69 (s, 1H), 6.89 (s, 1H), 4.25-3.97 (m, 4H), 3.75-3.55 (m, 5H), 3.32-3.12 (m, 2H), 2.96 (s, 6H), 1.26 (d, J = 8.0Hz, 3H).

[0171] Example 5: Synthesis of (R)-4-(3-methylmorpholine)-6-(1H-pyrazol-3-yl)-2,3-dihydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridine-1(6H)-sulfonamide (Compound 5)

[0172] [ka]

[0173] Step 1: To a solution of compound 2.4 (238 mg, 1.0 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (80 mg, 2.0 mmol) under ice-bath conditions. The reaction mixture was stirred at this temperature for 0.5 h. Benzyl chloroformate (340 mg, 2.0 mmol) was then added and the mixture was stirred at room temperature overnight. Water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 2) to give compound 5.1 (250 mg, 67% yield) as a yellow solid. m / z: [M+H] + 372.2.

[0174] Step 2: Compound 5.1 (150 mg, 0.4 mmol) in N,N-dimethylformamide (2 mL) was slowly added dropwise with phosphorus oxychloride (0.5 mL), and the reaction mixture was stirred at 80 °C overnight. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 2) to give compound 5.2 (100 mg, 63% yield) as a yellow oil. m / z: [M+H] + 400.2.

[0175] Step 3: To a solution of compound 5.2 (100 mg, 0.25 mmol) in dichloromethane (1 mL) and ethanol (1 mL) was added 3-hydrazino-1H-pyrazole (75 mg, 0.75 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 5.3 (167 mg, crude product) as a yellow solid. m / z: [M+H] + 480.2.

[0176] Step 4: A solution of compound 5.3 (167 mg, crude product) in N-methylpyrrolidone (3 mL) was microwave-activated at 180 °C for 2 hours. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol / dichloromethane = 0 to 3 / 100) to give compound 5.4 (60 mg, 52% yield over two steps) as a yellow oil. m / z: [M+H] + 460.2.

[0177] Step 5: To a solution of compound 5.4 (60 mg, 0.13 mmol) in dichloromethane (10 mL), N,N-diisopropylethylamine (52 mg, 0.4 mmol), (Boc)2O (44 mg, 0.2 mmol), and 4-dimethylaminopyridine (3 mg) were added. The reaction mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 2) to give compound 5.5 (40 mg, 55% yield) as a yellow solid. m / z: [M+H] + 560.2.

[0178] Step 6: To a solution of compound 5.5 (40 mg, 0.07 mmol) in methanol (4 mL), Pd / C (10%, 40 mg) was added, and the reaction mixture was purged with hydrogen and stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 5.6 (30 mg, 100% yield) as a yellow solid. m / z: [M+H] + 426.2.

[0179] Step 7: To a solution of compound 5.6 (60 mg, 0.14 mmol) in pyridine (10 mL), N-(tert-butoxycarbonyl)sulfonyl chloride (27 mg, 0.12 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 5.7 (20 mg, 24% yield) as a yellow oil. m / z: [M+H] + 605.2.

[0180] Step 8: To a solution of compound 5.7 (20 mg, 0.03 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was purified by prep-HPLC (basic conditions) to give compound 5 (2 mg, yield: 16%) as a gray solid. m / z: [M+H] + 405.2; 1H NMR (400 MHz, DMSO-d6): δ 13.18-12.44 (br. s, 1H), 8.28 (s, 1H), 7.82 (d, J = 2.4Hz, 1H), 6.82 (d, J = 2.4Hz, 1H), 4.10-3.85 (m, 5H), 3.74-3.70 (m, 1H), 3.63-3.54 (m, 4H), 3.22-3.07 (m, 3H), 1.15 (d, J = 6.4Hz, 3H).

[0181] Example 6: Synthesis of (R)-4-(6-(1H-pyrazol-3-yl)-1-((trifluoromethyl)sulfonyl)-1,2,3,6-tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridin-4-yl)-3-methylmorpholine trifluoroacetic acid (Compound 6)

[0182] [ka]

[0183] Step 1: To a solution of compound 5.4 (0.54 g, 1.17 mmol) in tetrahydrofuran (6 mL) was added sodium hydride (94 mg, 2.35 mmol) under ice-bath conditions. The reaction mixture was stirred at 0 °C for 0.5 h. 2-(trimethylsilyl)ethoxymethyl chloride (0.39 g, 2.35 mmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 0.5 h. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 1) to give compound 6.1 (360 mg, 52% yield) as a yellow solid. m / z: [M+H] + 590.2.

[0184] Step 2: To a solution of compound 6.1 (360 mg, 0.61 mmol) in methanol (5 mL), Pd / C (10%, 120 mg) was added, and the reaction mixture was purged with hydrogen and stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 6.2 (280 mg, 100% yield) as a yellow oil. m / z: [M+H] + 456.2.

[0185] Step 3: To a solution of compound 6.2 (34 mg, 0.08 mmol) in pyridine (2 mL), trifluoromethanesulfonyl chloride (25.2 mg, 0.15 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 6.3 (55 mg, crude product) as a yellow oil. m / z: [M+H] + 588.2.

[0186] Step 4: To a solution of compound 6.3 (55 mg, crude product) in trifluoroacetic acid (1 mL) and dichloromethane (1 mL), triethylsilane (73.1 mg, 0.63 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. The residue was purified by prep-HPLC (acidic conditions) to give compound 6 (12 mg, 26% yield over two steps) as a pale yellow solid. m / z: [M+H] + 458.2; 1 H NMR (400 MHz, DMSO-d6): δ 12.97 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 6.85 (s, 1H), 4.50-4.32 (m, 2H), 4.24-4.18 (m, 1H), 4.02-3.86 (m, 1H), 3.76-3.52 (m, 7H), 1.34 (d, J = 8.0Hz, 3H).

[0187] Example 7: Synthesis of (R)-4-(3-methylmorpholinyl)-1-(methylsulfonyl)-6-(1H-pyrazol-3-yl)-1,2,3,6-tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridine-8-carbonitrile (Compound 7)

[0188] [ka]

[0189] Step 1: A mixture of compound 2.6 (0.51 g, 1.48 mmol), hydrazine hydrate (3 mL), and ethylene glycol dimethyl ether (5 mL) was stirred at room temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 3 / 2) to give compound 7.1 (270 mg, 54% yield) as a yellow solid. m / z: [M+H] + 338.2.

[0190] Step 2: Under nitrogen protection, N-iodosuccinimide (0.27 g, 1.2 mmol) was added to a solution of compound 7.1 (0.27 g, 0.8 mmol) in N,N-dimethylformamide (2.5 mL). The reaction mixture was stirred at 40 °C for 16 h. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 2 / 1) to give compound 7.2 (120 mg, 32% yield) as a yellow solid. m / z: [M+H] + 464.2.

[0191] Step 3: A mixture of compound 7.2 (100 mg, 0.22 mmol), 3-fluoro-N,N-dimethyl-1H-pyrazole-1-sulfonamide (84 mg, 0.44 mmol), cesium carbonate (215 mg, 0.66 mmol), and N,N-dimethylformamide (5 mL) was stirred at 100 °C for 10 h. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 3 / 2) to give compound 7.3 (30 mg, 21% yield) as a yellow solid. m / z: [M+H] + 637.2.

[0192] Step 4: Under nitrogen protection, a mixture of compound 7.3 (30 mg, 47 μmol), zinc powder (1.6 mg, 24 μmol), zinc cyanide (16.5 mg, 0.14 mmol), cuprous iodide (9 mg, 47 μmol), and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 0.01 mmol) in N,N-dimethylformamide (2.5 mL) was purged with nitrogen and microwave-induced cleavage at 120 °C for 5 h. After cooling to room temperature, the reaction was quenched by the addition of water. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 3 / 2) to give compound 7.4 (15 mg, 60% yield) as a yellow oil. m / z: [M+H] + 536.2.

[0193] Step 5: A solution of compound 7.4 (15 mg, 28 μmol) in a mixture of trifluoroacetic acid (0.2 mL) and dichloromethane (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (basic conditions) to give compound 7 (1.55 mg, 13% yield) as a pale yellow solid. m / z: [M+H] + 429.2.

[0194] Example 8: Synthesis of (R)-3-methyl-4-(1-(methylsulfonyl)-6-(1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c][1,7]naphthyridin-4-yl)morpholine (Compound 8)

[0195] [ka]

[0196] Step 1: To a solution of (R)-8-chloro-2-(3-methylmorpholinyl)-1,7-naphthyridin-4-ol (6 g, 21.4 mmol) in dichloromethane (200 mL), N,N-diisopropylethylamine (5.5 g, 42.8 mmol) and N-phenylbis(trifluoromethanesulfonimide) (9.2 g, 25.7 mmol) were added. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 2 / 3) to give compound 8.1 (8 g, 91% yield) as a yellow solid. m / z: [M+H] + 412.2.

[0197] Step 2: To a solution of compound 8.1 (3.6 g, 8.6 mmol) in 1,4-dioxane (100 mL), 2,2-dimethoxyethylamine (1.2 g, 10.3 mmol), tris(dibenzylideneindeneacetone)dipalladium (394 mg, 0.43 mmol), Xantphos (249 mg, 0.43 mmol), and potassium phosphate (3.6 g, 17.2 mmol) were added. The reaction mixture was purged with nitrogen three times and then stirred at 110 °C under nitrogen protection for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 2 / 3) to give compound 8.2 (2.2 g, 70% yield) as a yellow solid. m / z: [M+H] + 367.2.

[0198] Step 3: To a solution of compound 8.2 (2.1 g, 5.7 mmol) in acetonitrile (30 mL) was added boron trifluoride ethyl etherate (2 g, 14.2 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate, the aqueous phase was extracted with dichloromethane, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 7 / 10) to give compound 8.3 (1 g, 58% yield) as a yellow solid. m / z: [M+H] + 303.2.

[0199] Step 4: To a solution of compound 8.3 (100 mg, 0.3 mmol) in tetrahydrofuran (3 mL) was added sodium hydride (36 mg, 0.9 mmol) under ice-bath conditions, and the reaction mixture was stirred at 0 °C for 0.5 h. Next, 2-(trimethylsilyl)ethoxymethyl chloride (140 mg, 0.9 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was then quenched with saturated aqueous sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 2 / 3) to give compound 8.4 (120 mg, 92% yield) as a yellow solid. m / z: [M+H] + 433.2.

[0200] Step 5: To a solution of compound 8.4 (100 mg, 0.24 mmol) in 1,4-dioxane (4 mL) and water (1 mL), 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinacol ester (68 mg, 0.34 mmol), 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16 mg, 0.02 mmol), and cesium carbonate (79 mg, 0.24 mmol) were added sequentially. The reaction mixture was purged with nitrogen and then microwave-activated at 120 °C for 0.5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol / dichloromethane = 0 to 3 / 100) to give compound 8.5 (60 mg, 46% yield) as a yellow oil. m / z: [M+H] + 549.2.

[0201] Step 6: To a solution of compound 8.5 (60 mg, 0.1 mmol) in tetrahydrofuran (2 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 0.8 mL), and the reaction mixture was stirred at 50 °C for 6 hours. Water was added to quench the reaction, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane / methanol = 0 to 3 / 100) to give compound 8.6 (40 mg, 95% yield) as a yellow oil. m / z: [M+H] + 419.2.

[0202] Step 7: In an ice-water bath, sodium hydride (12 mg, 0.3 mmol) was added to a solution of compound 8.6 (40 mg, 0.1 mmol) in tetrahydrofuran (6 mL), and the reaction mixture was stirred at 0 °C for 0.5 hours. Methanesulfonyl chloride (34 mg, 0.3 mmol) was then added, and the reaction mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to quench the reaction, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 8.7 (30 mg, 60% yield) as a yellow oil. m / z: [M+H] + 497.2.

[0203] Step 8: To a solution of compound 8.7 (30 mg, 0.06 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After stirring the reaction mixture at room temperature for 1 hour, the reaction was quenched with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (basic conditions) to give compound 8 (17 mg, yield: 68%) as a yellow solid. m / z: [M+H] + 413.2; 1 H NMR (400 MHz, DMSO-d6): δ 13.41 (s, 1H), 8.56-8.51 (m, 2H), 7.96 (d, J = 3.6Hz, 1H), 7.63 (s, 1H), 7.41 (s, 1H), 7.21 (d, J = 3.6Hz, 1H), 4.63-4.55 (m, 1H), 4.06-4.03 (m, 1H), 3.95-3.86 (m, 2H), 3.81 (s, 3H), 3.76 -3.62 (m, 3H), 1.27 (d, J = 6.8Hz, 3H).

[0204] Example 9: Synthesis of (R)-3-methyl-4-(1-(methylsulfonyl)-7-(1H-pyrazol-3-yl)-2,3,4,7-tetrahydro-1H-pyrazolo[3,4-h][1,6]naphthyridin-5-yl)morpholine trifluoroacetate (Compound 9)

[0205] [ka]

[0206] Step 1: To a solution of 5,7-dichloro-1,6-naphthyridine (4.4 g, 22.1 mmol) in dimethyl sulfoxide (73 mL), N,N-diisopropylethylamine (8.57 g, 66.3 mmol) and (R)-3-methylmorpholine (2.46 g, 24.3 mmol) were added, and the reaction mixture was stirred at 110 °C overnight. The reaction mixture was then cooled to room temperature and quenched with ice water. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0-1 / 1) to give compound 9.1 (5.1 g, 87% yield) as a yellow solid. m / z: [M+H] + 264.2.

[0207] Step 2: Compound 9.1 (1.5 g, 5.69 mmol), dimethyl sulfoxide (20 mL), and cesium fluoride (1.73 g, 11.4 mmol) were added sequentially to a closed tube, and the reaction mixture was stirred at 145 °C for 3 days. The reaction mixture was then cooled to room temperature and quenched with ice water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 1) to give compound 9.2 (0.9 g, 64% yield) as a yellow solid. m / z: [M+H] + 248.2.

[0208] Step 3: To a solution of compound 9.2 (0.85 g, 3.44 mmol) in methanol (50 mL) was added palladium on carbon (10%, 0.85 g). The reaction mixture was purged with hydrogen and stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was then filtered through diatomaceous earth, the filter cake was washed with methanol, and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 1) to give compound 9.3 (0.64 g, 74% yield) as a colorless oil. m / z: [M+H] + 252.2.

[0209] Step 4: To a solution of compound 9.3 (0.53 g, 2.11 mmol) in anhydrous pyridine (7 mL) was added methanesulfonyl chloride (2.8 mL) under ice-bath conditions. The reaction mixture was stirred in a closed tube at 40 °C for 2 hours and then concentrated under reduced pressure. The residue was poured into water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 1) to give compound 9.4 (0.33 g, 48% yield) as a yellow oil. m / z: [M+H] + 330.2.

[0210] Step 5: Under nitrogen protection, phosphorus oxychloride (0.38 g, 2.5 mmol) was added dropwise to a solution of compound 9.4 (0.33 g, 1 mmol) in N,N-dimethylformamide (5 mL). The reaction was stirred at 80 °C for 4 h. Water was then added to quench the reaction and the mixture was stirred for 1 h. The aqueous phase was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0-2 / 1) to give compound 9.5 (221 mg, 62% yield) as a yellow solid. m / z: [M+H] + 358.2.

[0211] Step 6: To a solution of compound 9.5 (0.25 g, 0.7 mmol) in ethanol (95%, 5 mL) was added 3-hydrazino-1H-pyrazole (0.27 g, 2.8 mmol), and the reaction mixture was stirred at room temperature for 20 min. The reaction mixture was then concentrated under reduced pressure. Water (5 mL) was added to the residue, and the aqueous phase was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 9.6 (0.3 g, 98% yield) as a yellow solid. m / z: [M+H] + 438.2.

[0212] Step 7: Compound 9.6 (0.3 g, 0.69 mmol) was dissolved in N-methylpyrrolidone (3 mL). The reaction mixture was purged with nitrogen three times and then microwaved at 180 °C for 20 minutes. The reaction mixture was then cooled to room temperature and quenched by adding water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated under reduced pressure. The residue was purified by prep-HPLC (acidic conditions) to give compound 9 (103 mg, 28% yield) as an off-white solid. m / z: [M+H] + 418.2; 1 H NMR (400 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.86 (d, J = 2.4Hz, 1H), 6.81 (d, J = 2.4Hz, 1H), 3.84-3.70 (m, 6H), 3.68-3.62 (m, 1H), 3.49-3.42 (m, 1H), 3.34-3.27 (m, 1H), 3.26 (s, 3H), 3.03-2.93 (m, 1H), 2.88-2.77 (m, 1H), 2.71-2.61 (m, 1H), 2.12-2.00 (m, 1H), 1.88-1.75 (m, 1H), 1.02 (d, J = 6.4Hz, 3H).

[0213] Example 10: Synthesis of (R)-3-methyl-4-(9-(methylsulfonyl)-3-(1H-pyrazol-3-yl)-3H-pyrazolo[3,4-c]isoquinolin-5-yl)morpholine trifluoroacetate (Compound 10)

[0214] [ka]

[0215] Step 1: To a solution of 1,3-dichloroisoquinoline (10 g, 50.5 mmol) in acetonitrile (250 mL), concentrated sulfuric acid (10 mL) and N-bromosuccinimide (10.8 g, 60.6 mmol) were added, and the reaction mixture was stirred at room temperature for 3 days. After filtration, the filter cake was dried under vacuum to give compound 10.1 (7.4 g, 53% yield) as a white solid. m / z: [M+H]+ 275.8.

[0216] Step 2: To a solution of compound 10.1 (6.39 g, 23.1 mmol) in dimethyl sulfoxide (96 mL), N,N-diisopropylethylamine (8.95 g, 69.2 mmol) and (R)-3-methylmorpholine (3.27 g, 32.3 mmol) were added, and the reaction mixture was stirred at 110 °C overnight. The reaction mixture was then cooled to room temperature and quenched with ice water. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 10.2 (6.13 g, 78% yield) as a yellow solid. m / z: [M+H] + 341.0.

[0217] Step 3: To a solution of compound 10.2 (3 g, 8.78 mmol) in dimethyl sulfoxide (75 mL), sodium methanesulfinate (3.59 g, 35.1 mmol) and cuprous iodide (6.69 g, 35.1 mmol) were added, and the reaction mixture was stirred at 120 °C for 6 h under nitrogen protection. The reaction mixture was then cooled to room temperature and poured into saturated aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give compound 10.3 (1.8 g, 60% yield) as a yellow solid. m / z: [M+H] + 341.0.

[0218] Step 4: Compound 10.3 (1.8 g, 5.29 mmol), dimethyl sulfoxide (25 mL), and cesium fluoride (2.41 g, 15.9 mmol) were added sequentially to a closed tube, and the reaction mixture was stirred at 150 °C for 5 h. The reaction mixture was then cooled to room temperature and quenched with ice water. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 0 to 1 / 2) to give compound 10.4 (1.03 g, 60% yield) as a yellow solid. m / z: [M+H] + 325.0.

[0219] Step 5: A solution of phosphorus oxychloride (0.5 mL) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 10 minutes. Compound 10.4 (100 mg, 0.31 mmol) was then added to the above reaction solution. The reaction mixture was stirred at 80 °C for 3 hours, cooled to room temperature, and poured into ice water (20 mL) and stirred for 1 hour. Ethyl acetate (10 mL) was added and the pH was adjusted to 8 with saturated aqueous sodium carbonate. 3-Hydrazino-1H-pyrazole (100 mg, 1.02 mmol) was added. The resulting mixture was stirred overnight at room temperature, then water (10 mL) was added. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (dichloromethane / methanol = 10 / 1) to give compound 10.5 (70 mg, yield: 52%) as a yellow oil. m / z: [M+H] + 433.2.

[0220] Step 6: A solution of compound 10.5 (70 mg, 0.16 mmol) in N-methylpyrrolidone (2.1 mL) was microwaved in a closed tube at 180 °C for 20 minutes. The reaction mixture was cooled to room temperature, and water (10 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (acidic conditions) to give compound 10 (10 mg, yield: 15%) as a yellow solid. m / z: [M+H] +413.2; 1 H NMR (400 MHz, CDCl3) δ 9.05-9.07 (m, 1H), 8.61-8.68 (m, 2H), 7.76-7.78 (m, 1H), 7.67-7.71 (m, 1H), 7.10- 7.12 (m, 1H), 4.05- 4.08 (m, 3H), 3.91-3.95 (m, 1H), 3.68-3.72 (m, 2H), 3.35-3.38 (m, 1H), 3.31 (s, 3H), 1.22-1.24 (m, 3H).

[0221] Example 11: Synthesis of (R)-4-(1-cyclopropyl-6-(1H-pyrazol-3-yl)-1,2,3,6-tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridin-4-yl)-3-methylmorpholine (Compound 11)

[0222] [ka]

[0223] Step 1: Under nitrogen protection, to a solution of compound 2.4 (250 mg, 1.05 mmol) in acetonitrile (6 mL), cyclopropylboronic acid (180 mg, 2.1 mmol), copper acetate (191 mg, 1.05 mmol), and sodium carbonate (223 mg, 2.1 mmol) were added sequentially. The reaction mixture was stirred at 70 °C for 5 h. After cooling to room temperature, water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 2) to give compound 11.1 (220 mg, 75% yield) as a pale yellow solid. m / z: [M+H] + 278.2.

[0224] Step 2: Under nitrogen protection, a solution of compound 11.1 (220 mg, 0.8 mmol) in N,N-dimethylformamide (4 mL) was added with phosphorus oxychloride (0.3 g, 2.01 mmol). The reaction mixture was stirred at 80 °C for 4 h. After cooling to room temperature, ice water was added to quench the reaction, and stirring was continued for 2 h. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 1) to give compound 11.2 (230 mg, 94% yield) as a pale yellow solid. m / z: [M+H] + 306.2.

[0225] Step 3: To a solution of compound 11.2 (0.15 g, 0.49 mmol) in ethanol (95%, 6 mL) was added 3-hydrazino-1H-pyrazole (0.2 g, 2.0 mmol), and the reaction mixture was stirred at room temperature for 0.5 h. Water was added to quench the reaction, and the aqueous phase was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 11.3 (0.18 g, crude product) as a yellow solid.

[0226] Step 4: A solution of compound 11.3 (0.18 g, crude product) in N-methylpyrrolidone (3 mL) was purged with nitrogen three times and then microwaved at 180 °C for 1 hour. The reaction mixture was then cooled to room temperature, and water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure. The residue was purified by prep-HPLC (basic conditions) to give compound 11 (22.3 mg, 12% yield) as a pale yellow solid. m / z: [M+H] + 366.2; 1H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 7.60 (d, J = 4.0Hz, 1H), 6.71 (s, 1H), 4.20-3.98 (m, 2H), 3.80-3.76 (m, 1H), 3.70-3.48 (m, 6H), 3.16-2.98 (m, 2H), 2.68-2.60 (m, 1H), 1.34 (d, J = 8.0Hz, 3H), 0.92-0.80 (m, 4H).

[0227] Example 12: Synthesis of (R)-3-methyl-4-(1-methyl-6-(1H-pyrazol-3-yl)-tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridin-4-yl)morpholine (Compound 12)

[0228] [ka]

[0229] Step 1: To a solution of compound 2.4 (200 mg, 0.84 mmol) in tetrahydrofuran (3 mL) was added sodium hydride (67.4 mg, 1.7 mmol) under ice-bath conditions. The reaction mixture was stirred at 0 °C for 0.5 h, followed by the addition of iodomethane (470 mg, 3.4 mmol). The reaction mixture was stirred at room temperature for 0.5 h, followed by the addition of water to quench the reaction. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 1 / 2) to give compound 12.1 (170 mg, 81% yield) as a pale yellow solid. m / z: [M+H] + 252.2.

[0230] Steps 2-4: Compound 12 was obtained as a pale yellow solid from compound 12.1 by following the synthesis method of steps 2-4 of compound 11. m / z: [M+H] + 340.2; 1H NMR (400 MHz, CDCl3): δ 8.02 (s, 1H), 7.60 (d, J = 4.0Hz, 1H), 6.72 (s, 1H), 4.14-3.98 (m, 2H), 3.80-3.76 (m, 1H), 3.70-3.48 (m, 6H), 3.16-2.98 (m, 5H), 1.34 (d, J = 8.0Hz, 3H).

[0231] Example 13: Synthesis of (R)-4-(6-(1H-pyrazol-3-yl)-1-(pyridin-3-yl)-1,2,3,6-tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridin-4-yl)-3-methylmorpholine trifluoroacetate (Compound 13)

[0232] [ka]

[0233] Step 1: To a solution of compound 2.4 (300 mg, 1.26 mmol) in 1,4-dioxane (5 mL), 3-iodopyridine (310 mg, 1.51 mmol), (2-bicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (158 mg, 0.19 mmol), and cesium carbonate (820 mg, 2.52 mmol) were added sequentially. The reaction mixture was purged with nitrogen three times and then stirred at 110 °C under a nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0 to 2 / 3) to give compound 13.1 (190 mg, 48% yield) as a yellow solid. m / z: [M+H] + 314.8.

[0234] Steps 2-4: Compound 13 was obtained as a pale yellow solid from compound 13.1 by following the synthesis method of steps 2-4 of compound 11. m / z: [M+H] + 402.8; 1H NMR (400 MHz, DMSO-d6): δ 8.81 (d, J = 2.4Hz, 1H), 8.58-8.54 (m, 1H), 8.10-8.05 (m, 1H), 7.92-7.88 (m, 1H), 7.78-7.72 (m, 1H), 7.51 (s, 1H), 6.91 (d, J = 2.4Hz, 1H), 4.35-4.15 (m, 4H), 4.01-3.94 (m, 1H), 3.82-3.78 (m, 2H), 3.74-3.63 (m, 4H), 1.26 (d, J = 6.4Hz, 3H).

[0235] Example 14: Synthesis of (R)-2-(4-(3-methylmorpholinyl)-6-(1H-pyrazol-3-yl)-2,3-dihydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridin-1(6H)-yl)ethanol trifluoroacetate (Compound 14)

[0236] [ka]

[0237] Step 1: To a solution of compound 5.4 (0.20 g, 0.44 mmol) in dichloromethane (2 mL), triethylamine (66 mg, 0.65 mmol), (Boc)2O (95.2 mg, 0.44 mmol), and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 2 h. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1 / 2) to give compound 14.1 (150 mg, 61% yield) as a yellow solid.

[0238] Step 2: Compound 14.1 (400 mg, 0.94 mmol) in methanol (5 mL) was added to 10% Pd / C (120 mg), and the mixture was stirred under hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 14.2 (300 mg, 71% yield) as a pale yellow foamy solid.

[0239] Step 3: To a solution of compound 14.2 (300 mg, 0.71 mmol) in tetrahydrofuran (3 mL), sodium hydride (56.4 mg, 1.4 mmol, 60%) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. 2-(2-Bromoethoxy)tetrahydro-2H-pyran (295 mg, 1.4 mmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 6 hours. Water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 14.3 (200 mg, 51% yield) as a yellow oil.

[0240] Step 4: A solution of compound 14.3 (50 mg, 0.09 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (2 mL) was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The residue was purified by prep-HPLC (acidic conditions) to give compound 14 (1.7 mg, 4% yield) as a pale yellow solid. m / z: [M+H] + 370.2; 1 H NMR (400 MHz, CD3OD): δ 8.07 (s, 1H), 7.81 (s, 1H), 6.69 (s, 1H), 4.32 (t, J = 4.0Hz, 2H), 3.95-4.00 (m, 6H), 3.76 (d, J = 12.0Hz, 1H), 3.34-3.74 (m, 4H), 3.26-3.30 (m, 1H), 1.28-1.38 (m, 3H).

[0241] Biological Examples Example 1: ATR Enzyme Test In this experiment, the phosphorylation level of the substrate protein p53 (Eurofins, 14-952) was detected by HTRF technology, and the activity of ATR / ATRIP (Eurofins, 14-953) kinase was measured. The reaction buffer (25 mM HEPES pH 8.0, 0.01% Brij-35, 1% glycerol, 5 mM DTT, 1 mg / mL BSA), stop buffer (12.5 mM HEPES pH 8.0, 0.005% Brij-35, 0.5% glycerol, 250 mM EDTA), and assay buffer (50 mM HEPES pH 7.0, 150 mM NaCl, 267 mM KF, 0.1% sodium cholate, 0.01% Tween 20) were prepared in advance. ATR / ATRIP was diluted to a working solution of 2 ng / μL in reaction buffer, and the substrate protein P53 was diluted to a working solution of 80 nM in reaction buffer. A 4 nM ATP (Sigma, A2383) working solution (containing 40 mM MnCl) was prepared in reaction buffer. Compounds were diluted three-fold with DMSO and then diluted with reaction buffer to form working solutions. 2.5 μL / well of the working solutions were added to a 384-well plate and centrifuged at 1500 rpm for 40 seconds. Next, 2.5 μL of the working ATR / ATRIP solution, P53 working solution, and ATP working solution were added to the 384-well plate, centrifuged at 1500 rpm for 40 seconds, and incubated at room temperature for 30 minutes. After the reaction was completed, 5 μL of stop buffer was added to each well and centrifuged at 1500 rpm for 40 seconds. An antibody working solution containing 0.083 μg / mL anti-phospho-p53(Ser15)-K (CisBio, cat. 61P08KAE) and 5 μg / mL anti-GST-d2 (CisBio, cat. 61GSTDLA) was prepared in assay buffer. 5 μL / well of the solution was added to a 384-well plate, centrifuged at 1500 rpm for 40 seconds, and incubated overnight at room temperature. TR-FRET was detected using a microplate reader (Tecan, Infinite M1000 Pro). Data were analyzed using Graphpad software, and a four-parameter logistic curve was fitted to determine the IC values ​​of the inhibitors. 50 The values ​​were calculated (Table 1).

[0242] [Table 1]

[0243] Example 2: Cell proliferation test In this study, the biological activity of compounds was evaluated using a cellular assay. LOVO (Nanjing Kebai Biotechnology Co., Ltd.), a human colon cancer cell line, was cultured in Dulbecco's Modified Eagle's Medium (MODE) in 96-well plates, supplemented with 10% fetal bovine serum and 1% P / S, at 37°C and 5% CO2. Compound concentrations ranged from 4.5 nM to 30 μM. Stock solutions of the compounds to be tested were dissolved in DMSO and added to the culture medium at the indicated concentrations and incubated for 72 hours. Negative control cells were treated with vehicle alone. In some experiments, a known ATR inhibitor was added as a positive control. Cell activity was assessed using the Cell titer glo kit (CTG, Promega) according to the instructions in the product manual. Data were analyzed using Graphpad software, and IC 50 The values ​​and fitting curves of the compounds were obtained (Table 2).

[0244] [Table 2]

[0245] Example 3: Cytochrome oxidase P450 inhibitory effect test The inhibitory effects of compounds on CYP2C19, 2D6, and 3A4 isoforms were evaluated using LC-MS / MS. In this method, a test compound was mixed with a solution of human liver microsomes containing a CYP model substrate, and the mixture was incubated in the presence of NADPH. The amount of metabolites of the model substrate in the reaction mixture was measured to determine the inhibitory IC values ​​of the compounds on CYP2C19, 2D6, and 3A4. 50 The specific experimental method is as follows.

[0246] Test compounds were prepared in DMSO at a 10 mM stock concentration and then diluted to 4 mM with acetonitrile. Simultaneously, reference inhibitor solutions corresponding to the CYP subtypes were prepared. For example, the reference inhibitor was ketoconazole. Both were prepared separately (8 mL of inhibitor DMSO stock solution + 12 mL of acetonitrile), resulting in a 400X concentration of the sample. The above solution was then diluted three-fold with a DMSO / acetonitrile mixture (v / v: 40 / 60) to prepare the final test solutions. Seven concentration points were set for each test compound, with the initial final test concentration being 10 μM. NADPH, CYP enzyme model substrates, and human liver microsome solution were diluted to the appropriate concentrations with preheated potassium phosphate buffer (0.1 M, pH 7.4). Human liver microsome solution was purchased from BD Gentest (20 mg / mL, Corning, product number #452161).

[0247] To each well containing test compound in a 96-well plate, 400 mL of human liver microsome solution (0.2 mg / mL) was added, followed by 2 mL of the final test sample of the test compound prepared by gradient dilution as described above. For each corresponding reference inhibitor well, 200 mL of human liver microsome solution (0.2 mg / mL) and 1 mL of the final test sample were added. 15 mL of each well was dispensed into a 96-well plate. After the microsome solution was mixed evenly, 30 mL of the test compound / reference inhibitor-human liver microsome mixture was transferred to the 96-well plate containing the substrate. The mixture was mixed thoroughly and preheated at 37°C for 5 minutes. The reaction was then initiated by adding 15 mL of 8 mM NADPH solution preheated to 37°C. Each test included a duplicate well control, as well as a blank control without the addition of test substance. A 96-well plate containing a total volume of 60 mL of reaction mixture was incubated at 37°C. After incubation, 120 μL of cold acetonitrile solution containing the internal standard was added to each well to terminate the reaction. The 96-well plate was then shaken on a microplate shaker for 5 minutes (600 rpm / min) and centrifuged at 6000 rpm for 20 minutes at 4°C. Next, 40 μL of supernatant was removed from each well and transferred to another 96-well plate. 80 μL of ultrapure water was added to each well, mixed on a shaker for 5 minutes (600 rpm / min), and centrifuged at 6000 rpm for 20 minutes at 4°C. LC-MS / MS detection was then performed. The inhibition rate was determined by comparing the amount of model substrate metabolites at each test concentration with that without the addition of the test substance. Using GraphPad Prism 5.0 software, a nonlinear regression (sigmoidal (non-linear) dose-response model) analysis was performed with the logarithm of the test concentration on the horizontal axis and the inhibition rate on the vertical axis to calculate the IC value of the test compound. 50 The results are shown in Table 3 below.

[0248] [Table 3]

[0249] Example 4: Cardiac Safety Evaluation - hERG Study In this experiment, we used a CHO cell line stably transfected with hERG cDNA and expressing the p15 hERG channel. Cells were cultured in medium (Ham's SF12, 10% v / v FBS, 100 μg / mL hygromycin B, 100 μg / mL Geneticin) (Invitrogen) at 37°C in a humidified incubator containing 5% CO2. Cells were grown under the above conditions until they reached approximately 80–90% confluence. They were treated with Detachin (Genlantis) for 3–5 minutes. After 15–20 rounds of dropwise centrifugation at 37°C, the cells were resuspended in CHO-S-SFMII medium (serum-free medium, Invitrogen) buffered with HEPES (25 mM). Cells used for QPatch studies must meet the following criteria: most suspended cells are single and isolated by microscopic examination; viability is greater than 95%. The final suspension had a cell density of 3–8 × 10 before application to the QPatch mixing chamber. 6 Cells meeting the above criteria can be used for recording within 4 hours of harvesting.

[0250] The compounds to be tested were prepared as 10 mM DMSO stock solutions. Six doses (30, 10, 3, 1, 0.3, and 0.1 μM) were selected and fitted with IC 50 The final DMSO concentration was 0.1% or less. The IC of the positive control, cisapride, was 50 The estimated doses are 3, 1, 0.3, 0.1, 0.03, and 0.01 μM, respectively. The composition of the internal solution for electrophysiological recordings was: CaCl2 2 mM, MgCl2 1 mM, KCl 4 mM, NaCl 145 mM, glucose 10 mM, HEPES 10 mM, pH 7.4 (NaOH). The composition of the external solution was: CaCl2 374 mM, MgCl2 1.75 mM, KCl 120 mM, HEPES 10 mM, EGTA 5 mM, Na-ATP 4 mM, pH 7.25 (KOH). (All reagents used were from Sigma.)

[0251] Whole-cell recordings were performed using an automated QPatch (Sophion Biosciences, Denmark). To assess current stability, cells were recorded for 120 seconds. The above voltages were then applied to the cells every 15 seconds throughout the entire process. Only stable cells with recording parameters exceeding threshold were allowed to enter the drug testing procedure. All experiments were performed at approximately 25°C. An external solution containing 0.1% DMSO (Vector) was applied to the cells to establish a baseline. After allowing the current to stabilize for 3 minutes, the test compound was tested. Compound solution was added, and cells were maintained in the test solution for a maximum of 4 minutes until the compound's effect reached a steady state. For dose-response measurements, compounds were applied to the cells in cumulative concentrations, from low to high. After testing the compound, the cells were washed out with external solution.

[0252] Data were analyzed using Sophion Assay software (measurement software V5.0), Microsoft Excel, and Graphpad Prism 5.0, and the IC values ​​of the compounds were calculated. 50 The results are shown in Table 4 below.

[0253] [Table 4]

[0254] Example 5: In vivo efficacy study of OCI-LY19 human B-cell lymphoma subcutaneously transplanted tumor model in mice Cell Culture: Human B-cell lymphoma OCI-LY19 cells were maintained in monolayer in MEM-α medium containing 10% fetal bovine serum at 37°C in a 5% CO2 incubator. Tumor cells were subcultured twice weekly. Exponentially growing cells were harvested and counted for inoculation.

[0255] Experimental animals: BALB / c nude mice, 6-8 weeks old, 19-22 g, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.

[0256] As shown in Table 5 below, a total of six experimental groups were set up for the vehicle, positive control (AZD6738, CAS number: 1352226-88-0), and Compound 2.

[0257] [Table 5]

[0258] Experimental method: OCI-LY19 cell line (3.0 × 10 6 The experimental mice were subcutaneously inoculated with 0.1 mL of the drug per mouse into the right dorsal region. Tumor growth was monitored periodically, and the tumor growth rate was measured when the tumor reached approximately 100 mm. 3 At that time, the mice were randomly divided into groups according to tumor size and body weight and administered according to the administration schedule shown in Table 5. During the entire experiment, the body weight and tumor size of the mice were measured twice a week.

[0259] Tumor size calculation formula: Tumor volume (mm 3 ) = 0.5 × (tumor long diameter × tumor short diameter 2 ). The experimental results are shown in Table 6 and FIG.

[0260] [Table 6]

[0261] The results show that compared with the positive control AZD6738, the compounds of the present invention can exhibit superior efficacy in the OCI-LY19 human B-cell lymphoma subcutaneously xenografted tumor model in mice.

Claims

1. A compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (where, X is NR ５ and X １ is CR ３ａ or CR ３ａ R4a and X ２ is CR ３ｂ or CR ３ｂ R4b and X ３ is a connecting bond, U is N, U １ and U ２ are each independently C; V is NR ６ or CR ７ and V １ is N and V ２ is CR ７ｂ and V ３ is a connecting bond or CR ７ｃ and R １ is hydrogen or C １－６ is alkyl, R ２ is methyl, R ３ａ and R3b are each independently hydrogen, halogen, cyano, nitro, C １－６ Alkyl, C ２－６ Alkynyl, C ２－６ Alkenyl, C ６－１０ Aryl, C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ６－１０ Aryl C １－６ Alkyl, C ３－８ Cycloalkyl C １－６ Alkyl, 3- to 8-membered heterocycloalkylC １－６ Alkyl, 5-6 membered heteroaryl C １－６ Alkyl, -SR ａ , -OR ａ , -OC(O)R ａ , -OC(O)OR ａ , —OC(O)NR ａ R ｂ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -C(O)N(R ｂ ) OR ａ , —C(O)NR ｂ S (O) ２ R ａ , —C(═NH)R ａ , -NR ａ R ｂ , -NR ｂ C(O)R ａ , -N(R ｂ )C(O)OR ａ , -N(R ｂ )C(O)NR ａ R ｂ , -NR ｂ S (O) ２ R ａ , -NR ｂ C(=NH)R ａ , -NR ｂ C(=NH)NR ｂ R ａ , -S(O) １－２ R ａ , -S(O) ２ NR ａ R ｂ , -S(O)(=NCN)R ａ , -S(O)(=NR ｂ ) R ａ or -NR ｂ S (O) ２ NR ａ R ｂ wherein said C １－６ Alkyl, C ２－６ Alkynyl, C ２－６ Alkenyl, C ６－１０ Aryl, C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ６－１０ Aryl C １－６ Alkyl, C ３－８ Cycloalkyl C １－６ Alkyl, 3- to 8-membered heterocycloalkylC １－６ Alkyl or 5-6 membered heteroaryl C １－６ Alkyl is unsubstituted or optionally substituted with halogen, cyano, nitro, -SR ａ , -OR ａ , -OC(O)R ａ , -OC(O)OR ａ , —OC(O)NR ａ R ｂ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , —C(O)NR ｂ S (O) ２ R ａ , -NR ａ R ｂ , -NR ｂ C(O)R ａ , -N(R ｂ )C(O)OR ａ , -N(R ｂ )C(O)NR ａ R ｂ , -NR ｂ C(=NH)R ａ , -NR ｂ C(=NH)NR ａ R ｂ , -NR ｂ S (O) ２ R ａ , -NR ｂ S (O) ２ NR ａ R ｂ , -S(O) １－２ R ａ , -S(O) ２ NR ａ R ｂ , -S(O)(=NCN)R ａ and -S(O)(=NR ｂ ) R ａ and substituted at any position with 1 to 3 substituents selected from R ４ａ and R4b are each independently hydrogen, halogen, C １－６ Alkyl, C １－６ Alkoxy, halogenated C １－６ Alkyl or halogenated C １－６ is an alkoxy, R ５ is hydrogen, C １－６ Alkyl, C ２－６ Alkynyl, C ２－６ Alkenyl, C ６－１０ Aryl, C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ６－１０ Aryl C １－６ Alkyl, C ３－８ Cycloalkyl C １－６ Alkyl, 3- to 8-membered heterocycloalkylC １－６ Alkyl, 5-6 membered heteroaryl C １－６ Alkyl, -SR ａ , -OR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -C(O)N(R ｂ ) OR ａ , —C(O)NR ｂ S (O) ２ R ａ , —C(═NH)R ａ , -S(O) １－２ R ａ , -S(O) ２ NR ａ R ｂ , -S(O)(=NCN)R ａ or -S(O)(=NR ｂ ) R ａ wherein said C １－６ Alkyl, C ２－６ Alkynyl, C ２－６ Alkenyl, C ６－１０ Aryl, C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ６－１０ Aryl C １－６ Alkyl, C ３－８ Cycloalkyl C １－６ Alkyl, 3- to 8-membered heterocycloalkylC １－６ Alkyl or 5-6 membered heteroaryl C １－６ Alkyl is unsubstituted or optionally substituted with halogen, cyano, nitro, -SR ａ , -OR ａ , -OC(O)R ａ , -OC(O)OR ａ , —OC(O)NR ａ R ｂ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , —C(O)NR ｂ S (O) ２ R ａ , -NR ａ R ｂ , -NR ｂ C(O)R ａ , -N(R ｂ )C(O)OR ａ , -N(R ｂ )C(O)NR ａ R ｂ , -NR ｂ C(=NH)R ａ , -NR ｂ C(=NH)NR ａ R ｂ , -NR ｂ S (O) ２ R ａ , -NR ｂ S (O) ２ NR ａ R ｂ , -S(O) １－２ R ａ , -S(O) ２ NR ａ R ｂ , -S(O)(=NCN)R ａ and -S(O)(=NR ｂ ) R ａ and substituted at any position with 1 to 3 substituents selected from R6 is hydrogen, C １－６ Alkyl, C １－６ Alkoxy, halogenated C １－６ Alkyl, halogenated C １－６ Alkoxy, C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ６－１０ Aryl, 5- to 10-membered heteroaryl, C ３－８ Cycloalkyl C １－６ Alkyl or 3- to 8-membered heterocycloalkylC １－６ alkyl, wherein said C ６－１０ The aryl or 5- to 10-membered heteroaryl is unsubstituted or optionally substituted with halogen, cyano, —R ｃ , -OR ｃ , -NR ｃ R ｄ , -N(CN)R ｃ , -N(OR ｄ ) R ｃ , -S(O) ０－２ R ｃ , -C(O)R ｃ , -C(O)OR ｃ , —C(O)NR ｃ R ｄ , —C(NH)NR ｃ R ｄ , -NR ｄ C(O)R ｃ , -NR ｄ C(O)NR ｃ R ｄ , -NR ｄ S (O) ２ R ｃ and -OC(O)R ｃ and substituted at any position with 1 to 3 substituents selected from R ７ , R ７ｂ and R ７ｃ are each independently hydrogen, halogen, cyano, C １－６ Alkyl, C １－６ Alkoxy, halogenated C １－６ Alkyl, halogenated C １－６ Alkoxy, C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ６－１０ Aryl, 5- to 10-membered heteroaryl, C ３－８ Cycloalkyl C １－６ Alkyl or 3- to 8-membered heterocycloalkylC １－６ alkyl, wherein said C ６－１０ The aryl or 5- to 10-membered heteroaryl is unsubstituted or optionally substituted with halogen, cyano, —R ｃ , -OR ｃ , -NR ｃ R ｄ , -N(CN)R ｃ , -N(OR ｄ ) R ｃ , -S(O) ０－２ R ｃ , -C(O)R ｃ , -C(O)OR ｃ , —C(O)NR ｃ R ｄ , —C(NH)NR ｃ R ｄ , -NR ｄ C(O)R ｃ , -NR ｄ C(O)NR ｃ R ｄ , -NR ｄ S (O) ２ R ｃ and -OC(O)R ｃ and substituted at any position with 1 to 3 substituents selected from Each R ａ , R ｂ , R ｃ and R ｄ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ６－１０ Aryl, 5-6 membered heteroaryl, C ３－８ Cycloalkyl C １－６ Alkyl, 3- to 8-membered heterocycloalkylC １－６ Alkyl, phenyl C １－６ Alkyl or 5-6 membered heteroaryl C １－６ alkyl, and the R ａ , R ｂ , R ｃ and R ｄ is unsubstituted or optionally halogen, hydroxyl, amino, carboxyl, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylamino, halogenated C １－６ Alkyl, halogenated C １－６ Alkoxy, C ２－６ Alkenyl and C ２－６ alkynyl, and substituted at any position with 1 to 3 substituents selected from

2. R １ is hydrogen, and R ２ 2. The compound of claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein is methyl.

3. R ３ａ and R3b are each independently hydrogen, halogen, cyano, C １－６ Alkyl, halogenated C １－６ Alkyl or halogenated C １－６ is an alkoxy, and / or R ４ａ and R4b are each independently hydrogen or C １－６ is alkyl, and / or R ５ is C １－６ Alkyl, phenyl, C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－８ Cycloalkyl C １－６ Alkyl, 3- to 8-membered heterocycloalkylC １－６ Alkyl, 5-6 membered heteroaryl C １－６ Alkyl, —S(O) １－２ R ａ , -S(O) ２ NR ａ R ｂ , -S(O)(=NCN)R ａ or -S(O)(=NR ｂ ) R ａ wherein said C １－６ Alkyl, phenyl, C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－８ Cycloalkyl C １－６ Alkyl or 3- to 8-membered heterocycloalkylC １－６ Alkyl is unsubstituted or optionally substituted with halogen, —CN, —SR ａ , -OR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ R ｂ , -NR ｂ C(O)R ａ , -NR ｂ S (O) ２ R ａ , -S(O) １－２ R ａ , -S(O) ２ NR ａ R ｂ , -S(O)(=NCN)R ａ and -S(O)(=NR ｂ ) R ａ and substituted at any position with 1 to 3 substituents selected from and / or R ６ and R ７ are each independently 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is unsubstituted or optionally substituted with halogen, cyano, —R ｃ , -OR ｃ , -NR ｃ R ｄ , -N(CN)R ｃ , -N(OR ｄ ) R ｃ , -S(O) ０－２ R ｃ , -C(O)R ｃ , -C(O)OR ｃ , —C(O)NR ｃ R ｄ , —C(NH)NR ｃ R ｄ , -NR ｄ C(O)R ｃ , -NR ｄ C(O)NR ｃ R ｄ , -NR ｄ S (O) ２ R ｃ and -OC(O)R ｃ and substituted at any position with 1 to 3 substituents selected from and / or R ７ｂ and R ７ｃ are each independently hydrogen, halogen, cyano, C １－６ Alkyl, C １－６ Alkoxy, halogenated C １－６ Alkyl or halogenated C １－６ is an alkoxy, and / or each R ａ are independently hydrogen, C １－６ Alkyl, C ３－８ cycloalkyl or 3- to 8-membered heterocycloalkyl, ａ is unsubstituted or optionally substituted with halogen, hydroxyl, amino, C １－６ Alkoxy, C １－６ Alkylamino, halogenated C １－６ Alkyl and halogenated C １－６ substituted at any position with 1 to 3 substituents selected from alkoxy; and / or each R ｂ are independently hydrogen or C １－６ is alkyl, and / or each R ｃ are independently hydrogen or C １－６ alkyl, １－６ Alkyl is unsubstituted or optionally substituted with halogen, hydroxyl, amino, C １－６ Alkoxy, C １－６ Alkylamino, halogenated C １－６ Alkyl and halogenated C １－６ substituted at any position with 1 to 3 substituents selected from alkoxy; and / or each R ｄ are independently hydrogen or C １－６ 2. The compound according to claim 1, its stereoisomers or pharmaceutically acceptable salts, characterized in that it is alkyl.

4. R ６ and R ７ are each independently pyrrolyl, pyrazolyl, or isoxazolyl, wherein said pyrrolyl, pyrazolyl, or isoxazolyl is unsubstituted or optionally substituted with halogen, cyano, —R ｃ , -OR ｃ , -NR ｃ R ｄ , -N(CN)R ｃ , -N(OR ｄ ) R ｃ , -S(O) ０－２ R ｃ , -C(O)R ｃ , -C(O)OR ｃ , —C(O)NR ｃ R ｄ , —C(NH)NR ｃ R ｄ , -NR ｄ C(O)R ｃ , -NR ｄ C(O)NR ｃ R ｄ , -NR ｄ S (O) ２ R ｃ and -OC(O)R ｃ The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, characterized in that it is substituted at any position with 1 to 3 substituents selected from:

5. base 【Chemistry 2】 2. The compound of claim 1, its stereoisomers or pharmaceutically acceptable salts, characterized in that: 【Transformation 3】

6. R ３ａ , R ３ｂ , R ４ａ and R ４ｂ are each independently hydrogen, and / or R ７ｂ is hydrogen, and / or R ６ and R ７ and each independently represent pyrrolyl, pyrazolyl, or isoxazolyl, or a stereoisomer or a pharmaceutically acceptable salt thereof, according to claim 5 .

7. The compound, its stereoisomer, or pharmaceutically acceptable salt thereof is a compound represented by formula (II), its stereoisomer, or pharmaceutically acceptable salt thereof: 【Chemistry 4】 Here, U １ and U ２ are C and V is NR ６ and V １ is N and V ２ is CR ７ｂ and Or, the compound, stereoisomer or pharmaceutically acceptable salt thereof is a compound represented by formula (III), stereoisomer or pharmaceutically acceptable salt thereof: 【Transformation 5】 Here, U １ and U ２ are each independently C, and V is CR ７ and V １ is N and V ２ is CR ７ｂ and V ３ is CR ７ｃ 2. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, characterized in that:

8. In the compound of formula (II), R ６ is pyrrolyl, pyrazolyl or isoxazolyl, wherein said pyrrolyl, pyrazolyl or isoxazolyl is unsubstituted or optionally substituted with halogen, cyano, -R ｃ , -OR ｃ , -NR ｃ R ｄ , -N(CN)R ｃ , -N(OR ｄ ) R ｃ , -S(O) ０－２ R ｃ , -C(O)R ｃ , -C(O)OR ｃ , —C(O)NR ｃ R ｄ , —C(NH)NR ｃ R ｄ , -NR ｄ C(O)R ｃ , -NR ｄ C(O)NR ｃ R ｄ , -NR ｄ S (O) ２ R ｃ and -OC(O)R ｃ and substituted at any position with 1 to 3 substituents selected from R ７ｂ is hydrogen, R ｃ and R ｄ are each independently hydrogen or C １－６ is alkyl, In the compound of formula (III), R ７ is pyrrolyl, pyrazolyl or isoxazolyl, wherein said pyrrolyl, pyrazolyl or isoxazolyl is unsubstituted or optionally substituted with halogen, cyano, -R ｃ , -OR ｃ , -NR ｃ R ｄ , -N(CN)R ｃ , -N(OR ｄ ) R ｃ , -S(O) ０－２ R ｃ , -C(O)R ｃ , -C(O)OR ｃ , —C(O)NR ｃ R ｄ , —C(NH)NR ｃ R ｄ , -NR ｄ C(O)R ｃ , -NR ｄ C(O)NR ｃ R ｄ , -NR ｄ S (O) ２ R ｃ and -OC(O)R ｃ and substituted at any position with 1 to 3 substituents selected from R ７ｂ and R ７ｃ are each independently hydrogen, R ｃ and R ｄ are each independently hydrogen or C １－６ 8. The compound according to claim 7, its stereoisomers or pharmaceutically acceptable salts, characterized in that it is alkyl.

9. The compound, its stereoisomer, or pharmaceutically acceptable salt thereof is a compound represented by formula (IIA), its stereoisomer, or pharmaceutically acceptable salt thereof: 【Transformation 6】 where: 【Transformation 7】 is a double bond or a single bond, Or, the compound, stereoisomer, or pharmaceutically acceptable salt thereof is a compound represented by formula (IIIA), stereoisomer, or pharmaceutically acceptable salt thereof: 【Transformation 8】 where: 【Chemistry 9】 The compound according to claim 1, its stereoisomers or pharmaceutically acceptable salts, characterized in that is a double bond or a single bond.

10. X １ and X ２ are each independently CH; Or X １ and X ２ are each independently CH ２ 10. The compound according to claim 9, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

11. R ５ is C １－６ Alkyl, phenyl, C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－８ Cycloalkyl C １－６ Alkyl, 3- to 8-membered heterocycloalkylC １－６ Alkyl, 5-6 membered heteroaryl C １－６ Alkyl, —S(O) １－２ R ａ , -S(O) ２ NR ａ R ｂ , -S(O)(=NCN)R ａ or -S(O)(=NR ｂ ) R ａ wherein said C １－６ Alkyl, phenyl, C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C ３－８ Cycloalkyl C １－６ Alkyl or 3- to 8-membered heterocycloalkylC １－６ Alkyl is unsubstituted or optionally substituted with halogen, —CN, —SR ａ , -OR ａ , -C(O)OR ａ , -C(O)R ａ , —C(O)NR ａ R ｂ , -NR ａ R ｂ , -NR ｂ C(O)R ａ , -NR ｂ S (O) ２ R ａ , -S(O) １－２ R ａ , -S(O) ２ NR ａ R ｂ , -S(O)(=NCN)R ａ and -S(O)(=NR ｂ ) R ａ and substituted at any position with 1 to 3 substituents selected from Each R ａ are independently hydrogen or C １－６ alkyl, １－６ Alkyl is unsubstituted or optionally substituted with halogen, hydroxyl, amino, C １－６ Alkoxy, C １－６ Alkylamino, halogenated C １－６ Alkyl and halogenated C １－６ substituted at any position with 1 to 3 substituents selected from alkoxy; Each R ｂ are independently hydrogen or C １－６ 10. The compound according to claim 9, its stereoisomers or pharmaceutically acceptable salts, characterized in that it is alkyl.

12. In the compound represented by formula (IIA), V １ is N and V ２ 10. The compound according to claim 9, a stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: is CH.

13. In the compound represented by formula (IIIA), V １ is N and V ２ and V ３ 10. The compound of claim 9, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein each is independently CH.

14. A compound, its stereoisomer or pharmaceutically acceptable salt according to claim 1, characterized in that the compound, its stereoisomer or pharmaceutically acceptable salt has any one of the following structures: 【Chemistry 10】 【change】 or a pharmaceutically acceptable salt thereof.

15. 15. A pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises a compound according to any one of claims 1 to 14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

16. Use of the compound according to any one of claims 1 to 14, its stereoisomer or pharmaceutically acceptable salt in the manufacture of a medicament for ATR inhibitor.

17. Use of a compound according to any one of claims 1 to 14, its stereoisomer or pharmaceutically acceptable salt in the manufacture of a medicament for treating and / or alleviating an associated disease caused by abnormalities in ATR levels.

18. 18. The use according to claim 17, characterized in that the disease associated with abnormalities in ATR levels is cancer.

19. 15. Use of a compound according to any one of claims 1 to 14, a stereoisomer or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer.

20. 15. Use of a compound, a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 in the manufacture of a medicament for treating cancer, wherein said compound, a stereoisomer or a pharmaceutically acceptable salt thereof is used in combination with one or more other therapeutic agents and / or methods for treating cancer.

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