ATR inhibitors and uses thereof

Abstract

A new compound with ATR inhibitory effect as shown in formula I and its use in preparing medicines.

Description

Technical Field

[0001] The present application relates to a class of new compounds with ATR inhibitory effect and use thereof in preparing medicines. Background Art

[0002] Ataxia-telangiectasia mutated gene and Rad 3 The related kinase ATR (ataxia telangiectasiamutated and Rad3-related, ATR) is a member of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family, which also includes ataxia telangiectasia mutated kinase (ATM), DNA-dependent protein kinase (DNA-PK), suppressor of genital formation gene-1 (SMG-1), mammalian target of rapamycin (mTOR) and transformation / transcription-related protein (TRAPP). ATR and ATM are key regulators of the cellular DNA damage response (DDR) pathway and are involved in maintaining genome integrity in response to DNA damage. ATR is a key member of the DDR that responds to damaged DNA replication. It is essential for maintaining genome stability and integrity and promoting cell survival. When intracellular DNA damage occurs, ATR is recruited to the site of DNA damage, and multiple proteins are then involved in regulating the activation of ATR. After ATR activation, it regulates some important cellular processes. Many cancer cells lack key tumor suppressor genes, which can make cancer cells more dependent on the ATR pathway than normal cells to regulate cellular DNA damage repair and promote cell survival, making ATR a promising target for cancer therapy. Inhibition of ATR may enhance the effectiveness of replication inhibitors. In addition, ATR inhibition may have a killing effect on cells with high RS levels (such as cells expressing proto-oncogenes or lacking tumor suppressor factors). Inhibition of ATR activity in these cells will produce lethal amounts of RS, leading to cell death.

[0003] There have been some reports on ATR inhibitors (WO2015 / 084384, WO2017 / 180723, WO2016 / 061097, WO2014 / 140644, etc.), but the existing ATR inhibitors are still in the clinical trial process, and no corresponding drugs have been marketed. Therefore, it may be necessary to develop more ATR inhibitor drugs with better effects and fewer side effects. Summary of the invention

[0004] The present application provides a compound represented by Formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0005]

[0006] in,

[0007] Ring A is selected from

[0008] Ring B is selected from The B ring may be further optionally substituted with one, two, three or four R B1 replace;

[0009] Each R B1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR B2 , -C 0～4 Alkylene-OC(O)R B2 , -C 0～4 Alkylene-C(O)R B2 , -C 0～4 Alkylene-C(O)OR B2 , -C 0～4 Alkylene-C(O)NR B2 R B3 , -C 0～4 Alkylene-NR B2 R B3 , -C 0～4 Alkylene-NR B2 C(O)R B3 ;

[0010] R B2 , R B3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;

[0011] R 1 and R 2 Together with the atoms connected to form

[0012] X 1 , X 2 , X 3 , X 4 Each independently selected from N or CR C1 ;

[0013] Y is selected from O, S or NR C1 ;

[0014] Each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR C2 , -C 0～4 Alkylene-OC(O)R C2 , -C 0～4 Alkylene-SR C2 , -C 0～4 Alkylene-S(O) 2 R C2 , -C 0～4 Alkylene-S(O)R C2 , -C 0～4 Alkylene-S(O) 2 NR C2 R C3 , -C 0～4 Alkylene-S(O)NR C2 R C3 , -C 0～4 Alkylene-S(O)(NH)R C2 , -C 0～4 Alkylene-S(O)(NH)NR C2 R C3 , -C 0～4 Alkylene-C(O)R C2 , -C 0～4 Alkylene-C(O)OR C2 , -C 0～4 Alkylene-C(O)NR C2 R C3 , -C 0～4 Alkylene-NR C2 R C3 , -C 0～4 Alkylene-NR C2 C(O)R C3 , -C 0～4 Alkylene-NR C2 S(O) 2 R C3 , -C 0～4 Alkylene-NR C2 S(O)R C3 , -C0～4 Alkylene-P(O)R C2 R C3 , -C 0～4 Alkylene-P(O)(OR C2 )R C3 , -C 0～4 Alkylene-P(O)(OR C2 )(OR C3 ),-C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein the alkylene, carbocyclic group, heterocyclic alkyl, aromatic ring, aromatic heterocycle may be further optionally replaced by one, two, three or four independent R C4 replace;

[0015] Alternatively, two independent R C1 Together with the atoms connected thereto, they form a 5- to 8-membered carbocyclic group, a 5- to 8-membered heterocyclic alkyl group, a benzene ring, or a 5- to 6-membered aromatic heterocyclic ring; wherein the carbocyclic group, heterocyclic alkyl group, aromatic ring, or aromatic heterocyclic ring may be further optionally replaced by one, two, three, or four independent R C4 replace;

[0016] R C2 , R C3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle);

[0017] Each R C4 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR C5, -C 0～4 Alkylene-OC(O)R C5 , -C 0～4 Alkylene-SR C5 , -C 0～4 Alkylene-S(O) 2 R C5 , -C 0～4 Alkylene-S(O)R C5 , -C 0～4 Alkylene-S(O) 2 NR C5 R C6 , -C 0～4 Alkylene-S(O)NR C5 R C6 , -C 0～4 Alkylene-S(O)(NH)R C5 , -C 0～4 Alkylene-S(O)(NH)NR C5 R C6 , -C 0～4 Alkylene-C(O)R C5 , -C 0～4 Alkylene-C(O)OR C5 , -C 0～4 Alkylene-C(O)NR C5 R C6 , -C 0～4 Alkylene-NR C5 R C6 , -C 0～4 Alkylene-NR C5 C(O)R C6 , -C 0～4 Alkylene-NR C5 S(O) 2 R C6 , -C 0～4 Alkylene-NR C5 S(O)R C6 , -C 0～4 Alkylene-P(O)R C5 R C6 , -C 0～4 Alkylene-P(O)(OR C5 )R C6 , -C 0～4 Alkylene-P(O)(OR C5 )(OR C6 ); or, two independent R C4 Together with the atoms connected to form

[0018] R C5 , R C6are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered aromatic heterocycle).

[0019] Alternatively, the present application provides a compound represented by Formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0020]

[0021] in,

[0022] Ring A is selected from

[0023] Ring B is selected from The B ring may be further optionally substituted with one, two, three or four R B1 replace;

[0024] Each R B1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR B2 , -C 0～4 Alkylene-OC(O)R B2 , -C 0～4 Alkylene-C(O)R B2 , -C 0～4 Alkylene-C(O)OR B2 , -C 0～4 Alkylene-C(O)NR B2 R B3 , -C 0～4 Alkylene-NR B2 R B3 , -C 0～4 Alkylene-NR B2 C(O)RB3 ;

[0025] R B2 , R B3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;

[0026] R 1 and R 2 Together with the atoms connected to form

[0027] X 1 , X 2 , X 3 , X 4 Each independently selected from N or CR C1 ;

[0028] Y is selected from O, S or NR C1 ;

[0029] Each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR C2 , -C 0～4 Alkylene-OC(O)R C2 , -C 0～4 Alkylene-SR C2 , -C 0～4 Alkylene-S(O) 2 R C2 , -C 0～4 Alkylene-S(O)R C2 , -C 0～4 Alkylene-S(O) 2 NR C2 R C3 , -C 0～4 Alkylene-S(O)NR C2 R C3 , -C 0～4 Alkylene-S(O)(NH)R C2 , -C 0～4 Alkylene-S(O)(NH)NRC2 R C3 , -C 0～4 Alkylene-C(O)R C2 , -C 0～4 Alkylene-C(O)OR C2 , -C 0～4 Alkylene-C(O)NR C2 R C3 , -C 0～4 Alkylene-NR C2 R C3 , -C 0～4 Alkylene-NR C2 C(O)R C3 , -C 0～4 Alkylene-NR C2 S(O) 2 R C3 , -C 0～4 Alkylene-NR C2 S(O)R C3 , -C 0～4 Alkylene-P(O)R C2 R C3 , -C 0～4 Alkylene-P(O)(OR C2 )R C3 , -C 0～4 Alkylene-P(O)(OR C2 )(OR C3 ),-C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein the alkylene, carbocyclic group, heterocyclic alkyl, aromatic ring, aromatic heterocycle may be further optionally replaced by one, two, three or four independent R C4 replace;

[0030] Alternatively, two independent R C1 Together with the atoms connected thereto, they form a 5- to 8-membered carbocyclic group, a 5- to 8-membered heterocyclic alkyl group, a benzene ring, or a 5- to 6-membered aromatic heterocyclic ring; wherein the carbocyclic group, heterocyclic alkyl group, aromatic ring, or aromatic heterocyclic ring may be further optionally replaced by one, two, three, or four independent R C4 replace;

[0031] R C2 , R C3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle);

[0032] Each R C4 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR C5 , -C 0～4 Alkylene-OC(O)R C5 , -C 0～4 Alkylene-SR C5 , -C 0～4 Alkylene-S(O) 2 R C5 , -C 0～4 Alkylene-S(O)R C5 , -C 0～4 Alkylene-S(O) 2 NR C5 R C6 , -C 0～4 Alkylene-S(O)NR C5 R C6 , -C 0～4 Alkylene-S(O)(NH)R C5 , -C 0～4 Alkylene-S(O)(NH)NR C5 R C6 , -C 0～4 Alkylene-C(O)R C5 , -C 0～4 Alkylene-C(O)OR C5 , -C 0～4 Alkylene-C(O)NR C5 R C6 , -C 0～4 Alkylene-NR C5 R C6 , -C 0～4 Alkylene-NR C5 C(O)R C6 , -C0～4 Alkylene-NR C5 S(O) 2 R C6 , -C 0～4 Alkylene-NR C5 S(O)R C6 , -C 0～4 Alkylene-P(O)R C5 R C6 , -C 0～4 Alkylene-P(O)(OR C5 )R C6 , -C 0～4 Alkylene-P(O)(OR C5 )(OR C6 ); or, two independent R C4 Together with the atoms connected to form

[0033] R C5 , R C6 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered aromatic heterocycle).

[0034] In certain preferred embodiments, Ring A is selected from Preferably selected from More preferably

[0035] Further, the B ring is selected from The B ring may be further optionally substituted with one, two, three or four R B1 replace;

[0036] Each R B1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OR B2 、-C(O)R B2 、-C(O)NR B2 R B3、-NR B2 R B3 、-NR B2 C(O)R B3 ; R B2 , R B3 are independently selected from hydrogen, -C 1～6 alkyl.

[0037] Preferably, each R B1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl; preferably selected from hydrogen, halogen, cyano, -C 1～4 Alkyl, halogen-substituted -C 1～6 Alkyl; more preferably selected from hydrogen, halogen, cyano, -C 1～3 Alkyl, halogen-substituted -C 1～6 alkyl;

[0038] More preferably, each R B1 They are independently selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, halomethyl, haloethyl, halopropyl; preferably selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monochloromethyl, dichloromethyl, trichloromethyl; more preferably selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, further preferably selected from hydrogen, fluorine, chlorine, bromine, methyl, such as fluorine or methyl.

[0039] Furthermore, the B ring is selected from

[0040] In certain preferred embodiments, Ring B is selected from Preferably selected from The B ring may be further optionally substituted with one, two, three or four R B1 Replacement, R B1 As defined above.

[0041] In certain preferred embodiments, Ring B is selected from

[0042] Preferably, Ring B is selected from

[0043] More preferably, Ring B is selected from

[0044] More preferably, the B ring is selected from

[0045] In certain preferred embodiments, R 1 and R 2 Together with the atoms connected to form

[0046] X 1 , X 2 , X 3 , X 4 Each independently selected from N or CR C1 ;

[0047] Y is selected from O, S or NR C1 , preferably S or NR C1 ;

[0048] Each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR C2 , -C 0～4 Alkylene-SR C2 , -C 0～4 Alkylene-S(O) 2 R C2 , -C 0～4 Alkylene-S(O)R C2 , -C 0～4 Alkylene-S(O) 2 NR C2 R C3 , -C 0～4 Alkylene-S(O)NR C2 R C3 , -C 0～4 Alkylene-NR C2 R C3 ; preferably selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～4 Alkylene-OR C2 , -C 0～4 Alkylene-S(O) 2 R C2 , -C 0～4 Alkylene-NR C2 R C3 ; More preferably selected from hydrogen, halogen, cyano, -C 1～3 Alkyl, -C1～3 Alkylene-OR C2 , -C 1～3 Alkylene-S(O) 2 R C2 ; Further preferably selected from hydrogen, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, -C 1～2 Alkylene-OR C2 , -C 1～2 Alkylene-S(O) 2 R C2 ; Further preferably selected from hydrogen, methyl, -C 1 Alkylene-OR C2 , -C 1 Alkylene-S(O) 2 R C2 wherein the alkylene group, carbocyclic group, heterocyclic alkyl group, aromatic ring, aromatic heterocyclic ring may be further optionally replaced by one, two, three or four independent R C4 replace;

[0049] R C2 , R C3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl; preferably selected from hydrogen, -C 1～6 Alkyl; more preferably selected from hydrogen, -C 1～4 Alkyl; further preferably selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; further preferably selected from hydrogen, methyl;

[0050] Each R C4 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl; preferably selected from hydrogen, -C 1～6 Alkyl; more preferably selected from hydrogen, -C 1～4 Alkyl; further preferably selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; further preferably selected from hydrogen, methyl. In certain preferred embodiments, CR C1 Selected from CH, C(C 1～6 alkyl), C(C 2～6 alkenyl), C(C 2～6 Alkynyl), C(halogen-substituted-C 1～6 alkyl), C(C 0～4Alkylene-OR C2 ), wherein the alkylene group may be optionally replaced by one, two, three or four independent R C4 Replacement; R C2 Selected from hydrogen, -C 1～6 Alkyl; each R C4 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl.

[0051] More preferably, CR C1 Selected from CH, C(C 1～4 alkyl), C(C 1～4 Alkylene-OR C2 ), wherein the alkylene group may be optionally replaced by one or two independent R C4 Replacement; R C2 Selected from hydrogen, -C 1～4 Alkyl; each R C4 are independently selected from hydrogen, -C 1～4 More preferably, CR C1 Selected from CH, C(C 1～3 alkyl), C(C 1～3 Alkylene-OR C2 ), wherein the alkylene group may be optionally replaced by one or two independent R C4 Replacement; R C2 is selected from hydrogen; each R C4 are independently selected from hydrogen, -C 1～3 Alkyl. For example, CR C1 Selected from CH, CCH 3 , C(C(CH 3 ) 2 OH).

[0052] In certain preferred embodiments, NR C1 Selected from NH, N(C 1～6 Alkyl), N(C 2～6 alkenyl), N(C 2～6 Alkynyl), N(C 0～4 Alkylene-SR C2 )、N(C 0～4 Alkylene-S(O) 2 R C2 )、N(C 0～4 Alkylene-S(O)R C2 ), wherein the alkylene group may be optionally replaced by one, two, three or four independent R C4 Replacement; R C2 Selected from hydrogen, -C 1～6 Alkyl, -C2～6 Alkenyl, -C 2～6 Alkynyl; each R C4 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl.

[0053] Further preferably, NR C1 Selected from NH, N(C 1～4 Alkyl), N(C 1～4 Alkylene-S(O) 2 R C2 ), wherein the alkylene group may be optionally replaced by one or two independent R C4 Replacement; R C2 Selected from hydrogen, -C 1～4 Alkyl; each R C4 are independently selected from hydrogen, -C 1～4 More preferably, NR C1 Selected from NH, N(C 1～3 Alkyl), N(C 1～3 Alkylene-S(O) 2 R C2 ), wherein the alkylene group may be optionally replaced by one or two independent R C4 Replacement; R C2 Selected from -C 1～3 Alkyl; each R C4 are independently selected from hydrogen, -C 1～3 Alkyl. For example, NR C1 Selected from N(CH 3 )、N(CH 2 S(O) 2 CH 3 )、N(CH(CH 3 )S(O) 2 CH 3 )、N(CH(CH 2 CH 3 )S(O) 2 CH 3 )、N(CH(CHCH 3 CH 3 )S(O) 2 CH 3 ) or N(C(CH 3 ) 2 S(O) 2 CH 3 ).

[0054] Furthermore, R 1 and R 2 Together with the atoms connected to form

[0055] Where R 1 and R 2 The aforementioned rings formed together with the atoms connected thereto may be further optionally replaced by one, two, three or four R C1 replace.

[0056] Furthermore, each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl, Preferably, each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl, Or preferably, each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl, More preferably, each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～4 alkyl, Further preferably, each R C1 are independently selected from hydrogen, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, More preferably, each R C1 are independently selected from hydrogen, methyl,

[0057] Furthermore, R 1 and R 2 Together with the atoms connected to form

[0058] Where R 1 and R 2 The ring formed together with the attached atoms may be further optionally substituted by one, two, three or four R C1 Replacement, R C1 As defined above. Preferably, R 1 and R 2 Together with the atoms connected to form They can be optionally replaced by one, two, three or four R C1 replace.

[0059] Furthermore, R 1 and R 2 Together with the atoms connected to form

[0060] In some embodiments, R 1 and R 2 Together with the atoms connected to form

[0061] In some embodiments, Ring A is selected from Preferably

[0062] Ring B is selected from Preferably selected from

[0063] R 1 and R 2 Together with the atoms connected to form

[0064] X 1 , X 2 , X 3 , X 4 Each independently selected from N or CR C1 ;

[0065] Y is selected from S or NR C1 ;

[0066] CR C1 Selected from CH, C(C 1～4 alkyl), C(C 1～4 Alkylene-OR C2 ), wherein the alkylene group may be optionally replaced by one or two independent R C4 Replacement; R C2 Selected from hydrogen, -C 1～4 Alkyl; each R C4 are independently selected from hydrogen, -C 1～4 Alkyl; preferably, CR C1 Selected from CH, C(C 1～3 alkyl), C(C 1～3 Alkylene-OR C2 ), wherein the alkylene group may be optionally replaced by one or two independent R C4 Replacement; R C2 is selected from hydrogen; each R C4 are independently selected from hydrogen, -C 1～3 Alkyl; for example, CR C1Selected from CH, CCH 3 , C(C(CH 3 ) 2 OH);

[0067] NR C1 Selected from NH, N(C 1～4 Alkyl), N(C 1～4 Alkylene-S(O) 2 R C2 ), wherein the alkylene group may be optionally replaced by one or two independent R C4 Replacement; R C2 Selected from hydrogen, -C 1～4 Alkyl; each R C4 are independently selected from hydrogen, -C 1～4 Alkyl; preferably, NR C1 Selected from NH, N(C 1～3 Alkyl), N(C 1～3 Alkylene-S(O) 2 R C2 ), wherein the alkylene group may be optionally replaced by one or two independent R C4 Replacement; R C2 Selected from -C 1～3 Alkyl; each R C4 are independently selected from hydrogen, -C 1～3 Alkyl; for example, NR C1 Selected from N(CH 3 )、N(CH 2 S(O) 2 CH 3 )、N(CH(CH 3 )S(O) 2 CH 3 )、N(CH(CH 2 CH 3 )S(O) 2 CH 3 )、N(CH(CHCH 3 CH 3 )S(O) 2 CH 3 ) or N(C(CH 3 ) 2 S(O) 2 CH 3 );

[0068] Preferred R 1 and R 2 Together with the atoms connected to form

[0069] Furthermore, the compound represented by Formula I is represented by Formula IIa or Formula IIb:

[0070]

[0071] wherein each group is as defined above.

[0072] Further, in Formula IIa or Formula IIb, Ring A is selected from

[0073] Ring B is selected from The B ring may be further optionally substituted with one, two, three or four R B1 replace;

[0074] Each R B1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OR B2 、-C(O)R B2 、-C(O)NR B2 R B3 、-NR B2 R B3 、-NR B2 C(O)R B3 ;

[0075] R B2 , R B3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;

[0076] X 1 , X 2 Each independently selected from N or CR C1 ;

[0077] Y is selected from O, S or NR C1 ;

[0078] Each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6Alkynyl, -C 0～4 Alkylene-OR C2 , -C 0～4 Alkylene-OC(O)R C2 , -C 0～4 Alkylene-SR C2 , -C 0～4 Alkylene-S(O) 2 R C2 , -C 0～4 Alkylene-S(O)R C2 , -C 0～4 Alkylene-S(O) 2 NR C2 R C3 , -C 0～4 Alkylene-S(O)NR C2 R C3 , -C 0～4 Alkylene-S(O)(NH)R C2 , -C 0～4 Alkylene-S(O)(NH)NR C2 R C3 , -C 0～4 Alkylene-C(O)R C2 , -C 0～4 Alkylene-C(O)OR C2 , -C 0～4 Alkylene-C(O)NR C2 R C3 , -C 0～4 Alkylene-NR C2 R C3 , -C 0～4 Alkylene-NR C2 C(O)R C3 , -C 0～4 Alkylene-NR C2 S(O) 2 R C3 , -C 0～4 Alkylene-NR C2 S(O)R C3 , -C 0～4 Alkylene-P(O)R C2 R C3 , -C 0～4 Alkylene-P(O)(OR C2 )R C3 , -C 0～4 Alkylene-P(O)(OR C2 )(OR C3 ),-C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein the alkylene, carbocyclic group, heterocyclic alkyl, aromatic ring, aromatic heterocycle may be further optionally replaced by one, two, three or four independent R C4 replace;

[0079] Alternatively, two independent R C1 Together with the atoms connected thereto, they form a 5- to 8-membered carbocyclic group, a 5- to 8-membered heterocyclic alkyl group, a benzene ring, or a 5- to 6-membered aromatic heterocyclic ring; wherein the carbocyclic group, heterocyclic alkyl group, aromatic ring, or aromatic heterocyclic ring may be further optionally replaced by one, two, three, or four independent R C4 replace;

[0080] R C2 , R C3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle);

[0081] Each R C4 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR C5 , -C 0～4 Alkylene-OC(O)R C5 , -C 0～4 Alkylene-SR C5 , -C 0～4 Alkylene-S(O) 2 R C5 , -C 0～4 Alkylene-S(O)R C5 , -C 0～4 Alkylene-S(O) 2 NR C5 RC6 , -C 0～4 Alkylene-S(O)NR C5 R C6 , -C 0～4 Alkylene-S(O)(NH)R C5 , -C 0～4 Alkylene-S(O)(NH)NR C5 R C6 , -C 0～4 Alkylene-C(O)R C5 , -C 0～4 Alkylene-C(O)OR C5 , -C 0～4 Alkylene-C(O)NR C5 R C6 , -C 0～4 Alkylene-NR C5 R C6 , -C 0～4 Alkylene-NR C5 C(O)R C6 , -C 0～4 Alkylene-NR C5 S(O) 2 R C6 , -C 0～4 Alkylene-NR C5 S(O)R C6 , -C 0～4 Alkylene-P(O)R C5 R C6 , -C 0～4 Alkylene-P(O)(OR C5 )R C6 , -C 0～4 Alkylene-P(O)(OR C5 )(OR C6 ); or, two independent R C4 Together with the atoms connected to form

[0082] R C5 , R C6 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered aromatic heterocycle).

[0083] Furthermore, each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～4 Alkylene-OR C2 , -C 0～4 Alkylene-S(O) 2 R C2 , -C 0～4 Alkylene-NR C2 R C3 , -C 0～4 Alkylene-(3- to 6-membered carbocyclic group), -C 0～4 Alkylene-(4- to 6-membered heterocycloalkyl), -C 0～4 Alkylene-(6-membered aromatic ring), -C 0～4 Alkylene-(5- to 6-membered aromatic heterocycle); wherein the alkylene, carbocyclic group, heterocyclic alkyl, aromatic ring, aromatic heterocycle may be further optionally replaced by one, two, three or four independent R C4 Substituted; preferably selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～4 Alkylene-OR C2 , -C 0～4 Alkylene-S(O) 2 R C2 , -C 0～4 Alkylene-NR C2 R C3 ; More preferably selected from hydrogen, halogen, cyano, -C 1～3 Alkyl, -C 1～3 Alkylene-OR C2 , -C 1～3 Alkylene-S(O) 2 R C2 ; Further preferably selected from hydrogen, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, -C 1～2 Alkylene-OR C2 , -C 1～2 Alkylene-S(O) 2 R C2 ; Further preferably selected from hydrogen, methyl, -C 1 Alkylene-OR C2 , -C 1 Alkylene-S(O) 2 R C2wherein the alkylene group, carbocyclic group, heterocyclic alkyl group, aromatic ring, aromatic heterocyclic ring may be further optionally replaced by one, two, three or four independent R C4 replace;

[0084] R C2 , R C3 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl; preferably selected from hydrogen, -C 1～6 Alkyl; more preferably selected from hydrogen, -C 1～4 Alkyl; further preferably selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; further preferably selected from hydrogen, methyl;

[0085] Each R C4 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～4 Alkylene-OR C5 , -C 0～4 Alkylene-S(O) 2 R C5 , -C 0～4 Alkylene-NR C5 R C6 ; preferably selected from hydrogen, -C 1～6 Alkyl; more preferably selected from hydrogen, -C 1～4 Alkyl; further preferably selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; further preferably selected from hydrogen, methyl; or, two independent R C4 Together with the atoms connected to form

[0086] R C5 , R C6 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl.

[0087] More specifically, the B ring is selected from

[0088] Preferably, Ring B is selected from Or preferably, Ring B is selected from More preferably, Ring B is selected from

[0089] Each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C1～6 alkyl, Preferably, each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl, Or preferably, each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl, More preferably, each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～4 alkyl, Further preferably, each R C1 are independently selected from hydrogen, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, More preferably, each R C1 are independently selected from hydrogen, methyl,

[0090] Furthermore, the compound represented by formula IIb is represented by formula III:

[0091]

[0092] wherein each group is as defined above.

[0093] Further, in Formula III, Ring A is selected from

[0094] Ring B is selected from

[0095] Y is selected from O, S or NR C1 ;

[0096] X 11 Selected from O, S, NR C4 or

[0097] R C1 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl;

[0098] R C4 Selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C1～6 alkyl.

[0099] In certain preferred embodiments, the compound represented by Formula I is represented by Formula IIc:

[0100]

[0101] wherein each group is as defined above.

[0102] Further, in Formula IIc, Ring A is selected from

[0103] Ring B is selected from The B ring may be further optionally substituted with one, two, three or four R B1 replace;

[0104] Each R B1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OR B2 、-C(O)R B2 、-C(O)NR B2 R B3 、-NR B2 R B3 、-NR B2 C(O)R B3 ;

[0105] X 1 , X 2 , X 3 , X 4 Each independently selected from N or CR C1 ;

[0106] Each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR C2 , -C 0～4 Alkylene-OC(O)R C2 , -C 0～4 Alkylene-SR C2 , -C 0～4 Alkylene-S(O) 2 R C2 , -C0～4 Alkylene-S(O)R C2 , -C 0～4 Alkylene-S(O) 2 NR C2 R C3 , -C 0～4 Alkylene-S(O)NR C2 R C3 , -C 0～4 Alkylene-S(O)(NH)R C2 , -C 0～4 Alkylene-S(O)(NH)NR C2 R C3 , -C 0～4 Alkylene-C(O)R C2 , -C 0～4 Alkylene-C(O)OR C2 , -C 0～4 Alkylene-C(O)NR C2 R C3 , -C 0～4 Alkylene-NR C2 R C3 , -C 0～4 Alkylene-NR C2 C(O)R C3 , -C 0～4 Alkylene-NR C2 S(O) 2 R C3 , -C 0～4 Alkylene-NR C2 S(O)R C3 , -C 0～4 Alkylene-P(O)R C2 R C3 , -C 0～4 Alkylene-P(O)(OR C2 )R C3 , -C 0～4 Alkylene-P(O)(OR C2 )(OR C3 ),-C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle); wherein the alkylene, carbocyclic group, heterocyclic alkyl, aromatic ring, aromatic heterocycle may be further optionally replaced by one, two, three or four independent R C4 replace;

[0107] Alternatively, two independent R C1Together with the atoms connected thereto, they form a 5- to 8-membered carbocyclic group, a 5- to 8-membered heterocyclic alkyl group, a benzene ring, or a 5- to 6-membered aromatic heterocyclic ring; wherein the carbocyclic group, heterocyclic alkyl group, aromatic ring, or aromatic heterocyclic ring may be further optionally replaced by one, two, three, or four independent R C4 replace;

[0108] R C2 , R C3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered aromatic heterocycle);

[0109] Each R C4 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR C5 , -C 0～4 Alkylene-OC(O)R C5 , -C 0～4 Alkylene-SR C5 , -C 0～4 Alkylene-S(O) 2 R C5 , -C 0～4 Alkylene-S(O)R C5 , -C 0～4 Alkylene-S(O) 2 NR C5 R C6 , -C 0～4 Alkylene-S(O)NR C5 R C6 , -C 0～4 Alkylene-S(O)(NH)R C5 , -C 0～4 Alkylene-S(O)(NH)NR C5 R C6 , -C0～4 Alkylene-C(O)R C5 , -C 0～4 Alkylene-C(O)OR C5 , -C 0～4 Alkylene-C(O)NR C5 R C6 , -C 0～4 Alkylene-NR C5 R C6 , -C 0～4 Alkylene-NR C5 C(O)R C6 , -C 0～4 Alkylene-NR C5 S(O) 2 R C6 , -C 0～4 Alkylene-NR C5 S(O)R C6 , -C 0～4 Alkylene-P(O)R C5 R C6 , -C 0～4 Alkylene-P(O)(OR C5 )R C6 , -C 0～4 Alkylene-P(O)(OR C5 )(OR C6 ); or, two independent R C4 Together with the atoms connected to form

[0110] R C5 , R C6 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-(3-10 membered carbocyclic group), -C 0～4 Alkylene-(4- to 10-membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered aromatic heterocycle).

[0111] Preferably, R B2 , R B3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl.

[0112] Furthermore, each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～4 Alkylene-OR C2 , -C 0～4 Alkylene-S(O) 2 R C2 , -C 0～4 Alkylene-NR C2 R C3 , -C 0～4 Alkylene-(3- to 6-membered carbocyclic group), -C 0～4 Alkylene-(4- to 6-membered heterocycloalkyl), -C 0～4 Alkylene-(6-membered aromatic ring), -C 0～4 Alkylene-(5-6 membered aromatic heterocycle); preferably selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～4 Alkylene-OR C2 , -C 0～4 Alkylene-S(O) 2 R C2 , -C 0～4 Alkylene-NR C2 R C3 ; More preferably selected from hydrogen, halogen, cyano, -C 1～3 Alkyl, -C 1～3 Alkylene-OR C2 , -C 1～3 Alkylene-S(O) 2 R C2 ; Further preferably selected from hydrogen, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, -C 1～2 Alkylene-OR C2 , -C 1～2 Alkylene-S(O) 2 R C2 ; Further preferably selected from hydrogen, methyl, -C 1 Alkylene-OR C2 , -C 1 Alkylene-S(O) 2 R C2 ; Most preferably hydrogen or methyl; wherein the alkylene, carbocyclic group, heterocyclic alkyl, aromatic ring, aromatic heterocyclic ring may be further optionally replaced by one, two, three or four independent R C4 replace;

[0113] R C2 , R C3 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl; preferably selected from hydrogen, -C 1～6 Alkyl; more preferably selected from hydrogen, -C 1～4 Alkyl; further preferably selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; further preferably selected from hydrogen, methyl;

[0114] Each R C4 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～4 Alkylene-OR C5 , -C 0～4 Alkylene-S(O) 2 R C5 , -C 0～4 Alkylene-NR C5 R C6 ; preferably selected from hydrogen, -C 1～6 Alkyl; more preferably selected from hydrogen, -C 1～4 Alkyl; further preferably selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; further preferably selected from hydrogen, methyl; or, two independent R C4 Together with the atoms connected to form

[0115] R C5 , R C6 are independently selected from hydrogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl.

[0116] More specifically, the B ring is selected from

[0117] Preferably, Ring B is selected from Or preferably, Ring B is selected from More preferably, Ring B is selected from

[0118] Each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl, Preferably, each R C1are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl, Or preferably, each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, halogen-substituted -C 1～6 alkyl, More preferably, each R C1 are independently selected from hydrogen, halogen, cyano, -C 1～4 alkyl, Further preferably, each R C1 are independently selected from hydrogen, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, More preferably, each R C1 are independently selected from hydrogen, methyl,

[0119] The present application also relates to any combination of the above-mentioned embodiments and preferred embodiments.

[0120] In some specific embodiments of the present application, the compound represented by formula I includes but is not limited to:

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127] The present application also provides a pharmaceutical composition, comprising any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0128] In certain embodiments, the above pharmaceutical composition further includes pharmaceutically acceptable carriers, excipients, and vehicles.

[0129] The present application also provides use of any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions in the preparation of ATR inhibitors.

[0130] The present application also provides any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, used as ATR inhibitors. Alternatively, the present application provides any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, used to inhibit ATR.

[0131] The present application also provides a method for inhibiting ATR activity in a subject, comprising administering any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical composition to a subject in need thereof.

[0132] The present application also provides the use of any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical compositions in the preparation of a method for treating or improving cancer.

[0133] The present application also provides a method for treating or improving cancer, comprising administering any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical composition to a subject in need thereof.

[0134] The present application also provides any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for treating or improving cancer. Alternatively, the present application provides the use of any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for treating or improving cancer.

[0135] In certain embodiments, the cancer is selected from colon cancer, rectal cancer, gastric cancer, esophageal cancer, primary peritoneal cancer, adrenocortical carcinoma, renal clear cell carcinoma, prostate cancer, bladder urothelial carcinoma, ovarian cancer, breast cancer, endometrial cancer, fallopian tube cancer, non-small cell lung cancer, or small cell lung cancer.

[0136] Definition and Description

[0137] Unless otherwise specified, the terms used in this application have the following meanings. A particular term should not be considered as uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

[0138] The compounds and derivatives provided in this application can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0139] Definitions of terms used in this application: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined in this document, the meaning that a person skilled in the art can give them should be given based on the disclosure and context.

[0140] "Substitution" means that the hydrogen atom in a molecule is replaced by another different atom or group; or the lone pair of electrons in an atom in a molecule is replaced by another atom or group. For example, the lone pair of electrons on the S atom can be replaced by an O atom to form

[0141] "May be further optionally substituted" means that "substitution" may but need not occur, and the description includes the case where it occurs or does not occur, ie, substituted or unsubstituted.

[0142] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1～6 The alkyl group refers to an alkyl group containing 1 to 6 carbon atoms.

[0143] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. Alkyl groups may also be part of other groups, such as -O(C 1～6 alkyl).

[0144] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon radical having the specified number of member atoms. a～b Alkylene refers to an alkylene group having from a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, the term "propylene" can be exemplified by the following structure: Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:

[0145] This application's -C 0 ~ 4 The alkylene group can be C 0 Alkylene, C 1 Alkylene (e.g. -CH 2 -), C 2 Alkylene (e.g. -CH 2 CH2 - etc.), C 3 Alkylene or C 4 Alkylene; C 0 Alkylene means that the group here does not exist and is connected in the form of a chemical bond, such as AC 0 Alkylene-B refers to AB, that is, the A group and the B group are directly connected by a chemical bond.

[0146] "Carbocyclyl" described in the present application refers to a partially saturated cyclic group with multiple carbon atoms and no cyclic heteroatoms having a single ring or multiple rings (fused, bridged, spiro) saturated or non-aromatic. The term "carbocyclyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of monocarbocyclyl groups include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of carbocyclyl groups of condensed carbocyclyl systems include dicyclohexyl, dicyclopentyl, dicyclooctyl, etc., and two such dicycloalkyl polycyclic structures are exemplified and named below: Biscyclohexyl and Examples of carbocyclyl groups of the bridged carbocyclyl system include adamantyl, etc. Examples of the carbocyclyl group of the spirocarbocyclyl system include The term "carbocyclic group" also includes the case where an aromatic ring is fused with a non-aromatic ring to form a partially saturated cyclic group, and the attachment point can be located at a non-aromatic carbon atom or an aromatic carbon atom, examples of which include 1,2,3,4-tetrahydronaphthalene-5-yl and 5,6,7,8-tetrahydronaphthalene-5-yl.

[0147] The term "unsaturated" as used herein refers to a group or molecule containing a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-oxygen double bond, a carbon-sulfur double bond, a carbon-nitrogen triple bond, and the like.

[0148] "Alkenyl" means a group having at least one site of vinyl unsaturation. A straight or branched hydrocarbon group. a～b Alkenyl refers to an alkenyl group having from a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0149] "Alkynyl" refers to a straight chain monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon radicals having one triple bond and one double bond. For example, C 2-6 Alkynyl is meant to include ethynyl, propynyl, and the like.

[0150] "Heterocycloalkyl" as described in the present application refers to a saturated ring or a non-aromatic partially saturated ring having a single ring or multiple rings (fused, bridged, spiro) containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It usually refers to a monovalent saturated or partially unsaturated monocyclic or polycyclic ring system with multiple ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Examples of heterocycloalkyl groups of monoheterocycloalkyl systems are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxaazepanyl, etc. Examples of heterocycloalkyl groups of fused heterocycloalkyl systems include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, etc. Examples of heterocycloalkyl groups of bridged heterocycloalkyl systems include etc. Examples of heterocycloalkyl groups of the spiroheterocycloalkyl system include Examples of partially saturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl, etc. The term "heterocycloalkyl" also includes a partially saturated cyclic group formed by condensing an aromatic ring containing at least one heteroatom with a non-aromatic ring, and the attachment point can be located at a non-aromatic carbon atom, an aromatic carbon atom or a heteroatom, examples include

[0151] "Aromatic ring" as described in the present application refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl is typically a monocyclic, bicyclic or tricyclic aromatic group having multiple carbon atoms. In addition, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.

[0152] The "aromatic heterocycle" described in the present application refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. An aromatic monocyclic or bicyclic hydrocarbon containing a plurality of ring atoms, wherein one or more ring atoms are selected from heteroatoms of O, N, and S. Preferably, one to three heteroatoms are contained. Heterocyclic aryl represents, for example, pyridyl, indolyl, quinoxalyl, quinolyl, isoquinolyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiapyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, etc.

[0153] The "halogen" described in the present application refers to fluorine, chlorine, bromine or iodine.

[0154] The "halogen-substituted alkyl" mentioned in the present application refers to an alkyl group in which one or more hydrogen atoms are substituted by halogen; 1～4 Alkyl refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are replaced by one or more halogen atoms; examples include monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, etc., such as monochloromethyl, dichloromethyl, trichloromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, etc. Similarly, the "halogen-substituted alkenyl" described in the present application refers to one or more hydrogen atoms in the alkenyl group being replaced by halogen; the "halogen-substituted alkynyl" described in the present application refers to one or more hydrogen atoms in the alkynyl group being replaced by halogen.

[0155] The "-OR", "-NRR" and the like described in the present application mean that the R group is connected to the oxygen atom or the nitrogen atom by a single bond.

[0156] The "-C(O)R", "-S(O) 2 The oxygen atom in R" is connected to the carbon atom or sulfur atom by a double bond.

[0157] The "-C(O)R", "-S(O) 2 R" means that the oxygen atom is connected to the carbon atom or the sulfur atom by a double bond, and the R group is connected to the oxygen atom or the sulfur atom by a single bond. Another example is "-S(O)(NH)R" means that the oxygen atom and the nitrogen atom are connected to the sulfur atom by a double bond, and the R group is connected to the sulfur atom by a single bond.

[0158] Described in this application It means that the oxygen atom and sulfur atom are connected to the substitution position through a double bond.

[0159] The group description in this application It is used to describe the position of the substitution group. The tetrahydropyrrole ring passes through The position of the ring is fused with other rings in the structure.

[0160] The "deuterated compound" of the present application refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0161] The term "subject" is equivalent to "patient" and "individual", and refers to a human or non-human animal (mammal, such as primate, rodent, etc.). "Mammal" includes humans and domestic animals (such as laboratory mammals and household pets, such as cats, dogs, pigs, sheep, cattle, sheep, goats, horses, rabbits), and non-domesticated mammals, such as wild mammals, etc.

[0162] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes inhibiting the progression of a disease or condition, and alleviating a disease or condition.

[0163] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients constituting a pharmaceutical dosage form and physiologically compatible with the receptor without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0164] The carrier, excipient, and / or vehicle described herein may be any pharmaceutically acceptable carrier, excipient, and / or vehicle, such as, but not limited to, solvents (such as water, saline, glycerol and ethanol), propellants, solubilizers, cosolvents, emulsifiers, colorants, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, antioxidants, penetration enhancers, pH regulators, surfactants, diluents, etc. For other available pharmaceutically acceptable pharmaceutical excipients, see, for example, Handbook of Pharmaceutical Excipients (4th edition), written by RC Luo et al., translated by Zheng Zemin, 2005, Chemical Industry Press.

[0165] The terms "salt", "pharmaceutically acceptable salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts formed by the above-mentioned compounds or their stereoisomers with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compounds. They can also be obtained by mixing the above-mentioned compounds, or their stereoisomers, with a certain amount of acid or base appropriately (for example, equivalent amounts). These salts may be precipitated in the solution and collected by filtration, or recovered after evaporation of the solvent, or obtained by freeze-drying after reaction in an aqueous medium.

[0166] In certain embodiments, one or more compounds of the present application can be used in combination with each other. It is also possible to select the compounds of the present application to be used in combination with any other active agent to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds can be administered to the subject simultaneously, separately or in order.

[0167] The words "include", "comprising" and "containing" and their equivalents should be understood as an open, non-exclusive meaning, i.e., "including but not limited to", meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0168] The compounds of the present application may exist in stereoisomer form. Unless otherwise indicated, the stereoisomers mentioned herein include geometric isomers and enantiomers. All these isomers and their mixtures are included within the scope of the present application.

[0169] The pharmaceutical composition and compound of the present application can be prepared into any suitable preparation, for example, solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc. The preparations can be prepared by methods well known in the art, such as conventional mixing methods, dissolution methods, tableting methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0170] Typical routes of administration of the pharmaceutical compositions and compounds of the present application include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0171] In this document, unless the context clearly indicates otherwise, singular terms include plural referents and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" is intended to include "and" and vice versa.

[0172] Unless otherwise specified, in this article, the parameter values ​​representing the amount of ingredients or physicochemical properties or reaction conditions, etc. should be understood to be modified by the term "about" in all cases. When the term "about" is used to describe the present application, the term "about" indicates the error value that exists, for example, it indicates a change within the range of ±5%, such as ±1% or ±0.1% of a particular value.

[0173] Obviously, based on the above content of this application, in accordance with common technical knowledge and customary means in this field, without departing from the above basic technical ideas of this application, other various forms of modifications, replacements or changes can be made.

[0174] For the purpose of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements regarding the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any reference to these publications herein does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

[0175] The above contents of the present application are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present application being limited to the following examples. All technologies implemented based on the above contents of the present application belong to the scope of the present application. DETAILED DESCRIPTION

[0176] The structures of the compounds were determined by nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). -6 The units of (ppm) were given. NMR measurements were performed using a nuclear magnetic spectrometer (Bruker AvanceIII 400 and Bruker Avance 300) and the measurement solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ) or deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane (TMS).

[0177] LC-MS was determined using a Shimadzu LC-MS 2020 (ESI). HPLC was determined using a Shimadzu LC-20A high pressure liquid chromatograph. MPLC (medium pressure preparative chromatography) used a Gilson GX-281 reverse phase preparative chromatograph. The thin layer chromatography silica gel plate used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm. Column chromatography generally uses Yantai Huanghai silica gel 200 to 300 mesh silica gel as a carrier.

[0178] The known starting materials of the present application can be synthesized by methods known in the art, or can be purchased from companies such as Anage Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0179] Unless otherwise specified in the examples, the reaction is carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. The term "room temperature" in this application refers to a temperature between 10°C and 25°C. Unless otherwise specified in the examples, M is moles per liter.

[0180] Example 1

[0181]

[0182] first step

[0183] Compound 1a (200.0 mg, 0.9 mmol) was dissolved in acetonitrile (3.0 mL), and (R)-3-methylmorpholine (100.0 mg, 0.9 mmol) and N-ethyldiisopropylamine (254.0 mg, 2.0 mmol) were added. The reaction solution was heated to 60°C for 1 hour. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain compound 1b (180.0 mg, 0.7 mmol, yield: 68.4%).

[0184] MS-ESI calculated value [M+H] + 268.1, measured value 268.1.

[0185] Step 2

[0186] Compound 1b (180.0 mg, 0.6 mmol) was dissolved in a mixed solution of 1,4-dioxane (6.0 mL) and water (3.0 mL), and then 4-indoleboric acid pinacol ester (246.0 mg, 1.0 mmol), anhydrous sodium carbonate (127.2 mg, 1.2 mmol) and bis(triphenylphosphine)palladium dichloride (II) (47.0 mg, 0.07 mmol) were added in sequence. After nitrogen replacement, the mixture was heated to 125°C for 1 hour. After the reaction was completed, ethyl acetate (3*10 mL) was added to extract the organic phase, the organic phases were combined and dried over anhydrous sodium sulfate, the desiccant was filtered and concentrated under reduced pressure, and compound 1 (14.8 mg, 0.04 mmol, yield: 6.3%) was obtained after column chromatography preparation, and HPLC purity: 97.2%.

[0187] MS-ESI calculated value [M+H] + 349.2, measured value 349.1.

[0188] 1 H NMR (400 MHz, DMSO-d 6)δ11.25(s,1H),8.25(s,1H),8.20(d,J=7.5Hz,1H),7.55–7.463(m,3H),7.20(t,J=7.7Hz,1H ),4.05-4.01(m,4H),3.85-3.72(m,4H),3.61(dd,J=12.5,9.4Hz,2H),1.36(d,J=6.8Hz,3H).

[0189] Example 2

[0190]

[0191] first step

[0192] Compound 2a (1.5 g, 8.0 mmol) was dissolved in acetonitrile (36.0 ml), and N,N-diisopropylethylamine (2.1 g, 16.1 mmol) and (R)-3-methylmorpholine (976.1 mg, 9.7 mmol) were added in sequence at 20°C. The resulting reaction solution was stirred at 20°C for 2 hours. After the reaction was completed, water (50.0 mL) was added for dilution, and ethyl acetate (50.0 mL*3) was used for extraction. The resulting organic phase was dried over anhydrous sodium sulfate and filtered. The resulting filtrate was distilled under reduced pressure to remove the solvent to obtain a crude product, which was purified by column chromatography to obtain compound 2b (940.0 mg, 3.7 mmol, yield: 45.6%).

[0193] MS-ESI calculated value [M+H] + 254.1, measured value 254.1.

[0194] Step 2

[0195] Compound 2b (940.0 mg, 3.7 mmol) and potassium tert-butoxide (831.6 mg, 7.4 mmol) were dissolved in ethylene glycol dimethyl ether (40.0 mL). The reaction solution was heated to 65°C, and a solution of chloromethyl methyl sulfide (536.8 mg, 5.6 mmol) in ethylene glycol dimethyl ether (5.0 ml) was slowly added dropwise, and the reaction was stirred at 65°C for 3 hours. After the reaction was completed, water (50.0 mL) was added for dilution, and ethyl acetate (50.0 mL*3) was used for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure to remove the solvent to obtain a crude product, which was purified by column chromatography to obtain compound 2c (216.0 mg, 0.7 mmol, yield: 17.1%).

[0196] MS-ESI calculated value [M+H] + 314.1, measured value 314.2.

[0197] Step 3

[0198] Compound 2c (165.0 mg, 0.5 mmol) was dissolved in methanol (5.0 ml), and a solution of potassium peroxymonosulfate (678.0 mg, 1.1 mmol) in water (2.5 mL) was slowly added at 0°C. The resulting reaction solution was stirred at 20°C for 3 hours. After the reaction was completed, the methanol was removed by concentration under reduced pressure, and water (50.0 mL) was added for dilution, and ethyl acetate (50.0 mL*3) was used for extraction. The obtained organic phase was dried over anhydrous sodium sulfate and filtered. The obtained filtrate was distilled under reduced pressure to remove the solvent to obtain a crude product, which was purified by column chromatography to obtain compound 2d (172.5 mg, 0.5 mmol, yield: 100%).

[0199] MS-ESI calculated value [M+H] + 346.1, measured value 346.2.

[0200] Step 4

[0201] Compound 2d (172.5 mg, 0.5 mmol), 4-indoleboric acid pinacol ester (129.0 mg, 0.5 mmol), bis(triphenylphosphine)palladium(II) dichloride (37.2 mg, 0.05 mmol), sodium carbonate (112.5 mg, 1.1 mmol) were added to a mixed solution of dioxane (4.0 mL) and water (2.0 mL), and reacted at 100° C. for 2 hours under nitrogen protection. After the reaction was completed, water (50.0 mL) was added for dilution, ethyl acetate (50.0 mL*3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was subjected to reduced pressure distillation to remove the solvent to obtain a crude product, which was separated by column chromatography and high performance liquid chromatography to prepare compound 2 (43.0 mg, 0.1 mmol, yield: 18.1%), HPLC purity: 95.1%.

[0202] MS-ESI calculated value [M+H] + 427.2, measured value 427.2.

[0203] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.27(s,1H),8.47(s,1H),8.19(dd,J=7.6,1.0Hz,1H),7.56(dd,J=8.0,1.0Hz,1H),7.49-7.45(m,2H),7.21(t,J=7.8Hz,1H) ,5.91(s,2H),4.40-4.15(m,2H),4.06(d,J=8.9Hz,1H),3.87–3.73(m,2H),3.67-3.45(m,2H),3.17(s,3H),1.39(d,J=6.7Hz,3H).

[0204] Example 3

[0205]

[0206] first step

[0207] Compound 3a (266.0 mg, 1.3 mmol) was dissolved in acetonitrile (10.0 mL), and then (R)-3-methylmorpholine (144.0 mg, 1.4 mmol) and N-ethyldiisopropylamine (362.0 mg, 2.8 mmol) were added. The reaction solution was heated to 60°C for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure, and the crude product was subjected to column chromatography to obtain compound 3b (332.0 mg, 1.2 mmol, yield: 92.0%).

[0208] MS-ESI calculated value [M+H] + 279.1, measured value 279.2.

[0209] Step 2

[0210] Compound 3b (332.0 mg, 1.2 mmol) was dissolved in a mixed solvent of 1,4-dioxane (8 mL) and water (4 mL). Then, 4-indoleboric acid pinacol ester (435.0 mg, 1.8 mmol), anhydrous sodium carbonate (253.0 mg, 2.4 mmol) and bis(triphenylphosphine)palladium(II) dichloride (84.0 mg, 0.1 mmol) were added in sequence, and the mixture was heated to 125°C and stirred for 1 hour after nitrogen replacement. After the reaction was completed, ethyl acetate (3*20 mL) was added to extract the organic phase, the organic phases were combined and dried over anhydrous sodium sulfate, the desiccant was filtered and concentrated under reduced pressure, and the compound 3 (106.2 mg, 0.3 mmol, yield: 24.8%) was prepared by column chromatography, and the HPLC purity was 99.6%.

[0211] MS-ESI calculated value [M+H] + 360.2, measured value 360.2.

[0212] 1 H NMR (400 MHz, DMSO-d 6)δ11.52(s,1H),8.56(d,J=8.6Hz,1H),8.07(d,J=7.5Hz,1H),7.71(d,J=8.0Hz,1H),7.65–7.50(m,2H),7.35–7.24(m,2H),5.1 0-4.90(m,1H),4.45-4.25(m,1H),4.07–3.91(m,2H),3.85-3.79(m,2H),3.72–3.67(m,1H),2.76(s,3H),1.56(d,J=6.8Hz,3H).

[0213] Example 4

[0214]

[0215] first step

[0216] Compound 4a (2.0 g, 9.7 mmol) was dissolved in acetonitrile (30.0 mL), and then (R)-3-methylmorpholine (1.0 g, 9.8 mmol) and N-ethyldiisopropylamine (2.5 g, 19.0 mmol) were added. The reaction solution was heated to 60°C for 1 hour. After the reaction was completed, the crude product was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain compound 4b (2.1 g, 7.8 mmol, yield: 81.3%).

[0217] MS-ESI calculated value [M+H] + 270.1, measured value 270.1.

[0218] Step 2

[0219] Compound 4b (800.0 mg, 2.9 mmol) was dissolved in anhydrous tetrahydrofuran (20.0 mL). After nitrogen replacement, n-butyl lithium (3.5 mL of n-hexane solution, 2.5 M, 8.9 mmol) was slowly added dropwise at -78 ° C. After the reaction was stirred at this temperature for two hours, anhydrous acetone (517.0 mg, 8.9 mmol) was added, and the reaction was continued at -78 ° C for 1 hour. After the reaction was completed, water (30.0 mL) was added to quench the reaction, and ethyl acetate (3*50.0 mL) was added to extract the organic phase. The organic phases were combined and dried over anhydrous sodium sulfate, and the desiccant was filtered and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by column chromatography to obtain compound 4c (360.0 mg, 1.1 mmol, yield: 36.9%).

[0220] MS-ESI calculated value [M+H] + 328.1, measured value 328.0.

[0221] Step 3

[0222] Compound 4c (330.0 mg, 1.0 mmol) was dissolved in a mixed solution of 1,4-dioxane (20 mL) and water (10.0 mL). Then, 4-indoleboric acid pinacol ester (367.0 mg, 1.5 mmol), anhydrous sodium carbonate (212.0 mg, 2.0 mmol) and bis(triphenylphosphine)palladium(II) dichloride (70.0 mg, 0.1 mmol) were added in sequence. After nitrogen replacement, the reaction was heated to 125°C for 1 hour. After the reaction was completed, ethyl acetate (3*20 mL) was added to extract the organic phase, the organic phases were combined and dried over anhydrous sodium sulfate, the desiccant was filtered and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by column chromatography to obtain compound 4 (335.3 mg, 0.8 mmol, yield: 81.7%), HPLC purity: 95.9%.

[0223] MS-ESI calculated value [M+H] + 409.2, measured value 409.3.

[0224] 1 H NMR (600 MHz, DMSO-d 6 )δ11.21(s,1H),8.12(d,J=7.5Hz,1H),7.51(d,J=8.0Hz,1H),7.48-7.40(m,2H ),7.35(s,1H),7.20(t,J=7.7Hz,1H),5.87(s,1H),4.90-4.80(m,1H),4.55-4.4 7(m,1H),4.10-4.02(m,1H),3.90-3.82(m,1H),3.80-3.72(m,1H),3.60(t,J=12 .0Hz,1H),3.53(t,J=12.0Hz,1H),1.62(d,J=9.8Hz,6H),1.38(d,J=6.9Hz,3H).

[0225] Example 5

[0226]

[0227] first step

[0228] Compound 2d (100.0 mg, 0.29 mmol) was dissolved in a mixed solvent of DMF (1.5 mL) and THF (1.5 mL), and the reaction was placed in an ice bath. NaH (14 mg, 0.58 mmol) was added 2 minutes later. The reaction was stirred in an ice bath under the protection of a nitrogen balloon for 20 minutes, and then MeI (61.60 mg, 0.43 mmol) was added. After the addition, the reaction was gradually heated to room temperature and stirred for 5 hours. TLC showed that the raw material 2d disappeared completely, and then water (5.0 mL) was slowly added to quench the reaction. The resulting solution was extracted with ethyl acetate (3*5.0 mL), the organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was directly used in the next reaction without separation and purification.

[0229] MS-ESI calculated value [M+H]+ 360.1, found value 360.2.

[0230] Step 2

[0231] The unpurified compound 5a (0.29 mmol) from the previous step was dissolved in a mixed solution of 1,4-dioxane (3.0 mL) and water (1.0 mL). Then, 4-indoleboric acid pinacol ester (81.0 mg, 0.33 mmol), anhydrous sodium carbonate (59.0 mg, 0.56 mmol) and bis(triphenylphosphine)palladium(II) dichloride (27.8.0 mg, 0.028 mmol) were added in sequence. After nitrogen substitution, the reaction was heated to 85°C for 2 hours. After the reaction was completed, water (3.0 mL) was added to quench, and then the organic phase was extracted with ethyl acetate (3*5.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography and then separated into diastereoisomers by SFC to obtain single compound 5-isomer 1 (17.4 mg, two-step yield 13.7%, fast fraction), purity: 98.4%; 5-isomer 2 (18.1 mg, two-step yield 14.2%, slow fraction), purity 98.6%. SFC conditions: Column: CHIRALPAK AS-3 150*3mm LD, 3μm, Mobile phase: A: CO 2 , B: ethanol, Gradient: A / B=78 / 22, Flow rate: 1mL / min, Column temp.: 35℃, ABPR: 14MPa. [P1, 4.14min; P2, 6.05min].

[0232] 5-isomer 1:MS-ESI calculated value [M+H] + 441.2, measured value 441.2.

[0233] 5-isomer 2:MS-ESI calculated value [M+H] + 441.2, measured value 441.2.

[0234] 5-isomer 1: 1 H NMR (400 MHz, DMSO-d 6 )δ11.28(s,1H),8.46(s,1H),8.20(d,J=7.3Hz,1H),7.56(d,J=8.0Hz,1H),7.49(t ,J=2.7Hz,1H),7.45(s,1H),7.21(t,J=7.7Hz,1H),6.18(q,J=7.0Hz,1H),5.46-4.2 8(brs,2H),4.07(d,J=8.4Hz,1H),3.84(d,J=11.6Hz,1H),3.76(dd,J=11.7,3.2Hz ,1H),3.66-3.40(m,2H),3.00(s,3H),2.03(d,J=7.1Hz,3H),1.39(d,J=6.7Hz,3H).

[0235] 5-isomer 2: 1 H NMR (400 MHz, DMSO-d 6 )δ11.28(s,1H),8.46(s,1H),8.20(d,J=7.4Hz,1H),7.56(d,J=7.9Hz,1H),7.49(t ,J=2.8Hz,1H),7.46(s,1H),7.21(t,J=7.7Hz,1H),6.19(q,J=7.0Hz,1H),5.46-4.3 9(brs,2H),4.07(d,J=8.4Hz,1H),3.84(d,J=11.6Hz,1H),3.76(dd,J=11.6,3.2Hz ,1H),3.65-3.43(m,2H),3.00(s,3H),2.04(d,J=7.1Hz,3H),1.39(d,J=6.8Hz,3H).

[0236] Example 6

[0237]

[0238] first step

[0239] Compound 2d (200.0 mg, 0.58 mmol) was dissolved in a mixed solvent of DMF (2.0 mL) and THF (2.0 mL), and the reaction was placed in an ice bath. NaH (93.0 mg, 2.32 mmol) was added 2 minutes later. The reaction was stirred in an ice bath under the protection of a nitrogen balloon for 20 minutes, and then MeI (329.4 mg, 2.32 mmol) was added. After the addition, the reaction was gradually heated to room temperature and stirred for 5 hours. TLC showed that the raw material 2d disappeared completely, and then water (5.0 mL) was slowly added to quench the reaction. The resulting solution was extracted with ethyl acetate (3*5.0 mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was separated and purified by column chromatography to obtain compound 6a (123.2 mg, yield: 56%).

[0240] 6a: MS-ESI calculated value [M+H] + 374.1, measured value 374.2.

[0241] Step 2

[0242] Compound 6a (100 mg, 0.28 mmol) was dissolved in a mixed solution of 1,4-dioxane (4.0 mL) and water (1.0 mL). Then, 4-indoleboric acid pinacol ester (78.1 mg, 0.32 mmol), anhydrous sodium carbonate (56.7 mg, 0.53 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18.8 mg, 0.027 mmol) were added in sequence. After nitrogen replacement, the reaction was heated to 60 ° C for 1 hour. After the reaction was completed, water (3.0 mL) was added to quench, and then the organic phase was extracted with ethyl acetate (3*5.0 mL). The organic phases were combined and dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by column chromatography and then purified by alkaline reverse phase preparation to obtain compound 6 (21.5 mg, yield 18.2%), purity: 93.1%.

[0243] 6: MS-ESI calculated value [M+H] + 455.2, measured value 455.2.

[0244] 1 H NMR (600 MHz, DMSO-d 6)δ11.25(s,1H),8.43(s,1H),8.05(d,J=7.5Hz,1H),7.57(d,J=8.0Hz,1H),7.48(s,1H),7.36(s,1H),7.23(t,J=7.9Hz,1H),5.25-4.37(brs ,2H),4.07(d,J=10.1Hz,1H),3.85(d,J=11.5Hz,1H),3.79-3.75(m,1H),3.65-3.43(m,2H),2.92(s,3H),2.36(m,6H),1.39(d,J=6.8Hz,3H).

[0245] Example 7

[0246]

[0247] first step

[0248] Referring to the method of Example 5, 7-isomer 1 and 7-isomer 2 were obtained using compound 5a (83.0 mg, 0.23 mmol), 6-nitrogen-4-indoleboric acid pinacol ester (67.3 mg, 0.28 mmol), anhydrous sodium carbonate (48.7 mg, 0.53 mmol) and bis(triphenylphosphine)palladium(II) dichloride (18.8 mg, 0.027 mmol). 7-isomer 1 (3.24 mg, two-step yield: 3.4%, fast fraction), purity: 94.2% (220 nm), compound 7-isomer 2 (3.16 mg, two-step yield 3.1%, slow fraction), purity: 97.8%. SFC separation conditions: Column: CHIRALCEL OJ-3 150*3 mml.D., 3 μm, Mobile phase: A: CO 2 , B: ethanol (0.2% DEA), Gradient: A / B=75 / 25, Flowrate: 1mL / min, Column temp.: 35℃, ABPR: 14MPa. [P1, 2.69min; P2, 4.06min]

[0249] 7-isomer 1: MS-ESI calculated value [M+H]+ 442.2, found value 442.3.

[0250] 7-isomer 2: MS-ESI calculated value [M+H]+ 442.2, found value 442.3.

[0251] 7-isomer 1: 11H NMR (600 MHz, DMSO-d 6 ) δ 11.80 (s, 1H), 9.22 (s, 1H), 8.85 (s, 1H), 8.48 (s, 1H), 7.76 (t, J = 2.8 Hz, 1H), 7.44 (t, J = 2.3 Hz, 1H), 6.24 (q, J = 7.0 Hz, 1H), 5.39 - 4.47 (brs, 2H), 4.07 (d, J = 10.4 Hz, 1H), 3.84 (d, J = 11.4 Hz, 1H), 3.77 (dd, J = 11.5, 3.2 Hz, 1H), 3.67 - 3.50 (m, 2H), 3.01 (s, 3H), 2.04 (d, J = 7.1 Hz, 3H), 1.40 (d, J = 6.7 Hz, 3H).

[0252] 7 - isomer 2: 1 1H NMR (600 MHz, DMSO-d 6 ) δ 11.81 (s, 1H), 9.21 (s, 1H), 8.85 (s, 1H), 8.48 (s, 1H), 7.76 (d, J = 2.8 Hz, 1H), 7.43 (s, 1H), 6.23 (q, J = 7.0 Hz, 1H), 5.42 - 4.42 (brs, 2H), 4.07 (d, J = 9.6 Hz, 1H), 3.88 - 3.82 (m, 1H), 3.76 (d, J = 11.7 Hz, 1H), 3.62 (m, 2H), 3.00 (s, 3H), 2.03 (d, J = 7.1 Hz, 3H), 1.40 (d, J = 6.8 Hz, 3H).

[0253] Example 8

[0254]

[0255] The first step

[0256] Referring to the method of Example 5, 8-isomer 1 and 8-isomer 2 were obtained by using compound 5a (150.0 mg, 0.42 mmol), 7-nitrogen-4-indoleboronic acid pinacol ester (123.0 mg, 0.51 mmol), anhydrous sodium carbonate (88.5 mg, 0.84 mmol) and bis(triphenylphosphine)palladium(II) dichloride (29.4 mg, 0.042 mmol). 8-isomer 1 (42.85 mg, two-step yield: 23.1%, fast fraction), purity: 99.0%, 8-isomer 2 (62.2 mg, two-step yield: 34.0%, slow fraction), purity: 99.4%. SFC conditions: Column: CHIRALPAK AD-3 150*3mm 1D, 3μm Mobile phase: A: CO 2 , B: ethanol, Gradient: A / B=77 / 23, Flow rate: 1mL / min Column temp.: 35℃, ABPR: 14MPa. [P1, 4.11min; P2, 5.16min].

[0257] 8-isomer 1:MS-ESI calculated value [M+H] + 442.2, measured value 442.1.

[0258] 8-isomer 2:MS-ESI calculated value [M+H] + 442.2, measured value 442.1.

[0259] 8-isomer 1: 1 H NMR (600 MHz, DMSO-d 6 )δ11.81(s,1H),8.51(s,1H),8.36(d,J=5.0Hz,1H),8.10(d,J=4.9Hz,1H),7. 63(t,J=2.9Hz,1H),7.45–7.35(m,1H),6.24(q,J=7.0Hz,1H),5.54-4.40(brs ,2H),4.08(d,J=10.3Hz,1H),3.85(d,J=11.7Hz,1H),3.77(d,J=11.7Hz,1H), 3.70-3.56(m,2H),3.02(s,3H),2.05(d,J=7.1Hz,3H),1.40(d,J=6.8Hz,3H).

[0260] 8-isomer 2: 1 H NMR (600 MHz, DMSO-d6 )δ11.81(s,1H),8.51(s,1H),8.36(d,J=5.0Hz,1H),8.09(d,J=4.9Hz,1H),7. 63(t,J=2.9Hz,1H),7.46-7.23(m,1H),6.23(q,J=7.1Hz,1H),5.41-4.48(brs ,2H),4.07(d,J=10.0Hz,1H),3.85(d,J=11.6Hz,1H),3.76(d,J=11.6Hz,1H), 3.67-3.61(m,2H),3.01(s,3H),2.04(d,J=7.1Hz,3H),1.40(d,J=6.7Hz,3H).

[0261] Example 9

[0262]

[0263] first step

[0264] Referring to the method of Example 5, compound 5a (150.0 mg, 0.42 mmol), 6-methyl-4-indoleboric acid pinacol ester (123.0 mg, 0.51 mmol), anhydrous sodium carbonate (88.5 mg, 0.84 mmol) and bis(triphenylphosphine)palladium(II) dichloride (29.4 mg, 0.042 mmol) were used to obtain 9-isomer 1 and 9-isomer 2. 9-isomer 1 (27.7 mg, two-step yield: 15.4%, fast fraction), purity: 99.6%, 9-isomer 2 (23.3 mg, 12.9%, slow fraction), purity: 99.7%. SFC separation conditions: Column: CHIRALPAK AD-3 150*3mm 1D, 3μm, Mobile phase: A: CO 2 , B: ethanol, Gradient: A / B=75 / 25, Flow rate: 1mL / min, Column temp.: 35℃, ABPR: 14MPa. [P1, 3.89min; P2, 5.28min].

[0265] 9-isomer 1:MS-ESI calculated value [M+H] + 455.2, measured value 455.1.

[0266] 9-isomer 2:MS-ESI calculated value [M+H] + 455.2, measured value 455.1.

[0267] 9-isomer 1: 1 H NMR(600MHz,DMSO-d 6 )δ11.10(s,1H),8.45(s,1H),8.02(s,1H),7.39(s,1H),7.36(s,2H),6.18(q,J=7.1Hz,1H),5.33-4.37(brs,2H),4.78(d,J=8.4Hz,1H),3.84(d,J=11.6Hz,1H),3.76(d,J=11.5Hz,1H),3.66-3.51(m,2H),3.00(s,3H),2.49(s,3H),2.03(d,J=7.1Hz,3H),1.39(d,J=6.7Hz,3H).

[0268] 9-isomer 2: 1 H NMR(600MHz,DMSO-d 6 )δ11.10(s,1H),8.45(s,1H),8.02(s,1H),7.38(s,1H),7.36(s,1H),7.35(s,1H),6.18(q,J=7.1Hz,1H),5.32-4.45(brs,2H),4.07(d,J=15.6Hz,1H),3.84(d,J=11.6Hz,1H),3.76(d,J=11.8,1H),3.68-3.55(m,J=11.8,2H),3.00(s,3H),2.49(s,3H),2.03(d,J=7.0Hz,3H),1.39(d,J=6.7Hz,3H).

[0269] Example 10

[0270]

[0271] The first step

[0272] Referring to the method of Example 5, compound 5a (150.0 mg, 0.42 mmol), 6-fluoro-4-indoleboric acid pinacol ester (123.0 mg, 0.51 mmol), anhydrous sodium carbonate (88.5 mg, 0.84 mmol) and bis(triphenylphosphine)palladium(II) dichloride (29.4 mg, 0.042 mmol) were used to obtain 10-isomer 1 and 10-isomer 2. 10-isomer 1 (61.14 mg, two-step yield: 32.1%, fast fraction), purity: 98.8%. 10-isomer 2 (50.3 mg, two-step yield: 26.3%, slow fraction), purity: 98.9%. SFC separation conditions: Column: CHIRALPAK AS-3 150*3mm 1D, 3μm, Mobile phase: A: CO 2 , B: ethanol, Gradient: A / B=78 / 22, Flow rate: 1mL / min, Columntemp.: 35℃, ABPR: 14MPa. [P1, 3.22min; P2, 4.53min].

[0273] 10-isomer 1:MS-ESI calculated value [M+H] + 459.2, measured value 459.2.

[0274] 10-isomer 2:MS-ESI calculated value [M+H] + 459.2, measured value 459.2.

[0275] 10-isomer 1: 1 H NMR (600 MHz, DMSO-d 6 )δ11.35(s,1H),8.48(s,1H),7.99(d,J=11.4,1H),7.50(s,1H),7.46(s, 1H),7.36(d,J=9.1Hz,1H),6.22(q,J=7.1Hz,1H),5.46-4.45(brs,2H),4 .07(d,J=10.0Hz,1H),3.85(d,J=11.6Hz,1H),3.76(d,J=11.7,1H),3.72 -3.52(m,2H),3.00(s,3H),2.03(d,J=7.0Hz,3H),1.40(d,J=6.7Hz,3H).

[0276] 10-isomer 2: 1 H NMR (600 MHz, DMSO-d6 )δ11.36(s,1H),8.48(s,1H),7.99(d,J=11.4Hz,1H),7.50(d,J=3.1Hz,1H),7 .46(d,J=2.9Hz,1H),7.35(d,J=9.1Hz,1H),6.23(q,J=7.1Hz,1H),5.36-4.45( brs,2H),4.07(d,J=8.4Hz,1H),3.84(d,J=11.6Hz,1H),3.76(d,J=11.7Hz,1H) ,3.67-3.46(m,2H),3.01(s,3H),2.03(d,J=7.1Hz,3H),1.40(d,J=6.8Hz,3H).

[0277] Embodiment 11

[0278]

[0279] first step

[0280] Compound 2d (150.0 mg, 0.43 mmol) was added to a mixed solution of N,N-dimethylformamide (8.0 mL) and tetrahydrofuran (8.0 mL), cooled to 0°C, and NaH (69.4 mg, 1.74 mmol) was added under nitrogen protection at 0°C, and stirred at 0°C for 30 minutes. Ethyl iodide (81.2 mg, 0.50 mmol) was added under nitrogen protection at 0°C, and stirred at 0°C for 30 minutes, then slowly heated to 25°C and continued to stir for 2.0 hours. After the reaction was completed, water (50.0 mL) was added to quench the reaction, and ethyl acetate (50.0 mL*3) was used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate after filtration was distilled under reduced pressure to remove the solvent to obtain a crude product, and the crude product was subjected to column chromatography to obtain compound 11a (71.0 mg, yield: 35.0%).

[0281] MS-ESI calculated value [M+H] + 374.1, measured value 374.3.

[0282] Step 2

[0283] Compound 11a (65.0 mg, 0.17 mmol), 4-indoleboric acid pinacol ester (66.4 mg, 0.26 mmol), bis(triphenylphosphine)palladium(II) dichloride (24.4 mg, 0.03 mmol), sodium carbonate (18.4 mg, 0.17 mmol) were added to a mixed solution of dioxane (15.0 mL) and water (5.0 mL), and reacted at 100° C. for 2.0 hours under nitrogen protection. After the reaction was completed, water (50.0 mL) was added for dilution, ethyl acetate (50.0 mL*3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was filtered and the solvent was removed by vacuum distillation to obtain a crude product. The crude product was separated by column chromatography, high performance liquid chromatography and supercritical liquid chromatography to prepare 11-isomer 1 and 11-isomer 2. 11-isomer 1 (11.0 mg, yield: 13.9%, fast fraction), purity: 95.0%. 11-isomer 2 (13.0 mg, yield: 16.5%, slow fraction), purity: 98.9%. SFC separation conditions: Column: CHIRALPAK AD-3 150*3mm LD, 3μm, Mobile phase: A: CO 2 , B: ethanol+0.1% TEA, Gradient: A / B=75 / 25, Flow rate: 1mL / min, Column temp.: 35℃, ABPR: 14MPa. [P1, 3.29min; P2, 4.37min].

[0284] 11-isomer 1:MS-ESI calculated value [M+H] + 455.2, measured value 455.1.

[0285] 11-isomer 2:MS-ESI calculated value [M+H] + 455.2, measured value 455.1.

[0286] 11-isomer 1: 1 H NMR (600 MHz, DMSO-d 6)δ: 11.34 (s, 1H), 8.54 (s, 1H), 8.23 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.50 - 7.44 (m, 1H), 7.29 (t, J = 7.7 Hz, 1H), 5.97 (dd, J = 11.7, 3.6 Hz, 1H), 5.50 - 4.51 (m, 2H), 4.13 (d, J = 10.1 Hz, 1H), 3.90 (d, J = 11.5 Hz, 1H), 3.82 (d, J = 12.1 Hz, 2H), 3.65 - 3.60 (m, 1H), 3.09 (s, 3H), 2.69 (dq, J = 13.1, 6.9 Hz, 1H), 2.55–2.50 (m, 1H), 1.50 - 1.41 (m, 3H), 0.92 (t, J = 7.2 Hz, 3H).

[0287] 11 - isomer 2: 1 H NMR(600 MHz, DMSO - d 6 )δ: 11.34 (s, 1H), 8.54 (s, 1H), 8.23 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.50 - 7.44 (m, 1H), 7.29 (t, J = 7.7 Hz, 1H), 5.97 (dd, J = 11.7, 3.6 Hz, 1H), 5.50 - 4.51 (m, 2H), 4.13 (d, J = 10.1 Hz, 1H), 3.90 (d, J = 11.5 Hz, 1H), 3.82 (d, J = 12.1 Hz, 2H), 3.65 - 3.60 (m, 1H), 3.09 (s, 3H), 2.69 (dq, J = 13.1, 6.9 Hz, 1H), 2.55–2.50 (m, 1H), 1.50 - 1.41 (m, 3H), 0.92 (t, J = 7.2 Hz, 3H).

[0288] Example 12:

[0289]

[0290] The first step

[0291] Compound 2d (400.0 mg, 1.16 mmol) was added to N,N-dimethylformamide (40.0 mL), cooled to -70°C, NaH (115.7 mg, 2.89 mmol) was added under nitrogen protection at -70°C, and stirred at -70°C for 30 minutes. 2-Isopropyl iodide (393.3 mg, 2.31 mmol) was added under nitrogen protection at -70°C, stirred at -70°C for 30 minutes, then slowly heated to 25°C and continued to stir for 3.0 hours. After the reaction was completed, water (50.0 mL) was added for dilution, ethyl acetate (50.0 mL*3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was subjected to reduced pressure distillation to remove the solvent to obtain a crude product, which was separated by column chromatography and high performance liquid chromatography to prepare compound 12a (83.0 mg, yield: 16.5%).

[0292] MS-ESI calculated value [M+H] + 388.1, measured value 388.3.

[0293] Step 2

[0294] Compound 12a (72.0 mg, 0.18 mmol), 4-boronic acid pinacol ester (67.7 mg, 0.28 mmol), bis(triphenylphosphine) palladium (II) dichloride (26.1 mg, 37.1 umol), sodium carbonate (43.3 mg, 408.4 μmol) were added to a mixed solution of dioxane (10.0 mL) and water (3.0 mL), and reacted at 100° C. for 3.0 hours under nitrogen protection. After the reaction was completed, water (50.0 mL) was added for dilution, ethyl acetate (50.0 mL*3) was used for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was filtered and the solvent was removed by reduced pressure distillation to obtain a crude product, and the crude product was separated by column chromatography, high performance liquid chromatography and supercritical liquid chromatography to prepare compounds 12-isomer 1 and 12-isomer 2.

[0295] 12-isomer 1 (8.0 mg, yield: 8.7%, fast fraction), purity: 99.0%; 12-isomer 2 (12.0 mg, yield: 13.1%, slow fraction), purity: 99.0%. SFC separation conditions: Column: CHIRALPAKAS-3 150*3mm LD, 3μm, Mobile phase: A: CO 2 , B: ethanol, Gradient: A / B=75 / 25, Flowrate: 1mL / min, Column temp.: 35℃, ABPR: 14MPa. [P1, 2.61min; P2, 5.01min].

[0296] 12-isomer 1:MS-ESI calculated value [M+H] + 469.2, measured value 469.1.

[0297] 12-isomer 2:MS-ESI calculated value [M+H] + 469.2, measured value 469.1.

[0298] 12-isomer 1: 1 H NMR (600MHz, DMSO-d6) δ: 11.29 (s, 1H), 8.49 (s, 1H), 8.17 (d, J = 7.5Hz, 1H), 7.58 (d, J = 8.0Hz, 1H), 7.51 (t, J = 2. 7Hz,1H),7.36(t,J=2.5Hz,1H),7.23(t,J=7.7Hz,1H),5.65(d,J=10.0Hz,1H),4.79(d,J=167.4Hz,1H),4.10–4. 04(m,1H),3.84(d,J=11.5Hz,1H),3.76(dd,J=11.5,3.2Hz,1H),3.61(dt,J=12.0,6.1Hz,2H),3.43–3.41(m,1H ), 3.03 (qd, J = 6.7, 3.4Hz, 1H), 2.93 (s, 3H), 1.41 (d, J = 6.7Hz, 3H), 1.35 (d, J = 6.6Hz, 3H), 0.83 (d, J = 6.7Hz, 3H).

[0299] 12-isomer 2: 1 H NMR(600MHz, DMSO-d6)δ:11.29(s,1H),8.49(s,1H),8.17(d,J=7.5Hz,1H),7.57(d,J=7.9Hz,1H),7.50( d,J=2.9Hz,1H),7.37(s,1H),7.22(t,J=7.7Hz,1H),5.65(d,J=10.0Hz,1H),5.03–4.57(m,1H),4.13–4. 02(m,1H),3.84(d,J=11.6Hz,1H),3.76(dd,J=11.7,3.2Hz,1H),3.62(t,J=11.4Hz,1H),3.47–3.45(m,2 H),3.07–2.99(m,1H),2.95(s,3H),1.40(d,J=6.7Hz,3H),1.35(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H).

[0300] Embodiment 13:

[0301]

[0302] first step

[0303] Compound 5a (80.0 mg, 0.22 mmol) was dissolved in a mixed solution of 1,4-dioxane (10.0 mL) and water (5.0 mL). Compound 13b (82.2 mg, 0.24 mmol), anhydrous sodium carbonate (70.0 mg, 0.66 mmol) and bis(triphenylphosphine)palladium(II) dichloride (15.6 mg, 0.02 mmol) were then added in sequence. After nitrogen replacement, the reaction was heated to 100 °C for 2 hours. After the reaction was completed, water (3.0 mL) was added to quench, and then the organic phase was extracted with ethyl acetate (3*5.0 mL), the organic phases were combined and dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography and high performance liquid chromatography to prepare compound 13 (25 mg, yield: 24.7%), purity: 99%.

[0304] 13: MS-ESI calculated value [M+H] + 460.2, measured value 460.1.

[0305] 1 H NMR (600 MHz, DMSO-d 6 )δ11.80(s,1H),8.50(s,1H),8.43(s,1H),7.79(t,J=2.6Hz,1H),7.00–6.99(m,1H),6.08(q,J=7.1Hz,1H),5.00-4.45(m,2H),4.03–4.01( m,1H),3.80-3.78(m,1H),3.73-3.72(m,1H),3.58-3.56(m,1H),3.38-3.28(m,1H),3.01(s,3H),2.00(dd,J=7.1,5.4Hz,3H),1.37(s,3H).

[0306] Compound 13 was further separated into diastereoisomers by SFC to obtain single compound 13-isomer 1 (10.0 mg, fast fraction), purity: 98.6%; 13-isomer 2 (7.0 mg, slow fraction), purity 99.0%. SFC conditions: Column: CHIRALPAK AD-3 150*3mm LD, 3μm, Mobile phase: A: CO 2, B: ethanol, Gradient: A / B=80 / 20, Flow rate: 1mL / min, Column temp.: 35℃, ABPR: 14MPa. [P1, 3.88min; P2, 5.81min].

[0307] 13-isomer 1:MS-ESI calculated value [M+H] + 460.2, measured value 460.1.

[0308] 13-isomer 2:MS-ESI calculated value [M+H] + 460.2, measured value 460.1.

[0309] 13-isomer 1: 1 H NMR (600 MHz, DMSO-d 6 )δ11.80(s,1H),8.50(s,1H),8.43(s,1H),7.79(t,J=2.6Hz,1H),7.00–6.99(m,1H),6.08(q,J=7.1Hz,1H),5.00-4.45(m,2H),4.03–4.01(m, 1H),3.80-3.78(m,1H),3.73-3.72(m,1H),3.58-3.56(m,1H),3.38-3. 28(m,1H),3.01(s,3H),2.00(dd,J=7.1,5.4Hz,3H),1.30-1.41(m,3H).

[0310] 13-isomer 2: 1 H NMR (600 MHz, DMSO-d 6 )δ11.80(s,1H),8.50(s,1H),8.43(s,1H),7.79(t,J=2.6Hz,1H),7.00–6.99(m,1H),6.08(q,J=7.1Hz,1H),5.00-4.45(m,2H),4.03–4.01(m, 1H),3.80-3.78(m,1H),3.73-3.72(m,1H),3.58-3.56(m,1H),3.38-3. 28(m,1H),3.01(s,3H),2.00(dd,J=7.1,5.4Hz,3H),1.30-1.41(m,3H).

[0311] Biological Examples

[0312] Experimental Example 1: Cell proliferation assay

[0313] In the present application, a cell proliferation assay was used to evaluate the biological activity of compounds against tumor cells. HT-29 cells (Chengdu Zhongyuan Gongchuang Technology Co., Ltd.) and LOVO cells (Nanjing Kebai Biotechnology Co., Ltd.) were inoculated in 96-well plates, with 5,000 HT-29 cells inoculated per well and 10,000 LOVO cells inoculated per well. RPMI-1640 medium containing 10% fetal bovine serum and 100 μg / mL Normocin was added to HT-29 cells for culture, and Dulbecco's Modified Eagle Medium (DMEM) medium containing 10% fetal bovine serum and 100 μg / mL Normocin was added to LOVO cells for culture. Incubate at 37°C and 5% CO 2 The cells were cultured overnight under the conditions to allow them to adhere to the wall. The next day, the culture medium in the cells was removed, 150 μL of fresh culture medium was added, and then 50 μL of culture medium containing 4 times the final concentration of the compound (final concentration range of 1 nM to 10 μM) was added, and the cells were placed in an incubator at 37°C and 5% CO. 2 The cells were cultured for 72 h under the same conditions. After 72 h of culture, the culture medium in the cells was removed again, and serum-free RPMI-1640 basal medium containing 10% CCK8 reagent was added. After incubation at 37 ° C for 1 h, the absorbance (OD) value was read at a wavelength of 450 nm using a microplate reader (BMG LABTECH). GraphPad Prism software was used to analyze the data, fit the compound inhibition growth curve, and calculate the IC 50 value.

[0314] Table 1:

[0315]

[0316]

[0317] Conclusion: Through the above experiments, it can be known that the compound of the present application has good anti-proliferation activity against HT-29 and LOVO cells.

[0318] Experimental Example 2: Detection of pCHK1 Cell Levels

[0319] HT-29 cells were seeded into 96-well clear-bottom black plates (Greiner Bio-one, Cat. No. 655090) at a density of 10,000 cells per well and incubated at 37°C and 5% CO 2 The cells were cultured overnight in an incubator. The next day, the culture medium in the cells was removed, 150 μL of fresh culture medium was added, and then 50 μL of culture medium containing 4 times the final concentration of the compound (final concentration range 1 nM to 10 μM) was added, and the cells were placed in an incubator at 37°C and 5% CO. 2The cells were cultured for 60 min under the same conditions. Then, 1 μL of 600 μM 4NQO was added to each well for treatment (final concentration was 3 μM) and cultured for another 60 min. An equal volume of DMSO was added to the negative control wells to replace 4NQO. After that, the culture medium in the cells was removed, and the cells were fixed with 4% paraformaldehyde, 150 μL per well, and incubated at room temperature for 15 min. After the cells were fixed, 0.1% (v / v) Triton X-100 was used to permeabilize the cells, 150 μL per well, and incubated at room temperature for 15 min. The cells were blocked with 1% blocking reagent (Roche), 100 μL per well, and incubated at room temperature for 60 min. After blocking, 50 μL of pCHK1 antibody (CST, Cat. No.: 2348, dilution ratio 1:250) diluted with 1% (w / v) blocking reagent was added to each well and incubated overnight at 2-8°C. The next day, remove the antibody from the wells, wash the cells with 0.05% (v / v) PBST, 200 μL per well, repeat 3 times. Then add 1% (w / v) blocking reagent diluted goat anti-rabbit fluorescent secondary antibody (Invitrogen, catalog number: A32731) and DAPI stain (Thermofisher, catalog number: 62247) (fluorescent secondary antibody dilution ratio is 1:1000 (v / v), DAPI dilution ratio is 1:2000 (v / v)), 50 μL per well, incubate at room temperature on an oscillator at 300 rpm in the dark for 2 hours. Then remove the antibody from the wells, wash the cells with 0.05% (v / v) PBST, 200 μL per well, repeat 3 times (keep the wash solution in the well for the last time). The fluorescence value of pCHK1 in the cell nucleus was obtained using a high-content imaging analysis system (GE, InCell Analyzer, model: 2200), and the relative level of pCHK1 was analyzed using GraphPad Prism software. The pCHK1 inhibition curve of the compound was fitted and the IC was calculated. 50 value.

[0320] Table 2:

[0321]

[0322]

[0323] Conclusion: Through the above experiments, it can be known that the compound of the present application has a good inhibitory effect on the phosphorylation level of CHK1 downstream of ATR in HT-29 cells.

[0324] Test Example 3: In vitro liver microsome stability test of compounds

[0325] The liver microsome stability experiment was conducted on the compounds of the present application.

[0326] Experimental methods:

[0327] The test compound (final concentration 1.5 μM) was co-incubated with human / mouse liver microsomes in the presence of NADPH, and the compound concentration in the incubation supernatant was detected within 60 minutes. The results of representative compounds are as follows:

[0328] Table 3

[0329] Compound No. <![CDATA[Human liver microsomes T 1 / 2 (min)]]> <![CDATA[Mouse liver microsomes T 1 / 2 (min)]]> AZD6738 >120 52 5-isomer2 >120 30 13 >120 81

[0330] Conclusion: The compounds of the present application have good metabolic stability in human / mouse liver microsomes.

[0331] Test Example 4: In vivo pharmacokinetic experiment of compound:

[0332] Test samples: Based on the above studies, some highly active and structurally representative compounds were selected for in vivo pharmacokinetic studies.

[0333] Experimental methods:

[0334] The purpose of this experiment is to determine the pharmacokinetic parameters of the compound and calculate its oral bioavailability in male CD-1 mice and male SD rats. 36 male CD-1 mice were selected and divided into 4 groups. AZD6738 and 5-isomer2 were administered intravenously and orally by gavage, with 9 animals in each group. Two groups of mice were administered intravenously at a dose of 1 mg / kg, and plasma samples were collected after administration (5, 15, 30 minutes and 1, 2, 4, 8, 24 hours); the other two groups of mice were administered orally by gavage at a dose of 10 mg / kg, and plasma samples were collected after administration (15, 30 minutes and 1, 2, 4, 8, 24 hours), and LC / MS analysis was performed to analyze the drug concentration in plasma, and the relevant pharmacokinetic parameters were calculated using Winnolin 5.2 software.

[0335] Twelve male SD rats were divided into 4 groups and given AZD6738 and 5-isomer2 by intravenous injection and oral gavage, with 3 animals in each group. Two groups of rats were given intravenous injection at a dose of 1 mg / kg. The other two groups of rats were given oral gavage at a dose of 10 mg / kg. The blood collection time point was the same as that of mice. Plasma was collected to analyze drug concentration and obtain relevant pharmacokinetic parameters.

[0336] The experimental results are as follows:

[0337] Table 4.1 Results of intravenous administration

[0338]

[0339] Table 4.2 Oral administration results

[0340]

[0341] Note: C 0 is the drug concentration in the body at 0 minutes; Cl (mL / min / kg) is the drug clearance rate in the body; T 1 / 2 (h) is the half-life; AUC is the drug exposure in vivo; C max is the maximum drug concentration in the body; F (%) is the oral bioavailability of the drug.

[0342] Experimental conclusion: The compound of the present application has good absorption and exposure after oral administration and is suitable for oral administration. In addition, the compound of the present application has obvious advantages in pharmacokinetics compared with the clinical phase II ATR inhibitor AZD6738, with Cmax of 1.6 times and AUC of 5.7 times in mice (p<0.05); Cmax of 1.4 times and AUC of 1.9 times in rats (p<0.05).

[0343] Experimental Example 5: In vivo efficacy study of LOVO CDX in colorectal cancer:

[0344] LOVO is a colorectal cancer cell line with MRE11A mutation (MRE11A is a key component of the ATM signaling pathway for DNA double-strand repair) and is sensitive to ATR inhibitors. This experiment will use the colorectal cancer LOVO CDX model to verify the inhibitory effect of ATR inhibitors on tumors with defects in the ATM signaling pathway.

[0345] 1. Experimental Animals

[0346] Species: Mouse

[0347] Strain: BALB / c Nude

[0348] Age: 8 weeks (arrival), 9 weeks (grouping)

[0349] Weight: 16-20g (arrival), 18-22g (grouping)

[0350] Gender: Female

[0351] Supplier: Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0352] 2. Experimental cells

[0353] LOVO cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. The culture medium used was DMEM plus 10% FBS serum, 37°C and 5% CO 2 Cultivated under conditions.

[0354] 3. Medicines

[0355] Test drug: Compound 5-isomer2, AZD6738

[0356] 4. Experimental Methods

[0357] LOVO cells were cultured in vitro (adherent growth), and cells in the logarithmic growth phase were collected. The cells were gently rinsed twice with PBS, and the cell pellet was gently blown with PBS to resuspend the cells to prepare a single cell suspension. After counting, the final cell concentration was adjusted to 5×10 6 5×10 cells / 100 μL were inoculated in the right armpit 6 The inoculation volume was 100 μL per animal. Tumor growth was observed regularly and the tumor was kept at an average size of 94 mm. 3 The mice were randomly divided into 5 groups according to tumor size and weight, with 8 mice in each group. The day the mice were grouped was defined as day 0. The drugs were administered according to the following table.

[0358] Table 5.1 Drug preparation method

[0359]

[0360] Table 5.2 Administration routes, doses and regimens in animal models

[0361]

[0362] Note: po means oral administration; QD means once a day administration.

[0363] The main observation indicators of this experiment are:

[0364] Relative tumor growth rate T / C (%), at a certain time point, the percentage of the relative tumor volume or tumor weight of the treatment group and the control group. The calculation formula is as follows: T / C% = T RTV / C RTV ×100%(T RTV : Average RTV of the treatment group; C RTV : Average RTV of the control group; RTV = V t / V 0 , V 0 is the tumor volume at the time of grouping, V t is the tumor volume after treatment). Or T / C% = T TW / C TW ×100%(T TW : Average tumor weight at the end of the experiment in the treatment group; C TW : Average tumor weight at the end of the experiment in the control group).

[0365] Relative tumor inhibition rate TGI (%) = (1-(mean T-mean T 0 ) / (mean C-mean C 0))×100%. Mean T and mean C are the average tumor volumes of the treatment group and the control group at a specific time, respectively. 0 and meanC 0 The mean tumor volumes of the treatment and control groups, respectively.

[0366] 5. Experimental Results

[0367] This study evaluated the efficacy of the compound 5-isomer2 in the human colorectal cancer CDX model. After 22 days of administration, the tumor volume of the control group reached 1739 mm 3 Compared with the control group, the TGI of AZD6738 group, 5-isomer2 low-dose group, 5-isomer2 medium-dose group, and 5-isomer2 high-dose group were 58.3%, 60.4%, 90%, and 93.3%, respectively. The reduction of tumor volume in mice in each dose group of compound 5-isomer2 was statistically significant (p<0.01).

[0368] Conclusion: Compound 5-isomer2 can significantly inhibit tumor growth in LOVO tumor-bearing mice, and the effect is dose-dependent. Compared with the clinical phase II ATR inhibitor AZD6738, the compound of the present application has better efficacy, which is manifested in better tumor growth inhibition rate at the same dose (AZD6738: 58.3%; 5-isomer2: 90%); under the same tumor inhibition rate, the compound of the present application uses a lower dose (AZD6738: 50mg / kg; 5-isomer2: 25mg / kg), which provides strong support for better efficacy and better safety in clinical transformation.

[0369] Test Example 6: Maximum Tolerated Dose (MTD) Study in Rats:

[0370] Objective: To observe the maximum tolerated dose of AZD6738 and 5-isomer2 in SD rats after a single oral gavage for 14 days, and to provide reference information for multiple dose toxicity studies.

[0371] Methods: This experiment set up 7 groups, namely the control group and the 500, 1000, 2000 mg / kg groups of AZD6738 and the 500, 1000, 2000 mg / kg groups of the compound 5-isomer2, with 10 mice in each group, half of which were male and half were female. Rats were given the control substance or the corresponding concentration of AZD6738 / 5-isomer2 by oral gavage at a volume of 5 μL / g, and the grouping was given once and then observed for 2 weeks. The day of administration was day 0.

[0372] During the experiment, the general condition of rats in each group was observed every day, and the body weight was measured twice a week. The experiment was terminated on the 14th day, and the rats were killed.

[0373] Results: The maximum tolerated dose (MTD) of AZD6738 for the test rats was less than 500 mg / kg, among which all rats in the high-dose group died, all female rats in the medium-dose group died, 3 male rats died, and 1 female rat died in the low-dose group; the maximum tolerated dose (MTD) of compound 5-isomer2 for the test rats was greater than 2000 mg / kg, among which rats in each dose group had no abnormalities.

[0374] Conclusion: The maximum tolerated dose level of compound 5-isomer2 in rats is much higher than that of AZD6738. It can be seen that the compound of the present application has a greater advantage in toxicity than the original compound AZD6738.

[0375] Example 7: Two-week toxicity study in rats:

[0376] Objective: To conduct a 2-week oral gavage toxicity study on AZD6738 and 5-isomer2 in SD rats to observe whether the test products may cause toxic reactions and determine the toxic target organs or tissues.

[0377] Methods: This experiment set up 7 groups, including the control group and the 50, 150, 450 mg / kg AZD6738 and 50, 150, 450 mg / kg 5-isomer2 groups, with 10 mice in each group, half male and half female. Rats were given the control substance or the corresponding concentration of AZD6738 / 5-isomer2 by oral gavage at a volume of 10 μL / g, once a day for 2 consecutive weeks. The first day of the administration period was the first day of the administration period.

[0378] During the experiment, the general condition of rats in each group was observed every day; body weight was measured twice a week during the administration period. At the end of the administration period, blood was collected from all surviving rats for hematology and blood biochemistry tests, and gross anatomical observation, organ weight and histopathological examination were performed after euthanasia.

[0379] Results: AZD6738 was highly toxic. All rats in the high-dose group died, all female rats died and two male rats died in the medium-dose group. For compound 5-isomer2, only one female rat died in the high-dose group, and the rest showed no abnormalities.

[0380] Conclusion: In the two-week toxicity study, the toxicity of the compound 5-isomer2 of the present application is much better than that of the original compound AZD6738.

[0381] The above results indicate that the compounds of the examples of the present application are superior to the positive compounds in terms of in vivo efficacy, pharmacokinetics and toxicology (maximum tolerated dose and 2-week toxicity study).

[0382] It is obvious to those skilled in the art that various modifications and variations can be made to the compounds, compositions and methods of the present application without departing from the spirit or scope of the present application. Therefore, the present application includes modifications and variations of the present application as long as they are within the scope of the claims and their equivalents.

Claims

1. A compound represented by formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 2. A compound of formula I according to claim 1, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, used as an ATR inhibitor.

3. A compound of formula I according to claim 1, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for treating or ameliorating cancer.

4. The compound of formula (I) according to claim 3, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The cancer is selected from colon cancer, rectal cancer, gastric cancer, esophageal cancer, primary peritoneal cancer, adrenocortical carcinoma, renal clear cell carcinoma, prostate cancer, bladder urothelial carcinoma, ovarian cancer, breast cancer, endometrial cancer, fallopian tube cancer, non-small cell lung cancer or small cell lung cancer.

5. A pharmaceutical composition comprising the compound of formula I according to claim 1, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 5, further comprising a pharmaceutically acceptable carrier, excipient, or vehicle.

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