CN115304598B

CN115304598B - Heterocyclic compound, and preparation method and application thereof

Info

Publication number: CN115304598B
Application number: CN202211018756.XA
Authority: CN
Inventors: 赵传武; 张莉; 张朝再; 李子真; 魏苗苗; 王佳; 高娜
Original assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Current assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Priority date: 2021-08-25
Filing date: 2022-08-24
Publication date: 2024-05-31
Anticipated expiration: 2042-08-24
Also published as: CN115304598A

Abstract

The invention provides a heterocyclic compound, and a tautomer, an optical isomer, a solvate, an isotope derivative or pharmaceutically acceptable salt thereof. The compound has medical application for treating cancers, can obviously inhibit the activity of ATM kinase, and has the advantages of good target selectivity, high in vivo bioavailability and high in vivo tumor inhibition rate.

Description

Heterocyclic compound, and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a novel compound with ATM kinase inhibition activity and application of the compound or a pharmaceutical composition in preparation of medicines.

Background

Hereditary ataxia telangiectasia (ataxia-TELANGIECTASIA, a-T) is an autosomal recessive hereditary disease which is clinically manifested by progressive cerebellar ataxia, facial telangiectasia, increased sensitivity to radiation, a marked increase in tumor incidence, etc. which occur in young age (Taylor A M,Harnden D G,Arlett C F,et al.Ataxia telangiectasia:a human mutation with abnormal radiation sensitivity.Nature,1975,258:427-429). is currently known to be due to ataxia telangiectasia mutant gene (ataxia telangiectasia mutated gene, ATM gene) mutation. ATM gene is located on chromosome 11q 22-23, has a length of 150kb, has 66 exons, and is one of the most exons found so far (Savitsky K,Bar Shira A,Gilad S,et al.A single ataxia telangiectasia gene with a product similar to PI-3kinase.Science,1995,268(5218):1749-1753).

ATM protein kinase is a coding product of ATM gene, is a serine/threonine protein kinase, contains 3056 amino acids, has a relative molecular mass of about 350kDa(CHEN G,LEE E.The product of the ATM gene is a370-kDa nuclear phosphoprotein.J Biol Chem,1996,271(52):33693-33697),, is a member (Watters,D,Khanna,K K,Beamish,H,et al.Cellular localisation of the ataxia-telangiectasia(ATM)gene product and discrimination between mutated and normal forms.Oncogene,1997,14:1911-1921.). belonging to phosphatidylinositol 3-kinase related kinase (PIKK) family, is distributed in nucleus and cytoplasm, is ubiquitous in tissue cells of higher eukaryotes, and is highly expressed in some tissue cells such as testis, spleen, thymus, etc. ATM participates in cell cycle regulation and DNA damage recognition and repair through the functional domain of the C terminal, and functions in a cell signaling pathway to activate cell cycle monitoring point (Canman CE,Lim DS,Cimprich KA et al.Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.Science,1998,281:1677-1679)、 to regulate DNA damage repair (matsuoka S,huang M,elledge SJ.linkage of ATM to cell cycle regulation by the Chk2 protein kinase.Science 1998;282:1893–1897)、 and regulate telomere (Kishi S,Lu KP.A critical role for Pin2/TRF1 in ATM-dependent regulation.Inhibition of Pin2/TRF1 function complements telomere shortening,radio sensitivity,and the G(2)/M checkpoint defect of ataxia-telangiectasia cells.)、 and regulate apoptosis (Lee Y,Barnes DE,Lindahl T,et al.Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm.Genes Dev.2000,14:2576-2580).

ATM protein kinase plays a major role in repairing DNA double strand breaks, maintaining DNA stability by directing downstream effector phosphorylation. When cells are subjected to DNA double strand damage by ionization or uv radiation, DNA Double Strand Breaks (DSBs) occur and the MRE11-RAD50-NBS1 (MRN) complex senses the DSBs and initiates DNA repair to recruit ATM protein kinases. ATM protein kinase serves as the primary sensor in the DSB repair process, recruiting and interacting with other proteins. ATM homodimers separate into active monomers at the DSB site and are catalytically activated by autophosphorylation and acetylation. DNA repair with other proteins to promote fragmentation (Lee JH,Paull TT,Activation and regulation of ATM kinase activity in response to DNA double-strand breaks.Oncogene 200726(56):7741–7748).

ATM can also regulate cell cycle through Chk2-p53/AKT pathway, thereby affecting proliferation and apoptosis (Lazzaro F,Giannattasio M,Puddu F,et al.Checkpoint mechanisms at the intersection between DNA damage and repair.DNA Repair,2009,8(9):1055-1067). of tumor cells, and activated ATM can also affect tumor occurrence, migration and invasion through ATM-Akt-GSK-3 beta pathway, transcription regulatory factor NF- κB and interleukin IL-8, and participate in DNA injury reaction through different mechanisms, thereby increasing drug resistance and resistance of tumor cells to radiotherapy and chemotherapy (Bo Peng,Janice Ortega,et al.Phosphorylation of proliferating cell nuclear antigen promotes cancer progression by activating the ATM/AKT/GSK3β/Snail signaling pathway.JBC 2019(295)9767).

ATM kinase inhibitors are used to treat solid or hematological tumors. At present, most of ATM inhibitors in clinical research are combined with radiotherapy and chemotherapy. Although there are several molecules in clinical research, such as AZD-1390 of Alstican and M-3541 of Merck, germany, there are drawbacks in that the in vivo availability is not high.

Disclosure of Invention

The invention provides a compound with novel structure and ATM kinase inhibitory activity.

Specifically, the invention provides a compound shown in a formula (I), and prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein the compound has the following structure:

wherein,

R ₁ and R ₂ are each independently selected from H, C _1-6 alkyl, C _3-10 cycloalkyl, said C _1-6 alkyl, C _3-10 cycloalkyl optionally substituted with 1, 2 or 3R ^a, which may be the same or different; or R ₁ and R ₂ together with the nitrogen atom to which they are attached form a 4-12 membered heterocycloalkyl, said 4-12 membered heterocycloalkyl optionally being substituted by 1, 2 or 3 identical or different R ^a;

R ^a is independently selected from the group consisting of hydrogen, halogen, amino, cyano, hydroxy, oxo, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 hydroxyalkyl, -NHC _1-6 alkyl, -N (C _1-6 alkyl) (C _1-6 alkyl), -CO-C _1-6 alkyl, -COO-C _1-6 alkyl, -NHCO-C _1-6 alkyl, -CONH-C _1-6 alkyl, C _3-6 cycloalkyl, 4-10 membered heterocyclyl, C _6-12 aryl, 5-10 membered heteroaryl, said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 hydroxyalkyl, -NHC _1-6 alkyl, -N (C _1-6 alkyl) (C _1-6 alkyl), -CO-C _1-6 alkyl, -COO-C _1-6 alkyl, -NHCO-C _1-6 alkyl, -CONH-C _1-6 alkyl, C _3-6 cycloalkyl, 4-10 membered heterocyclyl, C _6-12 aryl, 5-10 membered heteroaryl optionally substituted with one or more of the following substituents: halogen, cyano, hydroxy, nitro, oxo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 hydroxyalkyl, 4-10 membered heterocyclyl, C _6-12 aryl, 5-10 membered heteroaryl;

R ₃ is selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, and C _1-6 alkoxy;

R ₄ is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-10 cycloalkyl, C _6-14 aryl, 3-10 membered heterocyclyl, and 5-12 membered heteroaryl, said C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-10 cycloalkyl, C _6-14 aryl, 3-10 membered heterocyclyl, and 5-12 membered heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-10 cycloalkyl;

R ₅ is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-10 cycloalkyl, C _6-14 aryl, 3-10 membered heterocyclyl, and 5-12 membered heteroaryl, said C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-10 cycloalkyl, C _6-14 aryl, 3-10 membered heterocyclyl, and 5-12 membered heteroaryl being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-10 cycloalkyl;

l is C (R _L) or N;

R _L is selected from hydrogen, halogen, nitro, amino, cyano, hydroxy, carboxy, mercapto, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio;

A is selected from C _1-6 alkyl, C _3-10 cycloalkyl and 3-10 membered heterocycloalkyl, said C _1-6 alkyl, C _3-10 cycloalkyl and 3-10 membered heterocycloalkyl being optionally substituted with a substituent selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl;

Unless otherwise indicated, the heteroatoms in the heterocycloalkyl, heteroaryl, heterocyclyl groups described above are independently selected from O, N or S, the number of heteroatoms being 1,2, 3 or 4.

Preferably, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ₁ and R ₂ are each independently selected from H, C _1-4 alkyl, C _3-8 cycloalkyl, said C _1-4 alkyl, C _3-8 cycloalkyl being optionally substituted with 1, 2 or 3 identical or different R ^a; or R ₁ and R ₂ together with the nitrogen atom to which they are attached form a 4-10 membered heterocycloalkyl, said 4-10 membered heterocycloalkyl being optionally substituted by 1, 2 or 3 identical or different R ^a.

Further preferred, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ₁ and R ₂ are each independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, said methyl, ethyl, n-propyl, isopropyl, cyclopropyl being optionally substituted with 1, 2 or 3 same or different R ^a.

Further preferred, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ₁ and R ₂ together with the nitrogen atom to which they are attached form a 5-7 membered mono-heterocycloalkyl, 7-10 membered mono-spiroheterocycloalkyl, said 5-7 membered mono-heterocycloalkyl, 7-10 membered mono-spiroheterocycloalkyl optionally being substituted with 1,2 or 3 identical or different R ^a; the heteroatoms in the 5-7 membered mono-heterocycloalkyl are independently selected from O, N or S, the number of heteroatoms is 1 or 2; the heteroatoms in the 7-10 membered single spiro heterocycloalkyl group are independently selected from O, N or S, and the number of the heteroatoms is 1,2 or 3.

Further preferred, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ₁ and R ₂ together with the nitrogen atom to which they are attached form a 5-or 6-membered mono-heterocycloalkyl, 7-or 9-membered mono-spiroheterocycloalkyl, the heteroatoms in said 5-or 6-membered mono-heterocycloalkyl, 7-or 9-membered mono-spiroheterocycloalkyl being independently selected from O, N or S, the number of heteroatoms being 1,2 or 3; the 5-or 6-membered mono-heterocycloalkyl, 7-or 9-membered mono-spiroheterocycloalkyl is optionally substituted with 1,2 or 3 identical or different R ^a;

Further preferably, R ₁ and R ₂ together with the nitrogen atom to which they are attached form a 5-or 6-membered mono-heterocycloalkyl, 7-or 9-membered mono-spiroheterocycloalkyl, the heteroatoms in the 5-or 6-membered mono-heterocycloalkyl, 7-or 9-membered mono-spiroheterocycloalkyl being independently selected from O, N, the number of heteroatoms being 1 or 2; the 5-or 6-membered mono-heterocycloalkyl, 7-or 9-membered mono-spiroheterocycloalkyl is optionally substituted with 1,2 or 3 identical or different R ^a;

Further preferably, R ₁ and R ₂ together with the nitrogen atom to which they are attached form a 5-or 6-membered mono-heterocycloalkyl, the heteroatoms in the 5-or 6-membered mono-heterocycloalkyl being independently selected from N, the number of heteroatoms being 1 or 2; the 5-or 6-membered mono-heterocycloalkyl is optionally substituted with 1, 2 or 3R ^a which are the same or different;

Further preferably, R ₁ and R ₂ together with the nitrogen atom to which they are attached form a 6 membered mono-heterocycloalkyl, the heteroatoms in the 6 membered mono-heterocycloalkyl being independently selected from N, the number of heteroatoms being 2; the 6 membered mono-heterocycloalkyl is optionally substituted with 1,2 or 3R ^a which are the same or different;

further preferred, the compounds provided herein, or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ₁ and R ₂ together with the nitrogen atom to which they are attached form the following optionally substituted structure with 1,2 or 3 identical or different R ^a:

Further preferably, R ₁ and R ₂ together with the nitrogen atom to which they are attached form the following optionally substituted structure with 1,2 or 3R ^a, which may be the same or different:

Further preferably, R ₁ and R ₂ together with the nitrogen atom to which they are attached form the following optionally substituted structure with 1R ^a:

Preferably, the present invention provides a compound, or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein R ^a is independently selected from hydrogen, halogen, amino, cyano, hydroxy, oxo, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 hydroxyalkyl, -NHC _1-6 alkyl, -N (C _1-6 alkyl) (C _1-6 alkyl), -CO-C _1-6 alkyl, -COO-C _1-6 alkyl, -NHCO-C _1-6 alkyl, -CONH-C _1-6 alkyl, C _3-6 cycloalkyl, 4-10 membered heterocyclyl, said C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 hydroxyalkyl, -NHC _1-6 alkyl, -N (C _1-6 alkyl) (C _1-6 alkyl), -CO-C _1-6 alkyl, -COO-C _1-6 alkyl, -NHCO-C _1-6 alkyl, -CONH-C _1-6 alkyl, C _3-6 cycloalkyl, 4-10 membered heterocyclyl optionally substituted with one or two of the following substituents: halogen, cyano, hydroxy, nitro, oxo, C _1-6 alkyl.

Further preferred, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ^a is independently selected from hydrogen, halogen, amino, cyano, hydroxy, oxo, nitro, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 hydroxyalkyl, -NHC _1-4 alkyl, -N (C _1-4 alkyl) (C _1-4 alkyl), -CO-C _1-4 alkyl, -COO-C _1-4 alkyl, -NHCO-C _1-4 alkyl, -CONH-C _1-4 alkyl, C _3-6 cycloalkyl, 5-6 membered mono-heterocycloalkyl, said C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 hydroxyalkyl, -NHC _1-4 alkyl, -N (C _1-4 alkyl) (C _1-4 alkyl), -CO-C _1-4 alkyl, -COO-C _1-4 alkyl, -NHCO-C _1-4 alkyl, -CONH-C _1-4 alkyl, C _3-6 cycloalkyl, 5-6 membered mono-heterocycloalkyl optionally substituted with one or two of the following substituents: halogen, cyano, hydroxy, nitro, oxo, C _1-4 alkyl.

Further preferred, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ^a is independently selected from hydrogen, C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered mono-heterocycloalkyl, the heteroatoms in said 5-6 membered mono-heterocycloalkyl being selected from N, 1 or 2 in number of heteroatoms, said C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered mono-heterocycloalkyl optionally substituted with one or more of the following substituents: halogen, hydroxy, oxo, C _1-3 alkyl.

Further preferably, R ^a is independently selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered mono-heterocycloalkyl, wherein the heteroatoms in the 5-6 membered mono-heterocycloalkyl are selected from N, the number of heteroatoms is 1, and the C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered mono-heterocycloalkyl are optionally substituted with one or more halogens.

Further preferably, R ^a is independently selected from C _1-3 alkyl.

Preferably, R ^a is independently selected from hydrogen 、-C(O)CH₃、-C(O)CH₂CH₃、-C(O)CH₂F、-C(O)CHF₂、-C(O)CF₃、-NH(CH₃)、-N(CH₃)₂、-OCH₃、-OCH₂CH₃、 methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, piperidinyl, tetrahydropyrrolyl, optionally substituted with one or more fluoro, chloro, bromo.

Further preferred, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ^a is independently selected from hydrogen, halogen, amino, cyano, hydroxy, oxo, nitro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, monomethylamino, dimethylamino, formyl, acetyl, piperidinyl, tetrahydropyrrolyl.

Further preferably, R ^a is independently selected from -C(O)CH₃、-C(O)CH₂CH₃、-C(O)CH₂F、-C(O)CHF₂、-C(O)CF₃、-NH(CH₃)、-N(CH₃)₂、-OCH₃、-OCH₂CH₃、 methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, N-methyl,

Further preferred, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ^a is independently selected from hydrogen, halogen, hydroxy, amino, methyl, ethyl, isopropyl, cyclopropyl, monomethylamino, dimethylamino, formyl, acetyl, piperidinyl, tetrahydropyrrolyl.

Further preferably, R ₁ and R ₂ together with the nitrogen atom to which they are attached form the following optionally substituted structure with 1,2 or 3R ^a, which may be the same or different: Wherein R ^a is selected from C _1-6 alkyl, preferably C _1-3 alkyl, preferably methyl;

Further preferably, R ₁ and R ₂ together with the nitrogen atom to which they are attached form the following structure substituted with 1R ^a: Wherein R ^a is selected from C _1-6 alkyl, preferably C _1-3 alkyl, preferably methyl;

Further preferably, R ₁ and R ₂ together with the nitrogen atom to which they are attached form the following structure: Wherein R ^a is selected from C _1-6 alkyl, C _3-6 cycloalkyl; preferably a C _1-3 alkyl group; preferably methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl; methyl is further preferred.

Preferably, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ₁ and R ₂ together with the nitrogen atom to which they are attached and the R ^a substituent thereof form the structure:

Further preferably, R ₁ and R ₂ together with the nitrogen atom to which they are attached and the R ^a substituent thereof form the following structure:

preferably, the compounds provided by the invention or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ₃ is selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, methyl, ethyl, methoxy, ethoxy.

Further preferably, R ₃ is selected from halogen.

Further preferred, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ₃ is selected from F, cl, br; most preferably, R ₃ is selected from F.

Preferably, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ₄ is selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _3-6 cycloalkyl.

Further preferably, R ₄ is selected from C _1-3 alkyl.

Further preferred, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ₄ is selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, methyl, ethyl, propyl, isopropyl, methoxy. More preferably, R ₄ is selected from methyl.

Preferably, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ₅ is selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _3-6 cycloalkyl.

Further preferred, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ₅ is selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, methyl, ethyl, methoxy. More preferably, R ₅ is selected from hydrogen.

Preferably, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein L is C (R _L),R_L is selected from hydrogen, halogen, nitro, amino, cyano, hydroxy, carboxy, mercapto, methyl, ethyl, methoxy.

Further preferred, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein L is C (R _L),R_L is selected from hydrogen.

Preferably, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein a is selected from C _1-4 alkyl, C _3-6 cycloalkyl, and 4-6 membered heterocycloalkyl, said C _1-4 alkyl, C _3-6 cycloalkyl, and 4-6 membered heterocycloalkyl being optionally substituted with a substituent selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, methyl, ethyl, methoxy.

Further preferred, the compounds provided by the present invention or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein a is selected from methyl, ethyl, N-propyl, isopropyl, cyclopropyl, 5-6 membered monocyclic heterocycloalkyl, and the heteroatom in the 5-6 membered monocyclic heterocycloalkyl is selected from N or O, and the number of heteroatoms is 1 or 2.

Further preferably, a is selected from isopropyl, 6-membered monocyclic heterocycloalkyl, the heteroatoms in the 6-membered monocyclic heterocycloalkyl being selected from N or O, the number of heteroatoms being 1 or 2;

Further preferably, a is selected from isopropyl, 6-membered monocyclic heterocycloalkyl, the heteroatoms in the 6-membered monocyclic heterocycloalkyl being selected from O, the number of heteroatoms being 1;

Further preferably, a is selected from isopropyl, tetrahydropyranyl.

Further preferably, A is selected from isopropyl,

Preferably, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein a is selected from C _1-3 alkyl, said C _1-3 alkyl being optionally substituted with a substituent selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, methyl, ethyl, methoxy;

Further preferably, a is selected from C _1-3 alkyl;

Further preferably, a is selected from isopropyl.

Preferably, the compound provided by the invention or a prodrug, a tautomer, an optical isomer, a geometric isomer, a solvate, an isotopic derivative or a pharmaceutically acceptable salt thereof, wherein A is selected from 5-6 membered monocyclic heterocycloalkyl, a heteroatom in the 5-6 membered monocyclic heterocycloalkyl is selected from O, the number of heteroatoms is 1, and the 5-6 membered monocyclic heterocycloalkyl is optionally substituted by a substituent selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, methyl, ethyl and methoxy;

Further preferably, a is selected from 6-membered monocyclic heterocycloalkyl, the heteroatoms in the 6-membered monocyclic heterocycloalkyl being selected from O, the number of heteroatoms being 1;

Further preferably, A is selected from

Preferably, the compounds provided by the invention or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, are independently selected from the group consisting of R ^a, wherein R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is selected from C _1-6 alkyl or 5-6 membered monocyclic heterocycloalkyl; r ₁ and R ₂ together with the nitrogen atom to which they are attached form a 5-6 membered monocyclic heterocycloalkyl, said 5-6 membered monocyclic heterocycloalkyl being optionally substituted by 1, 2 or 3 identical or different R ^a; r ^a is independently selected from halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) (C _1-6 alkyl), -CO-C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl, the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl being selected from N, 1 in number of heteroatoms, the C _1-6 alkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) (C _1-6 alkyl), -CO-C _1-6 alkyl, -C _3-6 cycloalkyl, -5-6 membered monocyclic heterocycloalkyl optionally substituted by one or more halogen, hydroxy.

Further preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is selected from C _1-3 alkyl or 6-membered monocyclic heterocycloalkyl, wherein heteroatoms in the 6-membered monocyclic heterocycloalkyl are selected from O, and the number of the heteroatoms is 1; r ₁ and R ₂ together with the nitrogen atom to which they are attached form a 5-6 membered monocyclic heterocycloalkyl, the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl being selected from N, the number of heteroatoms being 1 or 2, the 5-6 membered monocyclic heterocycloalkyl being optionally substituted by 1, 2 or 3 identical or different R ^a; r ^a is independently selected from C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl, the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl being selected from N, the number of heteroatoms being 1, the C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl optionally substituted with one or more halogens.

Further preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is selected from isopropyl orR ₁ and R ₂ together with the nitrogen atom to which they are attached form a 5-6 membered monocyclic heterocycloalkyl, the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl being selected from N, the number of heteroatoms being 1 or 2, the 5-6 membered monocyclic heterocycloalkyl being optionally substituted by 1, 2 or 3 identical or different R ^a; r ^a is independently selected from C _1-6 alkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) (C _1-6 alkyl), -CO-C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl, the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl being selected from N, the number of heteroatoms being 1, the C _1-6 alkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) (C _1-6 alkyl), -CO-C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl optionally substituted with one or more halogens.

Further preferably, R ₃ is fluorine, R ₄ is methyl, R ₅ is hydrogen, L is CH, A is selected from isopropyl orR ₁ and R ₂ together with the nitrogen atom to which they are attached form the following optionally substituted structure with 1, 2 or 3R ^a, which may be the same or different: R ^a is independently selected from C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl, the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl being selected from N, the number of heteroatoms being 1, the C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl being optionally substituted by one or more halogens.

Further preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is selected from isopropyl orR ₁ and R ₂ together with the nitrogen atom to which they are attached form an optionally substituted/>, by 1,2 or 3 identical or different R ^a groupsR ^a is independently selected from C _1-3 alkyl, C _3-6 cycloalkyl; r ^a is preferably -C(O)CH₃、-C(O)CH₂CH₃、-C(O)CH₂F、-C(O)CHF₂、-C(O)CF₃、-NH(CH₃)、-N(CH₃)₂、-OCH₃、-OCH₂CH₃、 methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl,R ^a is preferably methyl.

Preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is isopropyl; r ₁ and R ₂ together with the nitrogen atom to which they are attached form a 5-6 membered monocyclic heterocycloalkyl, the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl being selected from N, the number of heteroatoms being 1 or 2, the 5-6 membered monocyclic heterocycloalkyl being optionally substituted by 1, 2 or 3 identical or different R ^a; r ^a is independently selected from hydroxy, C _1-6 alkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) (C _1-6 alkyl), -CO-C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl, wherein the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl are selected from N, 1 in number of heteroatoms, the C _1-6 alkyl, C _1-6 alkoxy, -NHC _1-6 alkyl, -N (C _1-6 alkyl) (C _1-6 alkyl), -CO-C _1-6 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl optionally substituted with one or more halogens.

Further preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is isopropyl; r ₁ and R ₂ together with the nitrogen atom to which they are attached form a 5-6 membered monocyclic heterocycloalkyl, the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl being selected from N, the number of heteroatoms being 1 or 2, the 5-6 membered monocyclic heterocycloalkyl being optionally substituted by 1, 2 or 3 identical or different R ^a; r ^a is independently selected from C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl, the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl being selected from N, the number of heteroatoms being 1, the C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl optionally substituted with one or more halogens.

Further preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is isopropyl; r ₁ and R ₂ together with the nitrogen atom to which they are attached form an optionally substituted with 1,2 or 3 identical or different R ^a groupsR ^a is independently selected from hydroxy, C _1-6 alkyl, C _3-6 cycloalkyl, said C _1-6 alkyl, C _3-6 cycloalkyl optionally substituted with one or more halogen, hydroxy, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy.

Further preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is isopropyl; r ₁ and R ₂ together with the nitrogen atom to which they are attached form an optionally substituted with 1,2 or 3 identical or different R ^a groupsR ^a is independently selected from C _1-3 alkyl, C _3-6 cycloalkyl.

Preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is isopropyl; r ₁ and R ₂ together with the nitrogen atom to which they are attached form an optionally substituted with 1, 2 or 3 identical or different R ^a groupsR ^a is independently selected from C _1-6 alkyl, said C _1-6 alkyl optionally substituted with one or more halogen, hydroxy, cyano, nitro, C _1-6 alkoxy.

Further preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is isopropyl; r ₁ and R ₂ together with the nitrogen atom to which they are attached form an optionally substituted with 1,2 or 3 identical or different R ^a groupsR ^a is independently selected from C _1-6 alkyl, said C _1-6 alkyl optionally substituted with one or more halogen, hydroxy, C _1-3 alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy).

Further preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is isopropyl; r ₁ and R ₂ together with the nitrogen atom to which they are attached form an optionally substituted with 1,2 or 3 identical or different R ^a groupsR ^a is independently selected from C _1-3 alkyl, wherein the C _1-3 alkyl is optionally substituted by one or more fluorine, chlorine and hydroxyl.

Further preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is isopropyl; r ₁ and R ₂ together with the nitrogen atom to which they are attached form an optionally substituted with 1,2 or 3 identical or different R ^a groupsR ^a is selected from C _1-3 alkyl. /(I)

Further preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is isopropyl; r ₁ and R ₂ together with the nitrogen atom to which they are attached form an optionally substituted with 1R ^a R ^a is selected from C _1-3 alkyl.

Further preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is isopropyl; r ₁ and R ₂ together with the nitrogen atom to which they are attached form an optionally substituted with 1R ^a R ^a is selected from methyl.

Preferably, the compounds provided herein or prodrugs, tautomers, optical isomers, geometric isomers, solvates, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is selected fromR ₁ and R ₂ together with the nitrogen atom to which they are attached form a 5-6 membered monocyclic heterocycloalkyl, the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl being selected from N, the number of heteroatoms being 1 or 2, the 5-6 membered monocyclic heterocycloalkyl being optionally substituted by 1, 2 or 3 identical or different R ^a; r ^a is independently selected from C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl, the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl being selected from N, the number of heteroatoms being 1, the C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl optionally substituted with one or more halogens.

Further preferably, R ₃ is fluorine, R ₄ is methyl, R ₅ is hydrogen, L is CH, A is selected fromR ₁ and R ₂ together with the nitrogen atom to which they are attached form the following optionally substituted structure with 1, 2 or 3R ^a, which may be the same or different: R ^a is independently selected from C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl, the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl being selected from N, the number of heteroatoms being 1, the C _1-3 alkyl, C _1-3 alkoxy, -NHC _1-3 alkyl, -N (C _1-3 alkyl) (C _1-3 alkyl), -CO-C _1-3 alkyl, C _3-6 cycloalkyl, 5-6 membered monocyclic heterocycloalkyl being optionally substituted by one or more halogens.

Further preferably, R ₃ is fluoro; r ₄ is methyl; r ₅ is hydrogen; l is CH; a is selected fromR ₁ and R ₂ together with the nitrogen atom to which they are attached form an optionally substituted/>, by 1,2 or 3 identical or different R ^a groupsR ^a is independently selected from C _1-3 alkyl, C _3-6 cycloalkyl; r ^a is preferably -C(O)CH₃、-C(O)CH₂CH₃、-C(O)CH₂F、-C(O)CHF₂、-C(O)CF₃、-NH(CH₃)、-N(CH₃)₂、-OCH₃、-OCH₂CH₃、 methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl,R ^a is preferably methyl.

Preferably, the present invention provides a compound or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof.

Further, the invention provides a pharmaceutical composition, which comprises the compound or a prodrug, a tautomer, an optical isomer, a geometric isomer, a solvate, an isotope derivative or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.

The present invention provides a pharmaceutical composition comprising a compound of the present invention or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, and another, two or more antitumor substances. Preferably, the anti-tumor substance comprises PARP inhibitors, topoisomerase inhibitors, cytotoxic chemotherapeutics, PD-L1 inhibitors, WEE1 inhibitors, and ATR inhibitors. Preferably, the PARP inhibitor comprises olaparib; the topoisomerase inhibitor comprises irinotecan, topotecan, etoposide; the cytotoxic chemotherapeutic drug comprises doxorubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin and epirubicin; the PD-L1 inhibitor comprises MEDI4736; the WEE1 inhibitor comprises AZD1775; the ATR inhibitor comprises AZD6738.

In a further aspect the present invention provides the use of a compound of the invention or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prophylaxis and/or treatment of a disease and/or condition mediated by ATM kinase, or at least in part by ATM kinase.

Further, the compound or a prodrug, a tautomer, an optical isomer, a geometric isomer, a solvate, an isotope derivative or a pharmaceutically acceptable salt thereof or the pharmaceutical composition is used for preparing medicines for preventing and/or treating cancers.

Further, the invention provides for the use wherein the cancer comprises solid tumors and hematological tumors. Preferably, the solid tumor comprises breast cancer, lung cancer, brain cancer, colorectal cancer, glioma, esophageal cancer (including gastroesophageal junction cancer), gastric cancer (including gastrointestinal junction cancer), ovarian cancer, head and neck cancer, liver cancer, and the hematological tumor comprises lymphoma and leukemia. Preferably, the cancer comprises breast cancer, non-small cell lung cancer, brain glioma, colorectal cancer, glioblastoma, esophageal cancer (including gastroesophageal junction cancer), gastric cancer (including gastrointestinal junction cancer), ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer, glioblastoma.

In a further aspect, the present invention provides a method for the prevention and/or treatment of a disease mediated by an ATM kinase inhibitor, which comprises administering to a subject in need thereof a compound of the present invention or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention; preferably, the disease is cancer; more preferably, the cancer comprises solid tumors and hematological tumors; more preferably, the solid tumor comprises breast cancer, lung cancer, brain cancer, colorectal cancer, glioma, esophageal cancer (including gastroesophageal junction cancer), gastric cancer (including gastrointestinal junction cancer), ovarian cancer, head and neck cancer, liver cancer, the hematological tumor comprising lymphoma and leukemia; more preferably, the cancer comprises breast cancer, non-small cell lung cancer, brain glioma, colorectal cancer, glioblastoma, gastric cancer (including gastrointestinal junction cancer), ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer, glioblastoma.

Further, the invention provides a use or method wherein the compound of the invention or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof or the pharmaceutical composition of the invention is administered simultaneously, separately or sequentially with radiation therapy.

Further, the present invention provides a use or a method, wherein the compound of the present invention or a prodrug, tautomer, optical isomer, geometric isomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention is used in combination with a chemoradiotherapy means or with another, two or more antitumor agents. Preferably, the anti-tumor substance comprises PARP inhibitors, topoisomerase inhibitors, cytotoxic chemotherapeutics, PD-L1 inhibitors, WEE1 inhibitors, and ATR inhibitors. Preferably, the PARP inhibitor comprises olaparib; the topoisomerase inhibitor comprises irinotecan, topotecan, etoposide; the cytotoxic chemotherapeutic drug comprises doxorubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin and epirubicin; the PD-L1 inhibitor comprises MEDI4736; the WEE1 inhibitor comprises AZD1775; the ATR inhibitor comprises AZD6738.

Definition of the definition

The terms "optional," "any," "optionally," or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

Unless otherwise indicated, the terms "optionally substituted", "… … optionally substituted", "… … optionally substituted", "optionally … … substituted" or "optionally … … substituted" mean that the hydrogen on the substituted group is unsubstituted or is independently substituted by a substituent at one or more substitutable positions of the substituted group, the substituent being independently selected from one or more deuterium, hydroxy, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -C (O) C _1-6 alkyl, -C (O) O-C _1-6 alkyl, -OC (O) -C _1-6 alkyl, -NH (C _1-6 alkyl), -N (C _1-6 alkyl) (C _1-6 alkyl), -C (O) NH-C _1-6 alkyl, -NHC (O) -C _1-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, 3-10 membered heterocyclyl, C _6-14 aryl, 5-12 membered heteroaryl groups.

The term "oxo" refers to the substitution of two H groups at the same substitution position with the same O to form a double bond, i.e., =o.

Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C _1-10 alkyl), further preferably containing 1 to 8 carbon atoms (C _1-8 alkyl), more preferably containing 1 to 6 carbon atoms (i.e., C _1-6 alkyl), e.g., "C _1-6 alkyl" refers to that the group is alkyl, and the number of carbon atoms on the carbon chain is between 1 and 6 (specifically 1,2, 3,4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.

Unless otherwise specified, the term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon atoms and hydrogen atoms. Alkenyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C _2-10 alkenyl), further preferably 2 to 8 carbon atoms (C _2-8 alkenyl), more preferably 2 to 6 carbon atoms (i.e., C _2-6 alkenyl), 2 to 5 carbon atoms (i.e., C _2-5 alkenyl), 2 to 4 carbon atoms (i.e., C _2-4 alkenyl), 2 to 3 carbon atoms (i.e., C _2-3 alkenyl), 2 carbon atoms (i.e., C ₂ alkenyl), for example "C _2-6 alkenyl" means that the group is alkenyl and the number of carbon atoms on the carbon chain is between 2 and 6 (specifically 2,3,4,5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.

The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, having at least one triple bond, unless otherwise specified. Alkynyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e. C _2-10 alkynyl), further preferably 2 to 8 carbon atoms (C _2-8 alkynyl), more preferably 2 to 6 carbon atoms (i.e. C _2-6 alkynyl), 2 to 5 carbon atoms (i.e. C _2-5 alkynyl), 2 to 4 carbon atoms (i.e. C _2-4 alkynyl), 2 to 3 carbon atoms (i.e. C _2-3 alkynyl), 2 carbon atoms (i.e. C ₂ alkynyl), for example "C _2-6 alkynyl" means that the group is alkynyl and the number of carbon atoms on the carbon chain is between 2 and 6 (in particular 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.

Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic radical having a specific number of carbon atoms, preferably containing 3 to 12 carbon atoms (i.e., C _3-12 cycloalkyl), more preferably containing 3 to 10 carbon atoms (C _3-10 cycloalkyl), even more preferably 3 to 7 carbon atoms (C _3-7 cycloalkyl), 4 to 6 carbon atoms (C _4-6 cycloalkyl), 5 to 6 carbon atoms (C _5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

The term "alkoxy", unless otherwise specified, refers to an-O-alkyl group, which is as defined above, i.e. comprising 1 to 20 carbon atoms, preferably comprising 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (in particular 1,2,3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-dimethylpropoxy, 1-ethylpropoxy, and the like.

The term "alkylthio" refers to the replacement of oxygen in the above "alkoxy" with sulfur, i.e. -S-alkyl, as defined above, i.e. comprising 1 to 20 carbon atoms, preferably comprising 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (in particular 1,2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, t-butylthio, pentylthio, 1-dimethylpropylthio, 1, 2-dimethylpropylthio, and the like.

The term "halogen" or "halo" refers to F, cl, br, I, unless otherwise specified. The term "haloalkyl" means that one, two or more hydrogen atoms or all hydrogen atoms in an alkyl group as defined above are replaced by halogen. Representative examples of haloalkyl groups include CCl₃、CF₃、CHCl₂、CH₂Cl、CH₂Br、CH₂I、CH₂CF₃、CF₂CF₃ and the like.

Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic non-aromatic substituent having ring carbon atoms and 1 to 4 ring heteroatoms, containing 3 to 20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S and the remaining ring atoms are C. Preferably contains 3 to 12 ring atoms (3 to 12 membered heterocyclic group), further preferably contains 3 to 10 ring atoms (3 to 10 membered heterocyclic group), or 3 to 8 ring atoms (3 to 8 membered heterocyclic group), or 3 to 6 ring atoms (3 to 6 membered heterocyclic group), or 4 to 6 ring atoms (4 to 6 membered heterocyclic group), or 5 to 6 ring atoms (5 to 6 membered heterocyclic group). The number of heteroatoms is preferably 1 to 4, more preferably 1 to 3 (i.e. 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl and the like. Polycyclic heterocyclyl groups include fused, spiro, fused and bridged heterocyclic groups. "heterocyclyl" may be a monocyclic ("monocyclic heterocyclyl") or a fused ("fused heterocyclyl" or "heterofused ring") and cyclic ("fused heterocyclyl"), bridged ("heterobridged heterocyclyl" or "bridged heterocyclyl") or spiro-fused ("heterospiroheterocyclyl" or "spiroheterocyclyl") ring system, such as a bicyclic system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. The heterocyclyl bicyclic ring system may include one or more heteroatoms in one or both rings. "heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused by one or more carbocyclyl groups, wherein the attachment point is on the carbocyclyl or heterocyclyl ring, or "heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused by one or more aryl or heteroaryl groups, or ring systems in which the cycloalkyl ring as defined above is fused by one or more heteroaryl groups, wherein the attachment point is on the heterocyclyl ring or cycloalkyl ring, and in such cases the number of elements of the heterocyclyl ring system is the number of ring system atoms after fusion. In certain embodiments, each instance of a heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridinyl, oxetanyl (oxiranyl) and thiiranyl (thiorenyl). Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiathiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl (thianyl). Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazahexanyl, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxazahexanyl (dioxazinanyl). Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepinyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azacyclooctyl, oxacyclooctyl, and thiacyclooctyl. Exemplary 5-membered heterocyclyl groups fused to a C ₆ aryl ring (also referred to herein as a 5, 6-bicyclic heterocycle) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6, 6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

Unless otherwise specified, "heterocycloalkyl" means a saturated "heterocyclyl" or "heterocycle" as defined above, with ring atoms being as defined above, i.e., containing from 3 to 20 ring atoms ("3-20 membered heterocycloalkyl"), and having a number of heteroatoms of from 1 to 4 (1, 2, 3, or 4), preferably from 1 to 3 (1, 2, or 3), wherein each heteroatom is independently selected from N, O or S. Preferably containing 3 to 12 ring atoms ("3 to 12 membered heterocycloalkyl"), more preferably containing 3 to 10 ring atoms ("3 to 10 membered heterocycloalkyl"), still more preferably containing 3 to 8 ring atoms ("3 to 8 membered heterocycloalkyl"), still more preferably containing 4 to 7 ring atoms ("4 to 7 membered heterocycloalkyl"), still more preferably containing 5 to 10 ring atoms ("5 to 10 membered heterocycloalkyl"), still more preferably containing 5 to 6 ring atoms ("5 to 6 membered heterocycloalkyl"). In certain embodiments, each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted with one or more substituents (a "substituted heterocycloalkyl"). The "heterocyclyl" or "heterocyclic" moiety above has given some exemplary "heterocycloalkyl" groups and includes, but is not limited to, aziridine, oxetane, thietanyl, tetrahydrofuranyl, oxahexidine, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiacyclohexyl, oxazolidinyl, dioxanyl, dithianyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolinidine, and the like. One of the heterocycloalkyl groups is "mono-spiroheterocycloalkyl" which refers to a cyclic structure having a specific number of carbon atoms and hetero atoms formed by two saturated rings sharing one ring carbon atom, and illustrative examples of mono-spiroheterocycloalkyl include (but are not limited to)Etc.

Unless otherwise specified, the term "aryl" or "aromatic ring radical" means a monocyclic, bicyclic and tricyclic aromatic carbocyclic ring system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms, and the term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, and the like.

Unless otherwise specified, the term "heteroaryl" or "heteroaryl cyclic" means an aromatic monocyclic or polycyclic ring system containing a 5-14 membered structure, or preferably a 5-10 membered structure, or preferably a 5-8 membered structure, more preferably a 5-6 membered structure, wherein 1,2,3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, the number of heteroatoms preferably being 1,2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo [2,3-b ] pyridyl, imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,5-a ] triazolo [1,5-a ] pyridyl, and the like.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts, such as the pharmaceutically acceptable salts of amines, carboxylic acids and other types of compounds, which are, unless otherwise specified, suitable for use in contact with the tissues of mammals, especially humans, without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and are well known in the art. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the free base or the free acid with a suitable reagent alone.

Unless otherwise specified, the term "isotopically-derivative" means that the compound of the present invention may be present in isotopically-labeled or enriched form, containing one or more atoms having an atomic weight or mass number different from the atomic weight or mass number of the largest number of atoms found in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes commonly used as isotopic labels are: hydrogen isotopes, ² H and ³ H; carbon isotopes: ¹³ C and ¹⁴ C; chlorine isotopes: ³⁵ Cl and ³⁷ Cl; fluorine isotopes: ¹⁸ F; iodine isotopes: ¹²³ I and ¹²⁵ I; nitrogen isotopes: ¹³ N and ¹⁵ N; oxygen isotopes: ¹⁵O,¹⁷ O and ¹⁸ O and sulfur isotopes ³⁵ S. These isotopically-labeled compounds can be used to study the distribution of a pharmaceutical molecule in a tissue. Particularly ² H and ¹³ C, are more widely used because they are easily labeled and conveniently detected. Substitution of certain heavy isotopes, such as heavy hydrogen (² H), enhances metabolic stability and increases half-life for reduced dosage and provides therapeutic advantages. Isotopically-labeled compounds generally begin with a starting material that has been labeled, and are synthesized using known synthetic techniques like synthesizing non-isotopically-labeled compounds.

The terms "solvate", "solvate" and "solvates" mean, unless otherwise specified, the physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In some cases, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may be present in a regular arrangement and/or in a disordered arrangement. Solvates may contain either stoichiometric or non-stoichiometric solvent molecules. "solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates and isopropanolamides. Solvation methods are well known in the art.

The term "optical isomer" refers to a substance that has identical molecular structure, similar physicochemical properties, but different optical rotation, unless otherwise specified.

Unless otherwise specified, the term "geometric isomer (cis/trans) isomer" may contain a carbon-carbon double bond or a carbon-nitrogen double bond in the E or Z configuration, where the term "E" represents a higher order substituent on the opposite side of the carbon-carbon or carbon-nitrogen double bond and the term "Z" represents a higher order substituent on the same side of the carbon-carbon or carbon-nitrogen double bond (as determined using Cahn-Ingold Prelog rules of preference). The compounds of the present invention may also exist as mixtures of "E" and "Z" isomers.

Unless otherwise specified, the term "tautomer" refers to structural isomers having different energies that can be converted to each other by a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers include interconversions by recombination of some of the bond-forming electrons.

Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) thereof, are all within the scope of the invention.

The term "prodrug" refers to a drug that is converted in vivo to the parent drug, unless otherwise specified. Prodrugs are often useful, which may improve some defined, undesirable physical or biological properties. Physical properties are often associated with solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too fast metabolism or poor bioavailability, which may itself be associated with physicochemical properties. For example, they may be bioavailable orally, whereas the parent is not. The solubility of the prodrug in the pharmaceutical composition is also improved compared to the parent drug. An example of a prodrug, but not limited thereto, may be any compound of the invention that is administered as an ester ("prodrug") to facilitate transport across the cell membrane, where water solubility is detrimental to mobility, but which is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, wherein the peptide is metabolized to reveal an active moiety.

The term "treatment" encompasses any treatment of a disease, disorder, and condition in a patient, unless otherwise specified, including: (a) Inhibiting the symptoms of, i.e., preventing the development of, diseases, disorders, and conditions; or (b) alleviating symptoms of diseases, disorders, and conditions, i.e., causing regression of the disease or symptoms; or (c) ameliorating or eliminating a disease, disorder, and condition or one or more symptoms associated with the disease.

Abbreviations used elsewhere herein for the preparation examples, and are:

DCM dichloromethane

DIEA N, N-diisopropylethylamine

DMF N, N-dimethylformamide

THF tetrahydrofuran

H hours

ML of

CDCl ₃ deuterated chloroform

The beneficial effects of the invention are as follows:

The invention provides an ATM kinase inhibitor with a novel structure, and discloses a preparation method and medical application thereof. In particular, the compounds of the invention have utility in the treatment of cancer, as shown by the results of enzymatic assays: compared with the positive control medicine AZD1390, the compound has the advantages that the selectivity of the compound to the ATM target is good, the activity of inhibiting ATM kinase is equivalent, but the bioavailability in the body and the exposure in brain tissues are far higher than those of the positive control medicine AZD1390, the tumor inhibition rate in the body is high, and unexpected technical effects are obtained. In addition, the invention researches a specific synthesis method, and the synthesis method has simple process and convenient operation, and is beneficial to large-scale industrial production and application.

Detailed Description

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials are presented herein for illustrative purposes only.

Example 1: synthesis of Compound 1:

step 1 Synthesis of intermediate-1

DMF (20 mL), SM-1 (1.50 g,4.52 mmol), isopropylamine (0.40 g,6.78 mmol) and DIEA (1.17 g,9.05 mmol) were added sequentially to a 100mL reaction flask, and the temperature was raised to 90℃for 3h. After the completion of the reaction by TLC, the reaction mixture was cooled to room temperature, water was added to precipitate a solid, the solid was collected by suction filtration, and the solid was rinsed with water and dried to give intermediate-1 (1.30 g, yield 81.2%). MS (m/z): 355.04/357.04[ M+H ] ⁺.

Step 2 Synthesis of intermediate-2

Into a 100mL reaction flask were successively added THF (10 mL), intermediate-1 (1.30 g,3.7 mmol), water (5 mL) and sodium hydroxide (0.37 g,9.25 mmol), and the mixture was heated to 60℃to react for 3 hours. After the completion of the reaction, TLC was followed by cooling the reaction solution to room temperature, adjusting pH to 5 with 1N hydrochloric acid, precipitating a solid, collecting the solid by suction filtration, rinsing the solid with water and drying to give intermediate-2 (0.96 g, yield 80.0%). MS (m/z): 327.01/329.01[ M+H ] ⁺.

Step 3 Synthesis of intermediate-3

DMF (15 mL), intermediate-2 (0.96 g,2.94 mmol), DIEA (0.76 g,5.88 mmol) and diphenyl azide phosphate (1.21 g,4.40 mmol) were added sequentially in a 100mL reaction flask and the temperature was raised to 60℃for 3h. After the completion of the reaction by TLC, the reaction mixture was cooled to room temperature, water was added to precipitate a solid, the solid was collected by suction filtration, and the solid was rinsed with water and dried to give intermediate-3 (0.78 g, yield 82.1%). MS (m/z): 324.01/326.01[ M+H ] ⁺.

Step 4 Synthesis of intermediate-4

DMF (15 mL) and intermediate-3 (0.78 g,2.40 mmol) were added sequentially to a 100mL reaction flask, cooled to 0deg.C, then NaH (0.23 g,9.60 mmol) was added, the reaction was carried out at this temperature for 0.5h, then methyl iodide (0.51 g,3.60 mmol) was added, and the reaction was carried out at room temperature overnight. After the completion of the reaction, TLC was monitored, and water was added to the reaction mixture to precipitate a solid, which was collected by suction filtration, rinsed with water and dried to give intermediate-4 (0.62 g, yield 77.5%). MS (m/z): 338.02/340.02[ M+H ] ⁺.

Step 5 Synthesis of intermediate-5

To a 100mL reaction flask was added, in order, 1, 4-dioxane (15 mL), intermediate-4 (0.62 g,1.83 mmol), 6-fluoropyridine-3-boronic acid (0.39 g,2.74 mmol), potassium carbonate (0.63 g,4.57 mmol), water (1.5 mL), and tetrakis (triphenylphosphine) palladium (0.21 g,0.18 mmol). Heating to 90 ℃ under the protection of nitrogen, and reacting for 2.5h. After TLC monitoring the reaction, the reaction was concentrated to dryness and the residue was purified by column chromatography (DCM: meoh=60:1) to give intermediate-5 (0.43 g, 66.2% yield). MS (m/z): 355.13[ M+H ] ⁺.

Step 6 Synthesis of Compound 1

In a 50mL reaction flask were added anhydrous THF (4 mL) and 3- (4-methylpiperazin-1-yl) propan-1-ol (80 mg,0.51 mmol), and after cooling to 0deg.C NaH (35 mg,0.89 mmol) was added in portions. After 0.5h at room temperature, intermediate-5 (88 mg,0.25 mmol) was added and the reaction was carried out overnight at room temperature. After the completion of the reaction by TLC, the reaction mixture was concentrated to dryness and purified by column chromatography (DCM: meoh=20:1 to 10:1) to give crude product, which was further purified by preparative thin layer chromatography to give compound 1 (23 mg, yield 18.7％),MS(m/z):493.17[M+H]⁺;¹HNMR(600MHz,CDCl₃)δ:8.694(s,1H),8.409(d,J＝1.8Hz,1H),8.205(d,J＝7.2Hz,1H),7.881-7.907(m,2H),6.890(d,J＝8.4Hz,1H),5.218(s,1H),4.435(t,2H),3.583(s,3H),2.599-2.624(m,10H),2.378(s,3H),2.035-2.070(m,2H),1.765(d,J＝6.6Hz,6H).

Referring to the preparation of compound 1, only the intermediate in step 6: replacement of 3- (4-methylpiperazin-1-yl) propan-1-ol gives the following example compound:

Example 24: synthesis of Compound 24:

step 1 Synthesis of intermediate-1

DMF (30 mL), SM-1 (2.50 g,7.52 mmol), 4-aminotetrahydropyran (1.14 g,11.28 mmol) and DIEA (1.94 g,15.04 mmol) were added sequentially in a 100mL reaction flask, and the temperature was raised to 90℃for 3h. After the completion of the reaction by TLC, the reaction mixture was cooled to room temperature, water was added to precipitate a solid, the solid was collected by suction filtration, and the solid was rinsed with water and dried to give intermediate-1 (2.55 g, yield 85.4%). MS (m/z): 397.05/399.05[ M+H ] ⁺.

Step 2 Synthesis of intermediate-2

Into a 100mL reaction flask were successively added THF (20 mL), intermediate-1 (2.55 g,6.42 mmol), water (5 mL) and sodium hydroxide (0.64 g,16.05 mmol), and the mixture was heated to 60℃to react for 3 hours. After the completion of the reaction, TLC was monitored, the reaction solution was cooled to room temperature, pH was adjusted to 5 with 1N hydrochloric acid, a solid was precipitated, the solid was collected by suction filtration, and the solid was rinsed with water and dried to give intermediate-2 (1.93 g, yield 81.3%). MS (m/z): 369.02/371.02[ M+H ] ⁺.

Step 3 Synthesis of intermediate-3

DMF (15 mL), intermediate-2 (1.93 g,5.22 mmol), DIEA (1.35 g,10.44 mmol) and diphenyl azide phosphate (2.15 g,7.83 mmol) were added sequentially in a 100mL reaction flask and the temperature was raised to 60℃for 3h. After the completion of the reaction by TLC, the reaction mixture was cooled to room temperature, water was added to precipitate a solid, the solid was collected by suction filtration, and the solid was rinsed with water and dried to give intermediate-3 (1.53 g, yield 80.0%). MS (m/z): 366.02/368.02[ M+H ] ⁺.

Step 4 Synthesis of intermediate-4

DMF (25 mL) and intermediate-3 (1.53 g,4.18 mmol) were added sequentially to a 100mL reaction flask, cooled to 0deg.C, then NaH (0.67 g,16.72 mmol) was added, the reaction was carried out at this temperature for 0.5h, then methyl iodide (0.89 g,6.27 mmol) was added, and the reaction was carried out at room temperature overnight. After the completion of the reaction, TLC was monitored, and water was added to the reaction mixture to precipitate a solid, which was collected by suction filtration, rinsed with water and dried to give intermediate-4 (1.19 g, yield 75.0%). MS (m/z): 380.03/382.03[ M+H ] ⁺.

Step 5 Synthesis of intermediate-5

A100 mL reaction flask was charged with 1, 4-dioxane (25 mL), intermediate-4 (1.19 g,3.14 mmol), 6-fluoropyridine-3-boronic acid (0.66 g,4.71 mmol), potassium carbonate (0.63 g,7.85 mmol), water (2.5 mL), and tetrakis (triphenylphosphine) palladium (0.36 g,0.31 mmol) in sequence. Heating to 90 ℃ under the protection of nitrogen, and reacting for 2.5h. After TLC monitoring the reaction, the reaction was concentrated to dryness and the residue was purified by column chromatography (DCM: meoh=50:1) to give intermediate-5 (0.74 g, 59.3% yield). MS (m/z): 397.14[ M+H ] ⁺.

Step 6 Synthesis of Compound 24

In a50 mL reaction flask were added anhydrous THF (5 mL) and 3- (4-methylpiperazin-1-yl) propan-1-ol (80 mg,0.51 mmol), and after cooling to 0deg.C NaH (35 mg,0.89 mmol) was added in portions. After 0.5h at room temperature, intermediate-5 (99 mg,0.25 mmol) was added and the reaction was carried out overnight at room temperature. After completion of TLC, the reaction solution was concentrated to dryness and purified by column chromatography (DCM: meOH=20:1-10:1) to give crude product, which was further purified by preparative thin layer chromatography to give compound 24 (30 mg, yield 22.4%), MS (m/z): 535.28[ M+H ] ⁺.

Reference to the preparation of compound 24, only the intermediate in step 6: replacement of 3- (4-methylpiperazin-1-yl) propan-1-ol gives the following example compound:

Effect example:

1. ATM enzyme inhibition activity assay of the compounds: ATM mobility change test (Caliper Mobility shift assayfor ATM).

(1) Test materials

Reagent name	Manufacturer' s	Goods number
			ATM	Millipore	14-933
ATP	Sigma	A7699-1G
			DMSO	Sigma	D2650
EDTA	Sigma	E5134
			5-FAM-AK-17	GL	524315
96-well plate	Corning	3365
			384-well plate	Corning	3575

(2) Step (a)

1. Preparing a1 x kinase basic buffer solution and a reaction stopping solution:

1) 1 Xkinase base buffer

50 mM HEPES,pH 7.5

0.0015% Brij-35 (polyoxyethylene lauryl ether)

100 mM Na₃VO₄

5 M NaCl

1 M MgCl₂

1 M MnCl₂

2)Stop buffer

100 mM HEPES,pH 7.5

0.015％Brij-35

0.2％Coating Reagent#3

50 mM EDTA

2. Preparation of test Compounds

1) Dissolution and dilution of the compound: the compounds were dissolved in DMSO and formulated as stock solutions at 10 mM or 5mM concentrations. 98. Mu.L of DMSO was added to the 96-well plate, and 2. Mu.L of 10 mM strength stock solution was added and mixed well to a concentration of 200. Mu.M. Another 96-well plate was taken, 45. Mu.L of DMSO was added, and 5. Mu.L of 200. Mu.M solution was added to make 20. Mu.M working solution.

2) The compound working solution was serially diluted in a 96-well plate in sequence by taking 10. Mu.L of a high concentration solution to 30. Mu.L of DMSO to transfer to the next well, and so on, to prepare 10 concentration gradients.

3) 100. Mu.L of DMSO was added to the blank wells as a compound-free enzyme-free blank.

4) Preparing an intermediate sample plate: the gradient concentration solutions prepared in the 96-well plates were each taken at 40 μl and transferred to a new 384-well plate as an intermediate sample plate.

3. Preparation of test plate

From the intermediate sample plate, 100nL of each compound solution was taken into 384-well plates as test plates.

4. Kinase reaction

1) The kinase was dissolved in a1 Xkinase base buffer to prepare a2 Xenzyme solution.

2) Mu.L of 2 Xenzyme solution was added to 384-well assay plates.

3) Incubate at room temperature for 10min.

4) The FAM-labeled polypeptide substrate and ATP were dissolved in a1 Xkinase base buffer to prepare a2 Xsubstrate peptide solution.

5) Mu.L of the 2 Xsubstrate peptide solution was added to each well of the 384-well assay plate.

6) Enzymatic reaction proceeds and terminates: after incubating the test plate with the enzyme solution and the substrate peptide solution at 37℃for a certain period of time, the reaction was terminated by adding 35. Mu.L of a reaction termination solution.

5. Reading the reaction well.

6. And performing curve fitting on the read values, and calculating the inhibition rate.

% Inhibition = (max-version)/(max-min) ×100; wherein "max" represents the total compound-free reaction Kong Kongdou value of DMSO; "min" represents the blank well read value; convertion represents test well read values.

The inhibition rate of different concentration% of the compound is calculated by using the formula

Y＝Bottom+(Top-Bottom)/(1+(IC₅₀/X)^HillSlope)

Calculate IC ₅₀.

(3) ATM inhibitory activity of the compound:

Numbering of compounds	ATM IC₅₀(nM)
		1	0.32
AZD1390	0.24

Note that: the positive control compound AZD1390 is the compound of example 2 in patent CN 201680052951.0.

In vitro enzymatic results show that the compounds of the invention are potent inhibitors of ATM kinase. The compounds of the invention inhibit the activity of ATM kinase with IC ₅₀ less than 1nM and partial compound with IC ₅₀ less than 0.5nM, for example, compound 1 inhibits the activity of ATM enzyme with IC ₅₀ of 0.32nM, which is equivalent to the inhibiting activity of positive control compound AZD 1390. .

2. ICW assay for intracellular inhibition of ATM phosphorylated KAP1 levels

(1) Principle of: KAP1 is one of the downstream substrate proteins of ATM. Intracellular ATM phosphorylates KAP1 to phospho-KAP1 (pKAP 1). Inhibiting ATM kinase activity, pKAP levels decrease. By performing an intracellular Western blot assay, intracellular pKAP protein levels are detected, indirectly reflecting ATM kinase activity, and thus, the inhibition of the compounds on ATM is assessed.

(2) Test materials and instruments

And (3) cells: human breast cancer cell MCF7

Materials and reagents:

consumable and instrument:

(3) Step (a)

1) Cell inoculation:

MCF7 cells were seeded in 384 well plates, 10000 per well (25 uL per well); incubated at 37℃with 5% CO ₂ overnight.

2) Activity detection:

a. the compounds were prepared as 100mM solutions in DMSO, then subjected to 1:3 gradient dilutions for a total of 10 concentrations, up to a maximum of 100. Mu.M.

B. The compound solutions prepared in step a were added to each well of the cell plate (Corning # 356663) using I-DOT One at 25nL to a final concentration of 100nM (highest dose).

C. The medicated cell plates were incubated at 37℃for 2h with 5% CO ₂. After 2h, the cell plates were irradiated at a dose of 10Gy and then incubated for a further 1h.

D. 25uL of 8% paraformaldehyde was added to each well, followed by incubation at room temperature for 20min.

E. 8% paraformaldehyde was discarded, 0.1% triton x-100 was added, and then incubated at room temperature for 30min.

F. odessey blocking buffer,50 uL/well, was added and incubated for 1.5h at room temperature.

G. Odessey blocking buffer was discarded, primary antibody (Phospho-KAP 1,1:2000 dilution) was added and incubated overnight at 4 ℃.

H. The primary antibody was removed and washed 5 times with PBS+0.1% Tween 20.

I. adding DNA dye DRAQ5 coated with secondary antibody (IRDye 800CW Goat anti-Rabbit,1:4000 dilution), and incubating at room temperature for 1h.

J. The secondary antibody was removed and washed 5 times with PBS +0.1% tween 20.

K. PBS +0.1% tween 20 was blotted with Odyssey.

3) Data analysis:

a. the relative ratio of each well Channal 800,800/Channal 700,700 was examined.

B. the percent KAP1 phosphorylation (% of KAP1 phosphorylation) was calculated according to the following formula:

％of KAP1 phosphorylation＝[(Ratio_cmpd-(Ratio)_Positive)/((Ratio)_Vehicle-(Ratio)_Positive]*100

(Ratio) _Positive: testing the average value of the test values of each positive control hole on the cell plate;

(Ratio) _Vehicle: average of the test values for each negative control well on the test cell plate.

C. IC ₅₀ for each compound was calculated and the effect-dose curve was plotted: IC ₅₀ was calculated by fitting Graphpad 8.0 to the percent of KAP1 phosphorylation and the logarithmic concentration of the compound.

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC₅₀-X)*HillSlope))

X:log of compound's concentration

Y:％of KAP1 phosphorylation

(4) Compound intracellular IC ₅₀ that inhibits ATM phosphorylation KAP1 levels:

at the cellular level, the compounds of the invention have an inhibitory effect on ATM phosphorylated KAP 1. Wherein the IC ₅₀ < 1nM of compound 1 inhibits the activity of ATM enzyme, and the inhibition activity of the compound is basically equivalent to that of the positive control compound AZD 1390.

3. Pharmacokinetic test in mice

(1) Animals: ICR mice, SPF grade, male, 30-40g.

(2) Test grouping and procedure

The mice were grouped according to the test protocol, with groups 4, test groups 1-3 and spare groups 4. Animals were fasted for 12h before dosing, and were not water-inhibited. The dosing solution was weighed on the day of the test based on animal weight and mice No. 1-4 were dosed sequentially. After administration, blood samples of mice No. 1-3 are collected according to the scheme, and if the mice in the test group cannot collect blood samples or die, blood samples of spare mice are collected at the time point, so that the samples at each time point are ensured to be equal to 3.

Sample collection: the stomach-filling administration group is arranged before administration (0), after the administration is finished, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h, 100 mu L of blood is taken from the eye socket vein of the mice and placed in a heparin sodium anticoagulation tube, the collected blood of the mice is centrifuged for 10min at 8000rmp within 2h, plasma is separated by transferring and subpackaging in a 1.5mL centrifuge tube, and the plasma is transferred to a refrigerator at-80 ℃ for storage for pharmacokinetic analysis.

(3) PK parameters in mice following compound administration

The above data indicate that the compounds of the present invention have higher exposure in mice, and that the exposure of some compounds, such as compound 1, in mice is superior to the positive control compound AZD1390.

4. Tissue distribution test of Compounds in mice

(1) Animals: ICR mice, SPF grade, female, 18-20g.

(2) Test grouping and procedure

Each group was divided into 5 time points according to the protocol, each time point was 3 animals, and 5 time points were collected and dissected into tissues, respectively. Animals were fasted for 12h before dosing, and were not water-inhibited. The drug solution is measured according to the weight of animals on the test day, and the administration mode is gastric lavage. After the completion of the gastric lavage, the mice were collected blood and tissues (heart and brain) for 0.25h, 1h, 4h, 8h, and 24h, respectively.

Plasma sample collection: after the end of the administration, 0.25h, 1h, 4h, 8h and 24h, 100 mu L of blood is taken from the orbit veins of the mice and placed in a heparin sodium anticoagulation tube, 5600rmp of the collected mouse venous blood is centrifuged for 10min within 2h, plasma is separated, and plasma transfer sub-packaging is carried out in a 1.5mL centrifuge tube and transferred to a refrigerator at the temperature of minus 80 ℃ for storage for pharmacokinetic analysis.

Tissue sample collection: after the end of the administration, tissues (heart and brain) were dissected for 0.25h, 1h, 4h, 8h and 24h, washed with physiological saline, and the filter paper was blotted to remove water, stored in a 1.5mL centrifuge tube, and stored in a refrigerator at-80 ℃ for pharmacokinetic analysis.

(3) Tissue distribution parameters of mice after administration of the Compounds

The data show that the compound has higher exposure in the brain, heart and plasma of mice, and is better than the positive compound AZD1390.

5. Drug effect test of compound combined with irinotecan liposome injection for human non-small cell lung cancer NCI-H441 transplanted tumor

(1) Animals: NU/NU mice, SPF grade, female, 20-30g.

(2) Test materials: irinotecan liposome injection (HE 072), specification 43mg:10mL, milky white liquid, lot number B37191202, available from Shijia, and Di Zhi Ji, were diluted to the appropriate concentration with 5% dextrose injection.

NCI-H441 cells (supplied by the south kyanite biotechnology limited), 1640 medium (gibco): fetal bovine serum (lanzhou balm) =90%: 10%, 37%, 5% CO ₂%.

(3) Test grouping and procedure:

NU/NU nude mice were subcutaneously vaccinated with human non-small cell lung cancer NCI-H441 cells and when the tumor volume average reached 170-172mm ³ (15 d post-vaccination), animals were equally grouped according to tumor volume (d 0), 6 per group. HE0722.5mg/kg was administered intraperitoneally once a week for 2 times, solvent control, compound 1 (6.25, 12.5, 25 mg/kg), AZD1390 25mg/kg, weekly monday to monday gavage, once a day, friday to sunday for two weeks (8 times). Tumor volumes were measured 2 times per week, mice were weighed daily, and data were recorded. The calculation formula of the tumor volume (V) is V=1/2×a×b ², wherein a and b respectively represent the long and short diameters of the tumor. Relative Tumor Volume (RTV) =vt/V0. V0 is the tumor volume measured at the time of divided cage administration (i.e., d 0), and Vt is the tumor volume at each measurement. Relative tumor volume proliferation rate T/C (%) =trtv/CRTV ×100% [ TRTV: treatment group RTV; CRTV: negative control group RTV ]. Tumor growth inhibition ratio TGI (%) = [1- (Ti-T0)/(Vi-V0) ]x100, where Ti represents the average tumor volume of a given group on a certain day; t0 is the average tumor volume of this dosing group at the beginning of dosing; vi is the average tumor volume of the vehicle control group on the same day (as Ti); v0 is the average tumor volume of the vehicle control group at the start of dosing. After the test is finished (d 17), the animals are sacrificed, tumors are peeled off, the tumor weights are weighed, and the tumor inhibition rate is calculated. Tumor weight inhibition ratio (%) = (1-dosing tumor weight/blank tumor weight) ×100.

^**P<0.01,^*** P <0.001 compared to veccle; ^##P<0.01,^### P <0.001 compared to irinotecan 2.5 mpk.

The result of the drug effect test of human non-small cell lung cancer NCI-H441 subcutaneous transplanted tumor shows that the compound of the invention obviously inhibits the growth of tumor, and the inhibition effect of partial compounds such as compound 1 on tumor volume and tumor weight is better than AZD1390.

6. Drug effect test of compound combined radiotherapy on GL-261-Luc homology model of brain glioma of mice

(1) Animals: c57BL/6 mice, SPF grade, female, 19-22g.

(2) Test materials and instruments:

GL-261-Luc tumor cells, DMEM medium: fetal bovine serum = 90%:10% CO ₂ at 37℃with the addition of 4. Mu. M L-Glu.

X-ray irradiation instrument, model: RS 2000X-Ray, manufacturer: radSource A

(3) Test procedure

1) In-situ tumor model establishment:

Female C57BL/6 mice were anesthetized with sultai 50 (60 mg/mL) and thiazine (1.5 mg/mL) and buprenorphine (0.1 mg/kg) was subcutaneously injected 30min before and 6h after surgery in order to relieve pain. The surgical field was sterilized with 70% ethanol solution. A sagittal incision was made on the parietal bone-occipital bone of the anesthetized mice using a sterile scalpel, and after the exposed skull surface was cleaned with 3% hydrogen peroxide solution, tumor cells were injected. After the injection was completed, the skull was cleaned with 3% hydrogen peroxide solution, wiped dry with a sterile dry cotton swab and the incision was sutured. The status of the mice was monitored continuously, ensuring complete recovery from anesthesia.

2) And (3) biological fluorescence detection:

The surgically inoculated mice were weighed and injected intraperitoneally with fluorescein (150 mg/kg). After injection for 10min, animals were anesthetized with a mixture of oxygen and isoflurane. When the animal is under complete anesthesia, the animal is moved into an imaging chamber for bioluminescence detection. The bioluminescence signal of the whole body of the animal was measured and the image recorded.

3) Test grouping:

bioluminescence detection was performed on day 2 post-surgery, tumor-bearing mice were randomly grouped according to bioluminescence intensity, the specific group was as follows, the order of administration was by intragastric administration of the compounds, and IR was performed 1h post-administration.

(4) Evaluation index:

After animals were grouped, bioluminescence was measured 1-2 times per week and T/C (%) values were calculated from the bioluminescence data, where T and C were the mean bioluminescence data for a day of treatment and solvent control groups, respectively. TGI (%) = [1- (Ti-T0)/(Vi-V0) ]x100, wherein Ti represents average bioluminescence data of a given group on a certain day; t0 is the mean bioluminescence data of this dosing group at the beginning of the dosing; vi is the mean bioluminescence data of the vehicle control on the same day (as Ti); v0 is the mean bioluminescence data of the vehicle control at the start of dosing.

(5) Test results:

Note that: ^*P<0.05,^**P<0.01,^*** P <0.001 compared to solvent control; ^#P<0.05,^##P<0.01,^### P <0.001 compared to IR.

The GL-261-Luc intracranial tumor pharmacodynamic test results show that the compound obviously inhibits the growth of tumors and enhances the tumor inhibition activity of irradiation in a dose-dependent manner. Compound 1 has a better sensitization than AZD1390 compared to the same dose of AZD1390.

Claims

1. A compound or an isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein said compound is:

2. A pharmaceutical composition characterized by: a compound of claim 1 or an isotopic derivative thereof or a pharmaceutically acceptable salt thereof.

3. Use of a compound according to claim 1 or an isotopic derivative thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 2 in the manufacture of a medicament for the treatment of a disease and/or condition mediated by ATM kinase, or at least in part by ATM kinase.

4. Use according to claim 3, characterized in that: the disease and/or condition mediated by ATM kinase is cancer.

5. Use according to claim 4, characterized in that: the cancers include solid tumors and hematological tumors.

6. Use according to claim 5, characterized in that: the solid tumor comprises breast cancer, lung cancer, brain cancer, colorectal cancer, glioma, esophageal cancer, gastric cancer, ovarian cancer, head and neck cancer, liver cancer, and the hematological tumor comprises lymphoma and leukemia.

7. Use according to claim 4, characterized in that: the cancer comprises breast cancer, non-small cell lung cancer, brain glioma, colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B cell lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer and glioblastoma.

8. Use of a compound according to claim 1 or an isotopic derivative thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 2 in the manufacture of a medicament for the prevention and/or treatment of cancer.

9. Use according to claim 8, characterized in that: the cancers include solid tumors and hematological tumors.

10. Use according to claim 9, characterized in that: the solid tumor comprises breast cancer, lung cancer, brain cancer, colorectal cancer, glioma, esophageal cancer, gastric cancer, ovarian cancer, head and neck cancer, liver cancer, and the hematological tumor comprises lymphoma and leukemia.

11. Use according to claim 8, characterized in that: the cancer comprises breast cancer, non-small cell lung cancer, brain glioma, colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B cell lymphoma, chronic lymphocytic leukemia, acute myelogenous leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, small cell lung cancer and glioblastoma.

12. Use according to claim 3 or 8, characterized in that: a compound of claim 1 or an isotopic derivative thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 2 in combination with another, two or more antineoplastic substances or treatments.

13. Use according to claim 12, characterized in that: the antitumor substance comprises PARP inhibitor, topoisomerase inhibitor, cytotoxic chemotherapeutic, PD-L1 inhibitor, WEE1 inhibitor and ATR inhibitor; the treatment means is radiotherapy.

14. Use according to claim 13, characterized in that: the PARP inhibitor comprises olaparib; the topoisomerase inhibitor comprises irinotecan, topotecan, etoposide; the cytotoxic chemotherapeutic drug comprises doxorubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin and epirubicin; the PD-L1 inhibitor comprises MEDI4736; the WEE1 inhibitor comprises AZD1775; the ATR inhibitor comprises AZD6738.

15. A pharmaceutical composition comprising a compound of claim 1 or an isotopic derivative thereof or a pharmaceutically acceptable salt thereof and another, two or more antineoplastic agents.

16. The composition of claim 15, wherein: the antitumor substance comprises PARP inhibitor, topoisomerase inhibitor, cytotoxic chemotherapeutic, PD-L1 inhibitor, WEE1 inhibitor and ATR inhibitor.

17. The composition of claim 16, wherein: the PARP inhibitor comprises olaparib; the topoisomerase inhibitor comprises irinotecan, topotecan, etoposide; the cytotoxic chemotherapeutic drug comprises doxorubicin, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, pirarubicin, amrubicin and epirubicin; the PD-L1 inhibitor comprises MEDI4736; the WEE1 inhibitor comprises AZD1775; the ATR inhibitor comprises AZD6738.