Application of substituted imidazo quinoxaline compound in preparation of anti-cancer drugs

Abstract

The invention provides an application of a substituted imidazo quinoxaline compound in preparation of an anti-cancer drug. Specifically, the invention provides an application of a compound shown as a formula IIIa or a formula IIIb or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a mixture of the stereoisomer, the tautomer or the pharmaceutically acceptable salt in preparation of drugs for treating or preventing DDR-mediated or ATM kinase-mediated cancers. # imgabs0 #

Description

[0001] This application is a divisional application of the invention patent application with international application number PCT / CN2020 / 114823, international application date September 11, 2020, application number 202080063663.1 entering the Chinese national phase, and invention name “Substituted imidazoquinoxaline compounds and their applications”. Technical Field

[0002] The present invention belongs to the field of pharmaceutical chemistry and particularly relates to the use of substituted imidazoquinoxaline compounds in the preparation of anti-cancer drugs. Background Art

[0003] Mammalian cells face a large number of external and internal challenges that cause DNA damage every day, including mutations in DNA bases. These mutations can cause changes in cell function, including the occurrence of malignant tumors, or directly cause cell death. Therefore, mammalian cells have evolved a set of sophisticated DNA damage repair mechanisms (DNA damage response, DDR) to cope with these challenges. This mechanism detects and repairs DNA damage through brief cell cycle pauses to ensure genome stability and cell survival.

[0004] DDR and cancer are inextricably linked. Scientific research has found that defects in the DDR repair mechanism can lead to cancer at multiple levels. For example, base mutations in DDR genes have been found to lead to a variety of cancers, including women with BRCA1 or BRCA2 gene base mutations who have a much higher risk of breast cancer and ovarian cancer than those without mutations. BRCA1 and BRCA2 are important components of DDR that repair double-strand breaks in DNA based on homologous recombination. Studies have also found that key proteins that regulate the cell cycle in DDR in a variety of malignant tumor cells are missing or have lost their function, including p53, ATM, ATR, BRCA1 / 2, and so on.

[0005] In recent years, with the development of science and the understanding of the cellular DDR mechanism, the development of new anti-cancer targeted therapeutic drugs targeting the mutation and loss of function of DDR component proteins has aroused great interest. For example, PARP inhibitors can specifically kill cancer cells with BRCA1 / 2 mutations by inhibiting the single-strand repair mechanism of DNA damage. This mechanism of action is called "synthetic lethality."

[0006] ATM kinase is one of the important components of DDR and belongs to the PI3K-related serine / threonine protein kinase family. The ATM kinase gene was cloned in 1995 when studying ataxia telangiectasia syndrome. The ATM gene is located on human chromosome 11q22-23 and is a coding sequence consisting of 66 exons and 9168 bases. ATM kinase is a large protein with a molecular weight of about 350kDa. ATM kinase is one of the important components of DDR. ATM kinase is activated when DNA damage causes double-strand breaks. Its function is to achieve cell cycle transition point pause by phosphorylating downstream proteins, repair damaged DNA through homologous recombination, or enter the cell apoptosis mechanism (Weber and Ryan, 2016).

[0007] ATM kinase signaling can be roughly divided into two mechanisms: the canonical mechanism is activated by DNA double-strand breaks. When cells detect DNA double-strand breaks, ATM kinase is transported to the break site and activated. Although the detailed activation mechanism is not clear, the activation process includes splitting from homodimers into active monomers (Bakkenist et al., 2003), autophosphorylation at Ser1981 and other sites, and acetylation. The activated ATM kinase further phosphorylates downstream substrates, including cell cycle checkpoint proteins (such as Chk1 and Chk2), DNA repair proteins (BRCA1 and RAD51) or apoptosis pathway proteins (p53). Studies have shown that there are more than 700 proteins that are phosphorylated after DNA double-strand breaks (Choi, Kipps and Kurzrock, 2016). In addition, ATM is also involved in functions that are not directly related to DNA damage, such as metabolism and stress response, which are generally referred to as non-canonical mechanisms (Cremona et al., 2013).

[0008] The development of new anticancer drugs using ATM kinase as a drug target mainly relies on two considerations. Radiotherapy or cytotoxic chemotherapy drugs, such as topoisomerase inhibitors and DNA methylation drugs, which are usually toxic to rapidly differentiating cancer cells due to DNA damage, have their cytotoxicity greatly reduced due to the presence of DDR. Therefore, combined with inhibitors that inhibit the function of DDR component proteins, such as PARP inhibitors and ATM inhibitors, can greatly enhance the efficacy of such drugs. Gilardini MontaniMS et al. (J Exp Clin Cancer Res, 2013, 32: 95) showed that reducing ATM expression can enhance the sensitivity of breast cancer cells to PARP inhibitors, providing a theoretical basis for the possibility of using ATM inhibitors and PARP inhibitors in combination to treat breast cancer. In addition, Kubota E et al. (Cell Cycle, 2014, 13 (13): 2129-2137) found that the expression level of ATM protein in gastric cancer cells was significantly correlated with the sensitivity of the PARP inhibitor olaparib, and the application of small molecule ATM inhibitors enhanced the sensitivity of p53-inactivated gastric cancer cells to olaparib. Therefore, the combined use of ATM inhibitors and PARP inhibitors may be used to treat gastric cancer. In addition, for cancer cells with DDR functional defects, ATM kinase inhibitors can be used alone through synthetic lethality and developed into targeted anticancer drugs for specific patient populations, with good efficacy and low toxicity.

[0009] Degorce SL et al. (J Med Chem, 2016, 59: 6281-6292) reported a series of 3-quinolinecarboxamides as ATM kinase inhibitors, and observed good efficacy of ATM kinase inhibitors in combination with irinotecan in animal models.

[0010] Genetic and pharmacological evidence shows that reducing ATM kinase activity can reduce the toxicity of mutant huntingtin (mHTT) in Huntington's disease (HD) cells and animal models, suggesting that selective inhibition of ATM may provide a new clinical intervention for the treatment of HD. Leticia TS et al. (J MedChem, 2019, 62: 2988-3008) reported an ATM inhibitor that can pass through the blood-brain barrier, showing good pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain, and its pharmacokinetic / pharmacodynamic (PK / PD) relationship is obvious.

[0011] Condensed heteroaryl compounds have been disclosed as kinase inhibitors. For example, WO2012034526 discloses fused heteroaryl compounds as PI3K kinase inhibitors. WO2015170081 discloses imidazoquinolinone as an ATM kinase inhibitor. WO2018127195 and WO2018153365 disclose substituted fused heteroaryl compounds as kinase inhibitors, especially ATM kinase inhibitors. Summary of the invention

[0012] The present invention provides novel substituted imidazo[1,5-a]quinoxaline compounds as shown in formula I, formula II, formula IIIa and formula IIIb as kinase inhibitors, especially ATM kinase inhibitors.

[0013] The present invention also provides a pharmaceutical composition comprising an effective amount of a compound of Formula I, Formula II, Formula IIIa or IIIb for treating cancer.

[0014] In one embodiment, the pharmaceutical composition may further contain one or more pharmaceutically acceptable carriers or diluents for treating cancer.

[0015] In one embodiment, the pharmaceutical composition may further contain at least one known anticancer drug or a pharmaceutically acceptable salt of the anticancer drug for treating cancer.

[0016] The present invention also relates to methods for preparing novel compounds of formula I, formula II, formula IIIa and IIIb. DETAILED DESCRIPTION

[0017] The present invention finds that the substituted imidazo[1,5-a]quinoxaline compound represented by formula I has kinase inhibitory activity and can be used as a kinase inhibitor, especially an ATM kinase inhibitor.

[0018] It should be understood that the features of the various embodiments described herein can be arbitrarily combined to form the technical solutions of this invention; the definition of each group herein is applicable to any embodiment described herein, for example, the definition of substituents of alkyl groups herein is applicable to any embodiment described herein, unless the embodiment has clearly defined substituents of alkyl groups.

[0019] Specifically, the present invention provides a compound represented by the following formula I or its stereoisomer, tautomer, N-oxide, hydrate, isotope-labeled compound, solvate or pharmaceutically acceptable salt, or a mixture thereof, or a prodrug thereof:

[0020]

[0021] In the formula, A1, A2 and A3 are each independently N, CR4, CR5 and CR6;

[0022] Cy is an aryl group which may be optionally substituted, a heteroaryl group which may be optionally substituted, a heterocyclic group which may be optionally substituted, or a cycloalkyl group which may be optionally substituted;

[0023] R1 is an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted amino group, an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;

[0024] R2 is H, optionally substituted alkyl or optionally substituted carbocyclyl;

[0025] R4, R5 and R6 are each independently hydrogen, halogen, alkyl, alkoxy, alkenyl, alkynyl, amino, nitro, cyano, amido, acyloxy, hydroxyl, thiol, alkylthio, azido or carboxyl; wherein the alkyl, alkoxy, alkenyl, alkynyl, amino, amido, acyloxy, hydroxyl, thiol, alkylthio and carboxyl groups can each be optionally substituted.

[0026] In the compounds of formula I of various embodiments of the present invention, preferably, A1 is N or CR4, A2 is N or CR5, and A3 is N or CR6. More preferably, A1 is CR4, A2 is CR5, and A3 is CR6; preferably, R4, R5, and R6 are each independently H, alkyl, alkoxy, or halogen; further preferably, R4 and R5 are H, and R6 is H, halogen, or alkoxy.

[0027] In the compounds of formula I of various embodiments of the present invention, Cy is preferably an optionally substituted 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, or an optionally substituted aryl. The heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl and pyrimidinyl; in some preferred embodiments, Cy is an optionally substituted pyrazolyl; in some preferred embodiments, Cy is an optionally substituted pyridyl; in some preferred embodiments, Cy is an optionally substituted phenyl. The aryl includes, but is not limited to, phenyl and naphthyl. The number of substituents on Cy can be 1, 2, 3, 4 or 5, including but not limited to halogen, alkyl, alkoxy, alkenyl, alkynyl, amino, nitro, cyano, amido, acyloxy, hydroxyl, sulfhydryl, alkylthio, azido, carboxyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, amino, amido, acyloxy, hydroxyl, sulfhydryl, alkylthio, carboxyl, carbocyclyl, heterocyclyl, aryl and heteroaryl can each be optionally substituted, such as optionally substituted by 1, 2 or 3 substituents selected from alkyl, aminoalkyl, alkoxy, hydroxyl, halogen, amino, heterocyclyl and heteroaryl. Preferably, the amino group is represented by NR 11 R 12 , where R 11 and R 12 are each independently selected from hydrogen and C 1-6Alkyl, or R 11 and R 12 Together with N, it forms an optionally substituted 4- to 8-membered heterocyclic group, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. The heterocyclic group may be optionally substituted by 1-3 substituents selected from halogen, alkyl and alkoxy.

[0028] In preferred embodiments, the substituents on Cy are as defined below for any of the embodiments of Formula II, IIIa and IIIb. In some embodiments, the substituents on Cy are halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 alkoxy, optionally substituted amino or optionally substituted heterocyclic group; preferably, the substituent on the alkyl group is selected from halogen, hydroxyl and amino, preferably halogen; preferably, the substituent on the alkoxy group is selected from halogen, hydroxyl, heteroaryl (preferably 5- or 6-membered nitrogen-containing heteroaryl, such as pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, etc.) and amino, preferably amino; preferably, the substituent on the heterocyclic group is preferably selected from C 1-4 Alkyl, halogen, hydroxyl and amino, preferably a heterocyclic group containing one N and / or one O, including but not limited to tetrahydrofuranyl, morpholinyl, piperidinyl and piperazinyl. Preferably, amino is represented by NR 11 R 12 , where R 11 and R 12 are each independently selected from hydrogen and C 1-6 Alkyl, or R 11 and R 12 Together with N, it forms a 4- to 8-membered heterocyclic group which may be optionally substituted, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, which may be optionally substituted by 1-3 substituents selected from halogen, alkyl and alkoxy. In some preferred embodiments, when Cy is a 6-membered ring, preferably, the optionally substituted C 1-6 The alkoxy group, the optionally substituted amino group or the optionally substituted heterocyclic group is located at the para position.

[0029] In the compound of formula I, preferably, R1 is an optionally substituted C 1-6 The preferred heterocyclic group is a heterocyclic group containing 1 O and / or 1 N, such as tetrahydropyranyl, morpholinyl, piperidinyl and piperazinyl. Preferably, the heteroaryl is a heteroaryl containing 1 to 3 nitrogen atoms, such as pyridinyl. The substituents of the heterocyclic group and the heteroaryl are preferably one or more (such as 1 to 3) selected from hydroxyl, C 1-4 Alkyl, amino, halogen, C 1-4 The substituents of the alkoxy and carboxyl groups are more preferably selected from C 1-4 Alkyl, halogen and C 1-4 Alkoxy. C1-6 The substituents on the alkyl group are one or more (e.g., 1 to 3) selected from amino, hydroxy, halogen and C 1-4 Substituents of the alkoxy group.

[0030] In the compound of formula I, preferably, R2 is C which may be optionally substituted 1-10 Alkyl, more preferably C 1-6 Alkyl, more preferably C 1-4 Alkyl, including but not limited to methyl, ethyl, propyl and isopropyl. When R2 is a carbocyclic group which may be optionally substituted, it is preferably a C 3-8 The substituents on the carbocyclic group are preferably 1 or 2 selected from hydroxyl, halogen, amino, C 1-4 Alkyl, C 1-4 Substituents of alkoxy and carboxyl groups.

[0031] In the compound of formula I, preferably, R4, R5 and R6 are each independently selected from H, alkyl, alkoxy or halogen.

[0032] The compound of formula I preferably has the structure shown in formula II below:

[0033]

[0034] wherein A1, A2 and A3 are each independently N, CR4, CR5 and CR6;

[0035] B1, B2, B3 and B4 are each independently N, CR7, CR8, CR9 and CR 10 ;

[0036] R1 is an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted amino group, an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;

[0037] R2 is an alkyl group which may be optionally substituted or a carbocyclic group which may be optionally substituted;

[0038] R3 is hydrogen, alkyl, alkoxy, amino, carbocyclyl, heterocyclyl, aryl or heteroaryl; wherein each of the alkyl, alkoxy, amino, carbocyclyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted;

[0039] R4, R5, R6, R7, R8, R9 and R 10 Each is independently hydrogen, halogen, alkyl, alkoxy, alkenyl, alkynyl, amino, nitro, cyano, amido, acyloxy, hydroxyl, thiol, alkylthio, azido or carboxyl; wherein the alkyl, alkoxy, alkenyl, alkynyl, amino, amido, acyloxy, hydroxyl, thiol, alkylthio and carboxyl groups can be optionally substituted.

[0040] In the compound of formula II according to various embodiments of the present invention, preferably, A1 is N or CR4, A2 is N or CR5, and A3 is N or CR6.

[0041] In the compounds of formula II according to various embodiments of the present invention, preferably, B1 is N or CR7, B2 is N or CR8, B3 is N or CR9; and B4 is N and CR 10 .

[0042] In the compound of formula II of each embodiment of the present invention, among A1, A2 and A3, preferably A1, A2 and A3 are CR4, CR5 and CR6 respectively; in some embodiments, one of A1, A2 and A3 is N, and the others are selected from two of CR4, CR5 and CR6. In some embodiments, when A1 is N, A2 and A3 are CR5 and CR6 respectively; when A2 is N, A1 and A3 are CR4 and CR6 respectively; when A3 is N, A1 and A2 are CR4 and CR5 respectively. Preferably R4, R5 and R6 are independently hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 Alkyl, more preferably each independently is hydrogen, halogen or C 1-4 In a preferred embodiment, R4 and R5 are each independently hydrogen or C 1-4 Alkyl, more preferably hydrogen; R6 is hydrogen, halogen or C 1-4 In some preferred embodiments, A1, A2 and A3 are CR4, CR5 and CR6 respectively, and R4, R5 and R6 are all hydrogen. In some embodiments, R4 and R5 are hydrogen, and R6 is halogen or C 1-4 Alkoxy.

[0043] In the compound of formula II of each embodiment of the present invention, preferably, one of B1, B2, B3 and B4 is N, such as the ring containing B1, B2, B3 and B4 is a pyridine ring; preferably, B2 is N, and the others are selected from CR7, CR8, CR9 and CR 10 More preferably, B1, B3 and B4 are CR7, CR9 and CR 10 Preferably, in some embodiments, R7, R8, R9 and R 10 are independently hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 More preferably, R7, R8, R9 and R 10 In some embodiments, B1, B2, B3 and B4 are CR7, CR8, CR9 and CR1, respectively. 10, which indicates that the ring containing B1, B2, B3 and B4 can be selected when it is a benzene ring. Preferably, R7, R8, R9 and R 10 are independently hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 More preferably, R7, R8, R9 and R 10 At least one is not hydrogen, preferably, R8 is not hydrogen, preferably halogen and halogenated C 1-4 In some embodiments, B1, B2, B3 and B4 are CR7, CR8, CR9 and CR 10 , for example, R8 is not hydrogen, but halogen, C 1-4 Alkoxy and halogenated C 1-4 Alkyl; R7, R9 and R 10 For hydrogen.

[0044] R1 of the compound of formula II of each embodiment of the present invention is preferably selected from optionally substituted C 1-6 Alkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl. Preferred alkyl groups are C 1-3 alkyl, such as methyl, ethyl and isopropyl. Preferred heteroaryl is a heteroaryl containing 1 to 3 N, such as pyridyl. Preferred heterocyclic group is a heterocyclic group containing 1 O and / or 1 N, such as tetrahydrofuranyl, morpholinyl, piperidinyl and piperazinyl. In a preferred embodiment, the optionally substituted heterocyclic group is tetrahydro-2H-furan-4-yl, 1-morpholinyl, piperidin-1-yl or piperazin-1-yl. The substituents on the heteroaryl or heterocyclic group are preferably one or more (such as 1-3) selected from hydroxyl, C 1-4 Alkyl, amino, halogen, C 1-4 The substituents of the alkoxy and carboxyl groups are more preferably selected from C 1-4 Alkyl, halogen and C 1-4 Preferably, when the heteroaryl or heterocyclic group is a 6-membered ring, the substituent is located at the meta position and / or the para position. 1-6 The substituents on the alkyl group are one or more (e.g., 1 to 3) selected from amino, hydroxy, halogen and C 1-4 Substituents of the alkoxy group.

[0045] In some preferred embodiments, R1 is unsubstituted isopropyl; in some preferred embodiments, R1 is unsubstituted tetrahydrofuranyl; in some preferred embodiments, R1 is optionally substituted with 1 or 2 C 1-4 Alkyl substituted morpholinyl, preferably the substituent is located at the meta position; in some preferred embodiments, R1 is optionally substituted by 1-3 C 1-4Alkyl substituted piperidinyl or piperazinyl, preferably, the substituent is located at the para position and / or meta position. In some embodiments, R1 of the compound of formula II of each embodiment of the present invention is preferably an optionally substituted heteroaryl. Exemplary heteroaryl groups include, but are not limited to, heteroaryl groups containing 1-3 nitrogen atoms, such as pyridyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl and pyrimidinyl; exemplary substituents include, but are not limited to, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, etc. Exemplary R1 is selected from:

[0046]

[0047] In the compounds of formula II of the present invention, R2 is preferably C 1-10 Alkyl, more preferably C 1-6 Alkyl, more preferably C 1-4 Alkyl, including but not limited to methyl, ethyl, propyl and isopropyl. When R2 of the compound of formula II is a carbocyclic group which may be optionally substituted, it is preferably a C 3-8 The substituents on the carbocyclic group are preferably 1 or 2 selected from hydroxyl, halogen, amino, C 1-4 Alkyl, C 1-4 Substituents of alkoxy and carboxyl groups.

[0048] R3 of the compound of formula II according to various embodiments of the present invention, when substituted, preferably has 1, 2 or 3 substituents, preferably selected from C 1-4 Alkyl, C 1-4 alkoxy, halogen, hydroxy, amino and heteroaryl. Preferably R3 is optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 alkoxy, optionally substituted amino or optionally substituted heterocyclic group, more preferably optionally substituted C 1-6 More preferably, R3 is an optionally substituted C 1-6 Alkoxy, -NR 11’ -C 1-6 Alkyl-NR 11’ R 12’ or an optionally substituted heterocyclic group, wherein R 11’ and R 12’ are each independently selected from hydrogen and C 1-4 Alkyl, or R 11’ and R 12’Together with N, it forms a 4- to 8-membered heterocyclic group which may be optionally substituted, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, and the heterocyclic group may be optionally substituted by 1-3 substituents, and the substituents are selected from halogen, alkyl and alkoxy. Preferably, the substituents on the alkoxy are selected from halogen, hydroxyl, heteroaryl (preferably 5- or 6-membered nitrogen-containing heteroaryl, such as pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, etc.) and amino, preferably amino; preferably, the substituents on the heterocyclic group are preferably selected from C 1-4 Alkyl, halogen, hydroxyl and amino, preferably heterocyclic group is a heterocyclic group containing one N and / or one O, including but not limited to tetrahydrofuranyl, morpholinyl, piperidinyl and piperazinyl. Preferably, amino is represented by NR 11 R 12 , where R 11 and R 12 are each independently selected from hydrogen and C 1-6 Alkyl, or R 11 and R 12 Together with N, it forms a 4- to 8-membered heterocyclic group which may be optionally substituted, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, and the heterocyclic group may be optionally substituted by 1-3 substituents selected from halogen, alkyl and alkoxy. Exemplary R3 include:

[0049]

[0050] In the particularly preferred compounds of formula II of the present invention, R2 is C 1-4 The remaining groups are as described in any of the above embodiments.

[0051] One group of preferred compounds of the present invention is represented by compounds of formula IIIa and IIIb or stereoisomers, tautomers, N-oxides, hydrates, isotopically labeled compounds, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof:

[0052]

[0053] Among them, B1, B3, B4, R1, R2, R3, R7, R8, R9 and R 10 As defined in formula I or II; R6 is hydrogen, halogen, alkyl or alkoxy.

[0054] In one or more embodiments of the compounds of Formula IIIa and IIIb, B1, B3, B4, R1, R2, R3, R7, R8, R9 and R 10 As described above for any one of the embodiments of formula I or II, respectively.

[0055] In one or more of the foregoing embodiments of compounds of Formula IIIa and IIIb, R2 is C 1-3The alkyl group is preferably a methyl group.

[0056] In one or more of the foregoing embodiments of the compound of formula IIIa, B1, B3 and B4 are CR7, CR9 and CR 10 ; R7, R9 and R 10 are independently hydrogen, halogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl. Preferably R7, R9 and R 10 All are hydrogen.

[0057] In one or more embodiments of the compound of formula IIIb, R8 is hydrogen, halogen, C 1-4 Alkoxy, C 1-4 Alkyl or halogenated C 1-4 Preferably, R8 is halogen, C 1-4 Alkoxy or halogenated C 1-4 Preferably, R7, R9 and R 10 are independently hydrogen, halogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl, preferably hydrogen.

[0058] In one or more of the foregoing embodiments of the compounds of Formula IIIa and IIIb, R1 is an optionally substituted C 1-6 Alkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl. Preferred alkyl groups are C 1-3 alkyl, such as isopropyl. Preferred heteroaryl is a heteroaryl containing 1 to 3 N, such as pyridyl. Preferred heterocyclic group is a heterocyclic group containing 1 O and / or 1 N, such as tetrahydrofuranyl, morpholinyl, piperidinyl and piperazinyl. In a preferred embodiment, the optionally substituted heterocyclic group is tetrahydro-2H-furan-4-yl, 1-morpholinyl, piperidin-1-yl or piperazin-1-yl. The substituents on the heteroaryl and heterocyclic groups are preferably one or more (such as 1-3) selected from hydroxyl, C 1-4 Alkyl, amino, halogen, C 1-4 The substituents of the alkoxy and carboxyl groups are more preferably C 1-4 Alkyl, halogen and C 1-4 Preferably, when the heteroaryl or heterocyclic group is a 6-membered ring, the substituent is located at the meta position and / or the para position. 1-6 The substituents on the alkyl group are one or more (e.g., 1 to 3) selected from amino, hydroxy, halogen and C 1-4 In some preferred embodiments, R1 is an unsubstituted isopropyl group; in some preferred embodiments, R1 is an unsubstituted tetrahydrofuranyl group; in some preferred embodiments, R1 is optionally substituted with 1 or 2 C 1-4Alkyl substituted morpholinyl, preferably the substituent is located at the meta position; in some preferred embodiments, R1 is optionally substituted by 1-3 C 1-4 Alkyl substituted piperidinyl or piperazinyl, preferably, the substituent is located at the para position and / or meta position. Exemplary R1 is selected from:

[0059]

[0060] In one or more of the above embodiments of the compound of formula IIIa, the ring containing B1, B3 and B4 is a pyridine ring which may be substituted. It should be understood that, herein, in addition to R3, the substituents on the ring containing B1, B3 and B4 may also include R7, R9 and R 10 Preferred R7, R9 and R 10 Each independently can be selected from halogen, C 1-4 Alkyl and halogenated C 1-4 alkyl.

[0061] In one or more of the foregoing embodiments of the compounds of formula IIIa and IIIb, when R3 is substituted, the substituents are preferably 1 to 3, preferably selected from C 1-4 Alkyl, C 1-4 alkoxy, halogen, hydroxy, amino and heteroaryl. Preferably R3 is optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 More preferably, R3 is an optionally substituted C 1-6 Alkoxy, -NR 11’ -C 1-6 Alkyl-NR 11’ R 12’ or an optionally substituted heterocyclic group, wherein R 11’ and R 12’ are each independently selected from hydrogen and C 1-4 Alkyl, or R 11’ and R 12’ Together with N, it forms a 4- to 8-membered heterocyclic group which may be optionally substituted, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, and the heterocyclic group may be optionally substituted by 1-3 substituents, and the substituents are selected from halogen, alkyl and alkoxy. Preferably, the substituents on the alkoxy are selected from halogen, hydroxyl, heteroaryl (preferably 5- or 6-membered nitrogen-containing heteroaryl, such as pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, etc.) and amino, preferably amino; preferably, the substituents on the heterocyclic group are preferably selected from C 1-4 Alkyl, halogen, hydroxyl and amino, preferably heterocyclic group is a heterocyclic group containing one N and / or one O, including but not limited to tetrahydrofuranyl, morpholinyl, piperidinyl and piperazinyl. Preferably, amino is represented by NR 11 R 12 , where R 11and R 12 are each independently selected from hydrogen and C 1-6 Alkyl, or R 11 and R 12 Together with N, it forms a 4- to 8-membered heterocyclic group which may be optionally substituted, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, and the heterocyclic group may be optionally substituted by 1-3 substituents selected from halogen, alkyl and alkoxy. Exemplary R3 include:

[0062]

[0063] In one or more of the foregoing embodiments of the compounds of formula IIIa and IIIb, R6 is hydrogen, halogen and C 1-4 Preferably, R6 is hydrogen.

[0064] In the foregoing one or more embodiments of Formula I, II, IIIa and IIIb, the optionally substituted alkyl, alkoxy, amino, carbocyclyl, heterocyclyl, aryl or heteroaryl described in R1 may be substituted with one or more substituents selected from the alkyl, alkoxy, amino, carbocyclyl, heterocyclyl, aryl or heteroaryl substituents described herein.

[0065] In the foregoing one or more embodiments of Formula I, II, IIIa and IIIb, the optionally substituted alkyl, alkoxy, amino, carbocyclyl, heterocyclyl, aryl or heteroaryl described by R3 may be substituted with one or more substituents selected from the alkoxy, amino, carbocyclyl, heterocyclyl, aryl or heteroaryl substituents described herein.

[0066] In one or more of the foregoing embodiments of Formula II, IIIa and IIIb, R4, R5, R6, R7, R8, R9 and R 10 The substituents of the alkyl, alkoxy, alkenyl, alkynyl, amino, amido, acyloxy, hydroxyl, thiol, alkylthio or carboxyl groups which may be substituted are selected from one or more of the substituents of the alkyl, alkoxy, alkenyl, alkynyl, amino, amido, acyloxy, hydroxyl, thiol, alkylthio or carboxyl groups described herein.

[0067] In one or more of the foregoing embodiments of Formula IIIb, R7, R8, R9 and R 10 The substituents of the alkyl, alkoxy, alkenyl, alkynyl, amino, amido, acyloxy, hydroxyl, thiol, alkylthio or carboxyl groups which may be substituted are selected from one or more of the substituents of the alkyl, alkoxy, alkenyl, alkynyl, amino, amido, acyloxy, hydroxyl, thiol, alkylthio or carboxyl groups described herein.

[0068] In one or more preferred embodiments of formula II, IIIa and IIIb: A1, A2 and A3 are CR4, CR5 and CR6 respectively, wherein R4, R5 and R6 are each independently hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 Alkyl, preferably each independently hydrogen, halogen and C 1-4 alkyl, more preferably R4 and R5 are H, R6 is H, halogen or alkoxy; the ring containing B1, B2, B3 and B4 (Formula II) or the ring containing B1, B3 and B4 (Formula IIIa) is a pyridine ring which may be optionally substituted and a benzene ring which may be optionally substituted, wherein R7, R8, R9 and R 10 are independently selected from hydrogen, C 1-6 Alkyl, halogen and halogenated C 1-6 Alkyl, preferably each independently halogen and halogenated C 1-4 Alkyl, more preferably R7, R9 and R 10 is H, R8 is halogen or halogenated C 1-4 Alkyl; R1 is optionally substituted C 1-6 Alkyl, optionally substituted with 1-4 C 1-6 Alkyl-substituted heterocyclic or heteroaryl, preferably selected from C 1-4 Alkyl, optionally substituted with 1-4 C 1-6 Alkyl-substituted tetrahydropyranyl, optionally substituted with 1-4 C 1-6 Alkyl-substituted piperidinyl, optionally substituted with 1-4 C 1-6 Alkyl-substituted morpholinyl and optionally 1-4 C 1-6 Alkyl substituted piperazinyl; R2 is C 1-6 Alkyl, preferably C 1-4 Alkyl, more preferably methyl; R3 is selected from optionally -NR 11 R 12 Substituted C 1-6 Alkyl, optionally substituted by -NR 11 R 12 Substituted C 1-6 Alkoxy and optionally -NR 11 R 12 A substituted heterocyclic group, wherein R 11 and R 12 are each independently selected from hydrogen and C 1-6 Alkyl; or R 11 and R 12 Together with N, it forms a 4- to 8-membered heterocyclic group which may be optionally substituted, such as azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl. Preferably, R6 is hydrogen, halogen and C 1-4 Alkoxy.

[0069] In one or more of the foregoing embodiments of Formula IIIa:

[0070] B1, B3 and B4 are CH;

[0071] R1 is optionally replaced by 1-2 C 1-6 The heterocyclic group substituted by alkyl is preferably substituted by 1-2 C 1-6 Alkyl substituted morpholinyl;

[0072] R2 is C 1-4 Alkyl, preferably methyl;

[0073] R3 is optionally -NR 11 R 12 Substituted C 1-6 Alkoxy and optionally -NR 11 R 12 A substituted heterocyclic group, wherein R 11 and R 12 are each independently selected from hydrogen and C 1-6 Alkyl; or R 11 and R 12 Together with N, it forms a 4- to 8-membered heterocyclic group substituted with 1-2 alkyl groups (such as azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl); preferably, optionally substituted with -NR 11 R 12 The substituted heterocyclic group is piperidinyl or piperazinyl, the ring nitrogen atom of which is attached to the rest of the compound, preferably by -NR 11 R 12 Group substitution;

[0074] R6 is hydrogen, halogen or C 1-4 alkoxy, preferably hydrogen; and

[0075] R7, R9 and R 10 For H.

[0076] In one or more of the foregoing embodiments of Formula IIIb:

[0077] R1 is optionally replaced by 1-2 C 1-6 The heterocyclic group substituted by alkyl is preferably substituted by 1-2 C 1-6 Alkyl substituted morpholinyl;

[0078] R2 is C 1-4 Alkyl, preferably methyl;

[0079] R3 is optionally -NR 11 R 12 Substituted C 1-6 Alkoxy and optionally -NR 11 R 12 A substituted heterocyclic group, wherein R11 and R 12 are each independently selected from hydrogen and C 1-6 Alkyl; or R 11 and R 12 Together with N, it forms a 4- to 8-membered heterocyclic group substituted with 1-2 alkyl groups (such as azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl); preferably, optionally substituted with -NR 11 R 12 The substituted heterocyclic group is piperidinyl or piperazinyl, the ring nitrogen atom of which is attached to the rest of the compound, preferably by -NR 11 R 12 Group substitution;

[0080] R6 is hydrogen, halogen or C 1-4 alkoxy, preferably hydrogen; and

[0081] R7, R9 and R 10 For hydrogen.

[0082] In one or more of the foregoing embodiments of Formula IIIb:

[0083] R1 is C 1-6 Alkyl, optionally substituted by 1-3 groups selected from halogen, C 1-4 Alkyl and C 1-4 Alkoxy-substituted heteroaryl, optionally substituted with 1-2 C 1-6 Alkyl substituted heterocyclic group, preferably, R1 is C 1-4 Alkyl, optionally with 1-2 C 1-6 Alkyl-substituted tetrahydropyranyl, optionally substituted with 1-2 C 1-6 Alkyl-substituted piperidinyl, optionally substituted with 1-2 C 1-6 Alkyl-substituted morpholinyl, optionally substituted by 1-2 groups selected from halogen and C 1-4 Alkoxy-substituted pyridyl and optionally 1-3 C 1-6 Alkyl substituted piperazinyl;

[0084] R2 is C 1-6 Alkyl, preferably C 1-4 Alkyl, more preferably methyl;

[0085] R3 is optionally -NR 11 R 12 Substituted C 1-6 Alkoxy, -NR 11’ -C 1-6 Alkyl-NR 11’ R 12’ , or optionally -NR 11 R 12 A substituted heterocyclic group, wherein R 11’ and R 12’are each independently selected from hydrogen and C 1-4 Alkyl, R 11 and R 12 are each independently selected from hydrogen and C 1-6 Alkyl; or R 11 and R 12 Together with N, it forms a 4- to 8-membered heterocyclic group substituted with 1-2 alkyl groups (such as azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl); preferably, optionally substituted with -NR 11 R 12 The substituted heterocyclic group is piperidinyl or piperazinyl, the ring nitrogen atom of which is attached to the rest of the compound, preferably by -NR 11 R 12 Group substitution;

[0086] R6 is hydrogen, halogen or C 1-4 Alkoxy;

[0087] R7, R9 and R 10 is hydrogen; and

[0088] R8 is hydrogen, halogen, C substituted by 1-4 halogens 1-4 Alkyl or C 1-4 Alkoxy.

[0089] In one or more of the foregoing embodiments, preferred examples of compounds of Formula I, Formula II, Formula IIIa and Formula IIIb include but are not limited to:

[0090] N,N-dimethyl-3-(4-(1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)phenoxy)propan-1-amine (Example 1);

[0091] N,N-dimethyl-3-((5-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine (Example 2);

[0092] N,N-dimethyl-3-(4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)phenoxy)propan-1-amine (Example 3);

[0093] N,N-dimethyl-3-(2-fluoro-4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)phenoxy)propan-1-amine (Example 4);

[0094] N,N-dimethyl-3-(4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)-2-(trifluoromethyl)phenoxy)propan-1-amine (Example 5)

[0095] N,N-dimethyl-1-(2-fluoro-4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)phenyl)piperidin-4-amine (Example 6);

[0096] N,N-dimethyl-1-(2-chloro-4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)phenyl)piperidin-4-amine (Example 7);

[0097] N,N-dimethyl-1-(4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)-2-(trifluoromethyl)phenyl)piperidin-4-amine (Example 8);

[0098] 1-(4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)-2-(trifluoromethyl)phenyl)piperidin-4-amine (Example 9);

[0099] N-methyl-1-(4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)-2-(trifluoromethyl)phenyl)piperidin-4-amine (Example 10);

[0100] N-ethyl-1-(4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)-2-(trifluoromethyl)phenyl)piperidin-4-amine (Example 11);

[0101] 3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxaline (Example 12);

[0102] 8-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxaline (Example 13);

[0103] N,N-dimethyl-3-((5-(3-methyl-1-morpholinylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine (Example 14);

[0104] N,N-dimethyl-3-((5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine (Example 15);

[0105] N,N-dimethyl-3-((5-(3-methyl-1-(piperidin-1-yl)imidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine (Example 16);

[0106] N,N-dimethyl-3-((5-(3-methyl-1-(4-methylpiperazin-1-yl)imidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine (Example 17);

[0107] N,N-dimethyl-3-((5-(3-methyl-1-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)imidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine (Example 18);

[0108] N,N-dimethyl-3-((5-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine (Example 19);

[0109] N,N-dimethyl-3-(2-fluoro-4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)phenoxy)propan-1-amine (Example 20);

[0110] N,N-dimethyl-3-(4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2-(trifluoromethyl)phenoxy)propan-1-amine (Example 21);

[0111] 1-isopropyl-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)imidazo[1,5-a]quinoxaline (Example 22);

[0112] 7-fluoro-1-isopropyl-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)imidazo[1,5-a]quinoxaline (Example 23);

[0113] N,N-dimethyl-1-(2-fluoro-4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)phenyl)piperidin-4-amine (Example 24);

[0114] N,N-dimethyl-1-(2-chloro-4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)phenyl)piperidin-4-amine (Example 25);

[0115] N,N-dimethyl-1-(4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2-(trifluoromethyl)phenyl)piperidin-4-amine (Example 26);

[0116] 1-(4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2-(trifluoromethyl)phenyl)piperidin-4-amine (Example 27);

[0117] N-methyl-1-(4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2-(trifluoromethyl)phenyl)piperidin-4-amine (Example 28);

[0118] N-ethyl-1-(4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2-(trifluoromethyl)phenyl)piperidin-4-amine (Example 29);

[0119] 8-(1,3-dimethyl-4H-1λ 4 -pyrazol-4-yl)-1-(3-fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methylimidazo[1,5-a]quinoxaline (Example 30);

[0120] (2S,6R)-4-(8-(6-(3-(azacyclotitan-1-yl)propoxy)pyridin-3-yl)-3-methylimidazo[1,5-a]quinoxalin-1-yl)-2,6-dimethylmorpholine (Example 31);

[0121] (2S,6R)-2,6-dimethyl-4-(3-methyl-8-(6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)imidazo[1,5-a]quinoxalin-1-yl)morpholine (Example 32);

[0122] (2S,6R)-2,6-dimethyl-4-(3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)imidazo[1,5-a]quinoxalin-1-yl)morpholine (Example 33);

[0123] (2S,6R)-4-(8-(6-(2-(1H-imidazol-2-yl)ethoxy)pyridin-3-yl)-3-methylimidazo[1,5-a]quinoxalin-1-yl)-2,6-dimethylmorpholine (Example 34);

[0124] (2S,6R)-4-(8-(6-(2-(1H-imidazo 1-4-yl)ethoxy)pyridin-3-yl)-3-methylimidazo[1,5-a]quinoxalin-1-yl)-2,6-dimethylmorpholine (Example 35);

[0125] 2-((5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)-N,N-dimethylethane-1-amine (Example 36);

[0126] 3-(4-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2-(trifluoromethyl)phenoxy)-N,N-dimethylpropane-1-amine (Example 37);

[0127] 1-(5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)-N,N-dimethylpiperidin-4-amine (Example 38);

[0128] 1-(4-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2-fluorophenyl)-N,N-dimethylpiperidin-4-amine (Example 39);

[0129] 1-(2-chloro-4-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)phenyl)-N,N-dimethylpiperidin-4-amine (Example 40);

[0130] 3-((5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-ethylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)-N,N-dimethylpropane-1-amine (Example 41);

[0131] 3-((5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-isopropylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)-N,N-dimethylpropane-1-amine (Example 42);

[0132] 3-((5-(1-((2S,6R)-2,6-dimethylmorpholinyl)imidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)-N,N-dimethylpropane-1-amine (Example 43);

[0133] N,N-dimethyl-3-((5-(1-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)imidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine (Example 44);

[0134] 1-(5-(1-((2S,6R)-2,6-dimethylmorpholinyl)imidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)-N,N-dimethylpiperidin-4-amine (Example 45);

[0135] N 1 -(5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)-N 3 ,N 3 - dimethylpropane-1,3-diamine (Example 46);

[0136] N 1 -(5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)-N 1 ,N 3 ,N 3 -trimethylpropane-1,3-diamine (Example 47);

[0137] 1-(5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)piperidin-4-amine (Example 48);

[0138] 1-(5-(1-((2S,6R))-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)-N-methylpiperidin-4-amine (Example 49);

[0139] 1-(5-(1-((2S,6R)-2,6-)dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)-N-ethylpiperidin-4-amine (Example 50);

[0140] 1-(5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)-N-isopropylpiperidin-4-amine (Example 51);

[0141] (2S,6R)-4-(8-(6-(4-(azetidin-1-yl)piperidin-1-yl)pyridin-3-yl)-3-methylimidazo[1,5-a]quinoxalin-1-yl)-2,6-dimethylmorpholine (Example 52);

[0142] 3-((5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine (Example 53);

[0143] 3-((5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)-N-1-methylpropylamine (Example 54);

[0144] 3-((5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)-N-1-ethylpropylamine (Example 55);

[0145] 3-((5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)-N-ethyl-N-methylpropan-1-amine (Example 56);

[0146] 3-((5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)-N,N-diethylpropan-1-amine (Example 57);

[0147] (2S,6R)-2,6-dimethyl-4-(3-methyl-8-(6-(3-morpholinylpropoxy)pyridin-3-yl)imidazo[1,5-a]quinoxalin-1-yl)morpholine (Example 58);

[0148] (2S,6R)-2,6-dimethyl-4-(3-methyl-8-(6-(3-(4-methylpiperazin-1-yl)propoxy)pyridin-3-yl)imidazo[1,5-a]quinoxalin-1-yl)morpholine (Example 59);

[0149] (2S,6R)-2,6-dimethyl-4-(3-methyl-8-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3-yl)imidazo[1,5-a]quinoxalin-1-yl)morpholine (Example 60);

[0150] 3-(4-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2-fluorophenoxy)-N,N-dimethylpropane-1-amine (Example 61);

[0151] 3-(2-chloro-4-(1-((2S,6R)-)2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)phenoxy)-N,N-dimethylpropane-1-amine (Example 62);

[0152] 1-(5-(1-((2R,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)-N,N-dimethylpiperidin-4-amine and 1-(5-(1-((2S,6S)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)-N,N-dimethylpiperidin-4-amine (Example 63);

[0153] 3-((5-(1-((2R,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)-N,N-dimethylpropan-1-amine and 3-((5-(1-((2S,6S)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)-N,N-dimethylpropan-1-amine (Example 64);

[0154] or a stereoisomer, tautomer, N-oxide, hydrate, isotope-labeled compound, solvate or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0155] As used herein, "hydrogen (H)" includes isotopes D and T thereof.

[0156] As used herein, "alkyl" refers to an alkyl group itself or a straight or branched chain group with a carbon chain length of up to ten carbon atoms. Useful alkyl groups include straight or branched chain C 1-10 Alkyl, preferably C 1-6 Alkyl groups, such as C 1-4 Alkyl. Typical C 1-10 Alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl. Alkyl may be optionally substituted with one or more substituents as defined herein.

[0157] As used herein, "alkenyl" refers to a group having at least one double bond in a straight or branched chain, and the carbon chain length is generally 2 to 10 carbon atoms. Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

[0158] As used herein, "alkynyl" refers to a group having at least one triple bond in a straight or branched chain, and the carbon chain length is generally 2 to 10 carbon atoms. Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.

[0159] Useful alkoxy groups include those represented by the above C 1-10 An oxy group substituted by one of the alkyl groups, such as C 1-6 Alkoxy or C 1-4 Alkoxy. The alkyl group in the alkoxy group may be arbitrarily substituted. The substituents of the alkoxy group include, but are not limited to, halogen, morpholino, amino (including alkylamino and dialkylamino) and carboxyl (including ester groups thereof).

[0160] Useful alkylthio groups include those represented by the above C 1-10 The alkyl group in the alkylthio group may be substituted with any alkyl group, and the alkyl group in the alkylthio group may be arbitrarily substituted. Also included are the sulfoxides and sulfones of such alkylthio groups.

[0161] Useful amino groups include -NR 11 R 12 , where R 11 and R 12 are each independently hydrogen and optionally substituted C 1-10 Alkyl (such as C 1-6 Alkyl or C 1-4 alkyl), an optionally substituted cycloalkyl, an aryl, an optionally substituted heteroaryl or an optionally substituted amino. 11 and R 12 Together with the N atom, it forms an optionally substituted 4- to 8-membered heterocyclic group such as piperidine, or R 11 and R 12 Together with the N atom and other N or O atoms, they form an optionally substituted 4- to 8-membered heterocyclic group, such as azetidinyl, pyrrolidinyl, piperazinyl or morpholinyl. The alkyl and heterocyclic rings may be arbitrarily substituted.

[0162] Useful halogens or halogen groups include fluorine, chlorine, bromine and iodine.

[0163] As used herein, "aryl" refers to an aromatic group by itself or as part of another group, which is a monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms.

[0164] Useful aromatic groups include C 6-14Aryl, preferably C 6-10 Aryl. Typical C 6-14 Aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylene and fluorenyl.

[0165] As used herein, "heteroaryl" refers to a group containing 5 to 14 ring atoms, and having 6, 10 or 14 π electrons shared in the ring system, and the ring atoms contained are carbon atoms and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur.

[0166] Useful heteroaryl groups include thienyl (phenylthio), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, xanthrenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, including but not limited to 2-pyridinyl, 3-pyridinyl and 4-pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl , cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perylene, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido[1,2-a]pyrimidin-4-one, tetrahydropenta[c]pyrazol-3-yl, pyrazolo[1,5-a]pyrimidinyl, pyrrolopyridinyl such as pyrrolo[2,3-b]pyridinyl, benzisoxazolyl such as 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-oxindolyl, thiadiazolyl and 2-oxobenzimidazolyl. When the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, for example, pyridinyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.

[0167] As used herein, "carbocycle" includes cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups are C 3-8 Cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0168] Useful partially saturated carbocyclic groups include cycloalkenyl groups such as cyclopentenyl, cycloheptenyl and cyclooctenyl.

[0169] As used herein, "heterocycle (heterocyclyl)" refers to a saturated or partially saturated 3-8-membered monocyclic ring, or a 7-10-membered bicyclic ring system, whose ring atoms consist of carbon atoms and 1-4 heteroatoms selected from O, N and S, wherein the heteroatoms nitrogen and sulfur can be arbitrarily oxidized, and the nitrogen can be arbitrarily quaternized, and includes the fusion of any heterocycle defined above with a benzene ring in the bicyclic ring system. If the resulting compound is stable, the carbon atom or nitrogen atom of the heterocycle can be substituted.

[0170] Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, tetrahydropyranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl, which groups may be optionally substituted.

[0171] Herein, when substituted, unless otherwise indicated, aryl, heteroaryl, carbocyclyl and heterocyclyl groups may be substituted with one or more (e.g., 1, 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, carboxyl, amino, nitro, cyano, C 1-6 Acylamino, C 1-6 Acyloxy, C 1-6 Alkoxy, aryloxy, alkylthio, C 1-6 Alkyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl (C 2-6 )Alkenyl, C 6-10 Aryl (C 2-6 ) alkynyl, saturated and unsaturated heterocyclic or heteroaryl, methylenedioxy, halogenated C 1-6 Alkyl, C 6-10 Aryl (C 1-6 ) alkyl, C 1-6 Hydroxyalkyl, urea, thiol, azido, carbonyl, di(C 1-10 The substituents themselves may also be optionally substituted with corresponding substituents as described herein.

[0172] Herein, when substituted, unless otherwise indicated, alkyl, alkoxy, alkylthio, alkenyl, alkynyl and cycloalkyl groups may be substituted with one or more (e.g., 1, 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, carboxyl, amino, nitro, cyano, C 1-6 Acylamino, C 1-6 Acyloxy, C 1-6 Alkoxy, aryloxy, alkylthio, C1-6 Alkyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl (C 2-6 )Alkenyl, C 6-10 Aryl (C 2-6 ) alkynyl, saturated and unsaturated heterocyclic or heteroaryl, methylenedioxy, C 1-6 Haloalkyl, C 6-10 Aryl (C 1-6 ) alkyl, C 1-6 Hydroxyalkyl, urea, thiol, azido, carbonyl, di(C 1-10 The substituents themselves may also be optionally substituted with corresponding substituents as described herein.

[0173] In preferred embodiments, when substituted, unless otherwise indicated, alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, carbonyl, carbocyclyl, aryl, heteroaryl and heterocyclyl groups may be substituted with one or more (e.g., 1, 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxy, carboxyl, amino, nitro, cyano, C 1-6 Acylamino, C 1-6 Acyloxy, C 1-6 Alkoxy, aryloxy, alkylthio, C 1-6 Alkyl, C 6-10 Aryl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl (C 2-6 )Alkenyl, C 6-10 Aryl (C 2-6 ) alkynyl, saturated or unsaturated heterocyclic or heteroaryl.

[0174] It should be understood that when serving as a substituent, the number of the aryl or aryl-containing substituent, the heteroaryl or heteroaryl-containing substituent, and the heterocyclic or heterocyclic-containing substituent is generally one.

[0175] As used herein, "arylalkyl" includes any of the above C 6-14 Aryl substituted C 1-10 Alkyl. Preferred arylalkyl groups are benzyl, phenethyl or naphthylmethyl.

[0176] As used herein, "arylalkenyl" includes any of the above C 6-14 Aryl substituted C 2-10 Alkenyl.

[0177] As used herein, "arylalkynyl" includes any of the above C 6-14 Aryl substituted C 2-10 Alkynyl.

[0178] As used herein, "aryloxy" includes any of the above C 6-14 The aryl group of the aryl-substituted oxy group may be optionally substituted. Useful aryloxy groups include phenoxy and 4-methylphenoxy.

[0179] As used herein, "arylalkoxy" includes C 1-10 The aryl group of the alkoxy group may be optionally substituted. Useful arylalkoxy groups include benzyloxy and phenylethoxy.

[0180] Useful haloalkyl groups include C substituted with one or more halogen atoms selected from fluorine, chlorine, bromine and iodine atoms. 1-10 Alkyl, preferably C substituted by one or more halogens selected from fluorine, chlorine, bromine and iodine atoms 1-6 Alkyl groups such as fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl.

[0181] Useful acylamino groups (amido groups) are any C 1-6 Acyl (alkanoyl), such as acetylamino, propionylamino, butyrylamino, pentanoylamino and hexanoylamino, and aryl-substituted C 1-6 Acylamino, for example, benzylamino. Useful acyl groups include C 1-6 Acyl, such as acetyl. The acyl itself may be optionally substituted, for example, may be optionally substituted by one or more (such as 6 or less) substituents selected from aryl and halogen, wherein the aryl may be optionally substituted. For example, examples of substituted acylamino include chloroacetylamino and pentafluorobenzamide.

[0182] Useful acyloxy groups are any C 1-6 Acyl (alkanoyl), such as formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy and hexanoyloxy. Similarly, the acyl group in the acyloxy group itself may be optionally substituted, for example, it may be optionally substituted with one or more (such as within 6) substituents selected from aryl and halogen.

[0183] Some of the compounds of the present invention may exist as stereoisomers, including optical isomers. The present invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as individual enantiomers which may be separated according to methods well known to those skilled in the art.

[0184] Examples of pharmaceutically acceptable salts include inorganic and organic acid salts, such as hydrochlorides, hydrobromides, phosphates, sulfates, citrates, lactates, tartrates, maleates, fumarates, mandelates and oxalates; and inorganic and organic base salts formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methylglucamine.

[0185] Examples of prodrugs of the compounds of the invention include simple esters of carboxylic acid-containing compounds (e.g., by reacting with C 1-4 esters obtained by condensation of hydroxyl groups (for example, by condensation of hydroxyl groups with C 1-4 Carboxylic acid, C 3-6 esters obtained by condensation of diacids or their anhydrides, such as succinic anhydride and fumaric anhydride); imines of compounds containing amino groups (for example, by reacting with C 1-4 imines obtained by condensation of aldehydes or ketones); carbamates of compounds containing amino groups, such as those described by Leu et al. (J Med Chem. 1999, 42: 3623-3628) and Greenwald et al. (J Med Chem 1999, 42: 3657-3667); acetals or ketal of compounds containing alcohols (such as those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0186] The compounds of the present invention can be prepared using methods known to those skilled in the art or the novel methods of the present invention. Specifically, the compounds of the present invention having formula I, formula II, formula IIIa or formula IIIb can be prepared as shown in the reaction examples in reaction scheme 1. 7-bromo-2-chloroquinoxaline, tributyl(1-ethoxyethylene)tin and bis(triphenylphosphine)palladium(II) chloride are heated in toluene to produce 1-(7-bromoquinoxaline-2-yl)-1-ethanone. Sodium cyanoborohydride, 1-(7-bromoquinoxaline-2-yl)-1-ethanone and ammonium acetate are reacted in methanol at room temperature to produce 1-(7-bromoquinoxaline-2-yl)ethane-1-amine. 1-(7-bromoquinoxalin-2-yl)ethane-1-amine and tetrahydropyran-4-carboxylic acid react in pyridine at room temperature in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole to prepare N-(1-(7-bromoquinoxalin-2-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide. Trifluoromethanesulfonic anhydride, N-(1-(7-bromoquinoxalin-2-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide and pyridine react in dichloromethane at room temperature to prepare 8-bromo-3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxaline. 8-Bromo-3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxaline and N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)propan-1-amine are reacted by heating in a mixed solvent of 1,4-dioxane and water under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex and cesium carbonate to obtain the target compound N,N-dimethyl-3-((5-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxaline-8-yl)pyridin-2-yl)oxy)propan-1-amine.

[0187] Reaction Scheme 1

[0188]

[0189] Other related compounds can be prepared by similar methods. For example, by replacing N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)propan-1-amine with N,N-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)propan-1-amine, the target compound N,N-dimethyl-3-(4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)-2-(trifluoromethyl)phenoxy)propan-1-amine can be prepared. By replacing N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)propan-1-amine with 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethylpiperidin-4-amine, the target compound N,N-dimethyl-1-(2-fluoro-4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)phenyl)piperidin-4-amine can be obtained. Substituting (1,3-dimethyl-1H-pyrazol-4-yl)boronic acid for N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)propan-1-amine can produce the target compound 8-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxaline. Substituting isobutyryl chloride for tetrahydropyran-4-carboxylic acid can produce the target compound 1-isopropyl-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)imidazo[1,5-a]quinoxaline. By replacing 7-bromo-2-chloroquinoxaline with 7-bromo-2-chloro-6-fluoroquinoxaline, the target compound 7-fluoro-1-isopropyl-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)imidazo[1,5-a]quinoxaline can be obtained.

[0190] The compounds of the present invention can be prepared as shown in the reaction example in Reaction Scheme 2. 1-(7-bromoquinoxalin-2-yl)ethane-1-amine, morpholine-4-carbonyl chloride and diisopropylethylamine (DIEA) react in DCM at room temperature to obtain the product N-(1-(7-bromoquinoxalin-2-yl)ethyl)morpholine-4-carboxamide. N-(1-(7-bromoquinoxalin-2-yl)ethyl)morpholine-4-carboxamide and POCl3 are heated to react to obtain the product 4-(8-bromo-3-methylimidazo[1,5-a]quinoxalin-1-yl)morpholine. 4-(8-bromo-3-methylimidazo[1,5-a]quinoxalin-1-yl)morpholine and N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)propan-1-amine are heated to react in a mixed solvent of 1,4-dioxane and water under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex and cesium carbonate to obtain the target compound N,N-dimethyl-3-((5-(3-methyl-1-morpholinylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine.

[0191] Reaction Scheme 2

[0192]

[0193] Other related compounds can be prepared by similar methods. For example, by replacing morpholine-4-carbonyl chloride with (2R,6S)-2,6-dimethylmorpholine-4-carbonyl chloride, the target compound N,N-dimethyl-3-((5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine can be prepared. By replacing morpholine-4-carbonyl chloride with (3R,5S)-3,4,5-trimethylpiperazine-1-carbonyl chloride, the target compound N,N-dimethyl-3-((5-(3-methyl-1-((3S,5R)-3,4,5-trimethylpiperazine-1-yl)imidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine can be prepared. The target compound (2S,6R)-2,6-dimethyl-4-(3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3-yl)imidazo[1,5-a]quinoxalin-1-yl)morpholine was prepared by replacing N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyridine with 2-(3-(piperidin-1-yl)propoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyridine. By replacing N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)propan-1-amine with 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethylpiperidin-4-amine, the target compound 1-(4-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2-fluorophenyl)-N,N-dimethylpiperidin-4-amine can be obtained.

[0194] The compounds of the present invention can be prepared as shown in the reaction examples in Reaction Scheme 3.

[0195] Reaction Scheme 3

[0196]

[0197] Other related compounds can be prepared by similar methods. For example, 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidin-4-amine is used to replace N 1 ,N 1 -Dimethyl-N 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propane-1,3-diamine can be used to prepare the target compound 1-(5-(1-((2S,6R)-2,6-)dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxaline-8-yl)pyridin-2-yl)piperidin-4-amine. Replace N-methyl-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidin-4-amine with N-methyl-1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidin-4-amine. 1 ,N 1 -Dimethyl-N 3 -(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propane-1,3-diamine can be used to prepare the target compound 1-(5-(1-((2S,6R)-2,6-)dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxaline-8-yl)pyridin-2-yl)-N-methylpiperidin-4-amine. Replace N 1 ,N 1 -Dimethyl-N 3 -(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propane-1,3-diamine can be used to obtain the target compound (2S,6R)-2,6-dimethyl-4-(3-methyl-8-(6-(3-(4-methylpiperazin-1-yl)propoxy)pyridin-3-yl)imidazo[1,5-a]quinoxaline-1-yl)morpholine. Replacing (2S,6R)-2,6-dimethylmorpholine with (2R,6R)-2,6-dimethylmorpholine can produce the target compounds 3-((5-(1-((2R,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)-N,N-dimethylpropan-1-amine and 3-((5-(1-((2S,6S)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)-N,N-dimethylpropan-1-amine.

[0198] An important aspect of the present invention is the discovery that compounds of Formula I, Formula II, Formula IIIa and Formula IIIb are kinase inhibitors, particularly ATM kinase inhibitors. One important and unexpected discovery is that when R2 is optionally substituted alkyl, particularly optionally substituted C 1-4When R2 is an optionally substituted alkyl group, especially a methyl group, the compounds of Formula I, Formula II, Formula IIIa and Formula IIIb are highly active ATM kinase inhibitors. Therefore, these compounds can be used to treat or prevent a variety of clinical conditions caused by DDR functional defects or diseases that benefit from the inhibition of kinase activity, which are also called DDR-mediated diseases or kinase-mediated diseases. Therefore, the present invention provides the use of compounds of Formula I, Formula II, Formula IIIa and Formula IIIb in the preparation of drugs for treating or preventing clinical conditions caused by DDR functional defects or diseases that benefit from the inhibition of kinase activity. In addition, the applicant further found that the compounds of Formula I wherein R2 is an optionally substituted alkyl group, especially an optionally substituted C 1-4 Alkyl, especially methyl, especially compounds defined by Formula II, Formula IIIa and Formula IIIb, are highly active ATM kinase inhibitors. Therefore, in preferred embodiments, the present disclosure particularly relates to the use of R2 as C 1-4 These compounds with alkyl groups are used to treat or prevent various clinical conditions caused by DDR functional defects, or to treat or prevent diseases that benefit from the inhibition of kinase activity, and are used to prepare drugs for treating or preventing clinical symptoms caused by DDR functional defects or diseases that benefit from the inhibition of kinase activity, as well as pharmaceutical compositions containing these compounds.

[0199] The present invention also includes a method for treating or preventing a DDR-mediated disease or a kinase-mediated disease, which comprises administering to a subject an effective amount of a compound of Formula I, Formula II, Formula IIIa or Formula IIIb, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically labeled compound, solvate or pharmaceutically acceptable salt, or a mixture thereof, or a prodrug thereof, or a pharmaceutical composition containing an effective amount of a compound of Formula I, Formula II, Formula IIIa or Formula IIIb, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically labeled compound, solvate or pharmaceutically acceptable salt, or a mixture thereof, or a prodrug thereof.

[0200] In the present invention, clinical conditions caused by DDR functional defects or diseases that benefit from the inhibition of kinase activity, or DDR-mediated or kinase-mediated diseases include, but are not limited to, cancer, including, but not limited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain Cancer, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer, prostate cancer and Huntington's disease. In the present invention, kinases include ATM (ataxia-telangiectasia mutated gene) kinases; therefore, in some embodiments, the cancer described in the present invention is an ATM kinase-mediated cancer, preferably a cancer that benefits from the inhibition of ATM kinase activity.

[0201] When implementing the treatment method of the present invention, an effective amount of a pharmaceutical preparation is administered to a patient with one or more of these symptoms. The pharmaceutical preparation contains an effective therapeutic concentration of a compound of Formula I, Formula II, Formula IIIa or Formula IIIb, and is formulated for oral, intravenous, local or external administration for the treatment of cancer and other diseases. The dosage is an amount that effectively improves or eliminates one or more symptoms. For the treatment of a specific disease, an effective amount is an amount sufficient to improve or alleviate the symptoms associated with the disease in some way. Such a dosage can be administered as a single dose, or it can be administered according to an effective treatment regimen. The dosage may cure the disease, but the administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired symptom improvement.

[0202] In another embodiment, a pharmaceutical composition is provided, which comprises a kinase inhibitor of formula I, formula II, formula IIIa or formula IIIb or its stereoisomers, tautomers, N-oxides, hydrates, isotopically labeled compounds, solvates or pharmaceutically acceptable salts, or mixtures thereof, or prodrugs thereof and a pharmaceutically acceptable carrier.

[0203] Another embodiment of the present invention relates to a pharmaceutical composition that can effectively treat cancer, wherein the compound of formula I, formula II, formula IIIa or formula IIIb, or its stereoisomer, tautomer, N-oxide, hydrate, isotope-labeled compound, solvate or pharmaceutically acceptable salt, or mixture thereof, or prodrug thereof, is used in combination with at least one known anticancer drug or pharmaceutically acceptable salt of an anticancer drug. In particular, it is used in combination with other anticancer drugs related to DNA damage and repair mechanisms, including PARP inhibitors Olaparib, Niraparib, Rucaparib, Talazoparib and Senaparib; HDAC inhibitors Vorinostat, Romidepsin, Panobinostat and Belinostat; and the like. And it is used in combination with other anticancer drugs related to cell division checkpoints, including Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as Palbociclib, ATR inhibitors, and the like. Other known anticancer drugs that can be used for anticancer combination therapy include, but are not limited to, alkylating agents such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, and carboplatin; topoisomerase I inhibitors such as camptothecin, irinotecan, and topotecan; topoisomerase II inhibitors such as doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, and menthopop; RNA / DNA antimetabolites such as 5-azacytidine, gemcitabine, 5-fluorouracil and methotrexate; DNA antimetabolites such as 5-fluoro-2′-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea and thioguanine; antimitotic agents such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel and docetaxel; antibodies such as monoclonal antibodies, panitumumab, nelazolizumab, nivolumab, pembrolizumab, Ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab tiuxetan, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, ofatumumab, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, and rituximab; kinase inhibitors such as imatinib, gemtuzumab, Felotinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pralsetinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, idelalisib, pazopanib, temozolomide, and everolimus.Other known anticancer drugs that can be used in anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguanidine, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegi, denosumab, thalidomide, lenalidomide, venetoclax, Aldesleukin (recombinant human interleukin-2) and Sipueucel-T (prostate cancer treatment vaccine).

[0204] In practicing the method of the present invention, the compound of the present invention and at least one known anticancer drug can be administered together as a single pharmaceutical composition. In addition, the compound of the present invention can also be administered separately from at least one known anticancer drug. In one embodiment, the compound of the present invention and at least one known anticancer drug are administered at about the same time, that is, all drugs are administered at the same time or successively, as long as the compound reaches a therapeutic concentration in the blood at the same time. In another embodiment, the compound of the present invention and at least one known anticancer drug are administered according to their respective dosage regimens, as long as the compound reaches a therapeutic concentration in the blood.

[0205] Another embodiment of the present invention is a bioconjugate composed of the compound that is effective in inhibiting tumors and acts as a kinase inhibitor. This bioconjugate that can inhibit tumors is composed of the compound and at least one known medical antibody, such as Herceptin or Rituxan, or growth hormone, such as EGF or FGF, or cytokine, such as interleukin 2 or 4, or any molecule that can bind to the cell surface. The antibody and other molecules can deliver the compound to its target, making it an effective anti-cancer drug. This bioconjugate can also enhance the anti-cancer effect of medical antibodies, such as Herceptin or Rituxan.

[0206] Another embodiment of the present invention relates to a pharmaceutical composition that can effectively inhibit tumors, comprising a kinase inhibitor of formula I, formula II, formula IIIa or formula IIIb, or a stereoisomer, tautomer, N-oxide, hydrate, isotope-labeled compound, solvate or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, in combination with radiotherapy. In this embodiment, the compound of the present invention and radiotherapy can be administered at the same time or at different times.

[0207] Another embodiment of the present invention relates to a pharmaceutical composition that can be effectively used for postoperative treatment of cancer, comprising a compound of formula I, formula II, formula IIIa or formula IIIb of a kinase inhibitor, or a stereoisomer, tautomer, N-oxide, hydrate, isotope-labeled compound, solvate or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof. The present invention also relates to a method of treating cancer in a mammal by surgically removing a tumor and then using the pharmaceutical composition of the present invention.

[0208] The pharmaceutical composition of the present invention includes a pharmaceutical preparation containing all the compounds of the present invention in an amount that can effectively achieve its intended purpose. Although each person's needs are different, those skilled in the art can determine the optimal dose of each part in the pharmaceutical preparation. Generally, the compound, or its pharmaceutically acceptable salt, is orally administered to a mammal daily in an amount of about 0.0025 to 50 mg / kg body weight. However, it is preferably administered orally at about 0.01 to 10 mg / kg per kilogram. If a known anticancer drug is also administered, its dosage should be effective to achieve its intended purpose. The optimal doses of these known anticancer drugs are well known to those skilled in the art.

[0209] The unit oral dose may include about 0.01 to 50 mg, preferably about 0.1 to 10 mg of the compound of the invention. The unit dose may be administered once or more, one or more tablets per day, each tablet containing about 0.1 to 50 mg, conveniently about 0.25 to 10 mg of the compound of the invention or its solvate.

[0210] In external preparations, the concentration of the compound of the present invention may be about 0.01 to 100 mg per gram of carrier.

[0211] The compounds of the present invention can be administered as raw drugs. The compounds of the present invention can also be administered as part of a suitable pharmaceutical preparation containing a pharmaceutically acceptable carrier (including excipients and adjuvants). These pharmaceutically acceptable carriers facilitate the processing of the compounds into pharmaceutical preparations that can be used for pharmaceutical purposes. Preferred pharmaceutical preparations, especially those oral and preferred administration types, such as tablets, lozenges and capsules, and solutions suitable for injection or oral administration, contain about 0.01% to 99%, preferably from about 0.25% to 75% of active compounds and excipients.

[0212] The scope of the present invention also includes non-toxic pharmaceutically acceptable salts of the compounds of the present invention. Acid addition salts are formed by mixing a non-toxic pharmaceutically acceptable acid solution with a solution of the compound of the present invention. The acid is, for example, hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, etc. Base addition salts are formed by mixing a non-toxic pharmaceutically acceptable base solution with a solution of the compound of the present invention. The base is, for example, sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, trishydroxymethylaminomethane, N-methylglucamine, etc.

[0213] The pharmaceutical preparations of the present invention can be administered to any mammal, as long as they can obtain the therapeutic effect of the compounds of the present invention. The most important of these mammals are humans and veterinary animals, although the present invention is not intended to be so limited.

[0214] The pharmaceutical preparation of the present invention can be administered by any route to achieve its intended purpose. For example, it can be administered parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, transdermally, orally, intrathecally, intracranially, nasally or externally. Alternatively or concurrently, it can be administered orally. The dosage of the drug will be determined based on the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

[0215] The pharmaceutical preparations of the present invention can be manufactured in a known manner. For example, they can be manufactured by conventional mixing, granulation, tableting, dissolution, or freeze-drying processes. When manufacturing oral preparations, solid excipients and active compounds can be combined and the mixture can be selectively ground. After adding appropriate amounts of auxiliary agents as needed or necessary, the granular mixture can be processed to obtain tablets or lozenge cores.

[0216] Suitable adjuvants are in particular fillers, for example sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate; and binders, for example starch pastes, including corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If necessary, disintegrants such as the starches mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, can be added. Auxiliary agents are in particular flow regulators and lubricants, for example, silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. If necessary, the tablet core can be provided with a suitable coating that can resist gastric juice. For this purpose, concentrated sugar solutions can be applied. This solution may contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. To prepare a coating resistant to gastric juices, suitable cellulose solutions may be used, for example cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate. Dyes or pigments may be added to the coating of the tablet or lozenge core, for example, for identification or to characterize the combination of active ingredient doses.

[0217] Other pharmaceutical preparations for oral administration include press-fit capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The press-fit capsules may contain the active compound in the form of particles, mixed with a filler such as lactose; a binder such as starch; and / or a lubricant such as talc or magnesium stearate, and a stabilizer. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid such as a fat or liquid paraffin, to which a stabilizer may be added.

[0218] Preparations suitable for parenteral administration include aqueous solutions of the active compound, such as solutions of water-soluble salts and alkaline solutions. In addition, oily injection suspensions of the appropriate active compound may be administered. Suitable lipophilic solvents or carriers include fats such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol 400, or hydrogenated castor oil, or cyclodextrin. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, and / or dextran. Suspension stabilizers may also be contained.

[0219] According to one aspect of the present invention, the compounds of the present invention are used in topical and parenteral formulations and are useful in the treatment of skin cancer.

[0220] The topical preparation of the present invention can be made into oil, cream, emulsion, ointment, etc. by preferably using a suitable carrier. Suitable carriers include plant or mineral oil, white mineral oil (white soft paraffin), branched fat or grease, animal fat and high molecular alcohol (grease with a concentration greater than C). 12 ). Preferred carriers are those in which the active ingredient can be dissolved. Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents that impart color or flavor, if desired. In addition, these topical preparations may contain transdermal penetration enhancers. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762.

[0221] Creams are preferably formulated with a mixture of mineral oil, self-emulsifying beeswax and water, mixed with the active ingredient dissolved in a small amount of oil such as almond oil. A typical cream example includes about 40 parts water, 20 parts beeswax, 40 parts mineral oil and 1 part almond oil.

[0222] Ointments can be prepared by mixing a vegetable oil containing the active ingredient, such as almond oil, with warm soft paraffin, and then allowing the mixture to cool. A typical ointment example includes about 30% by weight of almond oil and 70% by weight of white soft paraffin.

[0223] The following examples are illustrative, rather than limiting, methods and preparations of the present invention. Other suitable modifications and improvements to various conditions and parameters that are apparent to those skilled in the art and that are typically encountered in clinical treatment are within the spirit and scope of the present invention.

[0224] Example

[0225] General Notes

[0226] All reagents used were of commercial quality, and solvents were dried and purified according to standard methods. Mass spectrometry samples were analyzed using a single quadrupole mass spectrometer (Platform II, Agilent 6110) with electrospray ionization. Brücker Ascend 400 NMR was used to record at 400 MHz. 1For H NMR spectra, chemical shifts are reported in ppm downfield from TMS as an internal standard (0.00 ppm), and coupling constants, J values, are reported in Hz.

[0227] Example 1

[0228] N,N-Dimethyl-3-(4-(1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)phenoxy)propan-1-amine

[0229]

[0230] a) Preparation of 2-hydroxy-7-bromoquinoxaline: 2-hydroxyquinoxaline (10 g, 68.5 mmol) was dissolved in acetic acid (500 mL), and bromine (3.62 mL, 70.6 mmol) was slowly added dropwise at 10°C. After the addition was completed, the reaction solution was stirred at room temperature for 3 hours, and then the reaction mixture was cooled to 0°C, and water (500 mL) was added, and stirring was continued for 30 minutes, and the mixture was filtered, and the filter cake was washed with water (500 mL). After the solid was dried, the target product (13.5 g, 88% yield, yellow solid) was obtained. LC-MS (ESI): m / z (M+H) + / (M+2+H) + 225.1 / 227.1.

[0231] b) Preparation of 2-chloro-7-bromoquinoxaline: Dissolve 2-hydroxy-7-bromoquinoxaline (6 g, 26.7 mmol) in phosphorus oxychloride (60 mL). Under nitrogen protection, the reaction solution was stirred at 100 ° C for 2 hours. Cooled to room temperature, the solvent was removed under reduced pressure to obtain a crude product, and then extracted with ethyl acetate (100 mL). The organic phase was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product (6.23 g, 96% yield, light yellow solid). LC-MS (ESI): m / z (M+H) + / (M+2+H) + 243.0 / 245.1.

[0232] c) Preparation of 7-bromo-2-methylquinoxaline: 2-chloro-7-bromoquinoxaline (4.7 g, 19.3 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and triacetylacetonate iron was added. Then the reaction solution was cooled to 0°C, and methylmagnesium chloride (7 mL, 3 mol / L tetrahydrofuran solution) was slowly added to the reaction solution using a constant pressure dropping funnel. After the addition was complete, the reaction was continued to stir at 0°C for 5 hours. Then the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution to quench the reaction. After most of the tetrahydrofuran was removed under reduced pressure, the liquid was extracted with ethyl acetate (40 mL×2), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Column chromatography separation and purification (silica gel, ethyl acetate: petroleum ether = 0-40% as eluent) gave the target product (3.27 g, 76% yield, white solid). LC-MS (ESI): m / z (M+H) + / (M+2+H) + 223.1 / 225.1.

[0233] d) Preparation of 7-bromo-2-iodomethylquinoxaline: 7-bromo-2-methylquinoxaline (3.27 g, 14.66 mmol) was dissolved in acetonitrile, and copper sulfate pentahydrate solid and iodine were added thereto in sequence. The reaction solution was stirred at 70°C for 3 hours under nitrogen protection. After the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, and then the liquid was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated sodium sulfite aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (silica gel, ethyl acetate: petroleum ether = 0-30% as eluent) to obtain the target product (2.6 g, 50% yield, light yellow solid). LC-MS (ESI): m / z (M+H) + / (M+2+H) + 348.9 / 350.9.

[0234] e) Preparation of 7-bromo-2-azidomethylquinoxaline: 7-bromo-2-iodomethylquinoxaline (956 mg, 2.74 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), sodium azide (196 mg, 3.01 mmol) was added thereto, and the reaction solution was stirred at room temperature for 11 hours, 50 mL of water was added to the reaction solution, and the liquid was extracted with ethyl acetate (30 mL). The organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The target product (820 mg, crude product, yellow solid) was obtained by column chromatography separation and purification (silica gel, ethyl acetate: petroleum ether = 0-30% as eluent). LC-MS (ESI): m / z (M+H) + / (M+2+H) + 264.1 / 266.1.

[0235] f) Preparation of (7-bromoquinoxaline-2-yl)methylamine: 7-bromo-2-azidomethylquinoxaline (651 mg, 2.47 mmol) was dissolved in a mixed solution of tetrahydrofuran (8 mL) and water (4 mL), and triphenylphosphine (777 mg, 2.96 mmol) was added. Under nitrogen protection, the reaction solution was stirred at room temperature for 12 hours, and the pH was adjusted to 1-3 with 1 mol / L hydrochloric acid aqueous solution, and the liquid was extracted with ethyl acetate (20 mL), and the aqueous phase was collected. Then, the pH of the aqueous phase was adjusted to 8 with a saturated sodium bicarbonate solution, and the liquid was extracted with dichloromethane (20 mL×2), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered and removed under reduced pressure to obtain a crude product, which was directly used in the next step without purification (400 mg, crude product, brown solid). LC-MS (ESI): m / z (M+H) + / (M+2+H) + 238.1 / 240.1.

[0236] g) Preparation of N-((7-bromoquinoxalin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide: (7-bromoquinoxalin-2-yl)methylamine (400 mg, crude product, 1.68 mmol) was dissolved in N,N-dimethylformamide (8 mL), and N,N-diisopropylethylamine (0.88 mL, 5.04 mmol) and tetrahydropyran-4-carboxylic acid (262 mg, 2.02 mmol) were added thereto in sequence. Under nitrogen protection, the reaction solution was stirred at 80°C for 2 hours. After the reaction solution was cooled to room temperature, 40 mL of water was added, and the liquid was extracted with ethyl acetate (30 mL×2). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (silica gel, methanol: dichloromethane = 0-20%) to obtain the target product (275 mg, 46% yield, yellow solid). LC-MS(ESI):m / z(M+H) + / (M+2+H) + 350.1 / 352.1.

[0237] h) Preparation of 8-bromo-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxaline: N-((7-bromoquinoxalin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide (210 mg, 0.60 mmol) was dissolved in a mixed solution of N,N-dimethylformamide (1 mL) and ethyl acetate (6 mL) and the temperature was lowered to 0°C. Phosphorus oxychloride (410 mg, 3.6 mmol) was slowly added dropwise thereto. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 2 hours. The reaction solution was then slowly added dropwise to a saturated sodium bicarbonate aqueous solution, maintaining the pH at greater than 8, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by filtration to obtain a crude product, which was separated and purified by column chromatography (silica gel, methanol: dichloromethane = 0-15%) to obtain the target product (68 mg, crude product, yellow solid). LC-MS(ESI):m / z(M+H) + / (M+2+H) + 332.1 / 334.1.

[0238] i) Preparation of N,N-dimethyl-3-(4-(1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxaline-8-yl)phenoxy)propan-1-amine: 8-bromo-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxaline (68 mg, crude product, 0.20 mmol) was dissolved in a mixed solution of dioxane and water (1.6 mL / 0.4 mL), and N,N-dimethyl-3-(4-(1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxaline-8-yl)phenoxy)propan-1-amine was added sequentially. N-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propane-1-amine (125 mg, 0.41 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (15 mg, 0.02 mmol) and cesium carbonate (200 mg, 0.61 mmol), the reaction mixture was stirred at 100°C for 1 hour under nitrogen protection. When the reaction solution cooled to room temperature, the solvent was removed under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (silica gel, methanol: dichloromethane = 0-15%), and then further separated and purified by preparative liquid chromatography (C18 column, 0-100% acetonitrile / water as mobile phase) to obtain the target compound (6 mg, 7% yield, yellow solid). LC-MS (ESI): (M+H) + 431.30. 1H NMR (400MHz, DMSO-d6): δ8.96(s,1H),8.30–8.27(m,1H),7.99–7.95(m,1H),7.88–7.84(m,2H),7.77–7.71(m,2H),7.15–7.10(m,2H) ,4.11–4.01(m,5H),3.68–3.62(m,2H),2.39(t,J=7.1Hz,2H),2.17(s,6H),2.13–2.08(m,2H),2.04–1.96(m,2H),1.92–1.85(m,2H).

[0239] Example 2

[0240] N,N-Dimethyl-3-((5-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine

[0241] a) Preparation of 1-(7-bromoquinoxaline-2-yl)-1-ethanone: A toluene solution of 7-bromo-2-chloroquinoxaline (5 g, 20.53 mmol) and tributyl(1-ethoxyethylene)tin (9.27 g, 25.67 mmol, 8.66 mL) was evacuated under vacuum for 30 minutes. The reaction mixture was degassed and charged with nitrogen three times. Bis(triphenylphosphine)palladium(II) chloride (Pd(PPh3)2Cl2, 1.44 g, 2.05 mmol) was added, the reaction mixture was stirred under nitrogen atmosphere and heated at 80°C for 12 hours. Stirring was continued at 80°C for an additional 12 hours. The reaction mixture was evaporated to dryness, 1,4-dioxane (51 mL) was added thereto for suspension, 2 mol / L aqueous hydrochloric acid solution (51 mL) was added, and the resulting reaction mixture was stirred for 45 minutes. The residue was diluted with ethyl acetate (100 mL), the organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the obtained crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100 / 1 to 100 / 1.5) to obtain the target product (2.3 g, 4.61% yield, white solid). LC-MS (ESI): (M+H) + / (M+2+H) + 250.8 / 252.7. 1 H NMR (400MHz, DMSO-d6): δ9.40(s,1H),8.51–8.50(m,1H),8.15-8.14(m,2H),2.76(s,3H).

[0242] b) Preparation of 1-(7-bromoquinoxalin-2-yl)ethane-1-amine: Sodium cyanoborohydride (NaBH3CN, 402.96 mg, 6.41 mmol) was added in one portion to a solution of 1-(7-bromoquinoxalin-2-yl)-1-ethanone (2.3 g, 9.16 mmol) and ammonium acetate (NH4OAc, 7.06 g, 91.60 mmol) in methanol (50 mL) at 0° C. The reaction mixture was stirred at 25° C. for 12 hours. After removing methanol, 20 mL of water was added to the residue, and then an aqueous sodium hydroxide solution (w% = 5%) was added, and the pH of the resulting solution was adjusted to 13, extracted with dichloromethane (50 mL × 2), and the organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel chromatography (petroleum ether: ethyl acetate = 2 / 1, 1 / 1) to obtain the target product (0.7 g, 30.31% yield, brown oil). LC-MS (ESI): (M-16+H) + 235.0(16:NH2). 1 H NMR (400MHz, DMSO-d6): δ9.18(s,1H),8.27(d,J=2.4Hz,1H),8.02(d,J=8.8Hz,1H),7. 95(dd,J=2.4,8.8Hz,1H),4.28-4.23(m,1H),2.33-2.32(m,2H),1.41(d,J=6.8Hz,3H).

[0243] c) Preparation of N-(1-(7-bromoquinoxalin-2-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide: To a pyridine solution (4 mL) of 1-(7-bromoquinoxalin-2-yl)ethane-1-amine (0.4 g, 1.59 mmol) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 735.32 mg, 3.84 mmol) and 1-hydroxybenzotriazole (HOBT, 94.24 mg, 697.41 μmol), followed by tetrahydropyran-4-carboxylic acid (226.91 mg, 1.74 mmol). The resulting mixture was stirred at 25° C. for 6 hours. In another reactor, 1-(7-bromoquinoxaline-2-yl)ethane-1-amine (0.3 g, 1.19 mmol), tetrahydropyran-4-carboxylic acid (170.18 mg, 1.31 mmol), EDCI (551.49 mg, 2.88 mmol) and HOBT (70.68 mg, 523.06 μmol) in pyridine (3 mL) were added to the above solution, and the resulting mixture was stirred at 25°C for 6 hours. The two reaction mixtures were diluted with water (45 mL) and extracted with ethyl acetate (15 mL×3). The organic layers were mixed, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was crushed with methyl tert-butyl ether (5 mL) at 25°C for 30 minutes to obtain the target compound (0.7 g, crude product, gray solid). LC-MS (ESI): (M+H) + / (M+2+H) + 364.1 / 366.1. 1 H NMR (400MHz, DMSO-d6): δ8.95(s,1H),8.54(d,J=6.8Hz,1H),8.28(d,J=2Hz,1H),8.04(d,J=8.8Hz,1H),7.97(dd,J= 2.1,8.8Hz,1H),5.17-5.13(m,1H),3.86-3.84(m,2H),3.31-3.27(m,2H),1.63-1.56(m,3H),1.51(d,J=6.8Hz,3H).

[0244] d) Preparation of 8-bromo-3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxaline: Trifluoromethanesulfonic anhydride (Tf2O, 684 mg, 2.42 mmol, 0.4 mL) was added to a solution of N-(1-(7-bromoquinoxalin-2-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide (0.4 g, 1.10 mmol) in dichloromethane (4 mL), and the mixture was stirred at 25°C for 1 hour. Pyridine (588 mg, 7.43 mmol, 0.6 mL) was then added and the mixture was stirred at 25°C for 6 hours. Water (10 mL) was added at 0°C, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel chromatography (petroleum ether / EtOH=20 / 1) to obtain the target product (0.3 g, crude product, white solid). LC-MS (ESI): (M+H) + / (M+2+H) + 346.1 / 348.1.

[0245] e) Preparation of N,N-dimethyl-3-((5-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxaline-8-yl)pyridin-2-yl)oxy)propan-1-amine: 8-bromo-3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxaline (0.07 g, 202.18 μmol), N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) )pyridin-2-yl)oxy)propane-1-amine (87.29 mg, 285.08 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (Pd(dppf)Cl2, 14.79 mg, 20.22 μmol) and cesium carbonate (Cs2CO3, 131.75 mg, 404.37 μmol) in 1,4-dioxane and aqueous solution were evacuated in vacuo, replaced with nitrogen three times, and then the mixture was stirred at 90°C in a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with a mixed solvent of dichloromethane (10 mL) and methanol (1 mL), and the insoluble matter was removed by filtration to obtain a crude product, which was purified by preparative HPLC column (column: Waters Xbridge 150*25 mm*5 um; mobile phase (water (0.05% ammonium hydroxide v / v)-ACN); B%: 28%-58%, 10 min) to obtain the target compound (21 mg, 16.4% yield, 98.6% purity, gray solid).

[0246] The compounds of the following Examples 3-13 can be prepared by referring to the method of Example 2.

[0247]

[0248]

[0249]

[0250] Embodiment 14

[0251] N,N-dimethyl-3-((5-(3-methyl-1-morpholinylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propane-1-

[0252] amine

[0253] a) Preparation of N-(1-(7-bromoquinoxaline-2-yl)ethyl)morpholine-4-carboxamide: To a solution of 1-(7-bromoquinoxaline-2-yl)ethane-1-amine (0.3 g, 2.01 mmol) in dichloromethane (8 mL) were added morpholine-4-carbonyl chloride (455.08 mg, 1.81 mmol) and DIEA (259.22 mg, 2.01 mmol). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL×2). The organic phases were combined, washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product (0.56 g, yellow oil, 76.45% yield). LC-MS (ESI): (M+H) + 365.1.

[0254] Preparation of 4-(8-bromo-3-methylimidazo[1,5-a]quinoxaline-1-yl)morpholine: A mixture of N-(1-(7-bromoquinoxaline-2-yl)ethyl)morpholine-4-carboxamide (0.5 g, 1.37 mmol) and POCl3 (8.25 g, 53.80 mmol) was heated to 75°C and stirred at this temperature for 3 hours. At 0°C, 150 mL of water was added to quench the reaction, and then the pH value of the mixture was adjusted to 7 with saturated aqueous sodium carbonate solution and extracted with EA (100 mL×2). The organic phases were collected and combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target crude product (0.32 g, brown solid, 67.32% yield). LC-MS (ESI): (M+H) + 347.1.

[0255] c) Preparation of N,N-dimethyl-3-((5-(3-methyl-1-morpholinylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine: 4-(8-bromo-3-methylimidazo[1,5-a]quinoxalin-1-yl)morpholine (20.25 g, 720.03 umol), N,N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) cyclopentane-2-yl)pyridin-2-yl)oxy)propane-1-amine (440.95 mg, 1.44 mmol) was added to a solution of dioxane (15 mL) and water (1.5 mL) with Cs2CO3 (441.05 mg, 1.35 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (Pd(dppf)Cl2, 10.54 mg, 14.40 umol). The mixture was heated to 90°C and stirred for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EA (50 mL×2). The organic phases were combined, washed with brine (25 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to obtain the target compound (23.29 mg, yellow oil, yield 5.53%).

[0256] The compounds of Examples 15-45 described below can be prepared by referring to the method of Example 2 or 14.

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263] Embodiment 46

[0264] N 1 -(5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)-N 3 ,N 3 -Dimethylpropane-1,3-diamine

[0265] a) Preparation of 1-(5-bromo-2-nitrophenyl)-4-methylimidazole: K2CO3 (439.75 g, 3.18 mol) was added to a solution of 4-bromo-2-fluoro-1-nitrobenzene (350 g, 1.59 mol) and 4-methyl-1H-imidazole (137.15 g, 1.67 mol) in DMF (2800 mL). The reaction solution was stirred at 25°C for 12 hours, then the reaction solution was filtered and the filter cake was washed with DMF (800 mL). The filtrate was poured into water (8 L) and stirred for 10 minutes, then filtered, and the filter cake was washed with water (1 L). The obtained solid was slurried with MTBE (1 L) and then filtered, and the filter cake was washed with MTBE (400 mL). The obtained solid was vacuum dried to obtain the target compound (332 g, yellow solid, 73.98% yield).

[0266] b) Preparation of 4-bromo-2-(4-methylimidazol-1-yl)aniline: To a solution of 1-(5-bromo-2-nitrophenyl)-4-methylimidazole (120 g, 425.39 mmol) in EtOH (1200 mL) was added a solution of NH4Cl (227.55 g, 4.25 mol) in water (600 mL). Fe (47.51 g, 850.78 mmol) was added to the mixture and stirred at 25°C for 0.5 h, then Fe (71.27 g, 1.28 mol) was slowly added over 1.5 h and stirred at 35°C for 1 h. The reaction solution was filtered and the filter cake was washed with EtOH (800 mL), the pH was adjusted to 8 with saturated NaHCO3 solution, and the crude product was obtained by concentrating under reduced pressure. The crude product was slurried with water (1.5 L), filtered, and the filter cake was dried under vacuum. The filter cake was washed with MTBE (300 mL) to obtain the target compound (93 g, yellow solid, 86.72% yield).

[0267] c) Preparation of 8-bromo-3-methylimidazo[1,5-a]quinoxaline: To a solution of 4-bromo-2-(4-methylimidazol-1-yl)aniline (5 g, 19.83 mmol) in DMSO (50 mL) was added AcOH (2.38 g, 39.67 mmol, 2.27 mL). The reaction solution was stirred at 130°C for 36 hours. AcOH (2.38 g, 39.67 mmol, 2.27 mL) was added to the reaction solution and stirred at 130°C for another 24 hours. The reaction solution was diluted with EA (80 mL), washed with saturated brine (50 mL×3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was washed with MTBE (150 mL) to obtain the target compound (2.19 g, yellow solid, 41.08% yield). LC-MS (ESI): m / z (M+H) + 262.0.

[0268] d) Preparation of 8-bromo-1-chloro-3-methylimidazo[1,5-a]quinoxaline: NCS (4.42 g, 33.12 mmol) was added to a solution of 8-bromo-3-methylimidazo[1,5-a]quinoxaline (2.19 g, 8.15 mmol; 3.65 g, 13.93 mmol) in DCM (120 mL). The reaction solution was stirred at 25°C for 12 hours. The reaction solution was diluted with saturated NaHCO3 solution (200 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with saturated brine (100 mL×3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was washed with MTBE (30 mL) to obtain the target compound (5.3 g, yellow solid, 80.92% yield).

[0269] e) Preparation of (2S,6R)-4-(8-bromo-3-methylimidazo[1,5-a]quinoxaline-1-yl)-2,6-dimethylmorpholine: DIEA (6.93 g, 53.61 mmol, 9.34 mmol) and (2S,6R)-2,6-dimethylmorpholine (6.18 g, 53.61 mmol) were added to a solution of 8-bromo-1-chloro-3-methylimidazo[1,5-a]quinoxaline (5.3 g, 17.87 mmol) in DMSO (33 mL). The reaction mixture was stirred at 90°C for 12 hours. Then (2S,6R)-2,6-dimethylmorpholine (2.06 g, 17.87 mmol, 2.20 mL) was added to the reaction mixture and stirred at 90°C for another 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was washed with MTBE (35 mL) to obtain the target compound (5.45 g, yellow solid, 81.22% yield). 1 H NMR (400MHz, CDCl3): δ8.80(d,J=2.0Hz,1H),8.66(s,1H),7.71(d,J=8.4Hz,1H),7.53(dd,J=2.0,8.8H z,1H),4.07-4.00(m,2H),3.25(d,J=2.0Hz,1H),2.86-2.78(m,2H),2.56(s,3H),1.29(d,J=6.4Hz,6H).

[0270] f)N 1 -(5-(1-((2S,6R)-2,6-dimethylmorpholinyl)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)-N 3 ,N 3Preparation of -dimethylpropane-1,3-diamine: (2S,6R)-4-(8-bromo-3-methylimidazo[1,5-a]quinoxaline-1-yl)-2,6-dimethylmorpholine (100 mg, 266.48 μmol), N 1 ,N 1 -Dimethyl-N 3 -(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propane-1,3-diamine (113.87 mg, 373.07 μmol), Cs2CO3 (173.65 mg, 532.96 μmol) and Pd(dppf)Cl2 (9.75 mg, 13.32 μmol) were dissolved in dioxane (15 mL) and water (0.7 mL). The reaction system was replaced with nitrogen three times, and then the reaction solution was stirred at 90 ° C for 2 hours in a nitrogen atmosphere. The reaction solution was dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer plate (DCM: MeOH = 9: 1) to obtain a crude product. The crude product was slurried in MeCN at 25 ° C for 30 minutes to obtain the target product (24.87 g, yellow solid, 18.96% yield).

[0271] The compounds of Examples 47 to 64 described below can be prepared by referring to the method of Examples 2, 14 or 46.

[0272]

[0273]

[0274]

[0275]

[0276] Embodiment 65

[0277] In vitro ATM kinase assay was used to determine the in vitro inhibitory effect of the compound of Example 2 and its analogs on ATM

[0278] The ATM enzyme activity was detected using Cisbio's HTRF reagent in a 384-well plate (Greiner, #784075). 2.5 μL of the gradient concentration compound working solution diluted with buffer was added to the 384-well plate, followed by 2.5 μL of 120 nM p53 substrate (Eurofins, #14-952) and 2.5 μL of 2 ng / μL ATM enzyme (Eurofins, 14-933), and finally 2.5 μL of a mixture solution containing 240 μM ATP, 20 mM Mg(AcO)2, and 20 mM MnCl2. The mixture was centrifuged at 1000 rpm for 1 minute and reacted at room temperature in the dark for 30 minutes. 5 μL of EDTA stop solution (250 mM) was then added to terminate the reaction. Finally, 5 μL of detection mixture (Anti-phospho-p53(ser15)-K (Cisbio, #61P08KAE, 0.084 ng / μL) and Anti-GST-d2 (Cisbio, #61GSTDLA, 5.00 ng / μL)) was added to each well and incubated overnight at room temperature. The fluorescence values ​​at 665 nm and 615 nm were detected on the Envision 2104 instrument. The final concentrations of each reagent in the experiment were 12.5 mM HEPES (pH 8.0), 0.5% glycerol, 0.005% Brij-35, 0.625 mM DTT, 0.0125% BSA, 15 nM p53, 0.25 ng / μL ATM, 30 μM ATP, 2.5 mM Mg(AcO)2, 2.5 mM MnCl2, 62.5 mM EDTA, 0.021 ng / μL Anti-phospho-p53, and 1.25 ng / μL Anti-GST-d2.

[0279] Calculate the relative fluorescence ratio: Ratio 665nm / 615nm -Ratio 背景 , and calculated the inhibition rate % = (1-(relative fluorescence ratio of the test compound wells-relative fluorescence ratio of the positive control wells) / (relative fluorescence ratio of the negative control wells-relative fluorescence ratio of the positive control wells)) × 100, and analyzed the data using GraphPad Prism6.0 software, with the curve equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope)) to fit and calculate IC 50 Table 1 summarizes the inhibitory effects of some compounds on ATM kinase activity (inhibition rate %); Table 2 summarizes the ATM activation IC values ​​of some compounds. 50 value.

[0280] Table 1

[0281]

[0282]

[0283] Note: Example 1 herein is the compound of Example 37 of WO 2018 / 127195 A1.

[0284] Table 2

[0285] Example 15 31 32 33 38 39 40 <![CDATA[IC 50 (nM)]]> 0.31 0.62 0.10 0.20 0.20 0.20 0.20 Example 41 43 46 48 49 50 58 <![CDATA[IC 50 (nM)]]> 0.15 0.41 0.18 0.46 0.80 0.41 0.19 Example 59 AZD0156 <![CDATA[IC 50 (nM)]]> 0.19 0.30

[0286] Therefore, as determined by the ATM kinase assay, the compound of Example 2 and its analogs have a good inhibitory effect on ATM kinase.

[0287] Embodiment 66

[0288] The MTT assay was used to determine the effects of the compound of Example 2 and its analogs combined with CPT-11 on human colon cancer cells.

[0289] Inhibition of SW620 growth

[0290] The newly revived human colon cancer cell SW620 cells were cultured and subcultured until they were in good growth state. When the confluence reached about 90%, they were used for experiments. The SW620 cells were digested with trypsin, centrifuged at 800rpm for 5min, the supernatant was discarded, and the cells were resuspended with fresh culture medium (RPMI1640 culture medium + 10% FBS), counted, and inoculated into 96-well cell culture plates at an appropriate cell well density. They were placed in a 37℃ 5% CO2 incubator and cultured overnight. The mother solutions of the test compound and the reference compound AZD0156 were serially diluted with DMSO at a ratio of 1:3 and 1:10 to 8 concentrations: the first concentration was 1μM or 0.333μM, and the last concentration was a DMSO negative control (0μM, the final DMSO concentration was 1‰). 5μL of each concentration was added to 120μL culture medium (25-fold dilution) and oscillated to mix. Take the cells that have been cultured overnight, remove the culture medium, add 195 μL of fresh culture medium containing 205nM CPT-11 to each well, and then add 5 μL of diluted culture medium containing the test substance at the corresponding concentration, and then place the culture plate in a 37℃ 5% CO2 incubator for 5 days. Remove the original solution, add 100 μL of fresh serum-free DMEM culture medium containing MTT (0.5mg / mL) to each well, and continue to culture. After 4 hours, remove the original solution, add 100 μL DMSO to each well, shake in the dark for 10 minutes, and place it in a multifunctional reader to read the absorbance value at a wavelength of 552 / 690nm. Use Graph Pad Prism 6.0 software to analyze the data, and plot the inhibitory activity of the compound on cell proliferation using cell survival rate versus the logarithm of compound concentration as coordinates. Cell survival rate % = (OD 化合物 -OD背景 ) / (OD DMSO -OD 背景 )×100. IC 50 The values ​​were fitted with an S-shaped dose-response curve equation: Y = 100 / (1+10^(LogC-LogIC 50 )), where C is the concentration of the compound.

[0291] Table 3 summarizes the inhibitory effect of some compounds combined with CPT-11 on the growth of human colon cancer cell SW620 (IC 50 ).

[0292] Table 3

[0293] Example 1 2 3 4 5 6 7 8 <![CDATA[IC 50 (nM)]]> 123.1 19.2 40.2 41.1 19.5 12.6 25.9 24.1 Example 9 10 11 12 13 14 15 16 <![CDATA[IC 50 (nM)]]> 24.0 16.7 30.0 15.7 >1000 39.7 9.3 8.2 Example 17 18 19 20 21 22 24 25 <![CDATA[IC 50 (nM)]]> 27.4 6.5 17.6 35.9 29.6 16.3 20.8 66.6 Example 26 31 32 33 35 36 37 38 <![CDATA[IC 50 (nM)]]> 51.0 10.1 9.2 18.3 564.3 72.6 17.6 8.7 Example 39 40 41 42 43 45 46 47 <![CDATA[IC 50 (nM)]]> 7.3 8.1 54.3 852.2 17.9 20.93 46.9 17.9 Example 48 49 50 52 58 59 60 61 <![CDATA[IC 50 (nM)]]> 12.1 7.1 6.3 5.5 23.3 12.0 >1000 21.7 Example 62 63-A 63-B 64-A 64-B AZD0156 a b <![CDATA[IC 50 (nM)]]> 43.0 32.3 43.0 21.9 20.4 9.8 328.3 56.97 Example c d e <![CDATA[IC 50 (nM)]]> 170.3 127.7 152.0

[0294] Note: Example 1 herein is the compound of Example 37 of WO 2018 / 127195 A1; Examples a, b, c, d and e are the compounds of Examples 4, 26, 44, 45 and 47 of WO 2018 / 127195 A1, respectively.

[0295] Therefore, as determined by the MTT assay, the compound of Example 2 and its analogs have a good inhibitory effect on the growth of SW620 cells.

[0296] Embodiment 67

[0297] The inhibitory effect of the compound of Example 2 and its analogs on the growth of human breast cancer cells MDA-MB-468 was determined by MTT assay.

[0298] The newly revived human breast cancer cells MDA-MB-468 were cultured and subcultured until they were in good growth state. When the confluence reached about 90%, they were used for the experiment. The MDA-MB-468 cells were digested with trypsin, centrifuged at 800rpm for 5min, the supernatant was discarded, and the cells were resuspended with fresh culture medium (RPMI 1640 culture medium + 10% FBS), counted, and inoculated into 96-well cell culture plates at an appropriate cell pore density, and cultured in a 37℃ 5% CO2 incubator overnight. The mother solution of the test compound or reference compound AZD0156 was serially diluted with DMSO at a ratio of 1:3 and 1:10 to 8 concentrations: the first concentration was 1μM or 0.333μM, and the last concentration was a DMSO negative control (0μM, the final DMSO concentration was 1‰). 5μL of each concentration was added to 120μL culture medium (25-fold dilution) and oscillated to mix. Take the cells that have been cultured overnight, remove the culture medium, add 195 μL of fresh culture medium (RPMI 1640 + 5% FBS) to each well, and then add 5 μL of diluted culture medium containing the corresponding concentration of the test substance, and then place the culture plate in a 37°C 5% CO2 incubator for 7 days (change the medium once on the 4th day and continue culturing). Remove the original solution, add 100 μL of fresh serum-free DMEM culture medium containing MTT (0.5 mg / mL) to each well, and continue culturing. After 4 hours, remove the original solution, add 100 μL of DMSO to each well, shake in the dark for 10 minutes, and place it on a multi-function reader to read the absorbance value at a wavelength of 552 / 690nm. Use Graph Pad Prism 6.0 software to analyze the data, and plot the inhibitory activity of the compound on cell proliferation using cell survival rate versus the logarithm of compound concentration as coordinates. Cell survival rate % = (OD 化合物 -OD 背景 ) / (OD DMSO -OD 背景 )×100. IC 50 The values ​​were fitted with an S-shaped dose-response curve equation: Y = 100 / (1+10^(LogC-LogIC 50 )), where C is the concentration of the compound.

[0299] Table 4 summarizes the inhibitory effect data of some compounds on the growth of human breast cancer cells MDA-MB-468 (IC 50 ).

[0300] Table 4

[0301] Example 1 2 3 4 5 6 7 8 <![CDATA[IC 50 (nM)]]> 103.4 18.8 29.1 38.85 21.91 11.57 22.58 24.78 Example 9 10 11 12 13 14 15 16 <![CDATA[IC 50 (nM)]]> 23.1 16.44 31.1 14.37 781.6 25.99 7.98 10.62 Example 17 18 19 20 21 22 24 25 <![CDATA[IC 50 (nM)]]> 20.93 6.40 11.41 21.27 16.41 9.91 11.03 73.29 Example 26 31 32 33 35 36 37 38 <![CDATA[IC 50 (nM)]]> 48.58 9.2 7.6 18.54 419.0 58.8 24.86 6.9 Example 39 40 41 42 43 45 46 47 <![CDATA[IC 50 (nM)]]> 7.4 6.5 42.6 532.9 16.7 18.8 40.2 126.3 Example 48 49 50 52 58 59 60 61 <![CDATA[IC 50 (nM)]]> 7.6 4.5 8.1 6.1 17.8 9.2 832.2 20.8 Example 62 63-A 63-B 64-A 64-B AZD0156 a c <![CDATA[IC 50 (nM)]]> 34.0 31.1 25.5 16.6 13.8 9.87 950.4 183.3 Example d e <![CDATA[IC 50 (nM)]]> 106.2 145.2

[0302] Note: Example 1 herein is the compound of Example 37 of WO 2018 / 127195 A1; Examples a, c, d and e are the compounds of Examples 4, 44, 45 and 47 of WO 2018 / 127195 A1, respectively.

[0303] Therefore, as determined by the MTT assay, the compound of Example 2 and its analogs have a good inhibitory effect on the growth of MDA-MB-468 cells.

[0304] Although the present invention has been fully described, it will be appreciated by those skilled in the art that the same implementation can be performed in a wide range of and equivalent conditions, formulations and other parameter ranges without affecting the scope of the present invention or any embodiment thereof. All patents, patent applications and publications cited herein are incorporated herein by reference in their entirety.

Claims

1. Use of a compound of the following formula IIIa or IIIb, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a mixture thereof in the preparation of a medicament for treating or preventing DDR-mediated or ATM kinase-mediated cancer: in: B1, B3 and B4 are all CH; R1 is selected from C 1-4 Alkyl, optionally substituted with 1-4 C 1-6 Alkyl-substituted tetrahydropyranyl, optionally substituted with 1-4 C 1-6 Alkyl-substituted piperidinyl, optionally substituted with 1-4 C 1-6 Alkyl-substituted morpholinyl and optionally 1-4 C 1-6 Alkyl substituted piperazinyl; R2 is C 1-3 alkyl; R3: NR 11 R 12 Substituted C 1-6 Alkoxy, where R 11 and R 12 are each independently selected from hydrogen and C 1-6 Alkyl, or R 11 and R 12 Together with N, it may be optionally replaced by 1-3 C 1-4 Alkyl-substituted 4- to 8-membered heterocyclic group; -NR 11’ -C 1-6 Alkyl-NR 11’ R 12’ , where R 11’ and R 12’ Each is independently hydrogen or C 1-4 Alkyl; or optionally -NR 11 R 12 A substituted 3- to 8-membered heterocyclic group containing one N, wherein R 11 and R 12 are independently selected from hydrogen or C 1-6 Alkyl, or R 11 and R 12 Together with N, optionally 1-3 C 1-4 an alkyl-substituted 4- to 8-membered heterocyclic group; R6 is hydrogen or C 1-4 Alkyl; and R7, R8, R9 and R 10 are independently hydrogen, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

2. The use according to claim 1, characterized in that R1 is C 1-3 Alkyl, optionally substituted with 1-3 C 1-4 Alkyl-substituted tetrahydropyranyl, optionally substituted with 1-3 C 1-4 Alkyl-substituted piperidinyl, optionally substituted with 1-3 C 1-4 Alkyl-substituted morpholinyl and optionally 1-3 C 1-4 Alkyl substituted piperazinyl.

3. The use according to claim 1, characterized in that R2 is methyl or ethyl.

4. The use according to claim 1, characterized in that R3 is: NR 11 R 12 Substituted C 1-6 Alkoxy, where R 11 and R 12 are each independently selected from hydrogen and C 1-6 Alkyl, or R 11 and R 12 Together with N, it may be optionally replaced by 1-3 C 1-4 Alkyl-substituted azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; -NR 11’ -C 1-6 Alkyl-NR 11’ R 12’ , where R 11’ and R 12’ Each is independently hydrogen or C 1-4 Alkyl; or Optional -NR 11 R 12 Substituted piperidinyl, wherein R 11 and R 12 are independently selected from hydrogen or C 1-6 Alkyl, or R 11 and R 12 Together with N, optionally 1-3 C 1-4 Alkyl substituted azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

5. The use according to claim 1, characterized in that: R6 is hydrogen; and / or R7, R9 and R 10 is hydrogen, R8 is hydrogen, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

6. The use according to claim 1, characterized in that R1 is optionally replaced by 1-2 C 1-6 Alkyl-substituted morpholinyl; R2 is methyl or ethyl; R3 is -NR 11 R 12 Substituted C 1-6 Alkoxy or -NR 11 R 12 A substituted 3- to 8-membered heterocyclic group containing one N, wherein R 11 and R 12 are each independently selected from hydrogen and C 1-6 Alkyl, or R 11 and R 12 Together with N, it forms a 4- to 8-membered heterocyclic group substituted by 1-2 alkyl groups; or R3 is -NR 11’ -C 1-6 Alkyl-NR 11’ R 12’ , where R 11’ and R 12’ Each is independently hydrogen or C 1-4 alkyl; R6 is hydrogen; R7, R9 and R 10 is hydrogen; R8 is hydrogen, halogen or halogenated C 1-4 alkyl.

7. The use according to claim 1, characterized in that The compound of formula IIIb: R1 is C 1-4 Alkyl, optionally with 1-2 C 1-6 Alkyl-substituted tetrahydropyranyl, optionally substituted with 1-2 C 1-6 Alkyl-substituted piperidinyl, optionally substituted with 1-2 C 1-6 Alkyl-substituted morpholinyl and optionally 1-3 C 1-6 Alkyl substituted piperazinyl; R2 is methyl or ethyl; R3 is -NR 11 R 12 Substituted C 1-6 Alkoxy or -NR 11 R 12 A substituted 3- to 8-membered heterocyclic group containing one N, wherein R 11 and R 12 are each independently selected from hydrogen and C 1-6 Alkyl; or R 11 and R 12 Together with N, it forms a 4- to 8-membered heterocyclic group substituted by 1-2 alkyl groups; R6 is hydrogen, halogen or C 1-4 Alkoxy; R7, R9 and R 10 is hydrogen; and R8 is hydrogen, halogen or C substituted by 1-4 halogens 1-4 alkyl.

8. The use according to claim 1, characterized in that The compound is selected from: or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a mixture thereof.

9. The use according to any one of claims 1 to 8, characterized in that The cancer is selected from the group consisting of liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, gastric cancer, colon cancer, malignant pancreatic insulinoma, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, thyroid cancer, esophageal cancer, renal cell carcinoma, endometrial cancer, adrenocortical carcinoma, skin cancer, and prostate cancer.

10. The use according to claim 1, characterized in that The drug further contains at least one anticancer drug selected from the group consisting of busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-Fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, alanosine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, imatinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, temozolomide, everolimus, vorinostat , Romitriptyline, Tamoxifen, Letrozole, Fulvestrant, Mitoguanzone, Octreotide, Retinoic Acid, Arsenic, Zoledronic Acid, Bortezomib, Thalidomide, Lenalidomide, Venetoclax, Aldesleukin, Sipueucel-T, Palbociclib, Olaparib, Niraparib, Rucaparib, Talazoparib, Senaparib, Panitumumab, Necitumumab, Nivolumab, Ramucirumab, Bevacizumab, Pertuzumab, Trastuzumab, Cetuximab, Obituzumab, Ofatumumab, Rituximab, Alemtuzumab, Ibritumomab Tiuxetan, Tositumomab, Brentuximab, Daratumumab, Elotuzumab, Ofatumumab, Dinutuximab, Blinatumomab, and Ipilimumab.

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