Substituted imidazoquinoxaline compounds and uses thereof

Abstract

The disclosure provides substituted imidazo [1, 5-a] quinoxaline and related compounds as kinase inhibitors, and their uses. Specifically, the disclosure provides compounds of Formula I, or pharmaceutically acceptable salts thereof or prodrugs thereof, wherein, A 1-A 3, Cy and R 1-R 2 are defined herein. The compounds of Formula I are kinase inhibitors. Therefore, the compounds of the disclosure can be used to treat clinical conditions caused by DDR function defects, such as cancers. (I)

Description

SUBSTITUTED IMIDAZOQUINOXALINE COMPOUNDS AND USES THEREOF Technical Field This disclosure is in the field of medicinal chemistry. This disclosure especially relates to substituted imidazo[1,5-a]quinoxaline and related compounds, and their uses as kinase inhibitors, including ATM protein kinase inhibitors, and anticancer agents. Background Mammalian cells face a large number of external and internal challenges that cause DNA damage every day, including DNA base mutation These mutations cause changes in cell functions such as developing malignant tumors in mild case and cell death in severe cases. To protect against DNA damage, mammalian cells bave evolved to have a sophisticated DNA damage response (DDR) mechanism. This mechanism detects and repairs DNA damage during short pauses in cell cycle to ensure accuracy in DNA replication and genomic stability, and ultimately cell survival. DDR is closely associated with the occurrence of cancer. Scientific research has found that defects in DDR mechanism can cause cancer at multiple levels. For instance, mutations of DDR genes have been found to lead to the occurrence of a variety of cancers. Women who have mutations in BRCAT or BRCA2 genes, important DDR components to repair DNA double strand breaks via homologous recombination mechanism, have much higher risk to develop breast cancer or ovarian cancer than those who do not have such mutations. Studies also found that deletions or loss of function of DDR proteins that play important roles in cell cycle regulation, such as pS3, ATM, ATR, BRCAL1 / 2 and so on, may lead to a variety of malignancy. In recent years, with the development of science our understanding of the DDR mechanism has improved dramatically. Discovery of novel anticancer agents targeting mutations and loss of function of DDR component proteins has aroused great interest. For example, PARP inhibitors can selectively kill cancer cells with BRCA1 / 2 mutations by inhibiting single strand DNA damage repair pathway. The mechanism of losing functions of two pathways to lead cells death is called synthetic lethality. The protein kinase ataxia-telangiectasia mutated (ATM) is one of the important components in DDR. It belongs to PI3K related serine / threonine protein kinase family. ATM kinase gene was cloned in 1995 when studying telangiectatic ataxia syndrome. ATM gene is located on human chromosome 11q22-23 with a coding sequence of 9168 bases. The ATM gene has 66 exons and the ATM protein has a molecular weight of about 350 kDa. ATM kinase is activated when DNA damage causes double strand breaks. Tt phosphorylates proteins that initiate involved in activation of cell cycle checkpoint, leading to cell cycle arrest. Cells will either repair the damaged DNA or undergo apoptosis (Weber and Ryan, 2016). ATM kinase signaling pathway can be roughly divided into two mechanisms: the typical mechanism that is activated by DNA double strand breaks and the atypical mechanism that is not related to DNA. damage. When DNA double strand breaks are detected, ATM kinases are transported to the position of the breaks and are activated. Although the detailed activation mechanism is still unclear, the activation process includes the division of homodimers into active monomers (Bakkenist et al., 2003), self-phosphorylation at Ser1981 and other amino acids, and acetylation. Activated ATM kinases further phosphorylate downstream substrates including cell cycle checkpoint proteins (such as CHK1 and CHK2), DNA repairing proteins (BRCA1 and RADS1), or proteins of apoptosis pathway (p53). Studies have shown that more than 700 proteins are phosphorylated after DNA double strand breaks (Choi, Kipps and Kurzrock, 2016). For the atypical mechanism, ATM is involved in functions such as metabolism, stress response, etc., that are not directly related to DNA damage (Cremona et al., 2013). The development of new anticancer agents targeting ATM kinase mainly relies on two aspects of consideration. The DDR mechanism greatly reduced the cytotoxicity of radiotherapy or cytotoxic chemotherapeutic drugs, such as topoisomerase inhibitors, DNA methylation drugs, ete., which are targeting rapidly differentiated cancer cells by causing DNA damage. Therefore, agents that inhibit the function of DDR, such as PARP inhibitors and ATM inhibitors, can greatly enhance the efficacy of these drugs and used as combination Gilardini Montani MS et al. (J exp Clin Cancer Res, 2013, 32:95) have shown that reducing ATM expression can enhance the sensitivity of breast cancer cells to PARP inhibitors, which provides a theoretical basis for using ATM inhibitors and PARP inhibitors in combination for the treatment of breast cancer Furthermore, 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 cells to PARP inhibitor Olaparib, and small molecular ATM inhibitor enhanced the sensitivity of p33 inactivated gastric cancer cells to Olaparib. Therefore, the combination of ATM inhibitor and PARP inhibitor may be useful in treating gastric cancer. Accordingly, for cancer cells with DDR function defect, ATM kinase inhibitors may be used as single agent through synthetic lethality mechanism. Anticancer drugs targeting certain mechanism and patient population may have good efficacy and low toxicity. Degorce SL et al. (J Med Chem, 2016, 59: 6281-6292) reported a series of 3-quinoline formamide as ATM kinase inhibitors that had good efficacy in combination with irinotecan in animal models. Genetic and pharmacological evidences have shown that reducing the activity of ATM kinase can reduce the toxicity of mutant Huntington (mHTT) protein in cells and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM may provide a new clinical intervention for the treatment of HD. Leticia TS et al. (J Med Chem, 2019, 62:2988-3008) reported an ATM inhibitor that was able to cross the blood-brain barrier to have good pharmacodynamic (PD) effect that was consistent with the inhibitory effect on ATM kinase in mouse brain, an obvious pharmacokinetic / pharmacodynamic (PK / PD) relationship. Fused heteroaryl compounds bave been disclosed as kinase inhibitors. For example, WO02012034526 disclosed fused heteroaryl compounds as PI3K kinase inhibitors. W02015170081 discloses imidazoquinolinone as an ATM kinase inhibitor. W02018127195 and WO02018153365 disclosed substituted fused heteroaryl compounds as kinase inhibitors, especially as ATM kinase inhibitors. SUMMARY The disclosure provides novel substituted imidazo[1,5-a]quinoxaline compounds as represented in Formula I, Formula II, Formula lla and Formula IIIb as kinase inhibitors, especially as ATM kinase inhibitors. The disclosure also provides pharmaceutical compositions comprising an effective amount of the compounds of Formula I, Formula II, Formula Ia or Formula IIb, for the treatment of cancer. In a particular embodiment, the pharmaceutical composition may also comprise one or more pharmaceutically acceptable carriers or diluters, for the treatment of cancer, In a particular embodiment, the pharmaceutical composition may also comprise at least one known anticancer agent or pharmaceutically acceptable salts thereof, for the treatment of cancer. The disclosure is also directed to methods for the preparation of novel compounds of Formulae I, Formula II, Formula [11a and Formula Hb. DETAILED DESCRIPTION The disclosure found that substituted imidazo[1,5-a]quinoxaline compounds as represented in Formula I have kinase inhibitory activity and can be used as kinase inhibitors, especially as ATM kinase inhibitors. It should be understood that the characteristics of the embodiments described herein can be arbitrarily combined to form the technical solution of this disclosure. The definition of each group herein shall apply to any of the embodiments described herein. For example, the definitions of the substituents of alkyl herein shall apply to any of the embodiments described herein unless the substituents of alkyl are clearly defined in the embodiment. Specifically, the disclosure provides compounds as represented in Formula J} or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates, or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof: Ry 7 as Aq EV il aL 2] As NP wherein, Aj, A; and A; are independently N, CR, CRs and CRs: Cy is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclic group or an optionally substituted cycloalkyl; Ry is an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino, an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl or an optionally substituted heteroaryl; R, is H. an optionally substituted alkyl or an optionally substituted carbocyclic group: Rs, Rs and Rg are independently hydrogen, halogen, alkyl, alkoxy, alkenyl, alkynyl, amino, nitro, cyano, acylamino, acyloxy, hydroxy, sulfhydryl, alkylthio, azido or carboxyl; wherein the alkyl, alkoxy, alkenyl, alkynyl, amino, acylamino, acyloxy, hydroxy, sulfhydryl, alkylthio and carboxyl may be optionally substituted. In compound of Formula [ of each embodiment of the disclosure, preferably, Ay is N or CRs, Aj is N or CRs, Aj is N or CRs. More preferably, A) is CRy, Az is CRs, and Aj is CRs; preferably, Ri, Rs and Rg are independently H, alkyl, alkoxy or halogen; further preferably, Ry and Rs are H, and Rg is H, halogen or alkoxy, In compound of Formula I of each embodiment of the disclosure, 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 the substituent on Cy may be 1, 2,3, 4 or 5, and the substituent includes but is not limited to halogen, alkyl, alkoxy, alkenyl, alkynyl, amino, nitro, cyano, acylamino, acyloxy, hydroxy, sulfhydryl, alkylthio, azido, carboxyl, carbocyclic group, heterocyclic group, aryl ot beteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, amino, acylamino, acyloxy, hydroxy, sulthydryl, alkylthio, carboxyl, carbocyclic group, heterocyclic group, atyl and heteroaryl may be optionally substituted, for example, by 1, 2 or 3 substituents selected from alkyl, aminoalkyl, alkoxy, hydroxy, amino, heterocyclic group, and heteroaryl. Preferably, the amino is NR1iR1, wherein, Ry; and Ry, are independently selected from hydrogen or Cis alkyl, or Ry; and Ry; together with N form a 4 to 8-membered heterocyclic group, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl (such as morpholino), which can be optionally substituted by, such as 1-3 substituents selected from the group consisting of halogen, alkyl and alkoxy. In preferred embodiments, the substituent on Cy is as defined in any of the following embodiments of formulae II, 1ffa and lb. In some embodiments, the substituent on Cy is halogen, an optionally substituted Cy alkyl, an optionally substituted C).s alkoxy, an optionally substituted amino or an optionally substituted heterocyclic group; preferably, the substituent on the alkyl is selected from the group consisting of halogen, hydroxy and amino, preferably halogen; preferably, the substituent on the alkoxy is selected from the group consisting of halogen, hydroxy, heteroaryl (preferably 3 or S-membered nitrogen-containing heteroaryl, such as pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, etc), and amino, preferably amino, preferably, the substituent on the heterocyclic group is selected from the group consisting of Ci4 alkyl, halogen, hydroxy and amino, and the preferred heterocyclic group is a heterocyclic group containing one N and / or one O, including but not limited to tetrahydrofuranyl, morpholinyl (such as morpholino), piperidinyl and pipetazinyl. Preferably, the amino is NR; Ry, wherein Ry; and Ry» are independently selected from hydrogen or Cis alkyl, or R11 and Ry; together with N form a 4 to 8-membered heterocyclic group, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl (such as morpholino), which can be optionally substituted by, such as 1-3 substituents selected from the group consisting of halogen, alkyl and alkoxy. In some preferred embodiments, when Cy is a 6-membered ring, preferably, the substituted Ci. alkoxy, the substituted amino or the optionally substituted heterocyclic group is located at the para position. In compound of Formula I, preferably, Ri is an optionally substituted Cie alkyl, an optionally substituted heterocyclic group or an optionally substituted heteroaryl. Preferred heterocyclic group is a heterocyclic group containing one O and / or one N, such as tetrahydropyranyl, morpholinyl (such as morpholino), piperidinyl and piperazinyl. Preferred heteroaryl is a heteroaryl containing one to three nitrogen atoms, such as pyridyl. The substituent on the heterocyclic group and the heteroaryl is preferably one or more (such as 1-3) groups selected from the group consisting of hydroxy, Cj.4 alkyl, amino, halogen, Ci. alkoxy and carboxyl, more preferably C,. alkyl, halogen and C4 alkoxy. The substituent on the Ci alkyl may be one or more (such as 1-3) groups selected from the group consisting of amino, hydroxyl, halogen and C4 alkoxy. In compound of Formula 1, preferably, R; is an optionally substituted Cio alkyl, preferably Ci alkyl, more preferably Ci alkyl, including but not limited to methyl, ethyl, propyl and isopropyl. When R; is an optionally substituted carbocyclic group, preferred R; is an optionally substituted Cag cycloalkyl; the substituent on the carbocyclic group is preferably 1 or 2 substituents selected from the group consisting of hydroxy, halogen, amino, Ci alkyl, Ciy alkoxy and carboxyl. In compound of Formula I, preferably, Ri, Rs and Rs are independently selected from H, alkyl, alkoxy or halogen. Compounds of Formula I preferably have the structure as represented in the following Formula II: Ry N Rey#Pong, = 8 Ay NZ Ry YY J Ae oh = hs NA AZ ON hi wherein Aj, A; and Aj; are independently N, CR4, CRs and CR: Bi, Ba, B; and B; are independently N, CR5, CRs, CRy and CRyg; R; is an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino, an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl or an optionally substituted heteroaryl; R; is an optionally substituted alkyl or an optionally substituted carbocyclic group; Rs; is hydrogen, alkyl, alkoxy, amino, carbocyclic group, heterocyclic group, aryl or heteroaryl, wherein the alkyl, alkoxy, amino, carbocyclic group, heterocyclic group, aryl or heteroaryl may be optionally substituted. Ri, Rs, Re, Ra, Rs, Ry and Rig are independently hydrogen, halogen, alkyl, alkoxy, alkenyl, alkynyl, amino, nitro, cyano, acylamino, acyloxy, hydroxy, sulfhydryl, alkylthio, azido or carboxyl; wherein the alkyl, alkoxy, alkenyl, alkynyl, amino, acylamino, acyloxy, hydroxy, sulfhydryl, alkylthio and carboxy! may be independently optionally substituted. In compound of Formula II, preferably, A; is N or CRq4, A; 1s N or CRs, As is N or CRg In compound of Formula II, preferably, B) is N or CRs, By is N or CRg, Bs is N or CRy; and Bs is Nor CRyp. In compound of Formula 11, preferably, A;, A; and Aj are independently CRs, CRs and CRg, Tn some embodiments, one of Aj, Ay and A; is N, the others are two groups selected from the group consisting of CR4, CRs and CRs. In some embodiments, Ai is N, Az and A; are CRs and CR, respectively; or Az is N, Aj and Az are CR; and CRs, respectively; or Az is N, Aj and A; ate CR4 and CRs, respectively. Preferred Rs, Rs and Rg are independently hydrogen, halogen, Ci alkyl, Ci4 alkoxy or halogenated C4 alkyl, more preferably independently hydrogen, halogen or C4 alkoxy. In preferred embodiments, Ry and Rs are independently hydrogen or C,.; alkyl, more preferably hydrogen; Re is hydrogen, halogen or C1. alkoxy. In some preferred embodiments, Aj, Az and Az are CRy, CR; and CRg, respectively, and Ry, Rs and Re are hydrogen; in some other preferred embodiments, Ry and Rs are hydrogen, Rg is halogen or C4 alkoxy. In compound of Formula Il, preferably, one of By, By, Bs and Bs is N, for example, the ring containing Bi, Ba, B; and By is pyridine ring; preferably, B; is N, the others are three groups selected from CRy, CRs, CRy and CR jg, more preferably By, B; and Bs are CR7, CRq and CRyg, respectively; preferably, in these embodiments, Rv, Rs, Ro and Ry are independently hydrogen, halogen, C4 alkyl, C4 alkoxy and halogenated Cy alkyl, more preferably Rs, Rs, Re and Ryo are hydrogen. In some embodiments, By, Bz, Bz and Bs are CR+, CRg, CRs and CR, respectively, which means that the ring containing By, Bj, By and By is phenyl ring that may be optionally substituted. Preferably, Ry, Rs, Ro and Ry are independently hydrogen, halogen, C4 alkyl, Ci alkoxy and halogenated Ci alkyl. More preferably, at least one of Ry, Rg, Rs and Ryo is not hydrogen; preferably, Rg is not hydrogen, and is preferably selected from halogen and halogenated C;.4 alkyl In some embodiments, B:, By, By and B; are CR, CRs, CRy and CRyq, respectively; Ry is not hydrogen, for example, is halogen, Ci alkoxy or halogenated C14 alkyl; Ry, Ry and Rip are hydrogen, Ri of compound of Formula II is preferably selected from the group consisting of an optionally substituted Ci. alkyl, an optionally substituted heteroaryl and an optionally substituted heterocyclic group. Preferred alkyl is C5 alkyl, such as methyl, ethyl, and isopropyl. Preferred heteroaryl is a heteroaryl containing one to three nitrogen atoms, such as pyridyl. Preferred heterocyclic group is a heterocyclic group containing one O and / or one N, such as tetrahydrofuranyl, morpholinyl (such as morpholino), piperidinyl and piperazinyl. In preferred embodiments, the optionally substituted heterocyclic group is tetrahydro-2H-furan-4-yl, 1- morpholinyl, piperidin-1-yl or piperazin-1-yl. The substituent on the heteroaryl or the heterocyclic group is preferably one or more (such as 1-3) groups selected from a group consisting of hydroxy, C4 alkyl, amino, halogen, C4 alkoxy and carboxyl, more preferably C).4 alkyl, halogen and C4 alkoxy. Preferably, the substituent(s) are located at the meta position and / or para position when the heteroaryl or the heterocyclic group is a 6-membered ring. The substituent on the Cys alkyl may be one or more (such as 1-3) groups selected from the group consisting of amino, hydroxyl, halogen and C4 alkoxy. In some preferred embodiments, R) is unsubstituted isopropyl; in some preferred embodiments, R; is unsubstituted tetrahydrofuranyl; in some preferred embodiments, R, is morpholinyl that is optionally substituted by 1 or 2 C4 alkyls, preferably the substituent(s) are located at the meta position; in some preferred embodiments, R; is piperidinyl or piperazinyl that is optionally substituted by 1-3 Ci alkyls, preferably the substituent(s) are located at the para position and / or meta position. In some embodiments, R; of compound of Formula IT is preferably an optionally substituted heteroaryl. Exemplary heteroaryl includes but is not limited to heteroaryl containing 1-3 nitrogen ators, such as pyridyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl and pyrimidinyl, etc; exemplary substituents include but are not limited to halogen, Ci.4 alkyl and Cys alkoxy. Exemplary R; is selected from: oN MN oN 0X o\ oN ~N Fg Fd 5 > ; nl i t el 7 od / 7 i —, PF Ld, o- NAL NN NN TN TN TIN NN mn TA HNN NTN NTN “Nd Ad and R: of compound of Formula II is preferably Cio alkyl, more preferably Cis alkyl, more preferably C4 alkyl, including but not limited to methyl, ethyl, propyl and isopropyl. When R; of compound of Formula II is an optionally substituted carbocyclic group, preferred Ry is an optionally substituted Ca. cycloalkyl; the substituent on the carbocyclic group is preferably 1 or 2 substituents selected from the group consisting of hydroxy, halogen, amino, Ci alkyl, Ciy alkoxy and carboxyl. When R; of compound of Formula II is substituted, the number of the substituent is preferably 1, 2 or 3; preferred substituent is selected from Cj4 alkyl, C4 alkoxy, halogen, hydroxy, amino, and heteroaryl. Preferred R; is an optionally substituted C,4alkyl, an optionally substituted Cp. alkoxy, an optionally substituted amino or an optionally substituted heterocyclic group, more preferably a substituted Cre alkoxy, a substituted amino or a substituted heterocyclic group. More preferred Rj is a substituted Cy alkoxy, -NRy;-C16 alkyl-NR11-R;2 or a substituted heterocyclic group, wherein Ry; and Ry are independently selected from the group consisting of H and Ci alkyl or they together with N form 4 to 8-membered heterocyclic group, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl (morpholino), which can be optionally substituted by, such as 1-3 substituents selected from the group consisting of halogen, alkyl and alkoxy. Preferably, the substituent on the alkoxy is selected from the group consisting of halogen, hydroxy, 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 C4 alkyl, halogen, hydroxy and amino, preferably the heterocyclic group is a heterocyclic group containing one N and / or one O, including but not limited to tetrahydrofuranyl, morpholinyl, piperidinyl and piperazinyl. Preferably, the amino is NR; Ry, wherein, Ry and Ry; are independently selected from hydrogen or Ci. alkyl, or Ri and Ry; together with N form 4 to 8-membered heterocyclic group, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl (morpholino), which can be optionally substituted by, such as 1-3 substituents selected from the group consisting of halogen, alkyl and alkoxy. Exemplary Raz is selected from: HaN _~_.0O«, H N_~_0Ou, SO Ny O.. N O.. SNe a \ eS hn 4 N 0. N. QO. N 0. N 0. Sao Va AYN \ AN NA oN Oo NN oN TT oN Y ) . g \ ~ Soo NSO i NY NNO So Thou N 0. N O N O. SNS SNES xr J 1 i H | | so-N~UO., SoM. No A~UNL, UN A~UNG ; H I I, ~ HN. NY NY ; H | § Ril so-N~UO., SoM. No A~UNL, UN A~UNG sN SN H H H ’ ; TO } N N N N N « N Ww N. WW N. “w NN. Ww No 1 | 1 1 1 1 1 i 1 ENG “Ne, “No. “Ne, Co “UN. “Na *. and In the specially preferred compounds of Formula II, R; is C14 alkyl, and the other groups are as described in any of the above embodiments. One group of the preferred compounds of the disclosure is represented as compounds of Formulae lla and IIb or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates thereof or pharmaceutically acceptable salts thereof, or mixtures thereof or prodrugs thereof: oe Ry B®. SE Ry Ry T=N N Rip — ) XC D- 2 f Ne=N -~ Bi. / . ~ S . Rs. = Bs . , ~ | ~ I Ns bP : IY Nay, | : IIa “CC Rg wherein By, Ba, Bs, Ri, Ro, Ra, Rs, Rg, Ry and Ry are as defined in Formula I or II; Re is hydrogen, halogen, alkyl or alkoxy. In one or more embodiments of compounds of Forroulae IT1a and IIb, the By, Bs, By, Ry, Ry, Rs, Ry, Rg, Ro and Ryo are as described in any one of the foregoing embodiments of Formula IT or 11, respectively. In one or more of the foregoing embodiments of compounds of Formulae Ta and IIb, R; is Cy; alkyl, preferably methyl In one or more of the foregoing embodiments of compound of Formula Illa, B,, B; and By are CRy, CRy and CRyg, respectively; Rz, Re and Ryo are independently hydrogen, halogen, Cis alkyl or halogenated C14 alkyl. Preferably, Ry, Re and Ryo are all hydrogen. In one or more embodiments of compound of Formula IIIb, Ry is hydrogen, halogen, Ci4 alkoxy, Cis alkyl or halogenated C,.4 alkyl, preferably, Rg is halogen, C4 alkoxy and halogenated Ci.q alkyl. Preferably, Rs, Ro and Rye are independently hydrogen, halogen, Ci. alkyl or halogenated C1.4 alkyl, preferably hydrogen In one or more of the foregoing embodiments of compounds of Formulae Illa and IIIb, Ry is an optionally substituted Cs alkyl, an optionally substituted heteroaryl or an optionally substituted heterocyclic group. Preferred alkyl is Cis alkyl, such as isopropyl Preferred heteroaryl is a heteroaryl containing one to three nitrogen atoms, such as pyridyl. Preferred heterocyclic group is a heterocyclic group containing one O and / or one N, such as tetrahydrofuranyl, morpholinyl (such as morpholino), piperidinyl and piperazinyl. In preferred embodiments, the optionally substituted heterocyclic group is tetrahydro-2H-furan-4-yl, 1- morpholinyl, piperidin-1-yl or piperazin-1-yl. The substituent on the heteroaryl and the heterocyclic group is preferably one or more (such as 1-3) groups selected from hydroxy, Cj. alkyl, amino, halogen, C14 alkoxy and carboxyl, more preferably Ci alkyl, halogen and Cig alkoxy. Preferably, the substituent(s) are Jocated at the meta position and / or para position when the heteroaryl or the heterocyclic group is a 6-membered ring. The substituent on the Cy.¢ alkyl may be one or more (such as 1-3) groups selected from the group consisting of amino, hydroxyl, halogen and Ci. alkoxy. In some preferred embodiments, Ry is unsubstituted isopropyl; in some preferred embodiments, Ry is unsubstituted tetrahydrofuranyl; in some preferred embodiments, R, is morpholiny! that is optionally substituted by 1 or 2 Cy. alkyls, preferably the substituent(s) are located at the meta position; in some preferred embodiments, Ry is piperidinyl or piperazinyl that is optionally substituted by 1-3 Ci4 alkyls, preferably the substituent(s) are located at the para position and / or meta position. Exemplary Ry is selected from: oN MN oN 0X 0 oN hh: Fo 5 5 > rN i if t ul i dL 7 / 7 F —, 2X hat, o ~0 MAL NN NN TNNG TN TIN NN mn wl TN HANTN NTN NTN on dl Ad and In one or more of the foregoing embodiments of compound of Formula Illa, the ring containing By, Bs and By is optionally substituted pyridine ring. It should be understood that, in this disclosure, in addition to Rs, the substituents on the ring containing B,, Bs and By may also include Ry, Rg and Rye. Preferred Ry, Rg and Ry are independently selected from halogen, Ci alkyl and halogenated Cy.4 alkyl In one or more of the foregoing embodiments of compounds of Formulae I1la and IIIb, when Rj is substituted, the number of the substituent is preferably 1-3; preferred substituent is selected from Cig alkyl, Ci4 alkoxy, halogen, hydroxy, amino and heteroaryl. Preferred Rs is an optionally substituted Ci. alkyl, an optionally substituted C14 alkoxy, an optionally substituted amino, or an optionally substituted heterocyclic group. More preferred Rs is a substituted Cis alkoxy, -NR11-C1.6 alkyl-NRi1R12- or a substituted heterocyclic group, wherein Rip and Rip are independently selected from the group consisting of H and Cy. alkyl or they together with N form 4 to 8-membered heterocyclic group, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl (morpholino), which can be optionally substituted by, such as 1-3 substituents selected from the group consisting of halogen, alkyl and alkoxy. Preferably, the substituent on the alkoxy is selected from halogen, hydroxy, 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 Ci. alkyl, halogen, hydroxy and amino, preferably the heterocyclic group is heterocyclic group containing one N and / or one O, including but not limited to tetrahydrofuranyl, morpholiny], piperidinyl and piperazinyl. Preferably, the amino is NRyRiz, wherein, Rj; and Ryz are independently selected from hydrogen or Cre alkyl, or Ry and Riz together with N form a 4 to 8-membered heterocyclic group, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl (morpholino), which can be optionally substituted by, such as 1-3 substituents selected from the group consisting of halogen, alkyl and alkoxy. Exemplary R; is selected from: H o., N Oo, Soe J SY NH HN SE A ss HaN On ANON H | 1 1 | | | ~ooNa~UO, oN LO, NN _A~_O., CN (TW oo, \ SoMa Be N sooNAA o., NN oN . | soNeAUO, 0 M “0 ‘li NO NN On, So NOs hN~LO., SNES NTN SN Ho . Co i . NN | i NAAN 1 3 y Tr | i | | H | § | NAO SooNoe NAN NANG, ~oNs H H “oN NTS H H H | ; A SN SNS A A CN wah Pb ak ro a oa 3 | i | i 1 1 1 i I 1 So-Na. ooNa “Ne, So-Na “UN. Pg”. aE, iar Trt and Ch + « N In one or more of the foregoing embodiments of compounds of Formulae 11a and IIIb, Ry is hydrogen, halogen and Cy.s alkoxy. Preferably, Ry is hydrogen. In one or more of the foregoing embodiments of Formulae I, IT, [Ta and Tb, the optionally substituted alkyl, alkoxy, amino, carbocyclic group, heterocyclic group, aryl or heteroaryl for Ry may be substituted by one or more substituents selected from the substituents for the alkyl, alkoxy, amino, carbocyclic group, heterocyclic group, aryl or heteroaryl described herein. In one or more of the foregoing embodiments of Formulae I, I, Ila and IIb, the optionally substituted alkyl, alkoxy, amino, carbocyclic group, heterocyclic group, aryl or heteroaryl for Rs may be substituted by one or more substituents selected from the substituents for the alkoxy, amino, carbocyclic group, heterocyclic group, aryf or heteroaryl described herein. Tn one or more of the foregoing embodiments of Formulae II, Ila and IIb, the substituent(s) of the optionally substituted alkyl, alkoxy, alkenyl, alkynyl, amino, acylamino, acyloxy, hydroxy, sulfydryl, alkylthio or carboxyl for Ry, Rs, Rs, Rs, Rg, Rg and Ry is selected from one or more substituents for the alkyl, alkoxy, alkenyl, alkynyl, amino, acylamino, acyloxy, hydroxy, sulfydryl, alkylthio or carboxyl described herein. In one or more of the foregoing embodiments of Formula 1ltb, the substituent(s) of the optionally substituted alkyl, alkoxy, alkenyl. alkynyl, amino, acylanino, acyloxy, hydroxy, sulfydryl, alkylthio or carboxyl for Ry, Rs, Ro and Ry is selected from one or more substituents for the alkyl, alkoxy, alkenyl, alkynyl, amino, acylamino, acyloxy, hydroxy, sulfydryl, alkylthio or carboxyl described herein. In one or more preferred embodiments of Formulae II, Ila and IIb: Aj, A; and As are CRs, CRs and CRe, respectively, wherein, Rs, Rs and Rg are independently hydrogen, halogen, Cia alkyl, C14 alkoxy or halogenated C1. alkyl, preferably independently hydrogen, halogen and Ci. alkyl, more preferably Ry and Rs are H, Re is H, halogen or alkoxy; the ring containing By, By, Bs and By (Formula II) or the ring containing B;, Bs and Bi (Formula [Ifa) is optionally substituted pyridine ring or optionally substituted phenyl ring, wherein, Ry, Rs, Ry and Ry are independently selected from hydrogen, C,. alkyl, halogen and halogenated C4 alkyl, preferably independently halogen and halogenated C4 alkyl, more preferably Rs, Ry and Ry are H, Ry is halogen or halogenated C14 alkyl; R; is an optionally substituted Ci. alkyl, heteroaryl or heterocyclic group that is optionally substituted by 1-4 Cig alkyls, preferably selected from Cig alkyl, tetrahydropyranyl that is optionally substituted by 1-4 Ci alkyls, piperidinyl that is optionally substituted by 1-4 Ci alkyls, morpholinyl that is optionally substituted by 1-4 C4 alkyls and piperazinyl that is optionally substituted by 1-4 C5 alkyls; Rs is Cy alkyl, preferably Ci. alkyl, more preferably methyl: Rj is selected from Cr. alkyl that is optionally substituted by -NRj Ria, Crs alkoxy that is optionally substituted by ~NRi;Ryz, and heterocyclic group that is optionally substituted by -NR; R12, wherein, Ry; and Ry, are independently selected from hydrogen or Cis alkyl; or Ry; and Ry, together with N form 4 to 8-membered heterocyclic group that can be optionally substituted, such as azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl (such as morpholino), piperazinyl. Preferably, Re is hydrogen, halogen or Cs alkoxy. In one or more of embodiments of Formula 11a: Bi, B3, and Byare CH; Ri is a heterocyclic group optionally substituted by 1-2 substituents selected from the group consisting of Cr alkyl, preferably Ry is morpholinyl (such as morpholino) optionally substituted by 1-2 C4 alkyls; R, is C4 alkyl, preferably methyl; Rj is a Crs alkoxy optionally substituted by -NRy Ry, or a heterocyclic group optionally substituted by -NRyRp2, wherein Ry; and Ris are independently selected from hydrogen or Cig alkyl or Rjy and Rip together with the N atom form a 4 to 8-membered heterocyclic group (such as azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl (such as morpholino), piperazinyl) optionally substituted by 1-2 alkyls; preferably the heterocyclic group optionally substituted by ~ NRyR;2 is a piperidiny! or a piperazinyl with their ring nitrogen atom linking to the rest of the compound, which preferably is substituted by the -NR(1R1; group; and Rs 1s hydrogen, halogen or C14 alkoxy, preferably hydrogen. In one or more of embodiments of Formula IIb R, is a heterocyclic group optionally substituted by 1-2 substituents selected from the group consisting of Cys alkyl, preferably R, is morpholiny! (such as morpholino) optionally substituted by 1-2 C15 alkyls; Ry is Ci.4 alkyl, preferably methyl; Rs is a Cie alkoxy optionally substituted by -NRyRyz, or a heterocyclic group optionally substituted by -NRj Riz, wherein Ry, and R)z are independently selected from hydrogen or C5 alkyl or Ry and R;» together with the N atom form a 4 to 8-membered heterocyclic group (such as azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl (such as morpholino), piperazinyl) optionally substituted by 1-2 alkyls: preferably the heterocyclic group optionally substituted by - NRiRy; is a piperidinyl or a piperazinyl with their ring nitrogen atom linking to the rest of the compound, which preferably is substituted by the -NR11R1: group; Rg is hydrogen, halogen or C4 alkoxy, preferably hydrogen; and Ry, Roand Rj are H. 1n one or more of embodiments of Formula IIb: Ri is a Ci. alkyl, a heteroaryl optionally substituted by 1-3 substituents selected from the group consisting of halogen, Ci.4 alkyl and Cys alkoxy, or a heterocyclic group optionally substituted by 1-2 substituents selected from the group consisting of Cys alkyl, preferably R; 1s C4 alkyl, tetrahydropyrany! optionally substituted by 1-2 Cis alkyls, piperidinyl optionally substituted by 1-2 Cy. alkyls, morpholinyl optionally substituted by 1-2 Ci alkyls, pyridyl optionally substituted by 1-2 substituents selected from the group cousisting of halogen and C4 alkoxy, or piperazinyl optionally substituted by 1-3 Cy. alkyls; R; is Cig alkyl, preferably Ci alkyl, more preferably methyl; R: 1s Cre alkoxy optionally substituted by -NRuR:, -NRii-Cre alkyl-NRj Ri» or heterocyclic group optionally substituted by -NRiiR1z, wherein Rip and Ry are independently selected from the group consisting of H and C4 alkyl, Ry and R;; are independently selected from hydrogen or Ci alkyl or Ry; and Ry; together with N form 4 to 8-membered heterocyclic group (such as azetidinyl, pyrrolidinyl, piperidinyl, and morpbolinyl (such as morpholino), piperazinyl) optionally substituted by 1-2 alkyls, preferably the heterocyclic group optionally substituted by -NR;:R,; is a piperidinyl or a piperazinyl with their ring nitrogen atom linking to the rest of the compound, which preferably is substituted by the -NR;R; group; Rs is hydrogen, halogen or C4 alkoxy; R;, Ry and Rip are H; and Rg is H, halogen, C4 alkyl substituted by 1-4 halogen, or C|.; alkoxy. In one or more of the foregoing embodiments, the preferred compound examples of Formula 1. Formula II, Formula Illa and Formula [Tb include bat are not limited to: N,N-dimethyl-3~(4-(1 «(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-§- vi)phenoxy)propan-1-amine (Example 1); N,N-dimethyl-3~((5-(3~methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[ 1,5 -a]quinoxalin-8- vhypyridin-2-y1l)oxy)propan-1-amine {Example 2); N,N-dimethyl-3~(4-(3-methyl-1 -(tetrahydro-2H-pyran-4-yDimidazo[1,5 -a]quinoxalin-8- yl)phenoxy)propan-1-amine (Example 3); 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-anine (Example 4); N,N-dimethyl-3-(4-(3-methyl-1 -(tetrahydro-2H-pyran-4-y})imidazo[1,5-a}quinoxalin-8-yl)- 2-(trifluoromethyl)phenoxy)propan-1 -amine (Exaraple 5); N,N-dimethyl-1-(2-fluoro-4-(3-methyl-1 (tetraby dro-2H-pyran-4-yl)imidazo[1,5- a]quinoxalin-8-yl)phenyl)piperidin-4-amine (Example 6); 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); N,N-dimethyl-1-(4-(3-rethyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)- 2-~(trifluoromethyl)phenylpiperidin-1-amine (Example 8); 1-(4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl}jimidazo[1,5-a]quinoxalin-8-yl)-2- (trifluoromethyl)pheny)piperidin-4-amine (Example 9); 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); N-ethyl-1-(4-(3-methyl-1-(tetrabydro-2H-pyran-4-yl)imidazo|[1,5-a]quinoxalin-8-y1)-2- (trifluoromethyl)phenyl)piperidin-4-amine (Example 11); 3-methyl-8-(6-(3-(piperidin-1 yl) propoxy)pyridin-3yl)-1 -(tetrahy dro-2H-pyran-4- yhimidazo|1,5-a}quinoxaline (Example 12); 8-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5- a]quinoxaline (Example 13); N,N-dimethyl-3-((5-(3-methyl-1-morpholinylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2- yhoxy)propan-1 -amine (Example 14); N,N-dimethy!-3-((5-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[1,5- a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine (Example 15); N,N-dimethy|-3-((5~(3-methyl-1-(piperidin-1-yl)imidazo[1,5-a}quinoxalin-8-yl)pyridin-2- vl)oxy)propan-1-amine (Example 16); N,N-dimethyl-3~((5-(3-methyl-1-(4-methylpiperazin-1-yl)imidazo[1,5-a]quinoxalin-8- yhpyridin-2-yl)oxy)propan-1 -amine (Example 17); N.N-dimethyl-3-((5-(3-methyl-1-((35,5R)-3,4,5 trimethylpiperazin-1 -yl)imidazo[1,5- a]quinoxalin-8-yl)pyridin-2-yl)oxy }propan-1 -amine (Example 18); N,N-dimethyl-3-((5-(1-isopropyl-3-methylimidazo{1,5-a]quinoxalin-8-y1)pyridin-2- yhoxy)propan-1 -amine (Example 19); N,N-dimethyl-3-(2-fluoro-4-(1 -isopropyl-3-methylimidazo[1,5-a]quinoxalin-8- yhphenoxy)propan-1-amine (Example 20); N,N-dimethy|-3-(4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2- (trifluoromethyl)phenoxy)propan-1-amine (Example 21); 1-isopropyl-3-methyl-8-(6-(3(piperidin-1-yl)propoxy)pyridin-3yl)imidazo[ 1,5- a]quinoxaline (Example 22): 7-fluoro-1-isopropyl-3-methyl-8-(6-(3-(piperidin-1 yl)propoxy)pyridin-3yl}imidazo[1,5- a]quinoxaline (Example 23); N,N-dimethyl-1-(2-fluoro-4-(1 -isopropyl-3-methylimidazo[1,5-a]quinoxalin-8- vl)phenyl)piperidin-4-amine (Example 24); N,N-dimethyl-1-(2-chloro-4~(1 -isopropyl-3-methylimidazo[1,5-a] quinoxalin-8- yDphenyl)piperidin-4-amine (Example 25); N.N-dimethyl-1-(4~(1-isopropyl-3-methylimidazo[ 1,5 -a]quinoxalin-8-yl)-2- (trifluoromethyl)phenyl)piperidin-d4-amine (Example 26); 1-(4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2- (trifluoromethyl)phenyl)piperidin-4-amine (Example 27); N-methyl-1-(4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-y1)-2- (trifluoromethyl)pbhenyl)piperidin-4-amine (Exaraple 28); N-ethyl-1-(4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2- (trifluoromethyl)phenyl)piperidin-4-amine (Exaraple 29); 8-(1,3-dimethyl-4H-11*-pyrazol-4-y1)-1-(3-fluoro-5-methoxypyridin-4-yl)-7-methoxy-3- methylimidazo[1,5-ajquinoxaline (Example 30); (28,6R)-4-(8~(6-(3-(azetidin-1-yl)propoxy)pyridin-3-yl)-3-methylimidazof1,5-a]quinoxalin- 1-y1)-2,6-dimethvlmorpholine (Example 31); (28,6R)-2,6-dimethyl-4-(3-methyl-8-(6-(3 -(pyrrolidin-1 -yl)propoxy)pyridin-3- yhimidazo[l,5-a]quinoxalin~-1-yl)morpholine (Example 32); (28,6R)-2,6-dimethyl-4-(3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3- vhimidazo[1,5-ajquinoxalin-1-yl)morpholine (Example 33); (28,6R)-4-(8-(6-(2-(1H-imidazol-2-yl)ethoxy)pyridin-3-yl)-3-methylimidazo[1,5- a]quinoxalin-1-yl)-2,6-dimethvimorpholine (Example 34). (2S,6R)-4-(8-(6~-(2-(1H-imidazol-4-yl)ethoxy)pyridin-3-yl)-3-methylimidazo[1,5- a]quinoxalin-1-y1)-2,6-dimethy morpholine (Example 35); 2-((5-(1-((28,6R)-2.6-dimethyImorpholino)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridio- 2-yDoxy}-N.N-dimethylethan-1-amine (Example 36); 3-((4-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[ 1,5-a]quinoxalin-8-yl)-2- (trifluoromethyl )phenoxy)-N,N-dimethylpropan-l -amine (Example 37); 1-(5-(1-((28,6R)-2,6-dimethylmorpholino)-3 -methylimidazo[ 1,5-a]quinoxalin-8~yl)pyridin- 2-y1)-N N-dimethylpiperidin-4-amine (Example 38); 1-(4-(1-((28,6R)-2,6-dimethylmorpholino)-3 -methylimidazo[1,5-a]quinoxalin-8-yI)-2- fluorophenyl)-N,N-dimethylpiperidin-4-amine { Example 39); 1-(2-chloro-4-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[1,5-a]quinoxalin-8- vl)phenyl)-N.N-dimethylpiperidin-4-amine (Example 40); 3-((5-(1-((28.6R)-2.6-dimethylraorpholine)-3-ethylimidazo[ 1,5-a}quinoxalin-8-yl)pyridin-2- vl)oxy)-N,N-dimethvlpropan-1-amine (Example 41); 3-((5~(1-((28S,6R)-2,6-dimethyImorpholino)-3-isopropylimidazo[1.5-a] quinoxalin-8- vl) pyridin-2-yl)oxy)-N,N-dimethylpropan-1-amine (Example 42); 3-((5~(1-((2S,6R)-2,6-dimethyImorpholino)imidazo[ 1,5-a]quinoxalin-8-yl)pyridin-2- yhoxy)-N,N-dimethylpropan-1-amine (Example 43); N.N-dimethyl-3-((5-(1-((38,5R)-3 4,5-trimethylpiperazin-1-yl)imidazo[1,5-aJquinoxalin-8- vDpvridin-2-yl)oxy)propan-1-amine (Example 44); 1-(5-(1-((28,6R)-2,6-dimethylmorpholinojimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-y1)-N,N- dimethylpiperidin-4-amine (Example 45); N 48 ~(1~((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[ 1,5-a]quinoxalin-8- vl)pyridin-2-y1)-N’? N*-dimethylpropane-1,3-diamine (Example 46); N51 -((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[1,5-a]quinoxalin-8- yl)pyridin-2-y1)-N' N* N'-trimethylpropane-1,3-diamine (Example 47); 1-(5-(1-((28,6R)-2,6-dimethylmorpholino)-3 -methylimidazo[ 1,5-a]quinoxalin-8-yDpyridin- 2-yDpiperidin-4-amine (Example 48); 1-(5-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[ 1,5-a]quinoxalin-8-ypyridin- 2-y1}-N-methylpiperidin-4-amine (Example 49); 1-(5-(1-((28,6R)-2,6-dimethylmorpholino)-3 -methylimidazo[ 1,5-a]quinoxalin-8-yl)pyridin- 2-y1)-N-ethylpiperidin-4-amine (Example 50); 1-(5-(1-((28,6R)-2,6~dimethylmorpholino)-3-methylimidazo[ 1,5-a]quinoxalin-8-y1)pyridin- 2-yl)-N-isopropylpiperidin-4-amine (Example 51); (28,6R)-4-(8-(6-(4-(azetidin-1-yl)piperidin-1-yl)pyridin-3-yl)-3-methylimidazo[1,5~ a]quinoxalin-1-yl)-2,6-dimethvimorpholine (Example 32). 3-((5-(1-((2S.6R)-2,6-dimethylmorpholino)-3-methy limidazo{1,5-a]quinoxalin-8-yl)pyridin- 2-vDoxy)propan-1-amine (Example 53); 3-((5-(1-((28.6R)-2.6-dimethylraorpholine)-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin- 2-yDoxy}-N-methylpropan-1-amine (Example 54); 3-((5-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazof1,5-a]quinoxalin-8-yl)pyridin- 2-yl)oxy)-N-ethylpropan-1 -amine (Example 35); 3-((5-(1-((28,6R)-2,6~dimethylmorpholino)-3-methy iraidazo[1,5~a]quinoxalin-8-yl)pyridin- 2-yD)oxy)-N-ethyl-N-methylpropan-1 -amine (Example 56); 3-((5-(1-((28,6R)-2,6-dimethyImorpholino)-3-methylimidazof1,5-a]quinoxalin-8-yl)pyridin- 2-yl)oxy)-N,N-diethylpropan-1-amine (Example 57); (28,6R)-2,6-dimethyl-4~(3-methyl-8-(6-(3-morpholinopropoxy)pyridin-3-yl}imidazo[1,5- a]quinoxalin-1-yl)morpholine (Example 58): (28.6R)-2,6-dimethyl-4-(3-methyl-8-(6-(3-(4-methylpiperazin-1-yl)propoxy)pyridin-3- vyl)imidazo|1,5-a}quinoxalin-1-yl)morpholine (Example 59); (28,6R)-2,6-dimethyl-4-(3-methyl-8-(6-(2~(4-methylpiperazin-1-yl)ethyl)pyridin-3- vylimidazo[1,5-a]quinoxalin-1-yl)morpholine (Example 60); 3-(4~(1-((28,6R)-2,6-dimethylmorpholino)-3 -methylimidazo[ 1,5-a]quinoxalin-8-yl)-2- fluorophenoxy)-N,N-dimethylpropan-1 -amine (Example 61); 3-(2~chloro~-4-(1-((28,6R)-2,6-dimethy morpholino) -3 -methylimidazo[1,5-a]quinoxalin-8~ vl)phenoxy)-N,N-dimethylpropan-1-amine { Example 62); 1-(5-(1-((2R.6R)-2,6-dimethylmorpholino)-3 -methylimidazo[1,5-a]quinoxalin-8-yl)pyridin- 2-y1)-N,N-dimethylpiperidin-4-amine and 1-(5-(1~((2S,68)-2,6-dimethylmorpholino)-3- methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2-y1)-N,N-dimethylpiperidin-4-amine (Example 63); 3-((5-(1-((2R,6R)-2,6-dimethylmorpholino)-3-methylimidazo[1,5-a}quinoxalin-8-yl)pyridin- 2-yDoxy)-N,N-dimethylpropan-1-amine and 3-((5-(1-((25,65)-2,6-dimethylmorpholino)-3- methylimidazo[1,5-ajquinoxalin-8-yl)pyridin-2-yl)oxy)-N,N-dimethylpropan-1-amine (Example 64); or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates, or pharmaceutically acceptable salts thereof, or mixtures thereof or prodrugs thereof. The term “hydrogen (H)” as employed herein includes its isotopes D and T. The term “alkyl” as used berein refers to alkyl itself or a straight or branched chain radical of up to ten carbons. Useful alkyl groups include straight-chain or branched Ci. alkyl groups, preferably Ci, alkyl groups, such as Cis alkyl groups. Typical Ci. alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec butyl, tert-butyl, 3-pentyl, hexyl! and octyl groups. Alkyl may be optionally substituted by one or more substituents as defined herein. The term “alkenyl” as used herein refers to a straight or branched chain radical of usually 2- 10 carbon atoms, having at least one double bond in the chain. Typical alkenyl groups include ethenyl, 1 -propeuyl, 2-propenvl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. The term “alkynyl” as used herein refers to a straight or branched chain radical of usually 2- 10 carbon atoms, having at least one triple bond in the chain. Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propyayl, I1-butynyl and 2-butynyl Useful alkoxy groups include oxygen substituted by one of the above mentioned Ci. alkyl groups, such as Crs alkoxy groups or Ci. alkoxy groups. The alkyl in the alkoxy may be optionally substituted. Substituents of alkoxy include, but are not limited to, halogen, morpholinyl, amino (including alkylamino and dialkylamino) and carboxyl (including ester groups thereof). Useful alkylthio groups include sulfur substituted by the one of the above mentioned Ci.j0 alkyl groups, and the alkyl in the alkylthio may be optionally substituted. Also included are the sulfoxides and sulfones of such alkylthio groups. Useful amino groups include -NR1;R 2, wherein R;) and R,; are independently hydrogen, optionally substituted Cio alkyl (such as Cis alkyl or Ci. alkyl), optionally substituted cycloalkyl, aryl, optionally substituted heteroaryl or optionally substituted amino. Alternatively, Ri and Ry together with the N form an optionally substituted 4 to 8-membered heterocyclic group, such as piperidine, or Ry; and Ry, together with the N and other N or O form an optionally substituted 4 to 8-membered heterocyclic group, such as azetidinyl, pyrrolidinyl, piperazinyl or morpholinyl. The alkyl and heterocyclic group may be optionally substituted. Useful halo or halogen groups include fluoro, chloro, bromo and iodo. The term “aryl” as used herein refers to the aryl itself or as part of other groups, and is a monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms. Useful aryl groups include Ce.4 ary) groups, preferably Ce.1o aryl groups. Typical Coq aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulyl, biphenyl, biphenylene and fluorenyl. The term “heteroaryl” as used herein refers to a group containing 5 to 14 ring atoms, with 6, 10 or 14 © electrons shared in the rings, and the contained ring atoms are carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, Useful heteroaryl groups include thienyl (thiophenyl), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-bjthienyl, thianthrenyl, fury! (furanyl), pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl, including but not limited to 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridiny], quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, B-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3- dione, 7-amino-isocoumarin, pyrido{1,2-a}pyrimidin-4-one, tetrahydrocyclopenta[c]pyrazol-3-yl, pytazolo[1,5~a]pyrinmidinyl, pyrrolopyridyl such as pyrrolo[2,3-b]pyridyl, benzoisoxazolyl such as 1,2-benzoisoxazol-3-yl, benzimidazolyl, 2-hydroxyindolyl, thiadiazolyl and 2- oxobenzimidazolyl. Where the heteroaryl contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N- oxide. The term “carbocycle (carbocyclic group)” as used herein include cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl is Css cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Useful partially saturated carbocyclic groups include cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl and cvclooctenyl. The term “heterocycle (heterocyclic group)” as used herein refers to a saturated or partially saturated 3-8 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and one to four heteroatoms selected from O, N, and § as ring atorus, wherein the nitrogen and sulfur beteroatoms can be optionally oxidized and the nitrogen can be optionally quaternized, and the term also includes any bicyclic ring system in which any of the above- defined heterocyclic rings is fused to a phenyl ring. The heterocycle can be substituted on carbon atom or nitrogen atom if the resulting compound is stable. Useful saturated or partially saturated heterocyclic group include tetrahydrofuranyl, tetrahydropyranyl, pyranyl, piperidinyl, piperaziny], pyrrolidiny], imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl, which may be optionally substituted. In this disclosure, unless otherwise described, when substituted, generally, the aryl, heteroaryl, carbocyclic group and heterocyclic group may be substituted by one or more (such as 1, 2, 3, or 4) substituents selected from the group consisting of: halo, hydroxy, carboxyl, amino, nitro, cyano, Cy acylamino, Cy. acyloxy, Ci alkoxy, aryloxy, alkylthio, Cy, alkyl, Cs.io aryl, Cis cycloalkyl, Cae chain alkenyl, Cas alkynyl, Cio aryl(Cag)chain alkenyl, Ceo aryl(Cs. ¢)alkynyl, saturated and unsaturated heterocyclic group or heteroaryl, methylenedioxy, halogenated Cis alkyl, Ceo aryl(Crs)alkyl, Cis hydroxyalkyl, ureido, thiol, azido, carbonyl, di(Cj.10 alkyDamino, alkylsulfonyl, aminosuifonyl, dialkylaminosulfonyl, and alkylsulfiniyl, and the like, wherein the substituent itself may also be optionally substituted by corresponding substituent(s) as described herein. In this disclosure, unless otherwise described, when substituted, generally, the alkyl, alkoxy, alkylthio, alkenyl, alkynyl and cycloalkyl may be substituted by one or more (suchas 1, 2,3, or 4) substituents selected from the group consisting oft halo, hydroxy, carboxyl, amino, nitro, cyano, C4 acylamino, Ci acyloxy, Cj alkoxy, aryloxy, alkylthio, Cy alkyl, Ce.10 aryl, Css cycloalkyl, Cys chain alkenyl, Cys alkynyl, Csig aryl(Cis)chain alkenyl, Coup aryl{Cos)alkynyl, saturated and unsaturated heterocyclic group or heteroaryl, methylenedioxy, Cis halogenated alkyl, Csao aryl(Cre)alkyl, Cis hydroxyalkyl, uvreido, thiol, azido, carbonyl, di(Ci.1o alkyl)amino, alkylsulfonyl, arminosulfonyl, dialkylaminosulfonyl, and alkylsulfiniyl, and the like, wherein the substituent itself may also be optionally substituted by corresponding substituent(s) as described herein. In preferred embodiments, unless otherwise described, when substituted, generally, the alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, carbonyl, carbocyclic group, aryl, heteroaryl and heterocyclic group may be substituted by one or more (such as 1, 2, 3, or 4) substituents selected from the group cousisting of? halo, hydroxy, carboxyl, amino, nitro, cyano, Cis acylamino, Cie acyloxy, Ci alkoxy, aryloxy, alkylthio, C1 alkyl, Ce.1n aryl, Css cycloalkyl, Ca chain alkenyl, Cys alkynyl, Ceo aryl(Cag)chain alkenyl, Cs.o aryl{Cag)alkynyl, saturated and unsaturated heterocyclic group or heteroaryl. It should be understood that, when the substituent is aryl or a substituent containing aryl, heteroaryl or a substituent containing heteroaryl, heterocyclic group or a substituent containing heterocyclic group, the number of the substituent is usually 1. The term “arylalkyl” includes C).jo alkyl substituted by any one of the obove Cys aryl. Preferred arylmethyl is benzyl, phenylethyl or naphthylmethyl. The term “arylalkenyl” includes Cs.10 alkenyl substituted by any one of the obove Cg.14 aryl. The term “arylalkynyl” includes Cj.10 alkynyl substituted by any one of the obove Ce.14 aryl. The term “aryloxy” includes oxygen substituted by any one of the obove Ce.4 aryl, and the aryl thereof can be optionally substituted. Useful aryloxy groups include phenoxy and 4- methylphenoxy. The term “arylalkoxy” includes Cj. alkoxy substituted by any one of the obove aryl, and the aryl thereof can be optionally substituted. Useful arylalkoxy groups include benzyloxy and phenylethoxy. Useful halogenated alkyl groups include Cj. alkyl substituted by one or more halogens selected from fluorine, chlorine, bromine and iodine atoms, preferably Cj. alkyl substituted by one or more halogens selected from fluorine, chlorine, bromine and iodine atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl. Useful acylamino (acylamido) groups are any Cis acyl (alkanoyl) attached to an amino nitrogen, e.g., acetamino, propionamido, butanoylamido, pentanoylarnido and hexanoylamido, as well as aryl-substituted C4 acylamino groups, e g.. benzoylamido. Useful acyl groups include Cus acyl groups, such as acetyl. The acyl itself may be optionally substituted, for example, by one or more (e.g., less than 6) substituents selected from aryl and halogen, wherein the aryl may be optionally substituted. For example, examples of substituted acylamino groups include chloroacetamide and pentafluorobenzoylamino, Useful acyloxy groups are any Cis acyl (alkanoyl) attached to an oxygen (-O-), e.g, formyloxy, acetoxy, propionyloxy, butanoyloxy, pentanoyloxy and hexanoyloxy. Similarly, the acyl in the acyloxy itself may be optionally substituted, for example, by one or more (e.g., less than 6) substituents selected from aryl and halogen. Some of the compounds of the present disclosure may exist as stereoisomers including optical isomers. The disclosure includes all stereoisomers and the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art. Examples of pharmaceutically acceptable salts include inorganic and organic acid salts, such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate; and inorganic and organic base salts formed with bases, such as sodium hvdroxy, tris(thyvdroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl-glucamine. Examples of prodrugs of the compounds of the disclosure include the simple esters of carboxylic acid-containing compounds (e.g., those obtained by condensation with a C4 alcohol according to methods koown in the art); esters of hydroxyl-containing compounds (e.g., those obtained by condensation with a Cy carboxylic acid, Ca diacid or anhydride thereof such as succinic anhydride and fumaric anhydride, according to methods known in the art), imines of amino-containing compounds (e.g., those obtained by condensation with a Ci.4 aldehyde or ketone according to methods known in the art); carbamate of amino-containing corapounds, such as those described by Leu, et al. (J. Med. Chen. 1999, 42:3623-3628) and Greenwald, er al. (J. Med. Chem. 1999, 42:3657-3667), and acetals and ketals of alcohol-containing compounds (e.g., those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art). The compounds of this disclosure may be prepared using methods known to those skilled in the art, or the novel methods of this disclosure. Specifically, the compounds of this disclosure with Formula I, Formula II, Formula Illa or Formula IIIb can be prepared as illustrated by the exemplary reaction in Scheme 1. 7-Bromo-2-chloroquinoxaline, tributyl(1-ethoxyethylene)tin and bis(triphenylphosphine)palladium(il) chloride were reacted in toluene under heating to produce 1-(7-bromoquinexalin-2-yl}-1 -ethanone Sodium cyanoborohydride, 1-(7- bromoquinoxalin-2-yl)-1-ethanone and ammonium acetate were reacted in methanol at room temperature to produce 1-(7-bromoquinoxalin-2-yl)ethan-1-amive. 1-(7-Bromoquinoxalin-2- yl)ethan-1-amine and tetrahydropyran-4-carboxylic acid were reacted in pyridine in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole at room temperature to produce N-(1-(7-bromoquinoxalin-2-yl)etbyl)tetrahydro-2H-~pyran-4- formamide Trifluoromethanesulfonic anhydride, N-(1-(7-bromoquinoxalin-2- yhethyl)tetrahydro-2H-pyran-4-formamide and pyridine in dichloromethane were reacted at room temperature to produce 8-bromo-3-methyl-1~(tetrahydro-2H-pyran-4-yl)imidazo[1,5~ ajquinoxaline, 8-Bromo-3-methyl-1-(tetrahydro-2H-pyran-4-yl}imidazo[1,5-a]quinoxaline and N,N-dimethyl-3-((5-(4,4,5.5tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)propan-1- amine were reacted under heating in a mixed solvent of 1,4-dioxane and water with the catalysis of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex and cesium carbonate to produce the target compound NN -dimethyl-3-((5-(3-methyl-1- (tetrahydro-2H-pyran-4-vl)}imidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine. Scheme 1 OX OH De 1) PAPPRgCR toluene Ugh MeOH Ud EDC, HOBT, Py. “Cy® 4 7 ao NH, ort NH OAg, NaBH,CN “Cry MeOH A N FNP 2) HC! (aq.), dioxane ° Ny T,0, Py. l N ON. A hyo o f , NAN EDCI, HOBT, Py. 0 | Ame A 5 Sere 2 N > Y T10, Py. oO NH a Y e ocM EB 7 AN AON om The HS y ML 7 Br. NP Pd{dppfiCia, C82C04, Divxane, HO ( lt Other related compounds can be prepared similarly. For example, replacement of 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-y1)-2- (trifluoromethyl)phenoxy)propan-T-amine produced the target compound N,N-dimethyl-3-(4-(3- methyl-1-(tetrahydro-2H-pyran-4-yl}imidazo{1,5-a|quinoxalin-8-y1)-2- (trifluoromethyl)phenoxy)propan-1-amine. Replacement of 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 produced the target compound ~~ N,N-dimethyl-1-(2-fluoro-4-(3-methyl-1-(tetrahydro-2H-pyran-4- vhimidazo[1,5-a]quinoxalin-8-yl)phenyl)piperidin-4-amine. Replacement of N,N-dimethyl-3-((5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylypyridin-2-yl)oxy) propan-1-amine with (1,3- dimethyl-1H-pyrazol-4-yl)boronic acid produced the target compound 8-(1,3-dimethyl-1H- pyrazol-4-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-ylimidazo[1.5-a]quinoxaline. Replacement of tetrahydropyran-4-carboxylic acid with isobutyryl chloride produced the target compound 1- isopropyl-3-methyl-8-(6-(3-(piperidin-1-yDpropoxy)pyridin-3-yDimidazo[1,5-a]quinoxaline. Replacement of 7-bromo-2-chloroquinoxaline with 7-bromo-2-chloro-6-fluoroquinoxaline produced the target compound 7-fluoro-1-isopropyl-3-methyl-8-(6-(3-(piperidin-1- yhproposy)pyridin-3~yl)imidazo[l,5-a]quinoxaline. The compounds of this disclosure can be prepared as illustrated by the exemplary reaction in Scheme 2. 1-(7-Bromoquinoxalin-2-yl}ethan-1-amine, morpholine-4-carbonyl chloride and diisopropylethylamine (DIEA) were reacted in DCM at room temperature to produce N«(1-(7- bromoquinoxalin-2-yl)ethyl)morpholine-4-formamide. N-(1-(7-Bromoquinoxalin-2- yl)ethylymorpholine-4-formamide and POCI; were reacted under heating to produce 4-(8-bromo- 3-methylimidazo[ 1,5-a]quinoxalin-1-yhmorpholine. 4-(8-Bromo-3-methylimidazo[1,5- aJquinoxalin-1-yl)morpholine and N N-dimethyl-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yhpyridin-2-yl)oxy)propan-1-amine were reacted under heating in a mixed solvent of 1,4- dioxane and water with the catalysis of [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex and cesium carbonate to produce 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. Scheme 2 ~~ ~N POCly Amon 0 ,e 3 9 ary a DIEA DCM. Ht NR gsc NH, N * - Ba Ny SA ALJ NNN oN ye od y fi’ o Br, NP Pd(dppiCh, Cs,COs, dioxane, HO [A Nd ON Br o N PLN NN Ne=N Na ny 7 a Other related compounds can be prepared similarly. For example, replacement of morpholine-4-carbonyl chloride with (2R,68)-2,6-dimethylmorpholine-4-carbonyl chloride produced the target compound N,N-dimethyl-3-((5-(1-((28,6R)-2,6-dimethylmorpholinyl)-3- methylimidazo{1,5-ajquinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine. Replacement of morpholine-4-carbonyl chloride with (3R,58)-3,4,5-trimethylpiperazine-1-carbonyl chloride produced the target compound N,N-dimethyl-3-((5-(3-methyl-1-((35,5R)-3,4.5- trimethylpiperazin-1-yl)imidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine. Replacement of NN-dimethyl-3-((5-(4,4.5,5-tetramethy!-1,3,2~dioxaborolan-2~yl)pyridin-2- yljoxy)propan-1-amine with 2+(3-(piperidin-1-yhpropoxy)-5-(4,4,5 5-tetramethyl-1,3 2- dioxaborolan-2-yl)pyridin-2-yD)pyridine produced the target compound (28,6R)-2,6-dimethyl-4- (3-methyl-8~(6~(3-(piperidin-1-yl)propoxy)pyridin-3-yl)jimidazo[1,5-a]quinoxalin-1- yl)morpholine. Replacement of N,N-dimethyl-3-((5-(4.4,5,5-tetramethyl-1.3,2-dioxaborolan-2- ylpyridin-2-yl)oxy)propan-1-amine with 1~(2-fluoro-4-(4,4,5.5-tetramethyl-1,3.2-dioxaborolan- 2-yl)phenyl)-NN-dimethylpiperidin-4-amine produced the target compound 1-(4-(1-((2S,6R)- 2,6-dimethylmorpholinyl)-3-methylimidazo[1,5 -a]quinoxalin-8-yl)-2-tfluoropheny])-N,N- dimethylpiperidin-4-amine. The compounds of this disclosure can be prepared as illustrated by the exemplary reaction in Scheme 3. Scheme 3 =N HN A AcOH KCOy EtOHMH,0 =N =N 7 FN ro FemH,Cl rT yy ore LA EGH / H;0 1 NO, oe FP Ny Gi i dd 0g 7 EE EN hod KoCOs oT FeNHOl Br, S N= aol Bs NP nes OME 28°C A EOHH,0 TX MSO (1) XT NO, NO; og.asec Ny re WN ou =N = CE LA 2 DCM N 25°C 2 al A YE TT ee DMSO, 90°C p, _. pM. dloxane / H0. 90 °C i ANAUNH 2 o o N Ca,005, Pd(dppiCly PD dloxanelti;0, 80°C. al NNR YN DIPEA Br NP een TX ip DMSO, 80°C | > ai : Other related compounds can be prepared similarly. For example, replacement of N',N'- dimethyl-N*-(5-(4,4,5 5 -tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propane-1,3-diamine with 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidin-4-amine produced the target compound 1-(5~(1-((2S,6R)-2,6-dimethylmorpholino)-3-raethylimidazo[1,5- a]quinoxalin-8-yl)pyridin-2-yl)piperidin-4-amine. Replacement of N' N'-dimethyl-N*(5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylypyridin-2-yhpropane-1,3-diamine with N-methyl-1- (6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-y}pyridin-3-yl)piperidin-4-amine produced the target compound 1-(5-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[1,5-a]quinoxalin- 8-yl)pyridin-2-y1)-N-methylpiperidin-4-amine. Replacement of N',N'-dimethyl-N>-(5-(4,4,5,5- tetramethyl-1,3.2-dioxaborolan-2-yl)pyridin-2-yl)propane-1,3-diamine with 1-methyl-4-(3-((5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yljpyridin-2-yl)oxy) propyl )piperazine produced the target compound (28,6R)-2,6-dimethyl-4-(3-methyl-8~(6-(3-(4-methylpiperazin-1- yl)propoxy)pyridin-3-yl)imidazo[1,5-a]quinoxalin-1-ylymorpholine. Replacement of (2S,6R)-2,6- dimethylmorpholine with (2R,6R)-2,6-dimethylmorpholine produced the target compounds 3-((5- (1-((2R,6R)-2,6-dimethylmorpholino)-3-methylimidazo[1,5 -a]quinoxalin-8-yl)pyridin-2-yl)oxy)- N,N-dimethylpropan-1-amine and 3-((5-(1-((28.68)-2,6-dimethylmorpholino)-3- methylimidazo|1,5-a}quinoxalin-8-yl)pyridin-2-y1)oxy)-N ,N-dimethylpropan-1-amine. One important aspect of the present disclosure is the finding that the compounds of Formula 1, Formula II, Formula Ia and Formula TTIb are kinase inhibitors, especially ATM kinase inhibitors. Therefore, these compounds can be used to treat or prevent a variety of clinical conditions caused by DDR function defects or to treat or prevent diseases that benefit from inhibition of kinase activity. These diseases are also called DDR-mediated diseases or kinase- mediated diseases. Therefore, the disclosure provides uses of compounds of Formula I, Formula II, Formula Ila and Formula IIb in the preparation of medicaments for the treatment or prevention of clinical conditions caused by DDR function defects or of diseases that benefit from inhibition of kinase activity. Additionally, the applicant further discovers that the compounds of Formula 1 with R; being an optionally substituted alkyl, especially an optionally substituted C;.4 alkyl, particularly methyl, especially those defined by Formula II, Formula Illa and Formula IIb, are highly active ATM kinase inhibitors. Therefore, in the preferred embodiments, the present disclosures particularly relate to use of these compounds with Ra being a Cy alkyl group to treat or prevent a variety of clinical conditions caused by DDR function defects or to treat or prevent diseases that benefit from inhibition of kinase activity, in the preparation of medicaments for the treatment or prevention of clinical conditions caused by DDR function defects or of diseases that benefit from inhibition of kinase activity, and pharmaceutical composition containing these compounds. The present disclosure also includes methods for the treatment or prevention of DDR- mediated diseases or kinase-rediated diseases, comprising administering to an object in need an effective amount of the compound of Formula I, Formula II, Formula Illa or Formula IIIb or a stereoisomer, a tautomer, a N-oxide, a hydrate, an isotope-substituted derivative, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture thereof or prodrug thereof, or a pharmaceutical composition comprising an effective amount of the compound of Formula I, Formula II, Formula {ila or Formula IIb or a stereoisomer, a tautomer, a N-oxide, a hydrate, an isotope-substituted derivative, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture thereof or a prodrug thereof, In the disclosure, the clinical conditions caused by DDR function defects or diseases that benefit from inhibition of kinase activity, or DDR-mediated or kinase-mediated diseases include but are not limited to cancers, including but not limited to 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, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, teval cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, prostate cancer and Huntington's disease. In the disclosure, the kinase includes ATM (ataxia-telangiectasia mutant gene) kinase; therefore, in some embodiments, the cancer described in the disclosure is an ATM kinase- mediated cancer, preferably a cancer benefit from inhibition of ATM kinase activity. In practicing the therapeutic methods of the disclosure, effective amounts of pharmaceutical preparations are administered to a patient exhibiting one or more of these symptoms. The pharmaceutic preparation comprises therapeutically effective concentrations of the compound of Formula 1, Formula II, Formula Illa or Formula Ib for oral, intravenous, local or topical application, for the treatment of cancer and other diseases. The amounts are effective to ameliorate ot eliminate one or more symptoms. An effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate or in some manner relieve symptoms associated with a disease. Such amount may be administered as a single dosage or may be administered according to an effective regimen. The amount may cure the disease but, typically, is administered in order to ameliorate symptoms of a disease. Typically, repeated administration is required to achieve the desired amelioration of symptom. In another embodiment, there is provided a pharmaceutical composition comprising the compound of Forraula I, Formula II, Formula ITTa or Formula IIIb or a stereocisomer, a tautomer, a N-oxide, a hydrate, an isotope-substituted derivative, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture there of or a prodrug thereof as a kinase inhibitor, and a pharmaceutically acceptable carrier. Another embodiment of the present disclosure is directed to a pharmaceutical composition effective to treat cancer, comprising the compound of Formula I, Formula 11, Formula Ila or Formula ITIb or a stereoisomer, a tautomer, a N-oxide, a hydrate, an isotope-substituted derivative, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture there of or a prodrug thereof as a kinase inhibitor, in combination with at least one known anticancer agent or a pharmaceutically acceptable salt thereof. In particular, the compound herein can be combined with other anticancer agents related to the mechanism of DNA damage and repair, including PARP inhibitors Olaparib, Niraprib, Rucaparib, Talazoparib and Senaparib; HDAC inhibitors Volinota, Romididesin, Papiseta and Bailesta: and so on. And the compound herein can be combined with other anticancer agents related to cell division checkpoints, including Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as Palbociclib, ATR inhibitors, and so on. Other known anticancer agents which may be used for anticancer combination therapy include, but are not limited to alkylating agents, such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin and carboplatin; topoisomerase I inhibitors, such as camptothecin, irinotecan and topotecan; topoisomerase IT inhibitors, such as doxorubicin, epirubicin, aclacinomycin, mitoxantrone, elliptinium and etoposide; RNA / DNA antimetabolites, such as S-azacytidine, gemcitabine, S-fluorouracil, capecitabine, and methotrexate; DNA antimetabolites, such as S-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea and thioguanine; antimitotic agent, such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel and docetaxel; antibodies, such as mAb, panitumuruab, necitumumab, nivolumab, perbrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T-DMI, ofatumumab, dinutuximab, blinatumomab, ipilimumab, avastin, herceptin and mabthera; kinase inhibitors, such as imatinib, gefitinib, erlotinib, osirertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, verourafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, ponatinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, Idelalisib, pazopanib, Torisel and everolimus. Other known anticancer agents which may be used for anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, Ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, Venetoclax, Aldesleukin (recombinant human interleukin-2) and Sipueucel-T (prostate cancer treatment vaccine). In practicing the methods of the present disclosure, the compound(s) of the disclosure may be administered together with at least one known anticancer agent in a unitary pharmaceutical composition. Alternatively, the compound(s) of the disclosure may be administered separately from at least one known anticancer agent. In one embodiment, the compound(s) of the disclosure and at least one known anticancer agent are administered substantially simukaneously, i.e. all compound(s) or agent(s) are administered at the same time or one after another, provided that the compound(s) or agent(s) reach therapeutic concentrations in the blood at the same time. In another embodiment, the compound(s) of the disclosure and at least one known anticancer agent are administered according to individual dosage regimens, provided that the compound(s) reach therapeutic concentrations in the blood. Another embodiment of the present invention is a bioconjugate comprising the compound of the disclosure that can effectively inhibit tumors and act as a kinase inhibitor. The bloconjugate that can inhibit tumors comprises or consists of the compound of the disclosure and at least one known therapeutically useful antibody, such as trastuzumab or rituximab, or growth factor, such as EGF or FGF, or cytokine, such as [L-2 or IL-4, or any molecule that can bind to cell surface. The antibodies and other molecules could deliver the compound(s) described herein to the targets, making it an effective anticancer agent. The bioconjugates could also enhance the anticancer effects of the therapeutically useful antibodies, such as trastuzumab or rituximab. Another embodiment of the present disclosure is directed to a pharmaceutical composition effective to inhibit tumor, comprising the compound of Formula I, Formula II, Formula Illa or Formula IIIb, or a sterecisomer, a tautomer, a N-oxide, a hydrate, an isotope-substituted derivative, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture thereof or a prodrug thereof as a kinase inhibitor, in combination with radiation therapy. In this embodiment, the compound(s) of the disclosure may be administered at the same time or at a different time as the radiation therapy. Yet another embodiment of the present disclosure is directed to a pharmaceutical composition effective for post-surgical treatment of cancer, comprising the compound of Formula [, Formula II, Formula IIa or Formula IIIb, or a stereoisomer, a tautomer, a N-oxide, a hydrate, an isotope-substituted derivative, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture thereof or a prodrug thereof as a kinase inhibitor. The disclosure also relates to a method of surgically removing tumor and then treating the cancer of the mammal with the pharmaceutical composition of the disclosure. Pharmaceutical compositions of the disclosure include all pharmaceutical preperations which contain the compounds of the present disclosure in an amount that is effective to achieve its intended purpose. While individual needs are different, the skill of the art could determination determine optimal amounts of each component in the pharmaceutical preperations. Typically, the compounds or the pharmaceutically acceptable salts thereof may be administered to mammals orally at a dose of about 0.0025 to 50 mg per kg body weight per day. Preferably, from approximately 0.01 mg / kg to approximately 10 mg / kg body weight is orally administered. If a known anticancer agent is also administered, it is administered in an amount that is effective to achieve its intended purpose. The optimal amounts of such known anticancer agents are well known to those skilled in the art The unit oral dose may comprise from approximately 0.01 to approximately 50 mg, preferably approximately 0.1 to approximately 10 mg of the compound of the disclosure. The unit dose may be administered one or more times, with one or more tablets daily, each containing from approximately 0.1 to approximately 50 mg, conveniently approximately 0.25 to 10 mg of the compound of the disclosure or solvates thereof. In a topical formulation, the compound(s) of the disclosure may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier. The compound(s) of the disclosure may be administered as a raw chemical. The compounds of the disclosure may also be administered as part of a suitable pharmaceutical preparation containing pharmaceutically acceptable carriers (comprising excipients and auxiliaries). Such pharmaceutically acceptable carriers facilitate the manufacture of pharmaceutically acceptable preparations from the compound(s). Preferably, the pharmaceutical preparations, particularly oral preparations and those used for the preferred administration routes, such as tablets, dragees, and capsules, as well as solutions suitable for injection or oral administration, contain from approximately 0.01% to 99%, preferably from approximately 0.25% to 75% of active compound(s), together with excipient(s). Also included within the scope of the present disclosure are the non-toxic pharmaceutically acceptable salts of the compound(s) of the present disclosure. Acid addition salts are formed by mixing a solution of the compound(s) of the present disclosure with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like. Base addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pbarmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methylglucamine and the like. The pharmaceutical preperations of the disclosure may be administered to any mammal, so long as they may experience the therapeutic effects of the compound(s) of the disclosure. Foremost among such raammals are humans and veterinary animals, although the disclosure is not intended to be so limited. The pharmaceutical preperations of the present disclosure may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes. Alternatively or additionally, administration may be by oral route. The dosage administered will be dependent upon the age, health, and weight of the subject, the combined therapy, frequency of treatment, and the desired therapeutic efficacy. The pharmaceutical preparations of the present disclosure can be manufactured in a known manner, e.g, by conventional mixing, granulating, dragee-making, dissolving, or lyophilizing, Pharmaceutical preparations for oral use may be obtained by combining the active compounds with solid excipient(s), optionally grinding the resulting mixture, adding suitable auxiliaries if desired or necessary, processing the mixture of granules, thereby obtaining tablets or dragee cores. Suitable excipients are, in particalar, fillers, such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol; cellulose preparations and / or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, including maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone. If desired, disintegrating agents may be added, such as the above-mentioned starches and carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, in particular, flow-regulating agents and lubricants, e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. If desired, dragee cores can be provided with suitable coatings against gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, tale, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings against gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used. Dyes or pigments may be added to the tablets or dragee coatings, e.g, a combination for identification or to characterize a dose of active compound(s). Other pharmaceutical preparations, which may be used orally, include push-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active compounds in the form of granules, which may be mixed with fillers, such as lactose: binders, such as starches; and / or lubricants, such as talc or magnesium stearate; and stabilizers. In soft capsules, the active compound(s) are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin. In addition, in which stabilizers may be added. Suitable formulations for parenteral administration include aqueous solutions of the active compounds, e.g, aqueous solutions and alkaline solutions of water-soluble salts. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, e.g., sesame oil, or synthetic fatty acid esters, e.g, ethyl oleate or triglycerides or polyethylene glycol-400, or cremophor, or cyclodextrins, Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, e.g., sodium carboxymethyl cellulose, sorbitol, and / or dextran. Optionally, suspension stabilizers may also be contained. In accordance with one aspect of the present disclosure, compounds of the disclosure are provided in topical and parenteral formulations and are used for the treatment of skin cancer. The topical formulations of this disclosure can be formulated as oils, creams, lotions, ointraents and the like by suitable carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C1). Preferred carriers are those in which the active ingredient(s) are soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers may be included in these topical formulations. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762. Creams are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water, which is mixed with the active ingredient(s), dissolved in a small amount of an oil, such as almond oil. A typical example of such a cream is one which includes approximately 40 parts water, approximately 20 parts beeswax, approximately 40 parts mineral oil and approximately 1 part almond oil. Ointments may be formulated by mixing a solution of the active ingredient(s) in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool. A typical example of such ointments is one which includes approximately 30% by weight of almond oil and approximately 70% by weight of white soft paraffin. The following examples are illustrative, but not limiting, of the methods and preparations of the present disclosure. Other suitable modifications and adaptations of various conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art are within the spirit and scope of the disclosure. Example General remarks All reagents were of commercial quality. Solvents were dried and purified by standard methods. Mass spectrum analyses were recorded on a Platform II (Agilent 6110) single quadrupole mass spectrometer equipped with an electrospray interface. 'H NMR spectra was recorded at 400 MHz, on a Bricker Ascend 400 apparatus. Chemical shifts were recorded in ppm from low-field relative to internal TMS (0.00 ppm), and J coupling constants were reported in hertz (Hz). Example | N,N-dimethyl-3-(4-(1 -{tetrahydro-2H-pyran-4-yl)imidazo{1,5-ajquinoxalin-8- ylyphenoxy)propan-1-amine ON | MOA hp iP YY = N a) Preparation of 2-hydroxy-7-bromoquinoxaline: 2-hydroxyquinoxaline (10 g, 68.5 mmol) was dissolved in acetic acid (500 mL), and liquid bromine (3.62 mL, 70.6 mmol) was slowly added dropwise at 10°C. After the addition, the reaction solution was reacted under stirring at room temperature for 3 hours, then the reaction mixture was cooled to 0°C, water (S00 mL) was added, and stirring was continued for 30 minutes. The reaction mixture was filtered, the filter cake was washed with water (300 mL), and the solid was dried to obtain the target product (13.5 2. 88% yield, yellow solid). LC-MS (ESI): m / z (M+ HY A(M+2+H)™225.1 / 227.1. b) Preparation of 2-chloro-7-bromoquinoxaline: 2-hydroxy-7-bromoquinoxaline (6 g, 26.7 mmol) was dissolved in phosphorus oxychloride (60 mL). Under the protection of nitrogen, the reaction solution was reacted under stirring at 100°C for 2 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure to obtain a crude product, and then the crude product was extracted and separated with ethyl acetate (100 rl.). The organic phase was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried with 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 (MH) / (M+2+H)" 243.0 / 245.1. ¢) Preparation of 7-bromo-2-methylquinoxaline: 2~chloro-7-bromogquinoxaline (4.7 g, 19.3 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml), ferric acetylacetonate was added, and the reaction solution was cooled to 0°C. Methylmagnesium chloride (7 ral, 3 roll tetrahydrofuran solution) was slowly added into the reaction solution with a constant pressure dropping funnel. After dropping, the reaction was continued stirring at 0°C for 5 hours. Then the reaction solution was slowly poured into saturated ammonium chloride aqueous solution to quench the reaction. After most tetrahydrofuran was removed under reduced pressure, the mixture was extracted and separated with ethyl acetate (40 mLx2). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by column chromatography (silica gel, ethyl acetate: petroleum ether = 0-40% as eluent) to obtain the target product (3.27 g, 76% yield, white solid). LC-MS (ESI): m / z (M-+H) / (M+2+H)" 2293 1 / 2251. d) Preparation of 7-bromo-2-iodomethylquinoxaline: 7-bromo-2-methylquinoxaline (3.27 g, 14.66 mmol) was dissolved in acetonitrile, copper sulfate pentahydrate solid and iodine were added successively, and the reaction solution was reacted under stirring at 70°C for 3 hours under the protection of nitrogen. After the reaction liquid was cooled to room temperature, the solvent was removed under reduced pressure, and then the mixture was extracted and separated with ethyl acetate (100 mL). The organic phase was washed with saturated sodium sulfite aqueous solution and saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was isolated 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 vellow solid). LC-MS (ESI): m / z (M+H) " / (M+2-+H)" 348 9 / 3509. ¢) Preparation of 7-bromo-2-azidomethylquinoxaline: 7-bromo-2-iodomethylquinoxaline (956 rg, 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 reacted under stirring at room temperature for 11 hours. Then the reaction solution was added with 50 mL water, and extracted and separated with ethyl acetate (30 mL). The organic phase was washed with saturated brine for 3 times, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by coluran chromatography (silica gel, ethyl acetate: petroleum ether = 0-30% as eluent) to obtain the target product (820 mg, crude product, yellow solid). LC-MS (ESI): m / z (M+H) / (M+2+H)™ 264.1 / 266.1. f) Preparation of (7-bromoquinoxalin-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 the protection of nitrogen, the reaction solution was reacted under stirring at room temperature for 12 hours. The pH value of the reaction solution was adjusted to 1-3 with 1 mol / L hydrochloric acid aqueous solution. The mixture was extracted and separated with ethyl acetate (20 mL). The aqueous phase was collected, and then the pH of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted and separated with dichloromethane (20 mL x2). The organic phase was collected, dried with anhydrous sodium sulfate and filtered, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was directly used in the next reaction (400 mg, crude product, brown solid). LC-MS (ESI): m / z (M+H) 7 / (M+2-+H)" 238.1 / 240.1 g) Preparation of N-({7-bromoquinoxalin-2-ylymethy / jtetrahydro-2H-pyran-4-formamide: (7-bromogquinoxalin-2-yl)methylamine (400 mg, crude product, 1.68 mmol) was dissolved in N,N-dimethylformamide (8 ml), and N,N-diisopropyletbylamine (0.88 ml, 5.04 mmol) and tetrahydropyran-4-carboxylic acid (262 mg, 2.02 mmol) were added successively. Under the protection of nitrogen, the reaction solution was reacted under stirring at 80°C for 2 hours. After the reaction solution was cooled to room temperature, 40 mL of water was added, and the mixture was extracted and separated with ethyl acetate (30 mL x2). The organic phase was washed twice with saturated brine, dried with anhydrous sodium sulfate, and filtered, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was isolated and purified by colamn chromatography (silica gel, methanol: dichloromethane = 0-20%) to obtain the target product (275 mg, 46% yield, yellow solid). L.C-MS (ESI): m / z (M+H) / (M+2+H)" 350.1 / 352.1. h) Preparation of 8-bromo-1-(tetrahydro-2H-pyran-4-yl}imidazo[1,5-a]quinoxaline: N-((7- bromoquinoxalin-2-yl)methyljtetrahydro-2H-pyran-4-formamide (210 mg, 0.60 mmol) was dissolved in a mixed solution of NN-dimethylformamide (1 mL) and ethyl acetate (6 mL) and cooled to 0°C. Phosphorus oxychloride (410 mg, 3.6 mmol) was slowly added dropwise thereto. After dropping, the reaction mixture was heated to room temperature and stirred for 2 hours. Then, the reaction solution was slowly added dropwise to saturated sodium bicarbonate aqueous solution, and the pH value was kept above 8. The solution was extracted and separated with ethyl acetate (20 mLx2). The organic phase was washed twice with saturated brine, and dried with anhydrous sodium sulfate, and the solvent was removed by filtration to obtain a crude product. The crude product was isolated and purified by coluran chromatography (silica gel, methanol: dichloromethane = 0-15%) to obtain the target product (68 mg, crude product, yellow solid). LC- MS (ESI): nv / z (M+H) / (M+2+H)" 332.1 / 334.1. 1) Preparation of N,N-dimethyl-3-(4-(1~(tetrahydro-2H-pyran-4-yl)imidazo[1,5- a]quinoxalin-8~yl)phenoxy)propan-1-amine: 8-bromo-1-(tetrabydro-2H-pyran-4-yl)imidazo[1,5- a]quinoxaline (68 rg, crude product, 0.20 mmol) was dissolved in a mixed solution of dioxane and water (1.6 mL / 0.4 mL), N,N-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)propan-1-amine (125 mg, 0.41 mmol), 1,1 bis(diphenylphosphino)ferrocenedichloropalladium(I) (15 mg, 0.02 mmol) and cesium carbonate (200 mg, 0.61 mmol) were added thereto successively, and the reaction mixture was reacted ander stirring at 100°C for 1 hour under the protection of nitrogen. When the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure to obtain a crude product. The crude product was isolated and purified by column chromatography (silica gel, methanol: dichloromethane = 0-15%) and then further isolated 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. 'H NMR (400 MHz, DMSO-dg): 8 8.96 (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, SH), 3.68 — 3.62 (m, 2H), 2.39 (t. J = 7.1 Hz, 2H), 2.17 (5. 6H), 2.13 = 2.08 (m, 2H), 2.04 — 1.96 (m, 2H), 1.92 — 1.85 (m, 2H). Example 2 N.N-dimethyl-3-((5-(3-methyi-1-(tetrahydro-2H-pyran-4-yl)imidazof1,5-a]quinoxalin-8- yDpyridin-2-yDoxy)propan-1-amine a) Preparation of 1-(7-bromoquinoxalin-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 vacuum puroped for 30 minutes. The reaction mixture was degassed and filled with nitrogen for 3 times. Bis(triphenylphosphine)palladium(Il) chloride (Pd(PPh:),Cl;, 1.44 g, 2.05 mmol) was added. The reaction mixture was stirred in 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 and suspended, 2 molL hydrochloric acid aqueous 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, and evaporated to dryness. The resulting 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. 'H NMR (400 MHz, DMSO-d): § 9.40 (s, 1H), 8.51 ~ 8.50 (m, 1H), 8. 15-8.14 (m, 2H), 2.76 (s, 3H). b) Preparation of 1-(7-bromoquinoxalin-2-yl)ethan-1-amine: Sodium cyanoborohydride (NaBH;CN, 402.96 mg, 6.41 mmol) was added to a solution of 1-(7-bromoquinoxalin-2-yl)-1- ethanone (2.3 g, 9.16 mmol) and ammonium acetate (NH:OAc, 7.06 g. 91.60 mmol) in methanol (50 mL). The reaction mixture was stirred at 25°C for 12 hours, After removing methanol, 20 mL of water was added to the residue, then sodium hydroxide aqueous solution (w%=5%) was added, the pH of the resulting solution was adjusted to 13, and the mixture was extracted with dichloromethane (50 mLx2). 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: NH). YH NMR (400 MHz, DMSO-dg): § 9.18 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.95 (dd, J = 2.4, 8,8 Hz, 1H), 4.28-4.23 (m, 1H), 2.33-2.32 (m, 2H), 1.41 (d, J =6.8 Hz, 3H). c) Preparation of N-(1-(7-bromoquinoxalin-2-yl)ethyl)tetrahydro-2H-pyran-4-formamide: A pyridine solution (4 mL) of 1-(7-bromoquinoxalin-2-yl)ethan-1-amine (0.4 g, 1.59 mmol) was added with 1~(3-dimethylaminopropy!)-3-ethylcarbodiimide hydrochloride (EDCI, 735.32 mg, 3.84 mmol) and 1-bydroxybenzotriazole (HOBT, 94.24 mg, 697.41 pmol), and then added with tetrahydropyran-4-carboxylic acid (226.91 mg, 1.74 mmol). The resulting mixture was stirred at 25°C for 6 hours. In another reactor, a pyridine solution (3 mL) of 1-(7-bromoquinoxalin-2- ylethan-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 umol) 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 mLx3). 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. The crude product 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. 'H NMR (400 MHz, DMSO0-de): & 8.95 (s, 1H), 8.54 (d, J = 6.8 Hz, 1H), 8.28 (d, J = 2 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.97 (dd, J = 2.1, 8.8 Hz, IH), 517-513 (m, 1H), 3.86-3.84 (m, 2H), 3.31-3.27 (m, 2H), 1.63-1.56 (m, 3H), 1.51 (d, J = 6.8 Hz, 3H). d) Preparation of 8-bromo-3-methy!-1-(tetrahydro-2H-pyran-4-yl}imidazo[1,5-a]quinoxaline: Trifluoromethanesulfonic anhydride (T£,0, 684 mg, 2.42 mmol, 0.4 mL) was added to a dichloromethane (4 mL) solution of N-(1~(7-bromogquinoxalin-2-yl)ethyljtetrahydro-2H-pyran-4- formamide (0.4 g, 1.10 mmol), the resulting mixtare was stirred at 25°C for 1 hour, then pyridine (588 mg, 7.43 mmol, 0.6 mL) was added, and the resulting mixture was stirred at 25°C for 6 hours. The mixture was added with water (10 mL) at 0°C and extracted with ethyl acetate (10 mLx3). The organic phases were combined, washed with brine (15 mL), dried with 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 e) Preparation of N,N-dimethyl-3-((5-(3-methyl-1-(tetrahy dro-2H-pyran-4-yl}imidazo[1,5- ajquinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine: A 1,4-dioxane and water solution of 8- bromo-3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[ 1,5-a]quinoxaline (0.07 g, 202.18 pmol), N,N-dimethyl-3-((5-(4,4,5,5-tettamethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxy)propan-1- amine (87.29 mg, 285.08 pmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (Pd(dppf)Cla, 14.79 mg, 20.22 pmol) and cesium carbonate (Cs,CO3, 131.75 mg, 404.37 pmol) are vacuum pumped, the atmosphere was replaced with nitrogen for 3 tires, and then the mixture was stirred at 90°C in nitrogen atmosphere for 16 hours. The resulting reaction mixture was diluted with a mixed solvent of dichloromethane (10 ml) and methanol (1 mL), and filtered to remove insoluble substance to obtain a crude product, which was purified by preparative high performance liquid chromatography column (column: Waters Xbridge 150%25mm* S 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% vield, 98.6% purity, gray solid ). The following compounds of Examples 3-13 were prepared using methods similar to that described in Example 2. Compound structure ! MW | LC-MS (ESD | YUNMR, 400 Mbz M+H)" “3 346.3 | $ hry TS Nan 1 Hip 4557 | | ‘N’ (MH) 3 445.4 oN Ho | 4445 . A 0 a es | ~ LAA (MAH) 4 463.0 | Rn Bn N a=, (M-+H)™ 5 513.5 Example Compound structure Tomw | LoS Es) | HNMR, 400 MHz i | DMSO-d: 38.96 (5, 1B). 8.61 ¢d, J=24 | lz, 15, 5.25 1d, J 16 Ha, 1H), 815 7, dd, J = 2.8, 88 Ha, 11), 7.94 (0.7 = 84 | ; Hz, 13D). 7.85 = 16. Hz IF), 7.00 2 | Amoyny ha | 445.57 | my vis . . PR Nm fig ™| WT yy GITRERR TI, 364 FE 132 HL CL 1200. 403-399 om, SH). 3.66-3.60 (1 250), | 12,67 (5, 3H). 2362.33 (m 2H), 215 5. L6H) . 2,092.01 (oy 2H), 200-194 (m. , , LOH), 192-187 (me 21D) : [CDCI 38.75 (5, 1H), B15 @. J 20 Hz. 1H), 7.95 (d, F100 Hz 1H), 7.70 (dd J & 20 Hz, J= 10.0 Hz, 1H), 7.58 (d, J= 68 Nem Oey oN (M4H)" Hz, 2H), 705 (d, J 6.4 Hz, 2H), 423 - 3 | AP] 414.58 4454 1420 (im 2H), 4.15 (LJ=6.2 THz. 2th, 381+ aid 13.73 (nu LH), 3.72 - 3.66 (mn, 2H), 2.69 - 12.67 (m, 2H), 2.63 (5, 3H. 2.42 is, 6H), : 4 1227-217 (m 2H), 2.16 - 2.10 (my, 41) ' [CDC 38.76 (5, TH). 8.13 (5. 1H), 8.13 ] 5 R00 (an, 1H), 7.68-7.67 im. 1H), 7 667.62 [Aer Oui Mn GH | Om, THD, 736-7.30 (m, 2H), 7.167. 14 (m, 4 AA A | rm | on hy 4630 2H), 424-418 (m4, 3763.66 (3H), TN 12.63 (5, 3H). 2.57-2.51 (m,2H), 2.27 (5, | | | GT). 2.26+2.20 (sn, 4H). 2.09-205 (m. 2 | ' | CDCL:b 8.74 (5, LED, 8.15 (5, TH), 5.02- om 18.00 Gn 11D, 7.84 (5, 1D, 7.77 (d, J = 9.2 | z Lot _ Hz, UH), 769 (A J = 6.4 Hz, TH.7.18 (d. 7 [mtn ~ MH 1 wr Th 0 5 Cd | sass | CT sR, TH), 4.23.20 (mH), 3.72 pry [ 3 13,65 tu, 3H, 2.64 (5, 3H), 2,532.51 > i | (n.2H), 2.20 (5, 8H), 2.20:2.16 (m, 2H), . ; | 2.04 Ad, J 76.0, 13.2 He, 2) DN, | So Png NN 1 be Nee | 483.63 | Sart? Naasy” —N 13 A 5 Re Pst 45 | 3621 a Sad - pa re MN 614s | ha ; i 7 17.46 (n, 110), 4 2404.20 (m, 260, 3,713.63 (3H), 3.243.210 (d, J = 6742, 7H), 2.88- 12.76 Gn, 4H), 277-275 on, TH), 2.64 (5, L3H), 2282.27 (in 21), 2.20-2 21 (am, 2D), | 1210-202 (m, 280. 1.671 51 (m, 2H), [121-118 (m. 3H) [CDCI 68.77 (5. TH), 8.44 @.7= 2.4 Hz, L1H 8.02 (d, J 2 Hz, 140), 801d J = 8 | R on He 14D), 7.85-7.66 (an, 1H). 7.65 ¢d, J = | LA ion : S jos Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 12 Sd Ae] 4856 | 4865 4-41 (on 2H), 4.22419 (m 2H), 124 |3.76:3.66 (310). 2.63 65, 31, 2 54-2.50 | | (1 2000, 2.44 (s. 3H), 229-226 (3H). 12,192.06 (m. 2H). 204-202 m, 2H), 1163-158 (mn 4H), 149-142 (in. 2H) og [CDCI 68745. TH), 798795 Gm. 2H), ait Sl 17.53:7.50 (m, 24D, 420-418 (nu 2.3.95 | 13 wh eas | 301 (s, 3H), 373-362 (on, 3H), 263 (5, SED, 2 J i 12.50 (5. 3H), 2.33-2.23 (m. 2H), 2.14-2.11 | % Lm 200 Example 14 N.N-dimethyl-3-{{5-(3-methyl-1-morpholinylimidazo[1,5-a]quinoxalin-8-y)pyridin-2- vDoxyipropan-1-amine a) Preparation of N-{1-(7-bromogquinoxalin-2-vljethymorpholine-4-formamide: A dichloromethane (8 mL) solution of I -(7-bromoquinoxalin-2-yl)ethan-1-amine (0.3 g, 2.01 mmol) was added with morpholine-4-formyl chloride (455.08 mg, 1.81 wmol) 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 mb ~2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (0.56 g, yellow oil, 76.45% yield). LC-MS (EST). (M+H)"365.1 b) Preparation of 4-(8-bromo-3-methylimidazo[1,5-a]quinoxalin-1-yhmorpholine: A mixture of N-(1-(7-bromoquinoxalin-2-yljethyl)morpholine-4-formamide (0.5 g, 1.37 mmol) and POCI; (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 of the mixture was adjusted to 7 with saturated sodium carbonate aqueous solution, and the mixture was extracted with EA (100 ml.x2), The organic phases were collected and combined, dried over anhydrous sodium sulfate, and 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. c) Preparation of NN-dimethyl-3-((5-(3-methyl-1-morpholinylimidazof1,5-a]quinoxalin-8- yhpyridin-2-yl)oxy)propan-1-amine. A solution of 4-(3-bromo-3-methylimidazo[1,5- alquinoxalin-i-ylmorpholine (20.25 g, 720.03 pmol), N,N-dimethyl-3-((5-(4,4,5,5 -tetramethyl- 1,3.2-dioxaborolan-2-yljpyridin-2-yoxy)propan-l-amine (44095 mg, 1.44 mmol) in dioxane (15 mL) and water (1.5 mL) was added with Cs,C05 (441.05 mg, 1.35 mmol) and [1.1'- bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (Pd{dppt)Cl. 10.54 mg, 14.40 pmol). 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 (30 mLx2). The organic phases were combined, washed with brine (25 mLx2), dried with anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain the target compound (23.29 my, vellow oil, vield 5.53%). The following compounds of Examples 15-43 were prepared using methods similar to that described in Example 2 or 14 HNMR, 400 MEz $n oa rN RT | 8.40 Hz, 1H), 6.25 (dd, J = 2.40 Hz, J = Nem Ou ” ; ll | 6.56 | 4473 | R40 Hz LHD, $45 (d J = 880 Ha, 1H), tL ji i 297 (t, J = 16.00 Hz, 2H), 248 - 2.44 (m. | 135 Sr ar TeN 3461 0 475) #4 Armor TK | 47461 | Nas rg, Nags i TL hg (MHI) Ne =N 16 4433 ' ' CDOD S741 (5, 1H), 7.34 (d, J= 2.00 Fiz, 1K, 7.01 d, J = 2,00 Hz, 11), 6.57 _— (dd, J = 2.40, 8.40 Hz, 1), 6.33 d, J = EW 8.40 Hz, 1H), 6.25 (dd, J = 240 Hz, J = i | a 1 ~ Ki | 446.56 447.3 R40 Hz, 1H), 5.48 (d. J = 8.80 He, 1H), ’ Lr, 2 297 6,7=600 Hz, 2H, 2.48 - 2.44 (m. | 2002.35 2.32 (m 2H, 1.86 - 1.80 (mw. | OF), 1.42, 611), 1.095, 36), 0.77 - \ | 0.72 (m, 2H) ’ ! CDCl: 69.09 (5. 1H), 8.68 5, 1H). 8.43 - | 8.38 (m, 1H), 8.10 (d. J = 7.6 Hz, 1H). od 7.85 (dd, J + 2.3, $.6 Ha, 1H), 7.71 ~7.63 | Oe TNA Cd (m. TH), 6.91 (d. J=8.6 Hz, 1H). 4.51 (t, | is write x | wel | 4752 ” Sh Nh ges | J= 5.8 Hy, 2H), 4.00-3.96 (ny, 2H), 3.46 - | Veg 3.24 (ny 4H), 2.94 - 2.88 (oy, 8H), 2.68 i (5, 3D), 2.48 - 2.25 (on, 2H), 1.28 (d. J = 4.6 Hz, 6H) CDCl: 58.83 (d, J= 2.0 Hz, H), 8.66 (5. I 1H), 8.48 8.47 (m, H), 7.02 - 7.88 (m, |e wha ansy | PIDT | UD. 0 2 84H IF, 689d, | a TP asa J=8.4 Ha, H), 4.46 (1, J= 6.0 Hz, 2H), TI “oth 347 344 (m0 2H), 3.02 2.93 (m, 2H), 2.91 = 2.89 (m, 2H), 2.58 (5, 6H), 2.57 (5. \ NT Soon at 7 Aor Begin Nan wid | Nog Anon Ne 2m i i i Cr ed — i ed ; — | Arsen Ny | 48765 | Napa oN ? iJ oa po 4 An, Oueny Than ; Nah ng Hf | 403,57 | Fg pl | Amory th aN y path rg eg | 42053 | J 3H), 221 2.20 (m, 2H), 1.90 - 180 (ay | 41D, £80 1,45 (m 2H), CDCl: 88.83 (4, J = 2.0 Ha, 1H). 8.66 (5, TH). 8.50 (d, J = 2.32 Hz, 1H), 7.86- ha 7.98 (mm, 2H). 7.59 (dd. J = $.31, 1.96Hiz, | oo | ety fe | isos | sos 1, 659 (J 0.56 i, Li, 44 J Neg no MP | = (1.42 Fz, 207), 3.343 45 (m, 2H), 3.25 | L A 332 Gn, 2H), 2.95 (4, J = 12.10 Ha, 2H), | 2.30-2.60 (ro, SIT), 2.36-2.42 {m, 5H), ! 228-235 (m 6H), 1.98-2.00 (om. 2H) CDCl: 5836 (d,J= 15 Hy, 1H), 864 | 8.70 Gn, TH), 5.48 (d, J = 2.1 Ha, 1H), wd 7.85 7.93 Gn, 2H), 7.59 (d, J = 8.9 Hz, } od 1), 6.54 - 6.91 (m, 1H), 4.44, J = 6.4 | 1 | ery hy | 48765 | 4884 Fiz 2H), 332d, J = 115 Hy, 2H), 296 Ret ADO - ' (LJ 112 Ha, 2H), 2.58 (5, 3H), 2.45 + hE 2.36 (m, 4H). 2.37 (5. 3H), 2.24 ~ 2.34 (m, 6H), 197 - 2.09 (m, 2H), 117 (4, J = | ! ! CDCL3 8.75 (5, 1H), $47 (d, J=2.8 Hz, | 1H. 8.22 (d, J+ 16 Mz, 1H). 7.80 (d, J» | $4H, 1H), 789-786 (n, 1H), 7.64 (A. On J+ 8 Hz, 14D), 6.90 (d. J= 8.8 Hz, 1H). 19 LI NPN | 40353 | 4043 443 (1, J= 6.4 Fl, 7H), 387-382 (m, E Ad ' 1H), 2.63 (5. 3H), 2.50 (L J= 6.8 Hz, 2H), 2.30 (s, 6H), 2.02 (1, J= 7.6Hz. 2H, 161 4d, = 6.5 Hz , 3H), 157 Gs, 31) CDC: 8.74 (5, THD. 8.20 (d, J= 8.4 He, | 1H), 7.97, J= 84 Hz, 1H), 764 d, J= | Hm Ong ” 84H, (FD), 741-736 (m, 21D, 703 41, 2 pha A 7 | 92053 | 4214 | JS Hr IH), 419 (1J= 6.4 Hr, 2), Lote 3.88 3.81 an, 1). 2.63 (5. 3H), 255 (| J 72 Hz, 2H), 230 (5, 6H). 2.10 2.03 (m, 2H), 1.63 (5. 6H) CDCI56 8.75 is, 1H), 8.21 (5, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 2.0 Hz, , , 1H). 7.76 (d, J = 2.0 Te. 1H), 7.66 (dd, J | | ete Ne Cl =84.16Hz, 1H), 717 J=88 Hr, 2 rab a Bog | 47054 | 4715 oon Tr] | 1H), 4.21 (1.7 = 6.0 Hz, 2H), 3.87-3.80 TEN em, 1D, 2.64 (5, 3H), 236 (1. = 70 He, | 2H), 2.31 (5. 6 H), 2.09-2.03 (mn, 2H), 1.62 (d, J = 6.8 Hz, 6H) Choo, . 7.63 d, J= 1.6, 8.0 Hz, 1H), 6.88 (d, J- 2 dh Aree | 4436 | aS 440, LH), 442 (1, = 6.4 Hz, 2H), Lad 387 3.81(m, 1H), 2.63 (s. 3H), 2.55 « 33 | LA i A pi 45.50 | Arby Nog J FRE tg { ag , Sy - Fo | 460.04 | UL ay Nae Name WT i 26 1 | 495.50 | 496.2 Agni Np | Clay Tl rh aphy : ) CDCL:38.75 (5, TH), 8.21 (d, J= 2.4 He, | 1H), 7.95 (d, J= 3.2 Ho, 1H), 765 @.J= | LL 2.0, 8.4 Hz, TH), 730 - 7.33 (my, 2H), “ v L IN », 7.09 (1, = 9.2 Hz, 1H), 3.88 -3.82 (ny, 24 TA Ne HSS) | 4465 1H), 2.62 (d, J= 8.4 Hz, 2H), 282-275 | Ly i (mn, 2H), 2.63 (5. 3H), 2.37 (5, 6H). 2.37 - | fai 235 (mn LD), 197 (& J+ 88 Hz 28), 179 - 1.76 (in, 2H) , 163 (5, 3F), 161 G5, | y ; 3H) ; ! DMSO-46 8.74 6s. 1H), 8.21 (A.J =24. | Hz, 160). 7.97 (d, J=8.4 Hz, 1H). 7.67 en 7.64 (0 210. 7.51 (dd S84, 2.0 Ha, 2s Sy - | une] wp TED. 7.184 JA 14, 180. 3.84 om. Gang Me i 1H), 3.56 (br d, J=12.0 Hz, 7H), 2.77 = | 2.75 (in, 2H), 2.63 (s, 3H), 2.38 is, 6H), 1.99 1.96 (mn 2H), 184 - 1.79 (m 2H), | : CDCl: 58.96 (5. TH), 8.30 (s, 1H), 8.07- | : £08 {m, 1H), 7.98-7.94 {, 2H), 7 8%- i “Ny . } 7.86 (in, 1H), 767 (4. T= 8.0 Hz, 1H), 26 TY Ts | 495.59 | 4962 4.05-3.98 (m, 1H),3.09 (d, J = 12.0 Hz, EOL 2H), 2.82 (T= 11 Hz, SH), 2.54 (5. 3H), | oo 224 (5, GH), 188-185 (m, 2H), 1.59- ; 1.53 (0, 2H). 147d, J = 6.4 He, 6H). I FN. 4 } T 1 SN ory, AN 7 re A | 467.54 | } — i — J : n -N, =N a NL CET ONT Ig ” 1 T | Aes } ~My . 3. 481.57 | RTT om who p 29 ey he 8 495.59 | - fal NE TY v frm ON | : } 54 3 “ i | 433.47 | ni ww 30 DP 347 at ¥ 1 i | ' | i od - Ld © - / Soli a dh. a -N | eNO Nek . TL | 196.62 | ha r oN wt al Fr JN { - Aen P gn, yedt . I xn #7 pet | 500.65 | Hats prs i eh iy ea 33 To ar tN w= | 81466 1 5152 LN Bn | TY) bd 514.66 | LINEN Na i : CDCI, 38.84 (d= 16 Tis, 11D), 8.68 (5, 1H), 8.44 (d, J =2.0 Hz, 1H), 791 (d, | Jo 8.4 Hy, 1H), 7.84 (dd, J = 2.4, 8. 4 Hz, | ol 1H), 7.59 (dd, T= 2.0, 8.4 Hy, 1H), 6.87 ] LN | (d, 78.0 Hz, 1H), 4.42(t, J = 6.412, 3 Oy Th | ses2 | awa [0 Nr E 2H), 4.03 -3.96 (m, 2H), 3.36-329 (m, Lng 6H), 2.85 (1, T= 11.4 Hz, 2 1), 2.91-260 | (m, 2H), 2.58 (5. 3H), 2.19-2.18 (m, 2H). | 1971.94 (m, 2H), 1.27 (d, I=6.4 Hz, 1 i SH) i MeOD: 58.97 (s. 111), 8.79 (s, 16). 8.48 | (d, = 24 Hz, 1H), 8.04 (dd, =8.6,26 | ; HZ, IF), 788d, J=$4 Hy, 1H), 774 os I (J = 84 Hz, 1H). 6.97 (d, J = 8.4 Hz, | An TO | $0065 | 5002 IH), 443 (t, T= 6.4 Fz, 2H), 4.02-3.97 Hie TY pe ' (my, 2H), 331 (t, J = 1.6 Hz, 2H), 2.78~ Sw 2.72 (on 4H), 2.68 (d. T= 2.0 Fiz, 4H), 2.57 (5, 3H), 2.12-2.06 (tn, 2H), 1.90- 1.80 (mn, 4H), 1.22 (d, J = 6.0 Hz, 6H) CDCIo 884 d, T= 1.6 He, 1H). 868s, | 1H), 845 (A. J = 2.0 Hz, 1H) 791 (d, J = | SOT, 1H), 7.84 (dd, J = 8.2, 2.6 Ta, a of, 1H). 7.60 (d, J = 7.6 Hz. TH), 688 (d, J = | I dp od R8 Hz LED. 442 tJ = 6.4 Fz, 26), 33 eit itty wr | s1a66 | 5152 : HNN | i 4,003.96 (on, 2H), 3.30 (4, J = 12 Hz, Ll 2H), 2.85 (1, J = 11.2 Hz 2 H). 2.58 6s. 3H), 2.55-2.44 (im 6H), 2,112.09 (m. 2H, 1.64-1.62 (m, 3H), 1.48-1.26 (m, 3H), 127d, J = 6.4 Hz, 6H) ol T i - 34 Be eB gen, | | Ter hha | 183.58 | NH Ry rg NP | J Labs , 1 NT i EN — NN | Noro gin 5% | Sem Net | ma HN Fahy F == 4 Eh af FN 36 ONT Ne Teg TN Nal Ty AQ | ] YY ee | 460.58 | 461.2 | 160.58 | od, -—¢ iy ~ ~N Sr ng Y aN, ! Bags og Nag? th i - 137 oS Ns ey NN | 541.61 0 5422 I -t Marmite oN ~ | AmB TR | sane porte A ret | LA i - “ fis iid Neg, An eng oN i i Nay eX b 39 Tr Ogg NaMo | 516650 5175 | 516.65 | - ol TT -— { N ” NN SA edi v autopgst Nad Rah? ’ MeOD: 68.94 (d, I= 2.4 Hz, 1H), 8.77 (5, | 1H). 8.47 (5, 1H), 8.12 (5, 1H), 8.03 (dd, 5 I= 2.4 Hz, J= 8.4 Hz, 1H), 787-785 (m, | ny 3 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.15 (5. 1H), | 35 Sytem TT | 48358 | 4842 6.9% (d, J= 8.4 Hy, 1H), 4.61 (1, J=64 | her Patra i Hz, 2H), 4.01-3.94 (m, 2H), 3.35-3.31 Set (un. 2H), 3.18 (1, J= 6.6 Hz, 2H), 2.74 (t. | J= 11.0 Hy, 20), 2.57 (s, 3H), 1.22 (d, F= | freee 6OHz 6H) oo] CDCl;:5 8.84 (d, J = 2.0 Hz, TH), 8.68 (s, | 1H), 844 (4, J = 2.4 He, 1H), 7.91 A, J = | pd, 8.0 Hz, 1, 7.84 (dd, J = 8.8, 2.4 HZ, wwe A | woss | siz 1H), 7.60 (dd, J = 8.4, 1.6 HZ, 1H), 6.94 | Neh mg | (@ J = 8.8 Hz, 1H), 4.54 4.51 (m, 2H), LA 4,00-3.96 (m, 2FD), 3.32-3.29 (m, 2H), 2.88-2.79 (m, 4H), 2.5% (5, 3H), 2.40 Gs, ! CDCL;5 8.86 (d, J = 1.6 Hz, 1H), 8.68 (5. 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 20 Hz, 1H), 7.76 (dd. J = 8.4, L6 Hz, ol 1H), 7.63 (dd, J = 8.6, 1.8 Hz, 1H), 7.16 2 A Bn a rt | seve] saz (d, f= 8.8 Hz 1H), 4.21 ¢t, J=6.0 Hz, fpr re BP | 2H), 4.03-3.95 (mn, 2H), 330d, J = 11.2 | Lal, He, 2H), 2.86 (t, J = 11.2 Hz, 2H), 2.59 (5, 31), 2.54 (1, J = 7.2 Hz, 2H), 2.29 s, 6H), 2.08-2.02 (m, 2H), 128 (4, J=6.4 ! CDCI::68.83 (A. J = 1.6 Hz, 1H), 8.65 Gs. 1H), 8.51 (d, J =2.0 Hz, 1H), 7.88 (d, J = 8.4 Hy, 1H), 7.74 (dd, J = 8.6, 2.6 HZ, He aL 1H), 7.60 (dd, J = 8.4, 2.0 HZ, 1H), 6.80 | a WY | (7 = 88 Hz, 1H), 448 4.44 (m, 2H), 38 ey oh | 499.66 | 500.4 ; Reo mg ogi | 4,063.98 (mn, 2H), 3.31 (d, J =7.6 HZ, Ln. Wo 2H), 2.98-2.92 (m, 2H), 2.85 (1, / = 11.6 HZ, 2H), 2.58 (s, 3H), 2.45-2.36 (m. 1H), | 2.35 (5, 6H), 2.01-1.97 (m, 2H), 1.63- 1.60 (m, 2H), 1.27 (d, J = 6.4 HZ, 6H) CDCL;:5 8.82 (5, 1H), 8.67 (s, 1H), 7.89 (@ J =8.0Hz, 1H), 761 (dd, J=86, 18 | oh ok Hz, 1H), 7.37731 (m, 2H), 7.07, J= “ ho | st6es | sins | BSH IHL 404-400 Gn 2M. 366.0. | pA ag HP | = 11.6 Hz, 2H), 3.32 (d, J = 11.6 Hz, 2H), LL 2.89-2.78 (m, 4H), 2.58 (s, 3H), 2.5%- 249m, 1H), 249 5,64), 2132.00 (m | , 2H), 1.88-1.80 (m, 2H), 1.28 (d, J = 6.4 3H er aagf N==N | 833.12 1 3333 HCI | 533.12 | Ao CY” J _— {oo hod y ll 41 AT TT el | 488 64 | 4895 2632.60 Km ey TR | 1H), 4.35 (t. J= 6.6 Hz, 2H), 3.89-3.85 at msi | sn | 489.5 ) Hogi omg le 7 i (m, 2H), 2.93-2.87 (mm, 2H), 2.63-2.60 athe (m, 2H), 2.59-2.52 (m. 2H). 2382.34 (m, 2H), 2.15 (s, GH), 1.90-1.85 (m, 2H), 1.28 (t, I= 7.4 Hz3H), 1.15 (d, J=6.4 Hz, 3 N - H News Ooo, had = i 42 Sl rN 502.66 | 503.6 obi orn Wi Bed i ‘7 L — LT ot wif 5% ais. TE 43 | 460.58 | 4612 Rena gn, TN NCS CDCl: 58.83-8.81 (m, 1H), 858-851 (10, 1H), 8.43839 (my, 1H), 7.71 (d, T= 5.6 Hz, 1H), 7.63 (s, 1H), 7.51-7.48 (m, “0 Ne 1H), 7.32-7.30 (mn, 1H), 4.03-3.98 (m, 10 “ Ti | $3312] S333 | 2H), 3.72368 (in, 2H). 3.51346 (m, a O Y 2H), 337-328 (m, 1H), 5.03293 (im, WV 4H), 2.85 (s, 6H), 2.70 (5, 3H), 244-239 | (in 2H), 2202.12 (m, 2H), 134-126 (m, 6H) DMSO-d: 58.90 (5, 1H), 8.82 (s, 1H), 8.52 (d, J=1.6 Hz, TH), 8.04 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.86 (d, ]=8.0 Hz, 1H), ot 7.77 (d, J=6.8 Hz, 1H), 6.99 (d, 7=8 4 Hz, | np =A 1H), 435 (1. I= 6.6 Hz, 2H), 3.89385 # TTR ep BREE] OS 21), 293287 (m 21), 2.63260 Lathe (m. 2H), 259-252 (m, 2H), 2.38-2.34 (m, 2H), 2.15 (5. GH), 1.90-185 (1m, 2H), 128 (t, T= 74 Hz 3H), 1.15 (4, J=6.4 Fiz, ; SH) MeOD: 59.02 (d, J = 2.0 Hz, 1H), §.84 (s. TH), 8.51 (s, 1H), 8.07 @d, J = 2.4 Hz. | , 8.4 Hz 1H), 7.87 (d, J = 8.4 Hz, 1H), I 7.75-7.73 (m, 1H), 7.00 (4, T = 8.4, 1H), 2 SN | 50266 | 5036 | 449 (LT =60 Hz 2H), 400 3.97 (m, Sy 3 ' 2H), 3.47 3.75 (m, 2H), 3.35 -3.33 (m, or 1H), 3.21 3,17 (um, 2H), 2.83 2.81 (m, 8H), 2.26 -2.20 (m, 2H), 1.42 (4, = 6.8 HZ, 6H), 1.23 (d, J = 6.0 He, 6) DMSO-d: 8.91 (s, 1H), 8.89 (5, 1H), 8.54(d, J= 2.4 He, 1H), $07 @d, T= 2.2 i Hz, J= 8.6 Hz, 1H), 7.93 (d, J=8.4 Hz, Ey 1H), 7.83 (dd, I= 1.6 Hz, J 8.4 Hz, 1H), 3 AY Te 46038 | 4612 | 7736, 1H), 700d, J+ 88 Ha LED, 437 | Ty my (t, T= 6.6 Hz, 2H), 3.93-3.87 (m, 2H), 337-334 (m, 2H), 3.69-3.62 (m, 2H), 2,522.50 (m, 2H), 2.25 (5, 6H), 1.96- 1.89 (m, 2H), 1.16 (d. I= 6.4 Hz, 6H) 7 t - + 5 , 44 | 47363 | NE N ~ 0 a. ad Merman - Negi ong Nod Loh Cn i | od. A oh (da “ty ti | 485.64 | [RE NPN ! : ! CDCl: 38.92 (d, 12.0 Hz, LH), 8.74 (s, 1 1H), 8.52(d, J=24 Fz, LH). 796d, I=8.4 Hz, 1H), 7.83-7.81 (ny 1 H), 7.64 | Ans s- (dd, 1=2.0 Hz, 8.4 Hz, 1 H), 7.62 (5. LF). | CA ma N | ) 6.83 (A F=8.4 Hz 1 H), 465d, J=132 ¥* TN od | HOSE BO 2H) 4.06-4.00 (m 2 H, 3383.32 Nop ray Nog . 2 H), 5 Lhd (m, 3 H), 2.98-2.95 (m. 2 H), 2.90-2.84 cr (m, 2H), 278 (5, 6 H), 2.34 (d, I=13.6 Hz, 2 H), 1.88-1.80 (m, 2 H), 129-125 L i (in, 6 H), I] Example 46 Nis ~(1+((28,6R})-2,6-dimethylmorpholino)-3-methylimidazo[1,5-a]quinoxalin-8-y)pyridin-2- yl N°? No.di methylpropane-1,3-diamine a) Preparation of 1~(S-bromo-2-nitrophenyl)-4-methylimidazole: 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) was added K;COQ3 (439.75 g, 3.18 mol). The mixture was stirred at 25 °C for 12 hrs, and then the reaction mixture was filtered and the filter cake was washed with DMF (800 mL). The filtrate was poured into HoO (8 L) and stirred for 10 min, then the mixture was filtered and the filter cake was washed with H;0 (1 L). The solid was slurry with MTBE (1 L) and filtered, the filter cake was washed with MTBE (400 mL). The solid was dried under reduced pressure to give the target product (332 g, 1.18 mol, 73.98% yield) as a yellow solid. b) Preparation of 4-bromo-2-(4-methylimidazol-1-ylaniline: To a solution of 1-(5-bromo-2- nitrophenyl)-4-methylimidazole (120 g, 425.39 mmol) in EtOH (1200 mL) was added NH4Cl1 (227.55 g, 4.25 mol) in H20 (600 ml). To the mixture was added Fe (47.51 g, 850.78 mmol) and stirred at 25 °C for 0.5 hr. Then to the mixture was added Fe (71.27 g, 1.28 mol) during 1.5 hrs and stirred at 35 °C for 1 hr. The reaction mixture was filtered and the filter cake was washed with EtOH (800 mL), the pH of the mixture was adjusted to 8 with saturated NaHCO; solution, and the mixture was concentrated under reduced pressure to give a residue. The residue was slurried with Hp0 (1.5 L) and filtered, the filtered cake was dried under reduced pressure to give a residue. The residue was washed with MTBE (300 mL) to give the target product (93 g, 368.89 mmol, 86.72% yield) as a vellow solid. ¢) 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 mixture was stirred at 130 °C for 36 h. To the mixture was added AcOH (2.38 g, 39.67 mmol, 2.27 mL) and stirred at 130 °C for 24 h. The reaction mixture was diluted with EA (80 mL) and washed with brine (50 ml. * 3), dried over Na;S0y, filtered and concentrated under reduced pressure to give a residue. The residue was washed with MTBE (15 ml) to give the target product (2.19 g, 8.16 mmol, 41.08% yield, 97.54% purity) as a yellow solid. LC-MS (ESI): / z (M+H)" 262.0 d) Preparation of 8-bromo-1-chloro-3-methylimidazo[1,5-aJquinoxaline: 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) was added NCS (4.42 g, 33.12 mmol). The mixture was stirred at 25 °C for 12 hrs. The mixture was diluted with saturated NaHCO3 solution (200 mL) and extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (100 mL * 3), dried over Na,80;, filtered and concentrated under reduced pressure to give a residue. The residue was washed with MTBE (30 mL) to give the target product (5.3 g, 17.87 mmol, 80.92% yield) as a yellow solid. e) Preparation of (28,6R)-4~(8-bromo-3-methylimidazo[1,5-a]quinoxalin-1-y1)-2,6- dimethylmorpholine: To a solution of 8-bromo-1-chloro-3-methylimidazo[1,5-a]quinoxaline (5.3 g, 17.87 mmol) in DMSO (33 mL) was added DIPEA (6.93 g, 53.61 mmol, 9.34 mL) and (28,6R)-2,6-dimethylmorpholine (6.18 g, 53.61 mmol). The mixture was stirred at 90°C for 12 hrs. Then to the mixture was added {28,6R)-2,6- dimethylmorpholine (2.06 g, 17.87 mmol, 2.20 mL) and stirred at 90 °C for 12 hrs. The reaction mixture was diluted with H,0 (100 mL) and extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (100 mL * 3), dried over Na,SOy, filtered and concentrated under reduced pressure to give a residue. The residue was washed with MTBE (35 mL) to give the target product (5.45 g, 14.52 mmol, 81.22% yield) as a yellow solid. *H NMR (400 MHz, CDCl). & 8.80 (d, J= 2.0 Hz, 1H), 8.66 (s, 1H), 7.71 (d, J= 8.4 Hz, 1H), 7.53 (dd, J= 2.0, 8.8 Hz, 1H), 4.07 - 4.00 (m, 2H), 3.25 (d, J=2.0 Hz, 1H), 2.86 - 2.78 (m, 2H), 2.36 (s, 3H). 1.29 (d, J = 6.4 Hz, 6H) f) Preparation of N-(5-(1-((2S,6R)-2,6-dimethylmorpholino) 3 -methylimidazo[1,5- alquinoxalin-8-yl)pyridin-2-y1)-N°,N°-dimethylpropane-1,3-diamine: To a mixture of (2R,68)-4- (8-bromo-3-methyl-imidazo[1,5-a]quinoxalin-1-yl)-2,6-dimethyl-morpholine (100 mg, 266.48 pmol), N’ N'-dimethyl-N*-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propane- 1,3-diamine (113.87 mg, 373.07 pmol), Cs;CO;3 (173.65 mg, 532.96 pmol) in dioxane (15 mL) and HO (0.7 mL) was added Pd(dppf)Cl; (9.75 mg, 13.32 pmol). The reactor was degassed and purged with N; for 3 times, and then the mixture was stirred at 90 °C for 2 hrs under N; atmosphere. The reaction mixture was dried over NaSOs, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-TLC (8104, DCM: MeOH = 9:1). The crude product was triturated with MeCN at 25 °C for 30 min to give the title compound (24.87 mg, 18.96% yield) as a vellow solid. The following compounds of Examples 47-64 were prepared using methods similar to that described in Example 2, 14 or 46. Compound structure MW | LC-MS (EST) 'H NMR, 400 MHz 1.26 - | Armin TA, PR po | 487.65 | pe | J 5 Bi 4 | HR. on £5 i I oN NP | PTY YN | 47160 | FI | smn Noy Loe 0 a } ; [who 0 wR, Yeotf | 485.62 | Rother 7 fhe 50 Chere NEN 49965 | 5003 7 CDCl; 38.82 (& J=2.0 Hz, 1H), 8.65, | 1H), 842 (d, J= 2.0 Hz, 1H), 787 @ J= 8.4 H, 2H), 7.71 (dd, J= 2.4 Hz 8. 8 Hz, o-{ 1H), 7.58 (dd, J= 2.0 Hz, 8.4 Hz, 1H), 3 2 wo 3 fom Be TN | 6.53 (d, = 8.8 Hz, 1H), 5.57 (5, 1H), a6 | Amey Yel | 47361 | 4744 4 D s |, fh No | 4023.97 (m, 2H), 3.46 (5, 2H). 3.30 @, | Loe J= 11.2 Hz, 2H), 2.84 (t, J= 11.2 Hz, 2H), | 2.58 (5, 3H), 2.49 (4, = 6 8 Hz, 2), 2.31(s, 6H), 1.90 - 1.83 (m 2H), 1.26 1 (d, J=6.4 Hz, 6H) ] ! CDCl: 58.82 (d, J= 1.6 He, 1H), 8.64 (5. | 1H), 8.50 (d, J= 2.8 Hz, 1H), 7.87 (4, J= 8.4 Hz, 1H), 7.73 (dd, J=2.4, 8.8 Hz, od 1H), 7.59 (dd, J= 1.6, 8.4 Hz, 1H), 6.66 | | hd . i Hit on, Ted el (d, J= 8.8 Hz, 1H), 4.06-3.99 (m, 2H), | eet Ye | 48765 | 4884 | NO | | 3.66 (t, J= 7.6 Hz, 2H), 3.32 (d, J= 11.2 1A Hz, 2H), 3.15 (s, 3H), 2.85 (1, J= 7.6 Hz, 2H), 2.56 (5, 3H), 2.37 (t, I=7.6 Hz, 2H), | 2.28 (s. 6H), 187-181 Gm, 2H), 1.27 @, frm J-6AHz el). ! CDCl: 38.81 (d, J=2.0 Hz, 1H), 8.65 (s, 1H), 8.50 (d, J=2.0 Hz. 1H), 7.87 (d. I=8.4 Hz, 1H), 7.76 (4d, 1=2.4 Hz, 8.8 | He od Hz, 1H), 7.57 (dd. J=2.0 Hz, 10.0 Hz, ” hho" lame] ama 1H), 6.80 (d, J=8.4 Hz, 1H), 4.47. Neg Noi | 1=13.6 Hz, 2H), 4.01-3.98 (m, 2H), 3.33- | Eh 3.28 (m, 3H), 3.02 (t, J = 7.8 Hz2H), 2.83 (t, J = 108 Hz, 2H), 2.57 (s, 3H), 2.15 (d, J=10.4 Hz, 2H), 1.77-169 (mm, 2H), 1.26 (d, J=6.4 Hz, 6H) CDCl: 38.83 (4, J = 1.6 Hz, 1H). 8.65 (5, 1H), 8.51 (d, J = 2.0 Hz, 1H), 7.88 (d, J=84 Hz, 1H), 7.75 (dd, T= 9.0, 2.6 Hz, | i EN 1H), 7.59 (dd, J = 8.4, 1.6 Hz, 1H), 6.80 Chom, TNA, Co (d 759.2 He, 1H), 4.38-4.38 (mw. 2H), 49 “0 FN 485.62 | 4863 i | 405-3.98 (on, 2H), 3.31 (d, T= 11.6 Hz, 0 2H), 3.08 -3.01 (m, 2H), 2.85 (1, I= 11.2 Hz, 2H), 2.75-2.64 (m, 1H), 2.58 (5, SH), 2.51 (5, 3H), 2.06-2.03 (m, 2H), 1.51- frre I MBLIR ATI... | *y ail ! CDCl: 68.83 (4. 1=2.0 Hz, 1H), 8.65 , 2 3 (s, 1H), 8.51 (d, T= 2.4 Hz, 1H), 7.88 (d. 50 Sry TT ey | 499.65 | 5003 T=84 Hy, IH), 7.75 (dd, J =2.4, 8.8 Hz, id - b 1H), 7.59 (dd, J = 1.6, 8.0 Hz, 1H), 6.80 tg | (d,)=9.2Hz, 1H). 4.37(d, J = 8.8 Hz, 3.71 (s, 1H). 1.48-1.44 (m, 2H), I L 2 WN EW o CT dh = | or fy aN | 1) dS [508 ny | Dn, Loe ed ! Forty i | 511.67 | Fotngm, Fo ! Fo ~N # gol, 7 itd | HN orn os Th | * pe | 46.54 | Easel ; Roster / o-! ’ 2H), 4043.98 (n, 2H), 3.71 (5, 1H), | 331(d T= 112Hz 2H), 3.05 -2.98 (n. | 2H), 287-273 (m, SH), 2.58 (5, 3H), 204-200 (0, 2H), 148-144 (m, 2H), 127, T= 6.0Hz, 6H), 1.16 (, T= 7.0 Hz, 3H) CDCl: 38.81 (d, J= 1.6 Hz, 1H), 864s. | 1H), 8.50 (d, J= 2.0 Hz, 1H), 7.86 (d, = | 8.4 Hz 1H), 7.75 (dd. I= 2.0, 88 Hy, [Hon od 1H), 7.58 dd, I= 1.6, 8.4 Hz, 1H), 6.79 Ch md | (d,J= 9.2 Hz, 1H), 448 (d, J= 13.2 Hz, 8 TUT | SBE SHE i, 4023.97 (m 21D, 3.33328 (m, TAL 3H). 3163.10 (m, 1H). 2.99293 (m. 2H), 2.86-2.81 (m, 2H), 2.57 (s, 3H), 2.15 | (mn 2H), 179-172 (m, 2H), 131d, T= 6.4 Hz, 6H), 1.26 (d, F= 6.0 Hz, 6H). CDCl: 58.83 (5, 1H), 8.82 (5, 1H). 8.49 | (d.1=2.0 Fiz, 1H), 7.89 (d, I= 8.4 Hz, 1H), 7.76 (dd, T= 2.4 Hz, 8.8 Fiz, 1H), | The, ol 7.59 (d, J= 6.4 Hz, 1H), 6.7% (d, I= 8.8 i i -— J a o hm Sm | sg] sins | FIMNASHAI 40H 28,400 fh my Ho i 4.00 (m, 2H), 3.88 (1 J= 7.4 Hz, 410). EAL, 4 3.31 (d, J= 11.6 Hz, 2H), 2.98-2.82 (m, SH), 2.58 (5, 3H, 2.44-2.42 (m, 2H). 2,01-1.98 (m. 2H), 1.75-1.73 (nn 2H), 1.27 (d J= 6.4 Hz. 3H). CDCL: 68.84 (4, 1-L6 He, 11), 868 6, | 1H), 8.45-8.44 (d, J=2.0 Hz, 1H), 7.93~ i” 7.91 (d, J+8.4 Hz, TH). 7.86-7.83 (m. . h 1H), 7617.58 (m, 1H), 6.596.87 (d, 53 | aruaPogy - = | 4654 | 4473 J=8.8 Hz, 1H), 4.48 (t, ]=6.4 Hz, 2H), rT = ' 400-3.96 (m, 2H), 3.31 (d, J=11.2 Hz, wii 2H), 2.94 (t, J=6.8 Hz, 2H), 2.88-2.52 (m, 2H), 2.58 (5, 3H), 2.02-1.96 (m, 2H). 1.27 | frre A IOOME OH) ee] MeOD: 69,289.13 (m, 1H), 8.77-8.76 or (in, 1H) 8.52 (s, 1H) 8.41-8.37 (m, 1H) . wa 7.91-7.84 (my, 2H) 748-734 (m, 2H) se | Tae ~~ | 160.57 | 4613 | 4.514048 (1 J=6.4 Hz, 2H) 4.02-3.99 (m, Bar TY ” i 2H) 3.70-3 48 (mn, 4H) 3.19 (5, 4H) 2.50- | ~— 275 (m. 1H) 2.72 (s, 3H) 2.15-2.00 (m, 2H) 1.21 (d, J=2.4 Hz, 6H) Hy in” ll | ety TRY 4746 | Nh Mg ] Lote pil od cpp 36 Saran a Es Tee 4RR 62 1 4893 Sar Bh i rl | 488.62 | Ney oh, oy oN i Lsthygd o 4 i | - Jd | SNe OL Re va | 1 = 502.65 | Nooo pony Nyt | LAL eg J 8% i; _— ed, | oy i Cotman, Tt | Map | 516.63 | WP ot wt i, | sy [= ip) —~ g Sones | 520.68 | Neg og oN, | 1A 2.85 it, J= 7.2 Hz,2H). 2.60- : ! CDCI 38.79 (d 7-20 Hz, 1H), 8.75 G5, | 1H), 871s, 1H), 7.957.90 (m 2), i 7.81 (d, J=2.4 Hz, 1H), 7.53-7.50 (my gp ed 1H), 7.03-7.00 (im, 1H), 4.67-4.63 (ny 5 SPB ea | 4746 | 4753 | 2H).3.92-3.80 (nu, 28), 3.78-3.63 (my, Rett 2H), 3.61-3.59 (m. 2H), 3.27 @, J=12.0 hE Hz, 2H). 2.90-2.84 (m, 2H), 2.59 (5, 3H), | 222219 (m 2H), 143-140 (3H), CDCl: $8.72 (d, 7=1.6 He, 1H), 8.70 5, | LH), 7.88 (d, J=84 He IH), 772d. 12.8 Hz LH), 7.68-7.65 (tu. 1H), 748 od (@d.J=20 Hz, 8.0 Ha, 1H), 6.73 @,1=95 | hte, TR Ll Hz, 1H), 4.12-4.09 (m, 2H), 4.09-3.95 56 Pata | 48862 | 4893 i A i Rha (im, 2H), 3.28 (d, J=11.2 Hz, 2H), 2.88- ot 283 (m2), 2.38 (5, 3H), 243-239 (my | 4H), 2.21 (5. 3H), 2,032.00 (m, 2H), 129-127 (d, J=6.4 Hz, 6H). 1.03-1.00 @, | 1=7.2 Hz, 3H) CDCl: $8.72 (d, 71.6 Hz 1H), 867 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.69 d, i J=4.0 Hz IED), 7.67-7.64 (mn. 1H), 748 y - (dd. J=2.0 Hz, 8.4 Fz, 1H), 6.73 (d, 1=9.2 5 | Pankey Th | 50265 | 503.4 Hz, 1H), 4.10 (t, J=6.8 Hz. 2H), 3.97-5.94 | ey (mn. 2H), 3.29 (d, J=11.6 Hz, 2H), 2.88~ ha 283 (m, 21, 2.58 5.37, 2542.50 (| 6H), 2.03-1.98 (m, 2H), 1.28 (&, J=6.4 Hz, 6H), 0.99 (1, J=7,2 Hz, 6H) CDCl: 58.84 (s. 1H), 868 (5, 1H). 8.44 (d, J=2.0 Ha, 1H), 7.82 - 7.94 (m, 2H), i” o, 7.60 (d, J=8.0 Hz, 1H), 6.88 (d, J=8.4 Hz, | RK mi, | 1H), 4.46 (i, J= 5.6 Hz, 2H), 3.93 - 4.03 geen | 51663 | 5172 o i Sohn No i (m, 2H), 3.85-3.67 (m, 4H), 3.32-2.89 LAL (mn. 2H), 285 1, 7= 7.0 Hr, 2H), 258.5, | 3H), 2.73 = 2.41 (m, 6H), 2.03 - 2.21 (m, | 2H). 1.27 (d, J=6.4 Hz, 6H) CDCl; 58.84 (I-20 Hz, IH), 868, | 1H), 8.44 (d, 1=2.0 Hz, 1H), 7.91 @, , 1=8.4 Hz, TH), 7.84 (dd, 1=2.4 Hz, 84 | A ay Hz, 1H), 7.59 (dd, J=2.0 Hz, 8.8 Hz, 1H), s “rnp” | 52068 | 5303 | 6.87 (d, J=84 Hz, IH), 4.43 (LJ=6.4 Hz, | “CE 2H), 4.00-3.95 (m, 2H). 3.30 (d, J=11.2 Hz, 2H), 2.85 (t, I= 7.2 Hz, 2H), 2.60- 3.50 (m, 13H), 2.31 (5, 3H), 2.05-2.02 , (m, 2H), 1.26 (d, J=6.4 Hz, 6H) ot 5 : - - LO i oN 61 | “TTY Y=N | 4916 | 4923 | NE | hh pa HE Kathy # ot -—N ¢ oN : | Arty ~ | 508.05 | Spain MP arent REY | i aF) 4044.20 (HL, 21), 2.02=0.42 1H, | “0 "i 1H), 3.32-3.29 (m, 1H), 3.18-3.15 (m, Ny? ] ey 1H), 2.98-2.97 (m, 2H), 2.67-2.66 (m, hpi 1H), 2.58 (5. GH), 2.41-2.39 (m, 1H), NF | i 2.35 (s. 3H). 1.96-1.93 (m. 2H). 1.62- 63 and | 499.65 | 3500.3 | 1499.65 | | ! TO | Na. N oe 2.98-2.95 (m, 2H), 2.71-2.68 (m, ’ CDCl: 38.90 (d, = 1.6 Hz, 1H), 8.83 (d, 1 J= 2.0 Hz, 1H), 8.69 (s, 1H), 7.94, a ol J=8.4 Hz, 1H), 7.88-7.85 (m, 1H), 7.65- ) 1 bp Tod i 7.63 (my, 1H), 7.35 (d, J=2.0 Hz, 8.0 Hz, 60 nd Sy =H | 499.65 | 5003 NI NPN | | 1H), 4.01-3.94 (m, 2H), 3.29 (d, J= 11.2 1 ie Hz, 2H), 3.11-3.09 (m, 2H), 2.97-2.94 (my, 2H), 2.87-2.77 (mn, 10H), 2.58 (s, 3H), 2.44 (5, 3H), 1.26 (d, J=6.4 Hz, 6H). | CDCl: 58.80 (d, J=1.6 Hz, 1H), 8.67(s, | 1H), 7.89 (d, J=8.4 Hz, 1H), 7.59 @d, o 1-16 Hz, 8.0 Hz, LH), 7.38733 (um, 2H), | a | A oy - =” | wre | ma 7047.00 (m, 1H), 4.21-4.18 (m, 2H), eng Ni | 4033.97 (m, 2H), 3.31(d, J=11.2 Hz, 1A 2H), 288-282 (m, 2H), 261-260 (m. 2H), 2.58 (5. 3H), 2.35 (5, 6H), 2.13206 | ; (mn, 2H), 1.28 (d, J=6.0 Hz, 6H) ! CDCl: 58.78 (d, 1=2.0 Hz, 1H), 8.67 (5, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.65 (d, ot J=2.4 Ha, 1H), 7.60 (dd, 1=2.0 Hz, 8.4 ; ~ Hz, 1H), 7.49 (dd, 7=2.0 Hz, 8.4 Hz, 1H), 62 | Mere Sy -* rh, | 508.05 | 508.2 7.08 (d, J=8.4 Hz, 1H), 4.224.19 (m, grips 2H), 4053.98 (m, 2H), 3.32 (¢, J=11.2 RY He, 2H), 2.89-2.83 (m, 2H), 2.75-2.71 (mm, 2H, 2.58 (s, 3H), 2.42 (5. 6H), 2.20 | 2.13 (m, 2H), 1.30 (d. J=6.4 He, 6H) 63-A: CDCl: 8.82 (d, J=2.0 Hz, 1H), 8.65 (s, 1H), 8.51 (d, J=2.4 Fiz, 1H), 7.89 (d. J=8.4 Hz, TH), 7.76 (dd, I=2.8 Hz, 8.8 Hz, 1H), 7.59 (dd. J=2.0 Hz, 8.0 Hz, 1H), 6.79 (d, J=9.2 Hz, 1H), 4.464 43 (m, ¥ 2H), 4.32-4.28 (m, 2H), 3.52-3.49 (m, “0 a) 1H), 3.32-3.29 (in, 1H), 3.18-3.15 (m, Ne? en 1H), 2.98-2.97 (m, 2H), 2.67-2.66 (m, hpi 1H), 2.58 (5, 6H), 2.41-2.39 (m, LH), og | 2.35 (s, 3H), 1.96-1.93 (mm, 2H), 1.62- 63 and | 499.65 | 500.3 2 \ ] | 1.61 (m, 2H), 1.54 (d, J=6.0 Hz, 3H), Lh wl 1.16 (d, J=6.0 Hz, 3H). TO | 63-B: CDCl: 38:83 (d, J=2.0 Hz. LH), pr 8.66 (s, 1H), 8.52 (d, J=2.0 Hz, 1H), 7.89 N (d,J=8.4 Hz, 1H), 7.78 (dd, 1=2.8 Hz, 8.8 Hz, 1H), 7.59 (dd, F=2.0 He, 8.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 4.55-4.52 (m, 2H), 4.32-4.27 (m, 2H), 3.54-3.52 (m, 1H), 3.31-3.29 (im, 1H), 3.18-3.15 (m, 1H), 2.98-2.95 (m, 2H), 2.71-2.68 (m, 2.58-2.55 (in, 1H). 0 ANON Non LES J gp | » TW i 64 an | 4146 | 4752 ’ 1H), 267 (5. 3H). 2.58255 qm, 11D), | 2.55 (s, 6H), 2.15-2.12 (m, 210), 1.74- 1.71 (mn. 2H), 1.53 (4 J=6.8 Hz, 3H), bree ; LI6@I=60HZ 3H) 64-A: CDCly: 5 8.85 (d= 20 Hz, 1H), | 8.68 (5. LH), 8.44 (d, I= 2.4 Hz, 1H), 7.92 | (d,J=84 Hz, IF), 7.86 (0d, T= 2.4.84 Hz, 1H), 7.59 (dd, I= 1.6, 8.0 Hz, 1H), 6.87 (d, J= 8.4 Haz, 1H), 4.470, J= 6.4 Hz, | 2H), 429-425 (m, 2H), 3.50349 (m, : 1H), 3.29 (, J= 10.8 Hz, 1H), 3.16 d, I= | \ LS 11.2 Haz, 1H), 2.88285 (n 2H), 2.69 (, | Aaa Ty I= 10.8 Hz, TH), 2.60-2.57 (ov, 9H), 2.24- | Ters - | 222 Gn 2H), 1.49 (d, J= 68 Hz, 3H), ~ ; LIS (d, J= 6.4 Hz, 3H). 64 - | 4146 | 4752 ) A i 64-B: CDCl: 8.85 (d, J= 2.0 Fz, 1H), | ie 8.69 (s, 1H), 8.44 (d, J= 2.4 Hz, 14), 7.92 | Ap hp. (d,J=80 Hr, 1H), 787(dd. J=2.8,88 ~ YY Hz, 1H), 7.59 (dd, J= 2.0. 8.4 Hz, 1H), ¥ 6.87 (d, J= $.8 Hz, 1H), 4.49 (1, J+ 6.0 Hz, 210), 4314.25 (im, 2H), 3.53-3.50 (m, 1H), 3.28 (@ J= 11.2 Hz, 1H), 3.15 (d, J= 12.0 Hz, 1H), 3.10-2.85 (m. 2H), 2822.62 (m, TH), 2.58 (5, 3H), 2.34- 231 (my 2H), 1.50 (d, J= 6.4 Hz, 3H), 1.16 (d. J= 6.0 Hz, 3H) Example 65 Determination of the inhibitory effect in vitro of the compound of Example 2 and its analogues on ATM using in vitro ATM kinase assay ATM enzymatic activity was measured using Cisbio’s HTRF reagent in a 384-well plate (Greiner, #784075). 2.5 ul. of gradient concentration compound working solution diluted with buffer was added to the 384-well plate, then 2.5 pL. of 120 nM p33 substrate (Eurofins, #14-952) and 2.5 pL of 2ng / uL. ATM enzyme (Eurofins, 14-933) were added successively, and finally 2.5 ul of a mixture solution containing 240 uM ATP, 20 mM Mg(AcO); and 20 mM MnCl, was added. The mixtures were centrifuged at 1000 rpm for | minute, and reacted in dark for 30 minutes at room temperature. Then, 5 uL of EDTA termination solution (250mm) was added to terminate the reaction. After Spl of detection mixture (Anti-phospho-p53 (ser15)-K (Cisbio, #61POSKAE, 0.084ng / ul) and Anti-GST-d2 (Cisbio, #61GSTDLA, 5.00ng / pL)) was finally added to each well, the mixtures were cultured at room temperature over night, and the fluorescence values at 665 nm and 615 nm were measured on Envision 2104. The final concentration of each reagent of the experiment was as follows: 12.5mM HEPES (pH8.0), 0.5% glycerol, 0.005% Brij-35, 0.625mM DTT, 0.0125% BSA, 15 nM p53, 0.25ng / ul. ATM, 30uM ATP, 25mM Mg(AcO);, 2.5mM MnCh, 62.5mM EDTA, 0.021ng / pL Anti-phospho-pS3, 1.25ng / uL. Anti-GST-d2. Relative fluorescence ratio was calculated: Ratiogssun / s1snm-RatiOpuckgrouna, and inhibition rate % = (1 ~(relative fluorescence ratio of test compound well - relative fluorescence ratio of positive control well) / (relative fluorescence ratio of negative control well - relative fluorescence ratio of positive control well))x100 was calculated. Data were analyzed using GraphPad Prism6.0 and fitted using the curve equation: Y = Bottom+{(Top-Bottom) / (1+10(LogICs¢-X)*HillSlope)), and ICsy values were calculated. Table 1 summarizes the inhibitory effects of some compounds on ATM kinase activity (Inh%); Table 2 summarizes the ICs, values of ATM kinase activity of some compounds. Example | 1 | 2 | 3 . 4 LeAatie 1 i ~ hd : " i | Conc.) | 10010] . 10] . ial 10 : 10 : nh% 9 | 71] 25 196 | 59} us 93 , 97 , Example | 5 . 6 | 7 . 8 Ee emerge ——————————————————— Conc.) |, 10 | Lot 10] . foil | 01 10]. 01, into ss 8 99 oa] 27 Cone. (mM) 10 | L | 01} 10 0010 S01 10 C01 | IL | 1 Li 1 . J. eed nh% | 99 196 | 28 { 99 | 74 i 13 | 97 | 78 . 11 {i 98 | 91 | 40 Example 9 ; 10 1n ; 12 7 Conc.) 10 | 1 [oa | 10] Lo Lod ] Col 10 Col | I : : aay — Inh% 99

[96] 28 199 | 1 3 or | 78 ou 9s | or] 40 Conc. (mM) 10 10 C10 S01 10 C01 | Cone. (nd) Je Ae Lo wid nh% | 15 | 93 | 97 | 7 | 8% i C071 P91 | 88 fF 9 | Example } 3 ; 14 16 ; 17 i Conc. (nM) 10 10 10 0.1 10 01 | A ad wd —t ad Inh% 15 { 93 97 8 7 | 91 | 35 ! 9 Example | 18 . 19 | 20 . 21 rete is a Conc. (iM) | 10 | 1 | 01 | . . i . nh% 30 | 88 82 67 Example | 22 ' 24 | 25 ' 26 ES np 2 | -“ | Conc.sM) |, 10 | 1 ol 10] . {ol . , . nt% iE EE Example | B : 36 | 37 ' AZDO156 LX:AIpPic 0 | JO Jf i ALLUULIOD Come a 10 , ng » Note: Example | herein is the compound of Example 37 of WO 2018 / 127195 Al. | Example 15 31 32 33 38 39, 40 LCM) | 031 0.62 0.10 0.20 0.20 020 © 020 ICs; mM) | 0.15 0.41 0.18 0.46 } 0.80 041 019 Example 59 AZDH156 ) | ) . 019 | 030 {Co mM) | 031 0.62 0.10 020 020 020 020 Example 59 AZDO156 | Con | 019 030 Therefore, as determined by the ATM kinase assay, the compound of Example 2 and its analogues have good inhibitory effect on ATM kinase. Example 66 Determination of the inhibitory effect of the compound of Example 2 and its analogues in combination with CPT-11 on the proliferation of human colon cancer cell SW620 using MTT assay The human colon cancer cells SW620 were cultured in RPMI 1640 medium with 10% FBS and used at about 90% confluence for experiments. The SW620 cells were digested with trypsinase and centrifuged at 800 rpm for 3 minutes. The supernatant was discarded and the cell pellets were resuspended with fresh medium (RPMI 1640 +10%FBS) . The cells were seeded into 96-well cell culture plates with appropriate cell density and incubated at 37°C overnight in a 5% CO: incubator. The stock solutions of the test compounds and the reference compound AZD0156 were serially diluted to 8 concentrations with DMSO at ratios of 1:3 and 1:10, respectively. The first concentration was 1 pM or 0.333uM, the last concentration was DMSO negative control (0 uM). 5 uL of solutions of each concentration was added to 120 ul of medium (a 25 times dilution) and mixed by shaking. The cells were cultured overnight and the culture medium was replaced with 195 uL / well of fresh medium containing 205 nM CPT-11 and 5 pL / well of medium containing the test compound (the final concentration of DMSO was 1%). The culture plates were returned to incubator and cultured at 37°C, 5% CO; for 5 days. At the day of experiment, medium was discarded and replaced with 100 pL of fresh serum-free DMEM medium containing MTT (0.5 mg / mL), and the culture was continued. 4 hours later, the medium was discarded and replaced with 100 uL / well of DMSO, the plate was shaken for 10 minutes in dark and the absorbance was measured at the wavelengths of 552 and 690 nm using a multi-function plate reader. Data were analyzed by Graph Pad Prism 6.0. The inhibitory effects of compounds on cell proliferation were plotted based on cell viability vs. the logarithm of compound concentration Cell viability %=(ODcompound~ODbackgronad) (ODoms0-ODoackground) x 100. The 1Csy values were fitted by a sigmoidal dose response curve equation Y=100 / (1+10"(LogC-LoglCso)), wherein C was the concentration of a compound. Table 3 summarizes the inhibitory effect data (ICs) of some compounds combined with CPT-11 on the proliferation of human colon cancer cell SW620. Table 3 Example 1 2 3 4 5 6 7 8 Com) | 1230 1 192 402, 4LL 195 126, 259 241, Example | 9 , 10 no, 1, 13 Mo, 15, 6 CoM | 240 | 167 300 157, >1000 97, 93, 82 Example | 17 , 18 vow om 2, ou 8, CoM) | 274 | 65 176, 359, 296 163, 208 | 666 Example | 26 31 2 3 35 %¥ 3 8 Com | 510 | 101 92 183, 5643 n6 , 176, BT, Example | 30 40 aa 2a FE TE Com | 73 8.1 543 852.2 17.9 20.93 46.9 17.9 Example 48 49 0 52 ; 58 59 i 60 61 | CoM | 121 | 71 63 5.5 om» 20 © osw00 | 207 LC SO J. OR. ONG... NMG. R.A Example | 62 | 634A 63B |, 648 , 64B | AZDOISS | a , b Com) | 430 | 323 $50, 209, 204 | 98 . 383 , 3697 RC [fmm sma fr—————— ICM | 1703 | 1277 | 1820 ; ; ’ . ; Note: Example 1 herein is the compound of Example 37 of WO 2018 / 127195 Al; Examples a, b, ¢, d and e are compounds of Examples 4, 26, 44, 45 and 47 of WO 2018 / 127195 Al, respectively. Therefore, as determined by MTT assay, the compound of Example 2 and its analogues have good inhibitory effect on the proliferation of SW620 cell. Example 67 Determination of the inhibitory effect of the compound of Example 2 and its analogues on the proliferation of human breast cancer cell MDA-MB-468 using MTT assay The human breast cancer cells MDA-MB-468 were cultured in RPMI 1640 medium with 10% FBS and used at 90% confluence. The MDA-MB-468 cells were digested with trypsinase and centrifuged at 800 rpm for 5 minutes. The supernatant was discarded and the cell pellets were resuspended with fresh medium and counted. Cells were seeded to 96-well cell culture plates with appropriate cell density and incubated overnight at 37°C, 5% CO,. The stock solutions of test compounds or the reference compound AZDO0156 were serially diluted to 8 concentrations with DMSO at ratios of 1:3 and 1:10, respectively: the first concentration was 1 pM or 0.333uM and the last concentration was DMSO negative control (0 pM). 5 pl of solutions of each concentration was added to 120 pL of medium (diluted by 25 times) and mixed by shaking. The culture medium of cells cultured overnight was discarded and replaced with 195 pL / well of fresh medium (RPMI 1640+5%FBS) and 5 pl / well of diluted medium containing the test compound of corresponding concentrations (the final concentration of DMSO was 1%o), and the culture plate was then returned to 5% CO, incubator at 37°C for 7 days (on the fourth day, dressing was changed once and culture was continued). On the day of experiment, culture medium was discarded and replaced with 100 pL / well of fresh serum-free DMEM medium containing MTT (0.5 mg / mL), and the culture was continued. After 4 hours, medium was discarded and replaced with 100 uL / well of DMSO, the plates were shaken for 10 minutes in darkness and the absorbance was measured at the wavelengths of 532 and690 nm using a multi-function plate reader. Graph Pad Prism 6.0 was used to analyze the data. The inhibitory effects of compounds on cell proliferation were plotted based on cell viability vs. the logarithm of compound concentration. Cell viability %6=(0Dompound-0Dvackpround / (ODpaiso-ODpackgronaa) x 100. The ICs values were fitted by a sigmoidal dose response curve equation Y=100 / (1+10(LogC-LogICs)), wherein C was the concentration of a compound, Table 4 summarizes the inhibitory effect data (ICs) of some compounds on the proliferation of human breast cancer cell MDA-MB-468 Example | 1 2 3 4 5 6 7 8 ICsy (nM) 103.4 | 188 291 38.85 ; 2191 11.57 , 22.358 24.78 ¢ ICsy (nM) 23.1 16.44 311 14.37 781.6 25.99 7.98 10.62 Example 17 18 19 | 20 : 21 2 | 24 25 | ICs; (nM) 11.41 21.27 16.41 9.91 11.03 73.29 Example | 26 | 31 2, 3, 3 % 8 Example 39 40 41 \ 42 ' 43 45 , 46 47 | Example | 48 | 49 0 |, sm, 58 9, 6 oa ICs (nM) 7.6 4.5 _ 81 _61 ' 17.8 _92 832.2 20.8 Example | 62 | 63A | 63B | 64-A | 64B AZD0IS6 | a ¢ ; Example d € ' ' | . Cy mM) ) Note: Example 1 herein is the compound of Example 37 of WO 2018 / 127195 Al; Examples a, ¢ and d are compounds of Examples 4, 44, 45 and 47 of WO 2018 / 127195 Al, respectively. Therefore, as determined by MTT assay, the compound of Example 2 and its analogues have good inhibitory effect on the proliferation of MD A-MB-468 cells, Having now fully described this disclosure, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the disclosure or any embodiment thereof All patents, patent applications and publications cited herein are fully incorporated by reference herein in their entirety.

Claims

WHATIS CLAIMED IS:

1. A compound of Formula I, or a stereoisomer, a tautomer, a N-oxide, a hydrate, an isotope-substituted derivative, a solvate thereof or a pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof’ ha R, 3 AINE RAS = } 7 bP Ay "™~ Sy 4 AY wherein A) is N or CRs; Asis N or CRs; As is N or CRe: Cy is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclic group ot an optionally substituted cycloalkyl; Ri is an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino, an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted arvl or an optionally substituted heteroaryl; Ry is an optionally substituted alkyl or an optionally substituted carbocylic group; Ry, Rs and Re are independently hydrogen, halogen, alkyl, alkoxy, alkenyl, alkynyl, amino, nitro, cyano, acylamino, acyloxy, hydroxy, sulfhydryl, alkylthio, azido or carboxyl: wherein, the alkyl, alkoxy, alkenyl, alkynyl, amino, acylamino, acyloxy, hydroxy, sulfhydryl, alkylthio and carboxyl may be independently optionally substituted.

2. The compound of claim 1, wherein the coropound of Formula I has the structure of Formula II* Ry 11 "pe N = Ry Bs r The Bag, By I. wherein Ay is N or CRs; Asis N or CRs; Az is N or CRg; BiisN or CR7; B2 is N or CRg; Bs is N or CRy; and By is N or CRyy; Ri is an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino, an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl or an optionally substituted heteroaryl; Rais an optionally substituted alkyl or an optionally substituted carboeylic group: Rs ts hydrogen, alkoxy, amino, carbocyclic group, heterocyclic group, aryl or heteroaryl; wherein the alkoxy, amino, carbocyclic group, heterocyclic group, aryl or heteroaryl may be independently optionally substituted; Rs, Rs, Rs, Ra, Rg, Ry and Rig are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, alkenyl, alkynyl, amino, nitro, cyano, acylamino, acyloxy, hydroxy. sulfhydryl, alkylthio, azide and carboxyl; wherein the alkyl, alkoxy, alkenyl, alkynyl, amino, acylamino, acyloxy, hydroxy, sulfhydryl, alkylthio and carboxyl may be independently optionally substituted.

3. The compound of claim 2, wherein, A;, A; and Aj are CRy, CRs and CRs, respectively, wherein Rs, Rs and Rs are independently hydrogen, halogen, C).s alkyl, C4 alkoxy or halogenated C4 alkyl; the ring containing Bi, Bj, By and By is an optionally substituted pyridine ring or an optionally substituted phenyl ring; preferably, the ring containing Bi, By, B; and Bs is a pyridine ring in which By is N; Ri is an optionally substituted C.¢ alkyl, heteroaryl or heterocyclic group that is optionally substituted by 1-4 Cys alkyls; preferably, Ry is selected from the group consisting of Cr alkyl, tetrahydropyranyl that is optionally substituted by 1-4 Cy alkyls, piperidinyl that is optionally substituted by 1-4 Cy alkyls, morpholinyl that is optionally substituted by 1-4 Cj alkyls and piperazinyl that is optionally substituted by 1-4 C5 alkyls; Ry is Crs alkyl, preferably methyl; R; is selected from: hydrogen, Cis alkoxy that is optionally substituted by -NRuR;s, = NRy;=Cr6 alkyl-NR;; ‘Rip and heterocyclic group that is optionally substituted by -NRuR;s, wherein, Ri and Ry» are independently selected from the group consisting of H and C4 alkyl or they together with the N atom they link to form a 4 to 8-membered heterocyclic group optionally substituted by 1-3 substituents selected from the group consisting of halogen, alkyl and alkoxy, and Ry; and Ry; ate independently selected from hydrogen or Cir alkyl, or Ry; and Riz together with the N atom they link to form a 4 to 8-ruembered heterocyclic group, such as azetidinyl, pyrrolidinyl and piperidinyl, which is optionally substituted by 1-3 substituents selected from the group consisting of halogen, alkyl and alkoxy; and R4, Rs, Re, Ry, Rg, Ro and Ry are independently hydrogen, halo, C14 alkyl or halogenated Cra alkyl, 4. The compound of claim 2, wherein the compound is a compound of Formula Illa or Formula IIIb, or a stereoisomer, a tautomer, a N-oxide, a hydrate, an isotope-substituted derivative, a solvate thereof or a pharmaceutically acceptable salt thereof, or a mixture or a prodrug thereof’ Ry Ry No wh - 1 ow Re ila 1b Ry N Y = Ry Ran A B, ) Tl . NS 3 , Re Te R, Re. Rio Non Rs ZX RH la RF 7 wherein Bi, Bs, Ba, Ri, Ra, Ri, Ra, Rg, Ro and Rig are as defined in claim 2; Rs 1s hydrogen, halogen, alkyl or alkoxy.

5. The compound of claim 4, wherein, the ring containing B), Bs and Bj is an optionally substituted pyridine ring; Ris an optionally substituted C:.. alkyl, heteroaryl or heterocyclic group that is optionally substituted by 1-4 C; 4 alkyls; preferably, Ry is selected from the group consisting of Cy alkyl, tetrahydropyrany] that is optionally substituted by 1-4 Cy. alkyls, piperidinyl that is optionally substituted by 1-4 Cy alkyls, morpholinyl that is optionally substituted by 1-4 Cys alkyls and piperazinyl that is optionally substituted by 1-4 Cj. alkyls; Ry is Ci alkyl; Rs is selected from: hydrogen, Cig alkoxy that is optionally substituted by -NRuRp, - NRir-Cie alkyl-NRi1Riz, and heterocyclic group that is optionally substituted by -NRyiR1a, wherein Rip and Ry are independently selected from the group consisting of H and Ci. alkyl or they together with the N atom they link to form a 4 to 8-membered heterocyclic group optionally substituted by 1-3 substituents selected from the group consisting of halogen, alkyl and alkoxy, and Rj; and Ry; are independently selected from hydrogen or Ci alkyl, or Ry; and Riz together with N form a 4 to 8-membered heterocyclic group, such as azetidinyl, pyrrolidiny] and piperidinyl, which is optionally substituted by 1-3 substituents selected from the group consisting of halogen, alkyl and alkoxy; Rg 1s hydrogen, halogen, C4 alkyl or C; alkoxy, preferably hydrogen; and Ry, Rs, Re and Rp are independently hydrogen, Ci. alkoxy, halogen, C4 alkyl or halogenated C.4 alkyl; preferably, Ry, Ro and Ry are all hydrogen, Rg is hydrogen, halogen, Ci. 4 alkoxy, Cis alkyl or halogenated C,. alkyl, preferably, Rs is balogen, Ci.4+ alkoxy and halogenated Cy.q alkyl 6. The compound of claim 4, wherein in Formulae Ila and Th: R, is a heterocyclic group optionally substituted by 1-2 substituents selected from the group consisting of C4 alkyl, preferably R, is morpholinyl (such as morpholino) optionally substituted by 1-2 C16 alkyls; Riis Ci.4 alkyl, preferably methyl; Rj is a Cy alkoxy optionally substituted by -NR11R1, or a heterocyclic group optionally substituted by -NR;1R13, wherein Rj; and R» are independently selected from hydrogen or Ci.¢ alkyl or Ry; and Ry; together with the N atom form a 4 to 8-membered heterocyclic group (such as azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl (such as morpholino), piperazinyl) optionally substituted by 1-2 alkyls; preferably the heterocyclic group optionally substituted by -NR Ry; is a piperidinyl or a piperazinyl with their ring nitrogen atom linking to the rest of the compound, which preferably is substituted by the -NRyR1; group; Rs is hydrogen, halogen or Cy.4 alkoxy, preferably hydrogen; and in Formula Illa, By, Bs, and B; are CH; in Formula I1Ib, R4, Ro and Ryg are FL 7. The compound of claim 4, wherein in Formula IIIb: Ry is a Cis alkyl, a heteroaryl optionally substituted by 1-3 substituents selected from the group consisting of halogen, Ci alkyl and Cig alkoxy. or a heterocyclic group optionally substituted by 1-2 substituents selected from the group consisting of Cy alkyl, preferably Ry is Cra alkyl, tetrahydropyrany] optionally substituted by 1-2 Cig alkyls, piperidinyl optionally substituted by 1-2 Ci. alkyls, morpholinyl optionally substituted by 1-2 Ci alkyls, pyridyl optionally substituted by 1-2 substituents selected from the group consisting of halogen and C4 alkoxy, or piperazinyl optionally substituted by 1-3 Cig alkyls; Ry is Crs alkyl, preferably C15 alkyl, more preferably methyl; R; is Cis alkoxy optionally substituted by -NRnRjs, -NR;;-Cis alkyl-NRi Ry» or heterocyclic group optionally substituted by -NR, Ry, wherein R;;- and Ry» are independently selected from the group consisting of H and C4 alkyl, Ry; and Ry; are independently selected from hydrogen or Cis alkyl or Ri: and Rj; together with N form a 4 to 8-membered heterocyclic group (such as azetidinyl, pyrrolidinyl, piperidinyl, and morpholiny! (such as morpholino), piperazinyl) optiovally substituted by 1-2 alkyls; preferably the heterocyclic group optionally substituted by -NRpRy; is a piperidinyl or a piperazinyl with their ring nitrogen atom linking to the rest of the compound, which preferably is substituted by the - NR, R;2 group; Rs is hydrogen, halogen or C4 alkoxy; Ry, Ry and Rig are H; and Rg is H, halogen, C4 alkyl substituted by 1-4 halogen, or Cy. alkoxy.

8. The compound of any of claims 4-7, wherein: R, 1s selected from the group consisting of: on MM on ol oN ol fF x & NM pm TN ££ NN gg NK ££ = A Std Sd A A i NeNC NANG TNAND TNN TTNAN NN m= Nl TA NTN HNN NTN : hd, "NA, _ ny R, is C13 alkyl, preferably methyl: Ra is selected from the group consisting of: SO NM oe oh Hy N CY < J HN ~~ On, NS | ~oo NAO \ ~_No~_0 \ SN NAO. Sw TN oN NP - ™ “3 NY Thon. NNO SNA ON, So NOs, HAN H » hel NPL. N \ J \ SooN~. NaN, NUN ~soNAU Dy soN~ " NN ! | SoMa H H H : H H H ; O N N N N N « N ow No Wo No “w N “w N I 1 ~N., CI. Suite, PLN % ~ooNG me Sele * and 9. A compound selected from the group consisting of’ N,N-dimethyl-3~((5-(3~-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[ 1,5-a]quinoxalin-8- yhpyridin-2-yDoxy)propan-1 -amine; N.N-dimethyl-3-(4-(3-methyl-1-(tetrabydro-2H-pyran-4-yl)imidazo[ 1,5-a]quinoxalin-8- vyl)phenoxy)propan-1 -amine; N,N-dimethyl-3-(2-fluoro-4-(3-methyl-1-(tetrahy dro-2H-pyran-4-yl)imidazo[1,5- a]quinoxalin-8-yl)phenoxy)propan-1-aniine; N,N-dimethyl-3-(4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[ 1,5-a]quinoxalin-8- y1)-2-(trifluoromethyl)phenoxy)propan-1 -amine; N,N-dimethyl-1-(2-fluoro-4-(3-methyl-1-(tetrahy dro-2H-pyran-4-yl)imidazo[1,5- a]quinoxalin-8-vl)phenvi)piperidin-4-amine; 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; N.N-dimethyl-1-(4-(3-methyl-1 -(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8- yl)-2-(trifluoromethyl)phenyl)piperidin-1-amine; 1-(4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-yl)-2- (trifluoromethyl)phenyl)piperidin-4-amine; N-methyl-1-(4-(3-methyl-1-(tetrahy dro-2H-pyran-4-yljirmidazo[1,5-a]quinoxalin-8-y1)-2- (trifluoromethyl)phenylpiperidin-d4-amine; N-ethyl-1-(4-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]quinoxalin-8-y1)-2- (trifluoromethyl)phenylpiperidin-4-amine; 3-methyl-8-(6-(3-(piperidin-1yl)propoxy)pyridin-3yl)-1-(tetrahy dro-2H-pyran-4- yvhimidazo[1,5-a]quinoxaline; 8-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazo[1,5- a]quinoxaline; N,N-dimethyl-3-((5-(3-methyl-1-morpholinylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2- vloxy)propan-1-amine; N,N-dimethyl-3-((5-(1-((28,6R)-2,6-dimethylmorpholino)-3-roethylimidazo[1,5- aJquinoxalin-8-yl)pyridin-2-yoxy)propan-1 -amine; N,N-dimethyl-3-((5-(3-methyl-1-(piperidin-1-ylimidazo[1,5-aJquinoxalin-8-yl)pyridin-2- vl)oxy)propan-1-amine; N,N-dimethy!-3-((5-(3-methyl-1-(4-methylpiperazin-1-yl}imidazo[1,5-a]quinoxalin-8~ vhpyridin-2-y1)oxy)propan-1-amine; N,N-dimethyl-3~((5-(3~-methyl-1-((38,5R)-3 4,5 trimethyl piperazin-1-yl)imidazo[1,5~ a]quinoxalin-8-yl)pyridin-2-yl)oxy)propan-1-amine; N,N-dimethyl-3-((5-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)pyridin-2- vDoxy)propan-1-amine; N,N-dimethyl-3-(2-fluoro-4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8- vl)phenoxy)propan-1 -amine; N,N-dimethyl-3-(4-(1 -isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2- (trifluoromethyl)phenoxy)propan-1-amiue; 1-isopropyl-3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3yl)imidazo[ 1,5- a]quinoxaline; 7-fluoro-1-isopropyl-3-methyl-8~(6-(3 ~(piperidin-1 yl)propoxy)pyridin-3yl)imidazo[1,5- a]quinoxaline; N.N-dimethyl-1-(2-fluoro-4-(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8- yl)phenyl)piperidin-4-amine; N,N-dimethyl-1-(2-chloro-4-(1 -isopropyl-3-methylimidazo[1,5-a] quinoxalin-8- yl)phenyl)piperidin-4-amine; N.N-dimethyl-1-(4~(1-isopropyl-3-methylimidazo[1,5-a]quinoxalin-8-yl)-2- (trifluoromethyl)phenyl)piperidin-4-amine; 1-(4-(1-1sopropyl-3-methylimidazo[1,5-a]quinoxalin-8-y1)-2- (trifluoromethyl)phenyl)piperidin-4-amine; N-methyl-1-(4-(1-isopropyl-3-methylimidazo[ 1,5 -a]quinoxalin-8-yl)-2- (trifluoromethyl)phenylpiperidin-d4-amine; N-ethyl-1-(4-(1-isopropyl-3-methylimidazof1,5-a]quinoxalin-8-yl)-2- (trifluoromethyl)phenyDpiperidin-4-amine; 8~(1,3-dimethyl-4H-1 Apyrazol-4 «y1)-1-(3 fluoro-5-methoxypyridin-4-yl)-7-methoxy-3- methylimidazo[1,5-a]quinoxaling; (28.6R)-4-(8-(6-(3-(azetidin-1-yl)propoxypyridin-3-yl)-3-methylimidazof1,5- a]quinoxalin-1-yl)-2,6-dimethylmorpholine; (28,6R)-2,6-dimethyl-4-(3 -methyl-8-(6-(3~(pyrrolidin-1-yl)propoxy)pyridin-3- vDimidazo[1,5-a]quinoxalin-1-y)morpholine; (28,6R)-2,6-dimethyl-4-(3-methyl-8-(6-(3-(piperidin-1-yl)propoxy)pyridin-3- vDimidazo[1,5-a]quinoxalin-1-yDmorpholine; (28,6R)-4-(8-(6-(2-(1 H-irnidazol-2-yljethoxy) pytidin-3-yD)-3-roethylimidazo[1,5- a]quinoxalin-1-yl)-2,6-dimethyvimorpholine; (28,6R)-4-(8-(6~(2-(1H-imidazol-4-yl)ethoxy)pyridin-3-yl)-3-methylimidazo[1,5- a]quinoxalin-1-y1)-2,6-dimethylmorpholine; 2-((5-(1-((28,6R)-2,6-dimethylmorpholino)-3~methylimidazo[ 1,5-a]quinoxalin-8- yDpyridin-2-yljoxy)-N,N-dimethylethan-1-amine; 3-((4-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[ 1,5-a]quinoxalin-8-yl)-2- (trifluoromethyl)phenoxy)-N,N-dimethylpropan-1-amine; 1-(5-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[1,5-a]quinoxalin-8- yD pyridin-2-y1)-N,N-dimethylpiperidin-4-anine; 1-(4-(1-((28,6R)-2,6-dimethylmorpholino)-3-rmethylimidazo[ 1,5-a]quinoxalin-8-y1)-2- fluorophenyl)-N, N-dimethylpiperidin-4-amine; 1-(2-chloro-4-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[1,5-a]quinoxalin-8- vl)phenyl)-N N-dimethylpiperidin-4-amine; 3((5-(1-((28,6R)-2,6-dimethylmorpholino)-3~ethylimidazo[ 1, 5-a]quinoxalin-8-yl)pyridin- 2~yDoxy)-N,N-dimethylpropan-1-amine; 3-((5-(1~((28,6R)-2,6-dimethylmorpholino)-3-isopropylimidazo[1,5-a}quinoxalin-8- yDpyridin-2-yl)oxy)-N,N-dimethylpropan-1-amine; 3-((5-(1~((28,6R)-2,6-dimethylmorpholino)imidazo[ 1,5-a}quinoxalin-8-y1)pyridin-2- vl)oxy)-N.N-dimethylpropan-1-amine; N.N-dimethyl-3-((5-(1-((38,5R)-3 4,5-trimethylpiperazin-1-ylimidazo[1,5-aJquinoxalin- 8-yl)pyridin-2-yl)oxy)propan-1-amine; 1-(5-(1-((28,6R)-2,6-dimethylmorpholino)imidazo[1,5-a]quinoxalin-8-yl)pyridin-2-yl)- N.N-dimethylpiperidin-4-amine; NL(5-(1-((28,6R)-2,6-dimethylmorpholine)-3-methylimidazo[ 1,5-a] quinoxalin-8- vhpyridin-2-y1)-N 3 N? -dimethylpropane-1,3-diamine; N'-(5-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[ 1,5-a] quinoxalin-8- vhpyridin-2-y1)-N A NN? ~trimethylpropane-1,3-diamine; 1-(5-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[ 1, 5-a]quinoxalin-8- yvhpyridin-2-yl)piperidin-4-amine; 1-(5-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[1,5-a]quinoxalin-8- yDpyridin-2-yl)-N-methylpiperidin-4-amine; 1-(5-(1-((2S,6R)-2,6-dimethylmorpholino)-3-methylimidazo[1,5-a]quinoxalin-8- vl pyridin-2-v1)-N-ethvlpiperidin-4 -amine; 1-(5-(1-((28,6R)-2,6-dimethylmorpholino)-3-raethylimidazo[1,5-a]quinoxalin-8- vDpvridin-2-y1)-N-isopropylpiperidin-4-amine; (28,6R)-4-(8-(6-(4-(azetidin-1-yDpiperidin-1-ypyridin-3-yl)-3-methylimidazo[1,5- a]quinoxalin-1-yl)-2,6-dimethyvimorpholine; 3-((5-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazof1,5-a]quinoxalin-8~ vhpyridin-2-y1)oxy)propan-1-amine; 34((5-(1-((28,6R)-2,6-dimethylmorpholino)-3~methylimidazo[ 1,5 -a]quinoxalin-8- yDpyridin-2-yljoxy)-N-methylpropan-1-amine, 3-((5-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[ 1,5-a]quinoxalin-8- vl pyridin-2-yl)oxy)-N-ethylpropan-1-amine; 3-((5~(1-((2S,6R)-2,6-dimethylmorpholino)-3-methylimidazo[1,5-a]quinoxalin-8- yD pyridin-2-yl)oxy)-N-ethyl-N-methylpropan-1-amine; 3-((5-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[ 1,5 -a]quinoxalin-8- vDpyridin-2-yl)oxy)-N.N-diethylpropau-1-amine; (28,6R)-2,6-dimethyl-4~(3-methyl-8-(6-(3-morpholinopropoxy)pyridin-3-yl)imidazo[1,5- a]quinoxalin-1-yl)morpholine: (28,6R)-2,6-dimethyl-4-(3-methyl-8~(6~(3 -(4~-methylpiperazin-1-yl)propoxy)pyridin-3- vl)imidazo[1,5-a]quinoxalin-1-yl morpholine; (28.6R)-2,6-dimethyl-4-(3-methyl-8-(6-(2-(4-methylpiperazin-1-yl)ethyl)pyridin-3- yDimidazo[1,5-a]quinoxalin-1-yl)morpholine; 3-(4-(1-((28,6R)-2,6-dimethylmorpholino)-3-methylimidazo[1,5-aJquinoxalin-8-yl)-2- fluorophenoxy)-N,N-dimethylpropan-1 -amine; 3-(2~chloro~4-(1-((28,6R)-2,6-dimethylmorpholino)-3 -methylimidazo[1,5-a]quinoxalin-8- yl)phenoxy)-N,N-dimethylpropan-1-amine; 1-(5-(1-((2R,6R)-2,6-dimethylrorpholine)-3 -methylimidazo[ 1,5-a]quinoxalin-8- yvl)pyridin-2-y1)-N,N-dimethylpiperidin-4-amine and 1-(5-(1-((25,65)-2,6- dimethylmorpholino)-3-rethylimidazo|1,5-a]quinoxalin-8-yl)pyridin-2-y1)-N,N- dimethylpiperidin-4-amine; 3-((5-(1-((2R,6R)-2,6-dimethylmorpholino)-3-methylimidazo[1,5-a}quinoxalin-8- yhpyridin-2-yl)oxy)-N N-dimethylpropan-1-amine and 3-((5-(1-((28.68)-2,6- dimethylmorpholino)-3~methylimidazo[ 1,5-a]quinoxalin-8-yDpyridin-2-yl)oxy)-N,N- dimethylpropan-1-amine: or a stereoisomer, a tautomer, a N-oxide, a hydrate, an isotope-substituted derivative, a solvate thereof or a pharmaceutically acceptable salt thereof, or a mixture thereof or a prodrug thereof 10. Use of the compound of any one of claims 1-9 in the manufacture of a medicament for the treatment or prevention of a disease caused by a DDR function defect or a disease that beuefit from inhibition of kinase activity; preferably, the disease is cancer.

11. The use of claim 9, wherein the cancer is selected from the group cousisting of: liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Jung cancer, Wilms tumor, cervical cancer, testicular caocer, soft tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, malignant melanoma, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, teval cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, prostate cancer or Huntington's disease.

12. The use of claim 11, wherein the medicament for administration further includes at least one known anticancer agent or a pharmaceutically acceptable salt of the anticancer agent; preferably, the medicament for administration further includes at least one anticancer agent selected from the group consisting of: busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxy ellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, S~-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, alanosine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, Ofaturaumab, avastin, herceptin, mabthera, imatinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, torisel, everolimus, vorinostat, romidepsin, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, 2zoledronic acid, bortezomib, thalidomide, lenalidomide, Venetoclax, Aldesleukin, Sipueucel-T, Palbociclib, Olaparib, Niraparib, Rucaparib, Talazoparib or Senaparib.

13. The use of claim 11, wherein the medicament is used in combination with radiotherapy.

14. A pharmaceutical composition comprising the compound of any one of claims 1-9 and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14, wherein the composition further comprises at least one known anticancer agent or a pharmaceutically acceptable salt of the anticancer agent; preferably, the composition further comprises at least one anticancer agent selected from the group consisting of: busulfan, melphalan, chlorarabucil, cyclophosphamide, ifosfarnide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorabicin, epirubicin, aclarabicin, mitoxantrone, methylhydroxy ellipticine, etoposide, S-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, alanosine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, paniturouroab, Ofatumumab, avastin, herceptin, mabthera, imatinib, gefitinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, torisel, everolimus, vorinostat, romidepsin, tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, thalidomide, lenalidomide, Venetoclax, Aldesleukin, Sipueucel-T, Palbociclib, Olaparib, Niraparib, Rucaparib, Talazoparib or Senaparib.