Substituted fused heteroaromatic bicyclic compound as kinase inhibitor and application thereof

Abstract

The invention provides a substituted fused heteroaromatic bicyclic compound as a kinase inhibitor and application of the substituted fused heteroaromatic bicyclic compound. Specifically, the invention provides application of a compound as shown in a formula I, or a stereoisomer or a pharmaceutically acceptable salt thereof, or a mixture thereof in preparation of a medicine for treating or preventing ATR kinase-mediated cancers. # imgabs0 #

Description

This application is a divisional application of the invention patent application with international application number PCT / CN2020 / 098159, international application date June 24, 2020, national application number CN 202080047282.4 entering the national phase, and invention name “Substituted fused heteroaromatic bicyclic compounds as kinase inhibitors and their applications”. Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and particularly relates to substituted fused heteroaromatic bicyclic compounds and their use as therapeutically effective kinase inhibitors and anticancer drugs. Background Art

[0002] Ataxia telangiectasia mutated gene Rad3-related kinase (ATR) is a protein kinase that responds to DNA damage in cells. After activation, ATR can regulate cell life processes through a variety of signals, including cell cycle blockade, inhibition of replication origins, initiation of replication forks, and repair of DNA double strands (Enriquez-Rios V et al., 2017). ATR kinase works together with ATM (ataxia telangiectasia mutated) kinase and many other proteins to regulate cellular responses to DNA damage, commonly referred to as DNA damage response (DDR). When cells recognize DNA damage through DDR, they immediately activate the DNA repair program, activate cell cycle checkpoints, hinder the normal progress of the cell cycle, and thus provide time for DNA repair. Without DDR, cells are more sensitive to DNA damage caused by endogenous cell damage or chemotherapy and radiotherapy used to treat cancer, and are more susceptible to death.

[0003] Healthy cells can rely on different proteins for DNA repair, including ATM and ATR kinase in DDR. Under normal circumstances, these proteins can repair DNA by regulating downstream regulatory factors. However, many cancer cells have defects in the DNA repair pathway, showing a great dependence on the remaining intact DNA repair proteins, including ATR. ATR is a key member of the DDR that responds to damaged DNA replication. It is essential for maintaining the stability and integrity of the genome and promoting cell survival. When intracellular DNA damage occurs, ATR is recruited to the site of DNA damage, and a variety of proteins are then involved in regulating the activation of ATR. After ATR activation, it regulates some important cellular processes. Many cancer cells lack key tumor suppressor genes, which can make cancer cells more dependent on the ATR pathway than normal cells to regulate cell DNA damage repair and promote cell survival, making ATR a promising target for cancer treatment.

[0004] ATR inhibitors can be used alone or in combination with DNA damaging agents for cancer treatment; because they cut off the DNA replication mechanism, which is more important for cell survival in many cancer cells than in healthy normal cells. In fact, ATR inhibitors have been shown to be effective in cancer cells as single agents and as effective sensitizers for radiotherapy and chemotherapy. At the same time, ATR inhibitors can also be combined with other targeted drugs related to DDR, such as PARP inhibitors.

[0005] A variety of ATR kinase inhibitors have been disclosed, for example, WO2011154737 discloses morpholino pyrimidine compounds as ATR kinase inhibitors; WO2016020320 discloses 2-(morpholin-4-yl)-1,7-naphthyridine compounds as ATR kinase inhibitors. WO2018153968 discloses an ATR kinase inhibitor for the treatment of hyperproliferative diseases. WO2020049017 discloses 5-morpholino-4-yl-pyrazolo[4,3-b]pyridine derivatives as ATR kinase inhibitors. WO2020087170 discloses morpholino five-membered heterocyclic pyridine compounds as ATR kinase inhibitors. Summary of the invention

[0006] The present invention provides substituted fused heteroaromatic bicyclic compounds having structures as shown in Formula I, II, IIIa, IIIb and IV, and such compounds can be used as kinase inhibitors.

[0007] The present invention also provides a pharmaceutical composition comprising an effective amount of a compound of Formula I, II, IIIa, IIIb or IV for treating cancer.

[0008] In one embodiment, the pharmaceutical composition may further contain one or more pharmaceutically acceptable carriers or diluents for treating cancer.

[0009] In one embodiment, the pharmaceutical composition may further contain at least one known anticancer drug or a pharmaceutically acceptable salt of the anticancer drug for treating cancer.

[0010] The present invention also relates to methods for preparing novel compounds of formula I, II, IIIa, IIIb and IV. DETAILED DESCRIPTION

[0011] It should be understood that the features of the various embodiments described herein can be arbitrarily combined to form the technical solutions of this invention; the definition of each group herein is applicable to any embodiment described herein, for example, the definition of substituents of alkyl groups herein is applicable to any embodiment described herein, unless the embodiment has clearly defined substituents of alkyl groups.

[0012] Specifically, the present invention provides a compound represented by the following formula I, its stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or salts, or mixtures thereof, or prodrugs thereof: wherein A1 and A4-A6 are each independently CR5 or N; A2 and A3 are each independently C or N; preferably, when one of A2 and A3 is C, the other is N or C; more preferably, when one of A2 and A3 is N, the other is C; R1 is an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted cycloalkyl group, an optionally substituted heteroaryl group, Wherein, * indicates the connection position of the group to the rest of the compound; R2 is halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, –NR8R9, –(CO)R8, –(CO)OR8, –(CO)NR8R9, –(SO)R6, –(SO2)R6, –SR6, –(SO2)NR8R9, –NR8(SO2)R6, –((SO)=NR7)R 10 、–N=(SO)R6R 10 、–SiR7R 10 R 11 , –(PO)(OR8)2, –(PO)(OR8)R 10 or –(PO)(R 10 )2, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are each optionally substituted; wherein in -N=(SO)R6R 10 R6 and R in the group 10 together form a 5- to 8-membered heterocycloalkyl; R3 and R4 are each independently hydrogen or C1-C6 alkyl; R5 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, amino, nitro, cyano, amido, acyloxy, hydroxyl, sulfhydryl, alkylthio, azido or carboxyl; wherein the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, amino, amido, acyloxy, hydroxyl, sulfhydryl, alkylthio and carboxyl groups may each be optionally substituted; R6 is optionally substituted alkyl or optionally substituted alkylaryl (preferably phenyl); R7 is hydrogen, optionally substituted alkyl, -(CO)OR8 or -(CO)NR8R9; R8 and R9 are each independently hydrogen, an optionally substituted C1-C 10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or R8 and R9 together with the attached N and C form an optionally substituted 4- to 7-membered cyclic amino group, which optionally contains one or more additional heteroatoms selected from O, N and S; R 10 C1-C4 alkyl, or in –N=(SO)R6R 10 In the case of groups, R6 and R 10 Together with the attached S, they form a 5- to 8-membered heterocycloalkyl group; and R 11 It is hydrogen or C1-C4 alkyl.

[0013] In one or more embodiments, in the compound of formula I, A1 is N or CH. Preferably, A1 is N.

[0014] In one or more of the foregoing embodiments of the compound of formula I, at least 2 or 3 of A1, A2, A3, A4, A5 and A6 are N.

[0015] In one or more of the aforementioned embodiments of the compound of formula I, one of A2 and A3 is N and the other is C. Preferably, in some embodiments, in the compound of formula I, A2 is N and A3 is C.

[0016] In one or more of the foregoing embodiments of the compound of formula I, A5 is N or CH. Preferably, A5 is N.

[0017] In one or more of the foregoing embodiments of the compound of Formula I, at least A1, A2 and A5 are N.

[0018] In one or more of the foregoing embodiments of the compounds of Formula I, R5 is hydrogen.

[0019] In one or more of the foregoing embodiments of the compound of formula I, the five-membered and six-membered heteroaryl groups containing A2 and A3 are selected from the following groups: Preferably: More preferably: Wherein, *1, *2 and *3 represent the connection positions of the group with the morpholinyl group, R1 and R2 of the compound of formula I, respectively.

[0020] In one or more of the foregoing embodiments of the compound of Formula I, R2 is C3-C6 cycloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -NR8R9, -NR8(SO2)R6 or -N=(SO)R6R 10 , wherein the C3-C6 cycloalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are each optionally substituted; wherein R8 and R9 are each independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or optionally substituted phenyl; R 10 C1-C4 alkyl, or in –N=(SO)R6R 10 R6 and R 10 Together with the connected S, it forms a 5- to 8-membered heterocycloalkyl; preferably, R2 is an optionally substituted C3-C6 cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclyl or an optionally substituted heteroaryl; more preferably, the heteroaryl is a 5- or 6-membered heteroaryl containing at least one nitrogen atom, preferably a 5-membered heteroaryl containing two nitrogen atoms. Preferably, R2 is an optionally substituted cycloalkyl, an optionally substituted phenyl, an optionally substituted pyrazolyl, an optionally substituted pyrrolyl, an optionally substituted imidazolyl, an optionally substituted triazolyl, an optionally substituted furanyl, an optionally substituted morpholinyl, an optionally substituted dihydropyranyl, an optionally substituted tetrahydropyranyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl or an optionally substituted pyrrolopyridyl. Preferably, the substituent on R2 is selected from an optionally substituted C1-C6 alkyl, a cyano group, a hydroxyl group, a carboxyl group, an amino group, a halogen group, an optionally substituted alkanesulfinyl group and an optionally substituted alkanesulfonyl group. Preferably, the C1-C6 alkyl is optionally substituted by one or more substituents selected from halogen. The number of substituents on R2 may be 1-3.

[0021] In one or more of the aforementioned embodiments of the compound of formula I, R3 is hydrogen; R4 is C1-C4 alkyl, such as methyl. Preferably, R3 is in R configuration.

[0022] In the aforementioned one or more embodiments of the compound of formula I, R1 is an optionally substituted alkylsulfonyl, an optionally substituted aryl, an optionally substituted heterocyclic radical, an optionally substituted cycloalkyl or an optionally substituted heteroaryl. Preferably, heteroaryl is a 5- or 6-membered heteroaryl containing at least one nitrogen atom, preferably a 5-membered heteroaryl containing two nitrogen atoms. Preferably, the substituents of alkylsulfonyl, heterocyclic radical, cycloalkyl, aryl and heteroaryl can be selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy and amino. Preferably, the number of substituents on R1 can be 1-3. More preferably, R1 is a sulfonyl substituted by a C1-C4 alkyl, optionally substituted by 1 or 2 substituents selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy and amino, pyrazolyl, pyrrolyl or imidazolyl. In certain embodiments, R1 is unsubstituted pyrazolyl, pyrrolyl or imidazolyl.

[0023] In one or more of the foregoing embodiments of the compound of formula I, an isotopically substituted derivative of a compound of formula I is a compound in which one or more hydrogen atoms are replaced by one or more D atoms.

[0024] One group of preferred compounds of the present invention is represented by a compound of formula II or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or salt thereof, or a mixture thereof, or a prodrug thereof: wherein A1-A6, R1 and R4 are as described in Formula I; Cy is C3-C6 cycloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -NR8R9, -NR8(SO2)R6 or -N=(SO)R6R 10 , wherein the C3-C6 cycloalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl can each be optionally substituted; wherein R8 and R9 are each independently hydrogen, optionally substituted C1-C 10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R8 and R9 together are an optionally substituted 4- to 7-membered cyclic amino group, the cyclic amino group optionally containing one additional heteroatom selected from O, N and S; R 10 C1-C4 alkyl, or in –N=(SO)R6R 10 R6 and R 10 Together they form a 5- to 8-membered heterocycloalkyl.

[0025] In one or more of the foregoing embodiments of the compound of formula II, A1 is N or CH. Preferably, A1 is N.

[0026] In one or more of the aforementioned embodiments of the compound of formula II, one of A2 and A3 is N and the other is C. Preferably, in some embodiments, in the compound of formula II, A2 is N and A3 is C.

[0027] In one or more of the foregoing embodiments of the compound of formula II, A5 is N or CH. Preferably, A5 is N.

[0028] In one or more of the foregoing embodiments of the compound of Formula II, R5 is hydrogen.

[0029] In one or more of the foregoing embodiments of the compound of formula II, the five-membered and six-membered heteroaryl groups containing A2 and A3 are selected from the following groups: Preferably: More preferably: Wherein, *1, *2 and *3 represent the connection positions of the group with the morpholinyl group, R1 and R2 of the compound of formula II, respectively.

[0030] In one or more of the foregoing embodiments of the compound of formula II, Cy is C3-C6 cycloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -NR8R9, -NR8(SO2)R6 or -N=(SO)R6R 10 , wherein the C3-C6 cycloalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are each optionally substituted; wherein R8 and R9 are each independently hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted phenyl; R 10 C1-C4 alkyl, or in –N=(SO)R6R 10 R6 and R in the group 10 Together with the connected S, a 5- to 8-membered heterocycloalkyl is formed. Preferably, Cy is an optionally substituted C3-C6 cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic radical or an optionally substituted heteroaryl. Preferably, heteroaryl is a 5- or 6-membered heteroaryl containing at least one nitrogen atom, preferably a 5-membered heteroaryl containing two nitrogen atoms. More preferably, Cy is an optionally substituted cyclopropyl, an optionally substituted phenyl, an optionally substituted pyrazolyl, an optionally substituted pyrrolyl, an optionally substituted imidazolyl, an optionally substituted triazolyl, an optionally substituted furanyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl, an optionally substituted morpholinyl, an optionally substituted dihydropyranyl, an optionally substituted tetrahydropyranyl or an optionally substituted pyrrolopyridyl. Preferably, the substituent on Cy is selected from C1-C6 alkyl, cyano, hydroxyl, carboxyl, amino, halogen, alkanesulfinyl and alkanesulfonyl. The number of substituents can be 1-3. In some embodiments, Cy is pyrazolyl optionally substituted by 1 or more (preferably 1, 2 or 3) C1-C6 alkyl groups; and preferably one or two ring N atoms of the pyrazolyl group are substituted; preferably, the C1-C6 alkyl group may be further substituted by one or more (such as 1-5) halogens. In some embodiments, Cy is pyrazolyl optionally substituted by one or two substituents selected from unsubstituted C1-C4 alkyl groups and C1-C4 alkyl groups substituted by 1-3 halogens.

[0031] In one or more of the above embodiments of the compound of formula II, R4 is a C1-C4 alkyl group, such as a methyl group. Preferably, R4 is in the R configuration.

[0032] In the aforementioned one or more embodiments of the compound of formula II, R1 is an optionally substituted alkylsulfonyl, an optionally substituted aryl, an optionally substituted heterocyclic radical, an optionally substituted cycloalkyl or an optionally substituted heteroaryl. Preferably, heteroaryl is a 5- or 6-membered heteroaryl containing at least one nitrogen atom, preferably a 5-membered heteroaryl containing two nitrogen atoms. Preferably, the substituents of alkylsulfonyl, aryl, heterocyclic radical, cycloalkyl and heteroaryl can be selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy and amino. Preferably, the number of substituents can be 1-3. More preferably, R1 is a sulfonyl substituted by a C1-C4 alkyl or a pyrazolyl, pyrrolyl or imidazolyl optionally substituted by 1 or 2 selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy and amino. In some embodiments, R1 is an unsubstituted pyrazolyl, an unsubstituted pyrrolyl or an unsubstituted imidazolyl.

[0033] One group of preferred compounds of the present invention is represented by compounds of formula IIIa and IIIb or stereoisomers, tautomers, N-oxides, hydrates, isotopically substituted derivatives, solvates or salts thereof, or mixtures thereof, or prodrugs thereof: wherein A1, A4, A5, A6, R1, R2 and R4 are as described in Formula I or Formula II.

[0034] In one or more of the foregoing embodiments of the compounds of formula IIIa and IIIb, A1 is N or CH. Preferably, A1 is N.

[0035] In one or more of the foregoing embodiments of the compounds of formula IIIa and IIIb, A4 is N or CH. Preferably, A4 is CH.

[0036] In one or more of the foregoing embodiments of the compounds of formula IIIa and IIIb, A5 is N or CH. Preferably, A5 is N.

[0037] In one or more of the foregoing embodiments of the compounds of formula IIIa and IIIb, A6 is N or CH. Preferably, A6 is CH.

[0038] In one or more of the foregoing embodiments of the compounds of formula IIIa and IIIb, the five-membered and six-membered heteroaryl groups containing A1, A4, A5 and A6 are selected from the following groups: Preferably: More preferably: Wherein, *1, *2 and *3 represent the connection positions of the group with the morpholinyl group, R1 and R2 of the compounds of formula IIIa and IIIb, respectively.

[0039] In the aforementioned one or more embodiments of the compound of formula IIIa and IIIb, R1 is an optionally substituted alkylsulfonyl, an optionally substituted aryl, an optionally substituted heterocyclic radical, an optionally substituted cycloalkyl or an optionally substituted heteroaryl. Preferably, the heteroaryl is a 5- or 6-membered heteroaryl containing at least one nitrogen atom, preferably a 5-membered heteroaryl containing two nitrogen atoms. Preferably, the substituents of heterocyclic radicals, cycloalkyls, aryls and heteroaryls can be selected from C1-C4 alkyls, halogens, hydroxyls, C1-C4 alkoxys and aminos. Preferably, the number of substituents can be 1-3. More preferably, R1 is a sulfonyl substituted by a C1-C4 alkyl or a pyrazolyl, pyrrolyl and imidazolyl optionally substituted by 1 or 2 selected from C1-C4 alkyls, halogens, hydroxyls, C1-C4 alkoxys and aminos. In some embodiments, R1 is an unsubstituted pyrazolyl, an unsubstituted pyrrolyl or an unsubstituted imidazolyl.

[0040] In one or more of the foregoing embodiments of the compounds of formula IIIa and IIIb, R2 is C3-C6 cycloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -NR8R9, -NR8(SO2)R6 or -N=(SO)R6R 10 , wherein the C3-C6 cycloalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are each optionally substituted; wherein R8 and R9 are each independently hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted phenyl; R 10 C1-C4 alkyl, or in –N=(SO)R6R 10 R6 and R 10Together with the connected S, a 5- to 8-membered heterocycloalkyl is formed. Preferably, heteroaryl is a 5- or 6-membered heteroaryl containing at least one nitrogen atom, preferably a 5-membered heteroaryl containing two nitrogen atoms. Preferably, R2 is an optionally substituted C3-C6 cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic radical or an optionally substituted heteroaryl. More preferably, R2 is an optionally substituted cyclopropyl, an optionally substituted phenyl, an optionally substituted pyrazolyl, an optionally substituted pyrrolyl, an optionally substituted imidazolyl, an optionally substituted triazolyl, an optionally substituted furanyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl, an optionally substituted morpholinyl, an optionally substituted dihydropyranyl, an optionally substituted tetrahydropyranyl or an optionally substituted pyrrolopyridyl. Preferably, the substituent on R2 is selected from C1-C6 alkyl, cyano, hydroxyl, carboxyl, amino, halogen, an optionally substituted alkanesulfinyl and an optionally substituted alkanesulfonyl. The number of substituents can be 1-3. In some embodiments, R2 is pyrazolyl optionally substituted by C1-C6 alkyl, preferably one or two ring N atoms of the pyrazolyl are substituted. More preferably, C1-C6 alkyl can be further substituted by one or more (such as 1-5) halogens. In some embodiments, R2 is pyrazolyl optionally substituted by one or two C1-C4 alkyl substituents selected from unsubstituted C1-C4 alkyl and substituted by 1-3 halogens.

[0041] In one or more of the foregoing embodiments of the compounds of formula IIIa and IIIb, R4 is C1-C4 alkyl, such as methyl.

[0042] One group of preferred compounds of the present invention is represented by a compound of formula IV or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or salt thereof, or a mixture thereof, or a prodrug thereof: wherein A4, A5, A6, R1, R2 and R4 are as described in Formula I, II, IIIa or IIIb;

[0043] In one or more of the foregoing embodiments of the compound of formula IV, A4 is N or CH. Preferably, A4 is CH.

[0044] In one or more of the foregoing embodiments of the compound of formula IV, A5 is N or CH. Preferably, A5 is N.

[0045] In one or more of the foregoing embodiments of the compound of formula IV, A6 is N or CH. Preferably, A6 is CH.

[0046] In one or more of the foregoing embodiments of the compound of formula IV, the five-membered and six-membered heteroaryl groups containing A4, A5 and A6 are selected from the following groups: Preferably: Wherein, *1, *2 and *3 represent the connection positions of the group with the morpholinyl group, R1 and R2 of the compound of formula IV, respectively.

[0047] In the aforementioned one or more embodiments of the compound of formula IV, R1 is an optionally substituted alkylsulfonyl, an optionally substituted aryl, an optionally substituted heterocyclic radical, an optionally substituted cycloalkyl or an optionally substituted heteroaryl. Preferably, the heteroaryl is a 5- or 6-membered heteroaryl containing at least one nitrogen atom, preferably a 5-membered heteroaryl containing two nitrogen atoms. Preferably, the substituents of the alkylsulfonyl, heterocyclic radical, aryl and heteroaryl can be selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy and amino. Preferably, the number of substituents can be 1-3. More preferably, R1 is a sulfonyl substituted by a C1-C4 alkyl or a pyrazolyl, pyrrolyl or imidazolyl optionally substituted by 1 or 2 selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy and amino. In some embodiments, R1 is an unsubstituted pyrazolyl, an unsubstituted pyrrolyl or an unsubstituted imidazolyl.

[0048] In one or more of the foregoing embodiments of the compound of formula IV, R2 is C3-C6 cycloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -NR8R9, -NR8(SO2)R6 or -N=(SO)R6R 10 , wherein the C3-C6 cycloalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are each optionally substituted; wherein R8 and R9 are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl or optionally substituted phenyl; R 10 C1-C4 alkyl, or in –N=(SO)R6R 10 R6 and R in the group 10Together with the connected S, a 5- to 8-membered heterocycloalkyl is formed. Preferably, heteroaryl is a 5- or 6-membered heteroaryl containing at least one nitrogen atom, preferably a 5-membered heteroaryl containing two nitrogen atoms. Preferably, R2 is an optionally substituted C3-C6 cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic radical or an optionally substituted heteroaryl. More preferably, R2 is an optionally substituted cyclopropyl, an optionally substituted phenyl, an optionally substituted pyrazolyl, an optionally substituted pyrrolyl, an optionally substituted imidazolyl, an optionally substituted triazolyl, an optionally substituted furanyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl, an optionally substituted morpholinyl, an optionally substituted dihydropyranyl, an optionally substituted tetrahydropyranyl or an optionally substituted pyrrolopyridyl. Preferably, the substituent on R2 is selected from an optionally substituted C1-C6 alkyl, a cyano group, a hydroxyl, a carboxyl group, an amino group, a halogen, an optionally substituted alkanesulfinyl and an optionally substituted alkanesulfonyl. The number of substituents can be 1-3. In some embodiments, R is a pyrazolyl optionally substituted by a C1-C6 alkyl, preferably one or two ring N atoms of the pyrazolyl are substituted. More preferably, the C1-C6 alkyl can be further substituted by one or more (such as 1-5) halogens. In some embodiments, R is a pyrazolyl optionally substituted by one or two substituents selected from unsubstituted C1-C4 alkyl and C1-C4 alkyl substituted by 1-3 halogens.

[0049] In one or more of the foregoing embodiments of the compound of formula IV, R4 is C1-C4 alkyl, such as methyl.

[0050] In one or more of the foregoing embodiments of the compounds of Formula I, II, III and IV, the five-membered and six-membered heteroaryl groups are selected from the following groups: Preferably: R1 is selected from alkylsulfonyl, heteroaryl substituted by 1-3 substituents selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy and amino (preferably pyrazolyl, pyrrolyl and imidazolyl), aryl substituted by 1-3 substituents selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy and amino, heterocyclyl substituted by 1-3 substituents selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy and amino, and cycloalkyl substituted by 1-3 substituents selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy and amino; preferably, R1 is heteroaryl substituted by 1-3 substituents selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy and amino (preferably pyrazolyl, pyrrolyl and imidazolyl) or alkylsulfonyl. R2 or Cy is selected from optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted heteroaryl; more preferably, R2 or Cy is selected from optionally substituted cyclopropyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted triazolyl, optionally substituted furanyl, optionally substituted morpholinyl, optionally substituted dihydropyranyl, optionally substituted tetrahydropyranyl, optionally substituted Preferably, the substituents of R2 or Cy are selected from C1-C6 alkyl, cyano, alkylsulfinyl, halogen, hydroxyl, carboxyl, amino and alkylsulfonyl, and the number of substituents is preferably 1-3; More preferably, R2 or Cy is pyrazolyl optionally substituted by unsubstituted C1-C6 alkyl or C1-C6 alkyl substituted by 1-3 halogens, and one or two ring N atoms of the pyrazolyl are preferably substituted. R3 is H; and R4 is a C1-C4 alkyl group, preferably a methyl group.

[0051] In one or more of the foregoing embodiments of the compound of formula I, A1 is N, A2 is N, A3 is C, A4 is CR5, A5 is CR5, and A6 is N; R1 is a heteroaryl group (preferably pyrazolyl, pyrrolyl and imidazolyl) optionally substituted by 1-2 C1-C4 alkyl groups, for example, a pyrazolyl group optionally substituted by a C1-C3 alkyl group; R2 is a heteroaryl group (preferably pyrazolyl, pyridyl, pyrrolopyridyl and imidazolyl) optionally substituted by one or two C1-C4 alkyl groups, an aryl group (preferably phenyl) optionally substituted by 1-2 C1-C4 alkylsulfonyl groups and halogens, or a heterocyclyl group (preferably morpholinyl) optionally substituted by one or two C1-C4 alkyl groups, such as 2,6-di(C1-C4 alkyl)-morpholinyl; one of R3 and R4 is H and the other is C1-C4 alkyl; each R5 is independently H or C1-C4 alkyl, preferably H.

[0052] In one or more of the foregoing embodiments of the compound of formula I, A1 is N, A2 is N, A3 is C, A4 is CR5, A5 is N, A6 is CR5; R1 is a heteroaryl group (preferably pyrazolyl, pyrrolyl and imidazolyl, more preferably pyrazolyl) optionally substituted with 1-2 C1-C4 alkyl groups, for example, a pyrazolyl group optionally substituted with a C1-C3 alkyl group; R2 is a substituted group selected from halogen, C1-C4 alkylsulfonyl, C1-C4 alkylsulfinyl, C1-C4 alkyl optionally substituted with 1-3 halogens; substituted heteroaryl (preferably pyrazolyl, pyrrolyl, pyridinyl, pyrrolopyridinyl, pyrimidinyl, triazolyl and imidazolyl); aryl (preferably phenyl) optionally substituted by 1-2 substituents selected from C1-C4 alkyl, cyano, C1-C4 alkylsulfonyl and halogen; or heterocyclyl (preferably morpholinyl, dihydropyranyl and tetrahydropyranyl) optionally substituted by one or two C1-C4 alkyl; R3 and R4 are each independently selected from H and C1-C4 alkyl; each R5 is independently H or C1-C4 alkyl, preferably H.

[0053] In one or more of the aforementioned embodiments of the compound of formula I, A1 is N, A2 is N, A3 is C, A4 is CR5, A5 is N, and A6 is CR5; R1 is pyrazolyl optionally substituted by C1-C3 alkyl; R2 is pyrazolyl optionally substituted by one or two substituents selected from unsubstituted C1-C4 alkyl and C1-C4 alkyl substituted by 1-3 halogens; R3 and R4 are each independently selected from H and C1-C4 alkyl; each R5 is H or C1-C4 alkyl, preferably H. In a more preferred embodiment, R2 is pyrazolyl optionally substituted by one or two substituents selected from unsubstituted C1-C4 alkyl and C1-C4 alkyl substituted by 1-3 halogens, and at most one of the nitrogen atoms of the pyrazolyl is substituted by a substituent, preferably one nitrogen atom of the pyrazolyl is substituted. In a more preferred or optional embodiment, one of R3 and R4 is H and the other is methyl.

[0054] In one or more of the foregoing embodiments of the compound of Formula I, A1 and A4-A6 are each independently N or CR5; A2 and A3 are each independently C or N; R1 is pyrazolyl optionally substituted by C1-C3 alkyl; R2 is pyrazolyl optionally substituted by one or two substituents selected from unsubstituted C1-C4 alkyl and C1-C4 alkyl substituted by 1-3 halogens; R3 and R4 are each independently selected from H and C1-C4 alkyl; each R5 is each independently H or C1-C4 alkyl, preferably H.

[0055] In one or more of the foregoing embodiments, preferred examples of compounds of formula I include but are not limited to: (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine (Example 1); (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 2); (R)-3-methyl-4-(8-(1-ethyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 3); (R)-3-methyl-4-(8-(1-isopropyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 4); (R)-3-methyl-4-(8-(1-methyl-1H-imidazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 5); (R)-3-methyl-4-(8-(6-methylpyridin-3-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 6); (R)-3-methyl-4-(8-(4-(methylsulfonyl)phenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 7); (R)-3-methyl-4-(8-(2-fluorophenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 8); (R)-3-methyl-4-(8-morpholinyl-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 9); (2S,6R)-2,6-dimethyl-4-(6-((R)-3-methylmorpholinyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine (Example 10); 4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 11); 4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine (Example 12); (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 13); (R)-3-methyl-4-(3-(1H-pyrazol-5-yl)-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 14); (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine (Example 15); (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (Example 16); (R)-3-methyl-4-(5-(methylsulfonyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolo[1,2-c]pyrimidin-3-yl)morpholine (Example 17); (R)-3-methyl-4-(1-(methylsulfonyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,5-c]pyrimidin-7-yl)morpholine (Example 18); (R)-3-methyl-4-(6-(methylsulfonyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolo[1,2-a]pyrazin-3-yl)morpholine (Example 19); (R)-3-methyl-4-(3-(methylsulfonyl)-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)morpholine (Example 20); (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-3-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 21); (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-2-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 22); (R)-4-(7-(1H-imidazol-4-yl)-4-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 23); (R)-3-methyl-4-(4-(6-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 24); (R)-4-(4-(2-fluorophenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 25); (R)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 26); (R)-4-(4,7-di(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 27); (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-2-yl)morpholine (Example 28); (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-3-yl)imidazo[5,1-f][1,2,4]triazin-2-yl)morpholine (Example 29); (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[3,4-f][1,2,4]triazin-6-yl)morpholine (Example 30); (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5-a][1,3,5]triazin-2-yl)morpholine (Example 31); (R)-4-(4-cyclopropyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 32); (S)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 33); (3R,5R)-3,5-dimethyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 34); (R)-3-methyl-4-(4-(4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 35); (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 36); (R)-4-(4-(1-ethyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 37); (R)-3-methyl-4-(4-(3-methyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 38); (R)-3-methyl-4-(7-(3-methyl-1H-pyrazol-5-yl)-4-(6-methylpyridin-3-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 39); (R)-4-(7-(1H-pyrazol-5-yl)-4-(o-methylphenyl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 40); (R)-4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 41); (R)-3-methyl-4-(4-(2-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 42); (R)-4-(4-(3-fluoropyridin-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 43); (R)-3-methyl-4-(4-(4-methyl-6-(methylsulfonyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 44); (R)-3-methyl-4-(4-(4-methylpyrimidin-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 45); (R)-3-methyl-4-(4-morpholinyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 46); (R)-4-(7-(1H-pyrazol-5-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 47); (R)-3-methyl-4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 48); (R)-3-methyl-4-(4-(2-methyl-4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 49); (3R)-3-methyl-4-(4-(2-methyl-6-(methylsulfinyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 50); (R)-3-methyl-4-(4-(3-methylpyridin-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 51); (R)-3-(2-(3-methylmorpholinyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl)benzonitrile (Example 52); (R)-4-(4-(3,6-dihydro-2H-pyran-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 53); (R)-4-(7-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 54); (R)-4-(7-(1H-pyrazol-5-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 55); (R)-4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 56); (R)-3-methyl-4-(4-(1-methyl-1H-imidazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 57); (R)-4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 58); (R)-4-(4-(1,5-dimethyl-1H-1,2,3-triazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 59); (R)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 60); (R)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 61); (R)-4-(4-(1-(difluoromethyl)-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 62); (R)-4-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 63); or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0056] Herein, A1-A6 should be selected so that the formed ring satisfies the bond valence theory.

[0057] As used herein, "hydrogen (H)" includes isotopes D and T thereof.

[0058] As used herein, "alkyl" refers to an alkyl group itself or a straight or branched chain group of up to ten carbon atoms. Useful alkyl groups include straight or branched C1-C 10 In some embodiments, the alkyl group is a C1-C4 alkyl group. 10 The alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups which may be optionally substituted.

[0059] As used herein, "alkenyl" refers to a straight or branched chain containing 2 to 10 carbon atoms, unless the carbon chain length is otherwise limited, wherein at least one double bond is contained between two carbon atoms in the chain; preferably C2-C6 alkenyl. Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

[0060] As used herein, "alkynyl" refers to a straight or branched chain containing 2 to 10 carbon atoms, unless the carbon chain length is otherwise limited, wherein at least one triple bond is contained between two carbon atoms in the chain; preferably C2-C6 alkynyl. Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.

[0061] Useful alkoxy groups include those having the above C1-C 10 Alkyl, preferably C1-C6 alkyl or C1-C4 alkyl substituted oxy, such as methoxy, ethoxy, etc. The alkyl in the alkoxy group may be optionally substituted. The substituent of the alkoxy group includes but is not limited to halogen, morpholinyl, amino, the amino group includes alkylamino and dialkylamino and carboxyl (including ester groups thereof).

[0062] Useful alkylthio groups include the above-mentioned C1-C 10 An alkyl-, preferably C1-C6-alkyl-substituted thio group, wherein the alkyl group in the alkylthio group may be optionally substituted. Also included are the sulfoxides and sulfones of such alkylthio groups.

[0063] Useful amino groups and optionally substituted amino groups include -NH2, -NHR8 and -NR8R9, wherein R8 and R9 are each independently hydrogen, optionally substituted C1-C 10 R8 and R9 together with the N to which they are attached form an optionally substituted 4- to 7-membered cyclic amino group, which optionally contains one or more (e.g., 2 or 3) additional heteroatoms selected from O, N and S.

[0064] As used herein, "aryl" refers to an aromatic group, either by itself or as part of another group, containing 6 to 14 carbon atoms, a monocyclic, bicyclic or tricyclic aromatic group. The aryl group may be substituted with one or more substituents described herein.

[0065] Useful aromatic groups include C6-C 14 Aryl, preferably C6-C 10 Aryl. Typically C6-C 14 Aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylene and fluorenyl.

[0066] As used herein, "carbocycle" includes cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl is C3-C8 cycloalkyl. Typical cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The carbocyclic group may be substituted with one or more substituents described herein.

[0067] Useful partially saturated carbocyclic groups include cycloalkenyl groups, such as C3-C8 cycloalkenyl groups, for example cyclopentenyl, cycloheptenyl and cyclooctenyl.

[0068] Useful halogens or halogen groups include fluorine, chlorine, bromine and iodine.

[0069] Useful acylamino (acylamino) is any C1-C6 acyl (alkanoyl) attached to the amino nitrogen, such as acetamido, acetamido, propionamido, butyrylamino, valeramido and acylamino, and aryl-substituted C1-C6 acylamino, such as benzamido. Useful acyl groups include C1-C6 acyl groups, such as acetyl. Acyl groups may be optionally substituted by groups selected from aryl and halogen, wherein aryl groups may be optionally substituted. When substituted by halogen, the number of halogen substituents may be in the range of 1-5. Examples of substituted acyl groups include chloroacetyl and pentafluorobenzoyl, etc.

[0070] Useful acyloxy groups are any C1-C6 acyl (alkanoyl) groups attached to oxygen (—O—), such as formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy, and hexanoyloxy.

[0071] As used herein, heterocycle (heterocyclic group) refers to a saturated or partially saturated 3-7-membered monocyclic ring, or a 7-10-membered bicyclic ring system, which is composed of carbon atoms and 1-4 heteroatoms selected from O, N, and S, wherein the heteroatoms nitrogen and sulfur can be oxidized at will, and the nitrogen can be quaternized at will, and includes the fusion of any heterocycle defined above with a benzene ring in the bicyclic ring system. If the resulting compound is stable, the carbon atoms or nitrogen atoms of the heterocycle can be substituted. The heterocyclic group can be substituted with one or more substituents described herein.

[0072] Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, 1,4-diazepanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetrahydroisoquinolinyl, tetronoyl and tetramoyl, which groups may be substituted with one or more substituents as described herein.

[0073] As used herein, "heteroaromatic ring" refers to a ring containing 5-14 ring atoms, and 6, 10 or 14 π electrons are shared in the ring system. The ring atoms are carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen and sulfur. The heteroaryl group may be substituted with one or more substituents described herein.

[0074] Useful heteroaryl groups include thienyl (phenylthio), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, xanthrenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (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, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl , β-carbolinyl, phenanthridinyl, acridinyl, perylene, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido[1,2-a]pyrimidin-4-one, tetrahydropenta[c]pyrazol-3-yl, benzisoxazolyl such as 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-hydroxyindolyl, thiadiazolyl, 2-oxobenzimidazolyl, imidazopyridazinyl, imidazopyridinyl, triazolopyridazinyl, pyrazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl or triazolopyrazinyl. When the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, for example, pyridinyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.

[0075] Herein, unless otherwise specified, when substituted, C1-C 10 The alkyl, cycloalkyl, heterocycloalkyl, alkoxy, heterocycloalkoxy, alkenyl, heterocycloalkenyl, alkynyl, amino, amido, acyloxy, carboxyl, hydroxyl, thiol, alkylthio, sulfonyl, sulfinyl, silyl, phosphono, phosphono, carbocyclyl, heterocyclyl, aryl or heteroaryl group may be substituted by one or more (e.g., 1, 2, 3 or 4) substituents selected from the group consisting of halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C6 10 The substituents may be substituted with halogen, hydroxy, carboxyl, amino, C1-C6 acylamino, C1-C6 acyloxy, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 acyloxy, C1-C6 alkyl, C1-C6 acyloxy, C1-C6 alkyl, C1-C6 acyloxy, and alkylsulfonyl.

[0076] It should be understood that in each embodiment herein, when the substituent is a heterocyclic group, an aryl group or a heteroaryl group, the number of the heterocyclic group, the aryl group or the heteroaryl group substituent is usually one.

[0077] Some of the compounds of the present invention may exist as stereoisomers, including optical isomers. The present invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as individual enantiomers which may be separated according to methods well known to those skilled in the art.

[0078] Examples of pharmaceutically acceptable salts include inorganic and organic acid salts, such as hydrochlorides, hydrobromides, phosphates, sulfates, citrates, lactates, tartrates, maleates, fumarates, mandelates and oxalates; and inorganic and organic base salts formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methylglucamine.

[0079] Examples of prodrugs of the compounds of the invention include simple esters of carboxylic acid-containing compounds (e.g., esters obtained by condensation with C1-C4 alcohols according to methods known in the art); esters of hydroxyl-containing compounds (e.g., esters obtained by condensation with C1-C4 carboxylic acids, C3-C6 diacids or their anhydrides, such as succinic anhydride and fumaric anhydride, according to methods known in the art); imines of amino-containing compounds (e.g., imines obtained by condensation with C1-C4 aldehydes or ketones according to methods known in the art); carbamates of amino-containing compounds, such as those described by Leu et al. (J. Med. Chem. 42:3623-3628 (1999)) and Greenwald et al. (J. Med. Chem. 42:3657-3667 (1999)); acetals or ketal acetals 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).

[0080] The present invention also includes all suitable isotopic derivatives of the compounds or their pharmaceutically acceptable salts. An isotopic derivative of a compound or its pharmaceutically acceptable salt of the present invention means that at least one atom is replaced by an atom with the same atomic number but an atomic mass different from the atomic mass found in nature. Isotopes of the compounds of the present invention and their pharmaceutically acceptable salts include, but are not limited to, H, C, N and O. For example, 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 35 S. 18 F. 36 Cl and125 I. Isotopic derivatives of the compounds of the present invention or pharmaceutically acceptable salts thereof can be prepared by conventional techniques using appropriate isotopic reagents.

[0081] The compounds of the present invention can be prepared using methods known to those skilled in the art or the novel methods of the present invention. The present invention describes novel methods for preparing compounds of formula I, II, IIIa, IIIb or IV, such as reaction schemes 1-7. Specifically, the compounds of the present invention having formula I can be prepared as shown in the reaction example in reaction scheme 1. 6-Chloro-8-bromoimidazo[1,2-b]pyridazine, N-iodosuccinimide and trifluoroacetic acid are reacted in chloroform at room temperature to obtain the product 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine. 8-Bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine and 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester are heated and reacted in a mixed solvent of dioxane and water under the catalysis of potassium phosphate trihydrate and tetrakistriphenylphosphine palladium to obtain the product 8-bromo-6-chloro-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine. 8-Bromo-6-chloro-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine and 1-methyl-1H-pyrazol-5-boronic acid pinacol ester are heated and reacted in a mixed solvent of dioxane and water under the catalysis of potassium phosphate trihydrate and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium to obtain the product 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine. 6-Chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine and (R)-3-methylmorpholine are reacted in toluene under heating under the catalysis of sodium tert-butoxide and tris(dibenzylideneacetone)dipalladium to obtain the product (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine-6-yl)morpholine. (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine and concentrated hydrochloric acid are reacted in ethanol at room temperature to obtain the target compound (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine. Reaction Scheme 1

[0082] Other related compounds can be prepared by similar methods. For example, replacing 1-methyl-1H-pyrazole-5-boronic acid pinacol ester with 1-methyl-1H-imidazol-5-boronic acid pinacol ester can obtain the target compound (R)-3-methyl-4-(8-(1-methyl-1H-imidazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine-6-yl)morpholine. Replacing 6-chloro-8-bromoimidazo[1,2-b]pyridazine with 8-bromo-6-chloroimidazo[1,2-a]pyridine can obtain the target compound (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine. The target compound (R)-3-methyl-4-(8-(6-methylpyridin-3-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine was prepared by replacing 1-methyl-1H-pyrazol-5-boric acid pinacol ester with 6-methylpyridine-3-boric acid pinacol ester. The target compound (R)-3-methyl-4-(8-(4-(methylsulfonyl)phenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine was prepared by replacing 1-methyl-1H-pyrazol-5-boric acid pinacol ester with 4-(methylsulfonyl)phenylboric acid pinacol ester.

[0083] The compounds of the present invention can be prepared as shown in the reaction example in Reaction Scheme 2. 8-Bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine, morpholine and DIEA are heated in THF to give the product 4-(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)morpholine. 4-(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)morpholine, 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester, Pd(PPh3)4 and K3PO4 aqueous solution are heated in dioxane to give the product 4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine. 4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine, (R)-3-methylmorpholine, t-BuONa, Pd(dba)2 and diphenyl phosphine were heated in toluene to give the product (3R)-3-methyl-4-(8-morpholine-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine. (3R)-3-methyl-4-(8-morpholin-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine and HCl methanol solution were reacted in methanol at room temperature to obtain the target compound (R)-3-methyl-4-(8-morpholinyl-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine. Reaction Scheme 2

[0084] Other related compounds can be prepared by similar methods. For example, using (2S,6R)-2,6-dimethylmorpholine instead of morpholine can produce the target compound (R)-3-methyl-4-(8-(2S,6R)-2,6-dimethylmorpholine-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine.

[0085] The compounds of the present invention can be prepared as shown in the reaction example in Reaction Scheme 3. 4-Bromo-1,2-dihydropyridazine-3,6-dione, (1-methyl-1H-pyrazol-5-yl)boric acid, potassium phosphate aqueous solution and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2) are heated in N,N-dimethylformamide (DMF) under nitrogen protection to obtain the product 4-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydropyridazine-3,6-dione. 4-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydropyridazine-3,6-dione and phosphorus oxychloride are heated to obtain the product 3,6-dichloro-4-(1-methyl-1H-pyrazol-5-yl)pyridazine. 3,6-Dichloro-4-(1-methyl-1H-pyrazol-5-yl)pyridazine and (R)-3-methylmorpholine are heated in N-methylpyrrolidone in the presence of N,N-diisopropylethylamine (DIEA) and CuBr to give the product (R)-4-(6-chloro-5-(1-methyl-1H-pyrazol-5-yl)pyridazine-3-yl)-3-methylmorpholine. (R)-4-(6-chloro-5-(1-methyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholine and Zn(CN)2 react in DMF and a small amount of water under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (DPPF) and Pd2(dba)3 to obtain the product (R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazine-3-carbonitrile. (R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazine-3-carbonitrile reacts at room temperature under hydrogen atmosphere under the catalysis of Raney nickel to obtain the product (R)-(4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazin-3-yl)methylamine. (R)-(4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazin-3-yl)methanamine and 1H-pyrazole-5-carboxylic acid are reacted in the presence of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and DIEA at room temperature in DMF to give the product N-((4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholinyl)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide. N-((4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholinyl)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide was heated in POCl3 to give the target compound (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine. Reaction Scheme 3

[0086] Other related compounds can be prepared by similar methods. For example, morpholine can be used to replace (R)-3-methylmorpholine to obtain the target compound 4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine; 1H-pyrrole-3-carboxylic acid can be used to replace 1H-pyrazole-5-carboxylic acid to obtain the target compound (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrole-3-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; 1H-imidazole-4-carboxylic acid can be used to replace 1H-pyrazole-5-carboxylic acid to obtain the target compound (R)-4-(7-(1H-imidazole-4-yl)-4 -(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (6-methylpyridin-3-yl)boric acid was used to replace (1-methyl-1H-pyrazol-5-yl)boric acid to obtain the target compound (R)-3-methyl-4-(4-(6-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (2-fluorophenyl)boric acid was used to replace (1-methyl-1H-pyrazol-5-yl)boric acid to obtain the target compound (R)-4-(4-(2-fluorophenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine.

[0087] The compounds of the present invention can be prepared as shown in the reaction example in Reaction Scheme 4. 3,6-dichloropyridazin-4-amine, hexane-2,5-dione and TsOH·H2O are heated in toluene to react to obtain the product 3,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine. 3,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine, (R)-3-methylmorpholine and DIEA are heated in NMP to react to obtain the product (R)-4-(6-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazin-3-yl)-3-methylmorpholine. (R)-4-(6-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine-3-yl)-3-methylmorpholine, Zn(CN)2, DPPF, Pd2(dba)3 and water were heated in DMF to give the product (R)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholine)pyridazine-3-carbonitrile. (R)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholine)pyridazine-3-carbonitrile was reacted at room temperature under H2 atmosphere and Raney nickel catalysis to give the product (R)-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholine)pyridazine-3-yl)methylamine. (R)-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methylamine, 1H-pyrazole-5-carboxylic acid, HATU and DIEA were added with K2CO3 in DMF and reacted at room temperature to obtain the product (R)-N-((4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide. (R)-N-((4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide was heated in POCl3 to give the product (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine. (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine was heated in TFA / H2O to give the product (R)-2-(3-methylmorpholine)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-ol.(R)-2-(3-methylmorpholino)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-ol and TEA were reacted in dry DCM at 0°C, and then Tf2O was added to react from 0°C to room temperature to give the product (R)-2-(3-methylmorpholino)-7-(1-((trifluoromethyl)sulfonyl)-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl trifluoromethanesulfonate. (R)-2-(3-methylmorpholine)-7-(1-((trifluoromethyl)sulfonyl)-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl trifluoromethanesulfonate, 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, K2CO3 and Pd(dppf)Cl2 were heated in dioxane for reaction, and then LiOH solution was added for reaction at room temperature to obtain the target compound (R)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine. Reaction Scheme 4

[0088] Other related compounds can be prepared by similar methods. For example, the target compound (R)-4-(7-(1H-pyrazol-5-yl)-4-(o-tolyl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine can be prepared by replacing 1-isopropyl-5-(4,4,5,5-tetramethyl-2-o-tolyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole with 4,4,5,5-tetramethyl-2-o-tolyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole. The target compound (R)-4-(4-(3-fluoropyridin-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine was prepared by replacing 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The target compound (R)-3-methyl-4-(4-(4-methylpyrimidin-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine was prepared by replacing 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine. The target compound (R)-4-(7-(1H-pyrazol-5-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine was prepared by replacing 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[0089] The compounds of the present invention can be prepared as shown in the reaction example in Reaction Scheme 5. 4,6-Dichloro-3-methylpyridazine, (R)-3-methylmorpholine and DIEA are heated in NMP to give the product (R)-4-(5-chloro-6-methylpyridazin-3-yl)-3-methylmorpholine. (R)-4-(5-chloro-6-methylpyridazin-3-yl)-3-methylmorpholine is heated with SeO2 in 1,4-dioxane to give the product (R)-4-chloro-6-(3-methylmorpholino)pyridazine-3-carboxaldehyde. (R)-4-chloro-6-(3-methylmorpholino)pyridazine-3-carboxaldehyde, (2,4-dimethoxyphenyl)methylamine and AcOH were first stirred in DCE at room temperature, and then NaBH(OAc)3 was added to react at room temperature to obtain the product (R)-1-(4-chloro-6-(3-methylmorpholino)pyridazine-3-yl)-N-(2,4-dimethoxybenzyl)methylamine. (R)-1-(4-chloro-6-(3-methylmorpholino)pyridazine-3-yl)-N-(2,4-dimethoxybenzyl)methylamine was heated in TFA to obtain the product (R)-(4-chloro-6-(3-methylmorpholino)pyridazine-3-yl)methylamine. (R)-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)methanamine, 1H-pyrazole-5-carboxylic acid, HATU and DIEA react at room temperature in DMF to obtain the product (R)-N-((4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide. (R)-N-((4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide is heated in POCl3 to obtain the product (R)-4-(4-chloro-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine. (R)-4-(4-chloro-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine, cyclopropylboronic acid, K3PO4·3H2O, Pd(OAc)2 and tricyclohexylphosphine were heated to react in a mixed solvent of 1,4-dioxane and toluene to obtain the target compound (R)-4-(4-cyclopropyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine. Reaction Scheme 5

[0090] The compounds of the present invention can be prepared as shown in the reaction example in Reaction Scheme 6. 1-Tetrahydropyran-2-ylpyrazole-3-carboxaldehyde, 6-chloro-3-hydrazinylpyridazin-4-amine and PhI(OAc)2 react in DCM at room temperature to give the product 6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine. 6-Chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine, HBr and t-BuONO are stirred in acetonitrile at 0°C, and then CuBr is added to react at room temperature to give the product 8-bromo-6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine. 8-Bromo-6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine, (2-methylpyrazol-3-yl)boric acid, Pd(PPh3)4 and K3PO4 solution were heated in 1,4-dioxane under nitrogen protection to give the product 6-chloro-8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine. 6-Chloro-8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine and morpholine are heated to react in sulfolane under nitrogen protection to obtain the product 4-(8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6-yl)morpholine. 4-(8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine was reacted with HCl / MeOH in methanol at room temperature to give the target compound 4-(8-(2-methylpyrazol-3-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine. Reaction Scheme 6

[0091] Other related compounds can be prepared by similar methods. For example, using (R)-3-methylmorpholine instead of morpholine can produce the target compound (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine.

[0092] The compounds of the present invention can be prepared as shown in the reaction example in Reaction Scheme 7. 5,7-Dichloropyrazolo[1,5-a]pyrimidine, 1-methyl-1H-pyrazol-5-boronic acid pinacol ester, Pd(dppf)Cl2 and K3PO4 are heated in dioxane to give the product 5-chloro-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine. 5-Chloro-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine, sodium tert-butylate, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP) and tris(dibenzylideneacetone)dipalladium are heated in toluene to give the product (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine. (R)-3-Methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine, N-iodosuccinimide (NIS) and trifluoroacetic acid (TFA) react in CHCl3 at room temperature to give the product (R)-4-(3-iodo-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine. (R)-4-(3-iodo-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine, 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, potassium phosphate trihydrate and Pd(dppf)Cl2 were heated in a mixed solvent of dioxane and water to give the product (3R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine. (3R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine and a solution of hydrogen chloride and dioxane are reacted in water at room temperature to obtain the target compound (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine. Reaction Scheme 7

[0093] An important aspect of the present invention is the discovery that the compound of formula I (including the compounds of formula II, IIIa, IIIb and IV described herein) or its stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof are kinase inhibitors, particularly ATR kinase inhibitors. Therefore, the compound of formula I (including the compounds of formula II, IIIa, IIIb and IV described herein) can be used to treat ATR kinase-mediated related diseases, such as cancer; or for the preparation of drugs for treating ATR kinase-mediated related diseases such as cancer.

[0094] The present invention also includes a method for treating or preventing kinase-mediated diseases, especially ATR kinase-mediated related diseases, comprising administering an effective amount of a compound of formula I (including compounds of formula II, IIIa, IIIb and IV as described herein) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, or a prodrug thereof, or a pharmaceutical composition containing an effective amount of a compound of formula I (including compounds of formula II, IIIa, IIIb and IV as described herein) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, or a prodrug thereof. In the present invention, the kinase-mediated diseases include cancer, especially ATR kinase-mediated cancer. ATR kinase-mediated diseases that can be treated or prevented by the methods or pharmaceutical compositions of the present invention include, but are not limited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, cancer, gastric cancer, colon cancer, malignant pancreatic insulinoma, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary neoplasia, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer and prostate cancer.

[0095] The present invention also includes the use for treating or preventing other diseases caused by excessive or abnormal cell proliferation, including proliferation or hyperproliferative diseases, such as myeloproliferative diseases, especially proliferation or hyperproliferative diseases caused by excessive or abnormal cell proliferation mediated by ATR kinase. Therefore, the present invention also includes the use of compounds of formula I (including compounds of formula II, IIIa, IIIb and IV described herein) or their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, or prodrugs thereof to prepare other diseases caused by excessive or abnormal cell proliferation, especially proliferation or hyperproliferative diseases caused by excessive or abnormal cell proliferation mediated by ATR kinase.

[0096] When implementing the treatment method of the present invention, an effective amount of a pharmaceutical preparation is administered to a patient with one or more of these symptoms. The pharmaceutical preparation contains an effective therapeutic concentration of a compound of formula I, II, IIIa, IIIb and IV, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, or a prodrug thereof, formulated for oral, intravenous, local or external administration, for the treatment of cancer and other diseases. The dosage is an amount that effectively improves or eliminates one or more symptoms. For the treatment of a specific disease, an effective amount is an amount that is sufficient to improve or alleviate the symptoms associated with the disease in some way. Such a dosage can be administered as a single dose, or it can be administered according to an effective treatment regimen. The dosage may cure the disease, but administration is usually for the purpose of improving the symptoms of the disease. Repeated administration is generally required to achieve the desired symptom improvement.

[0097] In another embodiment, a pharmaceutical composition is provided, which contains an ATR kinase inhibitor of formula I, II, IIIa, IIIb and IV or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, or prodrugs thereof and a pharmaceutically acceptable carrier.

[0098] Another embodiment of the present invention relates to a pharmaceutical composition that can effectively treat cancer, wherein the kinase inhibitor is a compound of formula I, II, IIIa, IIIb and IV, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, or a prodrug thereof, in combination with at least one known anticancer drug or a pharmaceutically acceptable salt of an anticancer drug. In particular, it is used in combination with other anticancer drugs related to DNA damage and repair mechanisms, including PARP inhibitors olaparib, niraparib, rucaparib, talazoparib and senaparib; HDAC inhibitors vorinostat, romidepsin, panobinostat and belinostat; and the like. And in combination with other anticancer drugs related to cell division checkpoints, including Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as palbociclib, ATM inhibitors, Wee1 inhibitors, DNA-PK inhibitors, and the like. Other known anticancer drugs that can be used for anticancer combination therapy include, but are not limited to, alkylating agents such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, and carboplatin; topoisomerase I inhibitors such as camptothecin, irinotecan, and topotecan; topoisomerase II inhibitors such as doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, and menthopop; RNA / DNA antimetabolites such as 5-azacytidine, gemcitabine, 5-fluorouracil and methotrexate; DNA antimetabolites such as 5-fluoro-2′-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea and thioguanine; antimitotic agents such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel and docetaxel; antibodies such as monoclonal antibodies, panitumumab, nelazolizumab, nivolumab, pembrolizumab, Ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab tiuxetan, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, ofatumumab, dinutuximab, blinatumomab, ipilimumab, Avastin, Herceptin, and rituximab; kinase inhibitors such as imatinib, gemtuzumab, Felotinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pralsetinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, idelalisib, pazopanib, temozolomide, and everolimus.Other known anticancer drugs that can be used in anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguanidine, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegi, denosumab, thalidomide, lenalidomide, venetoclax, Aldesleukin (recombinant human interleukin-2) and Sipueucel-T (prostate cancer treatment vaccine).

[0099] In practicing the method of the present invention, the compound of the present invention and at least one known anticancer drug can be administered together as a single pharmaceutical composition. In addition, the compound of the present invention can also be administered separately from at least one known anticancer drug. In one embodiment, the compound of the present invention and at least one known anticancer drug are administered at about the same time, that is, all drugs are administered at the same time or successively, as long as the compound reaches a therapeutic concentration in the blood at the same time. In another embodiment, the compound of the present invention and at least one known anticancer drug are administered according to their respective dosage regimens, as long as the compound reaches a therapeutic concentration in the blood.

[0100] Another embodiment of the present invention is a bioconjugate composed of the compound that is effective in inhibiting tumors and acts as a kinase inhibitor. This bioconjugate that can inhibit tumors is composed of the compound and at least one known medical antibody, such as Herceptin or Rituxan, or growth factors, such as EGF or FGF, or cytokines, such as interleukin 2 or 4, or any molecule that can bind to the cell surface. The antibody and other molecules can deliver the compound to its target, making it an effective anti-cancer drug. This bioconjugate can also enhance the anti-cancer effect of medical antibodies, such as Herceptin or Rituxan.

[0101] Another embodiment of the present invention relates to a pharmaceutical composition that can effectively inhibit tumors, comprising a kinase inhibitor represented by Formula I (including Formula II, IIIa, IIIb and IV compounds described herein), or a stereoisomer, tautomer, N-oxide, hydrate, isotope-substituted derivative, solvate or salt thereof, or a mixture thereof, or a prodrug thereof, in combination with radiotherapy. In this embodiment, the compound of the present invention and radiotherapy can be administered at the same time or at different times.

[0102] Another embodiment of the present invention relates to a pharmaceutical composition that can be effectively used for postoperative treatment of cancer, comprising a kinase inhibitor shown in Formula I, II, IIIa, IIIb or IV, or a stereoisomer, tautomer, N-oxide, hydrate, isotope-substituted derivative, solvate or salt, or a mixture thereof, or a prodrug thereof. The present invention also relates to a method of treating cancer in a mammal by surgically removing a tumor and then using the pharmaceutical composition of the present invention.

[0103] The pharmaceutical composition of the present invention includes a pharmaceutical preparation containing all the compounds of the present invention in an amount that can effectively achieve its intended purpose. Although each person's needs are different, those skilled in the art can determine the optimal dose of each part in the pharmaceutical preparation. Generally, the compound, or its pharmaceutically acceptable salt, is orally administered to a mammal daily in an amount of about 0.0025 to 50 mg / kg body weight. However, it is preferably administered orally at about 0.01 to 10 mg / kg per kilogram. If a known anticancer drug is also administered, its dosage should be effective to achieve its intended purpose. The optimal doses of these known anticancer drugs are well known to those skilled in the art.

[0104] The unit oral dose may include about 0.01 to 50 mg, preferably about 0.1 to 10 mg of the compound of the invention. The unit dose may be administered once or more, one or more tablets per day, each tablet containing about 0.1 to 50 mg, conveniently about 0.25 to 10 mg of the compound of the invention or its solvate.

[0105] In external preparations, the concentration of the compound of the present invention may be about 0.01 to 100 mg per gram of carrier.

[0106] The compounds of the present invention can be administered as raw drugs. The compounds of the present invention can also be administered as part of a suitable pharmaceutical preparation containing a pharmaceutically acceptable carrier (including excipients and adjuvants). These pharmaceutically acceptable carriers facilitate the processing of the compounds into pharmaceutical preparations that can be used for pharmaceutical purposes. Preferred pharmaceutical preparations, especially those oral and preferred administration types, such as tablets, lozenges and capsules, and solutions suitable for injection or oral administration, contain about 0.01% to 99%, preferably from about 0.25% to 75% of active compounds and excipients.

[0107] The scope of the present invention also includes non-toxic pharmaceutically acceptable salts of the compounds of the present invention. Acid addition salts are formed by mixing a non-toxic pharmaceutically acceptable acid solution with a solution of the compound of the present invention. The acid is, for example, hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, etc. Base addition salts are formed by mixing a non-toxic pharmaceutically acceptable base solution with a solution of the compound of the present invention. The base is, for example, sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, trishydroxymethylaminomethane, N-methyl-glucamine, etc.

[0108] The pharmaceutical preparations of the present invention can be administered to any mammal, as long as they can obtain the therapeutic effect of the compounds of the present invention. The most important of these mammals are humans and veterinary animals, although the present invention is not intended to be so limited.

[0109] The pharmaceutical preparation of the present invention can be administered by any route to achieve its intended purpose. For example, it can be administered parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, transdermally, orally, intrathecally, intracranially, nasally or externally. Alternatively or concurrently, it can be administered orally. The dosage of the drug will be determined based on the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

[0110] The pharmaceutical preparations of the present invention can be manufactured in a known manner. For example, they can be manufactured by conventional mixing, granulation, tableting, dissolution, or freeze-drying processes. When manufacturing oral preparations, solid excipients and active compounds can be combined and the mixture can be selectively ground. After adding appropriate amounts of auxiliary agents as needed or necessary, the granular mixture can be processed to obtain tablets or lozenge cores.

[0111] Suitable adjuvants are in particular fillers, for example sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate; and binders, for example starch pastes, including corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If necessary, disintegrants such as the starches mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, can be added. Auxiliary agents are in particular flow regulators and lubricants, for example, silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. If necessary, the tablet core can be provided with a suitable coating that can resist gastric juice. For this purpose, concentrated sugar solutions can be applied. This solution may contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. To prepare a coating resistant to gastric juices, suitable cellulose solutions may be used, for example cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate. Dyes or pigments may be added to the coating of the tablet or lozenge core, for example, for identification or to characterize the combination of active ingredient doses.

[0112] Other pharmaceutical preparations for oral administration include press-fit capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The press-fit capsules may contain the active compound in the form of particles, mixed with a filler such as lactose; a binder such as starch; and / or a lubricant such as talc or magnesium stearate, and a stabilizer. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid such as a fat or liquid paraffin, to which a stabilizer may be added.

[0113] Preparations suitable for parenteral administration include aqueous solutions of the active compound, such as solutions of water-soluble salts and alkaline solutions. In addition, oily injection suspensions of the appropriate active compound may be administered. Suitable lipophilic solvents or carriers include fats such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol 400, or hydrogenated castor oil, or cyclodextrin. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, and / or dextran. Suspension stabilizers may also be contained.

[0114] According to one aspect of the present invention, the compounds of the present invention are used in topical and parenteral formulations and are useful in the treatment of skin cancer.

[0115] The topical preparation of the present invention can be made into oil, cream, emulsion, ointment, etc. by preferably using a suitable carrier. Suitable carriers include plant or mineral oil, white mineral oil (white soft paraffin), branched fat or grease, animal fat and high molecular alcohol (grease with a concentration greater than C). 12 ). Preferred carriers are those in which the active ingredient can be dissolved. Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents that impart color or flavor, if desired. In addition, these topical preparations may contain transdermal penetration enhancers. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762.

[0116] Creams are preferably formulated with a mixture of mineral oil, self-emulsifying beeswax and water, mixed with the active ingredient dissolved in a small amount of oil such as almond oil. A typical cream example includes about 40 parts water, 20 parts beeswax, 40 parts mineral oil and 1 part almond oil.

[0117] Ointments can be prepared by mixing a vegetable oil containing the active ingredient, such as almond oil, with warm soft paraffin, and then allowing the mixture to cool. A typical ointment example includes about 30% by weight of almond oil and 70% by weight of white soft paraffin.

[0118] The present invention also relates to the use of the compounds of the present invention to prepare drugs for treating clinical conditions that are effective in inhibiting the activity of kinases (especially ATR kinases). These drugs may include the above-mentioned pharmaceutical compositions.

[0119] The following examples are illustrative, rather than limiting, methods and preparations of the present invention. Other suitable modifications and improvements to various conditions and parameters that are apparent to those skilled in the art and that are typically encountered in clinical treatment are within the spirit and scope of the present invention. Example General Notes All reagents used were of commercial quality, and solvents were dried and purified according to standard methods. Mass spectrometry samples were analyzed using a single quadrupole mass spectrometer (Platform II, Agilent 6110) with electrospray ionization. Brücker Ascend 400 NMR was used to record at 400 MHz. 1 For H NMR spectra, chemical shifts are reported in ppm from downfield with TMS as the internal standard (0.00 ppm), and coupling constants, J values, are reported in Hz. Example 1 (R)-3-Methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine a) Preparation of 8-bromo-6-chloro-3-iodoimidazo[1,2-a]pyridine: N-iodosuccinimide (3.94 g, 17.28 mmol) and trifluoroacetic acid (2.68 mL, 34.6 mmol) were added to a solution of 8-bromo-6-chloroimidazo[1,2-a]pyridine (4.0 g, 17.28 mmol) in chloroform (50 mL) at room temperature, and the reaction solution was stirred at room temperature for 2 hrs. The reaction was quenched with saturated aqueous sodium bicarbonate solution (80 mL). The reaction solution was extracted with dichloromethane (50 mL × 3), and the extract was washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by column chromatography (silica gel, dichloromethane: ethyl acetate = 1:0-7:3) to obtain the target product (5.5 g, 89% yield, yellow solid). LC-MS (ESI): m / z (M+H) + 356.62. b) Preparation of 8-bromo-6-chloro-3-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine: Tetrakistriphenylphosphine palladium (1.28 g, 1.11 mmol) was added to a solution of 8-bromo-6-chloro-3-iodoimidazo[1,2-a]pyridine (3 g, 8.4 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (2.57 g, 9.24 mmol) and potassium phosphate trihydrate (4.41 g, 16.8 mmol) in dioxane (50 mL) and water (5 mL). The reaction solution was stirred at 80° C. under nitrogen protection for 18 hr. Add water (100 mL), extract with dichloromethane (50 mL × 3), wash the extract with brine (50 mL × 2), dry with sodium sulfate, filter and concentrate to obtain a crude product, which is separated and purified by column chromatography (silica gel, dichloromethane: ethyl acetate = 4:0-7:3) to obtain the target product (1.05 g, 40.1% yield, yellow solid). LC-MS (ESI): m / z (M+H) + 380.8. c) Preparation of 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.38 g, 0.52 mmol) was added to a solution of 8-bromo-6-chloro-3-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine (1 g, 2.62 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.71 g, 3.40 mmol) and potassium phosphate trihydrate (1.4 g, 5.24 mmol) in dioxane (30 mL) and water (3 mL). The reaction solution was stirred at 100° C. under nitrogen for 16 hrs. Add water (50 mL), extract with dichloromethane (50 mL × 3), dry the extract with sodium sulfate, filter and concentrate to obtain a crude product, which is separated and purified by column chromatography (silica gel, dichloromethane: ethyl acetate = 4: 1-0: 1) to obtain the target product (0.8 g, 80.0% yield, yellow solid). LC-MS (ESI): m / z (M+H) + 383.0. d) Preparation of (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine: Under nitrogen protection, (R)-3-methylmorpholine (405.81 mg, 4.01 mmol), sodium tert-butoxide (257.05 mg, 2.67 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2,4,6-triisopropyl-1,1-biphenyl) 6-Chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine (400 mg, 668.68 mmol) was slowly added to a solution of )(2-amino-1,1-biphenyl-2-yl)palladium(II) (53.12 mg, 66.87 mmol) in tert-amyl alcohol (8.00 mL). After replacing the nitrogen, the reaction solution was stirred at 110°C for 0.5 hr. LCMS showed that the reaction was complete. After filtering the reaction solution, it was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The target product (200 mg crude product, yellow oil) was obtained by column chromatography separation and purification (silica gel, ethyl acetate: methanol = 10:1). LC-MS (ESI): m / z (M+H) + 448.2. e) Preparation of (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine: (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine (200 mg crude product) was dissolved in methanol (2 mL) at room temperature, and then 4M hydrochloric acid dioxane solution (5 mL) was added dropwise, and the reaction solution was stirred at 10°C for 0.5 h. LCMS monitoring showed that the raw material was completely consumed and the product was generated. The reaction solution was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The target product (9 mg, 5.6% yield, white solid) was obtained by preparative chromatography (carbon 18 silica gel column, 150×25 mm, 5 μm, 13-38% acetonitrile / 0.05% ammonia water as mobile phase). LC-MS (ESI): m / z (M+H) + 364.2. 1 H NMR (400MHz, DMSO-d6): δ13.15(s,1H),9.03(d,J=1.8Hz,1H),8.00(s,1H),7.92(s,2H),7.54(s,1H),7.40(d,J=2.0Hz,1H),6.81(d,J=2.0Hz ,1H),6.61(d,J=1.6Hz,1H),3.95-3.88(m,1H),3.85(s,3H),3.80-3.7 0(m,2H),3.68-3.60(m,2H),3.22-2.95(m,2H),0.99(d,J=6.8Hz,3H). Example 2 (R)-3-Methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine a) Preparation of 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine: N-iodosuccinimide (7.25 g, 32.25 mmol) and trifluoroacetic acid (3.35 mL, 43 mmol) were added to a solution of 6-chloro-8-bromoimidazo[1,2-b]pyridazine (5 g, 21.5 mmol) in chloroform (90 mL) at room temperature, and the reaction solution was stirred at room temperature for 2 hrs. The reaction was quenched with saturated aqueous sodium bicarbonate solution (100 mL). The reaction solution was extracted with dichloromethane (50 mL × 3), and the extract was washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by column chromatography (silica gel, dichloromethane: ethyl acetate = 1:0-49:1) to obtain the target product (5.2 g, 67.7% yield, yellow solid). LC-MS (ESI): m / z (M+H) + 357.57. b) Preparation of 8-bromo-6-chloro-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine: Tetrakistriphenylphosphine palladium (1.67 g, 1.45 mmol) was added to a solution of 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine (4 g, 14.51 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (4.03 g, 14.51 mmol) and potassium phosphate trihydrate (5.94 g, 22.32 mmol) in dioxane (50 mL) and water (5 mL). The reaction solution was stirred at 90° C. under nitrogen for 16 hrs. Add water (50 mL), extract with dichloromethane (50 mL × 3), wash the extract with brine (50 mL × 2), dry over sodium sulfate, filter and concentrate to obtain a crude product, which is separated and purified by column chromatography (silica gel, dichloromethane: ethyl acetate = 1: 0-4: 1) to obtain the target product (0.93 g, 16.7% yield, yellow solid). LC-MS (ESI): m / z (M+H) + 381.80. c) Preparation of 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine: [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (0.36 g, 0.47 mmol) was added to a solution of 8-bromo-6-chloro-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine (0.93 g, 2.43 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.66 g, 3.16 mmol) and potassium phosphate trihydrate (1.29 g, 4.86 mmol) in a mixture of dioxane (20 mL) and water (2 mL). The reaction solution was stirred at 100°C for 16 hrs under nitrogen protection. Water (30 mL) was added and extracted with dichloromethane (50 mL×3). The extract was dried over sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1-1:1) to obtain the target product (0.5 g, 53.8% yield, yellow solid). LC-MS (ESI): m / z (M+H) + 383.80. d) Preparation of (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine-6-yl)morpholine: 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine (500 mg, 1.3 mL) was added to a 1% ethanol solution at room temperature. mol) and (R)-3-methylmorpholine (657.48 mg, 6.5 mmol) were added to toluene (10 mL) and dissolved, and then sodium tert-butoxide (249.86 mg, 2.6 mmol) and tris(dibenzylideneacetone)dipalladium (119.04 mg, 0.3 mmol) and 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl (161.89 mg, 0.26 mmol) were added. Under nitrogen protection, the reaction solution was stirred at reflux for 16 hrs. The reaction solution was diluted with toluene (50 mL) and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The target product (0.12 g, 20.6% yield, yellow solid) was obtained by column chromatography separation and purification (silica gel, petroleum ether: ethyl acetate = 5: 1-0: 1). LC-MS (ESI): m / z (M+H) + 449.15. e) Preparation of (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine: Concentrated hydrochloric acid (1 mL) was added to a solution of (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (120 mg, 0.27 mmol) in ethanol (10 mL) at room temperature, and the reaction solution was stirred at room temperature for 2 hrs. The reaction solution was concentrated, and the residue was dissolved in methanol (2 mL). 1 drop of aqueous ammonia was added and separated and purified by preparative liquid chromatography (C18 column, 0-100% acetonitrile / water as mobile phase) to obtain the target compound (5.5 mg, 5.6% yield, yellow solid). The compounds of Examples 3-8 described below were prepared using a synthetic method similar to that described in Example 2, with the starting materials being 6-chloro-8-bromoimidazo[1,2-b]pyridazine, N-iodosuccinimide, 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester, the corresponding aryl or heteroaryl boronic acid pinacol ester and (R)-3-methylmorpholine. Example 9 (R)-3-Methyl-4-(8-morpholinyl-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine a) Preparation of 4-(6-chloro-3-iodoimidazo[1,2-b]pyridazine-8-yl)morpholine: A mixture of 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine (2.5 g, 6.98 mmol), morpholine (729.32 mg, 8.37 mmol, 736.69 μL) and DIEA (1.98 g, 15.35 mmol, 2.67 mL) in THF (50 mL) was replaced with nitrogen three times and stirred at 80° C. for 12 hours under nitrogen atmosphere. The reaction mixture was diluted with EA (100 mL), washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was washed with methyl tert-butyl ether (MTBE, 30 mL) to obtain the target compound (2.5 g, yellow solid, yield 98.30%). LC-MS(ESI):m / z(M+H) + 364.9. b) Preparation of 4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine: A mixture of 4-(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)morpholine (2.5 g, 6.86 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (2.10 g, 7.54 mmol), Pd(PPh3)4 (792.41 mg, 685.74 umol) and K3PO4 aqueous solution (3M, 6.86 mL) in dioxane (35 mL) was replaced with nitrogen three times, and the mixture was stirred at 90°C under a nitrogen atmosphere for 8 hours. The reaction mixture was diluted with EA (50 mL), washed with saturated brine (35 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel chromatography ( 40g Sepa Silica Flash Column, elution gradient 0-10% EA / PE, @50 mL / min) was used to purify the target product (0.94 g, white solid, yield 35.25%). LC-MS (ESI): m / z (M+H) + 389.2. c) Preparation of (3R)-3-methyl-4-(8-morpholin-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine: 4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine (0.94 g, 2.42 mmol), (R)-3-methyl A mixture of morpholine (1.22 g, 12.09 mmol), t-BuONa (464.64 mg, 4.83 mmol), Pd(dba)2 (278.00 mg, 483.48 umol) and diphenyl phosphine (BINAP, 301.05 mg, 483.48 μmol) in toluene (30 mL) was replaced with nitrogen three times, and the mixture was stirred at 100 ° C for 18 hours under a nitrogen atmosphere. The reaction mixture was diluted with EA (50 mL), washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel chromatography ( 20g Sepa Silica Flash Column, elution gradient 0-20% EA / PE, @50 mL / min) was used to purify the target product (0.18 g, yellow solid, yield 16.42%). LC-MS (ESI): m / z (M+H) +454.2. d) Preparation of (R)-3-methyl-4-(8-morpholinyl-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine: To a solution of (3R)-3-methyl-4-(8-morpholinyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (0.16 g, 352.78 umol) in methanol (4.5 mL) was added methanolic HCl solution (4 M, 4.41 mL). The resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was dissolved in methanol (20 mL) and adjusted to pH 7 with saturated sodium bicarbonate aqueous solution, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography column (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 17%-47%, 10min) to obtain the target compound (25 mg, off-white solid, yield 19.03%, purity 99.19%). LC-MS (ESI): m / z (M+H) + 370.1. 1 H NMR (400MHz, CD3OD): δ7.85(s,1H),7.74(d,J=2.4Hz,1H),7.12(d,J=2.0Hz,1H),6.22(s,1H),4.27(m,1H),4 .03(dd,J=3.2,11.6Hz,1H),3.92-3.90(m,4H),3.82-3.64(m,9H),3.38-3.35(m,1H),1.29(d,J=2.0Hz,3H). SFC:ee%,100%. Example 10 (2S,6R)-2,6-Dimethyl-4-(6-((R)-3-methylmorpholinyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine The compound of this example can be prepared by a synthetic method similar to that described in Example 9. LC-MS (ESI): m / z (M+H) + 398.4. 1H NMR (400MHz, CD3OD): δ7.82(s,1H),7.80-7.59(m,1H),7.21-7.01(m,1H) ,6.13(s,1H),4.60(s,1H),4.49-4.39(m,2H),4.27-4.24(m,1H),4.02(dd ,J=3.2,11.6Hz,1H),3.94-3.85(m,2H),3.83-3.74(m,3H),3.70-3.64(m ,1H),3.36(dd,J=4.0,12.8Hz,1H),2.63-2.55(m,2H),1.30-1.25(m,9H). Embodiment 11 4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine The compound of this example was prepared using a synthetic method similar to that described in Example 13. Yellow solid. LC-MS (ESI): m / z (M+H) + 351.30. 1 H NMR (400MHz, DMSO-d6): δ7.73(s,1H),7.65(d,J=1.7Hz,1H),7.44(s,1H),7.14(d,J=1.3Hz, 1H), 7.01 (s, 1H), 6.81 (d, J = 1.6Hz, 1H), 3.97 (s, 3H), 3.83-3.74 (m, 4H), 3.63-3.57 (m, 4H). Example 12 4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine a) Preparation of 6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine: 1-tetrahydropyran-2-ylpyrazole-3-carboxaldehyde (10.16 g, 56.40 mmol) and 6-chloro-3-hydrazinopyridazin-4-amine (9 g, 56.40 mmol) were dissolved in DCM (120 mL) and stirred at 10-20°C for 1 hour. Then PhI(OAc)2 (30.88 g, 95.88 mmol) was added to the reaction solution at 0°C and stirred at 10-20°C for 12 hours. The reaction solution was diluted with saturated brine (800 mL) and extracted with DCM (400 mL×3). The organic phases were combined and washed with saturated brine (400 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel chromatography ( X g Sepa Silica Flash Column, elution gradient 0-100%, PE:EA=1:3) to obtain the target product (8.7 g, yellow solid, yield 16.08%). LC-MS (ESI): m / z (M+H) + 319.9. b) Preparation of 8-bromo-6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine: To a solution of 6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (0.9 g, 2.81 mmol) in CH3CN (15 mL) were added HBr (69.01 mg, 281.47 μmol, 46.32 μL, purity 33%) and t-BuONO (493.43 mg, 4.79 mmol, 569.12 μL), and stirred at 0°C for 0.5 hours. Then, CuBr (605.65 mg, 4.22 mmol, 128.59 μL) was added. The reaction solution was stirred at 10-20°C for 12 hours. The reaction solution was diluted with water (80 mL) and extracted with EtOAc (150 mL × 3). The organic phases were combined and washed with saturated brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (SiO2, PE / EtOAc=5 / 1-1 / 1) to obtain the target product (380 mg, black solid, yield 7.04%). LC-MS (ESI): m / z (M+H) + 382.8. 1H NMR (400MHz, DMSO-d6): δ7.82(d,J=2.4Hz,1H),7.44(s,1H),7.44(d,J=3.2Hz,1H),5.63- 5.60(m,1H),4.12-4.09(m,1H),3.78-3.72(m,1H),2.21-2.10(m,3H),1.76-1.61(m,3H). c) Preparation of 6-chloro-8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine: At 10-20°C, 8-bromo-6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 312.80 μmol ) and (2-methylpyrazol-3-yl)boronic acid (39.39 mg, 312.80 μmol) in dioxane (6 mL) were added with Pd(PPh3)4 (36.15 mg, 31.28 μmol) and K3PO4 solution (2M, 469.20 μL), and then the reaction solution was degassed under vacuum and replaced with N2 several times, and stirred at 100-110°C for 1.5 hours. The reaction solution was diluted with water (30 mL) and extracted with EtOAc (40 mL×3). The organic phases were combined and washed with saturated brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin layer chromatography (SiO2, PE:EA=1:3) to obtain the target product (90 mg, yellow solid). LC-MS(ESI):m / z(M+H) + 384.9. d) Preparation of 4-(8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-6-yl)morpholine: A solution of 6-chloro-8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine (20 mg, 51.97 μmol) and morpholine (22.64 mg, 259.86 μmol, 22.87 μL) in sulfolane (0.5 mL) was degassed and replaced with N2 three times and stirred at 120-130°C for 3 hours. The reaction mixture was purified by preparative high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 24%-44%, 7min) to obtain the target product (97 mg, yellow solid). LC-MS (ESI): m / z (M+H) + 436.0. e) Preparation of 4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine: HCl / MeOH (4M, 229.63 μL) was added to a solution of 4-(8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine (40 mg, 91.85 μmol) in methanol (1.2 mL) at 0°C, and the reaction solution was stirred at 25°C for 15 hours. The reaction solution was filtered, and the filter cake was washed with EtOAc (0.5 mL×2) to give the target compound (57.42 mg, yellow solid, yield 86.91%). LC-MS(ESI):m / z(M+H) + 352.1. 1 H NMR (400MHz, DMSO-d6): δ7.94(d,J=2.0Hz,1H),7.60(d,J=2.0Hz,1H),7.54(s,1H),7.21( d,J=2.0Hz,1H),6.94(d,J=2.0Hz,1H),4.03(s,3H),3.80-3.77(m,4H),3.66-3.64(m,4H). Example 13 (R)-3-Methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine a) Preparation of 4-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydropyridazine-3,6-dione: 4-Bromo-1,2-dihydropyridazine-3,6-dione (4.0 g, 20.94 mmol), (1-methyl-1H-pyrazol-5-yl)boric acid (5.23 g, 41.90 mmol) and aqueous potassium phosphate solution (aq. K3PO4, 63 mL, 1 M) were dissolved in N,N-dimethylformamide (DMF, 60 mL). The air in the reaction flask was replaced with nitrogen. Under the protection of nitrogen, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, 1.67 g, 2.09 mmol) was added. After the resulting mixture was reacted at 100°C for 16 hours, the solvent was removed by concentration to obtain a crude product, which was washed with dichloromethane (DCM, 100 mL) to obtain a crude product of the target product (15.0 g, black solid). LC-MS (ESI): m / z (M+H) + 193.25. b) Preparation of 3,6-dichloro-4-(1-methyl-1H-pyrazol-5-yl)pyridazine: 4-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydropyridazine-3,6-dione (15.0 g, crude product, 20.94 mmol) was dissolved in phosphorus oxychloride (POCl3, 150 mL), heated to 100°C and stirred for 16 hours. The phosphorus oxychloride was removed to obtain a crude product, which was purified by silica gel column chromatography (EtOAc / PE, 10 to 30%) to obtain the target product (2.63 g, white solid, two-step yield 55%). LC-MS (ESI): m / z (M+H) + 229.15. 1 H NMR (400MHz, CDCl3): δ7.61 (d, J = 1.3 Hz, 1H), 7.51 (s, 1H), 6.49 (d, J = 1.3 Hz, 1H), 3.83 (s, 3H). c) Preparation of (R)-4-(6-chloro-5-(1-methyl-1H-pyrazol-5-yl)pyridazine-3-yl)-3-methylmorpholine: To a solution of 3,6-dichloro-4-(1-methyl-1H-pyrazol-5-yl)pyridazine (2.63 g, 11.53 mmol) in N-methylpyrrolidone (NMP, 50 mL) was added (R)-3-methylmorpholine (1.58 g, 11.53 mmol), CuBr (3.63 g, 25.37 mmol) and N,N-diisopropylethylamine (DIEA, 2.15 g, 15.5 mmol). The resulting mixture was stirred at 150 °C for 16 h. The reaction was quenched with water (50 mL) and diluted with dichloromethane (DCM, 100 mL). The organic phase was washed with water (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (EtOAc / PE, 5-20%) to obtain the target product (1.65 g, light red solid, yield 49%). LC-MS (ESI): m / z (M+H) + 294.25. 1 H NMR (400MHz, CDCl3): δ7.60(s,1H),6.79(s,1H),6.40(s,1H),4.36–4.27(m,1H),4.06(dd,J=11.4,3.3Hz,1H),3.97(dd,J=13.3 ,2.0Hz,1H),3.86–3.82(m,1H),3.80(s,3H),3.65(td,J=12.0,3.0Hz,1H),3.36(td,J=12.5,3.7Hz,1H),1.33(d,J=6.7Hz,3H). d) Preparation of (R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazine-3-carbonitrile: To a solution of (R)-4-(6-chloro-5-(1-methyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholine (0.5 g, 1.7 mmol) and DMF (10 mL) were added Zn(CN)2 (0.4 g 3.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (DPPF, 0.2 g, 0.36 mmol), Pd2(dba)3 (160 mg, 0.17 mmol) and 3 drops of water. The resulting mixture was stirred at 150°C for 6 hours. The solvent was removed by concentration under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (EtOAc / PE, 10 to 40%) to obtain the target product (0.4 g, light red oil, yield 82%). LC-MS (ESI): m / z (M+H) + 285.30. 1 H NMR (400MHz, CDCl3): δ7.59(d,J=1.8Hz,1H),6.66(s,1H),6.53(d,J=1.8Hz,1H),4.54–4.43(m,1H),4.23–4.13(m,1H),4.08(dd,J=14.8,5. 7Hz,1H),3.89(s,3H),3.84(brs,1H),3.78(dd,J=12.0,2.8Hz,1H),3.64(td,J=12.4,2.8Hz,1H),3.49–3.38(m,1H),1.38(d,J=6.8Hz,3H). e) Preparation of (R)-(4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazine-3-yl)methylamine: Raney nickel (~0.3 g) was added to a solution of (R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazine-3-carbonitrile (0.22 g, 0.77 mmol) in MeOH (7 mL). The resulting mixture was stirred at room temperature under hydrogen for 16 hours. After the reaction was completed, the resulting mixture was filtered with diatomaceous earth, and the filtrate was concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography column (C18, CH3CN / H2O, 5~30%, 0.1% TFA was added) to obtain the target product (0.1 g, colorless oil, yield 45%). LC-MS (ESI): m / z (M+H) + 289.30. 1H NMR (400MHz, CD3OD): δ7.61(s,1H),7.32(s,1H),6.51(s,1H),4.47–4.38(m,1H),4.14(s,2H),4.00(dt,J =16.5,9.0Hz,2H),3.85–3.72(m,4H),3.63(dd,J=16.4,7.3Hz,1H),3.33(brs,2H),1.28(d,J=6.4Hz,3H). f) Preparation of N-((4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholinyl)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide: To a solution of (R)-(4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazin-3-yl)methanamine (0.1 g, 0.35 mmol) in DMF (5 mL) were added 1H-pyrazole-5-carboxylic acid (0.05 g, 0.35 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 200 mg, 0.75 mmol) and DIEA (0.12 g, 0.87 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by preparative thin layer chromatography (DCM: MeOH = 20: 1) to obtain the target product (0.085 g, white solid, yield 64%). LC-MS (ESI): m / z (M+H) + 383.35. 1 H NMR (400MHz, CDCl3): δ10.40(s,1H),8.73(s,1H),7.62–7.52(m,2H),6.82–6.72(m,2H),6.45(s,1H),4.58(d,J=5.5Hz,2H),4.36–4.25(m,1H),4. 02(ddd,J=22.3,12.2,2.6Hz,1H),3.79(s,3H),3.64(ddd,J=15.7,12.1, 5.0Hz, 2H), 3.40–3.30 (m, 1H), 3.16–3.05 (m, 2H), 1.31 (d, J = 6.9Hz, 3H). g) Preparation of (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine: A solution of N-((4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholinyl)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (0.085 g, 0.22 mmol) in POCl3 (5 mL) was stirred at 150°C for 3 hours. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by preparative HPLC column (C18, CH3CN / H2O, 15-45%, 0.1% TFA was added) to obtain the target compound (0.02 g, yellow solid, yield 25%). LC-MS (ESI): m / z (M+H) + 365.25. 1 H NMR (400MHz, CD3OD) δ7.93(s,1H),7.84(s,1H),7.67(d,J=1.8Hz,1H),7.40(d,J=1.0Hz,1H),7.27(s,1H),6.80(d,J=1.7Hz,1H),4.46(d, J=6.3Hz,1H),4.11–4.02(m,2H),4.00(s,3H),3.87–3.80(m,2H),3.68(td,J=11.6,3.0Hz,1H),3.56–3.44(m,1H),1.41(d,J=6.8Hz,3H). Embodiment 14 (R)-3-methyl-4-(3-(1H-pyrazol-5-yl)-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl) Phytophenone The compound of this example was prepared using a synthetic method similar to that described in Example 2. Embodiment 15 (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl) Morpholine The compound of this example was prepared using a synthetic method similar to that described in Example 12. Off-white solid. LC-MS (ESI): m / z (M+H) + 366.1. 1H NMR (400MHz, CD3OD): δ7.88(br,s,1H),7.66(d,J=1.6Hz,1H),7.41(s,1H),7.28(s,1H),6.88(d,J=1.6Hz,1H),4.42(d,J=6.4Hz, 1H), 4.08-4.05 (m, 1H), 4.03 (s, 3H), 4.00-3.97 (m, 1H), 3.85 (s, 2H), 3.72-3.72 (m, 1H), 3.46-3.41 (m, 1H), 1.39 (d, J = 6.8Hz, 3H). Example 16 (R)-3-Methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine a) Preparation of 5-chloro-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine: To a solution of 5,7-dichloropyrazolo[1,5-a]pyrimidine (5 g, 26.59 mmol) in dioxane (100 mL) was added 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (5.53 g, 26.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.95 g, 2.66 mmol) and tripotassium phosphate (14.16 g, 53.19 mmol) in water (10 mL) at room temperature. After nitrogen replacement, the reaction mixture was stirred at 80°C for 16 hours. LCMS showed that the reaction was complete. After the reaction solution was cooled to room temperature, water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 2), the extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was separated and purified by column chromatography (silica gel, PE / EtOAc = 50 / 1-3 / 1) to obtain the target product (3.35 g, yellow solid, yield 53.91%). LC-MS (ESI): m / z (M+H) + 234.30. b) Preparation of (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine: 5-chloro-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine (500 mg, 2.14 mmol), sodium tert-butoxide (514.11 mg, 5.35 mmol), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, 133.24 mg, 213.99 mmol) and tris(dibenzylideneacetone)dipalladium (195.95 mg, 213.99 mmol) were dissolved in toluene (30 mL) at room temperature. The reaction solution was refluxed and stirred for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature and extracted with EtOAc (100 mL×3). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel chromatography (SiO2, PE / EtOAc=20 / 1-3 / 1) to obtain the target product (69 mg, yellow solid, yield 10.8%). 1 H NMR (400MHz, CDCl3): δ7.92(d,J=2.1Hz,1H),7.62(d,J=1.9Hz,1H),6.64(d,J=1.9Hz,1H),6.33(s,1H),6.22(d,J=2.2Hz,1H ), 4.34 (d, J = 6.3Hz, 1H), 4.06 (s, 2H), 3.89 (s, 3H), 3.81 (s, 2H), 3.65-3.58 (m, 1H), 3.39-3.32 (m, 1H), 1.36 (d, J = 6.8Hz, 3H). c) Preparation of (R)-4-(3-iodo-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine: N-iodosuccinimide (NIS, 40 mg, 177.98 μmol) and trifluoroacetic acid (TFA, 22, 55 mg, 197.76 μmol) were added to a solution of (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (59 mg, 197.76 μmol) in CHCl3 (5 mL) at room temperature. The reaction was stirred at room temperature for 2 hours and quenched with saturated sodium bicarbonate (5 mL). The mixed solution was concentrated to obtain a crude product, which was purified by silica gel chromatography (SiO2, PE / EtOAc=20 / 1-3 / 1) to obtain the target product (59 mg, yellow solid, yield 70.3%). LC-MS (ESI): (M+H) + :425.4. 1H NMR (400MHz, CDCl3): δ7.90(s,1H),7.62(d,J=1.9Hz,1H),6.62(d,J=2.0Hz,1H),6.33(s,1H),4.38(s,1H),4.22(d,J=13.4Hz,1H ), 4.07(dd,J=11.5,3.8Hz,1H),3.86(s,3H),3.83(s,2H),3.62(td,J=11.9,3.0Hz,1H),3.42-3.34(m,1H),1.25(d,J=3.7Hz,3H). d) Preparation of (3R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine: (R)-4-(3-iodo-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine (33 mg, 77.79 μm ol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (64.91 mg, 233.36 μmol), potassium phosphate trihydrate (41.43 mg, 155.57 μmol) and Pd(dppf)Cl2 (5.69 mg, 7.78 μmol) were dissolved in dioxane (8 mL) and water (1.5 mL). The reaction solution was stirred at 82 ° C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain a crude product, which was purified by silica gel chromatography (SiO2, PE / EtOAc=20 / 1-3 / 1) to obtain the target product (30 mg, yellow solid, yield 86.0%). LC-MS (ESI): m / z (M+H) + :449.47. e) Preparation of (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine: A mixture of (3R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine, 4M hydrogen chloride dioxane solution (1 mL) and water (1 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The pH value was adjusted to 8 by dropwise addition of aqueous ammonia. The mixture was purified by preparative HPLC (C18 column, 0-100% acetonitrile / water as mobile phase) to give the title compound (6.5 mg, yellow solid, yield 26.67%). LC-MS(ESI):m / z(M+H) + 365.1.1 H NMR (400MHz, CD3OD): δ8.28 (s, 1H), 7.64 (d, J = 2.0Hz, 1H), 7.63 (br d,J=1.2Hz,1H),6.90-6.83(m,1H),6.80(s,1H),6.76(d,J=2.0Hz,1H),4.65-4.57(m,1H),4.25(d,J=12.8Hz,1H),4.05(dd,J=3. 6,11.6Hz,1H),3.86(s,4H),3.81-3.75(m,1H),3.64(dt,J=2.8,12.0Hz,1H),3.42(dt,J=3.6,12.8Hz,1H),1.39(d,J=6.8Hz,3H). Embodiment 17 (R)-3-Methyl-4-(5-(methylsulfonyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolo[1,2-c]pyrimidin-3-yl)morpholine Embodiment 18 (R)-3-methyl-4-(1-(methylsulfonyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,5-c]pyrimidin-7-yl)morpholine Embodiment 19 (R)-3-Methyl-4-(6-(methylsulfonyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolo[1,2-a]pyrazin-3-yl)morpholine Embodiment 20 (R)-3-methyl-4-(3-(methylsulfonyl)-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyrazine-6-yl) morpholine Using a synthetic procedure similar to that described for Example 13, the compounds of Examples 21-25 below were prepared. Embodiment 26 (R)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine a) Preparation of 3,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine: 3,6-dichloropyridazin-4-amine, 2,5-diketohexane and TsOH·H2O were dissolved in toluene and stirred at 140°C for 16 hours in a Dean-Stark apparatus. The reaction solution was cooled to room temperature and the toluene layer was poured off. The residue was purified by silica gel column chromatography (EtOAc / PE, 10-20%) to obtain the target product (10.2 g, brown solid, yield: 35%). 1 H NMR (400MHz, CDCl3): δ7.47(s,1H),5.96(s,2H),1.99(s,6H). b) Preparation of (R)-4-(6-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine-3-yl)-3-methylmorpholine: To a solution of 3,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine (10.2 g, 42.3 mmol) in NMP (100 mL) was added (R)-3-methylmorpholine (5.1 g, 50.8 mmol) and DIEA (16.4 g, 126.9 mmol). The reaction solution was stirred at 190°C for 6 hours. After the reaction was complete, water (200 mL) was added to the reaction solution and extracted with EtOAc (100 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by silica gel column chromatography (EtOAc / PE, 10-30%) to give the target product (9.25 g, brown solid, yield: 71%). LC-MS (ESI): m / z (M+H) + 307.10. 1 H NMR (400MHz, CDCl3): δ6.77(d,J=4.6Hz,1H),5.94(d,J=4.6Hz,2H),4.16(d,J=7.6Hz,1H),4.02(dd,J=17.8,13.0 Hz, 2H), 3.80 (d, J = 4.5Hz, 2H), 3.62 (d, J = 12.1Hz, 1H), 3.35 (d, J = 12.7Hz, 1H), 1.99 (s, 6H), 1.28 (d, J = 6.2Hz, 3H). c) Preparation of (R)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile: (R)-4-(6-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine-3-yl)-3-methylmorpholine (9.25 g, 30.2 mmol), Zn(CN)2 (7.09 g 136.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene (DPPF, 7.54 g, 13.6 mmol) and Pd2(dba)3 (0.85 g, 0.93 mmol) were dissolved in DMF (100 mL) and water (2 mL). The reaction solution was stirred at 150°C for 6 hours. After the reaction was complete, water (200 mL) was added to the reaction solution and extracted with EtOAc (200 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by silica gel column chromatography (EtOAc / PE, 20-50%) to obtain the target product (8.4 g, brown solid, yield: 93%). 1 H NMR (400MHz, CDCl3): δ6.58(s,1H),5.97(s,2H),4.35(s,1H),4.20(d,J=13.8Hz,1H),4.13-4.05(m,1H) ,3.89-3.75(m,2H),3.70-3.61(m,1H),3.51-3.37(m,1H),2.07(d,J=5.0Hz,6H),1.36(d,J=6.8Hz,3H). d) Preparation of (R)-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazine-3-yl)methylamine: Raney nickel (~40 g, W / W) was added to a solution of (R)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile (8.4 g, 28.3 mmol) in methanol (100 mL). The reaction system was degassed and replaced with H2 three times, and the reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth and the filter cake was washed with methanol (90 mL×10). The combined filtrate was concentrated to obtain the target product (5.6 g, black solid). 1 H NMR (400MHz, MeOD): δ7.43 (s, 1H), 5.95 (s, 2H), 4.36 (s, 1H), 4.03 (d, J = 12.2Hz, 2H), 3.7 4-3.83(m,3H),3.60(d,J=11.6Hz,1H),3.35(s,2H),1.96(s,6H),1.27(d,J=7.0Hz,3H). e) Preparation of (R)-N-((4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide: (R)-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methylamine (5.6 g, 18.6 mmol), 1H-pyrazole-5-carboxylic acid (2.5 g, 22.3 mmol), HATU (4.3 g, 11.2 mmol) and DIEA (7.2 g, 55.8 mmol) were dissolved in DCM (60 mL). The reaction solution was stirred at room temperature overnight. After the reaction was complete, water (100 mL) was added to the reaction solution and extracted with DCM (100 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by silica gel column chromatography (MeOH / DCM, 1-3%) to give the target product (4.3 g, yellow solid, yield: 38%). LC-MS (ESI): m / z (M+H) + 396.20. 1 H NMR (400MHz, DMSO-d6): δ8.34(s,1H),7.81(s,1H),7.29(s,1H),6.61(s,1H),5.89(s,2H),4.38(s,1H),4.14-4.00(m ,3H),3.99-3.92(m,1H),3.75-3.66(m,2H),3.55-3.48(m,1H),3.20-3.15(m,2H),1.94(s,6H),1.16(d,J=6.6Hz,3H). f) Preparation of (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine: (R)-N-((4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholine)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (4.3 g, 10.9 mmol) was dissolved in POCl3 (40 mL) and stirred at 120°C for 4 hours. After the reaction was complete, the solvent was removed. Water (5 mL) was added to the residue and the pH was adjusted to 8 with aqueous ammonia (25% w / w), followed by extraction with DCM (40 mL×2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by silica gel column chromatography (EtOAc / PE, 20-100%) to give the target product (2.7 g, yellow solid, yield: 66%). LC-MS (ESI): m / z (M+H) + 378.11. 1H NMR (400MHz, CDCl3): δ7.71(s,1H),7.29(s,1H),7.24(s,1H),7.11(s,1H),6.37(s,1H),5.98(s,2H),4.16 -4.03(m,2H),3.95-3.75(m,3H),3.72-3.66(m,1H),3.52-3.41(m,1H),2.11(s,6H),1.37(d,J=6.7Hz,3H). g) Preparation of (R)-2-(3-methylmorpholine)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-ol: (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (2.7 g, 7.16 mmol) was dissolved in TFA / H2O (20 mL / 2.0 mL) and stirred at 85°C for 16 hours. After the reaction was complete, the solvent was removed. The crude product was purified by silica gel column chromatography (MeOH / DCM, 1-10%) to give the target product (1.5 g, yellow solid, yield: 71%). LC-MS (ESI): m / z (M+H) + 301.40. 1 H NMR (400MHz, DMSO-d6): δ13.33(s,1H),7.63(s,1H),7.46(s,1H),7.03(s,1H),5.93(s,1H),4 .06(s,1H),3.92(d,J=11.3Hz,1H),3.67(s,3H),3.48(s,1H),3.18-3.12(m,1H),1.15(s,3H). h) Preparation of (R)-2-(3-methylmorpholino)-7-(1-((trifluoromethyl)sulfonyl)-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl trifluoromethanesulfonate: (R)-2-(3-methylmorpholino)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-ol (1.5 g, 5 mmol) and TEA (1.5 g, 15.0 mmol) were dissolved in dry DCM (40 mL) at 0°C under nitrogen protection and stirred for 10 minutes. Then Tf2O (4.2 g, 15.0 mmol) was slowly added dropwise at 0°C and stirred for 30 minutes, then returned to room temperature and stirred for 1.5 hours. The reaction solution was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by silica gel column chromatography (DCM / PE, 10-30%) to obtain the target product (1.2 g, yellow solid, yield: 38%). LC-MS (ESI): m / z (M+H) + 565.05.1 H NMR (400MHz, CDCl3): δ8.16(s,1H),7.65(s,1H),7.42(s,1H),6.54(s,1H),4.16-4.03 (m,2H),3.83(m,3H),3.73-3.62(m,1H),3.44(d,J=13.4Hz,1H),1.38(d,J=6.8Hz,3H). i) Preparation of (R)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine: (R)-2-(3-methylmorpholine)-7-(1-((trifluoromethyl)sulfonyl)-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl trifluoromethanesulfonate (0.3 g, 0.53mmol), 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (150.2mg, 0.64mmol), K2CO3 (219.4mg, 1.59mmol) and Pd(dppf)Cl2 (77.6mg, 0.11mmol) were dissolved in dioxane (2mL). The reaction system was degassed and replaced with argon three times and stirred at 90°C for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and 2N LiOH (1mL) was added dropwise. After stirring at room temperature for 0.5 hours, the mixed solution was filtered and the filtrate was concentrated. The crude product was purified twice by preparative thin layer chromatography (MeOH / DCM=10:1) to obtain the target compound (17mg, yellow solid, yield: 8%). LC-MS (ESI): m / z(M+H) + 393.15. 1 H NMR (400MHz, MeOD): δ7.73(s,1H),7.68(s,1H),7.26(s,1H),7.19(s,1H),6. 77(s,1H),6.59(s,1H),4.61(dd,J=12.9,6.2Hz,1H),4.33(d,J=7.3Hz,1H),4 .07-3.99(m,1H),3.91(d,J=13.3Hz,1H),3.86-3.75(m,2H),3.67(t,J=11.9 Hz, 1H), 3.41 (t, J = 12.8Hz, 1H), 1.46 (d, J = 6.5Hz, 6H), 1.35 (d, J = 6.7Hz, 3H). Embodiment 27 (R)-4-(4,7-Di(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine The compound of this example was prepared using a synthetic method similar to that described for Example 26. The compound of Example 27 was a yellow solid. LC-MS (ESI): m / z (M+H) + 351.35. 1 H NMR (400MHz, DMSO-d6): δ13.43(s,1H),8.00(s,1H),7.95(s,1H),7.69(s,1H),7.22(t,J=3.2Hz,2H),7.12(s,1H),4.43(s,1H),4. 01(d,J=11.3Hz,1H),3.92(d,J=13.3Hz,1H),3.78(t,J=10.1Hz,2H),3.61-3.58(m,1H),3.29-3.26(m,1H),1.24(d,J=6.8Hz,3H). Embodiment 28 (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-2-yl)morpholine Embodiment 29 (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-3-yl)imidazo[5,1-f][1,2,4]triazin-2-yl) Phytophenone Embodiment 30 (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[3,4-f][1,2,4]triazine-6- morpholine Embodiment 31 (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5-a][1,3,5]triazin-2-yl) Phytophenone Embodiment 32 (R)-4-(4-cyclopropyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine a) Preparation of (R)-4-(5-chloro-6-methylpyridazine-3-yl)-3-methylmorpholine: 4,6-dichloro-3-methylpyridazine (3.0 g, 18.4 mmol), (R)-3-methylmorpholine (2.8 g, 27.6 mmol) and DIEA (4.8 g, 36.8 mmol) were dissolved in NMP (30 mL) and stirred at 150 ° C for 8 hours. After the reaction was complete, water (50 mL) was added to the reaction solution and extracted with EtOAc (40 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / PE, 10%-30%) to obtain the target product (0.55 g, yellow solid, yield: 13%). LC-MS (ESI): m / z (M+H) + 228.45. 1 H NMR (400MHz, CDCl3): δ6.81(s,1H),4.29-4.15(m,1H),4.04-3.95(m,1H),3.87-3. 73(m,3H),3.60(t,J=11.8Hz,1H),3.27(m,1H),2.58(s,3H),1.24(d,J=6.8Hz,4H). b) Preparation of (R)-4-chloro-6-(3-methylmorpholino)pyridazine-3-carboxaldehyde: (R)-4-(5-chloro-6-methylpyridazin-3-yl)-3-methylmorpholine (510 mg, 2.24 mmol) and SeO2 (298 mg, 2.68 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 95°C for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / PE, 10%-30%) to obtain the target product (370 mg, yellow solid, yield: 68%). 1 H NMR (400MHz, CDCl3): δ10.18(s,1H),6.78(s,1H),4.51(s,1H),4.17(d,J=13.2Hz,1H),4.08(d,J= 10.8Hz,1H),3.87-3.76(m,2H),3.64(t,J=11.8Hz,1H),3.54-3.33(m,1H),1.38(d,J=6.4Hz,3H). c) Preparation of (R)-1-(4-chloro-6-(3-methylmorpholino)pyridazine-3-yl)-N-(2,4-dimethoxybenzyl)methanamine: (R)-4-chloro-6-(3-methylmorpholino)pyridazine-3-carboxaldehyde (470 mg, 1.94 mmol) and (2,4-dimethoxyphenyl)methanamine (390 mg, 2.33 mmol) were dissolved in DCE (8 ml) and AcOH (349 mg, 5.82 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. Then NaBH(OAc)3 (822 mg, 3.88 mmol, 2.0 equiv) was added and stirred at room temperature overnight. Ice water (10 ml) was added to the reaction solution to quench and extract with EtOAc (15 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH=100 / 1-50 / 1) to give the target product (420 mg, yellow solid, yield: 55%). LC-MS (ESI): m / z (M+H) + 393.30. d) Preparation of (R)-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)methanamine: (R)-1-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)-N-(2,4-dimethoxybenzyl)methanamine (420 mg, 1.07 mmol) was dissolved in TFA (3 mL) and stirred at 80 °C for 3 hours. After removing the solvent, the residue was added with DCM (5 mL) and aqueous ammonia (~25% w / w, 0.5 mL). The resulting solution was stirred at room temperature for 5 minutes and then concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH=100 / 1-15 / 1) to give the target product (210 mg, yellow solid, yield: 81%). LC-MS (ESI): m / z (M+H) + 243.15. e) Preparation of N-((4-chloro-6-((R)-3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide: (R)-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)methylamine (190 mg, 0.78 mmol), 1H-pyrazole-5-carboxylic acid (88 mg, 0.78 mmol), HATU (593 mg, 1.56 mmol) and DIEA (202 mg, 1.56 mmol) were dissolved in DMF (4 mL). The reaction solution was stirred at room temperature overnight. The reaction solution was quenched with water (10 ml) and extracted with EtOAc (15 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH=100 / 1-10 / 1) to give the target product (181 mg, yellow solid, yield: 69%). LC-MS (ESI): m / z (M+H) + 337.20. f) Preparation of (R)-4-(4-chloro-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine: N-((4-chloro-6-((R)-3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (181 mg, 0.54 mmol) was dissolved in POCl3 (3 mL) and stirred at 120°C for 3 hours. After removing the solvent, the residue was diluted with DCM (15 mL) and washed with saturated NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (DCM / MeOH=100 / 1-10 / 1) to give the target product (88 mg, yellow solid, yield: 51%). LC-MS (ESI): m / z (M+H) + 319.20. 1 H NMR (400MHz, CDCl3): δ7.72(s,1H),7.64(s,1H),7.09(s,1H),6.57(s,1H),4.16-4.00( m,2H),3.86-3.78(m,2H),3.78-3.60(m,2H),3.48-3.36(m,1H),1.36(d,J=6.4Hz,3H). g) Preparation of (R)-4-(4-cyclopropyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine: (R)-4-(4-chloro-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (70 mg, 0.22 mmol), cyclopropylboronic acid (11,38 mg, 0.44 mmol), K3PO4·3H2O (176 mg, 0.22 mmol), Pd(OAc)2 (5 mg, 0.02 mmol) and tricyclohexylphosphine (11 mg, 0.04 mmol) were dissolved in 1,4-dioxane (1 mL) and toluene (1 mL) under N2 protection. The reaction system was degassed and replaced with N2 three times. The reaction solution was stirred at 100°C for 16 hours. After the reaction was complete, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (DCM / MeOH=10 / 1) to obtain the target compound (15 mg, light yellow solid, yield: 21%). LC-MS (ESI): m / z (M+H) + 325.25. 1 H NMR (400MHz, CDCl3): δ7.70(s,1H),7.61(s,1H),7.08(s,1H),6.07(s,1H),4.16-4.05(m,2H),3.87-3.81(m,2H),3. 75-3.63(m,2H),3.46-3.36(m,1H),2.15-2.07(m,1H),1.33(d,J=5.6Hz,3H),1.20-1.15(m,2H),1.03-0.97(m,2H). Using synthetic methods similar to those described for Examples 13, 26 or 32, the compounds of Examples 33-63 described below were prepared. Embodiment 64 The inhibitory effect of (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine and its analogs on ATR enzyme activity was determined by ATR enzyme activity assay. The ATR enzyme activity was detected using Cisbio's HTRF reagent in a 384-well plate (Greiner, #784075). The test compound was diluted to a 4-fold final concentration with a reaction buffer (25mM HEPES (pH8.0), 10mM MnCl2, 1% glycerol, 0.01% Brij-35, 5mM DTT and 0.1% BSA), and 2.5μL was added to the corresponding plate wells, followed by 2.5μL of 80nM p53 substrate (Eurofins, #14-952) and 2.5μL of 2ng / μL ATR / ATRIP enzyme (Eurofins, 14-953) solution, and finally 2.5μL of 40μM ATP solution was added, centrifuged at 1000rpm for 1 minute, and reacted at room temperature in the dark for 30 minutes. Then 5μL of EDTA stop solution (250mM) was added to terminate the reaction. After adding 5 μL of detection mixture (Anti-phospho-p53(ser15)-K (Cisbio, #61P08KAE, 0.084 ng / μL) and Anti-GST-d2 (Cisbio, #61GSTDLA, 5.00 ng / μL)) to each well, the fluorescence values ​​at 665 nm and 615 nm were detected on the Envision 2104 instrument. Calculate the relative fluorescence ratio: Ratio 665nm / 615nm -Ratio 背景 , and calculated the inhibition rate % = (1-(relative fluorescence ratio of the test compound wells-relative fluorescence ratio of the positive control wells) / (relative fluorescence ratio of the blank control wells-relative fluorescence ratio of the positive control wells)) × 100, and analyzed the data using GraphPad Prism6.0 software, with the curve equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope)) to fit and calculate IC 50 value. Table 1 summarizes the inhibitory effects of the compounds on ATR kinase activity (IC 50 ). Table 2 summarizes the inhibitory effects (Inh %) of the compounds on ATR kinase activity at 50 nM. Table 1 *: This IC 50 The values ​​were obtained by comparison with the compound of Example 13. Table 2 Example 11 33 35 36 38 44 Inh% 63 27 71 63 90 58 Therefore, according to the ATR enzyme activity experiment, (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazine-2-yl)morpholine (Example 13) and its similar compounds have a good inhibitory effect on ATR kinase activity. Embodiment 65 MTT assay was used to determine the expression of (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2- Inhibitory effects of 6-pyridazine-6-yl)morpholine and its analogs on the growth of human prostate cancer cell line DU145 The revived human prostate cancer cell DU145 was cultured and subcultured until the growth state was good. When the confluence reached about 90%, it was used for the experiment. The cells were digested with trypsin, centrifuged at 800rpm for 5min, the supernatant was discarded, and the cells were resuspended with fresh culture medium (DMEM culture medium + 10% FBS + non-essential amino acids), counted, and inoculated into 96-well cell culture plates at a density of 2000 cells per well, and placed in a 37℃ 5% CO2 incubator for overnight culture. The mother solution of the test substance (including the test compound and the reference compound BAY-1895344) was serially diluted with DMSO at a ratio of 1:3 and 1:10 to 8 concentrations, and 5μL of each concentration was added to 120μL culture medium (25-fold dilution) and oscillated to mix. Take the cells that have been cultured overnight, remove the culture medium, add 195 μL of fresh culture medium to each well, and then add 5 μL of diluted culture medium containing the corresponding concentration of the compound (the final concentration of the compound is shown in Table 3, and the final concentration of DMSO is 1‰), and then place the culture plate in a 37°C 5% CO2 incubator for 4 days. Remove the original solution, add 100 μL of fresh serum-free DMEM culture medium containing MTT (0.5 mg / mL) to each well, and continue to culture. After 4 hours, remove the original solution, add 100 μL of DMSO to each well, shake in the dark for 10 minutes, and place it in a multi-function reader to read the absorbance value at a wavelength of 552 / 690nm. Use Graph Pad Prism 6.0 software to analyze the data, and plot the inhibitory activity of the compound on cell proliferation using cell survival rate versus the logarithm of compound concentration as coordinates. Cell survival rate % = (OD 化合物 -OD 背景 ) / (OD DMSO -OD 背景 )×100. IC 50 The values ​​were fitted with an S-shaped dose-response curve equation: Y = 100 / (1+10^(LogC-LogIC 50 )), C is the concentration of the compound. Table 3 summarizes the inhibitory effect of the compounds on the growth of human prostate cancer cell line DU145 (IC 50 ). Table 3 Example 2 3 4 6 7 8 9 10 <![CDATA[IC 50 (nM)]]> 1217 1097 1093 913.7 1196 1108 1631 2298 Example 13 16 BAY-1895344 <![CDATA[IC 50 (nM)]]> 130.9 1374 33.92* *: This IC 50 The values ​​were obtained by comparison with the compound of Example 13. Therefore, as determined by the MTT assay, (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 2) has an inhibitory effect on the growth of DU145 cells. (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 13) has a good inhibitory effect on the growth of DU145 cells. Embodiment 66 MTT assay was used to determine the expression of (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2- Inhibitory effects of b]pyridazine-6-yl)morpholine and its analogs on the growth of human lung cancer cells NCI-H460 The revived human lung cancer cells NCI-H460 were cultured and subcultured until they were in good growth state. When the confluence reached about 90%, they were used for experiments. The cells were digested with trypsin, centrifuged at 800rpm for 5min, the supernatant was discarded, and the cells were resuspended with fresh culture medium (1640 culture medium + 10% FBS), counted, and inoculated into 96-well cell culture plates at a density of 2000 / 4000 cells per well, and placed in a 37℃ 5% CO2 incubator for overnight culture. The mother solutions of the test substances (including the test compounds and the reference compound BAY-1895344) were serially diluted with DMSO at a ratio of 1:3 and 1:10 to 8 concentrations, and 5μL of each concentration was added to 120μL culture medium (25-fold dilution) and oscillated to mix. Take the cells that have been cultured overnight, remove the culture medium, add 195 μL of fresh culture medium to each well, and then add 5 μL of diluted culture medium containing the corresponding concentration of compounds (the final concentration of DMSO is 1‰), and then place the culture plate in a 37℃ 5% CO2 incubator for 4 days. Remove the original solution, add 100 μL of fresh serum-free DMEM culture medium containing MTT (0.5 mg / mL) to each well, and continue to culture. After 4 hours, remove the original solution, add 100 μL of DMSO to each well, shake in the dark for 10 minutes, and place it on a multi-function reader to read the absorbance value at a wavelength of 552 / 690nm. Cell survival rate (%) = (OD 化合物 -OD 背景 ) / (OD DMSO -OD 背景) × 100. The data were analyzed using Graph Pad Prism 6.0 software, and the inhibitory activity of the compounds on cell proliferation was plotted as a graph of cell survival rate versus the logarithm of compound concentration. 50 The values ​​were fitted with an S-shaped dose-response curve equation: Y = 100 / (1+10^(LogC-LogIC 50 )), C is the concentration of the compound. Table 4 summarizes the inhibitory effect of the compounds on the growth of human lung cancer cells NCI-H460 (IC 50 ). Table 4 *: This IC 50 The values ​​were obtained by comparison with the compound of Example 13. Therefore, as determined by the MTT assay, (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 2) has an inhibitory effect on the growth of NCI-H460 cells. (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 13) has a good inhibitory effect on the growth of NCI-H460 cells. Embodiment 67 MTT assay was used to determine the expression of (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2- Inhibitory effects of b]pyridazine-6-yl)morpholine and its analogs on the growth of human colon cancer cells LoVo The revived human colon cancer cells LoVo were cultured and subcultured until they were in good growth state. When the confluence reached about 90%, they were used for experiments. The cells were digested with trypsin, centrifuged at 800rpm for 5min, the supernatant was discarded, and the cells were resuspended with fresh culture medium (1640 culture medium + 10% FBS), counted, and inoculated into 96-well cell culture plates at a density of 2000 / 4000 cells per well, and cultured in a 37°C 5% CO2 incubator overnight. The mother solutions of the test substances (including the test compounds and the reference compound BAY-1895344) were serially diluted with DMSO at a ratio of 1:3 and 1:10 to 8 concentrations, and 5μL of each concentration was added to 120μL culture medium (25-fold dilution) and oscillated to mix. Take the cells that have been cultured overnight, remove the culture medium, add 195 μL of fresh culture medium to each well, and then add 5 μL of diluted culture medium containing the corresponding concentration of compounds (the final concentration of DMSO is 1‰), and then place the culture plate in a 37℃ 5% CO2 incubator for 4 days. Remove the original solution, add 100 μL of fresh serum-free DMEM culture medium containing MTT (0.5 mg / mL) to each well, and continue to culture. After 4 hours, remove the original solution, add 100 μL of DMSO to each well, shake in the dark for 10 minutes, and place it on a multi-function reader to read the absorbance value at a wavelength of 552 / 690nm. Cell survival rate (%) = (OD 化合物 -OD 背景 ) / (OD DMSO -OD 背景 ) × 100. The data were analyzed using GraphPad Prism 6.0 software, and the inhibitory activity of the compounds on cell proliferation was plotted as a graph of cell survival rate versus the logarithm of compound concentration. 50 The values ​​were fitted with an S-shaped dose-response curve equation: Y = 100 / (1+10^(LogC-LogIC 50 )), C is the concentration of the compound. Table 5 summarizes the inhibitory effect of the compounds on the growth of human colon cancer cells LoVo (IC 50 ). Table 5 Example 5 11 12 13 15 21 22 23 <![CDATA[IC 50 (nM)]]> 557.2 167.7 3226 53.5 597.3 155.1 854.3 1528 Example 24 25 26 27 32 33 34 35 <![CDATA[IC 50 (nM)]]> 34.39 61.92 68.20 124.0 87.31 230.3 953.3 75.39 Example 36 37 38 39 40 41 42 43 <![CDATA[IC 50 (nM)]]> 114.0 45.02 127.9 30.74 21.83 49.52 44.69 23.12 Example 44 45 46 47 48 49 50 51 <![CDATA[IC 50 (nM)]]> 138.2 84.15 72.80 20.73 133.4 32.94 59.87 76.66 Example 52 55 61 BAY-1895344 <![CDATA[IC 50 (nM)]]> 41.87 51.02 175.3 26.02 *: This IC 50 The value is obtained by comparative experiment with the compound of Example 13. Therefore, as determined by the MTT assay, (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 2) has an inhibitory effect on the growth of LoVo cells. (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 13) has a good inhibitory effect on the growth of LoVo cells.

[0120] Although the present invention has been fully described, it will be appreciated by those skilled in the art that the same implementation can be performed in a wide range of and equivalent conditions, formulations and other parameter ranges without affecting the scope of the present invention or any embodiment thereof. All patents, patent applications and publications cited herein are incorporated herein by reference in their entirety.

Claims

1. Use of a compound of the following formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a mixture thereof in the preparation of a medicament for treating or preventing ATR kinase-mediated cancer: Where: The five-membered and six-membered heteroaryl groups containing A1, A2, A3, A4, A5 and A6 are the following groups: in, *1, *2 and *3 represent the connection positions of the group to the morpholinyl group, R1 and R2 of the compound, respectively; R1 is pyrazolyl, pyrrolyl or imidazolyl optionally substituted by 1 or 2 groups selected from C1-C4 alkyl and halogen; R2 is a 3-7 membered heterocyclyl, a 6-14 membered aryl or a 5-14 membered heteroaryl group optionally substituted by 1, 2 or 3 substituents selected from C1-C6 alkyl, halogen, C1-C4 alkanesulfinyl and C1-C4 alkanesulfonyl; R3 and R4 are each independently hydrogen or C1-C6 alkyl.

2. The use according to claim 1, characterized in that The R1 is an unsubstituted pyrazolyl group.

3. The use according to claim 1, characterized in that The R2 is phenyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, furanyl, morpholinyl, dihydropyranyl, tetrahydropyranyl, pyridinyl or pyrimidinyl, which is optionally substituted with one substituent selected from C1-C6 alkyl and C1-C4 alkylsulfonyl.

4. The use according to claim 1, characterized in that The R2 is phenyl, pyrazolyl, morpholinyl, pyridyl or imidazolyl, which is optionally substituted by one substituent selected from C1-C6 alkyl and C1-C4 alkylsulfonyl.

5. The use according to claim 1, characterized in that The compound of formula I is selected from: (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine; (R)-3-methyl-4-(8-(1-ethyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine; (R)-3-methyl-4-(8-(1-isopropyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine; (R)-3-methyl-4-(8-(1-methyl-1H-imidazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine; (R)-3-methyl-4-(8-(6-methylpyridin-3-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine; (R)-3-methyl-4-(8-(4-(methylsulfonyl)phenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine; (R)-3-methyl-4-(8-(2-fluorophenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine; (R)-3-methyl-4-(8-morpholinyl-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine; and (2S,6R)-2,6-Dimethyl-4-(6-((R)-3-methylmorpholinyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine.

6. The use according to claim 1, characterized in that The cancer is 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 insulinoma, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary neoplasia, thyroid cancer, esophageal cancer, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, essential thrombocythemia, adrenocortical carcinoma, skin cancer and prostate cancer.

7. The use according to claim 1, characterized in that: The drug further comprises at least one known anticancer drug, or a pharmaceutically acceptable salt thereof; preferably, the anticancer drug is selected from one or more of the following groups: busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyellipticine, mingtopop, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5 -Fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, panitumumab, necrotizumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab tiuxetan, tositumomab, brentuximab, daratumumab T-DM1, Ofatumumab, Dinutuximab, Blinatumomab, Ipilimumab, Avastin, Herceptin, Rituximab, Imatinib, Gefitinib, Erlotinib, Osimertinib, Afatinib, Ceritinib, Alectinib, Crizotinib, Erlotinib, Lapatinib, Sorafenib, Sunitinib, Nilotinib, Dasatinib, Pazopanib, Tecan, Everolimus, Vorinostat, Romidepsin, Panobinostat, Belinostat, Tamoxifen , letrozole, fulvestrant, mitoguanidine, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegi, denosumab, thalidomide, lenalidomide, venetoclax, recombinant human interleukin-2 Aldesleukin, prostate cancer treatment vaccine sipueucel-T, palbociclib, olaparib, niraparib, rucaparib, talazoparib and senaparib; and / or The drug is used in combination with radiation therapy.

8. A compound of the following formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a mixture thereof: Where: The five-membered and six-membered heteroaryl groups containing A1, A2, A3, A4, A5 and A6 are the following groups: in, *1, *2 and *3 represent the connection positions of the group to the morpholinyl group, R1 and R2 of the compound, respectively; R1 is pyrazolyl, pyrrolyl or imidazolyl optionally substituted by 1 or 2 groups selected from C1-C4 alkyl and halogen; R2 is a 3-7 membered heterocyclyl, a 6-14 membered aryl or a 5-14 membered heteroaryl group optionally substituted by 1, 2 or 3 substituents selected from C1-C6 alkyl, halogen, C1-C4 alkanesulfinyl and C1-C4 alkanesulfonyl; R3 and R4 are each independently hydrogen or C1-C6 alkyl.

9. The compound according to claim 8, or its stereoisomer or pharmaceutically acceptable salt, or a mixture thereof, characterized in that: The compound is as described in any one of claims 2 to 5.

10. A pharmaceutical composition comprising a compound according to any one of claims 8 to 9 and a pharmaceutically acceptable carrier; preferably, the composition further comprises at least one known anticancer drug, or a pharmaceutically acceptable salt of the anticancer drug; preferably, the at least one known anticancer drug is selected from the group consisting of busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methylhydroxyrosemide, alkali, mingtopop, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, monoclonal antibody, panitumumab, nexitumomab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alendronate Monoclonal antibody, Ibritumomab Tiuxetan, Tositumomab, Brentuximab, Daratumumab, Elotuzumab, T-DM1, Ofatumumab, Dinutuximab, Blinatumomab, Ipilimumab, Avastin, Herceptin, Rituximab, Imatinib, Gefitinib, Erlotinib, Osimertinib, Afatinib, Ceritinib, Alectinib, Crizotinib, Erlotinib, Lapatinib, Sorafenib, Sunitinib, Nilotinib, Dasatinib, Pazopanib, Tecan, Everolimus, Vorinostat, Romidepsin, Panibix he, belinostat, tamoxifen, letrozole, fulvestrant, mitoguanidine, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegi, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2), sipueucel-T (a vaccine for prostate cancer), palbociclib, olaparib, niraparib, rucaparib, talazoparib, and senaparib.

Images