Substituted imidazo[1,5-b]pyridazine compounds as kinase inhibitors and uses thereof

Abstract

This invention provides novel substituted imidazo[1,5-b]pyridazine compounds of Formula I, wherein A, R0, R1, R2, and R3 are as defined herein. Compounds of Formula I are kinase inhibitors, particularly ATR kinase inhibitors. Therefore, the compounds of this invention can be used to treat ATR-mediated diseases, disorders, and conditions, such as cancer.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry. In particular, this invention relates to substituted imidazo[1,5-b]pyridazine compounds and their use as therapeutically effective kinase inhibitors and anticancer drugs. Background Technology

[0002] Rad3-associated kinase (ATR), a mutant gene in ataxia-telangiectasia, is a protein kinase that responds to DNA damage in the cellular process. Once activated, ATR regulates various cellular life processes through a range of signals, including cell cycle arrest, inhibition of replication origins, initiation of replication forks, and repair of DNA double strands (Enriquez-Rios V et al., 2017). ATR kinase works alongside ATM (ataxia-telangiectasia mutant) kinase and many other proteins to regulate the cellular response to DNA damage, commonly referred to as the DNA damage response (DDR). When cells recognize DNA damage through DDR, they immediately activate the DNA repair program, triggering cell cycle checkpoints and disrupting the normal cell cycle, thus providing time for DNA repair. Without DDR, cells are more sensitive to endogenous cellular damage or DNA damage caused by chemotherapy and radiotherapy used to treat cancer, and are more prone to death.

[0003] Healthy cells rely on various proteins involved in DNA repair, including ATM and ATR kinase in DDR (Double Damage Repair). Under normal circumstances, these proteins repair DNA by regulating downstream regulatory factors. However, many cancer cells exhibit defects in DNA repair pathways, demonstrating a significant dependence on remaining intact DNA repair proteins, including ATR. ATR is a key member of DDR in the response to damaged DNA replication, crucial for maintaining genomic stability and integrity, and promoting cell survival. When intracellular DNA damage occurs, ATR is recruited to the site of DNA damage, and various proteins subsequently participate in regulating ATR activation. Once activated, ATR regulates several important cellular processes. Many cancer cells lack key tumor suppressor genes, making them more dependent on the ATR pathway than normal cells to regulate cellular DNA damage repair and promote cell survival, thus making ATR a promising target for cancer therapy.

[0004] ATR inhibitors can be used alone or in combination with DNA-damaging agents for cancer treatment because they disrupt DNA replication mechanisms, which are more crucial for cell survival in many cancer cells than in healthy cells. In fact, ATR inhibitors have been proven effective as single-active agents in cancer cells and can serve as effective sensitizers for radiotherapy and chemotherapy. Furthermore, ATR inhibitors can be used in combination with other DDR-related targeted therapies, such as PARP inhibitors.

[0005] Several ATR kinase inhibitors have been disclosed. For example, WO2011154737 discloses a morpholinopyrimidine compound as an ATR kinase inhibitor; WO2016020320 discloses a 2-(morpholin-4-yl)-1,7-naphthidine compound as an ATR kinase inhibitor; WO2020049017 discloses a 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivative as an ATR kinase inhibitor; WO2020087170 discloses... Substituted fused heteroaryl bicyclic compounds as ATR kinase inhibitors; WO2020259601 discloses substituted imidazopyridazine compounds as ATR kinase inhibitors; WO2021098811 discloses pyrazolopyridyl derivatives as ATR kinase inhibitors; CN112851668 discloses a series of compounds as ATR kinase inhibitors; CN113135942 discloses fused pyrimidine derivatives as ATR kinase inhibitors. Summary of the Invention

[0006] The present invention provides substituted imidazo[1,5-b]pyridazine compounds with structures as shown in Formula I (including Formulas II, III and IV), which 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 (including formulas II, III and IV) for the treatment of cancer.

[0008] In one specific embodiment, the pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers or diluents for the treatment of cancer.

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

[0010] This invention also relates to methods for preparing novel compounds of structural formula I (including formulas II, III and IV). Detailed Implementation

[0011] It should be understood that the features of the various embodiments described herein can be combined arbitrarily to form the technical solutions described herein; the definitions of each group herein apply to any embodiment described herein, for example, the definitions of alkyl substituents herein apply to any embodiment described herein, unless the alkyl substituents have been clearly defined in the embodiment.

[0012] Specifically, the present invention provides compounds of Formula I, their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts, mixtures thereof, or prodrugs thereof:

[0013]

[0014]

[0015] Where A is N or CH;

[0016] R0 is an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted carbocyclic group, an optionally substituted heteroaryl group, or an optionally heteroarylalkyl group;

[0017]

[0018] Where * indicates the connection position between the group and the rest of the compound;

[0019] R1 is a halogen, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl.

[0020] R2 is a halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclic, heterocyclic, aryl, heteroaryl, –(SO)R4, –(SO2)R4, –SR4, –NR6R7, –(CO)OR6, –(CO)NR6R7, –(SO2)NR6R7, –NR6(SO2)R4, –((SO)=NR5)R8, –N=(SO)R4R8, –SiR5R8R9, –(PO)(OR6)2, –(PO)(OR6)R8 or –(PO)(R8)2, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl groups may each be optionally substituted;

[0021] R3 is hydrogen or an optionally substituted C1-C6 alkyl group;

[0022] R4 is an optionally substituted alkyl or optionally substituted alkylaryl, with the preferred aryl being phenyl;

[0023] R5 is hydrogen, an alkyl group that may be optionally substituted, –(CO)OR6 or –(CO)NR6R7;

[0024] R6 and R7 are each independently hydrogen, and can be optionally substituted C1-C. 10 Alkyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl, or R6 and R7 together with the nitrogen and carbon atoms to which they are attached to form optionally substituted 4-7 membered cyclic amino groups, said cyclic amino groups optionally containing one or more additional heteroatoms selected from O, N and S;

[0025] R8 is a C1-C4 alkyl group, or in the –N=(SO)R4R8 group, R4 and R8 together with the S they are attached to form a 5- to 8-membered heterocyclic alkyl group; and

[0026] R9 is hydrogen or a C1-C4 alkyl group.

[0027] Preferably, in the definitions of the groups in Formula I above, unless otherwise specified, the carbocyclic group preferably contains 3-8 carbon atoms in the ring, such as C3-C8 cycloalkyl; the aryl group is preferably a 6-14 membered aryl group, the heteroaryl group is preferably a 5-10 membered heteroaryl group, and the heterocyclic group is preferably a 4-9 membered heterocyclic group.

[0028] In one or more embodiments of the compound of formula I, A is CH.

[0029] In one or more embodiments of the compound of formula I, R0 is an optionally substituted alkylsulfonyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted carbocyclic group, or an optionally substituted heteroaryl group. Preferably, the heteroaryl group is a 5- or 6-membered heteroaryl group containing at least one nitrogen atom, and more preferably a 5-membered heteroaryl group containing two nitrogen atoms. Preferably, the substituents of the alkylsulfonyl group, heterocyclic group, carbocyclic group, aryl group, or heteroaryl group are selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy, and amino groups. Preferably, the number of substituents on R0 can be 1-3. More preferably, R0 is a C1-C4 alkyl group, or a pyrazolyl group, pyrroleyl group, or imidazole group, substituted with one or two substituents selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy, and amino groups. In some embodiments, R0 is an unsubstituted pyrazolyl group, an unsubstituted pyrroleyl group, an unsubstituted imidazoleyl group, or a pyrazolyl group substituted with one C1-C4 alkyl group. In some embodiments, R0 is a 1H-pyrazol-5-yl group optionally substituted with a C1-C4 alkyl group.

[0030] In one or more of the preceding embodiments of the compound of formula I, R1 is a halogen, optionally surrounded by 1-6 derivatives selected from halogens, hydroxyl groups, and -NR. a R b The substituent is a C1-C6 alkyl, C3-C6 cycloalkyl, or C2-C6 alkenyl group, wherein R is a C1-C6 alkyl, C3-C6 cycloalkyl, or C2-C6 alkenyl group. a and R b Each is independently H and C1-C4 alkyl. Preferably, R1 is a halogen, C1-C4 alkyl, C3-C4 cycloalkyl, or C2-C4 alkenyl. More preferably, R1 is a halogen, C1-C3 alkyl, C3-C4 cycloalkyl, or C2-C3 alkenyl.

[0031] In one or more of the foregoing embodiments of the compound of formula I, R2 is a carbocyclic, heterocyclic, aryl, or heteroaryl group, wherein each of the carbocyclic, heterocyclic, aryl, and heteroaryl groups may be optionally substituted. Preferably, R2 is an optionally substituted aryl, optionally substituted heterocyclic, or optionally substituted heteroaryl group. Preferably, the aryl group is phenyl or naphthyl. Preferably, the heterocyclic group is a 4-7 member nitrogen- and / or oxygen-containing heterocyclic group, preferably selected from: tetrahydropyranyl, tetrahydrofuranyl, oxoheterobutyl, azacyclicbutyl, pyrrolidinyl, piperidinyl, and piperazineyl. Preferably, the heteroaryl group is a 5- or 6-member nitrogen-containing heteroaryl group, preferably selected from pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, and triazolyl. Preferably, R2 is an optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, or optionally substituted tetrahydropyranyl. Preferably, the substituents on R2 are selected from C1-C6 alkyl, halo-C1-C6 alkyl, cyano, halogen, and alkylsulfonyl (such as sulfonyl groups substituted with C1-C4 alkyl). The number of substituents can be 1 to 3. In some preferred embodiments, R2 is a phenyl group optionally substituted with 1 or 2 sulfonyl groups substituted with C1-C6 alkyl, halogen, cyano, and C1-C4 alkyl; a pyrazolyl or pyridyl group optionally substituted with 1 or 2 alkyl groups substituted with C1-C6 alkyl, halo-C1-C6 alkyl, and halogen; or a tetrahydropyranyl group optionally substituted with 1 or 2 alkyl groups substituted with C1-C6 alkyl, halo-C1-C6 alkyl, and halogen.

[0032] Preferably, R2 is selected from:

[0033]

[0034] Among them, R 10 It is H, C1-C3 alkyl, or halo-C1-C3 alkyl; each R 11 Independently, it is H or C1-C3 alkyl; R 12 H or a halogenated C1-C3 alkyl group; R 13 H or C1-C3 alkyl; R 14 It is H or C1-C3 alkyl; each R 15 R is independently H or C1-C3 alkyl, preferably C1-C3 alkyl; 16 It is H, halogen, or C1-C3 alkyl, preferably halogen or C1-C3 alkyl; R 17 For H or CN; R 18 The sulfonyl group is H or C1-C3 alkyl-substituted; R 19 H, halogen, C1-C3 alkyl, or halo-C1-C3 alkyl; R 20 H or C1-C3 alkyl; R 21It is a halogen, a C1-C3 alkyl group or a halogenated C1-C3 alkyl group, preferably a halogen; wherein, * indicates the connection position of R2 with the remainder of the compound.

[0035] Preferably, R2 is selected from:

[0036]

[0037] Among them, R 10 C 1-3 Alkyl groups, such as methyl, ethyl, and isopropyl; R 16 It is methyl or fluorine; R 19 It is methyl, fluorine, or trifluoromethyl; where * indicates the connection position of R2 with the rest of the compound.

[0038] More preferably, R2 is:

[0039]

[0040] In one or more of the preceding embodiments of the compound of formula I, R3 is optionally composed of 1 to 6 derivatives selected from halogens, hydroxyl groups, -NR... a R b C1-C6 alkyl groups substituted with halogenated C1-C4 alkyl substituents, wherein R a and R b Each is independently H and C1-C4 alkyl. Preferably, R3 is a C1-C4 alkyl, such as methyl. Preferably, R3 is in the R configuration.

[0041] In one or more of the preceding embodiments of the compound of formula I, R4 is an alkyl or alkylaryl group, optionally composed of 1 to 6 groups selected from halogens, hydroxyl groups, and -NR. a R b Substituents, wherein R a and R b Each is independently H and C1-C4 alkyl. In some embodiments, R4 is an optionally substituted C1-C4 alkyl or an optionally substituted C1-C4 alkyl aryl (preferably, the aryl is phenyl), optionally surrounded by 1-6 atoms selected from halogens, hydroxyl groups, and -NR. a R b Substituents, wherein R a and R b Each is independently H or C1-C4 alkyl.

[0042] In the groups described in R5, R6, and R7, when substituted, the substituents may be selected from halogens, hydroxyl groups, optionally with one or two groups selected from C1-C4 alkyl groups, halogens, hydroxyl groups, and -NR groups. a R b C1-C4 alkyl groups substituted with halogenated C1-C4 alkyl groups, -NR a Rb , halogenated C1-C4 alkyl and C3-C8 cycloalkyl, wherein, R a and R b Each is independently an H or C1-C4 alkyl group; the number of substituents can be 1-6. In some embodiments, R5 is H or optionally 1-6 selected from halogens, hydroxyl groups, and -NR. a R b The substituents of the C1-C4 alkyl group, wherein R a and R b Each is independently H or C1-C4 alkyl. In some embodiments, R6 and R7 are each independently hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R6 and R7 together with the atoms to which they are attached form an optionally substituted 4-7 membered cycloamino group, which optionally contains one or more additional heteroatoms selected from O, N, and S. In some embodiments, R8 is a C1-C4 alkyl group, or in -N=(SO)R4R8, R4 and R8 together with the atoms to which they are attached form a 5-8 membered heterocycloalkyl group.

[0043] One group of preferred compounds of the present invention is represented as compounds of formula II or their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts, or mixtures thereof, or their prodrugs:

[0044]

[0045] Wherein, A, R0, R1, R2 and R3 are defined as in any embodiment of Formula I above.

[0046] In one or more embodiments of the compound of formula II, A is CH.

[0047] In one or more embodiments of the compound of formula II, R0 is an optionally substituted alkylsulfonyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted carbocyclic group, or an optionally substituted heteroaryl group. Preferably, the heteroaryl group is a 5- or 6-membered heteroaryl group containing at least one nitrogen atom, and more preferably a 5-membered heteroaryl group containing two nitrogen atoms. Preferably, the substituents of the alkylsulfonyl group, heterocyclic group, carbocyclic group, aryl group, or heteroaryl group are selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy, and amino groups. Preferably, the number of substituents on R0 can be 1 to 3. More preferably, R0 is a C1-C4 alkyl group, or a pyrazolyl, pyrroleyl, or imidazolyl group, substituted with one or two substituents selected from C1-C4 alkyl, halogen, hydroxyl, C1-C4 alkoxy, and amino groups. In some embodiments, R0 is an unsubstituted pyrazolyl group, an unsubstituted pyrroleyl group, an unsubstituted imidazoyl group, or a pyrazolyl group substituted with a C1-C4 alkyl group. In some embodiments, R0 is a 1H-pyrazol-5-yl group optionally substituted with a C1-C4 alkyl group.

[0048] In one or more embodiments of the compound of formula II, R1 is a halogen, optionally surrounded by 1-6 derivatives selected from halogens, hydroxyl groups, and -NR. a R b The substituent is a C1-C6 alkyl, C3-C6 cycloalkyl, or C2-C6 alkenyl group, wherein R is a C1-C6 alkyl, C3-C6 cycloalkyl, or C2-C6 alkenyl group. a and R b Each of them is independently H or C1-C4 alkyl. Preferably, R1 is halogen, C1-C4 alkyl, C3-C4 cycloalkyl, or C2-C4 alkenyl. More preferably, R1 is halogen, C1-C3 alkyl, or C2-C3 alkenyl.

[0049] In one or more embodiments of the compound of formula II, R2 is a carbocyclic, heterocyclic, aryl, or heteroaryl group, wherein each of the carbocyclic, heterocyclic, aryl, and heteroaryl groups may be optionally substituted. Preferably, R2 is an optionally substituted aryl, optionally substituted heterocyclic, or optionally substituted heteroaryl group. Preferably, the aryl group is phenyl or naphthyl. Preferably, the heterocyclic group is a 4-7 member nitrogen- and / or oxygen-containing heterocyclic group, preferably selected from: tetrahydropyranyl, tetrahydrofuranyl, oxobutyranyl, azacyclicbutyranyl, pyrrolidinyl, piperidinyl, and piperazineyl. Preferably, the heteroaryl group is a 5- or 6-membered nitrogen-containing heteroaryl group, preferably selected from pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, and triazolyl. Preferably, R2 is an optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, or optionally substituted tetrahydropyranyl. Preferably, the substituents on R2 are selected from C1-C6 alkyl, halo-C1-C6 alkyl, cyano, halogen, and alkylsulfonyl (such as sulfonyl groups substituted with C1-C4 alkyl). The number of substituents can be 1 to 3. In a preferred embodiment, R2 is a phenyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halogen, cyano, and C1-C4 alkyl substituted sulfonyl groups, a pyrazolyl or pyridyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halo-C1-C6 alkyl, and halogen groups, or a tetrahydropyranyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halo-C1-C6 alkyl, and halogen groups.

[0050] Preferably, R2 is selected from:

[0051]

[0052] Among them, R 10 It is H, C1-C3 alkyl, or halo-C1-C3 alkyl; each R 11 Independently, it is H or C1-C3 alkyl; R 12 H or a halogenated C1-C3 alkyl group; R 13 H or C1-C3 alkyl; R 14 It is H or C1-C3 alkyl; each R 15 R is independently H or C1-C3 alkyl, preferably C1-C3 alkyl; 16 It is H, halogen, or C1-C3 alkyl, preferably halogen or C1-C3 alkyl; R 17 H or cyano; R 18 The sulfonyl group is H or C1-C3 alkyl-substituted; R 19 H, halogen, C1-C3 alkyl, or halo-C1-C3 alkyl; R 20 H or C1-C3 alkyl; R 21It is a halogen, a C1-C3 alkyl group or a halogenated C1-C3 alkyl group, preferably a halogen; wherein, * indicates the connection position of R2 with the remainder of the compound.

[0053] More preferably, R2 is selected from:

[0054]

[0055] Among them, R 10 C 1-3 Alkyl groups, such as methyl, ethyl, and isopropyl; R 16 It is methyl or fluorine; R 19 It is methyl, fluorine, or trifluoromethyl; where * indicates the connection position of R2 with the rest of the compound.

[0056] More preferably, R2 is:

[0057]

[0058] In one or more embodiments of the compound of formula II, R3 is optionally composed of 1-6 molecules selected from halogens, hydroxyl groups, -NR... a R b C1-C6 alkyl groups substituted with halogenated C1-C4 alkyl substituents, wherein R a and R b Each of them is independently H or C1-C4 alkyl. Preferably, R3 is a C1-C4 alkyl, such as methyl.

[0059] In one or more embodiments of the compound of formula II, R4 is an alkyl or alkylaryl group, optionally selected from 1 to 6 halogens, hydroxyl groups, and -NR groups. a R b Substituents, wherein R a and R b Each is independently an H or C1-C4 alkyl group. In some embodiments, R4 is an optionally substituted C1-C4 alkyl or optionally substituted C1-C4 alkyl aryl (preferably, the aryl group is phenyl), optionally surrounded by 1-6 groups selected from halogens, hydroxyl groups, and -NR. a R b Substituents, wherein R a and R b Each is independently H or C1-C4 alkyl.

[0060] In the groups described in R5, R6, and R7, when substituted, the substituents may be selected from halogens, hydroxyl groups, optionally with one or two groups selected from C1-C4 alkyl groups, halogens, hydroxyl groups, and -NR groups. a R b C1-C4 alkyl groups substituted with halogenated C1-C4 alkyl groups, -NR a R b, halogenated C1-C4 alkyl and C3-C8 cycloalkyl, wherein, R a and R b Each is independently an H or C1-C4 alkyl group; the number of substituents can be 1-6. In some embodiments, R5 is H or optionally 1-6 selected from halogens, hydroxyl groups, and -NR. a R b The substituents of the C1-C4 alkyl group, wherein R a and R b Each is independently H or C1-C4 alkyl. In some embodiments, R6 and R7 are each independently hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R6 and R7 together with the atoms to which they are attached form an optionally substituted 4-7 membered cycloamino group, which optionally contains one or more additional heteroatoms selected from O, N, and S. In some embodiments, R8 is a C1-C4 alkyl group, or in -N=(SO)R4R8, R4 and R8 together with the atoms to which they are attached form a 5-8 membered heterocycloalkyl group.

[0061] The preferred compounds of this invention are represented as compounds of formula III or their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts, mixtures thereof, or prodrugs thereof:

[0062] 209965 1PCCN

[0063]

[0064] Wherein, A, R1, and R2 are defined as in any of the embodiments of Formulas I and II above;

[0065] R 22 It is a hydrogen, halogen, or optionally substituted C1-C6 alkyl group.

[0066] In one or more embodiments of the compound of formula III, A is CH.

[0067] In one or more embodiments of the compound of formula III, R 22 H or optionally 1-6 selected from halogens, hydroxyl groups, and -NR a R b The C1-C6 alkyl group substituted with a substituent, wherein R a and R b Independently hydrogen or C1-C4 alkyl. Preferably, R 22 It is hydrogen or a C1-C3 alkyl group. In some embodiments, R 22 It is H.

[0068] In one or more embodiments of the compound of formula III, R1 is a halogen, optionally surrounded by 1-6 derivatives selected from halogens, hydroxyl groups, and -NR. a R b The substituent is a C1-C6 alkyl, C3-C6 cycloalkyl, or C2-C6 alkenyl group, wherein R is a C1-C6 alkyl, C3-C6 cycloalkyl, or C2-C6 alkenyl group. a and R b Each of them is independently H or C1-C4 alkyl. Preferably, R1 is halogen, C1-C4 alkyl, C3-C4 cycloalkyl, or C2-C4 alkenyl. More preferably, R1 is halogen, C1-C3 alkyl, or C2-C3 alkenyl.

[0069] In one or more embodiments of the compound of formula III, R2 is a carbocyclic, heterocyclic, aryl, or heteroaryl group, wherein each of the carbocyclic, heterocyclic, aryl, and heteroaryl groups may be optionally substituted. Preferably, R2 is an optionally substituted aryl, optionally substituted heterocyclic, or optionally substituted heteroaryl group. Preferably, the aryl group is phenyl or naphthyl. Preferably, the heterocyclic group is a 4-7 member nitrogen- and / or oxygen-containing heterocyclic group, preferably selected from: tetrahydropyranyl, tetrahydrofuranyl, oxoheterobutyl, azaheterobutyl, pyrrolidinyl, piperidinyl, and piperazineyl. Preferably, the heteroaryl group is a 5- or 6-membered nitrogen-containing heteroaryl group, preferably selected from pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, and triazolyl. Preferably, R2 is an optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, or optionally substituted tetrahydropyranyl. Preferably, the substituents on R2 are selected from C1-C6 alkyl, halo-C1-C6 alkyl, cyano, halogen, and alkylsulfonyl (such as sulfonyl groups substituted with C1-C4 alkyl). The number of substituents can be 1 to 3. In a preferred embodiment, R2 is a phenyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halogen, cyano, and C1-C4 alkyl substituted sulfonyl groups, a pyrazolyl or pyridyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halo-C1-C6 alkyl, and halogen groups, or a tetrahydropyranyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halo-C1-C6 alkyl, and halogen groups.

[0070] Preferably, R2 is selected from:

[0071]

[0072] Among them, R 10 It is H, C1-C3 alkyl, or halo-C1-C3 alkyl; each R 11 Independently, it is H or C1-C3 alkyl; R 12 H or a halogenated C1-C3 alkyl group; R 13 H or C1-C3 alkyl; R 14 It is H or C1-C3 alkyl; each R15 It is H or C1-C3 alkyl, preferably C1-C3 alkyl; R 16 It is H, halogen, or C1-C3 alkyl, preferably halogen or C1-C3 alkyl; R 17 H or cyano; R 18 The sulfonyl group is H or C1-C3 alkyl-substituted; R 19 H, halogen, C1-C3 alkyl, or halo-C1-C3 alkyl; R 20 H or C1-C3 alkyl; R 21 It is a halogen, a C1-C3 alkyl group or a halogenated C1-C3 alkyl group, preferably a halogen; wherein, * indicates the connection position of R2 with the remainder of the compound.

[0073] More preferably, R2 is selected from:

[0074]

[0075] Among them, R 10 C 1-3 Alkyl groups, such as methyl, ethyl, and isopropyl; R 16 It is methyl or fluorine; R 19 It is methyl, fluorine, or trifluoromethyl; where * indicates the connection position of R2 with the rest of the compound.

[0076] More preferably, R2 is:

[0077]

[0078] The preferred compounds of this invention are represented as compounds of formula IV or their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts, mixtures thereof, or prodrugs thereof:

[0079]

[0080] Wherein, R1 is defined as in any of the embodiments of Formulas I, II and III above;

[0081] Cy is a carbocyclic, heterocyclic, aryl, heteroaryl, -NR6R7, -NR6(SO2)R4, or -N=(SO)R4R8, wherein the carbocyclic, heterocyclic, aryl, and heteroaryl groups may optionally be substituted; wherein R4 is an optionally substituted alkyl or optionally substituted alkylaryl (preferably, the aryl group is phenyl); R6 and R7 are each independently hydrogen, optionally substituted C1-C 10Alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; or R6 and R7 together with the atoms to which they are attached form an optionally substituted 4-7 membered cycloamino, which optionally contains one or more additional heteroatoms selected from O, N and S; R8 is a C1-C4 alkyl, or in -N=(SO)R4R8, R4 and R8 together with the atoms to which they are attached form a 5-8 membered heterocycloalkyl.

[0082] In one or more embodiments of the compound of formula IV, when R1 is substituted, the substituent may be selected from 1-6 halogens, hydroxyl groups, and -NR. a R b , where R a and R b Each of them is independently H or C1-C4 alkyl. Preferably, R1 is halogen, C1-C4 alkyl, C3-C4 cycloalkyl, or C2-C4 alkenyl. More preferably, R1 is halogen, C1-C3 alkyl, or C2-C3 alkenyl.

[0083] In one or more embodiments of the compound of formula IV, Cy is a carbocyclic, heterocyclic, aryl, or heteroaryl group, wherein the carbocyclic, heterocyclic, aryl, and heteroaryl groups may be optionally substituted. Preferably, Cy is an optionally substituted aryl group, an optionally substituted heterocyclic group, or an optionally substituted heteroaryl group. Preferably, the aryl group is phenyl or naphthyl. Preferably, the heterocyclic group is a 4-7 membered heterocyclic group containing N and / or O. Preferably, the heterocyclic group is selected from tetrahydropyranyl, tetrahydrofuranyl, oxoheterobutyl, azirrobutyl, pyrrolidinyl, piperidinyl, and piperazineyl. Preferably, the heteroaryl group is a 5- or 6-membered heteroaryl group containing N. Preferably, the heteroaryl group is selected from pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, and triazolyl. Preferably, Cy is an optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, or optionally substituted tetrahydropyranyl. Preferably, the substituents of Cy are selected from C1-C6 alkyl, halo-C1-C6 alkyl, cyano, halogen, and alkylsulfonyl (e.g., sulfonyl groups substituted with C1-C4 alkyl). The number of substituents can be 1 to 3. In some preferred embodiments, Cy is a phenyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halogen, cyano, and sulfonyl groups substituted with C1-C4 alkyl; a pyrazolyl or pyridinyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halo-C1-C6 alkyl, and halogen; or a tetrahydropyranyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halo-C1-C6 alkyl, and halogen. In some embodiments, Cy is a pyrazolyl group optionally substituted with C1-C6 alkyl, and preferably, one or both ring N atoms of the pyrazolyl group are substituted.

[0084] In one or more embodiments of the compound of formula IV, Cy is selected from the following groups:

[0085]

[0086] Among them, R 10 It is H, C1-C3 alkyl, or halo-C1-C3 alkyl; each R 11 Independently, it is H or C1-C3 alkyl; R 12 H or a halogenated C1-C3 alkyl group; R 13 H and C1-C3 alkyl groups; R 14 It is H or C1-C3 alkyl; each R 15 R is independently H or C1-C3 alkyl, preferably C1-C3 alkyl; 16 Selected from H, halogens, or C1-C3 alkyl groups, preferably halogens or C1-C3 alkyl groups; R 17 H or cyano; R 18 The sulfonyl group is H or C1-C3 alkyl-substituted; R 19 H, halogen, C1-C3 alkyl, or halo-C1-C3 alkyl; R 20 H or C1-C3 alkyl; R 21 It is a halogen, a C1-C3 alkyl group or a halogenated C1-C3 alkyl group, preferably a halogen; wherein, * indicates the connection position of Cy with the remaining part of the compound.

[0087] In one or more embodiments of the compound of formula IV, Cy is selected from:

[0088]

[0089] Among them, R 10 C 1-3 Alkyl groups, such as methyl, ethyl, and isopropyl; R 16 It is methyl or fluorine; R 19 It is methyl, fluorine, or trifluoromethyl; where * indicates the connection position of Cy with the rest of the compound.

[0090] In one or more embodiments of the compound of formula IV, Cy is:

[0091]

[0092] In one or more of the foregoing embodiments, the preferred compounds of Formula I (including Formulas II, III and IV) include, but are not limited to:

[0093] (R)-3-methyl-4-(5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 1);

[0094] (R)-4-(4-(1-ethyl-1H-pyrazol-5-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 2);

[0095] (R)-3-methyl-4-(5-methyl-7-(1H-pyrazol-5-yl)-4-(o-tolyl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 3);

[0096] (R)-3-methyl-4-(5-methyl-4-(2-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 4);

[0097] (R)-3-methyl-4-(5-methyl-7-(1H-pyrazol-5-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 5);

[0098] (R)-3-(5-methyl-2-(3-methylmorpholino)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl)benzylnitrile (Example 6);

[0099] (R)-3-methyl-4-(5-methyl-7-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 7);

[0100] (R)-3-methyl-4-(5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(3-methyl-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 8);

[0101] (R)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 9);

[0102] (R)-4-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 10);

[0103] (R)-4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 11);

[0104] (R)-4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 12);

[0105] (R)-4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 13);

[0106] (R)-4-(4-(2-fluorophenyl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 14);

[0107] (R)-3-methyl-4-(5-methyl-4-(2-methyl-4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 15);

[0108] (R)-4-(4-(2-fluoropyridin-3-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 16);

[0109] (R)-3-methyl-4-(5-methyl-4-(6-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 17);

[0110] (R)-4-(4-(3-fluoropyridin-4-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 18);

[0111] (R)-4-(4-(1-(difluoromethyl)-1H-)pyrazol-5-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 19);

[0112] (R)-4-(5-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 20);

[0113] (R)-4-(5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 21);

[0114] (R)-4-(5-bromo-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 22);

[0115] (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)-5-vinylimidazo[1,5-b]pyridazin-2-yl)morpholine (Example 23);

[0116] (R)-4-(5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 24);

[0117] (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-5-(propen-2-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 25);

[0118] (R)-4-(5-isopropyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 26);

[0119] (R)-4-(5-bromo-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[5,1-f][1,2,4]triazol-2-yl)-3-methylmorpholine (Example 28);

[0120] (R)-3-methyl-4-(5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[5,1-f][1,2,4]triazol-2-yl)morpholine (Example 29);

[0121] Or its stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds or pharmaceutically acceptable salts, or mixtures thereof.

[0122] The term "hydrogen (H)" as used in this article includes its isotopes D and T.

[0123] As used in this article, "alkyl" refers to an alkyl group itself or a straight-chain or branched group with up to ten carbon atoms. Useful alkyl groups include straight-chain or branched C1-C1 groups. 10 Alkyl group, preferably C1-C6 alkyl. In some embodiments, the alkyl group is C1-C4 alkyl. Typical C1-C6 alkyl groups... 10Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl, and octyl, which can be optionally substituted.

[0124] As used herein, "alkenyl" refers to a straight or branched group containing 2-10 carbon atoms, unless the chain length is otherwise limited, wherein at least two carbon atoms in the chain contain a double bond; C2-C6 alkenyl is preferred. Typical alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

[0125] As used herein, "alkynyl" refers to a straight or branched group containing 2-10 carbon atoms, unless the chain length is otherwise limited, wherein at least two carbon atoms in the chain contain a triple bond; preferably C2-C6 alkynyl. Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl, and 2-butynyl.

[0126] Useful alkoxy groups include those formed by the above C1-C 10 Alkyl groups, preferably C1-C6 or C1-C4 alkyl-substituted alkyl groups, such as methoxy, ethoxy, etc. The alkyl group in the alkoxy group may be optionally substituted. Substituents in the alkoxy group include, but are not limited to, halogens, morpholino groups, amino groups, including alkylamino and dialkylamino groups, and carboxyl groups (including their ester groups).

[0127] Useful alkylthio groups include those formed by the above C1-C 10 Alkyl groups, preferably C1-C6 alkyl-substituted thio groups, wherein the alkyl group in the alkylthio group may be optionally substituted. Sulfoxides and sulfones of such alkylthio groups are also included.

[0128] Useful amino groups and arbitrarily substituted amino groups include –NH2, –NHR', and –NR'9R", where R' and R" are each independently hydrogen and optionally substituted C1-C. 10 Alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R' and R" together with the N to which they are attached form an optionally substituted 4- to 7-membered cycloamino group, said cycloamino group optionally containing one or more (e.g., 2, 3) additional heteroatoms selected from O, N and S.

[0129] As used herein, "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic group containing 6 to 14 carbon atoms, either as a single group or as part of another group. An aryl group may be substituted by one or more of the substituents described herein.

[0130] Useful aryl groups include C6-C 14 Aryl groups, preferably C6-C 10 Aryl group. Typical C6-C 14Aryl groups include phenyl, naphthyl, phenanthryl, anthraceneyl, indyl, azulel, biphenyl, biphenylene, and fumonisinyl.

[0131] The term "carbocyclic" as used herein includes cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups are C3-C8 cycloalkyl groups. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The carbocyclic group may be substituted with one or more of the substituents described herein.

[0132] Useful partially saturated carbocyclic groups include cycloalkenyl groups, such as C3-C8 cycloalkenyl groups, for example cyclopentenyl, cycloheptenyl, and cyclooctenyl.

[0133] Useful halogens or halogen groups include fluorine, chlorine, bromine, and iodine.

[0134] Useful acylamino groups (acylamino groups) are any C1-C6 acyl (alkanoyl) group attached to an amino nitrogen atom, such as acetamido, acetamido, propionyl, butyryl, pentanoyl, and hexanoyl, as well as aryl-substituted C1-C6 acylamino groups, such as benzoylamino. Useful acyl groups include C1-C6 acyl groups, such as acetyl. The acyl group may optionally be substituted with a group selected from aryl and halogen groups, wherein the aryl group may optionally be substituted. When halogenated, the number of halogen substituents may range from 1 to 5. Examples of substituted acyl groups include chloroacetyl and pentafluorobenzoyl.

[0135] Useful acyl groups are any C1-C6 acyl groups (alkanoyl groups) attached to oxygen (–O–), such as formyloxy, acetoxy, propionyloxy, butyryloxy, valeryloxy, and hexanoyloxy.

[0136] The heterocycles (heterocyclic groups) used herein refer to saturated or partially saturated 3-7 membered monocyclic rings, or 7-10 membered bicyclic, tricyclic, or tetracyclic systems, having fused, bridged, and / or spirocyclic 3-, 4-, 5-, 6-, 7-, or 8-membered rings. They consist of a carbon atom and 1-4 heteroatoms selected from O, N, and S, wherein the heteroatoms nitrogen and sulfur can be arbitrarily oxidized, and nitrogen can be arbitrarily quaternized. This includes the fusion of any heterocycle defined above with a benzene ring in bicyclic systems. If the resulting compound is stable, the carbon or nitrogen atom of the heterocycle can be substituted. The heterocyclic group can be substituted by one or more substituents described herein. The heterocyclic groups mentioned herein also include 5- to 8-membered heterocyclic alkyl groups, i.e., heterocyclic groups obtained by replacing one or more ring C atoms in a cycloalkyl group with heteroatoms selected from N, O, and S.

[0137] Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazine, oxazolyl, isoxazolyl, oxacyclobutyl, aziridine, 1,4-diazacycloheptyl, pyrroliyl, imidazoalkyl, imidazolinyl, indolyl, isoyindolyl, quininecycloyl, morpholinyl, thiomorpholinyl, isothiazolyl, thiazolyl, tetrahydroisoquinolinyl, tetronoyl, and tetramoyl, which may be substituted by one or more of the substituents described herein.

[0138] As used herein, a "heteroaryl ring" refers to a ring containing 5–14 ring atoms, with 6, 10, or 14 π electrons shared in the ring system. Furthermore, the ring atoms are carbon atoms and 1–3 heteroatoms selected from oxygen, nitrogen, and sulfur. A heteroaryl group may be substituted by one or more substituents as described herein.

[0139] Useful heteroaryl groups include thienyl (phenylthio), benzo[d]isothiazo-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, oxanthiinyl, phenoxanthiinyl, pyrroleyl, imidazolyl, pyrazolyl, pyridyl (including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indazinyl, isoindolyl, 3H-indolyl, indolyl, indazoleyl, purine, 4H-quinazinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthodinyl, quinazolinyl, terpineyl, pteridinyl, carbazoleyl β-Carboline, phenanthridine, acridine, naphthalene-intercalated diazoxide, phenanthridine, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazinyl, phenothiazinyl, 1,4-dihydroquinoxalin-2,3-dione, 7-aminoisocoumarin, pyrido[1,2-a]pyrimidin-4-one, tetrahydropentamembered[c]pyrazol-3-yl, benzisoxazolyl such as 1,2-benzisoxazol-3-yl, benzimidazole, 2-hydroxyindole, thiadiazo, 2-oxobenzisimidazole, imidazopyridinyl, imidazopyridinyl, triazolpyridinyl, pyrazolpyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridinyl or triazololopyridinyl. When a heteroaryl group contains a nitrogen atom in the ring, such nitrogen atom can be in the form of an N-oxide, such as pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.

[0140] Unless otherwise stated herein, C1-C as described in any embodiment herein, when superseded, refers to... 10Alkyl, cycloalkyl, heterocycloalkyl, alkoxy, heterocycloalkoxy, alkenyl, heterocycloalkenyl, alkynyl, amino, amide, acyloxy, carboxyl, hydroxyl, mercapto, alkylthio, sulfonyl, sulfinyl, silyl, phosphonocarboxyl, phosphonyl, carbocyclic, heterocyclic, aryl, or heteroaryl may be substituted by one or more (e.g., 1, 2, 3, or 4) substituents selected from the following groups: halogen, hydroxyl, carboxyl, amino, nitro, cyano, C1-C6 amide, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C 10 Aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic or heteroaryl, methylenedioxy, ureyl, mercapto, azide, carbonyl, alkylsulfonyl, aminosulfonyl, dialkylaminosulfonyl, and alkylsulfinyl, etc. The substituents themselves may also be optionally substituted. More preferably, the substituents include, but are not limited to, cyano, halo-C1-C6 alkyl, halogen, hydroxyl, carboxyl, amino, C1-C6 amide, C1-C6 acyloxy, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 acyl, and alkylsulfonyl.

[0141] It should be understood that in the embodiments described herein, when the substituent is cyano, alkylsulfonyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, the number of such cyano, alkylsulfonyl, heterocyclic, aryl, or heteroaryl substituent is usually one.

[0142] Some of the compounds of this invention may exist as stereoisomers, including optical isomers. This invention includes all stereoisomers and racemic mixtures of such stereoisomers, as well as individual enantiomers that can be isolated according to methods well known to those skilled in the art.

[0143] Examples of medicinal salts include inorganic and organic acid salts, such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, and oxalate; as well as inorganic and organic base salts formed with bases such as sodium hydroxyl, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methylglucosamine.

[0144] Examples of prodrugs of the compounds of the present invention include simple esters of compounds containing carboxylic acids (e.g., esters obtained by condensation with C1-C4 alcohols according to methods known in the art); esters of compounds containing hydroxyl groups (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 compounds containing amino groups (e.g., imines obtained by condensation with C1-C4 aldehydes or ketones according to methods known in the art); carbamates of compounds containing amino groups, such as those esters described by Leu et al. (J.Med.Chem.42:3623-3628 (1999)) and Greenwald et al. (J.Med.Chem.42:3657-3667 (1999)); and aldol acetals or ketal acetals of compounds containing alcohols (e.g., those acetals obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0145] The compounds of the present invention can be prepared using methods known to those skilled in the art or new methods of the present invention. Specifically, the compounds of the present invention having formula I (including formulas II, III and IV) can be prepared using the following reaction schemes 1-2. 4-Bromo-1,2-dihydropyridazine-3,6-dione reacts with a boric acid compound under the catalysis of Pd(dppf)Cl2 to prepare intermediate compound 2. Compound 2 is refluxed in POCl3 to prepare intermediate compound 3. Compound 3 reacts with (R)-3-methylmorpholine under heating in DIEA to prepare intermediate compound 4. Intermediate compound 6 can be prepared from compound 4 using the following two reaction schemes: (1) Scheme 1: Compound 4 reacts with Zn(CN)2 under the catalysis of Pd2(dba)3 and DPPF in DMF under heating to prepare intermediate compound 5-1. Compound 5-1 reacts with CH3MgI in tetrahydrofuran at room temperature under nitrogen protection to prepare compound 6. (2) Scheme 2: Compound 4 undergoes a coupling reaction with tributyl(1-ethoxyethylene)tin under the catalysis of Pd(PPh3)4 to give intermediate compound 5-2. Compound 5-2 undergoes deethylation under the catalysis of p-toluenesulfonic acid to give compound 6. Compound 6 reacts with hydroxylamine hydrochloride under heating in methanol to give intermediate compound 7. Compound 7 undergoes a reduction reaction under the catalysis of Raney nickel to give intermediate compound 8. Compound 8 condenses with 1H-pyrazole-5-carboxylic acid, which may be optionally substituted, under the catalysis of EDCI and HOBT to give intermediate compound 9. Compound 9 undergoes cyclization under heating in POCl3 to give the target compound. Wherein, R2 in the exemplary boric acid compound includes:

[0146]

[0147] Exemplary R 22It can be H or methyl. * indicates the position where the group is attached to the remainder of the compound.

[0148] Reaction scheme 1-2

[0149]

[0150] The compounds of this invention can be prepared as shown in the reaction examples of reaction scheme 3. 4-Bromo-1,2-dihydropyridazine-3,6-dione reacts with 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane under Pd(dppf)Cl2 catalysis to prepare intermediate compound 10. Compound 10 undergoes reduction under Pd / C catalysis to prepare intermediate compound 11. Compound 11 is refluxed in POCl3 to prepare intermediate compound 12. Compound 12 reacts with (R)-3-methylmorpholine under heating in DIEA to prepare intermediate compound 13. Compound 13 reacts with Zn(CN)2 under Pd2(dba)3 and DPPF catalysis in DMF under heating to prepare intermediate compound 14. Compound 14 reacts with CH3MgI at room temperature in tetrahydrofuran under nitrogen protection to give intermediate compound 15. Compound 15 reacts with hydroxylamine hydrochloride in methanol upon heating to give intermediate compound 16. Compound 16 undergoes reduction under hydrogen atmosphere catalyzed by Raney nickel to give intermediate compound 17. Compound 17 condenses with 1H-pyrazol-5-carboxylic acid under EDCI and HOBT catalysis to give intermediate compound 18. Compound 18 undergoes cyclization upon heating in POCl3 to give the target compound (R)-3-methyl-4-(5-methyl-7-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine.

[0151] Reaction scheme 3

[0152]

[0153] The compounds of the present invention can be prepared by the exemplary reaction method shown in reaction scheme 4. (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine is reacted with NBS to give the product (R)-4-(5-bromo-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine. Catalyzed by Ph(PPh3)4, (R)-4-(5-bromo-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine reacts with tributylvinyltin to give the product (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)-5-vinylimidazo[1,5-b]pyridazin-2-yl)morpholine. Under Pd / C catalysis, (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)-5-vinylimidazo[1,5-b]pyridazin-2-yl)morpholine was reduced to give the product (R)-4-(5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine.

[0154] Reaction scheme 4

[0155]

[0156] Other related compounds can be prepared using similar methods. For example, by replacing tributylvinyltin with tributylisopropenyltin, the target compound (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-5-(propenyl-2-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine can be prepared, and then the target compound (R)-4-(5-isopropyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine can be prepared. The target compound (R)-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[5,1-f][1,2,4]triazin-2-yl)morpholine can be prepared by replacing (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine. The target compound (R)-3-methyl-4-(5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[5,1-f][1,2,4]triazol-2-yl)morpholine can be obtained by smothering bromo-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[5,1-f][1,2,4]triazol-2-yl)morpholine.

[0157] An important aspect of this invention is the discovery that compounds of formula I (including compounds of formulas II, III, and IV as described herein) are kinase inhibitors, particularly ATR kinase inhibitors. Therefore, compounds of formula I (including compounds of formulas II, III, and IV as described herein) can be used to treat or prevent ATR kinase-mediated diseases, such as cancer; or to prepare medicaments for treating or preventing ATR kinase-mediated diseases such as cancer. Furthermore, an important and unexpected discovery is that compounds of formula I (such as compounds of formulas II, III, and IV) where R1 is a halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C2-C6 alkenyl are highly active ATR kinase inhibitors. Therefore, in preferred embodiments, this invention particularly relates to compounds where R1 is a halogen, C1-C4 alkyl, or C2-C4 alkenyl, preferably a halogen, C1-C3 alkyl, or C2-C3 alkenyl, for treating or preventing various clinical symptoms caused by DDR dysfunction, or for treating or preventing ATR kinase-mediated diseases.

[0158] The present invention also includes methods for treating or preventing kinase-mediated diseases, particularly ATR kinase-mediated diseases, and methods for treating or preventing diseases caused by DDR dysfunction, said methods comprising administering to a desired subject (especially mammals, more specifically humans) an effective amount of a compound of formula I (including compounds of formulas II, III, and IV as described herein) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable 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 formulas II, III, and IV as described herein) or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0159] In this invention, the kinase-mediated diseases include cancer, particularly ATR kinase-mediated cancer. Preferably, the ATR kinase-mediated cancer has DDR functional deficiency. ATR kinase-mediated diseases that can be treated or prevented by the methods or pharmaceutical compositions of this 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, and small cell lung cancer. Cancer, stomach cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocytosis, adrenocortical carcinoma, skin cancer, and prostate cancer.

[0160] This invention also includes methods for treating or preventing other diseases caused by excessive or abnormal cell proliferation, including proliferative or hyperproliferative disorders, such as myeloproliferative disorders, particularly proliferative or hyperproliferative disorders caused by ATR kinase-mediated excessive or abnormal cell proliferation. Therefore, this invention also includes the use of compounds of formula I (including compounds of formulas II, III, and IV as described herein), or their stereoisomers, tautomers, N-oxides, hydrates, solvates, isotopically labeled compounds, or pharmaceutically acceptable salts, or mixtures thereof, or their prodrugs, to prepare other diseases caused by excessive or abnormal cell proliferation, particularly proliferative or hyperproliferative disorders caused by ATR kinase-mediated excessive or abnormal cell proliferation.

[0161] In implementing the treatment methods 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, III, or IV, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound, or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, formulated for oral, intravenous, topical, or external administration for the treatment of cancer and other diseases. The dosage is the amount of medicine that effectively improves or eliminates one or more symptoms. For the treatment of a specific disease, an effective amount is an amount sufficient to improve or alleviate, in some way, the symptoms associated with the disease. Such a dosage may be administered as a single dose or may be administered according to an effective treatment regimen. The dosage may cure the disease, but administration is usually intended to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired symptom improvement.

[0162] In another embodiment, a pharmaceutical composition is provided comprising an ATR kinase inhibitor of a compound of formula I, II, III or IV, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, with a pharmaceutically acceptable carrier.

[0163] Another embodiment of the present invention relates to a pharmaceutical composition that can effectively treat cancer, comprising a kinase inhibitor of formula I, II, III or IV, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, in combination with at least one known anticancer drug or a pharmaceutically acceptable salt thereof. 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, pamiparib, fluzoparib and senaparib; HDAC inhibitors vorinostat, romidesin, pabistat and belistat; and so on. It is also used 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, MYT1 inhibitors, DNA-PK inhibitors, and so on. And its combination with other targeted anticancer drugs, including USP1 inhibitors, PRMT5 inhibitors, Polθ inhibitors, RAD51 inhibitors, etc.Other known anticancer drugs that can be used in 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, methyl hydroxyrosine, and mentholtoporp; 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, vincristine, vinorelbine, paclitaxel, ixaprilone, cabazitaxel, and docetaxel; antibodies such as monoclonal antibodies, panitumumab, nazotocin, nivolumab, pembrolizumab, etc. Ramucirumab, Bevacizumab, Pertuzumab, Trastuzumab, Cetuximab, Obinutuzumab, Ofamumab, Rituximab, Alemtuzumab, Tiimumab, Tosimomab, Bentuximab, Daremumab, Erotozumab, T-DM1, Ofatumumab, Dinutuximab, Blinatumomab, Ipilimumab, Avastin, Herceptin, and Rituximab; kinase inhibitors such as Imatinib, Genomicon. Fertrinib, Erlotinib, Ostinib, Afatinib, Ceritinib, Alectinib, Crizotinib, Erlotinib, Lapatinib, Sorafenib, Regorafenib, Vemurafenib, Dabrafenib, Aflibercept, Sunitinib, Nilotinib, Dasatinib, Bosutinib, Pramipinib, Ibrutinib, Cabozantinib, Lenvatinib, Vandetanib, Trametinib, Carbitinib, Axitinib, Tessiromoxetine, Idelalisib, Pazopanib, Tetracycline, and Everolimus. Other known anticancer drugs that can be used in combination therapy include tamoxifen, letrozole, fulvestrant, mitoxantridine, octreotide, retinoid, arsenic, zoledronic acid, bortezomib, carfilzomib, Ixazomib, vemodega, sondega, denosumab, thalidomide, lenalidomide, venetoclax, Aldesleukin (recombinant human interleukin-2), and Sipueucel-T (prostate cancer treatment vaccine).

[0164] In carrying out the method of the present invention, the compound of the present invention may be administered together with at least one known anticancer drug as a single pharmaceutical composition. Alternatively, the compound of the present invention may 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 approximately simultaneously, i.e., all drugs are administered simultaneously or sequentially, as long as the compound simultaneously reaches therapeutic concentrations in the blood. 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 therapeutic concentrations in the blood.

[0165] Another embodiment of the invention is a biocoupler, consisting of the said compound, that effectively inhibits tumors as a kinase inhibitor. This tumor-inhibiting biocoupler comprises the said compound with at least one known therapeutically active antibody, such as Herceptin or Rituxan, or a growth factor, such as EGF or FGF, or a cytokine, such as interleukin-2 or 4, or any molecule capable of binding to the cell surface. The antibody, along with other molecules, can deliver the compound to its target site, making it an effective anticancer drug. This biocoupler can also enhance the anticancer effects of therapeutically active antibodies, such as Herceptin or Rituxan.

[0166] Another embodiment of the invention relates to a pharmaceutical composition that can effectively inhibit tumors, comprising a kinase inhibitor of formula I (including formula II), or a usable salt or prodrug thereof, for combination therapy with radiotherapy. In this embodiment, the compound of the invention and radiotherapy may be administered at the same time or at different times.

[0167] Another embodiment of the invention relates to a pharmaceutical composition effective for postoperative treatment of cancer, comprising a kinase inhibitor of formula I, II, III or IV, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, isotopically labeled compound or pharmaceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof. The invention also relates to a treatment method involving surgical removal of a tumor followed by treatment of the cancer in the mammal with the pharmaceutical composition of the invention.

[0168] The pharmaceutical compositions of the present invention comprise pharmaceutical formulations in which the contents of all the compounds of the present invention effectively achieve their intended objectives. Although individual needs vary, those skilled in the art can determine the optimal dosage of each component of the pharmaceutical formulation. Generally, the compounds, or their available salicies, are administered orally to mammals daily at a dosage of about 0.0025 to 50 mg / kg body weight. However, it is preferable to administer orally at a dosage of about 0.01 to 10 mg / kg. If a known anticancer drug is also administered, its dosage should effectively achieve its intended purpose. The optimal dosages of these known anticancer drugs are well known to those skilled in the art.

[0169] A single oral dose may comprise about 0.01 to 50 mg, preferably about 0.1 to 10 mg, of the compound of the present invention. A single dose may be administered once or multiple times daily as one or more tablets, each tablet containing about 0.1 to 50 mg, preferably about 0.25 to 10 mg, of the compound of the present invention or a solvate thereof.

[0170] In topical formulations, the concentration of the compounds of the present invention can be from about 0.01 to 100 mg per gram of carrier.

[0171] The compounds of the present invention can be administered as unprocessed pharmaceutical products. They can also be administered as part of a suitable pharmaceutical formulation containing a pharmaceutically acceptable carrier (including excipients and adjuvants). These pharmaceutically acceptable carriers facilitate the processing of the compounds into pharmaceutically acceptable formulations. Preferred pharmaceutical formulations, particularly those for oral administration and preferred routes of administration such as tablets, lozenges, and capsules, as well as solutions suitable for injection or oral administration, contain about 0.01% to 99%, preferably from about 0.25% to 75%, of the active compound and excipients.

[0172] The scope of this invention also includes non-toxic, pharmaceutically acceptable salts of the compounds of this invention. Acid addition salts are formed by mixing a solution of a non-toxic, pharmaceutically acceptable acid with a solution of the compound of this invention. Examples of the acids include 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 solution of a non-toxic, pharmaceutically acceptable base with a solution of the compound of this invention. Examples of the bases include sodium hydroxide, potassium hydroxide, hydrocholine, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methylglucosamine, etc.

[0173] The pharmaceutical formulations of this invention can be administered to any mammal, provided they achieve the therapeutic effects of the compounds of this invention. Humans and veterinary animals are most important among these mammals, although this invention is not intended to be so limited.

[0174] The pharmaceutical formulation of this invention can be administered via any route to achieve its intended purpose. For example, it can be administered via parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, nasal, or topical routes. 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.

[0175] The pharmaceutical formulations of the present invention can be manufactured using known methods. For example, they can be manufactured by conventional mixing, granulation, tableting, dissolving, or freeze-drying processes. When manufacturing oral formulations, solid excipients and active compounds can be combined, and the mixture can be selectively ground. If desired or necessary, appropriate excipients can be added, and the granular mixture can be processed to obtain tablets or tablet cores.

[0176] Suitable excipients, especially fillers, include sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations and / or calcium phosphates, such as tricalcium phosphate or dicalcium phosphate; and binders, such as starch pastes including corn starch, wheat starch, rice starch, potato starch, gelatin, astragalus gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If desired, disintegrants, such as the starches mentioned above, as well as carboxymethyl starch, croscarmellose, agar, or alginate or its salts, such as sodium alginate, may be added. Adjuvants, especially flow conditioners and lubricants, include silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. If desired, a suitable coating that resists gastric juices can be provided to the tablet core. For this purpose, a concentrated sugar solution can be applied. This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. To prepare a gastric juice-resistant coating, a suitable cellulose solution, such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate, can be used. Dyes or pigments may be added to the coating of the tablet or tablet core, for example, for identification or to characterize the dosage of the active ingredient.

[0177] Other orally edible pharmaceutical formulations include compressible capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers such as glycerin or sorbitol. The compressible capsule may contain an active compound in particulate form, mixed with fillers such as lactose; binders such as starch; and / or lubricants such as talc or magnesium stearate, and stabilizers. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid such as oils or liquid paraffin, in which stabilizers may be added.

[0178] Suitable formulations for parenteral administration include aqueous solutions of the active compound, such as solutions of water-soluble salts and alkaline solutions. Additionally, oily injectable suspensions of the appropriate active compound can be administered. Suitable lipophilic solvents or carriers include oils such as sesame oils, synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol 400, or hydrogenated castor oil, or cyclodextrin. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and / or dextran. Suspension stabilizers may also be included.

[0179] According to one aspect of the invention, the compounds of the invention are formulated for external and parenteral use and are used to treat skin cancer.

[0180] The topical formulations of this invention can be formulated into oils, creams, emulsions, ointments, etc., using a preferred suitable carrier. Suitable carriers include plant or mineral oils, white mineral oil (white paraffin), branched-chain fatty acids or oils, animal fats, and high molecular weight alcohols (greater than C10). 12Preferred carriers are those in which the active ingredient can dissolve. Emulsifiers, stabilizers, moisturizers, and antioxidants may also be included, as well as agents that impart color or fragrance if desired. Furthermore, these topical formulations may contain transdermal penetration enhancers. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0181] Creams are preferably formulated with a mixture of mineral oil, self-emulsifying beeswax, and water, mixed with an active ingredient dissolved in a small amount of oil, such as almond oil. A typical example of a cream includes approximately 40 parts water, 20 parts beeswax, 40 parts mineral oil, and 1 part almond oil.

[0182] Ointments can be formulated by mixing a plant oil containing active ingredients, such as almond oil, with warm paraffin wax, and then allowing the mixture to cool. A typical example of an ointment consists of approximately 30% by weight almond oil and 70% by weight white paraffin wax.

[0183] This invention also relates to the preparation of medicaments using the compounds of this invention to treat clinical conditions that are effective in inhibiting kinase (particularly ATR kinase) activity. These medicaments may include the aforementioned pharmaceutical compositions.

[0184] The following examples are illustrative and not intended to limit the methods and formulations of the present invention. Other appropriate modifications and improvements to various conditions and parameters that will be apparent to those skilled in the art and that are commonly encountered in clinical treatment are all within the spirit and scope of the present invention.

[0185] Example

[0186] General instructions

[0187] All reagents used were commercially available, 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. Recording was performed at 400 MHz using a Brücker Ascend 400 NMR spectrometer. 1 1H NMR spectra, chemical shifts were recorded in ppm starting from the low field with TMS as the internal standard (0.00 ppm), and coupling constant J values ​​were in Hz.

[0188] Example 1

[0189] (R)-3-methyl-4-(5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)

[0190] phyto

[0191] a) Preparation of 4-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydropyridazine-3,6-dione: 4-bromo-1,2-dihydropyridazine-3,6-dione (70.0 g, 366.3 mmol), (1-methyl-1H-pyrazol-5-yl)boric acid (91.6 g, 732.6 mmol), and potassium phosphate aqueous solution (aq. K3PO4, 1000 mL, 1 M) were dissolved in N,N-dimethylformamide (DMF, 1000 mL). The air in the reaction flask was replaced with nitrogen. Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (Pd(dppf)Cl2, 8.0 g, 11.0 mmol) was added. The resulting mixture was reacted at 100°C for 16 hours, then concentrated to remove the solvent, yielding a crude product. This crude product (200.0 g, yellow solid) was washed with dichloromethane (DCM, 500 mL × 3) and used directly in the next step. LC-MS (ESI): 193.30 [M + H] + . 1 H NMR (400MHz, D2O): δ7.37(brs,1H), 6.80(brs,1H), 6.26(brs,1H), 3.56(s,3H).

[0192] 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 (crude product, 80.0 g, 0.4 mol) was dissolved in phosphorus oxychloride (POCl3, 400 mL), heated to 100 °C, and stirred for 16 hours. After the reaction was complete, phosphorus oxychloride was removed, and the mixture was quenched by slowly adding water (200 mL). The pH was adjusted to 9 with ammonia (~25% w / w). The mixture was extracted with EA (300 mL × 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude target product (27 g, black solid, two-step yield 81%), which was directly used in the next step. LC-MS (ESI): 229.20 [M+H] + . 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).

[0193] c. Preparation of (R)-4-(6-chloro-5-(1-methyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholine: To a solution of 3,6-dichloro-4-(1-methyl-1H-pyrazol-5-yl)pyridazine (50.0 g, 219.0 mmol) in N,N-diisopropylethylamine (DIEA, 84.7 g, 657.0 mmol), (R)-3-methylmorpholine (26.5 g, 262.8 mmol) was added. The resulting mixture was stirred at 150 °C for 6 hours. The reaction was quenched with water (1000 mL) and extracted with EA (400 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude target product (59.0 g, black solid, yield 92%), which was used directly in the next step. LC-MS (ESI): 294.30 [M+H] + . 1 H NMR (400MHz, CDCl3): δ7.58–7.53(m,1H),6.78(s,1H),6.36(s,1H),4.31(q,J=5.5,4.3Hz,1H),4.10–4.00(m,1H),3.96(d, J=13.1Hz,1H),3.83–3.77(m,5H),3.64(td,J=12.0,2.9Hz,1H),3.35(td,J=13.0,12.6,3.4Hz,1H),1.32(d,J=6.7Hz,3H).

[0194] d) Preparation of (R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazin-3-carboxynitrile: Under nitrogen protection, Zn(CN)₂ (0.4 g 3.4 mmol), Pd(dppf)Cl₂ (0.2 g 0.36 mmol), tris(dibenzylacetone)dipalladium (Pd₂(dba)₃, 160 mg 0.17 mmol), and an appropriate amount of water were added to a DMF (10 mL) solution of (R)-4-(6-chloro-5-(1-methyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholinium (0.5 g, 1.7 mmol). The resulting mixture was stirred at 150 °C for 6 hours. The solvent was removed by vacuum concentration to obtain a crude product, which was then purified by silica gel column chromatography (EA / PE, 10 to 40%) to obtain the target product (0.4 g, light red oil, yield 82%). LC-MS (ESI): 285.30 [M+H] + . 1HNMR (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).

[0195] Preparation of (R)-1-(4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazin-3-yl)acetone: Under nitrogen protection, a solution of CH3MgI in diethyl ether (3.0 M, 11.0 mL, 11.6 mmol) was added to a solution of (R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazin-3-carboxynitrile (3.3 g, 11.6 mmol) in tetrahydrofuran (THF, 20 mL). The resulting mixture was stirred at room temperature for 10 minutes. After the reaction was complete, the mixture was quenched with saturated ammonium chloride (20 mL) and extracted with EA (40 mL × 3). The organic phase was separated, dried, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (PE:EA = 10:1 to 1:1) to obtain the target product (1.3 g, brown solid, yield 37%). LC-MS (ESI): 302.10 [M+H] + .

[0196] f) Preparation of 1-(4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazin-3-yl)acetone oxime: Under nitrogen protection, hydroxylamine hydrochloride (1.2 g, 16.6 mmol) was added to a methanol (MeOH, 50 mL) solution of (R)-1-(4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazin-3-yl)acetone (500.0 mg, 1.7 mmol). The resulting mixture was stirred overnight at 70 °C. After the reaction was complete, water (50 mL) was added to the resulting mixture, and the mixture was extracted with EA (50 mL × 3). The organic phase was separated, dried, and concentrated to give the crude product (430.0 mg, brown solid, yield 82%). LC-MS (ESI): 317.15 [M+H] + .

[0197] Preparation of 1-(4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholino)pyridazin-3-yl)ethylamine: Raney nickel (approximately 3.3 g) was added to a MeOH (5 mL) solution of 1-(4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazin-3-yl)ethyl ketone oxime (330.0 mg, 1.0 mmol). The resulting mixture was stirred overnight at room temperature under H2 atmosphere. After the reaction was complete, the mixture was filtered, and the filter cake was washed with MeOH (20 mL × 5). The filtrate was concentrated to give the crude target product (210.0 mg, gray solid, yield 67%). LC-MS (ESI): 303.10 [M+H] + .

[0198] Preparation of h)N-(1-(4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholino)pyridazin-3-yl)ethyl)-1H-pyrazol-5-carboxamide: 1H-pyrazol-5-carboxylic acid (93.0 mg, 0.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 173.0 mg, 0.9 mmol), and 1-hydroxybenzotriazole (HOBT, 10.0 mg, 0.07 mmol) were added to a DCM solution of 1-(4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholino)pyridazin-3-yl)ethylamine (210.0 mg, 0.7 mmol) in 6 mL. The resulting mixture was stirred overnight at room temperature. After the reaction was complete, water (10 mL) was added to the mixture, and extraction was performed using DCM (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was slurried with EA (3 mL) to give the target product (160.0 mg, white solid, yield 58%). LC-MS (ESI): 397.20 [M + H) + .

[0199] Preparation of (i)(R)-3-methyl-4-(5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine: N-(1-(4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholino)pyridazin-3-yl)ethyl)-1H-pyrazol-5-carboxamide (50.0 mg, 0.13 mmol) was added to POCl3 (3 mL) and stirred at 110 °C for 4 hours. After the reaction was complete, the solvent was removed. Water (5 mL) was added to the mixture, and the pH was adjusted to 8 with ammonia (25% w / w). The resulting mixture was extracted with DCM (10 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative high performance liquid chromatography (C18, CH3CN / H2O, 15-40%, 0.1% HCOOH) to obtain the target compound (15.0 mg, pale yellow powder, yield 32%).

[0200] Example 2

[0201] (R)-4-(4-(1-ethyl-1H-pyrazol-5-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpho

[0202] phyto

[0203] a) Preparation of (R)-4-(6-(1-ethoxyvinyl)-5-(1-ethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholine: Under nitrogen protection, (R)-4-(6-chloro-5-(1-ethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholine (prepared by a similar method to Examples 1a-1c, 100.0 mg, 0.3 mmol) was dissolved in DMF (4 mL), and then CuI (6.0 mg, 11.0 mL, 0.03 mmol), Pd(PPh3)4 (33.0 mg, 0.3 mmol), LiCl (42.0 mg, 1.0 mmol), and tributyl(1-ethoxyvinyl)tin (590.0 mg, 1.6 mmol) were added. The reaction mixture was stirred at 100 °C for 5 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted with EA (20 mL × 3), the organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 5:1 to 1:1) to obtain the target product (60.0 mg, yellow solid, yield 54%). LC-MS (ESI): 344.15 [M + H) + .

[0204] b) Preparation of (R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazin-3-yl)ethyl-1-one: To a solution of (R)-4-(6-(1-ethoxyvinyl)-5-(1-ethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholino (300.0 mg, 0.9 mmol) in acetone (5 mL), p-toluenesulfonic acid (TsOH, 326.0 mg, 1.7 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the crude product was concentrated and purified by silica gel column chromatography (PE:EA = 5:1 to 1:1) to give the target product (270.0 mg, yellow solid, yield 98%). LC-MS (ESI): 316.35 [M+H] + .

[0205] c. Preparation of (R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)-pyridazin-3-yl)ethyl-1-oxime: Under nitrogen protection, hydroxylamine hydrochloride (1.3 g, 18.6 mmol) was added to a MeOH (10 mL) solution of (R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazin-3-yl)ethyl-1-one (580.0 mg, 1.8 mmol). The reaction mixture was stirred overnight at 70 °C. After the reaction was complete, the solvent was removed, and the mixture was dissolved in water (10 mL) and EA (20 mL). The organic phase was separated, dried, and concentrated to obtain the crude product (150.0 mg, brown solid, yield 25%). LC-MS (ESI): 331.25 [M+H] + .

[0206] d) Preparation of 1-(4-(1-ethyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholino)pyridazin-3-yl)ethyl-1-amine: Raney nickel (approximately 0.8 g) was added to a MeOH (5 mL) solution of (R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)-pyridazin-3-yl)ethyl-1-oxime (150.0 mg, 0.5 mmol). The reaction system was purged three times with H₂ and stirred at room temperature for 16 hours under H₂ atmosphere. After the reaction was complete, the mixture was filtered, and the filter cake was washed with MeOH (10 mL × 3). The filtrates were combined and concentrated to obtain the crude target product (120.0 mg, black solid). LC-MS (ESI): 317.30 [M+H] + .

[0207] Preparation of N-(1-(4-(1-ethyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholinyl)pyridazin-3-yl)ethyl)-1H-pyrazol-5-carboxamide: 1-(4-(1-ethyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholinyl)pyridazin-3-yl)ethyl-1-amine (120.0 mg, 0.4 mmol) was dissolved in DCM (4 mL), followed by the addition of 1H-pyrazol-5-carboxylic acid (51.0 mg, 0.5 mmol), EDCI (95.0 mg, 0.5 mmol), and HOBT (5.0 mg, 0.04 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, it was diluted with DCM (10 mL) and washed with water (10 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was homogenized with EA (4 mL) to obtain the target product (70.0 mg, white solid, two-step yield 38%). LC-MS (ESI): 411.25 [M+H] + .

[0208] Preparation of f)(R)-4-(4-(1-ethyl-1H-pyrazol-5-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine: N-(1-(4-(1-ethyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholinyl)pyridazin-3-yl)ethyl)-1H-pyrazol-5-carboxamide (70.0 mg, 17.0 mmol) was dissolved in POCl3 (7 mL) and stirred at 120 °C for 4 hours. After the reaction was complete, the solvent was removed under reduced pressure. The mixture was diluted with water (10 mL) and the pH was adjusted to 8 with ammonia (approximately 25% w / w). The mixture was extracted with DCM (10 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative liquid chromatography (DCM:MeOH = 10:1) to give the target compound (26.0 mg, yellow solid, yield 39%).

[0209] The compounds in Examples 3 to 6 described below can be prepared using synthetic methods similar to those described in Example 1 or Example 2.

[0210]

[0211]

[0212] Example 7

[0213] (R)-3-methyl-4-(5-methyl-7-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-b]pyridazin-2-yl)

[0214] phyto

[0215]

[0216] a) Preparation of 4-(3,6-dihydro-2H-pyran-4-yl)-1,2-dihydropyridazine-3,6-dione: 4-bromo-1,2-dihydropyridazine-3,6-dione (4.0 g, 20.9 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (8.8 g, 41.9 mmol), and potassium phosphate aqueous solution (aq. K3PO4, 62.8 mL, 1 M) were dissolved in N,N-dimethylformamide (DMF, 40 mL). The air in the reaction flask was replaced with nitrogen. Under nitrogen protection, Pd(dppf)Cl2 (1.5 g, 2.1 mmol) was added. The resulting mixture was reacted at 100°C for 16 hours, then filtered, and the filtrate was concentrated to obtain a crude product. After washing with DCM (40 mL × 3), the crude product of the target product (12.0 g, yellow solid) was obtained and used directly in the next reaction. LC-MS (ESI): 195.05 [M + H] + .

[0217] b) Preparation of 4-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridazine-3,6-dione: 10% Pd / C (2.0 g) was added to MeOH (40 mL) containing 12.0 g (61.9 mmol). The mixture was stirred overnight at room temperature under H2 atmosphere. After the reaction was complete, the mixture was filtered, and the filter cake was washed with MeOH (20 mL × 2). The filtrates were combined and concentrated to obtain crude product of the target product (12.0 g, gray solid), which was used directly in the next step. LC-MS (ESI): 197.05 [M + H] + .

[0218] c) Preparation of 3,6-dichloro-4-(tetrahydro-2H-pyran-4-yl)pyridazine: 12.0 g (61.2 mmol) of 4-(tetrahydro-2H-pyran-4-yl)-1,2-dihydropyridazine-3,6-dione was added to POCl3 (100 mL) and reacted at 100 °C for 16 hours. The solvent was removed, and the reaction was quenched by slow addition of water (20 mL). The pH was then adjusted to 9 with ammonia (~25% w / w). The mixture was extracted with EA (30 mL × 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10:1 to 1:1) to obtain the target product (1.0 g, white solid, 20% yield in 3 steps). LC-MS (ESI): 233.15 [M+H] + .

[0219] d) Preparation of (R)-4-(6-chloro-5-(tetrahydro-2H-pyran-4-yl)pyridazin-3-yl)-3-methylmorpholine: (R)-3-methylmorpholine (0.8 g, 7.8 mmol) was added to a solution of 3,6-dichloro-4-(tetrahydro-2H-pyran-4-yl)pyridazine (0.9 g, 3.9 mmol) in DIEA (1.5 g, 11.7 mmol). After reacting at 150 °C for 6 hours, the reaction was quenched with water (10 mL). The mixture was extracted with EA (10 mL × 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude target product (1.2 g, black solid), which was directly used in the next step. LC-MS (ESI): 297.90 [M+H] + .

[0220] Preparation of (R)-6-(3-methylmorpholino)-4-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxylonitrile: Under nitrogen protection, (R)-4-(6-chloro-5-(tetrahydro-2H-pyran-4-yl)pyridazin-3-yl)-3-methylmorpholino (1.3 g, 4.4 mmol), Zn(CN)2 (1.1 g, 8.8 mmol), 1,1'-bis(diphenylphosphine)ferrocene (DPPF, 0.5 g, 0.88 mmol), and Pd2(dba)3 (0.4 g, 0.44 mmol) were mixed in DMF (20 mL). After reacting at 150 °C for 6 hours, the mixture was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA, 10%–40%) to obtain the target product (1.2 g, pale yellow solid, yield 95%). LC-MS (ESI): 289.15 [M+H] + .

[0221] Preparation of (R)-1-(6-(3-methylmorpholino)-4-(tetrahydro-2H-pyran-4-yl)pyridazin-3-yl)acetone: Under nitrogen protection, a solution of CH3MgI in diethyl ether (3.0 M, 12.0 mL, 36.0 mmol) was added to (R)-6-(3-methylmorpholino)-4-(tetrahydro-2H-pyran-4-yl)pyridazin-3-carboxynitrile (1.2 g, 4.2 mmol) in THF (12 mL), and the mixture was stirred at room temperature for 10 minutes. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (20 mL), and the mixture was extracted with EA (40 mL × 3). The organic phase was separated, dried over anhydrous sodium sulfate, concentrated to obtain crude product, and purified by silica gel column chromatography (PE / EA = 10:1 to 1:1) to obtain the target product (850 mg, yellow solid, yield 67%). LC-MS (ESI): 306.10 [M+H] + .

[0222] Preparation of (R)-1-(6-(3-methylmorpholino)-4-(tetrahydro-2H-pyran-4-yl)pyridazin-3-yl)acetone oxime: Under nitrogen protection, hydroxylamine hydrochloride (1.8 g, 25.0 mmol) was added to a MeOH (10 mL) solution of (R)-1-(6-(3-methylmorpholino)-4-(tetrahydro-2H-pyran-4-yl)pyridazin-3-yl)acetone (750.0 mg, 2.5 mmol). The resulting mixture was stirred overnight at 70 °C. After the reaction was complete, water (10 mL) was added to the resulting mixture, and the mixture was extracted with EA (10 mL × 3). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to give the crude target product (750.0 mg, yellow solid, yield 95%). LC-MS (ESI): 321.35 [M+H] + .

[0223] Preparation of h)1-(6-((R)-3-methylmorpholino)-4-(tetrahydro-2H-pyran-4-yl)pyridazin-3-yl)ethylamine: Raney nickel (approximately 15.0 g) was added to a MeOH (10 mL) solution of (R)-1-(6-(3-methylmorpholino)-4-(tetrahydro-2H-pyran-4-yl)pyridazin-3-yl)ethyl ketone oxime (750.0 mg, 2.4 mmol). The resulting mixture was stirred overnight at room temperature under H2 atmosphere. After the reaction was complete, the mixture was filtered, and the filter cake was washed with MeOH (10 mL × 5). The filtrate was concentrated to give the crude target product (440.0 mg, gray solid). LC-MS (ESI): 307.30 [M+H] + .

[0224] i) Preparation of N-(1-(6-((R)-3-methylmorpholino)-4-(tetrahydro-2H-pyran-4-yl)pyridazin-3-yl)ethyl)-1H-pyrazole-5-carboxamide: 1H-pyrazole-5-carboxylic acid (188.0 mg, 1.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 347.6 mg, 1.8 mmol), and 1-hydroxybenzotriazole (HOBT, 19.0 mg, 0.14 mmol) were added to a DCM (5 mL) solution of 1-(6-((R)-3-methylmorpholino)-4-(tetrahydro-2H-pyran-4-yl)pyridazin-3-yl)ethylamine (440.0 mg, 1.4 mmol). The resulting mixture was stirred overnight at room temperature. After the reaction was complete, water (10 mL) was added to the mixture, and extraction was performed using DCM (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was slurried with EA (5 mL) to give the target product (380.0 mg, white solid, 40% yield in two steps). LC-MS (ESI): 401.30 [M + H) + .

[0225] Preparation of (j)(R)-3-methyl-4-(5-methyl-7-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine: N-(1-(6-((R)-3-methylmorpholino)-4-(tetrahydro-2H-pyran-4-yl)pyridazin-3-yl)ethyl)-1H-pyrazol-5-carboxamide (380.0 mg, 0.95 mmol) was added to POCl3 (10 mL) and stirred at 120 °C for 4 hours. After the reaction was complete, the solvent was removed. Water (10 mL) was added to the mixture, and the pH was adjusted to 8 with ammonia (25% w / w). The resulting mixture was extracted with DCM (10 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified twice using preparative thin-layer chromatography (DCM:MeOH = 10:1) to give the target compound (40.0 mg, pale yellow solid, yield 11%). LC-MS (ESI): 383.35 [M+H] + . 1 H NMR (400MHz, CDCl3): δ7.70(s,1H),7.06(s,1H),6.26(s,1H),4.22–4.02(m,4H),3.85(s,2H),3.72(t,J=13.5Hz,2H),3 .61(t,J=11.9Hz,2H),3.43(t,J=12.5Hz,1H),3.35–3.23(m,1H),2.70(s,3H),1.96–1.76(m,4H),1.35(d,J=6.8Hz,3H).

[0226] The compounds in Examples 8-19 below can be prepared using synthetic methods similar to those described in Example 1 or Example 2.

[0227]

[0228]

[0229]

[0230] Example 20

[0231] (R)-4-(5-fluoro-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine

[0232] (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (500.0 mg, 1.4 mmol) was dissolved in DMF (5 mL), and 1-fluoro-2,4,6-trimethylpyridine boron tetrafluoride (620.0 mg, 2.8 mmol) was added at room temperature. The reaction mixture was stirred at 60 °C for 5 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous Na₂SO₄, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (C18, acetonitrile / water, 10-40%, 0.1% formic acid) to obtain the product (11.0 mg, pale yellow solid, yield: 2.3%).

[0233] Example 21

[0234] (R)-4-(5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine

[0235] (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (100.0 mg, 0.3 mmol) was dissolved in DCM (5 mL), and NCS (36.6 mg, 0.3 mmol) was added at -20 °C. The reaction mixture was stirred at -20 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous Na2SO4, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (DCM / MeOH = 10:1) to obtain the product (15.0 mg, yellow solid, yield: 14%).

[0236] Examples 22-24

[0237] a) Preparation of (R)-4-(5-bromo-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 22): (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (500.0 mg, 1.37 mmol) was dissolved in DCM (5 mL), and NBS (122.3 mg, 1.71 mmol) was added at -20 °C. The reaction mixture was stirred at -20 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous Na₂SO₄, filtered to remove the desiccant, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by thin-layer chromatography (DCM / MeOH = 20:1) to give the product (180.0 mg, yellow solid, yield: 30%).

[0238] b) Preparation of (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)-5-vinylimidazo[1,5-b]pyridazin-2-yl)morpholine (Example 23): (R)-4-(5-bromo-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (740.0 mg, 1.7 mmol) was dissolved in DMF (15 mL), and tributylvinyltin (1.6 g, 5.0 mmol) and Pd(PPh3)4 (385.3 mg, 0.3 mmol) were added. The reaction system was purged with nitrogen three times. The mixture was stirred overnight at 100 °C, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / PE, 20-100%) to obtain the product (390.0 mg, yellow solid, yield: 60%).

[0239] c) Preparation of (R)-4-(5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 24): (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)-5-vinylimidazo[1,5-b]pyridazin-2-yl)morpholine (370.0 mg, 1.0 mmol) was dissolved in MeOH (20 mL), and 10% Pd / C (160.0 mg) was added. The reaction system was purged with hydrogen three times and stirred at room temperature for 36 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with methanol (40 mL × 5). The filtrates were combined and concentrated. The crude product was purified by silica gel thin-layer chromatography (DCM:MeOH = 10:1) to give the product (197.5 mg, yellow solid, yield: 53%).

[0240]

[0241]

[0242]

[0243] The compounds in Examples 25 and 26 described below can be prepared using synthetic methods similar to those described in Example 23 or Example 24.

[0244]

[0245]

[0246] Example 27

[0247] (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[5,1-f][1,2,4]triazin-2-yl)morpholine

[0248] This compound was prepared using a synthetic method similar to that described in Examples 1, 2, or 7, or by any known method. It is a yellow solid. LC-MS: 366.15 [M+1] + . 1H NMR (400MHz, CDCl3): δ7.94(s,1H),7.74(s,1H),7.65(s,1H),7.15(s,1H),7.09(s,1H),4.70–4.57(m,1H),4.28(s,3H),4.18(d, J=12.9Hz,1H),4.08(d,J=11.1Hz,1H),3.90–3.75(m,2H),3.65(t,J=11.7Hz,1H),3.45(t,J=11.7Hz,1H),1.41(d,J=6.8Hz,3H).

[0249] Examples 28-29

[0250] (R)-4-(5-bromo-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[5,1-f][1,2,4]triazol-2-yl)-3-methylmorpholine (Example 28) and (R)-3-methyl-4-(5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[5,1-f][1,2,4]triazol-2-yl)morpholine (Example 29) were prepared using known methods.

[0251] Example 30

[0252] The inhibitory effect of the compound of the present invention on ATR enzyme activity was determined by applying an ATR enzyme activity assay.

[0253] ATR enzyme activity was detected using Cisbio's HTRF reagent in a 384-well plate (Greiner, #784075). The test compound was serially diluted 4-fold with reaction buffer (25 mM HEPES (pH 8.0), 10 mM MnCl2, 1% glycerol, 0.01% Brij-35, 5 mM DTT, and 0.1% BSA). 2.5 μL of each solution was added to the corresponding well, followed by 2.5 μL of 80 nM p53 substrate (Eurofins, #14-952) and 2.5 μL of 2 ng / μL ATR / ATRIP enzyme solution (Eurofins, #14-953). Finally, 2.5 μL of 40 μM ATP solution was added. The plate was centrifuged at 1000 rpm for 1 minute and reacted at room temperature in the dark for 30 minutes. The reaction was then terminated by adding 5 μL of EDTA stop solution (250 mM). After adding 5 μL of the 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, fluorescence values ​​at 665 nm and 615 nm were detected on an Envision 2104 instrument. The relative fluorescence ratio was calculated. 665nm / 615nm -Ratio 背景 The inhibition rate % was calculated as follows: % = (1 – (relative fluorescence ratio of the test compound well – relative fluorescence ratio of the positive control well) / (relative fluorescence ratio of the blank control well – relative fluorescence ratio of the positive control well)) × 100. Data were analyzed using GraphPad Prism 6.0 software, and the curve equation was: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC)) 50 Fitting the data using -X)*HillSlope)) and calculating IC 50 value.

[0254] Table 1 summarizes the inhibitory effects (IC50) of the compounds on ATR kinase activity. 50 ).

[0255] Table 1

[0256] Example 1 2 3 4 5 6 7 8 <![CDATA[IC 50 (nM)]]> 1 3 2 3 3 5 1 4 Example 9 10 11 12 13 14 15 16 <![CDATA[IC 50 (nM)]]> 3 217 2 1 14 10 6 9 Example 17 18 20 21 22 23 24 25 <![CDATA[IC 50 (nM)]]> 18 10 41 6 2 2 2 1 Example 26 BAY-1895344 <![CDATA[IC 50 (nM)]]> 1 42

[0257] Therefore, the ATR enzyme activity assay showed that the compound of the present invention has a good inhibitory effect on ATR kinase activity.

[0258] Example 31

[0259] The inhibitory effect of the compound of this invention on the growth of human lung cancer cells NCI-H460 was determined using the MTT assay.

[0260] Resuscitated human lung cancer cells (NCI-H460) were passaged until they reached a good growth state and approximately 90% confluence, at which point they were used for experiments. Cells were digested with trypsin, centrifuged at 800 rpm for 5 min, the supernatant was discarded, and the cells were resuspended in fresh medium (1640 medium + 10% FBS). Cells were counted and seeded at a density of 2000 / 4000 cells per well in 96-well cell culture plates and incubated overnight at 37°C with 5% CO2. Stock solutions of the test substances (including the analyte and reference compound BAY-1895344) were serially diluted with DMSO at 1:3 and 1:10 ratios to eight concentrations. 5 μL of each concentration was added to 120 μL of medium (25-fold dilution) and vortexed to mix. Collect cells 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 compound (DMSO final concentration 1‰). Incubate the plate at 37℃ in a 5% CO2 incubator for 4 days. Remove the stock solution, add 100 μL of fresh serum-free DMEM culture medium containing MTT (0.5 mg / mL) to each well, and continue culturing. After 4 hours, remove the stock solution, add 100 μL of DMSO to each well, shake in the dark for 10 min, and read the absorbance at 552 / 690 nm wavelengths using a multi-functional absorber. Cell viability (%) = (OD 化合物 -OD 背景 ) / (OD DMSO -OD 背景 ()×100. Data were analyzed using Graph Pad Prism 6.0 software. The inhibitory activity of the compound on cell proliferation was plotted as cell viability versus the logarithm of the compound concentration. IC 50 The value was fitted with an S-shaped dose-response curve equation, which is: Y = 100 / (1 + 10^(LogC - LogIC)) 50 C is the concentration of the compound.

[0261] Table 2 summarizes the data on the inhibitory effects of the compounds on the growth of human lung cancer cells NCI-H460 (IC50). 50 ).

[0262] Table 2

[0263] Example 1 2 3 4 5 6 7 8 <![CDATA[IC 50 (nM)]]> 16.53 21.91 27.29 13.03 17.80 21.79 15.70 14.89 Example 9 10 11 12 13 14 15 16 <![CDATA[IC 50 (nM)]]> 30.21 97.32 30.08 28.00 33.23 32.00 12.50 12.49 Example 17 18 19 20 21 22 23 24 <![CDATA[IC 50 (nM)]]> 45.84 27.96 99.10 89.94 24.12 17.07 32.04 28.03 Example 25 26 27 BAY-1895344 <![CDATA[IC 50 (nM)]]> 8.64 22.81 68.34 21.99

[0264] Therefore, as determined by the MTT assay, the compound of this invention has a good inhibitory effect on the growth of NCI-H460 cells.

[0265] Example 32

[0266] The inhibitory effect of the compound of this invention on the growth of human colorectal cancer cells LoVo was determined using the MTT assay.

[0267] Resuscitated human colorectal cancer cells (LoVo) were passaged until they reached a good growth state and approximately 90% confluence, at which point they were used for experiments. Cells were digested with trypsin, centrifuged at 800 rpm for 5 min, the supernatant was discarded, and the cells were resuspended in fresh medium (1640 medium + 10% FBS). Cells were counted and seeded at a density of 2000 / 4000 cells per well in 96-well cell culture plates and incubated overnight at 37°C with 5% CO2. Stock solutions of the test substances (including the analyte and reference compound BAY-1895344) were serially diluted with DMSO at 1:3 and 1:10 ratios to eight concentrations. 5 μL of each concentration was added to 120 μL of medium (25-fold dilution) and vortexed to mix. Collect cells 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 compound (DMSO final concentration 1‰). Incubate the plate at 37℃ in a 5% CO2 incubator for 4 days. Remove the stock solution, add 100 μL of fresh serum-free DMEM culture medium containing MTT (0.5 mg / mL) to each well, and continue culturing. After 4 hours, remove the stock solution, add 100 μL of DMSO to each well, shake in the dark for 10 min, and read the absorbance at 552 / 690 nm wavelengths using a multi-functional absorber. Cell viability (%) = (OD 化合物 -OD 背景 ) / (OD DMSO -OD 背景 ()×100. Data were analyzed using Graph Pad Prism 6.0 software. The inhibitory activity of the compound on cell proliferation was plotted as cell viability versus the logarithm of the compound concentration. IC 50 The value was fitted with an S-shaped dose-response curve equation, which is: Y = 100 / (1 + 10^(LogC - LogIC)) 50 C is the concentration of the compound.

[0268] Table 3 summarizes the data on the inhibitory effects of the compounds on the growth of human colorectal cancer cells LoVo (IC50). 50 ).

[0269] Table 3

[0270] Example 1 2 3 4 5 6 7 8 <![CDATA[IC 50 (nM)]]> 26.74 43.57 49.49 26.89 25.50 44.10 24.62 17.87 Example 9 10 11 12 13 14 15 16 <![CDATA[IC 50 (nM)]]> 39.27 116.10 41.77 19.65 46.46 26.24 19.50 17.62 Example 17 18 19 20 21 22 23 24 <![CDATA[IC 50 (nM)]]> 49.06 47.20 99.33 79.07 22.44 24.10 39.08 38.81 Example 25 26 27 BAY-1895344 <![CDATA[IC 50 (nM)]]> 10.67 27.44 110.5 27.09

[0271] Therefore, as determined by the MTT assay, the compound of this invention has a good inhibitory effect on the growth of LoVo cells.

[0272] Example 33

[0273] Pharmacokinetic study of compound in mice after single oral administration

[0274] The compound of the present invention was prepared into a 0.5% homogeneous suspension of methylcellulose / water and administered to CD-1 (ICR) mice by gavage at a dose of 10 mg / kg. Plasma samples were collected at eight time points: 0.250, 0.500, 1.00, 2.00, 4.00, 6.00, 8.00, and 24.0 hours after administration. The concentration of the compound was determined by LC-MS / MS.

[0275] The pharmacokinetic parameters of the compounds in mice are summarized in Table 4.

[0276] Table 4

[0277] Example <![CDATA[t 1 / 2 (h)]]> <![CDATA[C max (of mL) -1) ]]> <![CDATA[AUC 0-t (ng·h·mL) -1 )]]> <![CDATA[AUC 0-inf (ng·h·mL) -1 )]]> 1 1.64 9343 98507 98517 4 3.2 9008 43376 43951 5 3.42 8933 30826 31662 14 3.75 10787 77348 78719 21 2.65 7343 42772 42925 22 5.88 7673 59010 63023 23 1.66 6608 22356 24116 24 5.40 15367 161501 171092 25 2.56 16867 70013 70195 26 5.82 7180 46439 48979 a 4.46 3023 12427 17986 b 0.5 713 2604 2779 c 3.71 2377 23051 26374 d 5.82 3130 14885 24053

[0278] Note:

[0279] 1)t 1 / 2 Elimination half-life; C max Maximum plasma drug concentration; AUC 0-t Area under the plasma drug concentration-time curve from time 0 to the last measurable concentration; AUC 0-inf Area under the plasma drug concentration-time curve from 0 to infinity.

[0280] 2) Examples a, b, c and d are examples 13, 25, 42 and 47 in WO2020259601A1, respectively.

[0281] The results showed that the compounds of the present invention have good oral absorption and high exposure levels in mice.

[0282] Example 34

[0283] MTT assay was used to determine the inhibitory effect of the compound in Example 1 on the proliferation of various human cancer cells.

[0284] Resuscitated human cancer cells (including human non-small cell lung cancer A549 cells, human breast cancer HCC1806 cells, human colorectal adenocarcinoma HCT116 cells, human ovarian cancer OVCAR-3 cells, and human large cell lung cancer NCI-H460 cells) were cultured and used for experiments when they reached approximately 90% confluence. Cells were digested with trypsin, centrifuged at 800 rpm for 5 minutes, the supernatant was discarded, and the pellet was resuspended in fresh medium (1640 medium + 10% FBS) and counted. Cells were seeded at a density of 2000–4000 cells per well in 96-well cell culture plates and incubated overnight at 37°C in a 5% CO2 incubator. Test substance stock solutions were serially diluted with DMSO at 1:3 and 1:10 to obtain eight concentrations. 5 μL of each dilution was added to 120 μL of medium (diluted 25-fold) and mixed by shaking. Remove the culture medium from the overnight cell culture plate, add 195 μL of fresh culture medium to each well, and add 5 μL of diluted culture medium containing the corresponding concentration of the test substance (DMSO final concentration 1‰). Then, incubate the plate at 37℃ in a 5% CO2 incubator for 4 days. After removing the original solution, add 100 μL of fresh serum-free DMEM medium containing MTT (0.5 mg / mL) to each well and continue culturing. After 4 hours, remove the original solution, add 100 μL of DMSO to each well, and shake the 96-well plate in the dark for 10 minutes. Read the absorbance at 552 / 690 nm wavelengths using a multi-functional absorber. Cell viability (%) = (OD 化合物 -OD 背景 ) / (OD DMSO -OD 背景 Data were analyzed using GraphPad Prism 6.0, with a resolution of 100 (3 x 100). The inhibitory activity of the compound on cell proliferation was plotted as cell viability against the logarithm of the compound concentration. IC50 50 The value was fitted with an S-shaped dose-response curve equation, which is: Y = 100 / (1 + 10^(LogC - LogIC)) 50 C is the concentration of the compound.

[0285] Example 1: Data on the inhibitory effect of the compound on the proliferation of human cancer cells (IC50). 50 See Table 5.

[0286] Table 5

[0287]

[0288] Therefore, by MTT assay, the compound of Example 1 showed good inhibitory effect on the proliferation of various human cancer cells.

[0289] Example 35

[0290] MTT assay for the synergistic inhibitory effect of the compound in Example 1 combined with senaparib on the proliferation of human ovarian cancer OVCAR-3 cells

[0291] Resuscitated human ovarian cancer OVCAR-3 cells were cultured and passaged, and used for experiments when the growth was good and the confluence reached about 90%. After the cells were digested with trypsin, they were centrifuged at 800 rpm for 5 minutes, the supernatant was discarded, and the precipitate was resuspended and counted with fresh medium (1640 medium + 10% FBS). The cells were seeded in a 96-well cell culture plate at an appropriate density and incubated overnight in a 37 °C, 5% CO2 incubator. The test compound stock solutions were serially diluted 4-5 concentrations with DMSO at a ratio of 1:3, and then 5 μL of each concentration of the dilution was added to 120 μL of medium (diluted 25-fold) and mixed by shaking. The overnight cell plates were removed from the medium, 190 μL of fresh medium was added to each well, 5 μL of the diluted compound or 5 μL of medium containing DMSO (final DMSO concentration of 1‰) was added respectively, and the culture plate was placed in a 5% CO2, 37 °C incubator for 3 days. After removing the original solution, 100 μL of fresh serum-free DMEM medium containing MTT (0.5 mg / mL) was added to each well and continued to be cultured. After 4 hours, the original solution was removed, 100 μL of DMSO was added to each well, the 96-well plate was shaken in the dark for 10 minutes, and the absorbance at a wavelength of 552 / 690 nm was read using a multi-functional reader. Cell survival rate (%) = (OD 化合物 - OD 背景 ) / (OD DMSO - OD 背景 ) × 100. The combination index (CI) was calculated using the software CalcuSyn.

[0292] The CI values of the combination of the compound in Example 1 and senaparib are summarized in Table 6.

[0293] Table 6. Combination index (CI)

[0294]

[0295] Note: CI < 0.1 indicates strong synergistic effect; 0.1 < CI < 1 indicates synergistic effect, and CI > 1 indicates no synergistic effect.

[0296] The experimental results show that the combination of the compound in Example 1 and senaparib has a good synergistic effect on inhibiting the proliferation of human ovarian cancer OVCAR-3 cells.

[0297] While the invention has been fully described, those skilled in the art will understand that the same practices can be carried out under broad and equivalent conditions, formulations, and other parameters without affecting the scope of the invention or any embodiments thereof. All patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

Claims

1. The compound of formula III or its pharmaceutically acceptable salt: III in: A is CH; R 22 H or optionally 1-6 selected from halogens, hydroxyl groups, and -NR a R b The C1-C6 alkyl group substituted with a substituent, wherein R a and R b Independently hydrogen or C1-C4 alkyl; R1 is a halogen, optionally surrounded by 1-6 derivatives selected from halogens, hydroxyl groups, and -NR. a R b The substituents of the C1-C6 alkyl group, wherein R a and R b Each is independently H or C1-C4 alkyl; R2 is an optionally substituted phenyl group, an optionally substituted 5-8 membered heterocyclic group, or an optionally substituted 5-6 membered heteroaryl group; In the definition of R2, "optionally substituted" means that the phenyl, 5-8-membered heterocyclic group, and 5-6-membered heteroaryl group are optionally substituted by 1-3 substituents selected from the group consisting of: C1-C6 alkyl, halo-C1-C6 alkyl, cyano, halogen, and C1-C4 alkylsulfonyl.

2. The compound of formula III as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein: A is CH; R 22 is hydrogen or C1-C3alkyl; R1 is a halogen or a C1-C4 alkyl group; R2 is optionally a 5-8 membered heterocyclic group, phenyl group, or 5-6 membered heteroaryl group substituted with 1-3 sulfonyl groups selected from C1-C6 alkyl, halogenated C1-C6 alkyl, cyano, halogen, and C1-C4 alkyl.

3. The compound of formula III as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The heterocyclic group is a 4-7 member nitrogen- and / or oxygen-containing heterocyclic group; and / or, the heteroaryl group is a 5- or 6-member nitrogen-containing heteroaryl group.

4. The compound of formula III as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The heterocyclic group is selected from tetrahydropyranyl, tetrahydrofuranyl, oxoheterobutyl, azaheterobutyl, pyrrolidinyl, piperidinyl, and piperazineyl; The heteroaryl group is selected from pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrrolithyl, and triazolyl; R2 is an optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyridyl, or optionally substituted tetrahydropyranyl.

5. The compound of formula III as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R2 is selected from: , , , , , and ; Among them, R 10 It is H, C1-C3 alkyl, or halo-C1-C3 alkyl; each R 11 Independently, it is H or C1-C3 alkyl; R 12 H or a halogenated C1-C3 alkyl group; R 13 H or C1-C3 alkyl; R 14 It is H or C1-C3 alkyl; each R 15 Independently, it is H or C1-C3 alkyl; R 16 H, halogen, or C1-C3 alkyl; R 17 For H or CN; R 18 The sulfonyl group is H or C1-C3 alkyl-substituted; R 19 H, halogen, C1-C3 alkyl, or halo-C1-C3 alkyl; R 20 H or C1-C3 alkyl; R 21 It is a halogen, a C1-C3 alkyl group, or a halo-C1-C3 alkyl group; wherein, This indicates the connection point between R2 and the rest of the compound.

6. The compound of claim 1 of formula III ###0005### or a pharmaceutically acceptable salt thereof. R2 is selected from: , , , , , , , , , , and ; Among them, R 10 C 1-3 Alkyl; R 16 It is methyl or fluorine; R 19 It is methyl, fluorine, or trifluoromethyl; among which, This indicates the connection point between R2 and the rest of the compound.

7. The compound of claim 1 of formula III or a pharmaceutically acceptable salt thereof, wherein, R2 is a phenyl group optionally substituted with one or two sulfonyl groups selected from C1-C6 alkyl, halogen, cyano, and C1-C4 alkyl; a pyrazolyl or pyridinyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halo-C1-C6 alkyl, and halogen; or a tetrahydropyranyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halo-C1-C6 alkyl, and halogen.

8. The compound of formula III as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R2 is: , , , , , , , , , , , , , , , , or .

9. The compound of formula IV or its pharmaceutically acceptable salt: IV in, R1 is as defined in claim 1 or 2; Cy is an optionally substituted phenyl group, an optionally substituted 4-9-membered heterocyclic group, or an optionally substituted 5-6-membered heteroaryl group, wherein Cy is optionally substituted by 1-3 substituents selected from C1-C6 alkyl, halo-C1-C6 alkyl, cyano, halogen, and C1-C4 alkylsulfonyl groups.

10. The compound of formula IV as claimed in claim 9, or a pharmaceutically acceptable salt thereof, wherein: R1 is a halogen or a C1-C3 alkyl group; Cy is a phenyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halogen, cyano, and sulfonyl groups substituted with C1-C4 alkyl; a pyrazolyl or pyridinyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halo-C1-C6 alkyl, and halogen; or a tetrahydropyranyl group optionally substituted with one or two substituents selected from C1-C6 alkyl, halo-C1-C6 alkyl, and halogen.

11. The compound of formula IV as claimed in claim 9, or a pharmaceutically acceptable salt thereof, wherein, Cy is a pyrazolyl group optionally substituted with a C1-C6 alkyl group.

12. The compound of formula IV according to claim 10 or 11, wherein, ###00010### IV or a pharmaceutically acceptable salt thereof. One or both ring N atoms of the pyrazol group are substituted.

13. The compound of formula IV as claimed in claim 9, or a pharmaceutically acceptable salt thereof, wherein: R1 is a halogen or a C1-C3 alkyl group; Cy is a phenyl group optionally substituted with one or two substituents selected from C1-C2 alkyl, C1-C2 alkylsulfonyl, and cyano groups; a pyridinyl group optionally substituted with one or two substituents selected from halogen, C1-C2 alkyl, and halo-C1-C2 alkyl groups; or one N atom of the pyrazolyl group optionally substituted with a C group. 1-2 Alkyl-substituted pyrazolyl group.

14. The compound of formula III or its pharmaceutically acceptable salt: III in: A, R 22 and R2are as defined in any one of claims 1 to 8; R1 is a C2-C6 alkenyl group.

15. The compound of claim 14 of formula III or a pharmaceutically acceptable salt thereof, wherein, R1 is a C2-C3 alkenyl group.

16. The compounds are selected from: (R)-3-methyl-4-(5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(4-(1-ethyl-1H-pyrazol-5-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-3-methyl-4-(5-methyl-7-(1H-pyrazol-5-yl)-4-(o-tolyl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(5-methyl-4-(2-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(5-methyl-7-(1H-pyrazol-5-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-(5-methyl-2-(3-methylmorpholino)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl)benzylnitrile; (R)-3-methyl-4-(5-methyl-7-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(3-methyl-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazine-2-yl)-3-methylmorpholine; (R)-4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazine-2-yl)-3-methylmorpholine; (R)-4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazine-2-yl)-3-methylmorpholine; (R)-4-(4-(2-fluorophenyl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-3-methyl-4-(5-methyl-4-(2-methyl-4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(4-(2-fluoropyridin-3-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-3-methyl-4-(5-methyl-4-(6-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(4-(3-fluoropyridin-4-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-(1-(difluoromethyl)-1H-)pyrazol-5-yl)-5-methyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(5-bromo-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)-5-vinylimidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-5-(propen-2-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(5-isopropyl-4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; Or its medicinal salt.

17. Use of the compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing ATR kinase-mediated diseases.

18. The use as described in claim 17, characterized in that, The disease in question is cancer.

19. The use of claim 18, wherein the cancer is selected from liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, gastric cancer, and colon cancer. Malignant pancreatic islet tumors, malignant carcinoid cancers, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocytosis, adrenocortical carcinoma, skin cancer, and prostate cancer.

20. The use of claim 17, wherein the given medicament further comprises at least one known anticancer drug, or a pharmaceutically acceptable salt of said anticancer drug; said anticancer drug is selected from one or more of the group consisting of: busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclarubicin, mitoxantrone, methyl hydroxyrosine, mentholtoporp, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nerabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vincristine, vinorelbine, paclitaxel, ixapril. Long, Cabazitaxel, Docetaxel, Monoclonal Antibody, Herceptinib, Imatinib, Gefitinib, Erlotinib, Ostinib, Afatinib, Celitinib, Alectinib, Crizotinib, Erlotinib, Lapatinib, Sorafenib, Sunitinib, Nilotinib, Dasatinib, Pazopanib, Tetracycline, Everolimus, Vorinostat, Romidhizine, Pabistat, Belistat, Tamoxifen, Letrozole Fulvestrant, Mitoguanidine, Octreotide, Retinoic Acid, Arsenic, Zoledronic Acid, Bortezomib, Carfilzomib, Ixazomib, Vemodil, Sonicil, Dinosema, Salidone, Lenalidomide, Venetoclax, Recombinant Human Interleukin-2, Prostate Cancer Treatment Vaccine, Palbociclib, Olaparib, Niraparib, Lucaparib, Tapazoparib, Pamiparib, Fluzoparib, and Senaparib.

21. The use as described in claim 20, characterized in that, The monoclonal antibodies are selected from: panitumumab, nezotuzumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, olbutuzumab, ofamumab, rituximab, alenumab, tiimozumab, tosimob, babutuzumab, daratumumab, erlotuzumab, ofamumab, daratumumab, belintoozumab, iprimma, Avastin, Herceptin, and rituximab.

22. The use of claim 17, wherein the drug is used in combination with radiotherapy.

23. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 16, and a pharmaceutically acceptable carrier.

24. The pharmaceutical composition of claim 23, wherein The pharmaceutical composition further comprises at least one known anticancer drug, or a pharmaceutically acceptable salt of said anticancer drug; said 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, methyl hydroxyrosine, mentholtoporp, 5-azacytidine, gemcitabine, 5-fluorouracil, methotrexate, 5-fluoro-2'-deoxyuridine, fludarabine, nerabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vincristine, vinorelbine, paclitaxel, ixaprilone, cabazitaxel. Docetaxel, monoclonal antibodies, T-DM1, imatinib, gefitinib, erlotinib, ostinotinib, afatinib, celitinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, tebuconazole, everolimus, vorinostat, romidesin, pabistat, belitistat, tamoxifen, letrozole, fluoride Vestrant, Mitoguanidine, Octreotide, Retinoic Acid, Arsenic, Zoledronic Acid, Bortezomib, Carfilzomib, Ixazomib, Vemodil, Sonicil, Dinosema, Salidone, Lenalidomide, Venetoclax, Recombinant Human Interleukin-2, Prostate Cancer Treatment Vaccine, Palbociclib, Olaparib, Niraparib, Lucaparib, Tapazoparib, Pamiparib, Fluzoparib, and Senaparib.

25. The pharmaceutical composition of claim 24, wherein The monoclonal antibodies are selected from: panitumumab, nezotuzumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, olbutuzumab, ofamumab, rituximab, alenumab, tiimozumab, tosimob, babutuzumab, daratumumab, erlotuzumab, ofamumab, daratumumab, belintoozumab, iprimma, Avastin, Herceptin, and rituximab.

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