Substituted fused heteroaromatic bicyclic compounds as kinase inhibitors and their uses

Abstract

The present disclosure provides novel substituted fused heteroaromatic compounds represented by formula I: TIFF2022541127000076.tif43142, where A1-A6 and R1-R4 are defined herein. The compounds of Formula I are kinase inhibitors, particularly ATR kinase inhibitors. Thus, the compounds of the present disclosure can be used to treat ATR-mediated diseases, disorders, and conditions, such as cancer.

Description

[Technical field]

[0001] The present disclosure is in the field of medicinal chemistry. Specifically, the present disclosure relates to substituted fused heteroaromatic Aromatic bicyclic compounds and their therapeutically effective kinase inhibitors and anticancer agents Regarding use as a [Background technology]

[0002] Ataxia telangiectasia and Rad3-related kinase ATR (ATR) is a protein kinase that responds to cell-mediated DNA damage. The cytosed ATR mediates cell cycle arrest, replication origin inhibition, replication fork initiation, and DNA biogenesis. It can regulate the life processes of cells through various signals, such as double strand repair (Enriq uez-Rios V et al., 2017). ATR kinase is involved in the regulation of ATM (ataxia telangiectasia mutations). It acts in conjunction with ataxia telangiectasia mutated kinase and many other proteins. This promotes the cellular response to DNA damage, commonly referred to as the DNA damage response (DDR). When cells detect DNA damage through the DDR, they immediately initiate the DNA repair process. They initiate apoptosis, activate cell cycle checkpoints, and disrupt normal cell cycle processes. DDR, thereby providing time for DNA repair. Without DDR, cells would develop cancer. Endogenous cell damage and D caused by chemotherapy and radiotherapy to treat They become more sensitive to NA damage and more likely to die.

[0003] Healthy cells can rely on different proteins for DNA repair, including ATM, ATR kinase, etc. in the DDR. Under normal circumstances, these proteins can repair DNA by regulating downstream regulators. However, many cancer cells have defects in DNA repair pathways and therefore rely more on the remaining intact DNA repair proteins, including ATR. ATR is a key member of the DDR that responds to damaged DNA replication and is crucial for maintaining genome stability and integrity and improving cell survival. When intracellular DNA damage occurs, ATR is recruited to the site of DNA damage, whereby various proteins are involved in regulating ATR activation. Activated ATR regulates several important cellular processes. Many cancer cells lack important tumor suppressor genes, which makes cancer cells more dependent on the ATR pathway than normal cells to regulate DNA damage repair and improve cell survival, making ATR a promising target for cancer therapy.

[0004] ATR inhibitors block the DNA replication mechanism that is more important for cell survival in many cancer cells than in healthy normal cells, so they can be used alone or in combination with DNA damaging agents for cancer treatment. In fact, ATR inhibitors have already been proven to be effective as single activators in cancer cells and as sensitizers for radiation therapy and chemotherapy. At the same time, ATR inhibitors can also be used in combination with other DDR-related targeting drugs, such as PARP inhibitors.

[0005] Various ATR kinase inhibitors have been disclosed. For example, WO2011154737 disclosed morpholino pyrimidine compounds as ATR kinase inhibitors; WO2016020320 disclosed 2-(morpholin-4-yl)-1,7-naphthyridine compounds as ATR kinase inhibitors; WO2018153968 disclosed ATR kinase inhibitors for use in a method for treating hyperproliferative diseases; WO2020049017 disclosed 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives as ATR kinase inhibitors; WO2020087170 disclosed morpholino 5-membered heterocyclic fused pyridine compounds as ATR kinase inhibitors. Summary of the Invention [Problem to be solved by the invention]

[0006] The present disclosure relates to substituted fused conjugates represented by formulae I, II, IIIa, IIIb and IV. The present invention provides novel aromatic bicyclic compounds which can be used as kinase inhibitors. The present disclosure further includes an effective amount of a compound of formula I, II, IIIa, IIIb or IV. A pharmaceutical composition for treating cancer is provided.

[0007] In a specific embodiment, the pharmaceutical composition for treating cancer further comprises one or more pharmaceutical The composition may contain a physiologically acceptable carrier or diluent. In a specific embodiment, the pharmaceutical composition for treating cancer further comprises at least one known or a pharma- ceutical acceptable salt thereof.

[0008] The present disclosure further relates to methods for preparing the novel compounds of formulas I, II, IIIa, IIIb and IV. Regarding the law. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The features of the embodiments described in this specification may be arbitrarily combined to form the technical solution of the present disclosure. It should be understood that the definitions of each group in this specification are as defined in the specification. For example, the alkyl substituent may be any of the embodiments described in the above specification. Unless expressly defined in the specification, the definitions of alkyl substituents herein are intended to be consistent with the present specification. This also applies to any of the embodiments described in the specification.

[0010] Specifically, the present disclosure relates to a compound represented by formula I:

[0011] [ka]

[0012] or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, provided that: A1 and A4 to A6 are independently CR5 or N; A2 and A3 are independently C or N; preferably, one of A2 and A3 is C and the other is N or C; more preferably, one of A2 and A3 is N and the other is C; R1 is an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted cycloalkyl group, an optionally substituted heteroaryl group;

[0013] [ka]

[0014] where * indicates the position where said group is attached to the remainder of the compound; R2 is a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group, a heteroaryl group, -NR8R9, -(CO)R8, -(CO)OR8, -(CO)NR8R9, -(SO)R6, -(SO2)R6, -SR6, -(SO2)NR8R9, -NR8(SO2)R6, -((SO)=NR7)R 10 , -N=(SO)R6R 10 , -SiR7R 10 R 11 , -(PO)(OR8)2, -(PO)(OR8)R 10 Or -(PO)(R 10 )2, wherein the C1-C6 alkyl group, the C1-C6 alkoxy group, the C3-C6 cycloalkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the carbocyclic group, the heterocyclic group, the aryl group and the heteroaryl group are each optionally substituted; and wherein -N=(SO)R6R10 R6 and R in 10 may together form a 5- to 8-membered heterocycloalkyl group; R3 and R4 are independently hydrogen or a C1-C6 alkyl group; R5 is hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, an amino group, a nitro group, a cyano group, an acylamino group, an acyloxy group, a hydroxy group, a thiol group, an alkylthiol group, an azide group, or a carboxy group; provided that the C1-C6 alkyl group, the C2-C6 alkoxy group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the amino group, the acylamino group, the acyloxy group, the hydroxy group, the thiol group, the alkylthiol group, and the carboxy group are each optionally substituted; R6 is an optionally substituted alkyl group or an optionally substituted alkylaryl group, preferably the aryl group is a phenyl group; R7 is hydrogen, an optionally substituted alkyl group, -(CO)OR8, or -(CO)NR8R9; R8 and R9 are independently hydrogen or optionally substituted C1-C 10 an alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; or R8 and R9 together with the N and C to which they are attached form an optionally substituted 4-7 membered cyclic amino group, optionally containing one or more additional heteroatoms selected from O, N, and S; R 10 is a C1-C4 alkyl group, or -N=(SO)R6R 10 In this case, R6 and R 10 together with the S to which they are attached form a 5-8 membered heterocycloalkyl group; R 11 is hydrogen or a C1-C4 alkyl group.

[0015] In one or more embodiments, A1 in the compound of formula I is N or CH. Preferably, A1 is N. In one or more of the above-described embodiments of the compound of Formula I, at least two or three of A1 through A6 are N.

[0016] In one or more of the above embodiments of the compound of formula I, one of A2 and A3 is N and the other is is C. Preferably, in some embodiments, in the compound of formula I, A2 is N So, A3 is C.

[0017] In one or more of the above embodiments of the compound of formula I, A5 is N or CH. Preferably, A5 is N. In one or more of the above embodiments of the compound of formula I, at least A1, A2 and A 5 is N.

[0018] In one or more of the above embodiments of the compound of formula I, R5 is hydrogen. In one or more of the above embodiments of the compound of formula I, the 5-membered-6 The fused heteroaryl group is:

[0019] [ka]

[0020] and preferably the 5-6 membered fused heteroaryl group containing A2 and A3 is:

[0021] [ka]

[0022] and more preferably, the 5-6 membered fused heteroaryl group comprising A2 and A3 is:

[0023] [ka]

[0024] where *1, *2 and *3 indicate the positions at which said groups are attached to the morpholinyl group, R1 and R2, respectively, in compounds of formula I.

[0025] In one or more of the above embodiments of the compound of formula I, R2 is a C3-C6 cycloalkyl group. -NR8R9, -NR 8(SO2)R6 or -N=(SO)R6R 10 wherein the C3-C6 cycloalkyl The cyclic, carbocyclic, heterocyclic, aryl and heteroaryl groups are each optionally substituted; provided that R8 and R9 are independently hydrogen, a C1-C6 alkyl group, a C3-C 6 is a cycloalkyl group or an optionally substituted phenyl group; R 10 is C1-C4 alkyl or -N=(SO)R6R 10 R6 and R in 10 are the S to which they bind Together they form a 5-8 membered heterocycloalkyl group. Preferably, R2 is an optionally substituted C3-C6 cycloalkyl groups, optionally substituted aryl groups, optionally substituted heteroaryl groups It is preferably a cyclic group or an optionally substituted heteroaryl group. The aryl group is a 5- or 6-membered heteroaryl group containing at least one nitrogen atom, preferably Preferably, R2 is a 5-membered heteroaryl group containing two nitrogen atoms. an optionally substituted cyclopropyl group, an optionally substituted phenyl group, an optionally substituted a pyrazolyl group, an optionally substituted pyrrolyl group, an optionally substituted imidazolyl group, optionally substituted triazolyl groups, optionally substituted furanyl groups, optionally substituted morpho an optionally substituted dihydropyranyl group, an optionally substituted tetrahydropyranyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group or an optionally substituted Preferably, the substituents in R2 are optionally substituted pyrrolopyridyl groups. C1-C6 alkyl groups, cyano groups, hydroxy groups, carboxy groups, amino groups, halogen groups optionally substituted alkylsulfinyl groups and optionally substituted alkylsulfonyl groups. Preferably, the C1-C6 alkyl group is selected from the group consisting of halogenyl groups. R2 is optionally substituted with one or more substituents selected from the group consisting of The number of the substituents in the alkyl group may be 1 to 3.

[0026] In one or more of the above embodiments of the compound of formula I, R3 is hydrogen; R4 is a C1-C4 alkyl group, such as a methyl group. Preferably, R3 is in the R-configuration. In one or more of the above embodiments of the compound of formula I, R1 is an optionally substituted alkylsulfonyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted cycloalkyl 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, preferably a 5-membered heteroaryl group containing two nitrogen atoms. Preferably, the substituents of the alkylsulfonyl group, the heterocyclic group, the cycloalkyl group, the aryl group, and the heteroaryl group may be selected from the group consisting of C1-C4 alkyl groups, halogens, hydroxy groups, C1-C4 alkoxy groups, and amino groups. Preferably, the number of substituents in R1 may be 1 to 3. More preferably, R1 is a sulfonyl group substituted by a C1-C4 alkyl group; or a pyrazolyl group, a pyrrolyl group, or an imidazolyl group optionally substituted by one or two substituents selected from the group consisting of a C1-C4 alkyl group, a halogen, a hydroxy group, a C1-C4 alkoxy group, and an amino group. In some embodiments, R1 is an unsubstituted pyrazolyl group, an unsubstituted pyrrolyl group, or an unsubstituted imidazolyl group.

[0027] In one or more of the above embodiments of the compound of formula I, isotopically substituted derivatives of the compound of formula I are compounds in which one or more hydrogen atoms are replaced by one or more D atoms.

[0028] One group of preferred compounds of the present disclosure are represented by formula II:

[0029] [ka]

[0030] or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, with the proviso that: A1-A6, R1 and R4 are as defined in formula I; Cy is a C3-C6 cycloalkyl group, a carbocyclic group, a heterocyclic group, an aryl group, a heteroaryl group, -NR8R9, -NR8(SO2)R6 or -N=(SO)R6R 10 wherein the C3-C6 cycloalkyl, carbocyclic, heterocyclic, aryl and heteroaryl groups are each optionally substituted; and wherein R8 and R9 are each independently hydrogen, an optionally substituted C1-C6 cycloalkyl, carbocyclic, heterocyclic, aryl or heteroaryl group. 10 R is an alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; or R and R are both an optionally substituted 4-7 membered cyclic amino group, optionally containing one additional heteroatom selected from O, N, and S; R 10 is a C1-C4 alkyl group, or -N=(SO)R6R 10 In this case, R6 and R 10 together form a 5- to 8-membered heterocycloalkyl group.

[0031] In one or more of the above embodiments of the compound of formula II, A1 is N or CH. Preferably, A1 is N. In one or more of the above embodiments of the compound of formula II, one of A2 and A3 is N and the other is C. Preferably, in some embodiments, A2 is N and A3 is C in the compound of formula II.

[0032] In one or more of the above embodiments of the compound of formula II, A5 is N or CH. Preferably, A5 is N. In one or more of the above embodiments of the compound of formula II, R5 is hydrogen.

[0033] In one or more of the above embodiments of the compound of formula II, the 5-6 membered fused heteroaryl group containing A2 and A3 is:

[0034] [ka]

[0035] and preferably the 5-6 membered fused heteroaryl group containing A2 and A3 is:

[0036] [ka]

[0037] and more preferably, the 5-6 membered fused heteroaryl group comprising A2 and A3 is:

[0038] [ka]

[0039] where *1, *2 and *3 indicate the positions at which said groups are attached to the morpholinyl group, R1 and R2, respectively, of the compound of formula II.

[0040] In one or more of the above embodiments of the compound of formula II, Cy is a C3-C6 cycloalkyl group, a carbocyclic group, a heterocyclic group, an aryl group, a heteroaryl group, -NR8R9, -NR8(SO2)R6, or -N=(SO)R6R10 wherein the C3-C6 cycloalkyl, carbocyclic, heterocyclic, aryl and heteroaryl groups are each optionally substituted; and wherein R8 and R9 are each independently hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted phenyl group; R 10 is a C1-C4 alkyl group, or -N=(SO)R6R 10 R6 and R in 10form a 5-8 membered heterocycloalkyl group together with the S to which they are attached. Preferably, Cy is an optionally substituted C3-C6 cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic 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, preferably a 5-membered heteroaryl group containing two nitrogen atoms. More preferably, Cy is an optionally substituted cyclopropyl group, an optionally substituted phenyl group, an optionally substituted pyrazolyl group, an optionally substituted pyrrolyl group, an optionally substituted imidazolyl group, an optionally substituted triazolyl group, an optionally substituted furanyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted morpholinyl group, an optionally substituted dihydropyranyl group, an optionally substituted tetrahydropyranyl group or an optionally substituted pyrrolopyridyl group. Preferably, the substituents in Cy are selected from the group consisting of an optionally substituted C1-C6 alkyl group, a cyano group, a hydroxy group, a carboxy group, an amino group, a halogen, an optionally substituted alkylsulfinyl group, and an optionally substituted alkylsulfonyl group. The number of substituents in Cy may be 1 to 3. In some embodiments, Cy is a pyrazolyl group optionally substituted with one or more, preferably one, two or three, C1-C6 alkyl groups; preferably, one or two N atoms in the pyrazolyl group are substituted with a C1-C6 alkyl group; preferably, the C1-C6 alkyl group may be further substituted with one or more, for example, one to five halogens. In some embodiments, Cy is a pyrazolyl group optionally substituted with one or two substituents selected from the group consisting of an unsubstituted C1-C4 alkyl group and a C1-C4 alkyl group substituted with one to three halogens.

[0041] In one or more of the above embodiments of the compound of formula II, R4 is a C1-C4 alkyl group, such as a methyl group. Preferably, R4 is in the R-configuration. In one or more of the above embodiments of the compound of formula II, R1 is an optionally substituted alkylsulfonyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted cycloalkyl 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, preferably a 5-membered heteroaryl group containing two nitrogen atoms. Preferably, the substituents of the alkylsulfonyl group, the aryl group, the heterocyclic group, the cycloalkyl group, and the heteroaryl group may be selected from the group consisting of C1-C4 alkyl groups, halogens, hydroxy groups, C1-C4 alkoxy groups, and amino groups. Preferably, the number of substituents may be 1 to 3. More preferably, R1 is a sulfonyl group substituted by a C1-C4 alkyl group; or a pyrazolyl group, a pyrrolyl group, or an imidazolyl group optionally substituted by one or two substituents selected from the group consisting of a C1-C4 alkyl group, a halogen, a hydroxy group, a C1-C4 alkoxy group, and an amino group. In some embodiments, R1 is an unsubstituted pyrazolyl group, an unsubstituted pyrrolyl group, or an unsubstituted imidazolyl group.

[0042] One group of preferred compounds of the present disclosure are represented by formulae IIIa and IIIb:

[0043] [ka]

[0044] or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, wherein A1, A4, A5, A6, R1, R2 and R4 are as defined in Formula I or II.

[0045] In one or more of the above embodiments of the compounds of formula IIIa and IIIb, A1 is N or CH. Preferably, A1 is N. In one or more of the above embodiments of the compounds of formula IIIa and IIIb, A4 is N or CH. Preferably, A4 is CH.

[0046] In one or more of the above embodiments of the compounds of formula IIIa and IIIb, A5 is N or CH. Preferably, A5 is N. In one or more of the above embodiments of the compounds of formula IIIa and IIIb, A6 is N or CH. Preferably, A6 is CH.

[0047] In one or more of the above embodiments of the compounds of formula IIIa and IIIb, the 5-6 membered fused heteroaryl group containing A1, A4, A5 and A6 is:

[0048] [ka]

[0049] and preferably the 5-6 membered fused heteroaryl group containing A1, A4, A5 and A6 is:

[0050] [ka]

[0051] more preferably, the 5-6 membered fused heteroaryl group containing A1, A4, A5 and A6 is:

[0052] [ka]

[0053] where *1, *2 and *3 indicate the positions at which said groups are attached to the morpholinyl groups, R1 and R2, in compounds of formula IIIa and IIIb, respectively.

[0054] In one or more of the above embodiments of the compounds of formula IIIa and IIIb, R1 is an optionally substituted alkylsulfonyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted cycloalkyl 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, preferably a 5-membered heteroaryl group containing two nitrogen atoms. Preferably, the substituents of the heterocyclic group, the cycloalkyl group, the aryl group and the heteroaryl group may be selected from the group consisting of C1-C4 alkyl groups, halogens, hydroxy groups, C1-C4 alkoxy groups and amino groups. Preferably, the number of substituents in R1 may be 1 to 3. More preferably, R1 is a sulfonyl group substituted by a C1-C4 alkyl group; or a pyrrolyl group, an imidazolyl group or a pyrazolyl group optionally substituted by one or two substituents selected from the group consisting of a C1-C4 alkyl group, a halogen, a hydroxy group, a C1-C4 alkoxy group and an amino group. In some embodiments, R1 is an unsubstituted pyrazolyl group, an unsubstituted pyrrolyl group, or an unsubstituted imidazolyl group.

[0055] In one or more of the above embodiments of the compounds of formula IIIa and IIIb, R2 is a C3-C6 cycloalkyl group, a carbocyclic group, a heterocyclic group, an aryl group, a heteroaryl group, -NR8R9, -NR8(SO2)R6, or -N=(SO)R6R 10 wherein the C3-C6 cycloalkyl, carbocyclic, heterocyclic, aryl and heteroaryl groups are each optionally substituted; and wherein R8 and R9 are each independently hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted phenyl group; R 10 is a C1-C4 alkyl group, or -N=(SO)R6R 10 In this case, R6 and R 10form a 5-8 membered heterocycloalkyl group together with the S to which they are attached. Preferably, the heteroaryl group is a 5- or 6-membered heteroaryl group containing at least one nitrogen atom, preferably a 5-membered heteroaryl group containing two nitrogen atoms. Preferably, R2 is an optionally substituted C3-C6 cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic group; more preferably, R2 is an optionally substituted cyclopropyl group, an optionally substituted phenyl group, an optionally substituted pyrazolyl group, an optionally substituted pyrrolyl group, an optionally substituted imidazolyl group, an optionally substituted triazolyl group, an optionally substituted furanyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted morpholinyl group, an optionally substituted dihydropyranyl group, an optionally substituted tetrahydropyranyl group or an optionally substituted pyrrolopyridyl group. Preferably, the substituents in R2 are selected from the group consisting of an optionally substituted C1-C6 alkyl group, a cyano group, a hydroxy group, a carboxy group, an amino group, a halogen, an optionally substituted alkylsulfinyl group, and an optionally substituted alkylsulfonyl group. The number of substituents in R2 may be 1 to 3. In some embodiments, R2 is a pyrazolyl group optionally substituted with an optionally substituted C1-C6 alkyl group, preferably one or two ring N atoms of said pyrazolyl group are substituted; preferably, said C1-C6 alkyl group may be further substituted with one or more, for example 1 to 5, halogens. In some embodiments, R2 is a pyrazolyl group optionally substituted with one or two substituents selected from the group consisting of an unsubstituted C1-C4 alkyl group and a C1-C4 alkyl group substituted with 1 to 3 halogens.

[0056] In one or more of the above embodiments of the compounds of formula IIIa and IIIb, R4 is a C1-C4 alkyl group, such as a methyl group. One group of preferred compounds of the present disclosure are represented by formula IV:

[0057] [ka]

[0058] or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, with the proviso that: A4, A5, A6, R1, R2 and R4 are as defined in formula I, II, IIIa or IIIb; In one or more of the above embodiments of the compound of formula IV, A4 is N or CH. Preferably, A4 is CH.

[0059] In one or more of the above embodiments of the compound of formula IV, A5 is N or CH. Preferably, A5 is N. In one or more of the above embodiments of the compound of formula IV, A6 is N or CH. Preferably, A6 is CH.

[0060] In one or more of the above embodiments of the compound of formula IV, the 5-6 membered fused heteroaryl group containing A4, A5 and A6 is selected from the group consisting of:

[0061] [ka]

[0062] preferably

[0063] [ka]

[0064] where *1, *2 and *3 indicate the positions at which said groups are attached to the morpholinyl group, R1 and R2, respectively, of the compound of formula IV.

[0065] In one or more of the above embodiments of the compound of formula IV, R1 is an optionally substituted alkylsulfonyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted cycloalkyl 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, preferably a 5-membered heteroaryl group containing two nitrogen atoms. Preferably, the substituents of the alkylsulfonyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be selected from the group consisting of C1-C4 alkyl groups, halogens, hydroxy groups, C1-C4 alkoxy groups, and amino groups. Preferably, the number of substituents in R1 may be 1 to 3. More preferably, R1 is a sulfonyl group substituted by a C1-C4 alkyl group; or a pyrazolyl group, a pyrrolyl group, or an imidazolyl group optionally substituted by one or two substituents selected from the group consisting of a C1-C4 alkyl group, a halogen, a hydroxy group, a C1-C4 alkoxy group, and an amino group. In some embodiments, R1 is an unsubstituted pyrazolyl group, an unsubstituted pyrrolyl group, or an unsubstituted imidazolyl group.

[0066] In one or more of the above embodiments of the compound of formula IV, R2 is a C3-C6 cycloalkyl group, a carbocyclic group, a heterocyclic group, an aryl group, a heteroaryl group, -NR8R9, -NR8(SO2)R6, or -N=(SO)R6R 10 wherein the C3-C6 cycloalkyl, carbocyclic, heterocyclic, aryl and heteroaryl groups are each optionally substituted; and wherein R8 and R9 are each independently hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl or an optionally substituted phenyl group; R 10 is a C1-C4 alkyl group, or -N=(SO)R6R 10 In this case, R6 and R 10form a 5-8 membered heterocycloalkyl group together with the S to which they are attached. Preferably, the heteroaryl group is a 5- or 6-membered heteroaryl group containing at least one nitrogen atom, preferably a 5-membered heteroaryl group containing two nitrogen atoms. Preferably, R2 is an optionally substituted C3-C6 cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic group; more preferably, R2 is an optionally substituted cyclopropyl group, an optionally substituted phenyl group, an optionally substituted pyrazolyl group, an optionally substituted pyrrolyl group, an optionally substituted imidazolyl group, an optionally substituted triazolyl group, an optionally substituted furanyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, an optionally substituted morpholinyl group, an optionally substituted dihydropyranyl group, an optionally substituted tetrahydropyranyl group or an optionally substituted pyrrolopyridyl group. Preferably, the substituents in R2 are selected from the group consisting of an optionally substituted C1-C6 alkyl group, a cyano group, a hydroxy group, a carboxy group, an amino group, a halogen, an optionally substituted alkylsulfinyl group, and an optionally substituted alkylsulfonyl group. The number of the substituents may be 1 to 3. In some embodiments, R2 is a pyrazolyl group optionally substituted with an optionally substituted C1-C6 alkyl group, preferably one or two ring N atoms of the pyrazolyl group are substituted; preferably, the C1-C6 alkyl group may be further substituted with one or more, for example 1 to 5, halogens. In some embodiments, R2 is a pyrazolyl group optionally substituted with one or two substituents selected from the group consisting of an unsubstituted C1-C4 alkyl group and a C1-C4 alkyl group substituted with 1 to 3 halogens.

[0067] In one or more of the above embodiments of the compound of formula IV, R4 is a C1-C4 alkyl group, such as a methyl group. In one or more of the above-mentioned embodiments of the compounds of formula I, II, IIIa, IIIb and IV, the 5-6 membered fused heteroaryl group is:

[0068] [ka]

[0069] and preferably

[0070] [ka]

[0071] and; R1 is an alkylsulfonyl group; a heteroaryl group (preferably a pyrazolyl group, a pyrrolyl group, and an imidazolyl group) optionally substituted with 1 to 3 substituents selected from the group consisting of a C1-C4 alkyl group, a halogen, a hydroxy group, a C1-C4 alkoxy group, and an amino group; an aryl group optionally substituted with 1 to 3 substituents selected from the group consisting of a C1-C4 alkyl group, a halogen, a hydroxy group, a C1-C4 alkoxy group, and an amino group; and cycloalkyl groups optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl groups, halogens, hydroxy groups, C1-C4 alkoxy groups, and amino groups; preferably, R1 is selected from the group consisting of heteroaryl groups (preferably pyrazolyl groups, pyrrolyl groups, and imidazolyl groups) optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C4 alkyl groups, halogens, hydroxy groups, C1-C4 alkoxy groups, and amino groups, or alkylsulfonyl groups; R2 or Cy is an optionally substituted C3-C6 cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group or an optionally substituted heteroaryl group; more preferably, R2 or Cy is an optionally substituted cyclopropyl group, an optionally substituted phenyl group, an optionally substituted pyrazolyl group, an optionally substituted pyrrolyl group, an optionally substituted imidazolyl group, an optionally substituted triazolyl group, an optionally substituted furanyl group, an optionally substituted morpholinyl group, an optionally substituted dihydropyranyl group, an optionally substituted tetrahydropyranyl group, an optionally substituted pyridyl group, an optionally substituted phenyl ... preferably, the substituents in R2 or Cy are selected from the group consisting of C1-C6 alkyl groups, cyano groups, alkylsulfinyl groups, halogens, hydroxy groups, carboxy groups, amino groups and alkylsulfonyl groups; preferably, the number of substituents may be 1 to 3; more preferably, R2 or Cy is a pyrazolyl group optionally substituted by an unsubstituted C1-C6 alkyl group or a C1-C6 alkyl group substituted by 1 to 3 halogens; preferably, one or two ring N atoms of the pyrazolyl group are substituted; R3 is H; R4 is a C1-C4 alkyl group, preferably a methyl group.

[0072] In one or more preferred embodiments of formula I, A1 is N, A2 is N, A3 is C, A4 is CR5, A5 is CR5, and A6 is N; R1 is a heteroaryl group optionally substituted with one or two C1-C4 alkyl groups (preferably pyrazolyl, pyrrolyl, and imidazolyl groups), e.g., a pyrazolyl group optionally substituted with a C1-C3 alkyl group; R2 is a heteroaryl group optionally substituted with one or two C1-C4 alkyl groups (preferably pyrazolyl, pyridinyl, an aryl group (preferably a phenyl group) optionally substituted by one or two substituents selected from the group consisting of a pyrrolopyridinyl group, a pyrrolopyridinyl group, and an imidazolyl group, a C1-C4 alkylsulfonyl group, and a halogen, or a heterocyclic group (preferably a morpholinyl group) optionally substituted by one or two C1-C4 alkyl groups, for example a 2,6-diC1-C4 alkyl group-morpholinyl group; one of R3 and R4 is H and the other is a C1-C4 alkyl group; each R5 is independently H or a C1-C4 alkyl group, preferably H.

[0073] In one or more preferred embodiments of formula I, A1 is N, A2 is N, A3 is C, A4 is CR5, A5 is N, and A6 is CR5; R1 is a heteroaryl group optionally substituted by one to two C1-C4 alkyl groups (preferably a pyrazolyl group, a pyrrolyl group, and an imidazolyl group, more preferably a pyrazolyl group), e.g., a pyrazolyl group optionally substituted by a C1-C3 alkyl group; R2 is a heteroaryl group optionally substituted by one or two substituents selected from the group consisting of halogen, a C1-C4 alkylsulfonyl group, a C1-C4 alkylsulfinyl group, and a C1-C4 alkyl group optionally substituted by one to three halogen atoms. R3 and R4 are independently selected from the group consisting of H or a C1-C4 alkyl group; each R5 is independently H or a C1-C4 alkyl group, preferably H.

[0074] In one or more preferred embodiments of formula I, A1 is N, A2 is N, A3 is C, A4 is CR5, A5 is N, and A6 is CR5; R1 is a pyrazolyl group optionally substituted with a C1-C3 alkyl group; R2 is a pyrazolyl group optionally substituted with one or two substituents selected from the group consisting of unsubstituted C1-C4 alkyl groups and C1-C4 alkyl groups substituted with 1 to 3 halogen atoms; R3 and R4 are independently selected from the group consisting of H and a C1-C4 alkyl group; and each R5 is independently H or a C1-C4 alkyl group, preferably H. In a further preferred embodiment, R2 is a pyrazolyl group substituted by one or two substituents selected from the group consisting of unsubstituted C1-C4 alkyl groups and C1-C4 alkyl groups substituted by 1 to 3 halogen atoms, and at most one nitrogen atom of said pyrazolyl group is substituted by said substituent, preferably one nitrogen atom of said pyrazolyl group is substituted. In further or alternative embodiments, one of R3 and R4 is H and the other is a methyl group.

[0075] In one or more preferred embodiments of formula I, A1 and A4-A6 are independently N or CR5; A2 and A3 are independently C or N; R1 is a pyrazolyl group optionally substituted with a C1-C3 alkyl group; R2 is a pyrazolyl group optionally substituted with one or two substituents selected from the group consisting of unsubstituted C1-C4 alkyl groups and C1-C4 alkyl groups substituted with 1 to 3 halogen atoms; R3 and R4 are independently selected from the group consisting of H and a C1-C4 alkyl group; and each R5 is independently H or a C1-C4 alkyl group, preferably H.

[0076] In one or more of the above embodiments, preferred compounds of formula I include, but are not limited to, the following: (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine (Example 1); (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 2); (R)-3-methyl-4-(8-(1-ethyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 3); (R)-3-methyl-4-(8-(1-isopropyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 4); (R)-3-methyl-4-(8-(1-methyl-1H-imidazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 5);

[0077] (R)-3-methyl-4-(8-(6-methylpyridin-3-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 6); (R)-3-methyl-4-(8-(4-(methylsulfonyl)phenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 7); (R)-3-methyl-4-(8-(2-fluorophenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 8); (R)-3-methyl-4-(8-morpholinyl-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 9); (2S,6R)-2,6-dimethyl-4-(6-((R)-3-methylmorpholino)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine (Example 10);

[0078] 4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 11); 4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine (Example 12); (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 13); (R)-3-methyl-4-(3-(1H-pyrazol-5-yl)-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 14); (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine (Example 15);

[0079] (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (Example 16); (R)-3-methyl-4-(5-(methylsulfonyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolo[1,2-c]pyrimidin-3-yl)morpholine (Example 17); (R)-3-methyl-4-(1-(methylsulfonyl)-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,5-c]pyrimidin-7-yl)morpholine (Example 18); (R)-3-methyl-4-(6-(methylsulfonyl)-1-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolo[1,2-a]pyrazin-3-yl)morpholine (Example 19); (R)-3-methyl-4-(3-(methylsulfonyl)-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)morpholine (Example 20);

[0080] (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-3-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 21); (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-2-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 22); (R)-4-(7-(1H-imidazol-4-yl)-4-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 23); (R)-3-methyl-4-(4-(6-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 24); (R)-4-(4-(2-fluorophenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 25);

[0081] (R)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 26); (R)-4-(4,7-di(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 27); (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-2-yl)morpholine (Example 28); (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-3-yl)imidazo[5,1-f][1,2,4]triazin-2-yl)morpholine (Example 29); (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[3,4-f][1,2,4]triazin-6-yl)morpholine (Example 30);

[0082] (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5-a][1,3,5]triazin-2-yl)morpholine (Example 31); (R)-4-(4-cyclopropyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 32); (S)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 33); (3R,5R)-3,5-dimethyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 34); (R)-3-methyl-4-(4-(4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 35);

[0083] (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 36); (R)-4-(4-(1-ethyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 37); (R)-3-methyl-4-(4-(3-methyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 38); (R)-3-methyl-4-(7-(3-methyl-1H-pyrazol-5-yl)-4-(6-methylpyridin-3-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 39); (R)-4-(7-(1H-pyrazol-5-yl)-4-(o-tolyl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 40);

[0084] (R)-4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 41); (R)-3-methyl-4-(4-(2-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 42); (R)-4-(4-(3-fluoropyridin-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 43); (R)-3-methyl-4-(4-(4-methyl-6-(methylsulfonyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 44); (R)-3-methyl-4-(4-(4-methylpyrimidin-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 45);

[0085] (R)-3-methyl-4-(4-morpholino-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 46); (R)-4-(7-(1H-pyrazol-5-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 47); (R)-3-methyl-4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 48); (R)-3-methyl-4-(4-(2-methyl-4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 49); (3R)-3-methyl-4-(4-(2-methyl-6-(methylsulfinyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 50);

[0086] (R)-3-methyl-4-(4-(3-methylpyridin-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 51); (R)-3-(2-(3-methylmorpholino)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl)benzonitrile (Example 52); (R)-4-(4-(3,6-dihydro-2H-pyran-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 53); (R)-4-(7-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 54); (R)-4-(7-(1H-pyrazol-5-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 55);

[0087] (R)-4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 56); (R)-3-methyl-4-(4-(1-methyl-1H-imidazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 57); (R)-4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 58); (R)-4-(4-(1,5-dimethyl-1H-1,2,3-triazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 59); (R)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 60);

[0088] (R)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 61); (R)-4-(4-(1-(difluoromethyl)-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 62); (R)-4-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (Example 63);

[0089] or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof.

[0090] In the present disclosure, it is to be understood that A1-A6 should be selected such that the resulting ring satisfies valence theory. As used herein, the term "hydrogen (H)" includes its isotopes D and T.

[0091] As used herein, the term "alkyl group" refers to an alkyl group itself or to a straight or branched chain radical containing up to 10 carbon atoms. Useful alkyl groups include straight or branched chain C1-C 10 The alkyl group includes an alkyl group, preferably a C1-C6 alkyl group. In some embodiments, the alkyl group is a C1-C4 alkyl group. Exemplary C1-C 10 Alkyl groups include optionally substituted methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl, and octyl groups.

[0092] The term "alkenyl" as used herein refers to a straight or branched chain radical having 2 to 10 carbon atoms and at least one double bond between two carbon atoms in the chain, preferably a C2-C6 alkenyl group, unless the chain length is otherwise limited. Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.

[0093] The term "alkynyl" as used herein refers to a straight or branched chain radical having 2 to 10 carbon atoms and at least one triple bond between two carbon atoms in the chain, preferably a C2-C6 alkynyl group, unless the chain length is otherwise limited. Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl groups.

[0094] Useful alkoxy groups include those C1-C 10Alkyl groups include oxygen substituted with alkyl groups, preferably C1-C6 alkyl groups or C1-C4 alkyl groups, such as methoxy and ethoxy groups. The alkyl groups in the alkoxy groups may be optionally substituted. Substituents for the alkoxy groups include, but are not limited to, halogens, morpholino groups, amino groups (including alkylamino groups and dialkylamino groups), and carboxy groups (including esters thereof).

[0095] Useful alkylthio groups include those C1-C 10 It includes sulfur substituted with an alkyl group, preferably a C1-C6 alkyl group. The alkyl group in the alkylthio group may be optionally substituted. Also included are sulfoxides and sulfones of these alkylthio groups.

[0096] Useful amino and optionally substituted amino groups include -NH2, -NHR8 and -NR8R9, where R8 and R9 are each independently hydrogen, optionally substituted C1-C 10 an alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; or R8 and R9 together with the N to which they are attached form a 4-7 membered cyclic amino group optionally containing one or more (e.g., 2, 3) additional heteroatoms selected from O, N, and S, and optionally substituted.

[0097] The term "aryl group" as used herein alone or as part of another group refers to a monocyclic, bicyclic or tricyclic aromatic group containing from 6 to 14 carbon atoms. Aryl groups may be optionally substituted with one or more substituents as described herein.

[0098] Useful aryl groups include C6-C 14 Aryl groups, preferably C6-C 10 Contains aryl groups. Typical C6-C 14 Aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azuryl, biphenyl, biphenylene and fluorenyl groups.

[0099] The term "carbocyclic group" as used herein includes cycloalkyl groups and partially saturated carbocyclic groups. Useful cycloalkyl groups are C3-C8 cycloalkyl groups. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups. Carbocyclic groups may be substituted with one or more substituents as described herein.

[0100] Useful partially saturated carbocyclic groups include cycloalkenyl groups, for example C3-C8 cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl, and cyclooctenyl groups. Useful halo or halogen groups include fluoro, chloro, bromo and iodo.

[0101] Useful acylamino groups (acylamide groups) are any C1-C6 acyl groups (alkanoyl groups) attached to the nitrogen of an amino group, such as, for example, acetamino, propionamido, butanoylamido, pentanoylamido and hexanoylamido groups, as well as C1-C6 acylamino groups substituted with aryl groups, such as, for example, benzoylamido. Useful acyl groups include C1-C6 acyl groups, such as acetyl groups. The acyl group may be optionally substituted with a group selected from the group consisting of aryl groups and halo, with the proviso that the aryl group may be optionally substituted. When the acyl group is substituted with halo, the number of halogen substituents may be 1 to 5. Examples of substituted acyl groups include chloroacetyl and pentafluorobenzoyl groups.

[0102] Useful acyloxy groups are any C1-C6 acyl group (alkanoyl group) attached to oxygen (-O-), such as, for example, formyloxy, acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy, and hexanoyloxy.

[0103] The term "heterocycle (heterocyclic group)" as used herein refers to a saturated or partially saturated 3- to 7-membered monocyclic ring system or a 7- to 10-membered bicyclic ring system consisting of carbon atoms and one to four heteroatoms independently selected from O, N and S, provided that the nitrogen and / or sulfur heteroatoms may be optionally oxidized, the nitrogen may be optionally quaternized, and the term further includes any bicyclic ring system in which any heterocycle as defined above is fused to a benzene ring. The heterocycle may be substituted at a carbon or nitrogen atom if the resulting compound is stable. The heterocyclic group may be substituted with one or more substituents as described herein.

[0104] Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, 1,4-diazepanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetrahydroisoquinolinyl, tetronoyl and tetramoyl groups, which may be optionally substituted with one or more substituents described herein.

[0105] The term "heteroaryl group (heteroaromatic ring)" as used herein refers to a group having 5 to 14 ring atoms and having 6, 10 or 14 pi electrons shared in a ring. The ring atoms are carbon atoms and 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur. Heteroaryl groups may be optionally substituted with one or more substituents described herein.

[0106] Useful heteroaryl groups include thienyl (thiophenyl), benzo[d]isothiazol-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl, which is a 2-pyridyl group), Examples of aryl groups include, but are not limited to, pyridyl, 3-pyridyl and 4-pyridyl groups, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthaldinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, and carbazolyl groups. , β-carbolinyl group, phenanthridinyl group, acridinyl group, perimidinyl group, phenanthrolinyl group, phenazinyl group, isothiazolyl group, phenothiazinyl group, isoxazolyl group, furazanyl group, phenoxazinyl group, 1,4-dihydroquinoxaline-2,3-dione, 7-amino-isocoumarin, pyrido[1,2-a]pyrimidin-4-one, tetrahydrocyclopenta[c]pyrazole-3 -yl group, benzisoxazolyl group such as 1,2-benzoisoxazolyl-3-yl group, benzimidazolyl group, 2-oxindolyl group, thiadiazolyl group, 2-oxobenzimidazolyl group, imidazopyridazinyl group, imidazopyridyl group, triazolopyridazinyl group, pyrazolopyrimidinyl group, pyrrolopyrimidinyl group, pyrrolopyridyl group, pyrrolopyrazinyl group or triazolopyrazinyl group. When the heteroaryl group contains a nitrogen atom in the ring, the nitrogen atom may be in the form of an N-oxide, for example a pyridyl N-oxide, a pyrazinyl N-oxide and a pyrimidinyl N-oxide.

[0107] In this disclosure, unless otherwise specified, the substituted C-C 10An alkyl group, a cycloalkyl group, a heterocyclic alkyl group, an alkoxy group, a heterocyclic alkoxy group, an alkenyl group, a heterocyclic alkenyl group, an alkynyl group, an amino group, an acylamino group, an acyloxy group, a carboxy group, a hydroxy group, a thiol group, an alkylthio group, a sulfonyl group, a sulfinyl group, a silyl group, a phosphocarboxy group, a phosphonyl group, a carbocyclic group, a heterocyclic group, an aryl group or a heteroaryl group is not limited to a halogen atom, a hydroxy group, a carboxy group, an amino group, a nitro group, a cyano group, a C1-C6 acylamino group, a C1-C6 acyloxy group, a C1-C6 alkoxy group, an aryloxy group, an alkylthio group, a C1-C6 alkyl group, a C1-C6 acyl group, a C6-C 10 It may be substituted with one or more (e.g., 1, 2, 3, or 4) substituents selected from the group consisting of aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, heteroaryl, methylenedioxy, ureido, thiol, azido, carbonyl, alkylsulfonyl, aminosulfonyl, dialkylaminosulfonyl, and alkylsulfinyl. The substituents themselves may be optionally substituted. Preferred substituents include, but are not limited to, halo, hydroxy, carboxy, amino, C1-C6 acylamino, C1-C6 acyloxy, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 acyl, and alkylsulfonyl.

[0108] It is to be understood that in each embodiment, when the substituent is a heterocyclic, aryl or heteroaryl group, the number is typically one. Some of the compounds of the present disclosure may exist as stereoisomers, including optical isomers. The present disclosure includes all stereoisomers and racemic mixtures of those stereoisomers, as well as single enantiomers that can be separated by methods known to those of ordinary skill in the art.

[0109] Examples of pharma- ceutically acceptable salts include inorganic and organic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, and oxalate salts; as well as inorganic and organic base salts formed with bases such as sodium hydroxide, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methylglucamine.

[0110] Examples of prodrugs of the compounds of the present disclosure include simple esters of carboxylic acid-containing compounds (e.g., obtained by condensation with C1-C4 alcohols according to methods well known in the art); esters of hydroxy-containing compounds (e.g., obtained by condensation with C1-C4 carboxylic acids, C3-C6 dibasic acids or their anhydrides, such as succinic anhydride or fumaric anhydride, according to methods well known in the art); imines of amino-containing compounds (e.g., obtained by condensation with C1-C4 aldehydes or ketones according to methods well known in the art); carbamates of amino-containing compounds, such as those described in Leu et al., (J. Med. Chem. 42:3623-3628 (1999)) and Greenwald et al., (J. Med. Chem. 42:3657-3667 (1999)); and acetals and ketals of alcohol-containing compounds (e.g., obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether, according to methods well known in the art).

[0111] The present disclosure further includes all suitable isotopic variations of the compounds of the present disclosure or their pharma- ceutically acceptable salts. An isotopic variation of the compounds of the present disclosure or their pharma- ceutically acceptable salts is defined as an isotopic variation in which at least one atom is replaced by an atom with the same atomic number but a different atomic mass than that commonly found in nature. Isotopes that can be incorporated into the compounds of the present disclosure and their pharma- ceutically acceptable salts include H, C, N, and O, e.g. 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O.35 S, 18 F, 36 Cl and 125 Suitable isotopic variations of the compounds of the present disclosure or pharma- ceutically acceptable salts thereof can be prepared by conventional techniques using appropriate isotopic variations of suitable reagents.

[0112] The compounds of the present disclosure can be prepared using methods known to those skilled in the art or novel methods according to the present disclosure. The present disclosure further relates to novel methods for preparing these novel compounds of formula I, II, IIIa, IIIb or IV, as illustrated in Schemes 1-7. Specifically, the compounds of the present disclosure having formula I can be prepared as shown in the exemplary reaction in Scheme 1. 6-chloro-8-bromoimidazo[1,2-b]pyridazine, N-iodosuccinimide and trifluoroacetic acid are reacted in chloroform at room temperature to prepare 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine. 8-Bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine was prepared by the reaction of 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine with 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester under heating in a mixture of dioxane and water under the catalysis of potassium phosphate trihydrate and tetratriphenylphosphine·palladium. 6-Chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine was prepared by the reaction of 8-bromo-6-chloro-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester in a mixture of dioxane and water under heating, catalyzed by potassium phosphate trihydrate and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium.Catalyzed by sodium tert-butoxide and tris(dibenzylideneacetone)dipalladium, 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine was reacted with (R)-3-methylmorpholine in toluene with heating to prepare (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine. The target compound, (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine, was prepared by reacting (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine with concentrated hydrochloric acid in ethanol at room temperature.

[0113] [ka]

[0114] Other related compounds can be prepared similarly. For example, 1-methyl-1H-pyrazole-5-boronic acid pinacol ester was substituted with 1-methyl-1H-imidazole-5-boronic acid pinacol ester to prepare the target compound (R)-3-methyl-4-(8-(1-methyl-1H-imidazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine; 6-chloro-8-bromoimidazo[1,2-b]pyridazine was substituted with 8-bromo-6-chloroimidazo[1,2-a]pyridine to prepare the target compound (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine. was prepared; 1-methyl-1H-pyrazole-5-boronic acid pinacol ester was replaced by 6-methylpyridine-3-boronic acid pinacol ester to prepare the target compound (R)-3-methyl-4-(8-(6-methylpyridin-3-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine; 1-methyl-1H-pyrazole-5-boronic acid pinacol ester was replaced by 4-(methylsulfonyl)phenylboronic acid pinacol ester to prepare the target compound (R)-3-methyl-4-(8-(4-(methylsulfonyl)phenyl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine.

[0115] Compounds of the present disclosure can be prepared as shown in the exemplary reaction in Scheme 2. 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine, morpholine and DIEA were reacted in THF with heating to prepare 4-(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)morpholine. 4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine was prepared by reacting 4-(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)morpholine, 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester, Pd(PPh3)4, and aqueous K3PO4 in dioxane with heating. (3R)-3-Methyl-4-(8-morpholin-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine was prepared by reacting 4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine, (R)-3-methylmorpholine, t-BuONa, Pd(dba)2, and binaphthyl diphenyl phosphate with heating in toluene. The target compound, (R)-3-methyl-4-(8-morpholinyl-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine, was prepared by reacting (3R)-3-methyl-4-(8-morpholin-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine with HCl / methanol solution in methanol at room temperature.

[0116] [ka]

[0117] Other related compounds can be prepared in a similar manner, for example by substituting (2S,6R)-2,6-dimethylmorpholine for morpholine to prepare the target compound (2S,6R)-2,6-dimethyl-4-(6-((R)-3-methylmorpholino)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine.

[0118] Compounds of the present disclosure can be prepared as shown in the exemplary reaction scheme 3. 4-Bromo-1,2-dihydropyridazine-3,6-dione, (1-methyl-1H-pyrazol-5-yl)boronic acid, aqueous potassium phosphate and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2) were reacted with heating in N,N-dimethylformamide (DMF) to prepare 4-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydropyridazine-3,6-dione. 4-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydropyridazine-3,6-dione was reacted with phosphorus oxychloride with heating to prepare 3,6-dichloro-4-(1-methyl-1H-pyrazol-5-yl)pyridazine. (R)-4-(6-chloro-5-(1-methyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholine was prepared by reacting 3,6-dichloro-4-(1-methyl-1H-pyrazol-5-yl)pyridazine and (R)-3-methylmorpholine in N-methylpyrrolidone in the presence of N,N-diisopropylethylamine (DIEA) and CuBr with heating. (R)-4-(1-Methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazine-3-carbonitrile was prepared by reacting (R)-4-(6-chloro-5-(1-methyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholine with Zn(CN)2 catalyzed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (DPPF) and Pd2(dba)3 in DMF and a small amount of water with heating. (R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazine-3-yl)methylamine was prepared by reacting (R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazine-3-carbonitrile with Raney Ni catalysis at room temperature under hydrogen atmosphere.N-((4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholinyl)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide was prepared by reacting (R)-(4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholinyl)pyridazin-3-yl)methylamine with 1H-pyrazole-5-carboxylic acid in the presence of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and DIEA at room temperature in DMF. The target compound, (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine, was prepared by reacting N-((4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholinyl)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide with heating in POCl3.

[0119] [ka]

[0120] Other related compounds can be prepared in a similar manner. For example, the target compound 4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine was prepared by replacing morpholine with (R)-3-methylmorpholine; the target compound (4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-3-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine was prepared by replacing 1H-pyrazole-5-carboxylic acid with 1H-pyrrole-3-carboxylic acid; the target compound (R)-4-(7-(1H-imidazol-4-yl)-4 ... (1-Methyl-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine was prepared; (1-methyl-1H-pyrazol-5-yl)boronic acid was replaced with (6-methylpyridin-3-yl)boronic acid to prepare the target compound (R)-3-methyl-4-(4-(6-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (1-methyl-1H-pyrazol-5-yl)boronic acid was replaced with (2-fluorophenyl)boronic acid to prepare the target compound (R)-4-(4-(2-fluorophenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine.

[0121] Compounds of the present disclosure can be prepared as shown in the exemplary reaction scheme 4. 3,6-dichloropyridazin-4-amine, hexane-2,5-dione, and TsOH·H2O were reacted in toluene with heating to prepare 3,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine. 3,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine, (R)-3-methylmorpholine, and DIEA were reacted in NMP with heating to prepare (R)-4-(6-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazin-3-yl)-3-methylmorpholine. (R)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile was prepared by reacting (R)-4-(6-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazin-3-yl)-3-methylmorpholine, Zn(CN)2, 1,1'-bis(diphenylphosphino)ferrocene (DPPF), Pd2(dba)3, and water in DMF with heating. (R)-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methanamine was prepared by reacting (R)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile, H2, and Raney nickel in MeOH at room temperature. (R)-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methanamine, 1H-pyrazole-5-carboxylic acid, HATU and DIEA were reacted in DMF at room temperature, then K2CO3 was added and the mixture was reacted at room temperature to prepare (R)-N-((4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide.(R)-N-((4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide was reacted with heating in POCl3 to prepare (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine. (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine was reacted with heating in TFA / HO to prepare (R)-2-(3-methylmorpholino)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-ol. (R)-2-(3-methylmorpholino)-7-(1-((trifluoromethyl)sulfonyl)-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl trifluoromethanesulfonate was prepared by reacting (R)-2-(3-methylmorpholino)-7-(1-((trifluoromethyl)sulfonyl)-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl trifluoromethanesulfonate with TEA in dry DCM at 0 °C, then adding TfO and reacting the mixture at 0 °C to rt. The target compound, (R)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl trifluoromethanesulfonate, 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, K2CO3 and Pd(dppf)Cl2 were reacted in dioxane with heating, then aqueous LiOH was added and the mixture was reacted at room temperature to prepare the target compound, (R)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine.

[0122] [ka]

[0123] Other related compounds can be prepared in a similar manner. For example, the target compound (R)-4-(7-(1H-pyrazol-5-yl)-4-(o-tolyl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine was prepared by replacing 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 4,4,5,5-tetramethyl-2-(o-tolyl)-1,3,2-dioxaborolane; The target compound, (R)-4-(4-(3-fluoropyridin-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine, was prepared by replacing 1-isopropyl-5-(4,4 The target compound, (R)-3-methyl-4-(4-(4-methylpyrimidin-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine, was prepared by replacing 1-isopropyl-5-(4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine; The target compound, (R)-4-(7-(1H-pyrazol-5-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine, was prepared by replacing 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine.

[0124] Compounds of the present disclosure can be prepared as shown in the exemplary reaction scheme 5. 4,6-dichloro-3-methylpyridazine, (R)-3-methylmorpholine and DIEA were reacted with heating in methyl-2-pyrrolidone (NMP) to prepare (R)-4-(5-chloro-6-methylpyridazin-3-yl)-3-methylmorpholine. (R)-4-(5-chloro-6-methylpyridazin-3-yl)-3-methylmorpholine was reacted with SeO2 in 1,4-dioxane with heating to prepare (R)-4-chloro-6-(3-methylmorpholino)pyridazine-3-carbaldehyde. (R)-1-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)-N-(2,4-dimethoxybenzyl)methanamine was prepared by reacting (R)-4-chloro-6-(3-methylmorpholino)pyridazin-3-carbaldehyde, (2,4-dimethoxyphenyl)methanamine and AcOH in 1,1-dichloroethane (DCE) at room temperature, then adding NaBH(OAc)3 and reacting the mixture at room temperature. (R)-1-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)-N-(2,4-dimethoxybenzyl)methanamine was prepared by reacting (R)-1-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)-N-(2,4-dimethoxybenzyl)methanamine in TFA with heating. N-((4-chloro-6-((R)-3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide was prepared by reacting (R)-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)methanamine with 1H-pyrazole-5-carboxylic acid in the presence of HATU and DIEA in DMF at room temperature. N-((4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide was reacted with heating in POCl3 to prepare (R)-4-(4-chloro-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine.The target compound, (R)-4-(4-cyclopropyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine, was prepared by the reaction of (R)-4-(4-chloro-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine, cyclopropylboronic acid, and K3PO4·3H2O with Pd(OAc)2 and tricyclohexylphosphine catalysis in a mixed solvent of 1,4-dioxane and toluene under heating.

[0125] [ka]

[0126] Compounds of the present disclosure can be prepared as shown in the exemplary reaction in Scheme 6. 1-tetrahydropyran-2-ylpyrazole-3-carbaldehyde, 6-chloro-3-hydrazino-pyridazin-4-amine and PhI(OAc)2 were reacted in DCM at room temperature to prepare 6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine. 6-Chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine, HBr and t-BuONO were reacted in CH3CN at 0°C, then CuBr was added and the mixture was reacted at room temperature to prepare 8-bromo-6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine. 6-Chloro-8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine was prepared by reacting 8-bromo-6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine, (2-methylpyrazol-3-yl)boronic acid, Pd(PPh3)4 and aqueous K3PO4 solution in dioxane under nitrogen protection with heating. 6-Chloro-8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine and morpholine were reacted in sulfolane under nitrogen protection with heating to prepare 4-[8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]morpholine.The target compound, 4-[8-(2-methylpyrazol-3-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]morpholine, was prepared by reacting 4-[8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]morpholine with HCl / MeOH in MeOH at room temperature.

[0127] [ka]

[0128] Other related compounds can be prepared in a similar manner, for example by substituting (R)-3-methylmorpholine for morpholine to prepare the target compound (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)morpholine.

[0129] Compounds of the present disclosure can be prepared as shown in the exemplary reaction in Scheme 7. 5,7-dichloropyrazolo[1,5-a]pyrimidine, Pd(dppf)Cl2 and aqueous K3PO4 were reacted in dioxane with heating to prepare 5-chloro-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine. (R)-3-Methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine was prepared by reacting 5-chloro-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine, sodium tert-butoxide, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP) and tris(dibenzylideneacetone)dipalladium in toluene at room temperature under heating. (R)-4-(3-iodo-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine was prepared by reacting (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine, N-iodosuccinimide (NIS) and trifluoroacetic acid (TFA) in CHCl3 at room temperature. (3R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine was prepared by reacting (R)-4-(3-iodo-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine, 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, potassium phosphate trihydrate, and Pd(dppf)Cl2 with heating in a mixture of dioxane and water.The target compound, (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine, was prepared by reacting (3R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine, HCl / dioxane and water at room temperature.

[0130] [ka]

[0131] One gist of the present disclosure is the discovery that the compounds of formula I (including the compounds of formulas II, IIIa, IIIb and IV described herein) or their stereoisomers, tautomers, N-oxides, hydrates, isotopically substituted derivatives, solvates or pharma- ceutically acceptable salts, or mixtures thereof, or prodrugs thereof, are kinase inhibitors, particularly ATR kinase inhibitors.Accordingly, the compounds of formula I (including the compounds of formulas II, IIIa, IIIb and IV described herein) can be used to treat ATR kinase-mediated related diseases, such as cancer, or can be used to prepare medicaments for treating ATR kinase-mediated related diseases, such as cancer.

[0132] The present disclosure further provides a method for treating or preventing a kinase-mediated disease, particularly an ATR kinase-mediated related disease, comprising administering to a subject in need thereof (particularly a mammal, more particularly a human) an effective amount of a compound of formula I (including the compounds of formulas II, IIIa, IIIb and IV described herein) or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula I (including the compounds of formulas II, IIIa, IIIb and IV described herein) or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof. In the present disclosure, the kinase-mediated disease includes cancer, particularly an ATR kinase-mediated cancer. ATR kinase mediated diseases that can be treated or prevented by the methods or pharmaceutical compositions of the present disclosure include liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain tumors, malignant melanoma, and the like. These include, but are not limited to, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urinary system tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer.

[0133] The present disclosure further includes the use for treating or preventing other diseases caused by excessive or abnormal cell proliferation, including proliferative or hyperproliferative diseases such as myeloproliferative diseases, particularly those caused by excessive or abnormal cell proliferation mediated by ATR kinase. Accordingly, the present disclosure further includes the preparation of a medicament for treating or preventing other diseases caused by excessive or abnormal cell proliferation, particularly those caused by excessive or abnormal cell proliferation mediated by ATR kinase, using a compound of formula I (including the compounds of formulas II, IIIa, IIIb and IV as described herein) or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof.

[0134] In carrying out the treatment method, an effective amount of the pharmaceutical formulation is administered to an individual exhibiting one or more symptoms of these disorders. The pharmaceutical formulation comprises a therapeutically effective concentration of a compound of formula I, II, IIIa, IIIb or IV or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or mixtures thereof, or prodrugs thereof, formulated for oral, intravenous, local or topical administration for the treatment of cancer or other diseases. The amount is effective to improve or eliminate one or more symptoms of the disorder. An effective amount of a compound for treating a particular disease is an amount sufficient to improve or in some way alleviate symptoms associated with the disease. Such an amount may be administered once or according to an effective regimen. The amount may be administered to cure the disease, but is typically administered to improve symptoms of the disease. Repeated administration is typically required to achieve the desired improvement in symptoms.

[0135] In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula I, II, IIIa, IIIb or IV or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof as an ATR kinase inhibitor, and a pharma- ceutically acceptable carrier.

[0136] Another embodiment of the present disclosure relates to a pharmaceutical composition effective for treating cancer, comprising a compound of formula I, II, IIIa, IIIb or IV or its stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt, or mixtures thereof, or prodrugs thereof, in combination with at least one known anticancer drug or its pharma- ceutically acceptable salt. Specifically, the compounds of the present disclosure can be combined with other anticancer drugs related to DNA damage and repair mechanisms, including PARP inhibitors such as Olaparib, Niraprib, Rucaparib, Talazoparib and Senaparib; HDAC inhibitors such as Volinota, Romididesin, Papiseta and Bailesta. The compounds of the present disclosure can also be used in combination with other anti-cancer drugs associated with cell division detection sites, including Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as Paposinib, ATM inhibitors, Wee1 inhibitors, DNA-PK inhibitors, and the like.Other known anticancer drugs that can be used in combination anticancer therapy include 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, acanthocytic cytochrome P450, mitoxantrone, elliptinium, and etoposide; RNA / DNA antimetabolites such as 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine and methotrexate; DNA antimetabolites such as 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea and thioguanine; anti-mitochondrial agents such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel and docetaxel; mAbs, panitinib, riboflavin ... Antibodies such as ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, ofatumumab, dinatuximab, blinatumomab, ipilimumab, Avastin, Herceptin and MabThera; imatinib, gefitinib, erlotinib, osimertinib , afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, ponatinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cobimetinib, axitinib, temsirolimus, idelalisib, pazopanib, torisel and everolimus, and other kinase inhibitors.Other known anticancer drugs that can be used in the combination anticancer therapy include tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin 2), and sipuucel-T (a prostate cancer treatment vaccine).

[0137] In carrying out the method of the present disclosure, the compound of the present disclosure may be administered together with at least one known anti-cancer drug in a single pharmaceutical composition. Alternatively, the compound of the present disclosure may be administered separately from at least one known anti-cancer drug. In one embodiment, the compound of the present disclosure and at least one known anti-cancer drug are administered substantially simultaneously, i.e., all drugs are administered simultaneously or sequentially, as long as the compounds can reach therapeutic levels in blood at the same time. In another embodiment, the compound of the present disclosure and at least one known anti-cancer drug are administered according to separate administration schedules, as long as the compounds can reach therapeutic levels in blood.

[0138] Another embodiment of the present disclosure relates to a bioconjugate that functions as a kinase inhibitor and includes a compound described herein and is effective in inhibiting tumors. The tumor-inhibiting bioconjugate is comprised of a compound described herein and at least one known therapeutically useful antibody, such as trastuzumab or rituximab, a growth factor, such as EGF or FGF, a cytokine, such as IL-2 or IL-4, or any molecule that can bind to a cell surface. The antibody or other molecule can deliver the compound described herein to its target, making it an effective anti-cancer drug. The bioconjugate may also enhance the anti-cancer effect of therapeutically useful antibodies, such as trastuzumab or rituximab.

[0139] Another embodiment of the present disclosure relates to a pharmaceutical composition comprising a kinase inhibitor of formula I (including compounds of formulas II, IIIa, IIIb and IV as described herein) or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or mixtures thereof, or prodrugs thereof, effective for inhibiting tumors in combination with radiation therapy. In this embodiment, the compound of the present disclosure may be administered simultaneously with radiation therapy or at different times.

[0140] A further embodiment of the present disclosure relates to a pharmaceutical composition comprising a kinase inhibitor of Formula I, II, IIIa, IIIb or IV or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, or a prodrug thereof, which is effective for the post-operative treatment of cancer. The present disclosure further relates to a method of treating cancer by treating a mammal following surgical removal of a tumor with a pharmaceutical composition described herein.

[0141] The pharmaceutical compositions of the present disclosure include all pharmaceutical formulations containing the compounds of the present disclosure in an amount effective to achieve the intended purpose. While individual needs vary, one of ordinary skill in the art can determine the optimal amount of each component in a pharmaceutical formulation. Typically, the compound or a pharma- ceutically acceptable salt thereof can be orally administered to a mammal at a dosage of about 0.0025 to 50 mg per kg of body weight per day. Preferably, it is orally administered at about 0.01 mg / kg to about 10 mg / kg of body weight. If a known anti-cancer agent is also administered, it is administered in an amount effective to achieve its intended purpose. The optimal amount of such known anti-cancer agents is well known to those of ordinary skill in the art.

[0142] A unit oral dose may contain from about 0.01 to about 50 mg, preferably from about 0.1 to about 10 mg, of a compound of the present disclosure. The unit dose may be administered one or more times per day, each containing from about 0.1 to about 50 mg, conveniently about 0.25 to 10 mg, of a compound of the present disclosure or a solvate thereof.

[0143] In topical formulations, the compounds of the present disclosure may be present in a concentration of about 0.01 to 100 mg per gram of carrier. The compounds of the present disclosure may be administered as raw chemicals. The compounds of the present disclosure may also be administered as part of a suitable pharmaceutical formulation that contains a pharma- ceutically acceptable carrier (including excipients and adjuvants), which facilitates processing of the compounds into pharma- ceutical acceptable preparations. Preferably, pharmaceutical preparations, especially oral preparations, and those used for preferred administration such as tablets, dragees and capsules, as well as solutions suitable for injection or oral administration, contain about 0.01% to 99%, preferably about 0.25% to 75%, of the active compound together with the excipients.

[0144] Non-toxic pharmaceutically acceptable salts of the compounds of the present disclosure are also included within the scope of the present disclosure. Acid addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, etc. Base addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methylglucamine, etc.

[0145] The pharmaceutical formulations of the present disclosure can be administered to any mammalian subject capable of experiencing the therapeutic effects of the compounds of the present disclosure. Foremost among such mammals are humans and veterinary animals, although the present disclosure is not intended to be limited thereto.

[0146] The pharmaceutical formulations of the present disclosure can be administered by any means that achieves the intended purpose. For example, they can be administered parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, transdermally, buccally, intrathecally, intracranially, intranasally, topically, etc. Alternatively or simultaneously, they can be administered by oral route. The dosage depends on the age, health condition, weight of the recipient, type of concurrent treatment, frequency of treatment, and the nature of the effect desired.

[0147] The pharmaceutical preparations of the present disclosure can be prepared in a known manner, for example by conventional mixing, granulation, dragee preparation, dissolving or lyophilization processes. The pharmaceutical preparations for oral administration can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliary agents as necessary to obtain tablets or dragee cores.

[0148] Specifically, suitable excipients are fillers such as lactose, sucrose, mannitol, sorbitol, and the like, cellulose preparations and / or calcium phosphates such as tricalcium phosphate and calcium hydrogen phosphate; and starch pastes including corn starch, wheat starch, rice starch, potato starch, and binders such as gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If necessary, disintegrants such as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof (e.g., sodium alginate), in addition to the above starches, may be added. Specifically, auxiliary agents are flow regulators and lubricants such as silica, talc, stearic acid or a salt thereof, e.g., magnesium stearate, calcium stearate, and / or polyethylene glycol. Dragee cores are, if necessary, provided with a suitable coating that is resistant to gastric juices. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. To produce coatings that are resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used. Dyes and pigments can be added to the tablets or dragee coatings, for example, for identification or to characterize dose combinations of active compounds.

[0149] Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. The push-fit capsules may contain the active compound in the form of granules, which may be 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 fatty oils or liquid paraffin. Stabilizers may also be added.

[0150] Suitable formulations for parenteral administration include aqueous solutions of the active compound, for example aqueous solutions of water-soluble salts or alkaline solutions. In addition, suspensions of the active compound may be administered as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate, triglycerides or polyethylene glycol-400, or cremophor, or cyclodextrins. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, for example sodium carboxymethylcellulose, sorbitol, and / or dextran. They may also optionally contain suspension stabilizers.

[0151] According to one aspect of the present disclosure, the compounds of the present disclosure are incorporated into topical parenteral formulations and used to treat skin cancer. The topical formulations of the present disclosure are preferably formulated as oils, creams, lotions, ointments, etc., by selection of an appropriate carrier. Suitable carriers include vegetable oils, mineral oils, white petrolatum (white soft paraffin), branched chain oils, animal fats, and high molecular weight alcohols (C 12 The preferred carriers are those in which the active ingredient can be dissolved. Emulsifiers, stabilizers, humectants, antioxidants, and agents imparting color and fragrance, if desired, may be incorporated. In addition, percutaneous absorption enhancers may be applied to these topical preparations. Examples of such enhancers are described in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0152] The cream is preferably prepared by mixing a mixture of mineral oil, self-emulsifying beeswax, and water with the active ingredient dissolved in a small amount of oil, such as almond oil. A typical example of such a cream contains about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil, and about 1 part almond oil.

[0153] An ointment can be prepared by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment contains about 30% by weight of almond oil and about 70% by weight of white soft paraffin.

[0154] The present disclosure further includes the use of the compounds of the present disclosure to prepare medicaments for treating clinical conditions depending on the effect of inhibiting the activity of kinases, particularly ATR kinase. These medicaments may include the pharmaceutical compositions described above.

[0155] The following examples are intended to illustrate, but not limit, the methods and compositions of the present disclosure. Other suitable modifications and optimizations of the various conditions and parameters commonly encountered in clinical treatment will be apparent to those skilled in the art and are within the spirit and scope of the present disclosure. EXAMPLES

[0156] General Description All reagents were of commercial quality. Solvents were dried and purified by standard methods. Mass spectral analyses were recorded on a Platform II (Agilent 6110) quadrupole mass spectrometer equipped with an electrospray interface. 1 H NMR spectra were recorded at 400 MHz on a Brucker Ascend 400 instrument. Chemical shifts are reported in parts per million (ppm) downfield from TMS (0.00 ppm) and J coupling constants are reported in Hertz (Hz).

[0157] Example 1 (R)-3-Methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine

[0158] [ka]

[0159] a) Preparation of 8-bromo-6-chloro-3-iodoimidazo[1,2-a]pyridine: N-iodosuccinimide (3.94 g, 17.28 mmol) and trifluoroacetic acid (2.68 mL, 34.6 mmol) were added to a solution of 8-bromo-6-chloroimidazo[1,2-a]pyridine (4.0 g, 17.28 mmol) in chloroform (50 mL) at room temperature. The reaction solution was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (80 mL). The reaction solution was extracted with dichloromethane (50 mL x 3). The extract was washed with brine solution (50 mL x 2), dried over sodium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, dichloromethane:ethyl acetate = 1:0-7:3) to give the target product (5.5 g, 89% yield, yellow solid). LC-MS (ESI): m / z(M+H) + 356.62.

[0160] b) Preparation of 8-bromo-6-chloro-3-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine: Tetratriphenylphosphine·palladium (1.28 g, 1.11 mmol) was added to a mixture of 8-bromo-6-chloro-3-iodoimidazo[1,2-a]pyridine (3 g, 8.4 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (2.57 g, 9.24 mmol) and potassium phosphate trihydrate (4.41 g, 16.8 mmol) in dioxane (50 mL) and water (5 mL). The mixture was stirred at 80 °C for 18 h under the protection of nitrogen. Water (100 mL) was added and the mixture was extracted with dichloromethane (50 mL × 3). The extract was washed with brine solution (50 mL x 2), dried over sodium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, dichloromethane:ethyl acetate = 4:0-7:3) to give the target product (1.05 g, 40.1% yield, yellow solid). LC-MS (ESI): m / z (M+H) + 380.8.

[0161] c) Preparation of 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.38 g, 0.52 mmol) was added to a mixture of 8-bromo-6-chloro-3-(1-methyl-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine (1 g, 2.62 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.71 g, 3.40 mmol) and potassium phosphate trihydrate (1.4 g, 5.24 mmol) in dioxane (30 mL) and water (3 mL). The reaction mixture was stirred at 100° C. for 16 h under nitrogen protection. Water (50 mL) was added and the mixture was extracted with dichloromethane (50 mL×3). The extract was dried over sodium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, dichloromethane:ethyl acetate=4:1-0:1) to give the target product (0.8 g, 80.0% yield, yellow solid). LC-MS (ESI): m / z(M+H) + 383.0.

[0162] d) Preparation of (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine: under nitrogen protection, 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-a]pyridine (400 mg, 668.68 mmol) The above was slowly added to a solution of (R)-3-methylmorpholine (405.81 mg, 4.01 mmol), sodium tert-butoxide (257.05 mg, 2.67 mmol) and methanesulfonate (2-di-tert-butylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (53.12 mg, 66.87 mmol) in tert-amyl alcohol (8.00 mL). The atmosphere of the reaction system was replaced with nitrogen, and the reaction solution was stirred at 110°C for 0.5 hours, and the completion of the reaction was indicated by LCMS. The reaction solution was filtered and concentrated under reduced pressure to remove the organic solvent, and the crude product was obtained and purified by column chromatography (silica gel, ethyl acetate:methanol = 10:1) to obtain the target product (200 mg, crude product, yellow oil). LC-MS (ESI): m / z(M+H) + 448.2.

[0163] e) Preparation of (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine: (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-6-yl)morpholine (200 mg, crude product) was dissolved in methanol (2 mL) at room temperature, followed by dropwise addition of 4M hydrochloric acid in dioxane (5 mL). The reaction was stirred at 10° C. for 0.5 h. Complete consumption of the starting material and formation of the product were monitored by LCMS. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the crude product was obtained and purified by preparative chromatography (C18 silica gel column, 150×25 mm, 5 μm, 13-38% acetonitrile / 0.05% ammonia as mobile phase) to give the target product (9 mg, 5.6% yield, white solid). LC-MS (ESI): m / z(M+H) + 364.2. 1 H NMR (400 MHz, DMSO-d6): δ 13.15 (s, 1H), 9.03 (d, J = 1.8 Hz, 1H), 8.00 (s, 1H), 7.92 (s, 2H), 7.54 (s, 1H), 7.40 (d, J = 2.0 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 3.95 - 3.88 (m, 1H), 3.85 (s, 3H), 3.80 - 3.70 (m, 2H), 3.68 - 3.60 (m, 2H), 3.22 - 2.95 (m, 2H), 0.99 (d, J = 6.8 Hz, 3H).

[0164] Example 2 (R)-3-Methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine a) Preparation of 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine: N-iodosuccinimide (7.25 g, 32.25 mmol) and trifluoroacetic acid (3.35 mL, 43 mmol) were added to a solution of 6-chloro-8-bromoimidazo[1,2-b]pyridazine (5 g, 21.5 mmol) in chloroform (90 mL) at room temperature. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with dichloromethane (50 mL x 3). The extract was washed with brine solution (50 mL x 2), dried over sodium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, dichloromethane:ethyl acetate = 1:0-49:1) to obtain the target product (5.2 g, 67.7% yield, yellow solid). LC-MS (ESI): m / z(M+H) + 357.57.

[0165] b) Preparation of 8-bromo-6-chloro-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine: Tetrakistriphenylphosphine·palladium (1.67 g, 1.45 mmol) was added to a mixture of 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine (4 g, 14.51 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (4.03 g, 14.51 mmol) and potassium phosphate trihydrate (5.94 g, 22.32 mmol) in dioxane (50 mL) and water (5 mL). The reaction solution was stirred at 90° C. under nitrogen protection for 16 hours, then water (50 mL) was added and the mixture was extracted with dichloromethane (50 mL×3). The extract was washed with brine solution (50 mL×2), dried over sodium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, dichloromethane:ethyl acetate=1:0-4:1) to give the target product (0.93 g, 16.7% yield, yellow solid). LC-MS (ESI): m / z(M+H) + 381.80.

[0166] c) Preparation of 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.36 g, 0.47 mmol) was dissolved in 8-bromo-6-chloro-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine. A solution of 1H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine (0.93 g, 2.43 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (0.66 g, 3.16 mmol) and potassium phosphate trihydrate (1.29 g, 4.86 mmol) in a mixture of dioxane (20 mL) and water (2 mL) was added. The reaction was stirred at 100° C. under nitrogen protection for 16 hours, then water (30 mL) was added and the mixture was extracted with dichloromethane (50 mL×3). The extract was dried over sodium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=10:1-1:1) to give the target product (0.5 g, 53.8% yield, yellow solid). LC-MS (ESI): m / z(M+H) + 383.80.

[0167] d) Preparation of (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine: 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazine (500 mg, (R)-3-methylmorpholine (657.48 mg, 6.5 mmol) were dissolved in toluene (10 mL) at room temperature, and then sodium tert-butoxide (249.86 mg, 2.6 mmol), tris(dibenzylideneacetone)dipalladium (119.04 mg, 0.3 mmol) and 2,2'-bis-(diphenylphosphino)-1,1'-binaphthylene (161.89 mg, 0.26 mmol) were added. Under the protection of nitrogen, the reaction solution was stirred at reflux for 16 hours. The reaction solution was diluted with toluene (50 mL) and then filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1-0:1) to obtain the target product (0.12 g, 20.6% yield, yellow solid). LC-MS (ESI): m / z(M+H) + 449.15.

[0168] e) Preparation of (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine: Concentrated hydrochloric acid (1 mL) was added to an ethanol solution (10 mL) of (3R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (120 mg, 0.27 mmol) at room temperature. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain a residue, which was dissolved in methanol (2 mL) and one drop of ammonia solution was added. The mixture was purified by preparative liquid chromatography (C18 column, 0-100% acetonitrile / water as mobile phase) to give the target product (5.5 mg, 5.6% yield, yellow solid).

[0169] The compounds of Examples 3 to 8 below were prepared by a synthetic process similar to that described in Example 2 starting from 6-chloro-8-bromoimidazo[1,2-b]pyridazine, N-iodosuccinimide, 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester, the corresponding aryl or heteroaryl boronic acid pinacol ester and (R)-3-methylmorpholine.

[0170] [ka]

[0171] [Table A]

[0172] [Table B]

[0173] Example 9 (R)-3-Methyl-4-(8-morpholino-3-(1H-pyrazol-5-yl) Imidazo[1,2-b]pyridazin-6-yl)morpholine

[0174] [ka]

[0175] a) Preparation of 4-(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)morpholine: After replacing the atmosphere of the reaction system with nitrogen three times, a mixture of 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine (2.5 g, 6.98 mmol), morpholine (729.32 mg, 8.37 mmol, 736.69 uL) and DIEA (1.98 g, 15.35 mmol, 2.67 mL) in THF (50 mL) was stirred at 80° C. under nitrogen atmosphere for 12 hours. The reaction mixture was diluted with EA (100 mL), washed with saturated brine solution (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was washed with methyl tert-butyl ether (MTBE, 30 mL) to give the target compound (2.5 g, yellow solid, yield 98.30%). LC-MS (ESI): m / z (M+H) + 364.9.

[0176] b) Preparation of 4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine: The atmosphere of the reaction system was replaced with nitrogen three times, and then a mixture of 4-(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)morpholine (2.5 g, 6.86 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (2.10 g, 7.54 mmol), Pd(PPh3)4 (792.41 mg, 685.74 umol) and K3PO4 aqueous solution (3 M, 6.86 mL) in dioxane (35 mL) was stirred at 90 °C under nitrogen atmosphere for 8 hours. The reaction mixture was diluted with EA (50 mL), washed with saturated brine solution (35 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by flash silica gel chromatography (ISCOR; 40 g Sepa FlashR silica flash column, elution gradient 0-10% EA / PE, @50 mL / min) to give the target product (0.94 g, white solid, 35.25% yield). LC-MS (ESI): m / z (M+H) + 389.2.

[0177] c) Preparation of (3R)-3-methyl-4-(8-morpholin-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine: The atmosphere of the reaction system was replaced with nitrogen three times, and then 4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine (0.94%) was obtained. A toluene solution (30 mL) of a mixture of (R)-3-methylmorpholine (1.22 g, 12.09 mmol), t-BuONa (464.64 mg, 4.83 mmol), Pd(dba)2 (278.00 mg, 483.48 umol) and 1.1'-binaphthyl-2.2'-diphenylphosphine (BINAP, 301.05 mg, 483.48 μmol) was stirred at 100 °C under nitrogen atmosphere for 18 hours. The reaction mixture was diluted with EA (50 mL), washed with saturated brine solution (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by flash silica gel chromatography (ISCOR; 20 g Sepa FlashR silica flash column, elution gradient 0-20% EA / PE, @50 mL / min) to give the target product (0.18 g, yellow solid, 16.42% yield). LC-MS (ESI): m / z (M+H) + 454.2.

[0178] d) Preparation of (R)-3-methyl-4-(8-morpholino-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine: HCl / methanol solution (4M, 4.41 mL) was added to a methanol solution (4.5 mL) of (3R)-3-methyl-4-(8-morpholin-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (0.16 g, 352.78 umol). The resulting mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in methanol (20 mL). The pH of the mixture was adjusted to 7 with saturated aqueous sodium bicarbonate, and then the mixture was concentrated under reduced pressure to obtain the crude product, which was purified by preparative high performance liquid chromatography column (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 17%-47%, 10min) to obtain the target compound (25mg, off-white solid, yield 19.03%, purity 99.19%). LC-MS (ESI): m / z(M+H) + 370.1. 1 H NMR (400MHz, CD3OD): δ 7.85 (s, 1H), 7.74 (d, J= 2.4 Hz, 1H), 7.12 (d, J= 2.0 Hz, 1H), 6.22 (s, 1H), 4.27 (m, 1H), 4.03 (dd, J= 3.2, SFC: ee%, 100%.

[0179] Example 10 (2S,6R)-2,6-Dimethyl-4-(6-((R)-3-methylmorpholino)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-8-yl)morpholine

[0180] [ka]

[0181] The compound of Example 10 was prepared by a synthetic process similar to that described in Example 9. LC-MS (ESI): m / z(M+H) + 398.4. 1 H NMR (400MHz, CD3OD): δ 7.82 (s, 1H), 7.80 - 7.59 (m, 1H), 7.21 - 7.01 (m, 1H), 6.13 (s, 1H), 4.60 (s, 1H), 4.49 - 4.39 (m, 2H), 4.27 - 4.24 (m, 1H), 4.02 (dd, J= 3.2, 11.6 Hz, 1H), 3.94 - 3.85 (m, 2H), 3.83 - 3.74 (m, 3H), 3.70 - 3.64 (m, 1H), 3.36 (dd, J= 4.0, 12.8 Hz, 1H), 2.63 - 2.55 (m, 2H), 1.30 - 1.25 (m, 9H).

[0182] Example 11 4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine

[0183] [ka]

[0184] The compound of Example 11 was prepared by a synthetic process similar to that described in Example 13. Yellow solid. LC-MS (ESI): m / z (M+H) + 351.30. 1H NMR (400 MHz, DMSO-d6): δ 7.73 (s, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.44 (s, 1H), 7.14 (d, J = 1.3 Hz, 1H), 7.01 (s, 1H), 6.81 (d, J = 1.6 Hz, 1H), 3.97 (s, 3H), 3.83 - 3.74 (m, 4H), 3.63 - 3.57 (m, 4H).

[0185] Example 12 4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazole -5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)mol Holin

[0186] [ka]

[0187] a) Preparation of 6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-8-amine: A solution of 1-tetrahydropyran-2-ylpyrazole-3-carbaldehyde (10.16 g, 56.40 mmol) and 6-chloro-3-hydrazino-pyridazin-4-amine (9 g, 56.40 mmol) in DCM (120 mL) was stirred at 10-20 °C for 1 h. Then, PhI(OAc)2 (30.88 g, 95.88 mmol) was added to the mixture at 0 °C and stirred at 10-20 °C for 12 h. The reaction mixture was diluted with brine (800 mL) and extracted with DCM (400 mL × 3). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCOR; SepaFlash® silica flash column at 100 x g, elution with 0-100% ethyl acetate / petroleum ether gradient, PE:EA=1:3) to give the target product (8.7 g, yellow solid, 16.08% yield). LC-MS (ESI): m / z (M+H)+ 319.9.

[0188] b) Preparation of 8-bromo-6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine: To a mixture of 6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (0.9 g, 2.81 mmol) in CH3CN (15 mL), HBr (69.01 mg, 281.47 umol, 46.32 uL, 33% purity), t-BuONO (493.43 mg, 4.79 mmol, 569.12 uL) were added, and the mixture was stirred at 0° C. for 0.5 hours. Then, CuBr (605.65 mg, 4.22 mmol, 128.59 uL) was added. The mixture was stirred at 10-20 °C for 12 h. The reaction mixture was diluted with H2O (80 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give the target product (380 mg, black solid, 7.04% yield). LC-MS (ESI): m / z (M+H) + 382.8. 1 H NMR (400MHz, DMSO-d6): δ 7.82 (d, J= 2.4 Hz, 1H), 7.44 (s, 1H), 7.44 (d, J= 3.2 Hz, 1H), 5.63 - 5.60 (m, 1H), 4.12 - 4.09 (m, 1H), 3.78 - 3.72 (m, 1H), 2.21 - 2.10 (m, 3H), 1.76 - 1.61 (m, 3H).

[0189] c) Preparation of 6-chloro-8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine: 8-Bromo-6-chloro-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 312.80 umo To a solution of (2-methylpyrazol-3-yl)boronic acid (39.39 mg, 312.80 umol) in dioxane (6 mL) was added Pd(PPh3)4 (36.15 mg, 31.28 umol) and aqueous K3PO4 (2M, 469.20 uL) at 10-20 °C, then the suspension was degassed under vacuum, purged with N2 several times, and stirred at 100-110 °C for 1.5 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-TLC (SiO2, PE:EA = 1:3) to give the target product (90 mg, yellow solid). LC-MS (ESI): m / z (M+H) + 384.9.

[0190] d) Preparation of 4-[8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]morpholine: A solution of 6-chloro-8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine (20 mg, 51.97 umol) and morpholine (22.64 mg, 259.86 umol, 22.87 uL) in sulfolane (0.5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 120-130 °C under N2 atmosphere for 3 h. The reaction mixture was purified by pre-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (0.05% HCl)-ACN]; B%: 24%-44%, 7min) to give the target product (97mg, yellow solid). LC-MS (ESI): m / z (M+H)+ 436.0.

[0191] e) Preparation of 4-[8-(2-methylpyrazol-3-yl)-3-(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]morpholine: To a solution of 4-[8-(2-methylpyrazol-3-yl)-3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]morpholine (40 mg, 91.85 umol) in MeOH (1.2 mL), HCl / MeOH (4 M, 229.63 uL) was added at 0° C., and the mixture was stirred at 25° C. for 15 hours. The reaction mixture was filtered and the cake was washed with EtOAc (0.5 mL×2) to obtain the target compound (57.42 mg, yellow solid, 86.91% yield). LC-MS (ESI): m / z (M+H) + 352.1. 1 H NMR (400MHz, DMSO-d6): δ 7.94 (d, J= 2.0 Hz, 1H), 7.60 (d, J= 2.0 Hz, 1H), 7.54 (s, 1H), 7.21 (d, J= 2.0 Hz, 1H), 6.94 (d, J= 2.0 Hz, 1H), 4.03 (s, 3H), 3.80 - 3.77 (m, 4H), 3.66 - 3.64 (m, 4H).

[0192] Example 13 (R)-3-Methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7 -(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)molybdate Ruholin

[0193] [ka]

[0194] a) Preparation of 4-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydropyridazine-3,6-dione: 4-Bromo-1,2-dihydropyridazine-3,6-dione (4.0 g, 20.94 mmol), (1-methyl-1H-pyrazol-5-yl)boronic acid (5.23 g, 41.90 mmol) and potassium phosphate aqueous solution (aq. K3PO4, 63 mL, 1 M) were dissolved in N,N-dimethylformamide (DMF, 60 mL). Air in the reaction valve was replaced with nitrogen, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2, 1.67 g, 2.09 mmol) was added under the protection of nitrogen. The resulting mixture was reacted at 100° C. for 16 hours, then the reaction mixture was concentrated to remove the solvent to obtain the crude product, which was washed with dichloromethane (DCM, 100 mL) to obtain the crude product of the target product (15.0 g, black solid). LC-MS (ESI): m / z (M+H) + 193.25.

[0195] b) Preparation of 3,6-dichloro-4-(1-methyl-1H-pyrazol-5-yl)pyridazine: 4-(1-methyl-1H-pyrazol-5-yl)-1,2-dihydropyridazine-3,6-dione (15.0 g, crude product, 20.94 mmol) was dissolved in phosphorus oxychloride (POCl3, 150 mL), and the mixture was heated to 100 °C and stirred for 16 h. The phosphorus oxychloride was removed to obtain the crude product, which was purified by silica gel column chromatography (EtOAc / PE, 10-30%) to give the target product (2.63 g, white solid, 55% yield for two steps). LC-MS (ESI): m / z(M+H) + 229.15. 1 H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 1.3 Hz, 1H), 7.51 (s, 1H), 6.49 (d, J = 1.3 Hz, 1H), 3.83 (s, 3H).

[0196] c) Preparation of (R)-4-(6-chloro-5-(1-methyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholine: (R)-3-methylmorpholine (1.58 g, 11.53 mmol), CuBr (3.63 g, 25.37 mmol) and N,N-diisopropylethylamine (DIEA, 2.15 g, 15.5 mmol) were added to a solution of 3,6-dichloro-4-(1-methyl-1H-pyrazol-5-yl)pyridazine (2.63 g, 11.53 mmol) in N-methylpyrrolidone (NMP, 50 mL). The resulting mixture was stirred at 150° C. for 16 h. The reaction was quenched with water (50 mL) and the mixture was diluted with dichloromethane (DCM, 100 mL). The organic phase was washed with water (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (EtOAc / PE, 5-20%) to give the target product (1.65 g, light red solid, 49% yield). LC-MS (ESI): m / z(M+H) + 294.25. 1 H NMR (400 MHz, CDCl3): δ 7.60 (s, 1H), 6.79 (s, 1H), 6.40 (s, 1H), 4.36 - 4.27 (m, 1H), 4.06 (dd, J = 11.4, 3.3 Hz, 1H), 3.97 (dd, J = 13.3, 2.0 Hz, 1H), 3.86 - 3.82 (m, 1H), 3.80 (s, 3H), 3.65 (td, J = 12.0, 3.0 Hz, 1H), 3.36 (td, J = 12.5, 3.7 Hz, 1H), 1.33 (d, J = 6.7Hz, 3H).

[0197] d) Preparation of (R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile: Zn(CN)2 (0.4 g, 3.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (DPPF, 0.2 g, 0.36 mmol), Pd2(dba)3 (160 mg, 0.17 mmol) and 3 drops of water were added to a solution of (R)-4-(6-chloro-5-(1-methyl-1H-pyrazol-5-yl)pyridazin-3-yl)-3-methylmorpholine (0.5 g, 1.7 mmol) in DMF (10 mL). The resulting mixture was stirred at 150 °C for 6 h. The reaction mixture was concentrated under reduced pressure to remove the solvent to obtain the crude product, which was purified by silica gel column chromatography (EtOAc / PE, 10-40%) to give the target product (0.4 g, light red oil, 82% yield). LC-MS (ESI): m / z(M+H) + 285.30. 1 H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 1.8 Hz, 1H), 6.66 (s, 1H), 6.53 (d, J = 1.8 Hz, 1H), 4.54 - 4.43 (m, 1H), 4.23 - 4.13 (m, 1H), 4.08 (dd, J = 14.8, 5.7 Hz, 1H), 3.89 (s, 3H), 3.84 (brs, 1H), 3.78 (dd, J = 12.0, 2.8 Hz, 1H), 3.64 (td, J = 12.4, 2.8 Hz, 1H), 3.49 - 3.38 (m, 1H), 1.38 (d, J = 6.8 Hz, 3H).

[0198] e) Preparation of (R)-(4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazin-3-yl)carbonitrile: Raney nickel (~0.3 g) was added to a solution of (R)-4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile (0.22 g, 0.77 mmol) in MeOH (7 mL). The resulting mixture was stirred at room temperature with hydrogen for 16 h. After the reaction was completed, the resulting mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product, which was purified by a preparative high-performance liquid chromatography column (C18, CH3CN / H2O, 5~30%, with 0.1% TFA) to obtain the target product (0.1 g, colorless oil, 45% yield). LC-MS (ESI): m / z(M+H) + 289.30. 1 H NMR (400 MHz, CD3OD): δ 7.61 (s, 1H), 7.32 (s, 1H), 6.51 (s, 1H), 4.47 - 4.38 (m, 1H), 4.14 (s, 2H), 4.00 (dt, J = 16.5, 9.0 Hz, 2H), 3.85 - 3.72 (m, 4H), 3.63 (dd, J = 16.4, 7.3 Hz, 1H), 3.33 (brs, 2H), 1.28 (d, J = 6.4 Hz, 3H).

[0199] f) Preparation of N-((4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-formamide: 1H-pyrazole-5-carboxylic acid (0.05 g, 0.35 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 200 mg, 0.75 mmol) and DIEA (0.12 g, 0.87 mmol) were added to a DMF solution (5 mL) of (R)-(4-(1-methyl-1H-pyrazol-5-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methylamine (0.1 g, 0.35 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was distilled under reduced pressure to remove the solvent, and the crude product was purified by preparative thin layer chromatography (DCM:MeOH=20:1) to give the target product (0.085 g, white solid, 64% yield). LC-MS (ESI): m / z(M+H) + 383.35. 1 H NMR (400 MHz, CDCl3): δ 10.40 (s, 1H), 8.73 (s, 1H), 7.62 - 7.52 (m, 2H), 6.82 - 6.72 (m, 2H), 6.45 (s, 1H), 4.58 (d, J = 5.5 Hz, 2H), 4.36 - 4.25 (m, 1H), 4.02 (ddd, J = 22.3, 12.2, 2.6 Hz, 1H), 3.79 (s, 3H), 3.64 (ddd, J = 15.7, 12.1, 5.0 Hz, 2H), 3.40 - 3.30 (m, 1H), 3.16 - 3.05 (m, 2H), 1.31 (d, J = 6.9 Hz, 3H).

[0200] g) Preparation of (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine: N-((4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-formamide (0.085 g, 0.22 mmol) in POCl3 (5 mL) was stirred at 150 °C for 3 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and the crude product was obtained and purified by a preparative high-performance liquid chromatography column (C18, CH3CN / H2O, 15-45%, with 0.1% TFA) to obtain the target compound (0.02 g, yellow solid, 25% yield). LC-MS (ESI): m / z(M+H) + 365.25. 1 H NMR (400 MHz, CD3OD): δ 7.93 (s, 1H), 7.84 (s, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.40 (d, J = 1.0 Hz, 1H), 7.27 (s, 1H), 6.80 (d, J = 1.7 Hz, 1H), 4.46 (d, J = 6.3 Hz, 1H), 4.11 - 4.02 (m, 2H), 4.00 (s, 3H), 3.87 - 3.80 (m, 2H), 3.68 (td, J = 11.6, 3.0 Hz, 1H), 3.56 - 3.44 (m, 1H), 1.41 (d, J = 6.8 Hz, 3H).

[0201] Example 14 (R)-3-Methyl-4-(3-(1H-pyrazol-5-yl)-8-(1H-pyridyl) (2,3-b)pyridin-4-yl)imidazo[1,2-b]pyridazine-6-yl morpholine

[0202] [ka]

[0203] The compound of Example 14 was prepared by a synthetic process similar to that described in Example 2.

[0204] Example 15 (R)-3-Methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3 -(1H-pyrazol-5-yl)-[1,2,4]triazolo[4,3-b]pyrida Din-6-yl)morpholine

[0205] [ka]

[0206] The compound of Example 15 was prepared by a synthetic process similar to that described in Example 12. Off-white solid. LC-MS (ESI): m / z(M+H) + 366.1. 1 H NMR (400 MHz, CD3OD): δ 7.88 (br, s, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.41 (s, 1H), 7.28 (s, 1H), 6.88 (d, J = 1.6 Hz, 1H), 4.42 (d, J = 6.4 Hz, 1H), 4.08 - 4.05 (m, 1H), 4.03 (s, 3H), 4.00 - 3.97 (m, 1H), 3.85 (s, 2H), 3.72 - 3.72 (m, 1H), 3.46 - 3.41 (m, 1H), 1.39 (d, J = 6.8 Hz, 3H).

[0207] Example 16 (R)-3-Methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3 -(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)molybdate Ruholin

[0208] [ka]

[0209] a) Preparation of 5-chloro-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine: To a solution of 5,7-dichloropyrazolo[1,5-a]pyrimidine (5g, 26, 59mmol) in dioxane (100mL) was added Pd(dppf)Cl2 and K3PO4 aqueous solution (14.16g, 53.19mmol, 10mL) at room temperature. The mixture was stirred at 80°C for 16 hours under the protection of nitrogen. After completion of the reaction, the reaction solution was cooled to room temperature and water (100mL) was added. The mixture was extracted with EtOAc (100Ml x 2), the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc = 50 / 1 to 3 / 1) to give the target product (3.35g, yellow solid, 53.91% yield). LC-MS (ESI): m / z (M+H) + 234.30.

[0210] b) Preparation of (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine: To a solution of 5-chloro-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine (500 mg, 2.14 mmol) in toluene (30 mL) was added sodium tert-butoxide (514.11 mg, 5.35 mmol), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP, 133.24 mg, 213.99 mmol) and tris(dibenzylideneacetone)dipalladium (195.95 mg, 213.99 mmol) at room temperature. The reaction was stirred at reflux under the protection of nitrogen for 16 hours. The mixture was cooled to room temperature and extracted with EtOAc (100 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc=20 / 1 to 3 / 1) to give the target product (69 mg, yellow solid, 10.9% yield). 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 6.64 (d, J = 1.9 Hz, 1H), 6.33 (s, 1H), 6.22 (d, J = 2.2 Hz, 1H), 4.34 (d, J = 6.3Hz, 1H), 4.06 (s, 2H), 3.89 (s, 3H), 3.81 (s, 2H), 3.65 - 3.58 (m, 1H), 3.39 - 3.32 (m, 1H), 1.36 (d, J = 6.8 Hz, 3H).

[0211] c) Preparation of (R)-4-(3-iodo-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine: (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (59 mg, 197.76 μmol) in CHCl3 solution (5 mL) was added with N-iodosuccinimide (NIS, 40 mg, 177.98 μmol) and trifluoroacetic acid (TFA, 22, 55 mg, 197.76 μmol) at room temperature. The resulting liquid was stirred at room temperature for 2 hours and quenched with saturated sodium bicarbonate (5 mL). The reaction mixture was concentrated to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc = 20 / 1 to 3 / 1) to give the target product (59 mg, yellow solid, 70.3% yield). LC-MS (ESI): (M+H) + : 425.4. 1H NMR (400 MHz, CDCl3): δ 7.90 (s, 1H), 7.62 (d, J = 1.9 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 6.33 (s, 1H), 4.38 (s, 1H), 4.22 (d, J = 13.4 Hz, 1H), 4.07 (dd, J =11.5, 3.8 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 2H), 3.62 (td, J = 11.9, 3.0 Hz, 1H), 3.42 - 3.34 (m, 1H), 1.25 (d, J = 3.7Hz, 3H).

[0212] d) Preparation of (3R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine: (R)-4-(3-iodo-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3-methylmorpholine (33 mg, 77.79 μl) To a solution of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (64.91 mg, 233.36 μmol), potassium phosphate trihydrate (41.43 mg, 155.57 μmol) in a mixed solvent of dioxane (8 mL) and water (1.5 mL), Pd(dppf)Cl2 (5.69 mg, 7.78 μmol) was added. The mixture was stirred at 82 °C for 2 h. After completion of the reaction, the reaction solution was concentrated to obtain the crude product, which was purified by column chromatography (SiO2, PE / EtOAc = 20 / 1 to 3 / 1) to obtain the target product (30 mg, yellow solid, 86.0% yield). LC-MS (ESI): m / z (M+H) + : 449.47.

[0213] e) Preparation of (R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine: A mixture of (3R)-3-methyl-4-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (30 mg, 66.89 μmol), 4M HCl / dioxane (1 mL) and water (1 mL) was stirred at room temperature for 2 hours, and then the mixture was concentrated under reduced pressure. The pH value was adjusted to 8 with one drop of ammonium hydroxide. The mixed liquid was purified by pre-HPLC (C18 column, 0-100% acetonitrile / water as mobile phase) to obtain the title compound (6.5 mg, yellow solid, 26.67%). LC-MS (ESI): m / z(M+H) + 365.1. 1 H NMR (400MHz, MeOD): δ 8.28 (s, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.63 (br d, J = 1.2 Hz, 1H), 6.90 - 6.83 (m, 1H), 6.80 (s, 1H), 6.76 (d, J = 2.0 Hz, 1H), 4.65 - 4.57 (m, 1H), 4.25 (d, J = 12.8 Hz, 1H), 4.05 (dd, J = 3.6, 11.6 Hz, 1H), 3.86 (s, 4H), 3.81 - 3.75 (m, 1H), 3.64 (dt, J = 2.8, 12.0 Hz, 1H), 3.42 (dt, J = 3.6, 12.8 Hz, 1H), 1.39 (d, J = 6.8 Hz, 3H).

[0214] Example 17 (R)-3-Methyl-4-(5-(methylsulfonyl)-1-(1H-pyrrolo[2, 3-b]pyridin-4-yl)pyrrolo[1,2-c]pyrimidin-3-yl)morpholin hmm

[0215] [ka]

[0216] Example 18 (R)-3-Methyl-4-(1-(methylsulfonyl)-5-(1H-pyrrolo[2, 3-b]pyridin-4-yl)imidazo[1,5-c]pyrimidin-7-yl)morpho Phosphorescence

[0217] [ka]

[0218] Example 19 (R)-3-Methyl-4-(6-(methylsulfonyl)-1-(1H-pyrrolo[2, 3-b]pyridin-4-yl)pyrrolo[1,2-a]pyrazin-3-yl)morpholine

[0219] [ka]

[0220] Example 20 (R)-3-Methyl-4-(3-(methylsulfonyl)-8-(1H-pyrrolo[2, 3-b]pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyrazine- 6-yl)morpholine

[0221] [ka]

[0222] The compounds of Examples 21-25 below were prepared by synthetic processes similar to those described in Example 13.

[0223] [ka]

[0224] [Table C]

[0225] [Table D]

[0226] Example 26 (R)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1 H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methyl Chilmorpholine

[0227] [ka]

[0228] a) Preparation of 3,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine: A solution of 3,6-dichloropyridazin-4-amine (20.0 g, 121.9 mmol), hexane-2,5-dione (16.7 g, 146.3 mmol) and TsOH·H2O (9.26 g, 48.76 mmol) in toluene (300 mL) was stirred at 140 °C for 16 h by Dean-Stark apparatus. The mixture was cooled to room temperature and the toluene layer was decanted. The residue was purified by chromatography on silica gel (EtOAc / PE, 10-20%) to give the title compound (10.2 g, brown solid, yield: 35%). 1 H NMR (400 MHz, CDCl3): δ 7.47 (s, 1H), 5.96 (s, 2H), 1.99 (s, 6H).

[0229] b) Preparation of (R)-4-(6-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazin-3-yl)-3-methylmorpholine: A solution of 3,6-dichloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazine (10.2 g, 42.3 mmol) in NMP (100 mL) gave (R)-3-methylmorpholine (5.1 g, 50.8 mmol) and DIEA (16.4 g, 126.9 mmol). The mixture was stirred at 190° C. for 6 h. After completion, water (200 mL) was added to the mixture and the mixture was extracted with EtOAc (100 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (EtOAc / PE, 10-30%) to give the title compound (9.25 g, brown solid, yield: 71%). LC-MS (ESI): m / z(M+H) + 307.10. 1 H NMR (400 MHz, CDCl3): δ 6.77 (d, J = 4.6 Hz, 1H), 5.94 (d, J = 4.6 Hz, 2H), 4.16 (d, J = 7.6 Hz, 1H), 4.02 (dd, J = 17.8, 13.0 Hz, 2H), 3.80 (d, J = 4.5 Hz, 2H), 3.62 (d, J = 12.1 Hz, 1H), 3.35 (d, J = 12.7 Hz, 1H), 1.99 (s, 6H), 1.28 (d, J = 6.2 Hz, 3H).

[0230] c) Preparation of (R)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile: To a solution of (R)-4-(6-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridazin-3-yl)-3-methylmorpholine (9.25 g, 30.2 mmol) in DMF (100 mL) was added Zn(CN)2 (7.09 g, 136.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene (DPPF, 7.54 g, 13.6 mmol), Pd2(dba)3 (0.85 g, 0.93 mmol) and water (2 mL). The mixture was stirred at 150° C. for 6 hours. After completion, the mixture was added with water (200 mL) and filtered. The filtrate was extracted with EtOAc (200 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (EtOAc / PE, 20-50%) to give the title compound (8.4 g, brown solid, yield: 93%). 1 H NMR (400 MHz, CDCl3): δ 6.58 (s, 1H), 5.97 (s, 2H), 4.35 (s, 1H), 4.20 (d, J = 13.8 Hz, 1H), 4.13 - 4.05 (m, 1H), 3.89 - 3.75 (m, 2H), 3.70 - 3.61 (m, 1H), 3.51 - 3.37 (m, 1H), 2.07 (d, J = 5.0 Hz, 6H), 1.36 (d, J = 6.8 Hz, 3H).

[0231] d) Preparation of (R)-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methanamine: To a solution of (R)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazine-3-carbonitrile (8.4 g, 28.3 mmol) in MeOH (100 mL) was added Raney Nickel (~40 g, W / W). The system was evacuated and backfilled with H2 three times and the mixture was stirred at rt for 16 h. Upon completion, the mixture was filtered through Celite and the cake was washed with MeOH (90 mL x 10). The combined filtrate was concentrated to give the title compound (5.6 g, black solid). 1 H NMR (400 MHz, MeOD): δ 7.43 (s, 1H), 5.95 (s, 2H), 4.36 (s, 1H), 4.03 (d, J = 12.2 Hz, 2H), 3.74-3.83 (m, 3H), 3.60 (d, J = 11.6 Hz, 1H), 3.35 (s, 2H), 1.96 (s, 6H), 1.27 (d, J = 7.0 Hz, 3H).

[0232] e) Preparation of (R)-N-((4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide: To a solution of (R)-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methanamine (5.6 g, 18.6 mmol) in DCM (60 mL) was added 1H-pyrazole-5-carboxylic acid (2.5 g, 22.3 mmol), HATU (4.3 g, 11.2 mmol) and DIEA (7.2 g, 55.8 mmol). The mixture was stirred at rt overnight. Then, K2CO3 (5.1 g, 37.2 mmol) was added and the mixture was stirred at rt for 1 h. After completion, water (100 mL) was added to the mixture and the mixture was extracted with DCM (100 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (MeOH / DCM, 1-3%) to give the title compound (4.3 g, yellow solid, yield: 38%). LC-MS (ESI): m / z(M+H) + 396.20. 1 H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.81 (s, 1H), 7.29 (s, 1H), 6.61 (s, 1H), 5.89 (s, 2H), 4.38 (s, 1H), 4.14 - 4.00 (m, 3H), 3.99 - 3.92 (m, 1H), 3.75-3.66 (m, 2H), 3.55 - 3.48 (m, 1H), 3.20 - 3.15 (m, 2H), 1.94 (s, 6H), 1.16 (d, J = 6.6 Hz, 3H).

[0233] f) Preparation of (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine: A solution of (R)-N-((4-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (4.3 g, 10.9 mmol) in POCl3 (40 mL) was stirred at 120° C. for 4 h. After completion, the solvent was removed. Water (5 mL) was added to the mixture, the pH was adjusted to 8 with aqueous ammonium hydroxide (25% w / w) and the mixture was extracted with DCM (40 mL×2). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (EtOAc / PE, 20-100%) to give the title compound (2.7 g, yellow solid, yield: 66%). LC-MS (ESI): m / z(M+H) + 378.11. 1 H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.29 (s, 1H), 7.24 (s, 1H), 7.11 (s, 1H), 6.37 (s, 1H), 5.98 (s, 2H), 4.16 - 4.03 (m, 2H), 3.95 - 3.75 (m, 3H), 3.72-3.66 (m, 1H), 3.52 - 3.41 (m, 1H), 2.11 (s, 6H), 1.37 (d, J = 6.7 Hz, 3H).

[0234] g) Preparation of (R)-2-(3-methylmorpholino)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-ol: (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (2.7 g, 7.16 mmol) in TFA / HO (20 mL / 2.0 mL) was stirred at 85° C. for 16 h. After completion, the solvent was removed. The residue was purified by chromatography on silica gel (MeOH / DCM, 1-10%) to give the title compound (1.5 g, yellow solid, yield: 71%). LC-MS (ESI): m / z(M+H) + 301.40. 1 H NMR (400 MHz, DMSO-d6): δ 13.33 (s, 1H), 7.63 (s, 1H), 7.46 (s, 1H), 7.03 (s, 1H), 5.93 (s, 1H), 4.06 (s, 1H), 3.92 (d, J = 11.3 Hz, 1H), 3.67 (s, 3H), 3.48 (s, 1H), 3.18 - 3.12 (m, 1H),1.15 (s, 3H).

[0235] h) Preparation of (R)-2-(3-methylmorpholino)-7-(1-((trifluoromethyl)sulfonyl)-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl trifluoromethanesulfonate: To a solution of (R)-2-(3-methylmorpholino)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-ol (1.5 g, 5 mmol) in dry DCM (40 mL) was added TEA (1.5 g, 15.0 mmol) under nitrogen atmosphere at 0 °C and stirred at 0 °C for 10 min. TfO (4.2 g, 15.0 mmol) was added slowly and the mixture was stirred at 0 °C for 30 min and then warmed to rt. After stirring for 1.5 h, the mixture was washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (DCM / PE, 10-30%) to give the title compound (1.2 g, yellow solid, yield: 38%). LC-MS (ESI): m / z(M+H)+ 565.05. 1 H NMR (400 MHz, CDCl3): δ 8.16 (s, 1H), 7.65 (s, 1H), 7.42 (s, 1H), 6.54 (s, 1H), 4.16 - 4.03 (m, 2H), 3.83 (m, 3H), 3.73 - 3.62 (m, 1H), 3.44 (d, J = 13.4 Hz, 1H), 1.38 (d, J = 6.8 Hz, 3H).

[0236] i) Preparation of (R)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine: (R)-2-(3-methylmorpholino)-7-(1-((trifluoromethyl)sulfonyl)-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl To a solution of trifluoromethanesulfonate (0.3 g, 0.53 mmol), 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (150.2 mg, 0.64 mmol) and K2CO3 (219.4 mg, 1.59 mmol) in dioxane (2 mL) was added Pd(dppf)Cl2 (77.6 mg, 0.11 mmol). The system was evacuated and backfilled with Ar three times and stirred at 90 °C for 16 h. Upon completion, the mixture was cooled to room temperature and 2N LiOH (1 mL) was added. After stirring at rt for 0.5 h, the mixture was filtered and the filtrate was concentrated. The residue was purified twice by Prep-TLC (MeOH / DCM=10:1) to give the target compound (17 mg, yellow solid, yield: 8%). LC-MS (ESI): m / z(M+H) + 393.15. 1H NMR (400 MHz, MeOD): δ 7.73 (s, 1H), 7.68 (s, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 6.77 (s, 1H), 6.59 (s, 1H), 4.61 (dd, J = 12.9, 6.2 Hz, 1H), 4.33 (d, J = 7.3 Hz, 1H), 4.07 - 3.99 (m, 1H), 3.91 (d, J = 13.3 Hz, 1H), 3.86-3.75 (m, 2H), 3.67 (t, J = 11.9 Hz, 1H), 3.41 (t, J = 12.8 Hz, 1H), 1.46 (d, J = 6.5 Hz, 6H), 1.35 (d, J = 6.7 Hz, 3H).

[0237] Example 27 (R)-4-(4,7-di(1H-pyrazol-5-yl)imidazo[1,5-b] Pyridazin-2-yl)-3-methylmorpholine

[0238] [ka]

[0239] The compound of Example 27 was prepared by a synthetic process similar to that described in Example 26. The compound of Example 27 was a yellow solid. LC-MS (ESI): m / z(M+H) + 351.35. 1H NMR (400 MHz, DMSO-d6): δ 13.43 (s, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.69 (s, 1H), 7.22 (t, J = 3.2 Hz, 2H), 7.12 (s, 1H), 4.43 (s, 1H), 4.01 (d, J = 11.3 Hz, 1H), 3.92 (d, J = 13.3 Hz, 1H), 3.78 (t, J = 10.1 Hz, 2H), 3.61 - 3.58 (m, 1H), 3.29 - 3.26 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H).

[0240] Example 28 (R)-3-Methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8 -(1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-2-yl)molybdate Ruholin

[0241] [ka]

[0242] Example 29 (R)-3-Methyl-4-(4-(1-methyl-1H-pyrazole-5 -yl)-7-(1H-pyrazol-3-yl)imidazo[5,1-f][1,2,4 ]Triazin-2-yl)morpholine

[0243] [ka]

[0244] Example 30 (R)-3-Methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3 -(1H-pyrazol-5-yl)-[1,2,4]triazolo[3,4-f][1, 2,4]Triazin-6-yl)morpholine

[0245] [ka]

[0246] Example 31 (R)-3-Methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-8 -(1H-pyrazol-5-yl)imidazo[1,5-a][1,3,5]triazine (2-yl)morpholine

[0247] [ka]

[0248] Example 32 (R)-4-(4-cyclopropyl-7-(1H-pyrazol-5-yl)imidazo [1,5-b]pyridazin-2-yl)-3-methylmorpholine

[0249] [ka]

[0250] a) Preparation of (R)-4-(5-chloro-6-methylpyridazin-3-yl)-3-methylmorpholine: A solution of 4,6-dichloro-3-methylpyridazine (3.0 g, 18.4 mmol), (R)-3-methylmorpholine (2.8 g, 27.6 mmol) and DIEA (4.8 g, 36.8 mmol) in NMP (30 mL) was stirred at 150 °C for 8 h. After completion of the reaction, water (50 mL) was added to the mixture and the mixture was extracted with EtOAc (40 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc / PE, 10%-30%) to give the title compound (0.55 g, yellow solid, yield: 13%). LC-MS (ESI): m / z(M+H) + 228.45. 1H NMR (400 MHz, CDCl3): δ 6.81 (s, 1H), 4.29 - 4.15 (m, 1H), 4.04 - 3.95 (m, 1H), 3.87 - 3.73 (m, 3H), 3.60 (t, J = 11.8 Hz, 1H), 3.27 (m, 1H), 2.58 (s, 3H), 1.24 (d, J = 6.8 Hz, 4H).

[0251] b) Preparation of (R)-4-chloro-6-(3-methylmorpholino)pyridazine-3-carbaldehyde: A mixture of (R)-4-(5-chloro-6-methylpyridazin-3-yl)-3-methylmorpholine (510 mg, 2.24 mmol) and SeO2 (298 mg, 2.68 mmol) in 1,4-dioxane (10 mL) was stirred at 95 °C for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc / PE, 10-30%) to give the title compound (370 mg, yellow solid, yield: 68%). 1 H NMR (400 MHz, CDCl3): δ 10.18 (s, 1H), 6.78 (s, 1H), 4.51 (s, 1H), 4.17 (d, J = 13.2 Hz, 1H), 4.08 (d, J = 10.8 Hz, 1H), 3.87-3.76 (m, 2H), 3.64 (t, J = 11.8 Hz, 1H), 3.54 - 3.33 (m, 1H), 1.38 (d, J = 6.4 Hz, 3H).

[0252] c) Preparation of (R)-1-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)-N-(2,4-dimethoxybenzyl)methanamine: To a solution of methyl (R)-4-chloro-6-(3-methylmorpholino)pyridazine-3-carbaldehyde (470 mg, 1.94 mmol) and (2,4-dimethoxyphenyl)methanamine (390 mg, 2.33 mmol) in DCE (8 ml) was added AcOH (349 mg, 5.82 mmol). The reaction solution was stirred at room temperature for 1 h. NaBH(OAc)3 (822 mg, 3.88 mmol, 2.0 equiv) was added in portions and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM / MeOH, 100 / 1 to 50 / 1) to give the title compound (420 mg, yellow solid, yield: 55%). LC-MS (ESI): m / z(M+H) + 393.30.

[0253] d) Preparation of (R)-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)methanamine: A solution of (R)-1-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)-N-(2,4-dimethoxybenzyl)methanamine (420 mg, 1.07 mmol) in TFA (3 mL) was stirred at 80° C. for 3 h. After removal of the solvent, DCM (5 mL) and aqueous ammonium hydroxide (~25% w / w, 0.5 mL) were added to the residue. The solution was stirred at rt for 5 min and then concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH, 100 / 1 to 15 / 1) to give the title compound (210 mg, yellow solid, yield: 81%). LC-MS (ESI): m / z(M+H) + 243.15.

[0254] e) Preparation of N-((4-chloro-6-((R)-3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide: To a solution of (R)-(4-chloro-6-(3-methylmorpholino)pyridazin-3-yl)methanamine (190 mg, 0.78 mmol) in DMF (4 mL) was added 1H-pyrazole-5-carboxylic acid (88 mg, 0.78 mmol), HATU (593 mg, 1.56 mmol) and DIEA (202 mg, 1.56 mmol). The mixture was stirred at rt overnight. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL×3). All organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM / MeOH, 100 / 1 to 10 / 1) to give the title compound (181 mg, yellow solid, yield: 69%). LC-MS (ESI): m / z(M+H) + 337.20.

[0255] f) Preparation of (R)-4-(4-chloro-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine: A solution of N-((4-(1-methyl-1H-pyrazol-5-yl)-6-((R)-3-methylmorpholino)-2,3-dihydropyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (181 mg, 0.54 mmol) in POCl3 (3 mL) was stirred at 120° C. for 3 h. After removal of the solvent, the residue was diluted with DCM (15 mL), washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM / MeOH, 100 / 1 to 10 / 1) to give the title compound (88 mg, yellow solid, yield: 51%). LC-MS (ESI): m / z(M+H) + 319.20. 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.64 (s, 1H), 7.09 (s, 1H), 6.57 (s, 1H), 4.16 - 4.00 (m, 2H), 3.86 - 3.78 (m, 2H), 3.78 - 3.60 (m, 2H), 3.48 - 3.36 (m, 1H), 1.36 (d, J = 6.4 Hz, 3H).

[0256] g) Preparation of (R)-4-(4-cyclopropyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine: To a mixture of (R)-4-(4-chloro-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine (70 mg, 0.22 mmol), cyclopropylboronic acid (11, 38 mg, 0.44 mmol), K3PO4·3H2O (176 mg, 0.22 mmol) in 1,4-dioxane (1 mL) and toluene (1 mL) was added Pd(OAc)2 (5 mg, 0.02 mmol) and tricyclohexylphosphine (11 mg, 0.04 mmol) under N2 protection. The system was evacuated and backfilled with N2 three times. The mixture was stirred at 100° C. for 16 h. After completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH=10 / 1) to give the target compound (15 mg, pale yellow solid, yield: 21%). LC-MS (ESI): m / z(M+H) + 325.25. 1 H NMR (400 MHz, CDCl3): δ 7.70 (s, 1H), 7.61 (s, 1H), 7.08 (s, 1H), 6.07 (s, 1H), 4.16 - 4.05 (m, 2H), 3.87 - 3.81 (m, 2H), 3.75 - 3.63 (m, 2H), 3.46 - 3.36 (m, 1H), 2.15 - 2.07 (m, 1H), 1.33 (d, J = 5.6 Hz, 3H), 1.20 - 1.15 (m, 2H), 1.03 - 0.97 (m, 2H).

[0257] The compounds of Examples 33-63 below were prepared by synthetic processes similar to those described in Example 13, Example 26, or Example 32.

[0258] [ka]

[0259] [Table E]

[0260] [Table F]

[0261] [Table G]

[0262] [Table H]

[0263] [Table I]

[0264] [Table J]

[0265] [Table K]

[0266] [Table L]

[0267] [Table M]

[0268] Example 64 ATR enzyme activity experiment using (R)-3-methyl-4-(8-(1-methyl-1H- Pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b Inhibition of ATR enzyme activity by ]pyridazin-6-yl)morpholine and its analogues Confirmation of effect ATR enzyme activity was measured in 384-well plates (Greiner, #784075) using HTRF reagent (Cisbio). Test compounds were diluted to 4x final concentration in reaction buffer (25mM HEPES (pH8.0), 10mM MnCl2, 1% glycerol, 0.01% Brij-35, 5mM DTT and 0.1% BSA). 2.5μL of diluted compound was added to the corresponding well, followed by 2.5μL of 80nM p53 substrate (Eurofins, #14-952) and 2.5μL of 2ng / μL ATR / ATRIP enzyme (Eurofins, 14-953) solution, and finally 2.5μL of 40μM ATP solution. The mixture was centrifuged at 1000rpm for 1min and reacted at room temperature for 30min in the dark. Then, 5 μL of EDTA stop solution (250 mM) was added to stop the reaction. Finally, 5 μL of detection mixture (Anti-phospho-p53(ser15)-K (Cisbio, #61P08KAE, 0.084 ng / μL) and Anti-GST-d2 (Cisbio, #61GSTDLA, 5.00 ng / μL)) was added to each well, and the fluorescence values ​​at 665 nm and 615 nm were measured using an Envision 2104 instrument. Relative fluorescence ratio: Ratio 665nm / 615nm -Ratio background was calculated and the inhibition %=(1-(relative fluorescence ratio of test compound wells-relative fluorescence ratio of positive control wells) / (relative fluorescence ratio of blank control wells-relative fluorescence ratio of positive control wells))×100 was calculated. Data was analyzed using GraphPad Prism 6.0 and fitted using the curve equation: Y=bottom+(top-bottom) / (1+10^((LogIC 50-X)*HillSlope)) and IC 50 The value was calculated.

[0269] Inhibitory effect of compounds on ATR kinase activity (IC 50 ) are summarized in Table 1. The inhibitory effect (Inh%) of 50 nM compounds on ATR kinase activity is summarized in Table 2.

[0270] [Table 1]

[0271] *: IC in question 50 Values ​​were obtained by comparison with the compound of Example 13.

[0272] [Table 2]

[0273] Therefore, as determined by ATR enzyme activity experiments, (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 13) and its analogs have excellent inhibitory effects on ATR enzyme activity.

[0274] Example 65 (R)-3-Methyl-4-(8-(1-methyl-1H-pyrazor)) 3-(1H-pyrazol-5-yl)-imidazo[1,2-b]piperidin Increase of human prostate cancer cells DU145 by (ridazin-6-yl)morpholine and its analogues Confirmation of the inhibitory effect on reproduction Thawed human prostate cancer cells DU145 were cultured and passaged until they were well grown and approximately 90% confluent, and used for the experiments. The cells were digested with trypsinase, centrifuged at 800 rpm for 5 min, the supernatant was discarded, and the residue was resuspended in fresh medium (DMEM medium + 10% FBS + non-essential amino acids) and counted. The cells were seeded at a density of 2000 cells / well in a 96-well cell culture plate and incubated overnight at 37°C in a 5% CO2 incubator. Stock solutions of test substances (including test compounds and reference compound BAY-1895344) were serially diluted into eight concentrations with DMSO at a ratio of 1:3 and 1:10, respectively. 5 μL of each concentration was added to 120 μL of medium (25-fold dilution) and mixed by shaking. The overnight cell plate was harvested, the medium was removed, 195 μL of fresh medium was added to each well, and 5 μL of diluted medium containing the corresponding concentration of the test substance was added (final concentrations of the compounds are shown in Table 3, and the final concentration of DMSO was 1‰), and then the culture plate was placed in a 5% CO2 incubator at 37°C for 4 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 the culture was continued. After 4 hours, the original solution was removed, 100 μL of DMSO was added to each well, and the 96-well plate was shaken in the dark for 10 minutes, placed in a multifunction reader, and the absorbance at wavelengths of 552 / 690 nm was read. The data was analyzed using GraphPad Prism 6.0. The inhibitory activity of the compounds against cell proliferation was plotted based on the logarithm of the cell viability and compound concentration. Cell viability %=(OD compound-OD background) / (OD DMSO -OD background) x 100. I C 50 The value is Y=100 / (1+10^(LogC-LogIC 50 )) was fitted with a sigmoidal dose-response curve equation.

[0275] The inhibitory effects of the compounds on the proliferation of human prostate cancer cells DU145 are summarized in Table 2.

[0276] [Table 3]

[0277] *: IC in question 50 Values ​​were obtained by comparison with the compound of Example 13.

[0278] Thus, as determined by MTT assay, (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 2) has an inhibitory effect on the proliferation of DU145 cells. (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 13) has a good inhibitory effect on the proliferation of DU145 cells.

[0279] Example 66 The effect of (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine and its analogs on human lung cancer cells NCI-H using MTT assay Confirmation of the inhibitory effect on the proliferation of 460 Thawed human lung cancer cells NCI-H460 were cultured at a confluence of about 90%. The cells were cultured and subcultured until they reached 100 μg / ml and then used in the experiments. Centrifuge at 400 rpm for 5 min, discard the supernatant, and replace the residue with fresh medium (1640 medium + 10% FBS ) and counted. Cells were plated in 96-well cell culture plates at 2000 / 400. 0 cells / well and incubated overnight at 37°C in a 5% CO2 incubator. The test substances (including the test compounds and the reference compound BAY-1895344) The stock solution was diluted to eight concentrations in DMSO at a ratio of 1:3 and 1:10, respectively. The diluted solution was serially diluted. 5 μL of each diluted solution was added to 120 μL of medium (25-fold dilution). The overnight cell plate was harvested, the medium was removed, and fresh medium was added to each well. Add 195 μL of the diluted medium and 5 μL of the diluted medium containing the corresponding concentration of the test substance. (The final concentration of DMSO was 1‰), and then the culture plates were incubated at 37°C for 4 days with 5% The plates were placed in an O2 incubator. After removing the original solution, MTT (0.5 mg / mL 100 μL of fresh serum-free DMEM medium containing 100 μL of ... After 2 h, the original solution was removed and 100 μL of DMSO was added to each well. The mixture was shaken in the dark for 10 minutes, placed in a multifunction reader, and measured for absorbance at wavelengths of 552 / 690 nm. The cell viability (%) = (OD compound - OD background) / (OD DMSO -OD background) × 100. Data were analyzed using GraphPad Prism 6.0. The inhibitory activity of compounds against cell proliferation was plotted based on the cell viability versus the logarithm of the compound concentration. IC 50 The value is Y=100 / (1+10^(LogC-Log I C 50 )) was fitted with a sigmoidal dose-response curve equation.

[0280] The inhibitory effects of the compounds on the proliferation of human lung cancer cells NCI-H460 are summarized in Table 3.

[0281] [Table 4]

[0282] *: IC in question 50 Values ​​were obtained by comparison with the compound of Example 13.

[0283] Thus, as determined by MTT assay, (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 2) has an inhibitory effect on the proliferation of NCI-H460 cells. (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 13) and its analogs have excellent inhibitory effects on the proliferation of NCI-H460 cells.

[0284] Example 67 (R)-3-Methyl-4-(8-(1-methyl-1H-pyrazor)) 3-(1H-pyrazol-5-yl)-imidazo[1,2-b]piperidin Effects of ridazin-6-yl morpholine and its analogues on the proliferation of human colon cancer cells LoVo Confirmation of inhibitory effect against Thawed human colon cancer cells LoVo were cultured and passaged until they grew well and reached approximately 90% confluence, and then used for the experiments. The cells were digested with trypsinase, centrifuged at 800 rpm for 5 min, the supernatant was discarded, and the residue was resuspended in fresh medium (1640 medium + 10% FBS) and counted. The cells were seeded in 96-well cell culture plates at a density of 2000 / 4000 cells / well and incubated overnight at 37°C in a 5% CO2 incubator. Stock solutions of test substances (including test compounds and reference compound BAY-1895344) were serially diluted into eight concentrations with DMSO at a ratio of 1:3 and 1:10, respectively. 5 μL of each dilution was added to 120 μL of medium (25-fold dilution) and mixed by shaking. The overnight cell plate was harvested, the medium was removed, 195 μL of fresh medium was added to each well, and 5 μL of diluted medium containing the corresponding concentration of the test substance was added respectively (final concentration of DMSO was 1‰), and then the culture plate was placed in a 5% CO2 incubator at 37°C for 4 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 the culture was continued. After 4 hours, the original solution was removed, and 100 μL of DMSO was added to each well, and the 96-well plate was shaken in the dark for 10 minutes, and then placed in a multifunction reader to read the absorbance at wavelengths of 552 / 690 nm. Cell viability (%) = (OD compound-OD background) / (OD DMSO -OD background) × 100. Data were analyzed using GraphPad Prism 6.0. The inhibitory activity of compounds against cell proliferation was plotted based on the cell viability versus the logarithm of the compound concentration. IC 50 The value is Y=100 / (1+10^(LogC-LogIC 50 )) was fitted with a sigmoidal dose-response curve equation.

[0285] The inhibitory effects of the compounds on the proliferation of human colon cancer cells LoVo are summarized in Table 5.

[0286] [Table 5]

[0287] *: IC in question 50 Values ​​were obtained by comparison with the compound of Example 13.

[0288] Thus, as determined by MTT assay, (R)-3-methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-6-yl)morpholine (Example 2) has an inhibitory effect on the proliferation of LoVo cells. (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine (Example 13) and its analogs have excellent inhibitory effects on the proliferation of LoVo cells.

[0289] Although the present disclosure has been fully described, it should be understood by those skilled in the art that the same may be practiced within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the present disclosure or any of its embodiments. All patents, patent applications and publications cited herein are fully incorporated herein by reference in their entirety.

Claims

Claim 1: A compound of formula IV: 【Chemistry 1】 or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, with the proviso that A 4 , A 5 and A 6 The 5-6 membered fused heteroaryl group containing: 【Chemistry 2】 and R 1 is a C 6 -C 14 aryl group, a saturated or partially saturated 3-7 membered monocyclic group or a 7-10 membered bicyclic group, C 3 -C 8 a cycloalkyl group or a heteroaryl group having 5 to 14 ring atoms, R 1 being optionally substituted with 1-3 substituents selected from the group consisting of a C 1 -C 4 alkyl group, a halogen, a hydroxy group, a C 1 -C 4 alkoxy group, and an amino group; R 2 is C3-C 6 Cycloalkyl group, C 6 -C 14 an aryl group, a saturated or partially saturated 3-7 membered monocyclic group or a 7-10 membered bicyclic group, or a heteroaryl group having 5 to 14 ring atoms, R 2 being optionally substituted with 1-3 substituents selected from the group consisting of a C 1 -C 6 alkyl group optionally substituted with 1-4 halogens, a cyano group, a hydroxy group, a carboxy group, an amino group, a halogen, a C 1 -C 4 alkylsulfinyl group, and a C 1 -C 4 alkylsulfonyl group; R 4 is hydrogen or C 1 -C 4 It is an alkyl group.

2. R 1 is a 5- or 6-membered heteroaryl group containing at least one nitrogen atom, optionally substituted with 1 to 3 substituents selected from the group consisting of a C 1 -C 4 alkyl group, a halogen, a hydroxyl group, a C 1 -C 4 alkoxy group, and an amino group; 10. A compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof.

3. R 1 is C 1 -C 4 Alkyl group, halogen, hydroxyl group, C 1 -C 4 a pyrazolyl group, a pyrrolyl group or an imidazolyl group optionally substituted with one or two substituents selected from the group consisting of an alkoxy group and an amino group, R 1 is an unsubstituted pyrazolyl group, an unsubstituted pyrrolyl group, or an unsubstituted imidazolyl group; 3. A compound according to claim 2, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof.

4. R 2 is a 5- or 6-membered heteroaryl group containing at least one nitrogen atom, optionally substituted with 1-3 substituents selected from the group consisting of a C 1 -C 6 alkyl group optionally substituted with 1-4 halogens, a cyano group, a hydroxyl group, a carboxyl group, an amino group, halogens, a C 1 -C 4 alkylsulfinyl group, and a C 1 -C 4 alkylsulfonyl group; A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof.

5. R 2 is a cyclopropyl group, a phenyl group, a pyrazolyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, a furanyl group, a pyridyl group, a pyrimidinyl group, a morpholinyl group, a dihydropyranyl group, a tetrahydropyranyl group or a pyrrolopyridyl group, each of which is optionally substituted with 1-3 substituents selected from the group consisting of a C 1 -C 6 alkyl group optionally substituted with 1-4 halogens, a cyano group, a hydroxyl group, a carboxy group, an amino group, a halogen, a C 1 -C 4 alkylsulfinyl group and a C 1 -C 4 alkylsulfonyl group; A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof.

6. R 2 is a pyrazolyl group optionally substituted with a C 1 -C 6 alkyl group optionally substituted with 1-4 halogens, or R 2 is a pyrazolyl group optionally substituted with 1 or 2 substituents selected from the group consisting of unsubstituted C 1 -C 4 alkyl groups and C 1 -C 4 alkyl groups substituted with 1-3 halogens; A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof.

7. The compound of claim 6, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, wherein one or two ring N atoms of the pyrazolyl group are substituted.

8. R 1 is 1 to 2 C 1 -C 4 a pyrazolyl group, a pyrrolyl group or an imidazolyl group optionally substituted by an alkyl group; R 2 is halogen, C 1 -C 4 Alkylsulfonyl group, C 1 -C 4 alkylsulfinyl group, C optionally substituted with 1 to 3 halogen atoms 1 -C 4 a pyrazolyl group, a pyrrolyl group, a pyridinyl group, a pyrrolopyridinyl group, a pyrimidinyl group, a triazolyl group or an imidazolyl group, each of which is optionally substituted by one or two substituents selected from the group consisting of alkyl groups; 1 -C 4 Alkyl group, -CN, C 1 -C 4 a phenyl group optionally substituted with one or two substituents selected from the group consisting of alkylsulfonyl groups and halogens, or one or two C 1 -C 4 a morpholinyl group, a dihydropyranyl group or a tetrahydropyranyl group optionally substituted by an alkyl group; R 4 is hydrogen or C 1 -C 4 is an alkyl group, 10. A compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof.

9. R 1 is C 1 -C 3 a pyrazolyl group optionally substituted by an alkyl group; R 2 is unsubstituted C 1 -C 4 C substituted with an alkyl group and 1 to 3 halogen atoms 1 -C 4 a pyrazolyl group optionally substituted by one or two substituents selected from the group consisting of alkyl groups; R 4 is C1-C 4 is an alkyl group, 10. A compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof.

10. R 4 is a methyl group, 10. A compound according to claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof.

11. The compound according to claim 1, wherein the compound is selected from the group consisting of: a stereoisomer, a tautomer, an N-oxide, a hydrate, an isotopically substituted derivative, a solvate, or a pharma- ceutically acceptable salt thereof, or a mixture thereof. 4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-3-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrrol-2-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(7-(1H-imidazol-4-yl)-4-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-3-methyl-4-(4-(6-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(4-(2-fluorophenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-(1-isopropyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4,7-di(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-cyclopropyl-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (S)-3-methyl-4-(4-(1-methyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(4-(4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-(1-ethyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-3-methyl-4-(4-(3-methyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(7-(3-methyl-1H-pyrazol-5-yl)-4-(6-methylpyridin-3-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(7-(1H-pyrazol-5-yl)-4-(o-tolyl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-(1,4-dimethyl-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-3-methyl-4-(4-(2-methylpyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(4-(3-fluoropyridin-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-3-methyl-4-(4-(4-methyl-6-(methylsulfonyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(4-(4-methylpyrimidin-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(4-morpholino-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(7-(1H-pyrazol-5-yl)-4-(2-(trifluoromethyl)pyridin-3-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-3-methyl-4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(4-(2-methyl-4-(methylsulfonyl)phenyl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (3R)-3-methyl-4-(4-(2-methyl-6-(methylsulfinyl)pyridin-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-methyl-4-(4-(3-methylpyridin-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-3-(2-(3-methylmorpholino)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-4-yl)benzonitrile; (R)-4-(4-(3,6-dihydro-2H-pyran-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(7-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(7-(1H-pyrazol-5-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-3-methyl-4-(4-(1-methyl-1H-imidazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)morpholine; (R)-4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-(1,5-dimethyl-1H-1,2,3-triazol-4-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-(1-(difluoromethyl)-1H-pyrazol-5-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine; (R)-4-(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)-7-(1H-pyrazol-5-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylmorpholine

12. Use of a compound according to any one of claims 1 to 11 or a stereoisomer, tautomer, N-oxide, hydrate, isotopically substituted derivative, solvate or pharma- ceutically acceptable salt thereof, or a mixture thereof, in the preparation of a medicament for treating or preventing an ATR kinase mediated disease.

13. The use according to claim 12, wherein the disease is cancer.

14. The cancers include liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain tumor, malignant melanoma, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoma, 14. The use according to claim 13, characterized in that the cancer is selected from the group consisting of thyroid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urinary system tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer or prostate cancer.

15. The use of claim 14, wherein the medicament further comprises at least one known anti-cancer drug or a pharma- ceutically acceptable salt thereof.

16. The anticancer drug may be busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclacinomycin, mitoxantrone, methylhydroxyellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxy- Uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositum Mab, brentuximab, daratumumab, elotuzumab, T-DM1, ofatumumab, dinatuximab, blinatumomab, ipilimumab, Avastin, Herceptin, MabThera, imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, torisel, everolimus, vorinostat, romidepsin, panobinostat, belinostat, tamoxifen The use according to claim 15, wherein the agent is selected from the group consisting of: cyclosporine, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin 2), sipuucel-T (prostate cancer therapeutic vaccine), palbociclib, olaparib, niraparib, rucaparib, talazoparib and senaparib.

17. The use according to claim 12, wherein the medicament is in combination with radiation therapy.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharma- ceutically acceptable carrier.

19. The pharmaceutical composition of claim 18, further comprising at least one known anticancer drug or a pharma- ceutically acceptable salt thereof.

20. The at least one known anticancer drug may be busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, epirubicin, aclacinomycin, mitoxantrone, methylhydroxyellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro- 2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, mAb, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab , tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, ofatumumab, dinatuximab, blinatumomab, ipilimumab, avastin, herceptin, mabthera, imatinib, gefitinib, erlotinib, osimertinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, sunitinib, nilotinib, dasatinib, pazopanib, torisel, everolimus, vorinostat, romidepsin, panobinostat, belinostat, 20. The pharmaceutical composition of claim 19, wherein the compound is selected from the group consisting of tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic trioxide, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin 2), sipuucel-T (prostate cancer therapeutic vaccine), palbociclib, olaparib, niraparib, rucaparib, talazoparib and senaparib.

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