Pyridazinamine compound and pharmaceutical use thereof

Abstract

The present application belongs to the field of medicinal chemistry, and relates to a pyridazinamine compound and the pharmaceutical use thereof, wherein the compound has a structure as shown in formula (I). Specifically, the present application further relates to a method for preparing the compound, a pharmaceutical composition thereof, and the use thereof in the treatment of diseases.

Description

Pyridazinamines and medical uses thereof

[0001] Cross-reference to Related Applications

[0002] This application claims the benefit of and priority to Chinese Patent Application No. 202410896310.X, filed July 4, 2024, Chinese Patent Application No. 202510335172.2, filed March 20, 2025, and Chinese Patent Application No. 202510878515.X, filed June 26, 2025, in the State Intellectual Property Office of the People’s Republic of China, and claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 288, 1 1 1, filed December 16, 2022, and U.S. Provisional Patent Application No. 63 / 288, 1 12, filed December 16, 2022, and claims the benefit of and priority to U.S. Nonprovisional Patent Application No. 17 / 872, 1 1 1, filed July 4, 2023, all of which are hereby incorporated by reference in their entirety. TECHNICAL FIELD

[0003] The present disclosure relates to pyridazinamines, methods of making the same, pharmaceutical compositions containing the same, and uses thereof in the treatment of disease. BACKGROUND

[0004] ALK was first discovered in a subtype of anaplastic large cell lymphoma (ALCL), hence the name anaplastic lymphoma kinase (ALK). ALK is located on the short arm of chromosome 2 (2p23) and encodes a polypeptide of 1620 amino acids, which is post-translationally modified to generate a mature ALK protein of 200-220 kDa. ALK protein belongs to the insulin receptor superfamily and is a transmembrane receptor tyrosine kinase that plays an important role in the development and function of the nervous system, and is also expressed in small intestine, testis, prostate, and colon, but not in normal lymphoid tissue, lung, and other tissues. In most normal cells, ALK is in an inactive state, and when the ALK gene is mutated, abnormal phosphorylation affects the spatial conformation of the ALK protein and the activity of the kinase, ultimately leading to the occurrence of tumors.

[0005] Currently, several ALK inhibitors have been approved for marketing, including the first generation crizotinib, the second generation alectinib, ceritinib, brigatinib, ensartinib, and the third generation lorlatinib. Among them, the third generation lorlatinib can be used for first-line treatment and can overcome the resistance problem of first and second generation ALK inhibitors. However, acquired resistance still occurs in most patients receiving third generation ALK inhibitors.

[0006] Studies have shown that a large number of ALK single-point mutations that exist after previous ALK inhibitor treatment can serve as the substrate for the generation of compound mutations (i.e., 2 or more ALK mutations occurring in the same allele or in cis) when treated with the third-generation ALK inhibitor loratinib. Among patients who experienced disease progression after sequential treatment with loratinib, about 30% had compound mutations, most commonly G1202R or I1171N-based compound mutations. Some compound mutations, such as G1202R+L1196, are resistant to all ALK inhibitors.

[0007] Therefore, there is an urgent need in the clinic to develop new ALK inhibitors to overcome the above-mentioned drug-resistant compound mutations and address patient needs. SUMMARY

[0008] The present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0009] wherein,

[0010] X 1 , X 2 each independently is selected from -O-, -S-, -NR X1 -, -C(O)-, or -C(R X1 )2-;

[0011] each R X1 is independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-6 alkyl, 3-6 membered cycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylamino, or halogenated diC 1-6 alkylamino;

[0012] Alternatively, two R X1 together form a 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl group optionally substituted with one or more R X1a

[0013] each R X1a is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 ​alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylamino, or halo-diC 1-6 alkylamino;

[0014] X 3 , X 4 , X 5 , X 6 , X 7 , X 8 are each independently selected from a single bond, -O-, -S-, -NR X2 -, -C(O)-, or -C(R X2 )2-;

[0015] each R X2 is independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-6 alkyl, 3-6 membered cycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylamino, or halo-diC 1-6 alkylamino;

[0016] Z 1 , Z 2 , Z 3 are each independently selected from N or CR Z ;

[0017] each R Z is independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-6 alkyl, 3-6 membered cycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylamino, or halo-diC 1-6 alkylamino;

[0018] Ring A is selected from 5-10 membered heteroaryl optionally substituted with one or more R A1 ;

[0019] R A1 is independently selected from deuterium, halogen, -OH, -NH2, -CN, or is optionally substituted with one or more R A2substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered cycloalkyl C 1-4 alkylene, or 3-12 membered heterocycloalkyl C 1-4 alkylene, 3-12 membered cycloalkyl-O-, 3-12 membered heterocycloalkyl-O-, 3-12 membered cycloalkyl-S-, 3-12 membered heterocycloalkyl-S-, 6-10 membered aryl, 5-10 membered heteroaryl, 6-10 membered aryl C 1-4 alkylene, or 5-10 membered heteroaryl C 1-4 alkylene;

[0020] each R A2 is each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 1-6 alkylamino, or halo-di-C 1-6 alkylamino;

[0021] Ring B is selected from 5-10 membered heteroaryl optionally substituted with one or more R B1 substituted 5-10 membered heteroaryl;

[0022] R B1 is each independently selected from deuterium, halogen, -OH, -NH2, -CN, or is optionally substituted with one or more R B2 substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered cycloalkyl C 1-4 alkylene, or 3-12 membered heterocycloalkyl C 1-4 alkylene;

[0023] each R B2 is each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylamino, or halo-diC 1-6 alkylamino;

[0024] said R X1 , R X1a , R X2 , R Z , R A2 , R B2 is optionally substituted with one or more substituents;

[0025] provided that when ring A is selected from A1 substituted with one or more R and -X 6 , ring B is not selected from B1 substituted with one or more R

[0026] In some embodiments, the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0027] wherein,

[0028] X 1 , X 2 are each independently selected from -O-, -S-, -NR X1 -, -C(O)-, or -C(R X1 )2-;

[0029] each R X1 is each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-6 alkyl, 3-6 membered cycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylamino, or halo-diC 1-6 alkylamino;

[0030] or, two R X1 together form a 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl group, optionally substituted with one or more R X1a

[0031] each R X1a is each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C​1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 1-6 alkylamino, or halo-di-C 1-6 alkylamino;

[0032] X 3 , X 4 , X 5 , X 6 , X 7 , X 8 are each independently selected from a single bond, -O-, -S-, -NR X2 -, -C(O)-, or -C(R X2 )2-;

[0033] each R X2 is independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-6 alkyl, 3-6 membered cycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 1-6 alkylamino, or halo-di-C 1-6 alkylamino;

[0034] Z 1 , Z 2 , Z 3 are each independently selected from N or CR Z ;

[0035] each R Z is independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-6 alkyl, 3-6 membered cycloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 1-6 alkylamino, or halo-di-C 1-6 alkylamino;

[0036] ring A is selected from the group consisting ofA1 substituted 5-10 membered heteroaryl;

[0037] R A1 each independently selected from deuterium, halogen, -OH, -NH2, -CN, or is optionally substituted with one or more R A2 substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered cycloalkyl C 1-4 alkylene, or 3-12 membered heterocycloalkyl C 1-4 alkylene;

[0038] each R A2 each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylamino, or halogenated diC 1-6 alkylamino;

[0039] Ring B is selected from optionally substituted 5-10 membered heteroaryl; B1 substituted 5-10 membered heteroaryl;

[0040] R B1 each independently selected from deuterium, halogen, -OH, -NH2, -CN, or is optionally substituted with one or more R B2 substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered cycloalkyl C 1-4 alkylene, or 3-12 membered heterocycloalkyl C 1-4 alkylene;

[0041] each R B2 each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6alkyl, halo-C 1-6 alkoxy, halo-C 1-6 alkylamino, or halo-di-C 1-6 alkylamino;

[0042] said R X1 , R X1a , R X2 , R Z , R A2 , R B2 are optionally substituted with one or more substituents.

[0043] In some embodiments, said R X1 , R X1a , R X2 , R Z , R A2 , R B2 are optionally substituted with one or more substituents, wherein the “substituents” are selected from the group consisting of a deuterium atom, a hydroxyl group, a thiol group, a halogen, an amino group, a nitro group, a nitroso group, a cyano group, an azido group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, an aldehyde group, an imine group, a C 1-12 alkyl, halo-C 1-12 alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3-12 membered cycloalkenyl, halo-3-12 membered cycloalkenyl, C 2-12 alkynyl, halo-C 2-12 alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C 1-12 heteroalkyl, halo-C 1-12 heteroalkyl, C 1-12 alkoxy, C 1-12 alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered aryl-C 1-12 alkylene, 6-10 membered aryl-C 1-12 alkoxy, 6-10 membered aryl-C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclyl-C 1-12 alkylene, 3-12 membered heterocyclyl-C 1-12 alkoxy, 3-12 membered heterocyclyl-C 1-12 alkylthio, C 1-12 acyl, C 1-12 acyloxy, carbamate, C 1-12amide, urea, epoxy, C 2-12 ester, oxo, and thioxo, optionally substituted with one or more substituents selected from: deuterium, oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, C 1-12 alkylamino, diC 1-12 alkylamino, halogenated C 1-12 alkylamino, halogenated diC 1-12 alkylamino, carboxyl, -C(O)O-C 1-12 alkyl, -OC(O)-C 1-12 alkyl, -C(O)NH2, -C(O)NH-C 1-12 alkyl, -C(O)N(C 1-12 alkyl)2, -NHC(O)-C 1-12 alkyl, -C(O)-C 1-12 alkyl, -S(O)-C 1-12 alkyl, -S(O)2-C 1-12 alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 alkyl, -S(O)2N(C 1-12 alkyl)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl C 1-12 alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryl C 1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered aryl C 1-12 alkylene, or 6-10 membered aryloxy.

[0044] In some embodiments, the R X1 , R X1a , R X2 , R Z , R A2 , R B2 are optionally substituted with one or more substituents selected from: deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 alkyl, 3-6 membered cycloalkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC1-3 alkylamino, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylamino, or halodiC 1-3 alkylamino.

[0045] In some embodiments, when ring A is selected from and -X 6 is attached, ring B is not selected from

[0046] In some embodiments, ring A is not selected from wherein -X 6 is attached.

[0047] In some embodiments, ring B is not selected from 1,2,3-triazolyl optionally substituted with one or more R B1 In some embodiments, ring B is not selected from B1 In some embodiments, ring B is not selected from

[0048] In some embodiments, at least one of X 1 , X 2 is selected from -C(O)- or -C(R X1 )2-.

[0049] In some embodiments, each X 1 , X 2 is independently selected from -O-, -NR X1 -, -C(O)-, or -C(R X1 )2-.

[0050] In some embodiments, each X 1 , X 2 is independently selected from -O- or -C(R X1 )2-.

[0051] In some embodiments, the structural unit -X 1 -X 2 - is selected from -OC(R X1 )2-, -OC(O)-, -C(R X1 )2O-, -C(O)O-, -NR X1 C(R X1 )2-, -NR X1 C(O)-, -C(R X1 )2NR X1 -, -C(O)NR X1 -, -C(R​X1 )2C(R X1 )2-、or -C(O)C(R X1 )2.

[0052] In some implementation schemes, structural unit-X 1 -X 2 -Selected from -OC(R) X1 )2-.

[0053] In some implementations, each R X1 Each is independently selected from H, deuterium, halogen, -OH, -NH2, -CN, and C. 1-4 Alkyl, 3-5 membered cycloalkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 Alkylamino or halogenated diC 1-4 Alkylamino; or, two Rs X1 Together they form an optional combination of one or more R X1a The following groups are substituted: 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl.

[0054] In some implementations, each R X1 Each is independently selected from H, deuterium, halogen, -OH, -NH2, -CN, and C. 1-3 Alkyl, 3-4 membered cycloalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC 1-3 Alkylamino, deuterated C 1-3 Alkyl, Halogenated C 1-3 Alkyl, Halogenated C 1-3 Alkoxy, halogenated C 1-3 Alkylamino or halogenated diC 1-3 Alkylamino; or, two Rs X1 Together they form an optional combination of one or more R X1a The following groups are substituted: 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl.

[0055] In some implementations, each R X1each independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, trifluoromethoxy, trifluoroethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino; or, two R X1 together form a group that is optionally substituted with one or more R X1a together form a group that is optionally substituted with one or more R

[0056] In some embodiments, each R X1 each independently selected from H, deuterium, -F, -Cl, methyl, ethyl, methoxy, methylamino, dimethylamino, trideuteromethyl, trifluoromethyl, or trifluoromethoxy; or, two R X1 together form a group that is optionally substituted with one or more R X1a together form a group that is optionally substituted with one or more R

[0057] In some embodiments, each R X1 each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, or C 1-4 alkyl. In some embodiments, each R X1 each independently selected from H or C 1-4 alkyl.

[0058] In some embodiments, each R X1a each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, haloC 1-4 alkyl, haloC 1-4 alkoxy, haloC 1-4 alkylamino, or halo-diC 1-4 alkylamino.

[0059] In some embodiments, each R X1a each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylamino, or halo diC 1-3 alkylamino.

[0060] In some embodiments, each R X1a is each independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, trifluoromethoxy, trifluoroethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0061] In some embodiments, each R X1a is each independently selected from deuterium, -F, -Cl, methyl, or methoxy.

[0062] In some embodiments, each R X1a is each independently selected from deuterium, -F, or -Cl.

[0063] In some embodiments, each R X1 is each independently selected from H, deuterium, -F, -Cl, methyl, ethyl, trideuteromethyl, or trifluoromethyl; or, two R X1 together form a group: tetrahydropyrrolyl, piperidinyl, or morpholinyl. In some embodiments, each R X1 is each independently selected from H or methyl.

[0064] In some embodiments, X 1 , X 2 is each independently selected from -O-, -NH-, -N(CH3)-, -C(O)-, -CH2-, or -CH(CH3)-.

[0065] In some embodiments, structural unit -X 1 -X 2- selected from -OCH2-, -OCH(CH3)-, -OC(O)-, -CH2O-, -CH(CH3)O-, -C(O)O-, -NHCH2-, -N(CH3)CH2-, -NHC(O)-, -N(CH3)C(O)-, -CH2NH-, -CH(CH3)NH-, -C(O)NH-, -C(O)N(CH3)-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(O)CH2-, -CH2C(O)-,

[0066] In some embodiments, the structural unit -X 1 -X 2 - is selected from

[0067] In some embodiments, the structural unit -X 1 -X 2 - is selected from In some embodiments, the structural unit -X 1 -X 2 - is selected from

[0068] In some embodiments, X 3 , X 4 at least one of which is selected from a single bond, -C(O)-, or -C(R X2 )2-.

[0069] In some embodiments, X 5 , X 6 at least one of which is selected from a single bond, -C(O)-, or -C(R X2 )2-.

[0070] In some embodiments, X 7 , X 8 at least one of which is selected from a single bond, -C(O)-, or -C(R X2 )2-.

[0071] In some embodiments, X 3 , X 4 , X 5 , X 6 , X 7 , X 8 are each independently selected from a single bond, -O-, -NR X2 -, -C(O)-, or -C(R X2 )2-.

[0072] In some embodiments, structural unit -X 3 -X 4 - is selected from a single bond, -O-, -NR X2 -, -C(O)-, or -C(R X2 )2-.

[0073] In some embodiments, structural unit -X 5 -X 6 - is selected from a single bond, -O-, -NR X2 -, -C(O)-, -C(R X2 )2-, -OC(R X2 )2-, -OC(O)-, -C(R X2 )2O-, -C(O)O-, -NR X2 C(R X2 )2-, -NR X2 C(O)-, -C(R X2 )2NR X2 -, -C(O)NR X2 -, -C(R X2 )2C(R X2 )2-, -C(R X2 )2C(O)-, or -C(O)C(R X2 )2-.

[0074] In some embodiments, structural unit -X 7 -X 8 - is selected from a single bond, -O-, -NR X2 -, -C(O)-, or -C(R X2 )2-.

[0075] In some embodiments, each R X2 is each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, 3-5 membered cycloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, or halogenated diC 1-4 alkylamino.

[0076] In some embodiments, each R X2 is each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-3 alkyl, 3-4 membered cycloalkyl, C 1-3 alkoxy, C1-3 alkylamino, diC 1-3 alkylamino, deuterated C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylamino, or halo diC 1-3 alkylamino.

[0077] In some embodiments, each R X2 is each independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, trifluoromethoxy, trifluoroethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0078] In some embodiments, each R X2 is each independently selected from H, deuterium, -F, -Cl, methyl, or methoxy.

[0079] In some embodiments, X 3 , X 4 , X 5 , X 6 , X 7 , X 8 is each independently selected from a single bond, -O-, -NH-, -N(CH3)-, -C(O)-, -CH2-, or -CH(CH3)-.

[0080] In some embodiments, structural unit -X 3 -X 4 - is selected from a single bond, -O-, -NH-, -N(CH3)-, -C(O)-, -CH2-, or -CH(CH3)-.

[0081] In some embodiments, structural unit -X 3 -X 4 - is selected from a single bond.

[0082] In some embodiments, structural unit -X 5 -X 6- is selected from a single bond, -0-, -NH-, -N(CH3)-, -C(O)-, -CH2-, -CH(CH3)-, -OCH2-, -OCH(CH3)-, -OC(O)-, -CH2O-, -CH(CH3)0-, -C(0)0-, -NHCH2-, -N(CH3)CH2-, -NHC(O)-, -N(CH3)C(0)-, -CH2NH-, -CH(CH3)NH-, -C(0)NH-, -C(0)N(CH3)-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH2C(0)-, or -C(0)CH2-.

[0083] In some embodiments, structural unit -X 5 -X 6 - is selected from -C(O)- or -CH2-.

[0084] In some embodiments, structural unit -X 7 -X 8 - is selected from a single bond, -0-, -NH-, -N(CH3)-, -C(O)-, -CH2-, or -CH(CH3)-.

[0085] In some embodiments, structural unit -X 7 -X 8 - is selected from a single bond.

[0086] In some embodiments, structural unit -X 3 -X 4 - is selected from a single bond, structural unit -X 5 -X 6 - is selected from -C(O)- or -CH2-, structural unit -X 7 -X 8 - is selected from a single bond.

[0087] In some embodiments, Z 1 , Z 2 , Z 3 is selected from CR Z .

[0088] In some embodiments, Z 1 , Z 2 , Z 3 is selected from N, two are selected from CR Z .

[0089] In some embodiments, Z 1 is selected from N, Z 2 , Z 3 is selected from CR Z . In some embodiments, Z2 selected from N, Z 1 , Z 3 selected from CR Z In some embodiments, Z 3 is selected from N, Z 1 , Z 2 selected from CR Z .

[0090] In some embodiments, Z 1 , Z 2 , Z 3 two are selected from N and one is selected from CR Z .

[0091] In some embodiments, Z 1 , Z 2 is selected from N, Z 3 selected from CR Z In some embodiments, Z 1 , Z 3 is selected from N, Z 2 selected from CR Z In some embodiments, Z 2 , Z 3 is selected from N, Z 1 selected from CR Z .

[0092] In some embodiments, Z 1 , Z 2 , Z 3 is selected from N.

[0093] In some embodiments, each R Z is each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-4 alkyl, 3-5 membered cycloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylamino, or halogenated diC 1-4 alkylamino.

[0094] In some embodiments, each R Z is each independently selected from H, deuterium, halogen, -OH, -NH2, -CN, C 1-3 alkyl, 3-4 membered cycloalkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, deuterated C1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, haloC 1-3 alkylamino, or haloDiC 1-3 alkylamino.

[0095] In some embodiments, each R Z is each independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, trifluoromethoxy, trifluoroethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0096] In some embodiments, each R Z is each independently selected from H, deuterium, -F, -Cl, or methyl.

[0097] In some embodiments, Z 1 , Z 2 , Z 3 is each independently selected from N, CH, or CF.

[0098] In some embodiments, Z 1 , Z 2 , Z 3 is selected from CH.

[0099] In some embodiments, ring A is selected from 5-9 membered heteroaryl optionally substituted with one or more R A1 .

[0100] In some embodiments, the heteroaryl is selected from monocyclic or bicyclic.

[0101] In some embodiments, ring A is selected from 5-9 membered heteroaryl optionally substituted with one or more R A1 . In some embodiments, the heteroaryl contains 1, 2, or 3 heteroatoms selected from N, O, or S.

[0102] In some embodiments, ring A is selected from 5-9 membered heteroaryl optionally substituted with one or more R A1 . In some embodiments, the heteroaryl contains 1, 2, or 3 heteroatoms selected from N, O, or S.

[0103] In some embodiments, ring A is selected from 5-9 membered heteroaryl optionally substituted with one or more R A1substituted 8- or 9-membered bicyclic heteroaryl comprising 1, 2, or 3 heteroatoms selected from N, O, or S.

[0104] In some embodiments, ring A is selected from optionally substituted A1 substituted furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyridazinyl, pyrazolopyridazinyl, or imidazopyridazinyl.

[0105] In some embodiments, ring A is selected from optionally substituted A1 substituted furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, ring A is selected from optionally substituted A1 substituted pyrazolyl, imidazolyl, triazolyl, or isoxazolyl.

[0106] In some embodiments, ring A is selected from optionally substituted A1 substituted benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyridazinyl, pyrazolopyridazinyl, or imidazopyridazinyl. In some embodiments, ring A is selected from optionally substituted A1 substituted imidazopyrimidinyl, pyrrolopyrazinyl, or imidazopyrazinyl. In some embodiments, ring A is selected from optionally substituted A1 substituted pyrrolopyridinyl, imidazopyridinyl.

[0107] In some embodiments, ring A is selected from optionally substituted A1 substituted pyrazolyl, imidazolyl, triazolyl, isoxazolyl, or imidazopyrazinyl. In some embodiments, ring A is selected from optionally substituted A1substituted pyrazolyl, imidazolyl, 1,2,3-triazolyl, or isoxazolyl. In some embodiments, ring A is selected from

[0108] In some embodiments, ring A is selected from A1 substituted pyrazolyl, imidazolyl, 1,2,3-triazolyl, or isoxazolyl. In some embodiments, ring A is selected from A1 substituted pyrazolyl, imidazolyl, 1,2,3-triazolyl, or isoxazolyl. In some embodiments, ring A is selected from In some embodiments, ring A is selected from A1 substituted pyrazolyl, imidazolyl, 1,2,3-triazolyl, or isoxazolyl. In some embodiments, ring A is selected from

[0109] In some embodiments, ring A is selected from A1 substituted pyrazolyl, imidazolyl, 1,2,3-triazolyl, or isoxazolyl. In some embodiments, ring A is selected from In some embodiments, ring A is selected from A1 substituted pyrazolyl, imidazolyl, 1,2,3-triazolyl, or isoxazolyl. In some embodiments, ring A is selected from

[0110] In some embodiments, ring A is selected from A1 substituted pyrazolyl, imidazolyl, 1,2,3-triazolyl, or isoxazolyl. In some embodiments, ring A is selected from In some embodiments, ring A is selected from A1 substituted pyrazolyl, imidazolyl, 1,2,3-triazolyl, or isoxazolyl. In some embodiments, ring A is selected from

[0111] In some embodiments, ring A is selected from A1 substituted pyrazolyl, imidazolyl, 1,2,3-triazolyl, or isoxazolyl. In some embodiments, ring A is selected from wherein — and X 6 are connected. In some embodiments, ring A is selected from A1 substituted pyrazolyl, imidazolyl, 1,2,3-triazolyl, or isoxazolyl. In some embodiments, ring A is selected from wherein — and X 6 are connected.

[0112] In some embodiments, ring A is selected from wherein — and X 6 are connected. In some embodiments, ring A is selected from Among them, ---- and X 6 Connected.

[0113] In some implementation schemes, R A1 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, or optionally influenced by one or more R. A2 The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl C 1-3 Alkylene, 3-10 membered heterocyclic alkyl C 1-3 Alkylene, 3-10 membered cycloalkyl-O-, 3-10 membered heterocycloalkyl-O-, 3-10 membered cycloalkyl-S-, 3-10 membered heterocycloalkyl-S-, 6-10 membered aryl, 5-10 membered heteroaryl, 6-10 membered aryl C 1-3 alkylene or 5-10 heteroaryl C 1-3 Alkylene.

[0114] In some implementation schemes, R A1 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, or optionally influenced by one or more R. A2 The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4 Alkylamino, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkyl C 1-3 Alkylene or 3-10 membered heterocyclic alkyl C 1-3 Alkylene. In some embodiments, R A1 Each is independently selected from one or more R options. A2 The following groups are substituted: 3-10-membered cycloalkyl-O-, 3-10-membered heterocycloalkyl-O-, 3-10-membered cycloalkyl-S-, 3-10-membered heterocycloalkyl-S-, 6-10-membered aryl, 5-10-membered heteroaryl, 6-10-membered aryl C 1-3 alkylene or 5-10 heteroaryl C 1-3 Alkylene.

[0115] In some implementation schemes, R A1 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, or optionally influenced by one or more R. A2 The following groups are substituted: C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, diC1-3 alkylamino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkylC 1-2 alkylene, or 4-6 membered heterocycloalkylC 1-2 alkylene. In some embodiments, R A1 each is independently selected from the group consisting of deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, or is optionally substituted with one or more R A2 methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, oxetanylmethyl, azetidinylmethyl, tetrahydrofuranylmethyl, tetrahydropyrrolylmethyl, imidazolidinylmethyl, pyrazolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, or morpholinylmethyl. In some embodiments, R 1-2 alkylene, or 5-6 membered heteroarylC 1-2 alkylene.

[0116] In some embodiments, R A1 each is independently selected from the group consisting of deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, or is optionally substituted with one or more R A2 methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, oxetanylmethyl, azetidinylmethyl, tetrahydrofuranylmethyl, tetrahydropyrrolylmethyl, imidazolidinylmethyl, pyrazolidinylmethyl, tetrahydropyranylmethyl, piperidinylmethyl, piperazinylmethyl, or morpholinylmethyl. In some embodiments, R A1 each is independently selected from the group consisting of deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, or is optionally substituted with one or more R A2The following groups are substituted: n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl-O-, cyclobutyl-O-, cyclopentyl-O-, cyclohexyl-O-, oxacyclobutyl-O-, azacyclobutyl-O-, tetrahydrofuranyl-O-, tetrahydropyrrolyl-O-, imidazoalkyl-O-, pyrazolyl-O-, tetrahydropyranyl-O-, piperidinyl-O-, piperazinyl-O-, morpholinyl-O-, cyclopropyl-S-, cyclobutyl-S-, cyclopentyl-S-, cyclohexyl-S-, oxacyclobutyl-S-, azacyclobutyl-S-, tetrahydrofuranyl-S-, tetrahydropyrrolyl-S-, imidazoalkyl-S- -, pyrazolyl-S-, tetrahydropyranyl-S-, piperidinyl-S-, piperazinyl-S-, morpholinyl-S-, phenyl, benzyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazoleyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrazinyl, furanylmethylene, pyrrolylmethylene, thiophenylmethylene, pyrazolylmethylene, imidazoleylmethylene, triazolylmethylene, oxazolylmethylene, isoxazolylmethylene, thiazolylmethylene, isothiazolylmethylene, pyridinylmethylene, pyrimidinylmethylene, pyrazinylmethylene, or pyrazinylmethylene.

[0117] In some implementation schemes, R A1 Each is independently selected from deuterium, -F, -Cl, -Br, -CN, or arbitrarily selected by one or more R. A2 The following groups are substituted: methyl, ethyl, cyclopropyl, cyclobutyl, cyclopropylmethylene, cyclobutylmethylene, isopropyl, isobutyl, methoxy, cyclopropyl-S-, phenyl, or

[0118] In some implementation schemes, R A1 Each is independently selected from deuterium, -F, -Cl, -Br, -OH, -NH2, or -CN.

[0119] In some implementation schemes, R A1 Each is independently selected from one or more R options. A2 The following groups are substituted: methyl, ethyl, cyclopropyl, cyclobutyl, cyclopropylmethylene, cyclobutylmethylene, isopropyl, isobutyl, methoxy, cyclopropyl-S-, phenyl, or

[0120] In some implementation schemes, R A1 Each is independently selected from deuterium, -F, -Cl, -Br, -CN, or arbitrarily selected by one or more R. A2 The substituted groups include: methyl, ethyl, cyclopropyl, cyclobutyl, cyclopropylmethylene, or cyclobutylmethylene. In some embodiments, R A1each independently selected from optionally substituted: isopropyl, isobutyl, methoxy, cyclopropyl-S-, -O-, -NH-, -N=, A2 substituted: isopropyl, isobutyl, methoxy, cyclopropyl-S-, -O-, -NH-, -N=, phenyl, or

[0121] In some embodiments, each R A2 each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, deuterated C 1-4 alkyl, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, halo-C 1-4 alkylamino, or halo-di-C 1-4 alkylamino.

[0122] In some embodiments, each R A2 each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, di-C 1-3 alkylamino, deuterated C 1-3 alkyl, halo-C 1-3 alkyl, halo-C 1-3 alkoxy, halo-C 1-3 alkylamino, or halo-di-C 1-3 alkylamino.

[0123] In some embodiments, each R A2 each independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, trifluoromethoxy, trifluoroethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0124] In some embodiments, each R A2 each independently selected from deuterium, oxo, -F, -Cl, or methyl. In some embodiments, each R A2 each independently selected from -OH.

[0125] In some embodiments, R A1each independently selected from deuterium, -F, -CI, -CN, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethylidenyl, cyclobutylmethylidenyl, isopropyl, isobutyl, methoxy, phenyl, or

[0126] In some embodiments, R A1 each independently selected from deuterium, -F, -CI, -CN, methyl, difluoromethyl, trifluoromethyl, ethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopropylmethylidenyl, or cyclobutylmethylidenyl. In some embodiments, R A1 each independently selected from isopropyl, isobutyl, methoxy, phenyl, or

[0127] In some embodiments, R A1 each independently selected from deuterium, -F, -CI, -CN, methyl, ethyl, cyclobutyl, or cyclopropylmethylidenyl. In some embodiments, R A1 each independently selected from isopropyl, isobutyl, trifluoromethyl, methoxy, cyclopropyl, phenyl, or

[0128] In some embodiments, ring A is selected from

[0129] wherein — and X 6 are connected.

[0130] In some embodiments, ring A is selected from wherein — and X 6 are connected. In some embodiments, ring A is selected from

[0131] wherein — and X 6 are connected.

[0132] In some embodiments, ring A is selected from wherein — and X6 is attached to X is attached to X 6 .

[0133] In some embodiments, ring A is selected from is attached to X 6 . In some embodiments, ring A is selected from is attached to X 6 . In some embodiments, ring A is selected from is attached to X 6 . In some embodiments, ring A is selected from is attached to X 6 . In some embodiments, ring A is selected from is attached to X 6 . In some embodiments, ring A is selected from is attached to X 6 .

[0134] In some embodiments, ring B is selected from 5-9 membered heteroaryl optionally substituted with one or more R B1 .

[0135] In some embodiments, ring B is selected from 5-9 membered heteroaryl optionally substituted with one or more R B1 In some embodiments, the heteroaryl contains 1, 2, or 3 heteroatoms selected from N, O, or S.

[0136] In some embodiments, ring B is selected from 5-9 membered heteroaryl optionally substituted with one or more R B1 In some embodiments, the heteroaryl contains 1, 2, or 3 heteroatoms selected from N, O, or S.

[0137] In some embodiments, ring B is selected from 5-9 membered heteroaryl optionally substituted with one or more R B1The following groups may be substituted: furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazoleyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzopyrrolyl, benzopyrazolyl, benzoimidazolyl, benzofuranyl, benzooxazolyl, benzoisooxazolyl, benzothiophenyl, benzothiazolyl, benzoisothiazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazolepyridyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazolepyrimidinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazolepyrazinyl, pyrrolopyridazinyl, or imidazolepyridazinyl.

[0138] In some implementations, ring B is selected from one or more Rs. B1 The following groups may be substituted: pyrazolyl, imidazoleyl, triazoleyl, thiazolyl, or pyridyl.

[0139] In some implementations, ring B is selected from one or more Rs. B1 The substituted groups include: pyrazolyl, imidazolyl, 1,2,3-triazolyl, thiazolyl, or pyridyl. In some embodiments, ring B is selected from those optionally replaced by one or more R groups. B1 Substituted pyrazol group.

[0140] In some implementations, ring B is selected from one or more Rs. B1 The following groups are substituted:

[0141] In some implementations, ring B is selected from one or more Rs. B1 The following groups are substituted: Among them, ---- and X 5 Connected.

[0142] In some implementation schemes, ring B is selected from... Among them, ---- and X 5 Connected.

[0143] In some implementation schemes, ring B is selected from... Among them, ---- and X 5 Connected.

[0144] In some implementation schemes, R B1 Each is independently selected from deuterium, halogen, -OH, -NH2, -CN, or optionally influenced by one or more R. B2 The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, diC 1-4alkylamino, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered cycloalkylC 1-3 alkylene, or 3-10 membered heterocycloalkylC 1-3 alkylene.

[0145] In some embodiments, R B1 each is independently selected from deuterium, halogen, -OH, -NH2, -CN, or is optionally substituted with one or more R B2 substituted with one or more R 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, diC 1-3 alkylamino, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 3-6 membered cycloalkylC 1-2 alkylene, or 4-6 membered heterocycloalkylC 1-2 alkylene.

[0146] In some embodiments, R B1 each is independently selected from deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, or is optionally substituted with one or more R B2 methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, cyclopropylmethylidene, cyclobutylmethylidene, cyclopentylmethylidene, cyclohexylmethylidene, oxetanylmethylidene, azetidinylmethylidene, tetrahydrofuranylmethylidene, tetrahydropyrrolylmethylidene, imidazolidinylmethylidene, pyrazolidinylmethylidene, tetrahydropyranylmethylidene, piperidinylmethylidene, piperazinylmethylidene, or morpholinylmethylidene.

[0147] In some embodiments, R B1 each is independently selected from deuterium, -F, -Cl, -Br, -CN, or is optionally substituted with one or more R B2 methyl or ethyl.

[0148] In some embodiments, each R B2 each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, diC 1-4 alkylamino, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4alkylamino, or halodicyano 1-4 alkylamino.

[0149] In some embodiments, each R B2 is each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, dicyano 1-3 alkylamino, dicyano 1-3 alkyl, halogen 1-3 alkyl, halogen 1-3 alkoxy, halogen 1-3 alkylamino, or halodicyano 1-3 alkylamino.

[0150] In some embodiments, each R B2 is each independently selected from deuterium, oxo, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, trideuteromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, trifluoromethoxy, trifluoroethoxy, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

[0151] In some embodiments, each R B2 is each independently selected from deuterium, oxo, -F, -Cl, or methyl.

[0152] In some embodiments, R B1 is each independently selected from deuterium, -F, -Cl, methyl, ethyl, difluoromethyl, trifluoromethyl, difluoroethyl, or trifluoroethyl.

[0153] In some embodiments, R B1 is each independently selected from deuterium, -F, -Cl, methyl, ethyl, difluoromethyl, trifluoromethyl, difluoroethyl, or trifluoroethyl.

[0154] In some embodiments, R B1 is each independently selected from deuterium, methyl, ethyl, difluoromethyl, trifluoromethyl, difluoroethyl, or trifluoroethyl.

[0155] In some embodiments, ring B is selected from wherein ---- is attached to X 5 In some embodiments, ring B is selected from wherein ---- is attached to X 5connected.

[0156] In some embodiments, the C 1-12 selected from C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 .

[0157] In some embodiments, the C 1-6 alkyl is selected from C 1-4 alkyl, C 1-3 alkyl, or C 1-2 alkyl.

[0158] In some embodiments, the C 1-6 alkylene is selected from C 1-4 alkylene, C 1-3 alkylene, or C 1-2 alkylene.

[0159] In some embodiments, the halogen of the present disclosure is selected from F, Cl, Br, or I.

[0160] In some embodiments, the halo of the present disclosure is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo of the present disclosure is fluoro.

[0161] In some embodiments, "one or more" of the present disclosure can refer to an integer from one to less than ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; or, "one or more" refers to one, two, three, four, five, or six; or, "one or more" refers to one, two, three, or four.

[0162] In some embodiments, the 3-12 membered of the present disclosure is selected from 3-10 membered, 3-8 membered, 3-6 membered, 3-5 membered, 3-4 membered, 4-7 membered, 4-6 membered, 4-5 membered, 5-8 membered, 5-7 membered, or 5-6 membered.

[0163] In some embodiments, the heterocycloalkyl of the present disclosure contains one or two heteroatoms selected from N or O.

[0164] In some embodiments, the heterocycloalkyl of the present disclosure contains one N atom.

[0165] In some embodiments, the heterocycloalkyl of the present disclosure contains one O atom.

[0166] In some embodiments, the heterocycloalkyl of the present disclosure contains 1 N atom and 1 O atom.

[0167] In some embodiments, the heteroaryl of the present disclosure contains 1 or 2 heteroatoms selected from N, O, or S.

[0168] In some embodiments, the heteroaryl of the present disclosure contains 1 or 2 N atoms.

[0169] In some embodiments, the heteroaryl of the present disclosure contains 1 N atom and 1 O atom.

[0170] In some embodiments, the heteroaryl of the present disclosure contains 1 N atom and 1 S atom.

[0171] In some embodiments, the heterocycloalkyl of the present disclosure comprises a monocyclic, spiro, fused, or bridged ring. In some embodiments, the heterocycloalkyl of the present disclosure comprises a monocyclic or spiro ring. In some embodiments, the heterocycloalkyl of the present disclosure comprises a monocyclic or bridged ring.

[0172] In some embodiments, in the compound of Formula (I), or a pharmaceutically acceptable salt thereof, all hydrogen atoms can be optionally substituted with one or more deuterium.

[0173] The present disclosure relates to a compound of Formula (II), Formula (II-A), Formula (II-B), or a pharmaceutically acceptable salt thereof,

[0174] wherein R X1 , X 5 , X 6 , Z 1 , Z 2 , Z 3 , R Z , ring A, ring B are as defined in the present disclosure.

[0175] The present disclosure relates to a compound of Formula (III), Formula (III-A), Formula (III-B), or a pharmaceutically acceptable salt thereof,

[0176] wherein Z 1 , Z 2 , Z 3 , R Z , ring A, ring B are as defined in the present disclosure.

[0177] In some embodiments, the present disclosure includes the above-defined variables and embodiments thereof, and any combination thereof.

[0178] The present disclosure also relates to the following compounds, or a pharmaceutically acceptable salt thereof: The present disclosure also relates to the following compounds, or a pharmaceutically acceptable salt thereof:

[0179] The present disclosure also relates to the following compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0180] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further includes a pharmaceutically acceptable excipient.

[0181] In another aspect, the present disclosure relates to a method of treating a disease in a mammal comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0182] In another aspect, the present disclosure relates to the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for the manufacture of a medicament for treating a disease.

[0183] In another aspect, the present disclosure relates to the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for treating a disease.

[0184] In another aspect, the present disclosure relates to a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for use in treating a disease.

[0185] In some embodiments, the disease is selected from an ALK-related disease.

[0186] In some embodiments, the disease (e.g., an ALK-related disease) is selected from a cancer.

[0187] In some embodiments, the cancer is selected from non-small cell lung cancer (e.g., ALK-positive non-small cell lung cancer) or anaplastic large cell lymphoma (e.g., ALK-positive anaplastic large cell lymphoma).

[0188] Technical effects

[0189] The compounds of the present disclosure have high ALK kinase inhibitory activity (e.g., WT type, G1202R mutant, or L1196M G1202R mutant ALK) and cell proliferation inhibitory activity (e.g., BaF3-EML4-ALK-V1-G1202R cells, BaF3-EML4-ALK-V1-G1202R / L1196M cells, Karpas299 (NPM1-ALK) cells, or NCI-H2228 (EML4-ALK-V3) cells), while showing good drugability in in vivo and in vitro pharmacokinetic (e.g., AUC, half-life), bioavailability, and / or pharmacodynamic studies.

[0190] Definitions

[0191] The following terms used in the present disclosure have the following meanings unless otherwise indicated. A particular term should not be construed as indefinite or unclear if not specifically defined, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0192] The term “substituted” means that any one or more hydrogen atoms or lone pair of electrons on a specified atom are replaced with a substituent, provided that the valence of the specified atom is normal and that the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms or one or two pairs of lone pair of electrons are replaced, and oxo does not occur on an aromatic group.

[0193] "substituents" described herein include all substituents mentioned herein in context, for example including those defined by the terms "alkyl", "alkylene", "heteroalkyl", "alkoxy", "alkylamino", "dialkylamino", "alkylthio", "alkenyl", "alkynyl", "cycloalkyl", "cycloalkenyl", "heterocyclyl", "heterocycloalkyl", "aryl", "heteroaryl", and the like related groups, and corresponding non-limiting or exemplary groups, some non-limiting examples of which include deuterium atom, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido group, sulfoxide group, sulfone group, sulfonamide group, carboxyl, carboxaldehyde group, imine group, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, aralkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroaralkoxy, heteroaralkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, ureido, epoxy group, and ester group, and the like, optionally substituted with one or more substituents selected from oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0194] In some embodiments herein, the substituents are selected from deuterium atom, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido group, sulfoxide group, sulfone group, sulfonamide group, carboxyl, aldehyde group, imine group, C 1-12 alkyl, halo-C 1-12 alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3-12 membered cycloalkenyl, halo-3-12 membered cycloalkenyl, C 2-12 alkynyl, halo-C 2-12alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C 1-12 heteroalkyl, halo-C 1-12 heteroalkyl, C 1-12 alkoxy, C 1-12 alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered aryl C 1-12 alkylene, 6-10 membered aryl C 1-12 alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclyl C 1-12 alkylene, 3-12 membered heterocyclyl C 1-12 alkoxy, 3-12 membered heterocyclyl C 1-12 alkylthio, C 1-12 acyl, C 1-12 acyloxy, carbamate, C 1-12 amide, urea, epoxy, C 2-12 ester, oxo and thioxo, and the like, optionally substituted with one or more substituents selected from: deuterium atom, oxo, hydroxyl, amino, nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, halo-C 1-12 alkoxy, C 1-12 alkylamino, di-C 1-12 alkylamino, halo-C 1-12 alkylamino, halo-di-C 1-12 alkylamino, carboxyl, -C(O)O-C 1-12 alkyl, -OC(O)-C 1-12 alkyl, -C(O)NH2, -C(O)NH-C 1-12 alkyl, -C(O)N(C 1-12 alkyl)2, -NHC(O)-C 1-12 alkyl, -C(O)-C 1-12 alkyl, -S(O)-C 1-12 alkyl, -S(O)2-C 1-12 alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 alkyl, -S(O)2N(C 1-12 alkyl)2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12alkylene, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 3-12 membered heterocyclylC 1-12 alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC1-12alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 alkylene or 6-10 membered aryloxy.

[0195] The term "substituted" or "by" means that a specified atom or group can be replaced with or by a specified other atom or group. For example, 1 or 2 or 3 -CH2- in -CH2CH2CH2- can be replaced with O, S, NH to give -O-CH2-CH2-, -O-CH2-, -CH2-O-CH2-, -CH2-O-, -CH2-CH2-O-, -O-, and the like.

[0196] The term "optionally" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl can be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, and the like), or fully substituted (CF2CF3). It will be understood by those skilled in the art that, for any group containing one or more substituents, no substitution or substitution pattern is introduced that is not spatially possible and / or synthetically feasible.

[0197] C m-n in this document is an integer having the indicated number of carbon atoms in the moiety. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0198] When any variable (e.g., R) occurs more than one time in a compound; each definition is independent. Thus, for example, if a group is substituted with 2 occurrences of R, then each R is selected independently of the other.

[0199] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a covalent bond.

[0200] When one of the variables is selected from a covalent bond, it indicates that the two groups to which it is attached are directly connected, such as L represents a covalent bond in A-L-Z means that the structure is actually A-Z.

[0201] When a recited linking group is not indicated as to its direction of attachment, its direction of attachment is arbitrary, such as in A-L-Z, where the linking group L is -M-W-, this structure can be either A-M-W-Z or A-W-M-Z.

[0202] When a substituent is bonded to two atoms of a ring, the substituent can be bonded to any atom of the ring. For example, the structural unit represents that it can be substituted at any position on the cyclohexyl or cyclohexadiene.

[0203] The term "halo" or "halogen" means fluoro, chloro, bromo, and iodo.

[0204] The term "hydroxy" means an -OH group.

[0205] The term "cyano" means a -CN group.

[0206] The term "mercapto" means an -SH group.

[0207] The term "amino" means an -NH2 group.

[0208] The term "nitro" means an -NO2 group.

[0209] The term "alkylene" means a saturated straight or branched chain divalent hydrocarbon radical of the general formula n H 2n having from 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6 alkylene" means an alkylene group having from 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or -CH2CH(CH3)-), butylene (-CH2CH2CH2CH2-, -CH2CH(CH3)CH2-, or -CH2CH2CH(CH3)-), and the like. The alkylene group is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0210] The term "alkyl" means a saturated straight or branched chain monovalent hydrocarbon group of the general formula n H 2n+1saturated hydrocarbon group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl group can be straight-chained or branched, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. For example, the term "C 1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). The alkyl group is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy. Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, and alkylthio groups has the same definition as above.

[0211] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and the hydrogen atoms attached thereto) are each independently replaced with the same or different heteroatom group. Unless otherwise indicated, the heteroalkyl group contains 1, 2, or 3 heteroatom groups, non-limiting examples of which include O, S, N, or NH, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6 heteroalkyl" refers to a heteroalkyl group containing 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom groups can be placed at any position in the heteroalkyl group (e.g., internal or terminal positions), including the position that connects the heteroalkyl group to the rest of the molecule. Typically, where more than one heteroatom group is present, the heteroatom groups are not adjacent to one another. Exemplary heteroalkyl groups include, but are not limited to, alkoxy, alkoxyalkylene, alkylamino, alkylaminoalkylene, dialkylamino, dialkylaminoalkylene, and the like. The heteroalkyl group is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0212] The term "alkoxy" refers to -O-alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Wherein the alkyl moiety is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0213] The term "alkylamino" refers to -NH-alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Wherein the alkyl moiety is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0214] The term "dialkylamino" refers to -N(alkyl)2, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Wherein the alkyl moieties are optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0215] The term "alkylthio" refers to -S-alkyl, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Wherein the alkyl moiety is optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0216] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon and hydrogen atoms, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl, 1 -butenyl, isobutenyl, 1,3- butadienyl, and the like. The alkenyl group is optionally substituted with one or more substituents selected from oxo, hydroxyl, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0217] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group having at least one triple bond, consisting of carbon and hydrogen atoms, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1 -propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡C-C≡CH), and the like. The alkynyl group is optionally substituted with one or more substituents selected from oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0218] The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents selected from oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0219] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and has at least one double bond and can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like. The cycloalkenyl group is optionally substituted with one or more substituents selected from oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0220] The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not a fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, fused or spirocyclic ring. Unless otherwise indicated, the heterocycle typically is a 3- to 12-membered, 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 3- to 7-membered or 4- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and / or boron (preferably 1 or 2 heteroatoms). Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like. The heterocyclyl group is optionally substituted with one or more substituents selected from oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0221] The term "heterocycloalkyl" refers to cyclic groups that are fully saturated and can exist as monocyclic, bridged cyclic, or spirocyclic. Unless otherwise indicated, the heterocycle is typically a 3- to 12-membered, 3- to 10-membered, 4- to 8-membered, 5- to 8-membered, 5- to 6-membered, 3- to 7-membered, or 4- to 6-membered ring containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon, and / or boron (preferably 1 or 2 heteroatoms). Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thiiranyl, aziridinyl, non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxinanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl. The heterocycloalkyl groups are optionally substituted with one or more substituents selected from oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0222] The term "aryl" refers to all-carbon monocyclic or fused polycyclic aromatic ring groups having a conjugated pi-electron system. For example, aryl groups can have from 6 to 20 carbon atoms, from 6 to 14 carbon atoms, or from 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracyl groups, and the like. The aryl group is optionally substituted with one or more substituents selected from hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C(0)0-alkyl, -OC(O)-alkyl, -C(0)NH2, -C(0)NH-alkyl, -C(0)N(alkyl)2, -NHC(0)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(0)2-alkyl, -S(0)2NH2, -S(0)2NH-alkyl, -S(0)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0223] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic system containing at least one ring atom selected from N, O, S, with the remaining ring atoms being C, typically having from 5 to 14 members, from 5 to 12 members, from 5 to 10 members, from 5 to 8 members, from 5 to 7 members, or from 5 to 6 members. Preferred heteroaryl groups have a single 4- to 8-membered ring, especially a 5- to 6-membered ring, or multiple fused rings comprising from 5 to 14, especially from 5 to 10, ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiophenyl, indolyl, isoindolyl, and the like. The heteroaryl group is optionally substituted with one or more substituents selected from hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxy, -C(0)0-alkyl, -OC(O)-alkyl, -C(0)NH2, -C(0)NH-alkyl, -C(0)N(alkyl)2, -NHC(0)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(0)2-alkyl, -S(0)2NH2, -S(0)2NH-alkyl, -S(0)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

[0224] Unless otherwise specified, the term "deuterated C1-12 "alkyl" refers to any of the above "C 1-12 "alkyl" wherein any number and position of H atoms are replaced by deuterium atoms. The C 1-12 deuterated alkyl group can be C 1-6 deuterated alkyl group or C 1-3 deuterated alkyl group. Examples of deuterated alkyl groups include, but are not limited to, -CH2D, -CHD2, -CD3, and the like.

[0225] The term "treatment" means the administration of a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0226] (i) inhibiting the disease or condition, i.e., arresting its development;

[0227] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0228] The term "prevention" means the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the disease or condition but has not yet been diagnosed as having it.

[0229] The term "therapeutically effective amount" means the amount of a compound of the disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder as described herein. The amount of a compound of the disclosure that will constitute a "therapeutically effective amount" will depend on the compound, the disease state being treated, the severity or the disease state, the age of the mammal, and the manner and

[0230] The term "pharmaceutically acceptable" in reference to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0231] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like can be mentioned.

[0232] The term "pharmaceutical composition" means a mixture of one or more compounds of the disclosure or salts thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the disclosure to an organism.

[0233] The term "pharmaceutically acceptable excipient" means an excipient that is not biologically or otherwise undesirable, i.e., the excipient can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The choice of a suitable excipient will depend on the particular mode of administration and the dosage of the compound of the disclosure to be administered.

[0234] The words "comprise" or "comprising" and variations thereof such as "comprises" or "comprising", when used in this publication, are to be interpreted as specifying the presence of the stated features or components and do not preclude the presence of one or more additional features or components.

[0235] The compounds and intermediates of the disclosure can also exist in different tautomeric forms and all such forms are embraced within the scope of the disclosure. The term "tautomer" or "tautomeric forms" refers to different energy structures that are interconvertible via a low energy barrier. For example, prototropic tautomers (also known as proton transfer tautomers) include interconversions via the migration of a proton, such as keto-enol and imine-enamine isomerization. A specific example of prototropic tautomers is the imidazole moiety, wherein a proton can migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0236] The disclosure also includes isotopically-labeled compounds of the disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc. For example, it is understood that compounds of the disclosure wherein one or more hydrogen atoms are replaced by deuterium atoms are within the scope of the compounds of the disclosure of Formula (I).

[0237] Certain isotopically-labeled compounds of the present disclosure (for example, with 3 H and 14 C) can be used in compound and / or substrate tissue distribution analysis. Tritiated (i.e., with 3 H), and carbon-14 (i.e., with 14 C), isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent in a procedure similar to those disclosed in the schemes and / or examples below.

[0238] In addition, substitution with heavier isotopes such as deuterium (i.e., 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and hence can be preferred in some circumstances. Deuterium substitution can be in any portion of the molecule.

[0239] The compounds of the present disclosure can be asymmetric, for example, having one or more stereogenic centers. Unless otherwise indicated, all stereoisomers (e.g., enantiomers and diastereomers) are included within the scope of the present disclosure. Compounds of the present disclosure containing an asymmetric carbon atom can be isolated in optically active or racemic forms. An optically active form can be obtained by resolution of a racemic mixture or by synthesis from an optically active starting material or reagent.

[0240] The compounds of the present disclosure can have one or more atropisomers, which refer to optically active isomers resulting from the restriction of free rotation about a single bond due to steric hindrance. Compounds of the present disclosure containing a chiral axis can be isolated in racemic form. When the energy barrier to free rotation of a single bond of a compound of the present disclosure containing a chiral axis is sufficiently high, its atropisomers can be isolated in optically active form.

[0241] Pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with suitable pharmaceutically acceptable excipients.

[0242] Pharmaceutical compositions of the present disclosure can be manufactured by methods well known in the art, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze drying, or lyophilizing processes.

[0243] In all of the methods of administering the compounds of general formula (I) described herein, the dosage administered daily is from 0.001 to 2000 mg / kg body weight, and the compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the embodiments set forth below with other chemical synthetic methods known to those skilled in the art, and equivalents thereof as known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present disclosure.

[0244] The chemical reactions of the specific embodiments of the present disclosure are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical changes being effected. In the synthetic schemes and examples described below, all substituents unless otherwise indicated are as previously defined. The chemical reactions described in the schemes and examples are performed in any suitable order unless otherwise indicated. The present disclosure contemplates methods of making the compounds of the present disclosure, and the starting materials are either commercially available or synthesized by the methods known to those skilled in the art.

[0245] when -X 5 -X 6 When -X X1 , X 5 , X 6 , Z 1 , Z 2 , Z 3 , R Z , ring A, ring B are as defined in the present disclosure.

[0246] Scheme 1

[0247] As shown in Scheme 1, compounds of formula (II-B) can be prepared from compound c. Compound a can be subjected to a boron esterification reaction to give compound b. Compound c and compound d can undergo a Grignard exchange reaction to give compound e, which is then reduced to give compound f, which is then subjected to a Suzuki coupling reaction with compound b to give compound h. Compound h can undergo a nucleophilic substitution reaction with 4-bromo-6-chloropyridazin-3-amine to give compound i, which is then subjected to an intramolecular Heck coupling reaction to give compounds of formula (II-B).

[0248] Each of the products resulting from the reactions in the above schemes can be obtained by the use of conventional isolation techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. The starting materials can be obtained either by synthesis or purchased from commercial suppliers (e.g., but not limited to, Aldrich or Sigma). These materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described in the present disclosure can be obtained as single isomers or as mixtures of isomers using the synthetic methods described.

[0249] The following abbreviations are used herein:

[0250] EA stands for ethyl acetate; DMF stands for N,N-dimethylformamide; DCM stands for dichloromethane; MeOH stands for methanol; TLC stands for thin layer chromatography; ACN stands for acetonitrile; TFA stands for trifluoroacetic acid; THF stands for tetrahydrofuran; NaNO2 stands for sodium nitrite; CuCl stands for copper chloride; NaHCO3 stands for sodium bicarbonate; Na2SO4 stands for sodium sulfate; NaCl stands for sodium chloride; NIS stands for N-iodosuccinimide; Na2SO3 stands for sodium sulfite; MgSO4 stands for magnesium sulfate; K2CO3 stands for potassium carbonate; X Phos Pd G2 stands for chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); PdCl2(dppf) stands for 1,1- bis(diphenylphosphino)ferrocene palladium dichloride; NaH stands for sodium hydride; NaOH stands for sodium hydroxide; AcOH stands for acetic acid; NaBH4 stands for sodium borohydride; NEt3 stands for triethylamine; NH4Cl stands for ammonium chloride; Pd(OAc)2 stands for palladium acetate; t-AmOH stands for tert-amyl alcohol; N2 stands for nitrogen; Et stands for ethyl; Pd(dppf)Cl2.DCM stands for [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex; S-PHOS stands for 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl; TES stands for triethylsilane; NBS stands for N-bromosuccinimide; Pd2(dba)3 stands for tris(dibenzylideneacetone)dipalladium; SEM stands for (trimethylsilyl)ethoxymethyl; SEMCl stands for 2-(trimethylsilyl)ethoxymethyl chloride; TBAF stands for tetra-n-butylammonium fluoride.

[0251] Commercially available compounds are used under the supplier's catalog name.

[0252] For the sake of clarity, the present application is further illustrated by examples, which are not intended to limit the scope of the disclosure. The present disclosure has been described in detail and specific embodiments thereof have been disclosed with particularity, but various changes, modifications and improvements can be suggested to one skilled in the art and it is intended that the application span all such changes, modifications and improvements as can be drawn within the scope of the application as claimed.

[0253] All reagents used in the present disclosure are commercially available and used without further purification. DETAILED DESCRIPTION

[0254] Example 1

[0255] Step 1:

[0256] Compound 1-G (1.45 g), compound 1-F (3.0 g) were added into 1,4-dioxane (100 mL), K2CO3 solution (3.3 g K2CO3 dissolved in 20 mL purified water) was added, PdCl2(dppf) (250 mg) was added, and the reaction was allowed to proceed at 75 °C for 5 hours under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, extracted with EA (100 mL) twice, the organic phases were combined, washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid outflow, and 3.04 g of intermediate 1-H was obtained by column chromatography. MS (ESI) m / z [M+H] + : 363.15

[0257] Step 2:

[0258] Intermediate 1-H (1.6 g) and THF (40 mL) were mixed, and the reaction system was cooled to 0-5 °C, NaH (352 mg) was added portionwise, stirred for 30 minutes, 4-bromo-6-chloropyridazin-3-amine (1.1 g) was added, and the reaction was allowed to proceed at 60-65 °C for 5 hours. After the reaction was completed, it was cooled to room temperature, quenched with purified water (40 mL), extracted with EA (40 mL*3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid outflow, and 700 mg of intermediate 1-I was obtained by column chromatography. MS (ESI) m / z [M-H] - : 488.1.

[0259] Step 3:

[0260] Intermediate 1-I (300 mg), n-butyl di(1-adamantyl)phosphine (87 mg), potassium tert-pentoxide (261 mg), Pd(OAc)2 (30 mg) and t-AmOH (10 mL) were mixed, stirred for 5 minutes, and the reaction was allowed to proceed under N2 atmosphere for 3 hours by microwave (120 °C, 150 W). The reaction temperature was reduced to room temperature, purified water (10 mL) and EA (10 mL) were added to the reaction solution, stirred for 5 minutes, separated, the organic phase was collected, washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid outflow, and 169 mg of compound 1 was obtained by column chromatography. MS (ESI) m / z [M+H] - : 454.18.

[0261] 1H NMR(500MHz, DMSO-d6)δ7.65(dd,J=10.2,2.7Hz,1H),7.63(s,1H),7.29–7.1 8(m,2H),6.55(s,2H),6.24(s,1H),5.34(qd,J=6.4,2.0Hz,1H),4.33(dq,J= 14.1,7.1Hz,1H),4.20(dq,J=14.2,7.2Hz,1H),3.88(s,3H),3.66(d,J=16.1 Hz,1H),2.78(d,J=16.0Hz,1H),1.75(d,J=6.3Hz,3H),1.25(t,J=7.1Hz,3H).

[0262] Example 2

[0263] Step 1:

[0264] 4.6 g of 3-chloro-4-iodo-1H-pyrazole and 3.0 g of cyclobutyl bromide were added to 50 mL of ACN, followed by 13.0 g of Cs₂CO₃. The mixture was heated to 75 °C and reacted for 15 hours. After the reaction was complete, the mixture was cooled to room temperature and extracted twice with 100 mL of EA. The combined organic phases were washed with 100 mL of saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated until no liquid flowed out. 4.9 g of intermediate 2-A was obtained by silica gel column chromatography. MS (ESI) m / z [M+H] + 282.97

[0265] Step 2:

[0266] Intermediate 2-A (4.6 g) was added to THF (100 mL), stirred, and cooled to -30 °C. A 1.3 M, 16.3 mL THF solution of the isopropyl magnesium chloride-lithium chloride complex was added dropwise. After stirring for 2 hours, a 3-iodo-1-methyl-1H-pyrazole-4-carboxaldehyde THF solution (3.2 g dissolved in 150 mL THF) was added dropwise, and the reaction was maintained at -30 °C for 2 hours. After the reaction was complete, an aqueous solution of ammonium chloride was added to quench the reaction. The mixture was extracted with EA (50 mL * 3), the organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated until no liquid flowed out to obtain 5.3 g of intermediate 2-B.

[0267] Step 3:

[0268] Intermediate 2-B (5.6 g), triethylsilane (11.2 mL) were added into DCM (200 mL), stirred for 5 min, cooled to -20 °C, trifluoroacetic acid (5.5 mL) was added dropwise, maintained at -20 °C for 2 h. After the reaction was completed, it was neutralized by adding sodium bicarbonate solution. EA (60 mL*3) was used to extract, the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. Silica gel column chromatography was used to separate to give 3.1 g of intermediate 2-C. MS (ESI) m / z [M+H] + :377.10.

[0269] Step 4:

[0270] Intermediate 2-C (1.25 g), compound 1-G (715 mg), Pd(dppf)Cl2.DCM (100 mg) were added into 1,4-dioxane (50 mL), potassium carbonate aqueous solution (910 mg of potassium carbonate dissolved in 15 mL of purified water) was added, warmed to 75 °C under N2atmosphere, stirred for 5 h. After the reaction was completed, it was cooled to room temperature, 100 mL of purified water was added, EA (50 mL*3) was used to extract, the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. Silica gel column chromatography was used to separate to give 1.08 g of intermediate 2-D.

[0271] Step 5:

[0272] Intermediate 2-D (1.08 g) was added into THF (50 mL), sodium hydride (333 mg) was added, stirred for 0.5 h, 4-bromo-6-chloropyridazin-3-amine (752 mg) was added, warmed to 60 °C for 9 h. After the reaction was completed, it was quenched by adding purified water (50 mL), EA (50 mL*3) was used to extract, the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. Silica gel column chromatography was used to separate to give 420 mg of intermediate 2-E.

[0273] Step 6:

[0274] Intermediate 2-E (420 mg), n-butyl bis (1-adamantyl) phosphine (150 mg), potassium tert-pentoxide (300 mg), Pd(OAc)2(50 mg) and t-AmOH (25 mL) were mixed, stirred for 5 min, reacted under N2atmosphere for 2 h by microwave (120 °C, 150 W). It was cooled to room temperature, purified water (10 mL) and EA (10 mL) were added to the reaction system, stirred for 5 min, separated, the organic phase was collected, washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow out. The concentrate was separated by silica gel column chromatography to give 34 mg of compound 2. MS (ESI) m / z [M+H] + :480.26.

[0275] 1 H NMR (500MHz, DMSO-d6) δ7.79–7.49(m,2H),7.24(ddt,J=10.9,8.3,4.3Hz,2H),6.57(s,2H),6.23(s,1H),5.36(d,J=6.5Hz,1H),5.27(t, J=8.3Hz,1H),3.88(s,3H),3.66(d,J=16.0Hz,1H),2.76(d,J=16.0Hz,1H),2.65–2.34(m,4H),1.75(d,J=6.1Hz,3H),1.73–1.53(m,2H).

[0276] Example 3

[0277] Step 1:

[0278] 1-Methyl-3-bromo-4-iodopyrazole (1.18 g) was added to anhydrous THF (20 mL), and the mixture was cooled to 0 °C. A 1.3 M, 3 mL THF solution of the isopropyl magnesium chloride-lithium chloride complex was added dropwise, and the mixture was stirred at 0 °C for 2 hours. Then, a 500 mg THF solution of 6-methylimidazo[1,2-a]pyridine-2-carboxaldehyde (dissolved in 30 mL THF) was added dropwise, and the mixture was stirred for 1 hour. After the reaction was complete, ammonium chloride solution was added to quench the reaction. The mixture was extracted twice with EA (80 mL), and the organic phases were combined. The mixture was washed with saturated NaCl solution (100 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated until no liquid flowed out to give 1.2 g of intermediate 3-A. MS (ESI) m / z [M+H] + 321.05

[0279] Step 2:

[0280] Intermediate 3-A (1.0 g) and triethylsilane (2 mL) were added to DCM (10 mL), stirred for 5 minutes, cooled to -20°C, and trifluoroacetic acid (2 mL) was added dropwise. The mixture was then heated to 40°C and reacted for 4 hours. After the reaction was complete, the mixture was cooled to room temperature and neutralized with sodium bicarbonate solution. Extraction was performed using EA (60 mL * 3), the organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. 750 mg of intermediate 3-B was obtained by silica gel column chromatography. MS (ESI) m / z [M+H] + 305.07.

[0281] Step 3:

[0282] Intermediate 3-B (750 mg), compound 1-G (625 mg), Pd(dppf)Cl2.DCM (150 mg) were added into 1,4-dioxane (40 mL), and then potassium carbonate aqueous solution (1.6 g of potassium carbonate dissolved in 10 mL of purified water) was added. The reaction was heated to 85°C under N2atmosphere and stirred for 5 hours. After the reaction was completed, it was cooled to room temperature, 100 mL of purified water was added, and the mixture was extracted with 50 mL*3 of EA. The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain 600 mg of intermediate 3-C. MS (ESI) m / z [M+H] + : 365.17.

[0283] Step 4:

[0284] Intermediate 3-C (600 mg) was added into THF (50 mL), and then sodium hydride (100 mg) was added. After being stirred for 0.5 hours, 4-bromo-6-chloropyridazin-3-amine (380 mg) was added, and the reaction was heated to 60°C and stirred for 8 hours. After the reaction was completed, the reaction was quenched by adding 50 mL of purified water, extracted with 50 mL*3 of EA, and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain 390 mg of intermediate 3-D. MS (ESI) m / z [M+H] + : 492.18.

[0285] Step 5:

[0286] Intermediate 3-D (390 mg), n-butyl di(1-adamantyl)phosphine (125 mg), potassium tert-pentoxide (300 mg), Pd(OAc)2(50 mg), and t-AmOH (15 mL) were mixed and stirred for 5 minutes. The reaction was heated to 120°C under N2atmosphere and subjected to microwave (150W) for 2 hours. After being cooled to room temperature, 10 mL of purified water and 10 mL of EA were added, stirred for 5 minutes, and the mixture was separated into an organic phase and an aqueous phase. The organic phase was washed with 10 mL of saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated to no liquid flow. The residue was separated by silica gel column chromatography to obtain 38 mg of compound 3. MS (ESI) m / z [M+H] + : 456.20.

[0287] 1H NMR (500 MHz, DMSO-d6) δ 8.93 (q, J = 1.3 Hz, 1H), 7.73 - 7.62 (m, 2H), 7.55 (d, J = 9.1 Hz, 1H), 7.36 - 7.06 (m, 2H), 7.20 (dd, J = 9.1, 1.8 Hz, 1H), 6.39 (d, J = 4.8 Hz, 3H), 5.39 - 5.13 (m, 1H), 4.01 (d, J = 15.4 Hz, 1H), 3.85 (s, 3H), 3.24 (d, J = 15.3 Hz, 1H), 2.29 (d, J = 1.1 Hz, 3H), 1.77 (d, J = 6.2 Hz, 3H).

[0288] Example 4

[0289] Step 1:

[0290] Ethyl 6-bromoimidazo[l,2-a]pyridine-2-carboxylate (10.76 g), cyclopropylboronic acid (5.16 g), Pd(dppf)Cl2.DCM (3.26 g) were added into 1,4-dioxane, and potassium phosphate was added with stirring. N2was replaced, and the temperature was raised to 100 °C, and the reaction was stirred for 16 h. After the reaction was completed, purified water (200 mL) was added to quench the reaction, and EA (150 mL) was used to extract twice, and the organic phase was combined, washed with saturated NaCl solution (150 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated, and silica gel column chromatography was used to separate to obtain 7.0 g of intermediate 4-A. MS (ESI) m / z [M+H] + : 231.19

[0291] Step 2:

[0292] 1-Methyl-3-bromo-4-iodopyrazole (7.3 g) was added into anhydrous THF (50 mL), and the temperature was lowered to 0 °C, and isopropyl magnesium chloride lithium chloride complex THF solution (1.3 M, 21.5 mL) was added dropwise, and the reaction was stirred at 0 °C for 2 h, and intermediate 4-A THF solution (3.56 g dissolved in 200 mL THF) was added dropwise, and the reaction was stirred for 1 h. After the reaction was completed, ammonium chloride solution was added to quench the reaction, and EA (150 mL) was used to extract twice, and the organic phase was combined, washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow to obtain 500 mg of intermediate 4-B. MS (ESI) m / z [M+H] + : 345.04.

[0293] Step 3:

[0294] Intermediate 4-B (500 mg) was added into MeOH (50 mL), stirred and cooled to -10 °C, NaBH4 (150 mg) was added portionwise, the reaction was carried out for 5 h. After the reaction was completed, purified water (100 mL) was added to quench the reaction. EA (50 mL*3) was added to extract, the organic phases were combined, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and purified by silica gel column chromatography to give 475 mg of intermediate 4-C. MS (ESI) m / z [M+H] + : 347.12.

[0295] Step 4:

[0296] Intermediate 4-C (475 mg), triethylsilane (2 mL) was added into DCM (10 mL), stirred for 5 min, cooled to -20 °C, trifluoroacetic acid (2 mL) was added dropwise, and the reaction was carried out at 40 °C for 4 h. After the reaction was completed, it was cooled to room temperature, and sodium bicarbonate solution was added dropwise for neutralization. EA (60 mL*3) was added to extract, the organic phases were combined, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and purified by silica gel column chromatography to give 425 mg of intermediate 4-D. MS (ESI) m / z [M+H] + : 331.10.

[0297] Step 5:

[0298] Intermediate 4-D (425 mg), compound 1-G (320 mg), Pd(dppf)Cl2.DCM (125 mg) was added into 1,4-dioxane (60 mL), and aqueous cesium carbonate solution (832 mg of cesium carbonate dissolved in 15 mL of purified water) was added, and the reaction was carried out at 85 °C under N2 atmosphere for 5 h. After the reaction was completed, it was cooled to room temperature, and purified water (100 mL) was added to quench the reaction, and EA (50 mL*3) was added to extract, the organic phases were combined, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and purified by silica gel column chromatography to give 454 mg of intermediate 4-E. MS (ESI) m / z [M+H] + : 391.27.

[0299] Step 6:

[0300] Intermediate 4-E (454 mg) was added into THF (50 mL), and sodium hydride (70 mg) was added, stirred for 0.5 h, and 4-bromo-6-chloropyridazin-3-amine (290 mg) was added, and the reaction was carried out at 60 °C for 8 h. After the reaction was completed, purified water (50 mL) was added to quench the reaction, and EA (50 mL*3) was added to extract, the organic phases were combined, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and purified by silica gel column chromatography to give 108 mg of intermediate 4-F. MS (ESI) m / z [M+H] + : 518.20.

[0301] Step 7:

[0302] Intermediate 4-F (108 mg), n-butyl di(1-adamantyl)phosphine (50 mg), potassium tert-pentoxide (120 mg), Pd(OAc)2(25 mg) and t-AmOH (15 mL) were mixed, stirred for 5 minutes, reacted under N2atmosphere by microwave (120 °C, 150 W) for 2 hours. After cooling to room temperature, purified water (10 mL) and EA (10 mL) were added, stirred for 5 minutes, separated, collected the organic phase, washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid effluent, and the concentrate was separated by silica gel column chromatography to obtain 20 mg of compound 4. MS (ESI) m / z [M+H] + : 482.26.

[0303] Example 5

[0304] Step 1:

[0305] 5-methylpyrazin-2-amine (25 g) and 1,1,3-trichloroacetone (91.7 g) were added to THF (500 mL), stirred at room temperature for 24 hours. After the reaction was completed, it was filtered and the filter cake was dried to obtain 15.6 g of intermediate 5-A.

[0306] Step 2:

[0307] Intermediate 5-A (15.6 g) was added to ethanol (500 mL) and stirred at 75 °C for 24 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain 16.5 g of intermediate 5-B.

[0308] Step 3:

[0309] Intermediate 5-B (16.5 g) was dissolved in a mixed solvent of THF / H2O (1:1, 500 mL), calcium carbonate (45.8 g) was added, and stirred at 75 °C for 72 hours. After the reaction was completed, it was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 13.66 g of intermediate 5-C.

[0310] Step 4:

[0311] Add 1-methyl-3-bromo-4-iodopyrazole (3 g) into anhydrous THF (30 mL), replace with nitrogen for 3 times, cool down to -25 °C, slowly drop in isopropyl magnesium chloride lithium chloride complex THF solution (1.3 M, 8.9 mL) into the system, control the internal temperature below -20 °C, stir the reaction for 1 hour, drop in intermediate 5-C THF solution (1.5 g, 30 mL THF), stir the reaction for 2 hours. After the reaction is completed, add saturated aqueous ammonium chloride solution (25 mL) to quench, extract with EA (50 mL*3), wash with saturated NaCl solution (30 mL), dry over anhydrous Na2SO4, filter, concentrate the filtrate, and separate by silica gel column chromatography to obtain 621 mg of intermediate 5-D.

[0312] Step 5:

[0313] Add intermediate 5-D (620 mg), triethylsilane (1.12 g) into DCM (9 mL), cool down to 0-5 °C in an ice bath, drop in TFA (1.25 mL), and stir the reaction at room temperature for 4 hours. After the reaction is completed, concentrate to remove the solvent, add EA (50 mL) and water (30 mL), and adjust the pH of the aqueous phase to 8-9 with saturated aqueous sodium carbonate solution, extract with EA (50 mL*3), combine the organic phases, dry over anhydrous Na2SO4, filter, concentrate the filtrate, and separate by silica gel column chromatography to obtain 540 mg of intermediate 5-E.

[0314] Step 6:

[0315] Add intermediate 5-E (540 mg), compound 1-G (585.5 mg), K2CO3 (731.5 mg), Pd(dppf)Cl2 (54 mg) into 1,4-dioxane / water (10 / 2 mL), replace with nitrogen for 3 times, and stir the reaction at 75 °C. After the reaction is completed, cool down to room temperature, add purified water (45 mL) to quench the reaction, extract with EA (60 mL*2), wash with saturated NaCl solution (80 mL), dry over anhydrous Na2SO4, filter, concentrate the filtrate, and separate by silica gel column chromatography to obtain 350 mg of intermediate 5-F.

[0316] Step 7:

[0317] Add intermediate 5-F (350 mg) into THF (20 mL), cool down to 0 °C, add sodium hydride (76.6 mg), stir for 30 min, add 3-amino-4-bromo-6-chloropyridazine (240 mg), and stir the reaction at 60 °C. After the reaction is completed, add purified water (30 mL) to quench, extract with EA (50 mL*2), wash with saturated NaCl solution (50 mL), dry over anhydrous Na2SO4, filter, concentrate the filtrate, and separate by silica gel column chromatography to obtain 110 mg of intermediate 5-G.

[0318] Step 8:

[0319] Step 1 : Intermediate 5-A was prepared according to the procedure described in Step 1 of Example 1, using Intermediate 4-A (1.0 g), 2-bromo-5-fluoro-pyridine (0.7 g), potassium phosphate (2.4 g), S-PHOS (0.2 g), and palladium acetate (0.1 g). LC-MS m / z [M+H] 323.0. + 457.29.

[0320] 1 H NMR (500 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.87 (s, 1H), 7.74 - 7.57 (m, 2H), 7.45 - 7.23 (m, 2H), 6.53 (s, 2H), 6.43 (s, 1H), 5.31 (d, J = 6.5 Hz, 1H), 4.10 (d, J = 15.3 Hz, 1H), 3.86 (s, 3H), 3.36 (s, 1H), 2.44 (s, 3H), 1.79 (d, J = 6.3 Hz, 3H).

[0321] Example 6

[0322] Step 1 :

[0323] Step 1 : Intermediate 5-A was prepared according to the procedure described in Step 1 of Example 1, using Intermediate 4-A (1.0 g), 2-bromo-5-fluoro-pyridine (0.7 g), potassium phosphate (2.4 g), S-PHOS (0.2 g), and palladium acetate (0.1 g). LC-MS m / z [M+H] 323.0. + :136.14.

[0324] Step 2:

[0325] Intermediate 6-A (4.5 g), 3-bromo pyruvic acid ethyl ester (9.0 g), sodium bicarbonate (5.6 g) and 1,4-dioxane (100 mL) were mixed, stirred for 5 min, warmed to 100 °C, and reacted for 6 h. After the reaction was completed, it was cooled to room temperature, purified water (200 mL) and EA (200 mL) were added, stirred for 5 min, separated, and the organic phase was collected. The organic phase was washed with saturated NaCl solution (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The concentrate was separated by silica gel column chromatography to give 3.8 g of intermediate 6-B. MS (ESI) m / z [M+H] + : 232.2.

[0326] Step 3:

[0327] 3-Bromo-4-iodo-1-methyl-1H-pyrazole (2.3 g) and anhydrous THF (30 mL) were mixed, stirred for 5 min, cooled to -20 to -30 °C, and isopropyl magnesium chloride lithium chloride complex THF solution (1.3 M, 6.6 mL) was added. The mixture was stirred for 2 h, and a THF solution of intermediate 6-B (1.5 g, 40 mL) was added. The mixture was stirred for another 1 h. After the reaction was completed, purified water (10 mL) was added to quench the reaction, and the mixture was warmed to room temperature. Purified water (100 mL) and EA (100 mL) were added, stirred for 5 min, separated, and the organic phase was collected. The organic phase was washed with saturated NaCl solution (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The concentrate was separated by silica gel column chromatography to give 550 mg of intermediate 6-C. MS (ESI) m / z [M+H] + : 346.11.

[0328] Step 4:

[0329] Intermediate 6-C (1 g) was added to anhydrous methanol (40 mL), stirred for 5 min, and cooled to 0 to 5 °C. Sodium borohydride (450 mg) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the methanol was removed by concentration, and purified water (20 mL) and EA (20 mL) were added. The mixture was stirred for 5 min, separated, and the organic phase was collected. The organic phase was washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give 950 mg of intermediate 6-D, which was used directly in the next reaction. MS (ESI) m / z [M+H] + : 348.12.

[0330] Step 5:

[0331] Intermediate 6-D (950 mg) was added into DCM (20 mL) and stirred for 5 min, cooled to 0-5 °C, TFA (1.5 g), TES (1.5 g) was added, stirred at room temperature overnight. After the reaction was completed, DCM (20 mL) was added, the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, stirred for 5 min, the organic phase was collected, washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and the concentrate was separated by silica gel column chromatography to obtain 600 mg of intermediate 6-E. MS (ESI) m / z [M+H] + : 332.01.

[0332] Step 6:

[0333] Intermediate 6-E (560 mg), compound 1-G (504 mg), anhydrous potassium carbonate (728 mg), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (56 mg), and 1,4-dioxane (20 mL), purified water (4 mL) were mixed, and the reaction was carried out at 75 °C for 8 h under N2 atmosphere. After the reaction was completed, the temperature was lowered to room temperature, purified water (20 mL) was added, EA (20 mL) was added, stirred for 5 min, the organic phase was collected, washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and the concentrate was separated by silica gel column chromatography to obtain 500 mg of intermediate 6-F. MS (ESI) m / z [M+H] + : 392.18.

[0334] Step 7:

[0335] Intermediate 6-F (500 mg) and THF (20 mL) were mixed, cooled to 0-5 °C, NaH (293 mg) was added in portions, stirred for 30 min, 4-bromo-6-chloropyridazin-3-amine (102 mg) was added, and the reaction was carried out at 60-65 °C overnight. After the reaction was completed, the temperature was lowered to room temperature, purified water (20 mL) was added to quench, EA (20 mL*3) was added to extract, the organic phase was collected, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid flow, and the concentrate was separated by silica gel column chromatography to obtain 130 mg of intermediate 6-G. MS (ESI) m / z [M+H] + : 519.09.

[0336] Step 8:

[0337] Intermediate 6-G (130 mg), n-butyl bis(1-adamantyl)phosphine (36 mg), potassium tert-pentoxide (107 mg), Pd(OAc)2(12 mg) and t-AmOH (10 mL) were mixed, stirred for 5 min, reacted under N2atmosphere by microwave (120 °C, 150 W) for 2 h. After the reaction was completed, it was cooled to room temperature, purified water (10 mL) and EA (10 mL) were added, stirred for 5 min, separated, the organic phase was collected, washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid efflux, and the concentrate was separated and purified by preparative column (purification condition: chromatographic column YMC AQ C18, specification 30*250 mm, 10 μm, mobile phase: A: water, B: acetonitrile; gradient: 10%-50% B-60 min, wavelength 254 nm, v = 30 ml / min, rt 54 min) to give 62 mg of compound 6. MS (ESI) m / z [M+H] + : 483.24.

[0338] 1 H NMR (500 MHz, DMSO) δ 8.97 (d, J = 31.2 Hz, 2H), 7.64 (d, J = 19.1 Hz, 2H), 7.31 (dt, J = 28.4, 8.1 Hz, 2H), 6.46 (d, J = 45.2 Hz, 3H), 5.29 (d, J = 7.3 Hz, 1H), 4.08 (d, J = 15.0 Hz, 1H), 3.84 (s, 3H), 2.13 (s, 1H), 1.77 (d, J = 5.9 Hz, 3H), 1.02 - 0.76 (m, 4H)

[0339] Example 7

[0340] Compound 7 was prepared according to the preparation method of Example 6, using 5-methoxy-2-aminopyrazine instead of intermediate 6-A in step 2. MS (ESI) m / z [M+H] + : 473.2.

[0341] Example 8

[0342] Step 1:

[0343] 1-Ethyl-3-chloro-4-iodopyrazole (500 mg) and anhydrous THF (10 mL) were mixed and stirred for 5 minutes. The mixture was then cooled to 0–5 °C, and 1.5 mL of isopropyl magnesium chloride and lithium chloride tetrahydrofuran solution (1.3 M) was added. The mixture was stirred for 1 hour, followed by 3 mL of 2-bromo-3-pyridinecarboxaldehyde THF solution (290 mg). Stirring continued for another hour. After the reaction was complete, 10 mL of purified water was added to quench the reaction. The mixture was then brought to room temperature, and 5 mL of purified water and EA (20 mL) were added. The mixture was stirred for 5 minutes, separated, and the organic phase was collected. The organic phase was then washed with 20 mL of saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated to obtain 500 mg of intermediate 8-A, which was directly used in the next reaction. MS (ESI) m / z [M+H] + 316.03.

[0344] Step 2:

[0345] Intermediate 8-A (500 mg) and TFA (5 mL) were mixed and stirred for 5 minutes. TES (2 mL) was added, and the mixture was heated to 60 °C and reacted for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, the reaction solution was concentrated, dichloromethane (20 mL) was added, and the pH was adjusted to 7–8 with saturated sodium bicarbonate aqueous solution. The mixture was stirred for 5 minutes, separated, and the organic phase was collected. The organic phase was then washed with saturated NaCl solution (20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated. 180 mg of intermediate 8-B was obtained by silica gel column chromatography. MS (ESI) m / z [M+H] + 300.02.

[0346] Step 3:

[0347] Intermediate 8-B (180 mg), compound 1-G (150 mg), anhydrous potassium carbonate (248 mg), 1,1-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (18 mg), 1,4-dioxane (10 mL), and water (2 mL) were mixed and reacted overnight at 75 °C under N2 protection. After the reaction was complete, the mixture was cooled to room temperature, purified water (10 mL), and EA (10 mL) were added. The mixture was stirred for 5 minutes, separated, and the organic phase was collected. The organic phase was then washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The concentrate was separated by silica gel column chromatography to obtain 230 mg of intermediate 8-C. MS (ESI) m / z [M+H] + 360.15.

[0348] Step 4:

[0349] Intermediate 8-C (230 mg) and THF (5 mL) were mixed, cooled to 0-5 °C, NaH (51 mg) was added in portions, stirred for 30 min, 4-bromo-6-chloropyridazin-3-amine (160 mg) was added, and the temperature was raised to 60-65 °C for overnight reaction. After the reaction was completed, it was cooled to room temperature, quenched with purified water (20 mL), extracted with EA (20 mL*3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow. The concentrate was separated by silica gel column chromatography to give 130 mg of intermediate 8-D. MS (ESI) m / z [M-H] - : 485.1.

[0350] Step 5:

[0351] Intermediate 8-D (130 mg), n-butyl di(1-adamantyl)phosphine (38 mg), potassium tert-pentoxide (115 mg), Pd(OAc)2(12 mg) and t-AmOH (10 mL) were mixed and stirred for 5 min. Under N2atmosphere, it was subjected to microwave (120 °C, 150 W) for 2 h. After cooling to room temperature, purified water (10 mL) and EA (10 mL) were added, stirred for 5 min, separated, collected the organic phase, washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow. The concentrate was separated by silica gel column chromatography to give 7 mg of compound 8. MS (ESI) m / z [M+H] + : 451.21.

[0352] Example 9

[0353] Step 1:

[0354] 3-Methylpyrazole (3 g) and DMF (50 mL) were mixed and stirred for 5 min, cooled to 0-5 °C, NIS (10.7 g) was added in portions, and the temperature was raised to room temperature for continued stirring for 3 h. Saturated aqueous sodium thiosulfate solution (50 mL) was added to quench the reaction, EA (100 mL) was added, stirred for 5 min, separated, and the organic phase was washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give 11 g of intermediate 9-A, which was directly used in the next step.

[0355] Step 2:

[0356] Intermediate 9-A (7.6 g), iodoethane (17.1 g), anhydrous potassium carbonate (15.2 g) and DMF (100 mL) were mixed and stirred at room temperature overnight. After the reaction was completed, purified water (200 mL) and EA (200 mL) were added, stirred for 5 minutes, separated, the organic phase was collected, washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and the concentrate was separated by silica gel column chromatography to obtain 5.1 g of intermediate 9-B. MS (ESI) m / z [M+H] + : 237.0.

[0357] Step 3:

[0358] Intermediate 9-B (2 g) and anhydrous THF (20 mL) were mixed and stirred for 5 minutes, cooled to -20 to -30 °C, and isopropyl magnesium chloride lithium chloride THF solution (1.3 M, 6.5 mL) was added, stirred for 2 hours, and 1-methyl-3-iodopyrazole-4-carboxaldehyde THF solution (1.6 g, 16 mL) was added, and stirring was continued for 1 hour. After the reaction was completed, purified water (10 mL) was added to quench the reaction, and the temperature was raised to room temperature, purified water (50 mL) and EA (50 mL) were added, stirred for 5 minutes, separated, the organic phase was collected, washed with saturated NaCl aqueous solution (50 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and the concentrate was separated by silica gel column chromatography to obtain 1.1 g of intermediate 9-C. MS (ESI) m / z [M+H] + : 347.1.

[0359] Step 4:

[0360] Intermediate 9-C (1.1 g) and DCM (20 mL) were mixed and stirred for 5 minutes, cooled to 0 to 5 °C, and TFA (1.8 g) and TES (1.85 g) were added, and stirring was continued at room temperature for 30 minutes. After the reaction was completed, DCM (20 mL) was added, and the pH was adjusted to 7 to 8 with saturated sodium bicarbonate aqueous solution, stirred for 5 minutes, separated, the organic phase was collected, washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and the concentrate was separated by silica gel column chromatography to obtain 1 g of intermediate 9-D. MS (ESI) m / z [M+H] + : 331.1.

[0361] Step 5:

[0362] Intermediate 9-D (1 g), compound 1-G (750 mg), anhydrous potassium carbonate (1.26 g), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (90 mg) and 1,4-dioxane (20 mL), water (4 mL) were mixed, and the reaction was carried out under N2 protection at 75°C for 2 hours. After the reaction was completed, the temperature was lowered to room temperature, purified water (20 mL) was added, EA (20 mL) was added, stirred for 5 minutes, separated, the organic phase was collected, washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and the concentrate was separated by silica gel column chromatography to obtain 1 g of intermediate 9-E. MS (ESI) m / z [M+H] + : 343.2.

[0363] Step 6:

[0364] Intermediate 9-E (1 g) and THF (20 mL) were mixed, and the temperature was lowered to 0-5°C, NaH (233 mg) was added in batches, stirred for 30 minutes, 4-bromo-6-chloropyridazin-3-amine (670 mg) was added, and the reaction was carried out at 60-65°C overnight. After the reaction was completed, the temperature was lowered to room temperature, purified water (20 mL) was added to quench, EA (20 mL*3) was added for extraction, the organic phases were combined, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid flow, and the concentrate was separated by silica gel column chromatography to obtain 420 mg of intermediate 9-F. MS (ESI) m / z [M+Na] + : 492.27.

[0365] Step 7:

[0366] Intermediate 9-F (420 mg), n-butyl bis(1-adamantyl)phosphine (128 mg), potassium tert-pentoxide (381 mg), Pd(OAc)2 (40 mg) and t-AmOH (10 mL) were mixed, stirred for 5 minutes, and the reaction was carried out under N2 atmosphere by microwave (120°C, 150W) for 2 hours. The temperature was lowered to room temperature, purified water (10 mL) and EA (10 mL) were added, stirred for 5 minutes, separated, the organic phase was collected, washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid flow, and the concentrate was separated by silica gel column chromatography to obtain 5 mg of compound 9. MS (ESI) m / z [M+H] + : 434.29.

[0367] Example 10

[0368] Referring to the preparation method of compound 9, 3-phenylpyrazole was used instead of 3-methylpyrazole in step 1 to prepare compound 10. MS (ESI) m / z [M+H] + : 496.35.

[0369] Example 11

[0370] Compound 11 was prepared according to the procedure for Compound 9, using 4-iodo-3-(trifluoromethyl)-1H-pyrazole instead of intermediate 9-A in Step 2. MS (ESI) m / z [M+H] + : 488.28.

[0371] Example 12

[0372] Step 1:

[0373] 5-Fluoro-2-iodobenzene methanol (800 mg) was added into MeOH (20 mL), followed by tetrahydroxydiboron (484 mg), potassium acetate (623 mg) and X Phos Pd G2 (250 mg), and the mixture was heated to 60 °C under nitrogen atmosphere for 5 h. After the reaction was completed, the reaction was quenched by purified water (100 mL), extracted by EA (100 mL) twice, the organic phase was combined and washed by saturated NaCl solution (100 mL) twice, dried by anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow to obtain 482 mg of intermediate 12-A.

[0374] Step 2:

[0375] Intermediate 12-A (482 mg) and Compound 1-F (855 mg) were added into 1,4-dioxane (10 mL), followed by K2CO3 solution (1.01 g of K2CO3 dissolved in 2 mL of purified water) and PdCl2(dppf) (80 mg), and the mixture was heated to 75 °C under nitrogen atmosphere for 5 h. After the reaction was completed, the mixture was cooled to room temperature, purified water (20 mL) and EA (20 mL*2) were added to extract, the organic phase was combined and washed by saturated NaCl solution (20 mL), dried by anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow, and then separated by silica gel column chromatography to obtain 870 mg of intermediate 12-B. MS (ESI) m / z [M+H] + : 349.24.

[0376] Step 3:

[0377] Intermediate 12-B (800 mg) and anhydrous THF (20 mL) were mixed, cooled to 0-5 °C, NaH (183 mg) was added in portions, stirred for 30 min, 4-bromo-6-chloropyridazin-3-amine (525 mg) was added, and the temperature was raised to 60-65 °C for overnight reaction. After the reaction was completed, it was cooled to room temperature, quenched with purified water (20 mL), extracted with EA (20 mL*3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid flow, and the concentrate was separated by silica gel column chromatography to give 520 mg of intermediate 12-C. MS (ESI) m / z [M+H] + : 476.19.

[0378] Step 4:

[0379] Intermediate 12-C (150 mg), n-butyl di(1-adamantyl)phosphine (45 mg), potassium tert-pentoxide (134 mg), Pd(OAc)2(14 mg) and t-AmOH (10 mL) were mixed and stirred for 5 min, and then reacted under N2atmosphere by microwave (120 °C, 150 W) for 2 h. After the reaction was completed, it was cooled to room temperature, purified water (10 mL) and EA (10 mL) were added, stirred for 5 min, separated, the organic phase was collected, washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid flow, and the concentrate was separated by silica gel column chromatography to give 3 mg of compound 12. MS (ESI) m / z [M+H] + : 440.2.

[0380] Example 13

[0381] Step 1:

[0382] 1-ethyl-1H-pyrazole-4-carboxaldehyde (1 g) and anhydrous THF (30 mL) were mixed and stirred for 5 min, cooled to -75 to -80 °C, n-butyllithium (2.5 M, 4.8 mL) was added, stirred for 30 min, 4,5-dibromo-2-methyl-2H-1,2,3-triazole tetrahydrofuran solution (3.2 g, 10 mL) was added dropwise, and the stirring reaction was continued for 2 h. After the reaction was completed, purified water (10 mL) was added to quench the reaction, the temperature was raised to room temperature, purified water (50 mL) and EA (50 mL) were added, stirred for 5 min, separated, the organic phase was collected, washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, filtered, concentrated, and the concentrate was separated by silica gel column chromatography to give 1.7 g of intermediate 13-A. MS (ESI) m / z [M+H] + : 286.12.

[0383] Step 2:

[0384] Intermediate 13-A (1.6 g) and dichloromethane (30 mL) were mixed and stirred for 5 minutes, cooled to 0-5 °C, TFA (5.1 g), TES (5.1 g) were added, and stirred at room temperature for 30 minutes. After the reaction was completed, dichloromethane (30 mL) was added, and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, stirred for 5 minutes, separated, and the organic phase was collected. The organic phase was washed with saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was separated by silica gel column chromatography to obtain 1.3 g of intermediate 13-B. MS (ESI) m / z [M+H] + : 270.1.

[0385] Step 3:

[0386] Intermediate 13-B (800 mg), compound 1-G (737 mg), anhydrous potassium carbonate (1.23 g), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex (80 mg), and 1,4-dioxane (30 mL), purified water (6 mL) were mixed, and the mixture was heated to 75 °C under N2protection for 3 hours. After the reaction was completed, the temperature was lowered to room temperature, purified water (30 mL) was added, EA (30 mL) was added, stirred for 5 minutes, separated, and the organic phase was collected. The organic phase was washed with saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was separated by silica gel column chromatography to obtain 613 mg of intermediate 13-C. MS (ESI) m / z [M+H] + : 330.24.

[0387] Step 4:

[0388] Intermediate 13-C (613 mg) and THF (30 mL) were mixed, cooled to 0-5 °C, NaH (150 mg) was added in portions, stirred for 30 minutes, 4-bromo-6-chloropyridazin-3-amine (427 mg) was added, and the mixture was heated to 60-65 °C overnight. After the reaction was completed, the temperature was lowered to room temperature, and purified water (30 mL) was added to quench the reaction. The mixture was extracted with EA (20 mL*3), and the organic phase was collected. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to no liquid was discharged. The concentrate was separated by silica gel column chromatography to obtain 300 mg of intermediate 13-D.

[0389] Step 5:

[0390] Intermediate 13-D (300 mg), n-butyl bis(1-adamantyl)phosphine (94 mg), potassium tert-pentoxide (280 mg), Pd(OAc)2(30 mg) and t-AmOH (10 mL) were mixed and stirred for 5 min, then subjected to microwave reaction (120 °C, 150 W) under N2atmosphere for 2 h. After the reaction was completed, it was cooled to room temperature, purified water (10 mL) and EA (10 mL) were added, stirred for 5 min, separated, the organic phase was collected and washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid efflux, and the concentrate was separated by silica gel column chromatography to obtain 5 mg of compound 13. MS (ESI) m / z [M+H] + : 421.25.

[0391] Example 14

[0392] Step 1:

[0393] 3-chloro-4-iodo-1H-pyrazole (4 g) was added to ACN (40 mL), bromomethylcyclopropane (3.5 g) was added, and cesium carbonate (12 g) was added with stirring, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, it was filtered, the filter cake was washed with EA, the filtrate was collected, concentrated to no liquid efflux, and 3.9 g of intermediate 14-A was obtained by silica gel column chromatography.

[0394] Step 2:

[0395] Intermediate 14-A (3.9 g) was added to anhydrous THF (80 mL), cooled to -20 °C under N2atmosphere, stirred for 30 min, and isopropylmagnesium chloride-lithium chloride THF solution (1.3 M, 10.6 mL) was added dropwise, and the reaction was stirred at -20 °C for 3 h. 1-methyl-3-iodo-pyrazole-4-carbaldehyde THF solution (3.2 g dissolved in 60 mL THF) was added dropwise, and the reaction was stirred for 1 h. After the reaction was completed, saturated NH4Cl (10 mL) and purified water (50 mL) were added to quench the reaction, and EA (50 mL) was extracted three times, the organic phase was collected, washed with saturated NaCl solution (50 mL) twice, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid efflux to obtain 4 g of intermediate 14-B.

[0396] Step 3:

[0397] Intermediate 14-B (4 g) was added into DCM (50 mL), triethylsilane (2.9 g) was added, the temperature was lowered to -15 °C, TFA (3 mL) was added dropwise, and the reaction was stirred for 4 h. After the reaction was completed, K2CO3 solution (5 g of K2CO3 was dissolved in 50 mL of purified water) was added dropwise to adjust pH ≥ 8, extracted with DCM twice, the organic phase was combined, washed with saturated NaCl solution (50 mL) twice, dried over anhydrous MgSO4, filtered, and the filtrate was concentrated to no liquid flow. The concentrate was separated by silica gel column chromatography to obtain 2.1 g of intermediate 14-C.

[0398] Step 4:

[0399] Compound 1-G (1.14 g) and intermediate 14-C (2.0 g) were added into 1,4-dioxane (40 mL), K2CO3 solution (2.2 g of K2CO3 was dissolved in 10 mL of purified water) was added, PdCl2(dppf) (250 mg) was added, and the reaction was stirred at 75 °C for 5 h under a nitrogen atmosphere. After the reaction was completed, the temperature was lowered to room temperature, extracted with EA (100 mL) twice, the organic phase was combined, washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow. The concentrate was separated by silica gel column chromatography to obtain 1.4 g of intermediate 14-D. MS (ESI) m / z [M+H] + : 389.15

[0400] Step 5:

[0401] Intermediate 14-D (1.3 g) and THF (30 mL) were mixed, the temperature was lowered to 0-5 °C, NaH (260 mg) was added in portions, stirred for 30 min, 4-bromo-6-chloropyridazin-3-amine (0.77 g) was added, and the reaction was stirred at 65 °C for 5 h. After the reaction was completed, the temperature was lowered to room temperature, purified water (30 mL) was added to quench the reaction, extracted with EA (30 mL*3), the organic phase was combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow. The concentrate was separated by silica gel column chromatography to obtain 400 mg of intermediate 14-E. MS (ESI) m / z [M+H] + : 516.15.

[0402] Step 6:

[0403] Intermediate 14-E (100 mg), n-butyl bis(1-adamantyl)phosphine (14 mg), potassium tert-pentoxide (84 mg), Pd(OAc)2(10 mg) and t-AmOH (4 mL) were mixed, stirred for 5 min, reacted by microwave (120 °C, 150 W) for 3 h under N2atmosphere. After cooling to room temperature, purified water (10 mL) and EA (10 mL) were added, stirred for 5 min, separated, the organic phase was collected and washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid effluent, and the concentrate was separated by silica gel column chromatography to give 15 mg of compound 14. MS (ESI) m / z [M+H] + : 480.18.

[0404] 1 H NMR (500 MHz, DMSO-d6) δ 7.66 (s, 2H), 7.24 (ddd, J = 10.9, 8.5, 4.4 Hz, 2H), 6.56 (s, 2H), 6.24 (s, 1H), 5.34 (d, J = 6.5 Hz, 1H), 4.19 (dd, J = 14.0, 7.6 Hz, 1H), 4.08 (dd, J = 14.0, 6.6 Hz, 1H), 3.88 (s, 3H), 3.67 (d, J = 15.9 Hz, 1H), 2.79 (d, J = 15.9 Hz, 1H), 1.75 (d, J = 6.3 Hz, 3H), 0.50 - 0.30 (m, 4H), 0.08 (q, J = 5.9, 4.6 Hz, 1H).

[0405] Example 15

[0406] Step 1:

[0407] 3,5-dibromo-1H-pyrazole (10 g) was added into DMF (50 mL), iodomethane (6.6 g) was added, potassium carbonate (12.2 g) was added, stirred at room temperature overnight. After the reaction was completed, the filter cake was filtered and washed with EA, the filtrate was collected and concentrated to no liquid effluent, and the concentrate was separated by silica gel column chromatography to give 9.4 g of intermediate 15-A.

[0408] Step 2:

[0409] Intermediate 15-A (9 g) was added to anhydrous THF (90 mL) and cooled to -78 °C under N2atmosphere for 30 min. n-Butyllithium solution in n-hexane (1.6 M, 28 mL) was added dropwise and the reaction was stirred at -78 °C for 0.5 h. Cyclopropylcarboxaldehyde THF solution (2.8 mL dissolved in 30 mL THF) was added dropwise and the reaction was stirred at -78 °C for 2 h. After the reaction was completed, the reaction was quenched by saturated NH4Cl (20 mL), purified water (50 mL), extracted with EA (100 mL) for 3 times, the organic phase was combined, washed with saturated NaCl solution (50 mL) for 2 times, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid outflow, and 3.8 g of intermediate 15-B was obtained by silica gel column chromatography.

[0410] Step 3:

[0411] Intermediate 15-B (3.5 g) was added to DCM (30 mL), triethylsilane (5 g) was added, cooled to -15 °C, TFA (10 mL) was added dropwise, and the reaction was stirred for 4 h. After the reaction was completed, NaHCO3solution was added dropwise until no bubbles were generated, extracted with DCM (150 mL) for 2 times, the organic phase was combined, washed with saturated NaCl solution (50 mL) for 2 times, dried over anhydrous MgSO4, filtered, the filtrate was concentrated to no liquid outflow, and 2.7 g of intermediate 15-C was obtained by silica gel column chromatography.

[0412] Step 4:

[0413] Intermediate 15-C (2.5 g), CuI (1.33 g), N,N'-dimethylethylenediamine (1.025 g), NaI (8.72 g) and 1,4-dioxane (50 mL) were mixed, heated to 90 °C under N2atmosphere and stirred overnight. After the reaction was completed, the reaction was cooled to room temperature, quenched by saturated NH4Cl (10 mL), purified water (20 mL), extracted with EA (30 mL) for 3 times, the organic phase was combined, washed with saturated NaCl solution (20 mL) for 2 times, dried over anhydrous MgSO4, filtered, the filtrate was concentrated to no liquid outflow, and 2.7 g of intermediate 15-D was obtained by silica gel column chromatography. MS (ESI) m / z [M+H] + : 263.01

[0414] Step 5:

[0415] Intermediate 15-D (2.5 g) was added to anhydrous THF (50 mL) and stirred for 30 min at -20 °C under N2 atmosphere. Isopropyl magnesium chloride-lithium chloride THF solution (1.3 M, 9.54 mL) was added dropwise and the reaction was stirred for 3 h at -20 °C. 1-Methyl-3-iodopyrazole-4-carboxaldehyde THF solution (2.02 g dissolved in 40 mL THF) was added dropwise and the reaction was stirred for 1 h. After the reaction was completed, the reaction was quenched by adding saturated NH4Cl (10 mL), purified water (50 mL), and extracted with EA (50 mL) for 3 times. The organic phase was combined and washed with saturated NaCl solution (50 mL) for 2 times, dried over anhydrous Na2SO4, filtered, and concentrated to no liquid flow. Intermediate 15-E (2.8 g) was obtained by silica gel column chromatography. MS (ESI) m / z [M+H] + : 373.05

[0416] Step 6:

[0417] Intermediate 15-E (2.3 g) was added to DCM and triethylsilane (1.5 g) was added. The reaction was stirred for 4 h at -15 °C after TFA (1.5 mL) was added dropwise. After the reaction was completed, the pH was adjusted to > 8 by adding K2CO3 solution (5 g K2CO3 dissolved in 50 mL purified water), extracted with DCM for 2 times, and the organic phase was combined and washed with saturated NaCl solution (20 mL) for 2 times, dried over anhydrous MgSO4, filtered, and concentrated to no liquid flow. Intermediate 15-F (1.8 g) was obtained by silica gel column chromatography. MS (ESI) m / z [M+H] + : 357.06

[0418] Step 7:

[0419] Compound 1-G (1.06 g) and intermediate 15-F (1.8 g) were added to 1,4-dioxane (30 mL) and K2CO3 solution (2.02 g K2CO3 dissolved in 10 mL purified water) was added. PdCl2(dppf) (357 mg) was added and the reaction was stirred for 5 h at 75 °C under N2 atmosphere. After the reaction was completed, the reaction was cooled to room temperature, extracted with EA (50 mL) for 2 times, and the organic phase was combined and washed with saturated NaCl solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to no liquid flow. Intermediate 15-H (1.7 g) was obtained by silica gel column chromatography. MS (ESI) m / z [M+H] + : 369.21

[0420] Step 8:

[0421] Intermediate 15-H (1.0 g) and THF (30 mL) were mixed, cooled to 0-5 °C, NaH (217 mg) was added in portions, stirred for 30 min, 4-bromo-6-chloropyridazin-3-amine (0.62 g) was added, and the reaction was allowed to warm to 65 °C and react for 5 h. After the reaction was completed, it was cooled to room temperature, quenched with purified water (30 mL), extracted with EA (30 mL*3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow. The concentrate was separated by silica gel column chromatography to give 500 mg of intermediate 15-I. MS (ESI) m / z [M+H] + : 496.20.

[0422] Step 9:

[0423] Intermediate 15-I (250 mg) was added to DMF (10 mL), and NBS (91 mg) was added under ice bath, and the reaction was stirred for 1 h. After the reaction was completed, it was warmed to room temperature, quenched with saturated NaS2O3 solution (10 mL), extracted with EA (20 mL*3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow. The concentrate was separated by silica gel column chromatography to give 300 mg of intermediate 15-J. MS (ESI) m / z [M+H] + : 574.11.

[0424] Step 10:

[0425] Intermediate 15-J (300 mg), bis(pinacolato)diboron (386 mg), n-butyl bis(1-adamantyl)phosphine (86 mg), Pd(OAc)2 (28 mg), and methanol (10 mL) were mixed, and a purified aqueous CsF solution (2M, 0.5 mL) was added. After stirring for 5 min, the reaction was carried out under N2 atmosphere by microwave (80 °C, 150 W) for 2 h. After cooling to room temperature, purified water (10 mL) and EA (20 mL) were added, stirred for 5 min, separated, and the organic phase was collected and washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow. The concentrate was separated by silica gel column chromatography to give 27 mg of compound 15. MS (ESI) m / z [M+H] + : 460.23.

[0426] 1H NMR(500MHz,DMSO-d6)δ7.69–7.41(m,2H),7.32–7.03(m,2H),6.51(s,1H),6.07(s,2H),5.43–5.14(m,1H),3.87(s,3H),3.82(s,3H) ,3.78(d,J=15.5Hz,1H),2.99–2.83(m,2H),2.64(dd,J=14.6,6.4Hz,1H),1.74(d,J=6.3Hz,3H),1.16(s,4H),0.93(p,J=6.4Hz,1H).

[0427] Example 16

[0428] Step 1:

[0429] 10.3 g of 3-bromopyrazole was added to 100 mL of DMF, followed by 32.8 g of iodoethane. Cesium carbonate (68.4 g) was then added and stirred overnight at room temperature. After the reaction was complete, the mixture was filtered, the filter cake was washed with EA, and the filtrate was collected. The filtrate was concentrated until no liquid flowed out, and then separated by silica gel column chromatography to obtain 6.2 g of intermediate 16-A.

[0430] Step 2:

[0431] Intermediate 16-A (5.9 g), N-methylpiperazine (4.05 g), Pd2(dba)3 (1.54 g), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (1.57 g), and 1,4-dioxane (100 mL) were mixed and reacted at 90 °C for 5 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature and extracted twice with EA (100 mL). The organic phases were combined, washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated until no liquid flowed out. Separation by silica gel column chromatography yielded 3.5 g of intermediate 16-B.

[0432] Step 3:

[0433] Intermediate 16-B (2.5 g) was added to anhydrous DMF (50 mL), and N-iodosuccinimide (4.34 g) was added in portions while stirring at room temperature. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched by adding saturated Na2SO3 solution (20 mL). The mixture was extracted twice with EA (50 mL), and the organic phases were combined. The mixture was washed twice with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated until no liquid flowed out. The filtrate was separated by silica gel column chromatography to obtain 2.1 g of intermediate 16-C.

[0434] Step 4:

[0435] Intermediate 16-C (1.9 g) was added to anhydrous THF (30 mL) and cooled to -20 °C under N2 atmosphere, stirred for 30 min, isopropyl magnesium chloride-lithium chloride THF solution (1.3 M, 4.8 mL) was added dropwise, the reaction was stirred for 3 h at -20 °C, 1-methyl-3-iodopyrazole-4-carboxaldehyde THF solution (1.1 g dissolved in 25 mL THF) was added dropwise, the reaction was stirred for 1 h. After the reaction was completed, the reaction was quenched by saturated NH4Cl (10 mL), purified water (50 mL), extracted with EA (50 mL) for 3 times, the organic phase was combined, washed with saturated NaCl solution (50 mL) for 2 times, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid flow, and 900 mg of intermediate 16-D was obtained by silica gel column chromatography.

[0436] Step 5:

[0437] Intermediate 16-D (900 mg) was added to DCM, triethylsilane (700 mg) was added, cooled to -15 °C, TFA (0.5 mL) was added dropwise, and the reaction was stirred for 4 h. After the reaction was completed, the pH was adjusted to ≥8 by adding saturated K2CO3 purified water solution, extracted with DCM (50 mL) for 2 times, the organic phase was combined, washed with saturated NaCl solution (10 mL) for 2 times, dried over anhydrous MgSO4, filtered, the filtrate was concentrated to no liquid flow, and 600 mg of intermediate 16-E was obtained by silica gel column chromatography.

[0438] Step 6:

[0439] Compound 1-G (630 mg), intermediate 16-E (600 mg) were added to 1,4-dioxane (15 mL), K2CO3 solution (790 mg K2CO3 dissolved in 5 mL purified water) was added, PdCl2(dppf) (140 mg) was added, and the reaction was stirred at 65 °C for 5 h under nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, extracted with EA (30 mL) for 2 times, the organic phase was combined, washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid flow, and 500 mg of intermediate 16-F was obtained by silica gel column chromatography. MS (ESI) m / z [M+H] + : 427.30

[0440] Step 7:

[0441] Intermediate 16-F (500 mg) and THF (15 mL) were mixed, cooled to 0-5 °C, NaH (94 mg) was added in portions, stirred for 30 min, 4-bromo-6-chloropyridazin-3-amine (292 mg) was added, and the reaction was allowed to warm to 70 °C overnight. After the reaction was completed, it was cooled to room temperature, quenched with purified water (10 mL), extracted with EA (20 mL*3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow. The concentrate was separated by silica gel column chromatography to give 120 mg of intermediate 16-G. MS (ESI) m / z [M+H] + : 554.26.

[0442] Step 8:

[0443] Intermediate 16-G (120 mg), n-butyl bis (1-adamantyl) phosphine (30 mg), potassium tert-pentoxide (92 mg), Pd(OAc)2(10 mg) and t-AmOH (5 mL) were mixed and stirred for 5 min. Under N2atmosphere, the reaction was carried out by microwave (120 °C, 150 W) for 3 h. After cooling to room temperature, purified water (10 mL) and EA (10 mL) were added, stirred for 5 min, separated, collected the organic phase, washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow. The concentrate was separated by silica gel column chromatography to give 10 mg of compound 16. MS (ESI) m / z [M+H] + : 518.28.

[0444] Example 17

[0445] Step 1:

[0446] 3-chloro-4-iodo-1H-pyrazole (22.8 g) and SEMCl (18.3 g) were added to ACN (150 mL), and a Cs2CO3solution (65.0 g) was added. The reaction was allowed to react at room temperature for 15 h. After the reaction was completed, it was cooled to room temperature, extracted with EA (200 mL) twice, the organic phases were combined, washed with saturated NaCl solution (200 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow. The concentrate was separated by silica gel column chromatography to give 30 g of intermediate 17-A.

[0447] Step 2:

[0448] Intermediate 17-A (16 g) was added into THF (100 mL), cooled to -25 °C, dropwise added isopropyl magnesium chloride lithium chloride complex THF solution (1.3 M, 41 mL), stirred for 2 hours, then dropwise added 3-iodo-1-methyl-1H-pyrazole-4-carboxaldehyde THF solution (8.5 g dissolved in 300 mL THF), maintained at -25 °C for 2 hours. After the reaction was completed, the reaction was quenched by adding aqueous ammonium chloride solution, extracted with EA (100 mL*3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow to obtain 18 g of intermediate 17-B.

[0449] Step 3:

[0450] Intermediate 17-B (18 g) and triethylsilane (36 mL) were added into DCM (200 mL), stirred for 5 minutes, cooled to -20 °C, dropwise added trifluoroacetic acid (18 mL), maintained at -20 °C for 2 hours. After the reaction was completed, neutralized by dropwise adding sodium bicarbonate solution. Extracted with EA (100 mL*3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated, and then purified by silica gel column chromatography to obtain 8.2 g of intermediate 17-C.

[0451] Step 4:

[0452] Intermediate 17-C (5.4 g), compound 1-G (2.46 g), and Pd(dppf)Cl2.DCM (250 mg) were added into 1,4-dioxane (100 mL), added aqueous potassium carbonate solution (4.9 mg of potassium carbonate dissolved in 20 mL of purified water), warmed to 75 °C under N2atmosphere, and stirred for 5 hours. After the reaction was completed, cooled to room temperature, added purified water 100 mL, extracted with EA (80 mL*3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated, and then purified by silica gel column chromatography to obtain 5.2 g of intermediate 17-D.

[0453] Step 5:

[0454] Intermediate 17-D (1.5 g) was added into anhydrous THF (30 mL), added TBAF tetrahydrofuran solution (1 M, 30 mL), warmed to 60 °C and stirred for 24 hours. After the reaction was completed, added ammonium carbamate solution (6 M, 40 mL) and stirred for 10 hours, then added purified water (50 mL) to quench the reaction. Extracted with EA (30 mL) for 3 times, the organic phases were combined, washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to no liquid flow to obtain 1.4 g of intermediate 17-E.

[0455] Step 6:

[0456] Intermediate 17-E (1.4 g) was added into ACN (100 mL), 3-bromochloropropane (870 mg), cesium carbonate (2.7 g) were added, the reaction was stirred at 75 °C. After the reaction was completed, the reaction was quenched by purified water (50 mL), extracted with EA (50 mL) twice, washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and 1.0 g of intermediate 17-F was obtained by silica gel column chromatography.

[0457] Step 7:

[0458] Intermediate 17-F (900 mg) was added into THF (50 mL), sodium hydride (150 mg) was added, after stirring for 0.5 h, 4-bromo-6-chloropyridazin-3-amine (400 mg) was added, and the reaction was stirred at 60 °C for 9 h. After the reaction was completed, the reaction was quenched by purified water (50 mL), extracted with EA (50 mL*3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated, and 400 mg of intermediate 17-G was obtained by silica gel column chromatography.

[0459] Step 8:

[0460] Intermediate 17-G (200 mg), n-butyl di(1-adamantyl)phosphine (50 mg), potassium tert-pentoxide (250 mg), Pd(OAc)2 (25 mg) and t-AmOH (15 mL) were mixed, stirred for 5 min, and the reaction was carried out by microwave (120 °C, 150 W) under N2 atmosphere for 2 h. After the reaction was completed, purified water (10 mL) and EA (10 mL) were added, stirred for 5 min, the organic phase was collected, washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated to no liquid flow, and 16 mg of compound 17 was obtained by silica gel column chromatography of the concentrate. MS (ESI) m / z [M+H] + : 500.27.

[0461] Example 18

[0462] Step 1:

[0463] 5 g of 1-(2,2-difluoroethyl)-4-iodo-1H-pyrazole was added to 75 mL of anhydrous THF, cooled to -20 °C, purged with nitrogen, and a 1.3 M, 15 mL THF solution of isopropyl magnesium chloride-lithium chloride complex was added dropwise. The mixture was stirred for 1 hour. 4.5 g of 3-iodo-1-methyl-1H-pyrazole-4-carboxaldehyde THF solution (dissolved in 150 mL of THF) was added dropwise, and the mixture was reacted at -15 °C for 1.5 hours. After the reaction was complete, a saturated ammonium chloride solution (100 mL) was added to quench the reaction. The mixture was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined. The solution was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated until no liquid flowed out to obtain 5 g of intermediate 18-A. MS (ESI) m / z [M+H] + 369.13

[0464] Step 2:

[0465] Intermediate 18-A (5 g) was added to (50 mL) DCM, cooled to -10 °C, and TFA (5.5 g) was added dropwise. The reaction was continued at -10 °C for 1 hour. After the reaction was complete, sodium carbonate aqueous solution was added to adjust the pH to 7, and the mixture was stirred for 0.5 hours. The mixture was separated, extracted twice with EA, and the organic phase was collected. The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated until no liquid flowed out. Silica gel column chromatography was used to separate 3.3 g of intermediate 18-B. MS (ESI) m / z [M+H] + 353.13

[0466] Step 3:

[0467] Intermediate 18-B (1 g) was added to a mixed solvent (1,4-dioxane:water = 5:1) (60 ml), followed by compound 1-G (334 mg), potassium carbonate (343 mg), and 1,1'-bis(diphenyl phosphonium)dichloroferrocene palladium (61 mg). After nitrogen purging, the mixture was heated to 75 °C and reacted for 2 hours. After the reaction was complete, it was cooled to room temperature, quenched with purified water, extracted twice with EA, and the organic phases were combined. The mixture was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated until no liquid flowed out. 700 mg of intermediate 18-C was obtained by silica gel column chromatography. MS (ESI) m / z [M+H] + 365.37

[0468] Step 4:

[0469] A solution of intermediate 18-C (400 mg) in THF (10 mL) was added to a previously ice-bath solution of sodium hydride (100 mg) in THF (10 mL), stirred in ice-bath for 0.5 h, then 4-bromo-6-chloropyridazin-3-amine in THF was added, and the reaction was allowed to warm to 60 °C for 5 h. After the reaction was completed, it was allowed to cool to room temperature, quenched with purified water, and extracted with EA twice. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness. Purification by silica gel column chromatography gave 50 mg of intermediate 18-D. MS (ESI) m / z [M+H] + : 492.9

[0470] Step 5:

[0471] Intermediate 18-D (50 mg) was added to tert-amyl alcohol (3 mL), followed by the addition of potassium tert-amylate (43 mg), n-butyl bis(1-adamantyl)phosphine (15 mg), palladium acetate (5 mg), and the reaction was allowed to proceed at 120 °C for 4 h under microwave irradiation. After cooling to room temperature, purified water was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with saturated NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness. Purification by silica gel column chromatography gave 22 mg of compound 18. MS (ESI) m / z [M+H] + : 456.45

[0472] Example 19

[0473] Compound 19 was prepared according to the procedure for the preparation of Reference Compound 4, using 6-bromoindolizine-2-carboxylic acid ethyl ester instead of 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. MS (ESI) m / z [M+H] + : 481.21.

[0474] Example 20

[0475] Step 1:

[0476] Step 1: (1.8 g) was dissolved in anhydrous THF (20 mL) and cooled to -20 °C under N2 atmosphere, stirred for 30 min, then isopropyl magnesium chloride lithium chloride complex THF solution (1.3 M, 5 mL) was added dropwise, and the reaction was continued for 1 h. Then ethyl 6-fluoroimidazo[l,2-a]pyridine-2-carboxylate (1040 mg) in THF was added dropwise, and the reaction was continued for 1 h. The reaction was quenched by saturated ammonium chloride solution (50 mL), extracted with EA (30 mL*3), and the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain 900 mg of intermediate 20-A. MS (ESI) m / z [M+H] + : 323.0

[0477] Step 2:

[0478] Intermediate 20-A (900 mg) was dissolved in methanol (30 mL) and cooled to 0 °C. Then sodium borohydride (180 mg) was added portionwise, and the reaction was slowly warmed to room temperature and reacted at room temperature for about 2 h. The reaction was quenched by saturated ammonium chloride solution (50 mL), extracted with EA (30 mL*3), and the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain 910 mg of intermediate 20-B. MS (ESI) m / z [M+H] + : 325.00

[0479] Step 3:

[0480] Intermediate 20-B (910 mg) was dissolved in dichloromethane (20 mL), and then TFA (3.4 g) and TES (3.5 g) were slowly added to the system at 0 °C. The reaction was carried out at room temperature overnight. The pH was adjusted to neutral by slowly adding saturated sodium bicarbonate solution to the system at 0 °C, and then extracted with DCM (30 mL*3), and the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to obtain 600 mg of intermediate 20-C. MS (ESI) m / z [M+H] + : 309.9.

[0481] Step 4:

[0482] Intermediate 20-C (600 mg), compound 1-G (700 mg) were dissolved in 1,4-dioxane (20 mL), K2CO3 solution (550 mg K2CO3 dissolved in 4 mL purified water) was added, PdCl2(dppf) (146 mg) was added, and the reaction was heated to 75 °C for 5 hours under a nitrogen atmosphere. After the reaction was completed, it was cooled to room temperature, extracted with EA (30 mL*3), the organic phases were combined, washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography was used to separate 550 mg of intermediate 20-D. MS (ESI) m / z [M+H] + : 369.2.

[0483] Step 5:

[0484] Intermediate 20-D (550 mg) and THF (40 mL) were mixed and stirred. The reaction system was cooled to 0-5 °C, NaH (1800 mg) was added to the reaction system in portions, stirred for 30 minutes, 4-bromo-6-chloropyridazin-3-amine (550 mg) was added, and the reaction was heated to 60-65 °C for 5 hours. After the reaction was completed, it was cooled to room temperature, quenched with purified water (40 mL), extracted with EA (40 mL*3), the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography was used to separate 250 mg of intermediate 20-E. MS (ESI) m / z [M+H] + : 496.1.

[0485] Step 6:

[0486] Intermediate 20-E (250 mg), n-butyl bis (1-adamantyl) phosphine (87 mg), potassium tert-pentoxide (261 mg), Pd(OAc)2 (30 mg), and t-AmOH (10 mL) were mixed and stirred for 5 minutes. The reaction was heated to 120 °C for 2 hours under a nitrogen atmosphere. The reaction temperature was reduced to room temperature, purified water (10 mL) and EA (10 mL) were added to the reaction, stirred for 5 minutes, separated, the organic phase was collected, washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification by preparative column chromatography gave 50 mg of compound 20. MS (ESI) m / z [M+H] + : 460.2.

[0487] Example 21

[0488] Step 1:

[0489] Ethyl 6-bromoimidazo[l,2-a]pyridine-2-carboxylate (15 g), 3,6-dihydro-2H-pyran-4- boronic acid pinacol ester (13.5 g), Pd(dppf)Cl2.DCM (3.26 g) were added into 1,4- dioxane (300 mL), and potassium phosphate (23.6 g) was added with stirring. N2 was replaced, and the temperature was raised to 100 °C, and the reaction was stirred for 16 h. After the reaction was completed, purified water (200 mL) was added to quench the reaction, and EA (150 mL) was used to extract 3 times, and the organic phase was combined, washed with saturated NaCl solution (150 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography was used to separate to obtain 9.0 g of intermediate 21-A.

[0490] Step 2:

[0491] Intermediate 21-A (6.5 g) was added into methanol (50 mL), and 10% palladium on carbon (650 mg) was added, and hydrogen was replaced 5 times, and the reaction was stirred for 3 h under a hydrogen atmosphere at room temperature. After the reaction was completed, filtration was performed, and the filtrate was concentrated under reduced pressure. Column chromatography was used to separate to obtain 5.4 g of intermediate 21-B. MS (ESI) m / z [M+H] + : 275.17.

[0492] Subsequently, referring to the preparation method of compound 4, intermediate 21-B was used to replace intermediate 4-A in step 2, and compound 21 was prepared by the above route. MS (ESI) m / z [M+H] + : 526.30.

[0493] Example 22

[0494] Step 1:

[0495] 3-Bromo-4-iodo-l-methylpyrazole (1.8 g) was dissolved in anhydrous THF (20 mL), and the temperature was lowered to -20 °C under an N2 atmosphere, and stirring was performed for 30 min. A THF solution (1.3 M, 5 mL) of isopropyl magnesium chloride lithium chloride complex was added dropwise to the reaction system, and the reaction was continued for 1 h. Then, a THF solution (1.3 M, 5 mL) of isopropyl magnesium chloride lithium chloride complex was added dropwise to the reaction system, and the reaction was continued for 1 h. Subsequently, 6-chloroimidazo[l,2-a]pyridine-2-carboxaldehyde (900 mg) was added dropwise to the reaction system, and the reaction was continued for 1 h. Saturated ammonium chloride solution (50 mL) was added to quench the reaction, and EA (30 mL*3) was used to extract, and the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.1 g of intermediate 22-A. MS (ESI) m / z [M+H] + : 341.0

[0496] Step 2:

[0497] Intermediate 22-A (2.1 g) was dissolved in dichloromethane (30 mL), then TFA (5.7 g) and TES (5.8 g) were slowly added to the system at 0 °C, after the addition, the reaction was carried out at room temperature overnight. At 0 °C, saturated sodium bicarbonate solution was slowly added to adjust the pH to neutral, then extracted with DCM (30 mL*3), the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography separation gave 1.2 g of intermediate 22-B. MS (ESI) m / z [M+H] + : 324.9

[0498] Step 3:

[0499] Intermediate 22-B (1.2 g) and compound 1-G (3.0 g) were dissolved in 1,4-dioxane (30 mL), K2CO3 solution (3.3 g K2CO3 dissolved in 6 mL purified water) was added, PdCl2(dppf) (250 mg) was added, and the reaction was carried out at 75 °C under nitrogen atmosphere for 5 hours. After the reaction was completed, it was cooled to room temperature, extracted with EA (30 mL*3), the organic phase was combined, washed with saturated NaCl solution (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography separation gave 900 mg of intermediate 22-C. MS (ESI) m / z [M+H] + : 385.2

[0500] Step 4:

[0501] Intermediate 22-C (900 mg) and THF (40 mL) were mixed and stirred. The reaction system was cooled to 0-5 °C, NaH (360 mg) was added to the reaction system in batches, stirred for 30 minutes, 4-bromo-6-chloropyridazin-3-amine (1.1 g) was added, and the reaction was carried out at 60-65 °C for 5 hours. After the reaction was completed, it was cooled to room temperature, quenched with purified water (40 mL), extracted with EA (40 mL*3), the organic phase was combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography separation gave 300 mg of intermediate 22-D. MS (ESI) m / z [M-H] + : 512.19

[0502] Step 5:

[0503] Intermediate 22-D (300 mg), n-butyl bis (1-adamantyl) phosphine (87 mg), potassium tert-pentoxide (261 mg), Pd(OAc)2(30 mg) and t-AmOH (10 mL) were mixed, stirred for 5 minutes, reacted under N2atmosphere by microwave (120 °C, 150 W) for 2 hours. The reaction temperature was reduced to room temperature, purified water (10 mL) and EA (10 mL) were added to the reaction solution, stirred for 5 minutes, separated, the organic phase was collected, washed with saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure, and 10 mg of compound 22 was obtained by column chromatography. MS (ESI) m / z [M-H]- + : 476.1.

[0504] 1 H NMR (500 MHz, DMSO-d6) δ 9.26 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 9.6 Hz, 1H), 7.66 (s, 1H), 7.65 - 7.59 (m, 1H), 7.40 (dd, J = 9.6, 2.1 Hz, 1H), 7.33 (dd, J = 8.5, 5.9 Hz, 1H), 7.29 (dt, J = 8.5, 4.2 Hz, 1H), 6.47 (s, 2H), 6.41 (s, 1H), 5.27 (d, J = 6.2 Hz, 1H), 4.05 (d, J = 15.4 Hz, 1H), 3.84 (s, 3H), 3.28 (d, J = 15.6 Hz, 1H), 1.77 (d, J = 6.3 Hz, 3H).

[0505] In vitro kinase inhibitory activity

[0506] 1.1 ALK (WT) kinase inhibitory activity assay

[0507] ALK (WT) kinase solution (concentration 0.025 ng / μL) was added to each well of the detection hole by 6 μL, and different compounds dissolved by DMSO were added to the detection hole by nanoliter injector, so that the final concentration of the compound was 100 nM-0.024 nM, 2 parallel duplicate wells in each group, and a control group was set. Incubate the above system for 30 minutes, mix ATP (concentration 10 μM) and ULight-poly GT substrate (manufacturer: PerkinElmer, concentration 0.5 μM) at 1:1, and add 4 μL to each well of the detection hole; after 2 hours of reaction at room temperature, add 5 μL of EDTA to terminate the reaction, and then add 5 μL of detection antibody (manufacturer: PerkinElmer, concentration 8 nM) and incubate at room temperature for 1 hour; PerkinElmer Envision multifunctional enzyme labeler is used for detection (excitation 320 nm, emission 615 nm / 665 nm), and four-parameter analysis is carried out in GraphPad Prism software to fit the dose-effect curve and calculate IC 50 value.

[0508] 1.2 ALK (G1202R) kinase inhibition activity assay

[0509] ALK (G1202R) kinase solution (concentration 0.01 ng / μL) was added to each well of the detection hole by 6 μL, and different compounds dissolved by DMSO were added to the detection hole by nanoliter injector, so that the final concentration of the compound was 100 nM-0.024 nM, 2 parallel duplicate wells in each group, and a control group was set. Incubate the above system for 30 minutes, mix ATP (concentration 10 μM) and ULight-poly GT substrate (manufacturer: PerkinElmer, concentration 0.5 μM) at 1:1, and add 4 μL to each well of the detection hole; after 2 hours of reaction at room temperature, add 5 μL of EDTA to terminate the reaction, and then add 5 μL of detection antibody (manufacturer: PerkinElmer, concentration 8 nM) and incubate at room temperature for 1 hour; PerkinElmer Envision multifunctional enzyme labeler is used for detection (excitation 320 nm, emission 615 nm / 665 nm), and four-parameter analysis is carried out in GraphPad Prism software to fit the dose-effect curve and calculate IC 50 value.

[0510] 1.3 ALK (L1196M G1202R) kinase inhibition activity assay

[0511] ALK(L1196M G1202R) kinase solution (concentration 0.01 ng / μL) was added to the detection hole at 6 μL per hole, and different compounds dissolved in DMSO were added to the detection hole by nanoliter injector to make the final concentration of the compound 100 nM-0.024 nM, 2 parallel holes per group, and a control group was set. Incubate the above system for 30 minutes, mix ATP (concentration 10 μM) and ULight-poly GT substrate (manufacturer: PerkinElmer, concentration 0.5 μM) at 1:1, and add 4 μL per hole to the detection hole; after 2 hours of reaction at room temperature, add 5 μL of EDTA to terminate the reaction, and then add 5 μL of detection antibody (manufacturer: PerkinElmer, concentration 8 nM), incubate at room temperature for 1 hour; PerkinElmer Envision multifunctional microplate reader for detection (excitation 320 nm, emission 615 nm / 665 nm), four-parameter analysis in GraphPad Prism software, fitting dose-effect curve, calculating IC 50 values.

[0512] Some experimental results are shown in Table 1.

[0513] Table 1

[0514] Note: A indicates IC 50 ≤ 10 nM.

[0515] Test Example 2 In vitro cell proliferation inhibition activity

[0516] 2.1 BaF3-EML4-ALK-V1-G1202R cell proliferation inhibition activity determination

[0517] Take well-grown BaF3-EML4-ALK-V1-G1202R cells, collect them into a centrifuge tube, and inoculate 6000 cells per hole (100 μL per hole) in a 96-well plate. After overnight culture in a cell incubator, use a nanoliter injector to add compounds to make the final concentration of the compound 100 nM-0.046 nM, 2 parallel holes per group, and a control group is set. After 72 hours of continuous culture in a cell incubator, add detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL per hole), incubate in a cell incubator for 3 hours, and then detect the absorbance value at 450 nm by PerkinElmer Envision microplate reader, and perform four-parameter analysis in GraphPad Prism software, fitting the dose-effect curve, and calculating IC 50 values.

[0518] 2.2 BaF3-EML4-ALK-V1-G1202R / L1196M cell proliferation inhibition activity determination

[0519] Take the BaF3-EML4-ALK-V1-G1202R / L1196M cells in good growth state, collect into centrifuge tube, inoculate 6000 cells per hole on 96 hole plate (100 μL / hole), after overnight culture in cell incubator, use nanoliter sample adding instrument to add compound, make the final concentration of compound 100 nM-0.046 nM, 2 parallel duplicate holes per group, set up control group at the same time. After 72 hours of continuous culture in cell incubator, add detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / hole), after 3 hours of incubation in cell incubator, detect the absorbance value at 450 nm by PerkinElmer Envision enzyme label instrument, carry out four parameter analysis in GraphPad Prism software, fit the dose-effect curve, calculate IC 50 value.

[0520] 2.3 Karpas299 (NPM1-ALK) cell proliferation inhibition activity determination

[0521] Take the Karpas299 (NPM1-ALK) cells in good growth state, collect into centrifuge tube, inoculate 6000 cells per hole on 96 hole plate (100 μL / hole), after overnight culture in cell incubator, use nanoliter sample adding instrument to add compound, make the final concentration of compound 1000 nM-0.46 nM, 2 parallel duplicate holes per group, set up control group at the same time. After 72 hours of continuous culture in cell incubator, add detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / hole), after 3 hours of incubation in cell incubator, detect the absorbance value at 450 nm by PerkinElmer Envision enzyme label instrument, carry out four parameter analysis in GraphPad Prism software, fit the dose-effect curve, calculate IC 50 value.

[0522] 2.4 NCI-H2228 (EML4-ALK-V3) cell proliferation inhibition activity determination

[0523] NCI-H2228 (EML4-ALK-V3) cells in good growth state were collected into centrifuge tubes, 500 cells per well were inoculated in a 96-well plate (100 μL / well), after overnight culture in a cell incubator, nanoliter sample adding instrument was used for compound adding, so that the final concentration of the compound was 1000 nM-0.46 nM, 2 parallel wells were set for each group, and a control group was also set. After 72 hours of continuous culture in a cell incubator, CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added, and after 3 hours of incubation in a cell incubator, the absorbance value was detected at 450 nm by PerkinElmer Envision microplate reader, and four-parameter analysis was performed in GraphPad Prism software to fit the dose-effect curve and calculate the IC 50 value.

[0524] Some experimental results are shown in Table 2.

[0525] Table 2

[0526] Note: A indicates IC 50 ≤ 50 nM.

[0527] Test Example 3 In vitro liver microsomal metabolic stability

[0528] The sample for liver microsomal incubation was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / ml), test compound and NADPH+MgCl2 solution at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / ml) and test compound. The sample was added with acetonitrile solution for protein precipitation to prepare supernatant, which was diluted and used for LC / MS / MS determination.

[0529] Some experimental results are shown in Table 3.

[0530] Table 3

[0531] Test Example 4 Mouse pharmacokinetics

[0532] ICR mice, weighing 18-22 g, were randomly divided into groups after 3-5 days of adaptation, 9 mice per group, the gavage group was given the relevant compound solution at a dose of 3 mg / kg by gavage, and the intravenous injection group was given the relevant compound solution at a dose of 1 mg / kg by intravenous injection.

[0533] The gavage blood sampling time points were 15 min, 2 h, 8 h and 24 h, and the intravenous injection blood sampling time points were 5 min, 15 min, 1 h, 2 h, 4 h, 8 h and 24 h. The orbital blood was collected to prepare the test plasma sample.

[0534] Take 30 μL of the plasma sample to be tested and the standard curve sample, add the internal standard-containing acetonitrile solution to precipitate the protein to obtain the supernatant, and dilute for LC / MS / MS determination.

[0535] The pharmacokinetic parameters were fitted by using a non-compartment model.

[0536] The compounds of the present application have good in vivo pharmacokinetic properties, for example, in terms of AUC, t 1 / 2 , and F, for example, the AUC (h*ng / mL) of the compound of the present application is > 19000 when the mouse is administered by gavage at 3 mg / kg; for example, the absolute bioavailability of the compound of the present application is > 82%. 0-24

[0537] Some experimental results are shown in Table 4.

[0538] Table 4

[0539] In vivo efficacy evaluation of Test Example 5

[0540] 5.1 Ba / F3 EML4-ALK-v1 G1202R / L1196M cell NOD-SCID mouse subcutaneous tumor transplantation model

[0541] SPF female NOD-SCID mice (source: Jiangsu Jizhuangkang Biotechnology Co., Ltd.) were inoculated subcutaneously with Ba / F3 EML4-ALK-v1 G1202R / L1196M cells in the right axillary fossa at 1×10 6 / each. When the average tumor volume reached 100-200 mm 3 , the animals were grouped.

[0542] The day of grouping was day 0, and from day 0, the animals were administered by gavage once a day. The tumor volume was measured 2-3 times a week, and the body weight of the mice was measured, and the data were recorded; the general performance of the mice was observed and recorded daily. After the experiment, the tumors were stripped and weighed, and photographed.

[0543] The detection indexes and calculation formulas are as follows:

[0544] Tumor volume, TV (mm 3 ) = 1 / 2 × (a × b 2 ); wherein a is the long diameter of the tumor, and b is the short diameter of the tumor.

[0545] Relative tumor volume, RTV = TV t / TV0; wherein TV0 is the tumor volume on day 0, and TV t is the tumor volume at each measurement.

[0546] Relative tumor proliferation rate, T / C (%) = T RTV ​ / C RTV TGI(TV)(%) = [1-(T-To) / (C-Co)]x100%; wherein, T: mean tumor volume of treatment group; To: mean tumor volume of treatment group at d0; C: mean tumor volume of control group; Co: mean tumor volume of control group at d0. RTV RTV of treatment group; C RTV RTV of control group.

[0547] TGI(TV)(%) = [1-(T-To) / (C-Co)]x100%; wherein, T: mean tumor volume of treatment group; To: mean tumor volume of treatment group at d0; C: mean tumor volume of control group; Co: mean tumor volume of control group at d0.

[0548] TGI(TW)(%) = (1-TW t / TW c ) x 100%; wherein, TW t : tumor weight of treatment group; TW c : tumor weight of control group.

[0549] BWC(%) = (Wt t -Wt0) / Wt0x100%; wherein, Wt0: mouse weight at d0, Wt t : mouse weight at each measurement.

[0550] The compounds of the present application have good in vivo efficacy, for example in TGI(TV)(%), TGI(TW)(%), and BWC(%); for example, when the mice are administered by gavage at 2-4 mg / kg, the TGI(TW)(%) of the compounds of the present application is ≥ 90% on the 21st day.

[0551] Some experimental results are shown in Table 5.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 each independently is selected from -O-, -S-, -NR X1 -, -C(O)-, or -C(R X1 )2-; Each R X1 Each is independently selected from H, deuterium, halogen, -OH, -NH2, -CN, and C. 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; or two R X1 together form an optionally substituted group selected from 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl; X1a together form an optionally substituted group selected from 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl; Each R X1a Each is independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; X 3 , X 4 , X 5 , X 6 , X 7 , X 8 each is independently selected from a single bond, -O-, -S-, -NR X2 -, -C(O)-, or -C(R X2 )2-; Each R X2 Each is independently selected from H, deuterium, halogen, -OH, -NH2, -CN, and C. 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; Z 1 , Z 2 , Z 3 are each independently selected from N or CR Z ; Each R Z Each is independently selected from H, deuterium, halogen, -OH, -NH2, -CN, and C. 1-6 Alkyl, 3-6 membered cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, diC 1-6 Alkylamino, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 1-6 Alkylamino or halogenated diC 1-6 Alkylamino; Ring A is selected from optionally substituted 5-10 membered heteroaryl; A1 substituted 5-10 membered heteroaryl; R A1 are each independently selected from deuterium, halogen, -OH, -NH2, -CN, or are optionally substituted with one or more R A2 substituted C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered cycloalkylC 1-4 alkylene, 3-12 membered heterocycloalkylC 1-4 alkylene, 3-12 membered cycloalkyl-O-, 3-12 membered heterocycloalkyl-O-, 3-12 membered cycloalkyl-S-, 3-12 membered heterocycloalkyl-S-, 6-10 membered aryl, 5-10 membered heteroaryl, 6-10 membered arylC 1-4 alkylene, or 5-10 membered heteroarylC 1-4 alkylene; each R A2 are each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylamino, or halogenated di-C 1-6 alkylamino; Ring B is selected from optionally substituted 5-10 membered heteroaryl; B1 substituted 5-10 membered heteroaryl; R B1 each independently is selected from deuterium, halogen, -OH, -NH2, -CN, or is an optionally substituted group: C B2 alkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 3-12 membered cycloalkylC 1-4 alkylene, or 3-12 membered heterocycloalkylC 1-4 alkylene; each R B2 are each independently selected from deuterium, oxo, halogen, -OH, -NH2, -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, di-C 1-6 alkylamino, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylamino, or halogenated di-C 1-6 alkylamino; said R X1 , R X1a , R X2 , R Z , R A2 , R B2 optionally substituted with one or more substituents; provided that when ring A is selected from optionally substituted A1 substituted and -X 6 when connected, ring B is selected from optionally substituted B1 substituted 2. The compound of formula (I) according to claim 1, wherein, or a pharmaceutically acceptable salt thereof. X 1 、X 2 each independently is selected from -O-, -NR X1 -, -C(O)-, or -C(R X1 )2-; or, the structural unit -X 1 -X 2 - is selected from -OC(R X1 )2- -OC(O)- -C(R X1 )2O- -C(O)O- -NR X1 C(R X1 )2- -NR X1 C(O)- -C(R X1 )2NR X1 - -C(O)NR X1 - -C(R X1 )2C(R X1 )2- or -C(O)C(R X1 )2; or X 1 , X 2 are each independently selected from -0-, -NH-, -N(CH3)-, -C(O)-, -CH2-, or -CH(CH3)-; or, structural unit -X 1 -X 2 - is selected from -OCH2-, -OCH(CH3)-, -OC(O)-, -CH2O-, -CH(CH3)O-, -C(O)O-, -NHCH2-, -N(CH3)CH2-, -NHC(O)-, -N(CH3)C(O)-, -CH2NH-, -CH(CH3)NH-, -C(O)NH-, -C(O)N(CH3)-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(O)CH2-, -CH2C(O)-, or a structural unit -X 1 -X 2 - is selected from or a structural unit -X 1 -X 2 - is selected from 3. The compound of formula (I) according to claim 1 or 2, wherein, or a pharmaceutically acceptable salt thereof. X 3 , X 4 , X 5 , X 6 , X 7 , X 8 each independently is selected from a single bond, -O-, -NR X2 -, -C(O)-, or -C(R X2 )2-; or, the structural unit -X 3 - X 4 - is selected from a single bond, -O-, -NR X2 <, -C(O)-, or -C(R X2 )2-; or, the structural unit -X 5 - X 6 - is selected from a single bond, -O-, -NR X2 -, -C(O)-, -C(R X2 )2-, -OC(R X2 )2-, -OC(O)-, -C(R X2 )2O-, -C(O)O-, -NR X2 C(R X2 )2-, -NR X2 C(O)-, -C(R X2 )2NR X2 -, -C(O)NR X2 -, -C(R X2 )2C(R X2 )2-, -C(R X2 )2C(O)-, or -C(O)C(R X2 )2-; or, the structural unit -X 7 -X 8 - is selected from a single bond, -O-, -NR X2 -, X2 -C(O)-, or -C(R X2 )2-; or X 3 , X 4 , X 5 , X 6 , X 7 , X 8 each independently is selected from a single bond, -O-, -NH-, -N(CH3)-, -C(O)-, -CH2-, or -CH(CH3)-; or a structural unit -X 3 -X 4 - is selected from a single bond, -0-, -NH-, -N(CH3)-, -C(O)-, -CH2-, or -CH(CH3)-; or a structural unit -X 3 - X 4 - is selected from a single bond; or a structural unit -X 5 -X 6 - is selected from a single bond, -0-, -NH-, -N(CH3)-, -C(O)-, -CH2-, -CH(CH3)-, -OCH2-, -OCH(CH3)-, -OC(O)-, -CH2O-, -CH(CH3)0-, -C(0)0-, -NHCH2-, -N(CH3)CH2-, -NHC(O)-, -N(CH3)C(O)-, -CH2NH-, -CH(CH3)NH-, -C(0)NH-, -C(0)N(CH3)-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH2C(0)-, or -C(0)CH2-; or the structural unit -X 5 - X 6 - is selected from -C(O)- or -CH2-; or a structural unit -X 7 -X 8 - is selected from a single bond, -0-, -NH-, -N(CH3)-, -C(O)-, -CH2-, or -CH(CH3)-; or a structural unit -X 7 - X 8 - is selected from a single bond.

4. The compound of formula (I) according to any one of claims 1 to 3, wherein, or a pharmaceutically acceptable salt thereof. Z 1 , Z 2 , Z 3 is selected from CR Z ; or one of Z 1 , Z 2 , Z 3 is selected from N, two are selected from CR Z ; or two of Z 1 , Z 2 , Z 3 are selected from N and one is selected from CR Z ; Or, Z 1 Z 2 Z 3 Selected from N; or Z 1 , Z 2 , Z 3 are each independently selected from N, CH, or CF; or Z 1 , Z 2 , Z 3 is selected from CH.

5. The compound of formula (I) according to any one of claims 1 to 4, wherein, ###00001### (I) or a pharmaceutically acceptable salt thereof. Ring A is selected from optionally substituted 5-9 membered heteroaryl; A1 substituted 5-9 membered heteroaryl; or, ring A is selected from optionally substituted 5-, 6-, 7-, 8-, or 9-membered heteroaryl; A1 substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or, ring A is selected from optionally substituted A1 substituted furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzisothiazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyridazinyl, pyrazolopyridazinyl, or imidazopyridazinyl; Alternatively, ring A can be selected from one or more R's. A1 The following groups may be substituted: pyrazolyl, imidazolyl, triazolyl, isoxazolyl, imidazopyrazinyl, pyrrolopyridyl, imidazopyridyl, pyrrolopyrimidinyl, imidazopyrimidinyl, pyrrolopyrazinyl, or imidazopyridazinyl; or, ring A is selected from optionally substituted groups: A1 substituted as follows: Alternatively, ring A is selected from wherein - and X 6 are connected.

6. The compound of formula (I) according to any one of claims 1 to 5, wherein Ring B is selected from optionally substituted 5-9 membered heteroaryl; B1 substituted 5-9 membered heteroaryl; or, ring B is selected from optionally substituted 5-, 6-, 7-, 8-, or 9-membered heteroaryl; and B1 substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted or, ring B is selected from optionally substituted B1 substituted furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzothienyl, benzothiazolyl, benzisothiazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyridazinyl, pyrazolopyridazinyl, or imidazopyridazinyl; or, ring B is selected from optionally substituted B1 substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R or, ring B is selected from optionally substituted B1 groups as follows: Alternatively, ring B is selected from wherein - and X 5 are connected.

7. The compound of Formula (I) according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of Formula (II), Formula (II-A), Formula (II-B), or a pharmaceutically acceptable salt thereof, wherein, R X1 , X 5 , X 6 , Z 1 , Z 2 , Z 3 , R Z , ring A, ring B are as defined in any one of claims 1 to 6; or it is selected from a compound of Formula (III), Formula (III-A), Formula (III-B), or a pharmaceutically acceptable salt thereof, wherein Z 1 , Z 2 , Z 3 , R Z , ring A, ring B are as defined in any one of claims 1 to 6.

8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, selected from the following compounds or a pharmaceutically acceptable salt thereof: or it is selected from the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

9. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8; optionally, further comprising a pharmaceutically acceptable excipient.

10. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the treatment of a disease.

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