Compound used as SMARCA2 / 4 inhibitor and application thereof

Abstract

The invention discloses a compound which is used as an SMARCA2 / 4 inhibitor and has a structural formula as shown in a formula I or a pharmaceutically acceptable salt thereof. The invention also discloses a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition thereof. The compound provided by the invention has better inhibitory activity on SMARCA2 / 4, and can be used as a dual inhibitor of SMARCA2 / 4.

Description

A compound used as a SMARCA2 / 4 inhibitor and its application Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a compound used as a SMARCA2 / 4 inhibitor and a pharmaceutically acceptable salt thereof, which can be used to treat diseases caused by SMARCA2 / 4 mutation or deletion. Background Art

[0002] SMARCA2 / 4 are key subunits of the SWI / SNF chromatin remodeling complex, also known as the BAF complex. Chromatin, the carrier of genetic information in eukaryotes, consists of DNA and nucleosomes and is normally highly compacted. When genes at specific loci require transcription, chromatin transitions from a compacted to a loosened state, a process that requires the involvement of chromatin remodeling complexes. Chromatin remodeling complexes utilize energy from ATP hydrolysis to reposition, assemble, migrate, and reorganize nucleosomes, altering chromatin structure and thereby changing the accessibility of transcription factors and cellular proteins to local DNA. When chromatin remodeling factors loosen chromatin, accessibility to chromatin DNA by RNA polymerase II and transcription factors is increased, thereby initiating gene transcription. Conversely, when chromatin becomes compacted, accessibility to chromatin DNA by RNA polymerase II and transcription factors is reduced, thereby repressing transcription of the associated genes. Chromatin remodeling, a crucial component of epigenetic regulation, plays a crucial role in eukaryotic DNA replication, transcription, recombination, and DNA repair, thereby controlling cell proliferation, division, and maturation. SWI / SNF regulates gene expression by altering chromatin disassembly and replacing nucleosome-stabilizing proteins. SMARCA4 (encoding the BRG1 protein) and SMARCA2 (encoding the BRM protein) are two mutually exclusive catalytic subunits of the SWI / SNF complex. They share 75% homology at the protein level and possess ATPase activity, providing energy for chromatin remodeling. The ATP-dependent chromatin remodeling activity of SMARCA2 or SMARCA4 is essential, primarily involved in double-strand break and nucleotide excision repair, playing a crucial role in double-strand damage repair. Therefore, SMARCA mutations can lead to uncorrected or inappropriate DNA damage repair, driving tumorigenesis and progression. Although both SMARCA2 and SMARCA4 are ATP hydrolases, their functions differ, resulting in distinct mutational profiles in malignant tumors, with co-mutations rarely occurring. SMARCA2 loss is relatively rare and can occur in rhabdoid tumors, esophageal cancer, bladder cancer, and gastric cancer. SMARCA4, on the other hand, is one of the genes frequently mutated in malignant tumors and is commonly found in ovarian clear cell carcinoma, renal cancer, hematologic tumors, and medulloblastoma, but is not usually accompanied by SMARCA2 mutations. In most SMARCA4-deficient tumors, SMARCA2 is upregulated to compensate for the loss of SMARCA4 function. SMARCA4 mutations make cell proliferation more dependent on its alternative ATPase, SMARCA2, making these tumor cells susceptible to SMARCA2 loss. Selective inhibition of SMARCA2 activity has been shown to be an effective treatment for the growth of SMARCA4-mutated cancer cells, a relationship known as synthetic lethality.In both in vitro and mouse xenograft studies, knocking down SMARCA2 protein expression using RNAi inhibited the growth of SMARCA4 mutant lung cancer tumors.

[0003] SMARCA proteins are multi-domain proteins. In addition to the conserved ATPase catalytic domain, they also contain bromodomains, which can help the complex bind to specific sites on chromatin by recognizing acetylated residues on the histone "tails." Currently, most SMARCA2 inhibitors under development target the bromodomain, with a few studies acting on the core ATPase catalytic domain. Although studies have found that the synthetic lethality of SMARCA2 and SMARCA4 can be achieved by knocking down SMARCA2 through RNAi or inhibiting ATPase activity, small molecule inhibitors targeting the bromodomain are unable to effectively inhibit tumor cell proliferation. Therefore, the SMARCA2 target contains a bromodomain that is easy to target as a drug but does not play a major role, and an ATPase domain that plays a major role but is more difficult to target as a drug. This structural feature makes the development of drugs that target SMARCA2 more difficult.

[0004] SMARCA2 / 4 and PB1, as part of the SWI / SNF chromatin remodeling complex, together form the VIII bromodomain. PFI-3 (1), developed by Pfizer and GSK, binds to the VIII bromodomain active pocket by replacing four conserved water molecules. However, the compound did not show good selectivity for SMARCA2 / 4 / PB1. Moreover, it did not show significant inhibitory activity in 148 types of cancer cells. Most importantly, the compound's tertiary amine-linked propylene ketone has poor chemical stability, which limits its exposure time in cells (Current Opinion in Chemical Biology, 2016, 33, 58-66; 10.1021 / acs.jmedchem; 6b0001210.1021 / acs.jmedchem.0c01242). Luo's group discovered a new SMARCA2 inhibitor through high-throughput screening. Although it showed good selectivity for SMARCA2, its pK D The value still needs to be improved. (Acta Pharmacol. Sin. 2018, 39, 1544–1552.).

[0005] Summary of the Invention

[0006] In response to the defects of the above-mentioned prior art inhibitor compounds against SMARCA2 / 4, which have poor stability and activity, the present invention provides a novel compound used as a SMARCA2 / 4 inhibitor. It has been verified that the novel inhibitor compound provided by the present invention has higher inhibitory activity than the existing compounds.

[0007] In one aspect, the present invention provides a A The compound of the structural formula shown or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] Cy1 is a saturated or unsaturated cycloalkyl group, a saturated or unsaturated heterocycloalkyl group containing a heteroatom selected from N, O and S, an aryl group, or a heteroaryl group containing a heteroatom selected from N, O and S, which is unsubstituted or substituted by one or more groups independently selected from halogen, cyano, haloalkyl, haloalkoxy, alkyl, hydroxyl, amino and alkylamino; preferably, Cy1 is a saturated or unsaturated 3-10 membered cycloalkyl group, a saturated or unsaturated 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O and S, a 6-10 membered aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by one or more groups independently selected from halogen, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl, hydroxyl, amino and C1-C6 alkylamino;

[0010] R is Squiggly lines indicate connection points;

[0011] R a CR aa or N;

[0012] R f Selected from C(R aa )2, CO, O, S and NR aa ;

[0013] W1 and W2 are CR aa or N;

[0014] R b 、R c 、R d 、R e Each occurrence is independently selected from C(R aa )2, CO, O, S and NR aa ;

[0015] R aaEach occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2 and -N(R g )-S(O)2-R g and nitro, wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo (=O), alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and nitro are substituted with one or more substituents; preferably, Raa Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a -C(O)-C1-C6 alkyl group, a nitro group, a cyano group, a C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 Heteroaryl, -NHR g , benzyloxycarbonyl (Cbz), carboxyl (-COOH), -N(R g )2、-NH(CO)R g , acetoxy (AcO) and -N(R g )2, wherein optionally, the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, nitro, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 Heteroaryl, carboxyl (-COOH), -NH(CO)R g , acetoxy (AcO) and -N(R g )2 is substituted by one or more substituents; preferably, R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a cyano group, a nitro group, a benzyloxycarbonyl group (Cbz), a carboxyl group (-COOH), a NH(CO)R g , acetoxy (AcO) and -N(R g ) 2, wherein optionally, the C1-C6 alkyl and C1-C6 alkoxy are each independently selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, nitro, C3-C8 cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10Heteroaryl, carboxyl (-COOH), -NH(CO)R g , acetoxy (AcO) and -N(R g )2 is substituted by one or more substituents;

[0016] m1, m2, m3, and m4 are each independently selected from 0, 1, 2, 3, 4, and 5 at each occurrence;

[0017] R1 is selected from H, deuterium atoms, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and nitro, wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo (=O), alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-Rg 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and nitro; preferably, R1 is selected from H, a deuterium atom, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a 3- to 15-membered cycloalkyl group, a 3- to 15-membered heterocycloalkyl group, a 6- to 14-membered aryl group, and a 5- to 14-membered heteroaryl group, wherein the 3- to 15-membered cycloalkyl group and the 3- to 15-membered heterocycloalkyl group are each independently a monocyclic, condensed, bridged, or spirocyclic group, and the 6- to 14-membered aryl group and the 5- to 14-membered heteroaryl group are each independently a monocyclic or condensed ring group, and optionally, the C1-C6 alkyl group, C2-C6 deuterated alkyl group, C1-C6 heteroalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, a 3- to 15-membered cycloalkyl group, a 3- to 15-membered heterocycloalkyl group, a 6- to 14-membered aryl group, and a 5- to 14-membered heteroaryl group C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 6-14 membered aryl, and 5-14 membered heteroaryl are each independently substituted by one, two or more groups independently selected from halogen, oxo (=O), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl, -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and nitro substituents;

[0018] Rg Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl, a deuterated alkyl, a heteroalkyl, an alkenyl, an alkynyl, an alkoxy, a haloalkyl, a haloalkoxy, a hydroxyl, a hydroxyalkyl, -C(O)-alkyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a benzyloxycarbonyl (Cbz), wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, a heterocyclyl, an aryl and a heteroaryl are each independently substituted with one or more substituents selected from the group consisting of halogen, an alkyl, a heteroalkyl, an alkoxy, a haloalkyl, a hydroxyl, a hydroxyalkyl, a cyano, an amino, a nitro, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, a carboxyl (-COOH), an alkylamino, -NH(CO)H, -NH(CO)alkyl and an acetoxy (AcO); preferably, R g Each occurrence is independently selected from H, a deuterium atom, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a C1-C6 hydroxyalkyl group, a -C(O)-C1-C6 alkyl group, a C6-C 10 Aryl, C5-C 10 Heteroaryl, C3-C 15 Cycloalkyl and C3-C 15 Heterocycloalkyl, wherein optionally, the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 15 Cycloalkyl, C3-C 15 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C 15 Cycloalkyl, C3-C 15 Heterocyclic group, C6-C 10 Aryl, C5-C 10 substituted with one or more substituents selected from heteroaryl, carboxyl (-COOH), C1-C6 alkylamino, -NH(CO)H, -NH(CO)-C1-C6 alkyl, and acetoxy (AcO); and

[0019] R2 and R3 are each independently selected from H, an alkyl group, a deuterium atom, F, Cl, Br, I, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group and a -C(=O)-alkyl group; preferably, R2 and R3 are each independently selected from H, a C1-C6 alkyl group, a deuterium atom, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 alkoxy group and a -C(=O)-C1-C6 alkyl group.

[0020] In one of the technical solutions,

[0021] Cy1 is an aryl or heteroaryl group, the aryl and heteroaryl groups are substituted by hydroxyl, amino or alkylamino, and are optionally substituted by a substituent selected from the following: halogen, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl; preferably, Cy1 is a 6-10 membered aryl group or a 5-10 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, O and S, the 6-10 membered aryl group and the 5-10 membered heteroaryl group are substituted by hydroxyl, amino or alkylamino, and are optionally substituted by a substituent selected from the following: halogen, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl; preferably, Cy1 is a phenyl group or a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, O and S, the phenyl group and the 5-6 membered heteroaryl group are substituted by hydroxyl, amino or alkylamino, and are optionally substituted by a substituent selected from the following: halogen, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl; and / or Cy1 is substituted by 1-3 C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl; preferably, Cy1 is phenyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, said phenyl and 5-6 membered heteroaryl are substituted by hydroxy, amino or alkylamino, and optionally substituted by a substituent each independently selected from the following: F, Cl, Br, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl and C1-C3 alkoxy; preferably, Cy1 is phenyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, said phenyl and 5-6 membered heteroaryl are substituted by at least one hydroxy, amino or alkylamino, preferably by one hydroxy, amino or alkylamino; and / or

[0022] R1 is selected from H, a deuterium atom, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a 3- to 15-membered cycloalkyl group, a 3- to 15-membered heterocycloalkyl group, a 6- to 14-membered aryl group, and a 5- to 14-membered heteroaryl group, wherein the 3- to 15-membered cycloalkyl group and the 3- to 15-membered The 6- to 14-membered aryl and 5- to 14-membered heteroaryl are each independently a monocyclic, fused, bridged, or spirocyclic group, the 3- to 15-membered heterocycloalkyl and the 5- to 14-membered heteroaryl are each independently a monocyclic or fused ring group, the 3- to 15-membered heterocycloalkyl and the 5- to 14-membered heteroaryl each independently contain 1, 2, 3, 4, or 5 heteroatoms each independently selected from N, O, and S, optionally, the C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3- to 15-membered cycloalkyl, 3- to 15-membered heterocycloalkyl, 6- to 14-membered aryl, and 5- to 14-membered heteroaryl are each independently substituted by one, two, or three substituted alkyl radicals. more substituents independently selected from F, Cl, Br, I, oxo (═O), hydroxy, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (—COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), —(CO)H, —NH(CO)—C1-C6 alkyl, 5-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and 9-fluorenylmethyloxycarbonyl (Fmoc); and / or

[0023] R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, a hydroxyl group, a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C3 alkoxy group, a C1-C3 haloalkyl group, a C1-C6 haloalkoxy group, a cyano group, a nitro group, a benzyloxycarbonyl group (Cbz), a carboxyl group (-COOH), a NH(CO)R g , acetoxy (AcO) and -N(R g )2, wherein optionally, the C1-C3 alkyl and C1-C3 alkoxy are each independently selected from halogen, C1-C3 alkyl, C1-C3 heteroalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, cyano, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclyl, phenyl, C5-C6 heteroaryl, carboxyl (-COOH), -N(CO)R g , acetoxy (AcO) and -N(R g )2 is substituted with one or more substituents; and / or

[0024] R gEach occurrence is independently selected from H, a deuterium atom, a C1-C3 alkyl group, a C1-C3 heteroalkyl group, a C1-C3 alkoxy group, a C2-C3 alkenyl group, a C2-C3 alkynyl group, a C1-C3 haloalkyl group, a C1-C3 haloalkoxy group, a C1-C3 hydroxyalkyl group, -C(O)-C1-C3 alkyl group, a phenyl group, a C5-C6 heteroaryl group, a C3-C6 cycloalkyl group and a C3-C6 heterocycloalkyl group, wherein optionally, the C1-C3 alkyl group, the C1-C3 heteroalkyl group, the C2-C3 alkenyl group, the C2-C3 alkynyl group, the C1-C3 alkoxy group, the C3-C6 cycloalkyl group, the C3-C6 heterocyclyl group, the aryl group and the C5-C 10 The heteroaryl groups are each independently selected from halogen, C1-C3 alkyl, C1-C3 heteroalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 10 Aryl, C5-C 10 substituted by one or more substituents selected from heteroaryl, carboxyl (-COOH), C1-C3 alkylamino, -NH(CO)H, -NH(CO)-C1-C3 alkyl, and acetoxy (AcO); and / or

[0025] R2 and R3 are each independently selected from H, a C1-C3 alkyl group, a deuterium atom, a C1-C3 haloalkyl group, a C1-C3 hydroxyalkyl group, a C1-C3 alkoxy group and -C(=O)-C1-C3 alkyl group.

[0026] In one of the technical solutions,

[0027] The compound has the structure shown in Formula I

[0028] wherein Cy1 is an aryl or heteroaryl group, said aryl and heteroaryl group being substituted by at least one hydroxyl group, amino group, or alkylamino group, and being optionally substituted by one or more groups independently selected from the following: halogen, cyano group, haloalkyl group, haloalkoxy group, alkyl group, and alkoxy group; preferably, Cy1 is a 6-10 membered aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, O, and S, said 6-10 membered aryl or heteroaryl group being substituted by at least one hydroxyl group, amino group, or alkylamino group, and being optionally substituted by one or more groups independently selected from the following: halogen, cyano group, C1-C6 haloalkyl group, C1-C6 haloalkoxy group, C1-C6 alkyl group, and C1-C6 alkoxy group.

[0029] R1 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and C1-C6 hydroxyalkyl; or, R1 is unsubstituted or substituted 3 to 15-membered cycloalkyl or, R1 is a 3 to 15-membered heterocycloalkyl having 1-3 heteroatoms independently selected from N, O and S, and the 3 to 15-membered cycloalkyl and 3 to 15-membered heterocycloalkyl are each independently a monocyclic, condensed, bridged or spirocyclic group; or R1 is an unsubstituted or substituted phenyl, or a substituted or unsubstituted 8 to 10-membered aryl, the 8 to 10-membered aryl is a monocyclic or condensed ring group; or, R1 is a 3 to 15-membered heterocycloalkyl having 1-3 heteroatoms independently selected from N, O and S. unsubstituted or substituted 5- to 6-membered heteroaryl, or R1 is an unsubstituted or substituted 8- to 10-membered heteroaryl having 1-3 heteroatoms independently selected from N, O and S, wherein the 8- to 10-membered heteroaryl is a monocyclic or condensed ring group; wherein the substituted 3- to 15-membered cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, 8- to 10-membered aryl, 5- to 6-membered heteroaryl and 8- to 10-membered heteroaryl are each independently substituted by one, two or more groups independently selected from halogen, oxo (=O), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, 3- to 15-membered cycloalkyl, 3- to 15-membered heterocycloalkyl, -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R gand nitro; preferably, substituted by one, two or more substituents independently selected from halogen, oxo (=O), hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), -NH(CO)-C1-C6 alkyl, acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, 5-8 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc);

[0030] R g Each occurrence is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, 3-15 membered cycloalkyl or 3-15 membered heterocycloalkyl; preferably, R g Each occurrence is independently H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl, and

[0031] R2 and R3 are each independently selected from H, alkyl and -C(=O)-alkyl.

[0032] In one of the technical solutions,

[0033] Cy1 is phenyl or a 5-6 membered heteroaryl, said phenyl and 5-6 membered heteroaryl being substituted by at least one hydroxyl, amino, or alkylamino group, and optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, haloalkyl, haloalkoxy, alkyl, and alkoxy; preferably, Cy1 is phenyl or a 5-6 membered heteroaryl, said phenyl or heteroaryl being substituted by at least one hydroxyl group, and optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, and C1-C6 alkoxy, preferably optionally substituted by one or more groups independently selected from the group consisting of F, Cl, Br, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, and C1-C3 alkoxy; preferably, Cy1 is phenyl, and said phenyl is substituted by one hydroxyl group; and / or

[0034] R1 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 haloalkoxy and C1-C4 hydroxyalkyl; or R1 is unsubstituted or substituted 3 to 15-membered cycloalkyl, or R1 is a 3 to 15-membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O and S, and the 3 to 15-membered cycloalkyl and 3 to 15-membered heterocycloalkyl are each independently a monocyclic, condensed or spirocyclic group; or R1 is an unsubstituted or substituted phenyl, or a substituted or unsubstituted 10-membered aryl, the 10-membered aryl is a condensed ring group; or R1 is a substituted or unsubstituted 5 to 6-membered aryl having 1-2 heteroatoms independently selected from N, O and S. wherein R1 is an unsubstituted or substituted 8- to 10-membered heteroaryl having 1-3 heteroatoms independently selected from N, O and S, and the 8- to 10-membered heteroaryl is a fused ring group; wherein the substituted 3- to 15-membered cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 10-membered aryl and 8- to 10-membered heteroaryl are each independently substituted by one, two or more groups independently selected from halogen, oxo (=O), carboxyl, benzyloxycarbonyl (Cbz), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), 5- to 8-membered heterocycloalkyl containing one nitrogen atom, 9-fluorenylmethyloxycarbonyl (Fmoc), hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkane C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, cyano, -(CO)H, -NH(CO)-C1-C6 alkyl, and nitro, preferably, each independently substituted with one, two or more substituents independently selected from Cl, Br, F, I, oxo, hydroxy, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Bo c), -(CO)H, -NH(CO)-C1-C6 alkyl, 5-6 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc) substituents, preferably, each independently substituted by one, two or more substituents independently selected from Cl, Br, F, I, oxo, hydroxy, methyl, hydroxymethyl, methoxy, amino, dimethylamino, cyano, nitro, carboxyl (-COOH), acetoxy (AcO), benzyloxycarbonyl (Cbz), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-CH3, 5-6 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc); and / or

[0035] R2 and R3 are each independently H, or C1-C6 alkyl; preferably R2 and R3 are each independently H, or C1-C3 alkyl; preferably R2 and R3 are each independently H.

[0036] In one of the technical solutions, the compound has the structure shown in Formula II,

[0037] in,

[0038] R1 is defined in any one of claims 1, 2, 3 or 4;

[0039] Preferably, R1 is an unsubstituted or substituted 4, 5, 6, 7, 8, 9, 10, or 11-membered cycloalkyl group, or R1 is a 4, 5, 6, 7, 8, 9, 10, or 11-membered heterocycloalkyl group having 1-2 heteroatoms independently selected from N, O, and S, wherein the cycloalkyl group and the heterocycloalkyl group are each independently a monocyclic, condensed, or spirocyclic group; or R1 is an unsubstituted or substituted phenyl group, or a substituted or unsubstituted 10-membered aryl group, wherein the 10-membered aryl group is a condensed ring group; or R1 is a 1- R1 is an unsubstituted or substituted 5- to 6-membered heteroaryl group having 2 heteroatoms independently selected from N, O and S, or R1 is an unsubstituted or substituted 8- to 10-membered heteroaryl group having 1-2 heteroatoms independently selected from N, O and S, and the 8- to 10-membered heteroaryl group is a condensed ring group; wherein the substituted cycloalkyl, heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 10-membered aryl and 8- to 10-membered heteroaryl groups are each independently substituted by one, two or more groups independently selected from Cl, Br, F, I, oxo, carboxyl, hydroxyl , C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-C1-C3 alkyl, 5-8 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc) substituents, preferably substituted with one, two or more substituents independently selected from the group consisting of Cl, Br, F, I, oxo, hydroxy, methyl, hydroxymethyl, methoxy, amino, dimethylamino, cyano, nitro, carboxyl (-COOH), acetoxy (AcO), benzyloxycarbonyl (Cbz), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-CH3, 5-6 membered heterocycloalkyl containing one nitrogen atom, and 9-fluorenylmethyloxycarbonyl (Fmoc);

[0040] Preferably, R1 is an unsubstituted or substituted 4-membered monocycloalkyl, 5-membered monocycloalkyl, 6-membered monocycloalkyl, 7-membered spirocycloalkyl, 8-membered spirocycloalkyl, 9-membered spirocycloalkyl, 10-membered spirocycloalkyl, 11-membered spirocycloalkyl, 8-membered fused-ring cycloalkyl, 9-membered fused-ring cycloalkyl, or 10-membered fused-ring cycloalkyl; or R1 is an unsubstituted or substituted 4-membered monocyclic heterocycloalkyl, 5-membered monocyclic heterocycloalkyl, 6-membered monocyclic heterocycloalkyl, having 1-2 heteroatoms independently selected from N, O and S. or the substituted cycloalkyl and heterocycloalkyl groups are each independently selected from Cl, Br, F, I, oxo, hydroxy, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkyl- ... substituted with 1-C3 haloalkyl, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-C1-C3 alkyl, 5-8 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc), preferably, each independently substituted with one The alkylene group may be substituted with one, two or more substituents independently selected from Cl, Br, F, I, oxo, hydroxy, methyl, hydroxymethyl, methoxy, amino, dimethylamino, cyano, nitro, carboxyl (-COOH), acetoxy (AcO), benzyloxycarbonyl (Cbz), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-CH3, 5-6 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc).

[0041] In one of the technical solutions, R1 is H, -CH3, or -C4H9;

[0042] or R1 is selected from the following groups optionally substituted by one or more substituents:

[0043] Wherein, m, n, m' and n' are each independently 1 or 2 each time they appear;

[0044] The one or more substituents are each independently selected from Cl, Br, F, I, oxo, carboxyl, hydroxyl, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-C1-C3 alkyl, containing one 5-8 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc); preferably, each independently selected from Cl, Br, F, I, oxo, hydroxy, methyl, hydroxymethyl, methoxy, amino, dimethylamino, cyano, nitro, carboxyl (-COOH), acetoxy (AcO), benzyloxycarbonyl (Cbz), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-CH3, 5-6 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc); and

[0045] Thick bars indicate connection points.

[0046] In one embodiment, R1 is selected from the following groups optionally substituted by one or more substituents:

[0047] wherein m, n, m' and n' are each independently selected from 1 or 2 at each occurrence;

[0048] The one or more substituents are each independently selected from Cl, Br, F, I, oxo, carboxyl, hydroxyl, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-C1-C3 alkyl, 5-8 membered heterocyclic alkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc); preferably, each independently selected from Cl, Br, F, I, oxo, hydroxyl, methyl, hydroxymethyl, methoxy, amino, dimethylamino, cyano, nitro, carboxyl (-COOH), acetoxy (AcO), benzyloxycarbonyl (Cbz), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-CH3, 5-6 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc);

[0049] R4, at each occurrence, is independently selected from H, Cl, Br, F, I, oxo, carboxyl, hydroxyl, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO )H, -NH(CO)-C1-C3 alkyl, 5-8 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc); preferably, R4 is independently H, F, Cl, Br, I, -OH, oxo, methyl, amino (-NH2), carboxyl (-COOH), methoxy, hydroxymethyl, dimethylamino, -(CO)H, -NH(CO)-CH3, 5-6 membered heterocycloalkyl containing one nitrogen atom;

[0050] R5, at each occurrence, is independently selected from H, Cl, Br, F, I, carboxyl, hydroxyl, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-C1-C3 alkyl, 5-8 membered heterocycloalkyl containing one nitrogen atom, and 9-fluorenylmethyloxycarbonyl (Fmoc); R5, at each occurrence, is independently H, C1-C3 alkyl, acetoxy (AcO), benzyl (Bn), benzyloxycarbonyl (Cbz), -(CO)H, tert-butyloxycarbonyl (Boc), or 9-fluorenylmethyloxycarbonyl (Fmoc); and

[0051] Thick bars indicate connection points.

[0052] In one of the technical solutions, the compound is selected from the following compounds:

[0053] The present invention also provides a pharmaceutical composition, characterized in that it contains an effective amount of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0054] The present invention also provides use of any of the compounds described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, in the preparation of a medicament for treating or preventing a disease or condition mediated by SMARCA2 / 4.

[0055] In one technical solution, the disease or condition mediated by SMARCA2 / 4 is cancer; preferably, the cancer is lung cancer, cervical cancer and / or breast cancer.

[0056] The present invention also provides any compound described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above, for use in treating or preventing a disease or condition mediated by SMARCA2 / 4; preferably, the disease or condition is cancer, preferably, the cancer is lung cancer, cervical cancer and / or breast cancer.

[0057] The present invention also provides a method for treating or preventing a disease or condition mediated by SMARCA2 / 4, comprising administering a therapeutically effective amount of any of the compounds described above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above to a subject in need thereof; preferably, the disease or condition is cancer, preferably, the cancer is lung cancer, cervical cancer and / or breast cancer.

[0058] Definition and detailed description

[0059] The compounds of the present invention include stereoisomers, isotope-labeled substances, solvates, polymorphs or prodrugs thereof.

[0060] Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrates. Generally speaking, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Solvated forms are generally equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polymorphic or amorphous forms. Generally, for the applications contemplated by the present invention, all physical forms are equivalent and are encompassed within the scope of the present invention.

[0061] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, atropisomers (or rotamers), and the like, as well as racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.

[0062] The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0063] The term "alkyl" as used herein refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0064] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- are replaced by heteroatoms selected from NH, O and S or one or more -CH- are replaced by N atoms; wherein the alkyl group is as defined above; the heteroalkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0065] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl and cycloalkyl are as defined herein. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0066] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0067] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond, wherein alkyl is as defined above. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0068] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or more cyclic hydrocarbon substituent, including, for example, monocyclic, condensed, bridged or spirocyclic groups. The cycloalkyl ring can contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) carbon atoms, more preferably 4 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl etc.

[0069] The cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably independently selected from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0070] The term "heterocycloalkyl" refers to a non-aromatic cyclic group in which one or more atoms constituting the ring are heteroatoms and the rest are carbon, and the heteroatoms include, but are not limited to, nitrogen atoms, oxygen atoms, and sulfur atoms. Preferred heterocycloalkyl groups are 3-10 membered saturated heterocycloalkyl groups. Unless otherwise specified in this specification, heterocycloalkyl groups may be monocyclic ("monocyclic heterocycloalkyl"), or bicyclic, tricyclic, or more heterocyclic ring systems, which may include fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocycloalkyl"). Heterocycloalkyl bicyclic ring systems may include one or more heteroatoms in one or both rings; and are saturated. Heterocycloalkyl groups include, but are not limited to, azetidinyl, glycidyl, thietanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, or isomers and stereoisomers thereof.

[0071] Heterocycloalkyl may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently and optionally selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring. The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably independently selected from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0072] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring. The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0073] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5-membered or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes a heteroaryl group as described above fused to an aryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. Heteroaryl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0074] The term "monocyclic" refers to a monocyclic group having one ring therein. The monocyclic ring may be saturated or partially saturated.

[0075] The term "bridged ring" refers to a polycyclic ring system that shares two or more carbon atoms. It can be divided into bicyclic bridged rings and polycyclic bridged rings. The former is composed of two alicyclic rings sharing two or more carbon atoms, while the latter is composed of three or more rings.

[0076] The term "spirocycle" refers to a polycyclic ring system in which two rings share a common carbon atom (called a spiro atom).

[0077] The term "fused ring" refers to a polycyclic structure formed by two or more cyclic structures sharing two adjacent ring atoms (ie, sharing a bond).

[0078] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0079] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0080] The term "amino" refers to -NH2.

[0081] The term "cyano" refers to -CN.

[0082] The term "nitro" refers to -NO2.

[0083] The term "target protein" refers to proteins and peptides with any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction. In some embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, proteins associated with the integral functions of the cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretion activity, electron transport activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity. Such proteins include proteins from eukaryotic and prokaryotic organisms, including microorganisms, viruses, fungi, and parasites, among many others, including humans, microorganisms, viruses, fungi, and parasites that are targets for drug therapy, other animals including domestic animals, microorganisms that are targets for testing antibiotics and other antimicrobials, plants, and even viruses, among many others.

[0084] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "optionally substituted cyclopropyl" means that the cyclopropyl group may but need not be substituted, and that the description includes instances where the cyclopropyl group is substituted and instances where the cyclopropyl group is not substituted.

[0085] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) the possible or impossible substitutions without undue effort.

[0086] The term "pharmaceutically acceptable salt" means that the compound can be converted into a corresponding salt by conventional methods, which is chemically or physically compatible with the other ingredients constituting a certain pharmaceutical dosage form and physiologically compatible with the receptor. The salt can be an acidic and / or basic salt formed by the compound with an inorganic and / or organic acid and / or with an inorganic and / or organic base, and also includes zwitterionic salts (inner salts), and also includes quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compound. They can also be obtained by appropriately mixing the compound of the present invention or its stereoisomers or solvates with a certain amount of acid or base. These salts may form a precipitate in the solution and be collected by filtration, or recovered after evaporation of the solvent, or obtained by cooling and drying after reaction in an aqueous medium. In particular, the salt is preferably a water-soluble, pharmaceutically acceptable, non-toxic acid addition salt, examples of which are salts formed between an amino group and an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed using other conventional methods in the art (e.g., ion exchange).

[0087] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present invention to an organism. The pharmaceutical compositions of the invention may include one or more pharmaceutically acceptable salts, antioxidants, aqueous and non-aqueous carriers, and / or adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants.

[0088] The pharmaceutical composition of the present invention can also be administered to a patient or subject in need of such treatment by any suitable route of administration, such as oral, parenteral, rectal, pulmonary, or topical administration. When administered orally, the pharmaceutical composition can be formulated into an oral preparation, such as an oral solid preparation, such as a tablet, capsule, pill, or granule; or an oral liquid preparation, such as an oral solution, oral suspension, or syrup. When formulated into an oral preparation, the pharmaceutical preparation can further contain suitable fillers, binders, disintegrants, lubricants, and the like.

[0089] The term "pharmaceutically acceptable carrier" refers to excipients that are non-irritating to organisms and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, liposomes, polymer micelles, or inorganic nanocarriers.

[0090] The pharmaceutical composition of the present invention can be prepared into any pharmaceutically acceptable dosage form for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration, for example, it can be formulated into tablets, lozenges, capsules, pills, solutions, suspensions, syrups, injections, suppositories, inhalants or sprays.

[0091] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient (such as a compound) that is sufficient to affect such treatment of the disease, disorder or symptom when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder. A "therapeutically effective amount" can vary with the compound, the disease, disorder and / or the symptoms of the disease or disorder, the severity of the disease, disorder and / or the symptoms of the disease or disorder, the age of the subject to be treated and / or the weight of the subject to be treated. In any given case, the appropriate amount will be clear to those skilled in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof that is effective for "treating" (as defined above) a disease or disorder of a subject. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination subject used to effectively treat a disease, disorder or condition. Specific embodiments

[0092] The following examples are directed to the intermediate compounds and final products identified in the specification and synthesis schemes. The following examples are used to describe the preparation of the compounds of the present invention in detail, but the chemical reactions described are disclosed based on their general applicability to the preparation of the compounds of the present invention. Sometimes, the reactions may not be applicable to each compound within the scope of the present invention as described. Those skilled in the art will readily recognize compounds for which this will occur. In these cases, the reactions can be successfully carried out by conventional modifications known to those skilled in the art. In all preparation methods, all starting materials are known or can be readily prepared using known starting materials.

[0093] The starting materials, chemical reagents, and solvents used in this disclosure are all commercially available and were purchased from companies such as Anage Chemical, Shanghai Bid Pharmaceutical, Beijing Inocare, Jiangsu Aikon, Sinopharm Group, Beijing Bailingwei, and Yunnan Xinlanjing.

[0094] The structures of the compounds synthesized in this application were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0095] Nuclear magnetic resonance (NMR) measurements were performed using a Bruker AVANCE-400 / 600 NMR spectrometer. Deuterated solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0096] Mass spectrometry (MS) was performed by Waters Acquity Plus device implementation.

[0097] High performance liquid chromatography (HPLC) was performed using a Waters 2489 instrument.

[0098] The medium-pressure flash preparative chromatograph was COMBIFLASH NEXTGEN 300+.

[0099] As the thin layer chromatography silica gel plate, Silica gel 60 thin layer chromatography silica gel plate (aluminum plate, containing fluorescence) was used.

[0100] The silica gel (100-200 mesh, 200-300 mesh) used in silica gel thin layer chromatography was purchased from Inokai.

[0101] The reaction progress in the examples was detected by thin layer chromatography (TLC), and the developing solvent used for monitoring the reaction and the eluent used for purifying the compound by column chromatography included: petroleum ether / ethyl acetate system and dichloromethane / methanol system.

[0102] Example 1: Preparation of 2-(6-amino-5-piperidin-4-ylethynyl)pyridazin-3-ylphenol (Compound 1c)

[0103] 1) tert-Butyl 4-((3-amino-6-chloropyridazin-4-yl)ethynyl)piperidine-1-carboxylate

[0104] Under nitrogen, compound 1 (100 mg, 1.0 eq), tert-butyl 4-ethynylpiperidine-1-carboxylate (120 mg, 1.2 eq), triethylamine (98 mg, 2.0 eq), cuprous iodide (9 mg, 0.1 eq), and bis(triphenylphosphine)palladium(II) dichloride (34 mg, 0.1 eq) were dissolved in N,N-dimethylformamide (2 mL) and heated to 115°C for 4 h. After completion of the reaction, the mixture was purified by preparative liquid chromatography to yield 1a (102 mg, 63%) as a white solid.

[0105] 1H NMR (400MHz, DMSO-d6) δ7.52(s,1H),6.78(s,2H),3.10(s,2H),2.94(tt,J=8.3,3.7Hz,1H),1.99(dq,J=12.6,6. 3,5.4Hz,1H),1.83(ddt,J=12.5,6.4,3.3Hz,2H),1.60(ddt,J=13.9,9.2,4.5Hz,2H),1.40(s,9H),1.24(s,1H).

[0106] LC-MS(ESI):[M+H] + =337.31

[0107] 2) tert-Butyl 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)piperidine-1-carboxylate

[0108] Under nitrogen, compound 1a (100 mg, 1.0 eq), (2-hydroxyphenyl)boronic acid (123 mg, 3.0 eq), potassium carbonate (123 mg, 3.0 eq), and (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (27 mg, 0.1 eq) were dissolved in a 1:5 water / 1,4-dioxane (0.4 ml / 2 ml) mixture and stirred overnight at 80°C. The resulting mixture was concentrated under vacuum and purified by preparative liquid chromatography to yield 1b (38 mg, 32%) as a white solid.

[0109] 1 H NMR(600MHz, Methanol-d4)δ8.09(s,1H),7.73(dd,J=7.9,1.4Hz,1H),7.26–7.23(m,1H),6.93–6.89(m,2H ),3.34(s,1H),2.19(t,J=7.6Hz,1H),2.03(d,J=6.0Hz,1H),1.98–1.94(m,2H),1.47(s,9H),1.28(s,4H).

[0110] LC-MS(ESI):[M+H] + =395.42

[0111] 3) 2-(6-amino-5-(piperidin-4-ylethynyl)pyridazin-3-yl)phenol

[0112] Compound 1b (20 mg, 1.0 eq) was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 h. The mixture was cooled to room temperature and filtered. Purification by preparative liquid chromatography afforded compound 1c (13 mg, 87%) as a white solid.

[0113] 1 H NMR (600MHz, Methanol-d4) δ8.39(s,1H),7.68(d,J=8.0Hz,1H),7.39(t,J=7.8Hz,1H),7.01(dt,J=7.2,2.9Hz,2H),3.4 6(ddd,J=12.2,6.1,3.7Hz,2H),3.27–3.18(m,3H),2.29–2.25(m,1H),2.06(dq,J=14.1,5.3Hz,2H),1.34–1.31(m,2H).

[0114] LC-MS(ESI):[M+H] + =295.33

[0115] Example 2: Preparation of 2-(6-amino-5-(pyrrolidin-3-ylethynyl)pyridazin-3-yl)phenol (Compound 2c)

[0116] 1) tert-Butyl 3-((3-amino-6-chloropyridazin-4-yl)ethynyl)pyrrolidine-1-carboxylate

[0117] Under nitrogen, compound 1 (100 mg, 1.0 eq), tert-butyl 3-ethynylpyrrolidine-1-carboxylate (112 mg, 1.2 eq), triethylamine (97 mg, 2.0 eq), cuprous iodide (9 mg, 0.1 eq), and bis(triphenylphosphine)palladium(II) dichloride (34 mg, 0.1 eq) were dissolved in N,N-dimethylformamide (2 mL) and heated to 115°C for 4 h. After completion of the reaction, the mixture was purified by preparative liquid chromatography to yield 2a (77 mg, 49%) as a white solid.

[0118] LC-MS(ESI):[M+H] + =323.28

[0119] 2) tert-Butyl 3-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)pyrrolidine-1-carboxylate

[0120] Under nitrogen, compound 2a (70 mg, 1.0 eq), (2-hydroxyphenyl)boronic acid (89.73 mg, 3.0 eq), potassium carbonate (89.91 mg, 3.0 eq), and methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (27 mg, 0.1 eq) were dissolved in water / 1,4-dioxane 1:5 (0.4 ml / 2 ml) and stirred overnight at 80°C. The resulting mixture was concentrated under vacuum and purified by preparative liquid chromatography to afford 2b (27 mg, 32%) as a white solid.

[0121] LC-MS(ESI):[M+H] + =381.44

[0122] 3) 2-(6-amino-5-(pyrrolidin-3-ylethynyl)pyridazin-3-yl)phenol

[0123] Compound 2b (20 mg, 1.0 eq) was dissolved in 2 ml of dichloromethane, and 2 ml of HCl / 1,4-dioxane was added and stirred at room temperature. The mixture was cooled to room temperature and filtered. Purification by preparative liquid chromatography gave a white solid (Compound 2c) (12 mg, 81%).

[0124] 1 H NMR (600MHz, Methanol-d4) δ8.36(s,1H),7.70–7.68(m,1H),7.37(t,J=7.3Hz,1H),7.00(dt,J=7.1,2.9Hz,2H),3.69(ddd,J=19.0,1 2.3,7.2Hz,2H),3.55(ddt,J=16.6,11.2,5.2Hz,2H),3.47–3.42(m,1H),2.50(dt,J=14.1,6.9Hz,1H),2.34(dd,J=13.6,6.7Hz,1H).

[0125] LC-MS(ESI):[M+H] + =281.29

[0126] Example 3: 2-(6-amino-5-(azetidinyl-3-ethyleneynyl)pyridazin-3-yl)phenol (Compound 3c)

[0127] 1) tert-Butyl 3-((3-amino-6-chloropyridazin-4-yl)ethynyl)azetidine-1-carboxylate

[0128] Under nitrogen, compound 1 (100 mg, 1.0 eq), tert-butyl 3-ethynylazetidine-1-carboxylate (104 mg, 1.2 eq), triethylamine (97 mg, 2.0 eq), cuprous iodide (9 mg, 0.1 eq), and 1,1'-bis(diphenylphosphine)palladium dichloride ferrocene(II) (34 mg, 0.1 eq) were dissolved in N,N-dimethylformamide (2 mL) and heated to 115°C for 4 h. After completion of the reaction, the mixture was purified by preparative liquid chromatography to yield 3a (60 mg, 80%) as a white solid.

[0129] 1 H NMR (600MHz, DMSO-d6) δ7.56(s,1H),7.01(s,2H),4.15–4.11(m,2H),4.00–3.95(m,2H),3.75(ddd,J=8.8,6.3,2.6Hz,1H),1.39(s,9H).

[0130] LC-MS(ESI):[M+H] + =309.26

[0131] 2) tert-Butyl 3-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)azetidine-1-carboxylate

[0132] Under nitrogen, compound 3a (120 mg, 1.0 eq), (2-hydroxyphenyl)boronic acid (161 mg, 3.0 eq), potassium carbonate (161 mg, 3.0 eq), and methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (35 mg, 0.1 eq) were dissolved in water / 1,4-dioxane 1:5 (0.4 / 2 ml) and stirred at 80°C overnight. The resulting mixture was concentrated under vacuum and purified by preparative liquid chromatography to give 3b (40 mg, 28%) as a white solid.

[0133] LC-MS(ESI):[M+H] + =367.40

[0134] 3) 2-(6-amino-5-(azetidinyl-3-ethylideneynyl)pyridazin-3-yl)phenol

[0135] Compound 1c (27 mg, 1.0 eq) was dissolved in 2 ml of dichloromethane, and HCl / 1,4-dioxane (2 ml) was added and stirred at room temperature. The mixture was cooled to room temperature and filtered. After completion of the reaction, purification by preparative liquid chromatography afforded compound 3c (12 mg, 61%) as a white solid.

[0136] 1 H NMR(600MHz,Methanol-d4)δ8.68(s,1H),7.68–7.64(m,1H),7.53–7.49(m,1H),7.13(q ,J=8.2,7.8Hz,3H),4.67(p,J=8.0Hz,1H),4.60(t,J=9.8Hz,2H),4.52(t,J=9.4Hz,2H).

[0137] LC-MS(ESI):[M+H] + =267.26

[0138] Example 4: (5-((2-azaspiro[3.3]hept-6-yl)ethynyl)-6-aminopyridazin-3-yl)phenol (Compound 4c)

[0139] 1) tert-Butyl 6-((3-amino-6-chloropyridazin-4-yl)ethynyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0140] Under nitrogen, compound 1a (128 mg, 1.0 eq), tert-butyl 6-ethynyl-2-azaspiro[3.3]heptane-2-carboxylate (163 mg, 1.2 eq), triethylamine (124 mg, 2.0 eq), cuprous iodide (12 mg, 0.1 eq), and bis(triphenylphosphine)palladium(II) dichloride (41 mg, 0.1 eq) were dissolved in N,N-dimethylformamide (2 mL) and heated to 115°C for 4 h. After completion of the reaction, the mixture was purified by preparative liquid chromatography to yield 4a (120 mg, 56%) as a white solid.

[0141] 1 H NMR(600MHz,DMSO-d6)δ7.48(s,1H),6.81–6.77(m,2H),3.88(s,2H),3.81(s,2H),3.23(q,J=8 .4Hz,1H),2.54(d,J=3.0Hz,1H),2.43–2.39(m,2H),1.99(dt,J=18.6,6.8Hz,1H),1.36(s,9H).

[0142] LC-MS(ESI):[MH] + =349.33

[0143] 2) tert-Butyl 6-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0144] Under nitrogen, compound 4a (80 mg, 1.0 eq), (2-hydroxyphenyl)boronic acid (95 mg, 3.0 eq), potassium carbonate (95 mg, 3.0 eq), and methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (21 mg, 0.1 eq) were dissolved in water / 1,4-dioxane 1:5 (0.4 / 2 ml) and stirred overnight at 80°C. The resulting mixture was concentrated under vacuum and purified by preparative liquid chromatography to afford 4b (30 mg, 32%) as a white solid.

[0145] 1 H NMR (600MHz, DMSO-d6) δ13.32(s,1H),8.17(s,1H),7.87(dd,J=8.0,1.3Hz,1H),7.26–7.23(m,1H),6.92–6. 84(m,4H),3.87(d,J=39.3Hz,4H),3.27(q,J=8.3Hz,1H),2.59–2.55(m,2H),2.47–2.43(m,2H),1.37(s,9H).

[0146] LC-MS(ESI):[MH] + =407.41

[0147] 3) 2-(5-((2-azaspiro[3.3]hept-6-yl)ethynyl)-6-aminopyridazin-3-yl)phenol

[0148] Compound 4b (30 mg, 1.0 eq) was dissolved in 2 ml of dichloromethane, and 2 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature, cooled to room temperature, and filtered. Purification by preparative liquid chromatography afforded compound 4c (10 mg, 44%) as a white solid.

[0149] 1 H NMR(600MHz,Methanol-d4)δ8.32(s,1H),7.69–7.65(m,1H),7.41–7.36(m,1H),7.03–6.97(m,2H), 4.19(s,2H),4.12(s,2H),3.44–3.39(m,1H),2.82–2.77(m,2H),2.63(ddd,J=10.7,8.4,2.2Hz,2H).

[0150] LC-MS(ESI):[MH] + =307.31

[0151] Example 5: (6-(2-azaspiro[3.5]non-7-yl)ethynyl)-6-aminopyridazin-3-yl)phenol (Compound 5c)

[0152] 1) tert-Butyl 7-((3-amino-6-chloropyridazin-4-yl)ethynyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0153] Under nitrogen, compound 1a (100 mg, 1.0 eq), tert-butyl 7-ethynyl-2-azaspiro[3.5]nonane-2-carboxylate (144 mg, 1.2 eq), triethylamine (97 mg, 2.0 eq), cuprous iodide (9 mg, 0.1 eq), and bis(triphenylphosphine)palladium(II) dichloride (34 mg, 0.1 eq) were dissolved in N,N-dimethylformamide (2 mL) and heated to 115°C for 4 h. After completion of the reaction, the mixture was purified by preparative liquid chromatography to yield 5a (157 mg, 86%) as a white solid.

[0154] 1 H NMR (600MHz, DMSO-d6) δ7.56 (s, 1H), 7.03 (s, 2H), 3.49 (d, J = 23.1Hz, 4H), 2. 70(s,1H),1.81(d,J=9.5Hz,4H),1.53(q,J=10.9,10.4Hz,4H),1.38(s,9H).

[0155] LC-MS(ESI):[M+H] + =405.45

[0156] 2) tert-Butyl 7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-2-azaspiro[3.5]nonane-2-carboxylate

[0157] Under nitrogen, compound 5a (90 mg, 1.0 eq), (2-hydroxyphenyl)boronic acid (99 mg, 3.0 eq), potassium carbonate (99 mg, 3.0 eq), and methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (22 mg, 0.1 eq) were dissolved in water / 1,4-dioxane 1:5 (0.4 / 2.0 ml) and stirred overnight at 80°C. The resulting mixture was concentrated under vacuum and purified by preparative liquid chromatography to afford 5b (30 mg, 28%) as a white solid.

[0158] 1H NMR (600MHz, DMSO-d6) δ8.22(s,1H),7.73–7.70(m,1H),7.33–7.31(m,1H),6.98(d,J=8.2Hz,1H),6.93(t, J=7.5Hz,1H),3.53(s,5H),3.10(qd,J=7.3,4.8Hz,1H),1.84(d,J=10.1Hz,4H),1.61–1.53(m,4H),1.38(s, 9H),1.22–1.16(m,2H).

[0159] LC-MS(ESI):[M+H] + =435.42

[0160] 3) 2-(5-((2-azaspiro[3.5]non-7-yl)ethynyl)-6-aminopyridazin-3-yl)phenol

[0161] Compound 5b (20 mg, 1.0 eq) was dissolved in 2 ml of dichloromethane, and HCl / 1,4-dioxane (2 ml) was added and stirred at room temperature. The mixture was cooled to room temperature and filtered. Purification by preparative liquid chromatography afforded compound 5c (10 mg, 64%) as a white solid.

[0162] 1 H NMR(600MHz,Methanol-d4)δ8.30(s,1H),7.69–7.67(m,1H),7.39–7.36(m,1H),7.00(dt,J=7.3,3.0Hz,2H), 3.88(s,2H),3.82(s,2H),2.86(s,1H),2.13–2.09(m,2H),2.03–1.97(m,2H),1.73(dt,J=21.6,10.2Hz,4H).

[0163] LC-MS(ESI):[M+H] + =335.31

[0164] Example 6: (5-((3-Azaspiro[5.5]undec-9-yl)ethynyl)-6-aminopyridazin-3-yl)phenol (Compound 6c)

[0165] 1) tert-Butyl 9-((3-amino-6-chloropyridazin-4-yl)ethynyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0166] Under nitrogen, compound 1 (60 mg, 1.0 eq), tert-butyl 9-ethynyl-3-azaspiro[5.5]undecane-3-carboxylate (96 mg, 1.2 eq), triethylamine (58.26 mg, 2.0 eq), cuprous iodide (5 mg, 0.1 eq), and bis(triphenylphosphine)palladium(II) dichloride (20 mg, 0.1 eq) were dissolved in N,N-dimethylformamide (2 mL) and heated to 115°C for 4 h. After completion of the reaction, the mixture was purified by preparative liquid chromatography to yield 6a (84 mg, 72%) as a white solid.

[0167] 1 H NMR(600MHz,DMSO-d6)δ7.48(s,1H),6.73(s,2H),3.29(s,4H),2.70–2.67(m, 1H),1.80–1.74(m,4H),1.62(q,J=10.3,9.3Hz,6H),1.40(s,2H),1.39(s,9H).

[0168] LC-MS(ESI):[M+H] + =405.45

[0169] 2) tert-Butyl 9-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0170] Under nitrogen, compound 6a (65 mg, 1.0 eq), (2-hydroxyphenyl)boronic acid (66 mg, 3.0 eq), potassium carbonate (67 mg, 3.0 eq), and (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (15 mg, 0.1 eq) were dissolved in a 1:5 water / 1,4-dioxane (0.4 ml / 2 ml) solution and stirred overnight at 80°C. The resulting mixture was concentrated under vacuum and purified by preparative liquid chromatography to yield 6b (33 mg, 44%) as a white solid.

[0171] LC-MS(ESI):[M+H] + =463.44

[0172] 3) 2-(5-((3-azaspiro[5.5]undec-9-yl)ethynyl)-6-aminopyridazin-3-yl)phenol

[0173] Compound 6b (30 mg, 1.0 eq) was dissolved in 2 ml of dichloromethane, and HCl / 1,4-dioxane (2 ml) was added and stirred at room temperature. The mixture was cooled to room temperature and filtered. Purification by preparative liquid chromatography afforded compound 6c (14 mg, 59%) as a white solid.

[0174] 1 H NMR(600MHz, Methanol-d4)δ8.32(s,1H),7.67(d,J=7.9Hz,1H),7.39(t,J=7.7Hz,1H),7.02–6.99(m,2H),3.21–3.18(m, 4H), 2.86 (s, 1H), 2.05 (q, J = 6.3Hz, 1H), 2.00–1.96 (m, 2H), 1.80 (d, J = 21.6Hz, 5H), 1.67 (s, 2H), 1.43 (t, J = 11.7Hz, 2H).

[0175] LC-MS(ESI):[M+H] + =363.83

[0176] Example 7: 2-(6-amino-5-(phenylethynyl)pyridazin-3-yl)phenol (Compound 7c)

[0177] 1) 6-Chloro-4-(phenylethynyl)pyridazin-3-amine

[0178] Under nitrogen, compound 1 (200 mg, 1 eq), phenylacetylene (117 mg, 1.2 eq), bis(triphenylphosphine)palladium(II) dichloride (67 mg, 0.1 eq), cuprous iodide (18 mg, 0.1 eq), and triethylamine (194 mg, 2 eq) were dissolved in N,N-dimethylformamide (2 ml). The temperature was raised to 115°C and the reaction was allowed to proceed for 4 h. After completion of the reaction, the mixture was purified by preparative liquid chromatography to yield the target compound 7a (51 mg, 23%).

[0179] LCMS M / Z(M+H)230.16 / 232.13.

[0180] 1 H NMR (600MHz, DMSO-d6) δ13.09(s,1H),8.10–8.07(m,2H),7.97(s,1H),7.56(t,J=7.5Hz,2H),7.53–7.50(m,1H),7.05(d,J=1.9Hz,1H).

[0181] 2) 2-(6-amino-5-(phenylethynyl)pyridazin-3-yl)phenol

[0182] Under nitrogen, compound 7a (46 mg, 1.0 eq), 2-hydroxyphenylboronic acid (82 mg, 3.0 eq), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 0.1 eq), and potassium carbonate (82 mg, 3.0 eq) were dissolved in a mixture of water / 1,4-dioxane (0.6 mL / 3 mL) and stirred overnight at 80°C. The resulting mixture was concentrated under vacuum and purified by preparative liquid chromatography to yield the target compound 7b (15 mg, 26%).

[0183] LCMS M / Z(M+H)288.21.

[0184] 1 H NMR(600MHz,DMSO-d6)δ13.57(d,J=37.7Hz,2H),8.64(d,J=1.2Hz,1H),8.21–8.16( m,2H),7.91–7.86(m,1H),7.65–7.58(m,3H),7.43–7.32(m,2H),7.09–7.01(m,2H).

[0185] Example 8: Preparation of 2-(6-amino-5-(pyridin-3-vinyl)pyridazin-3-yl)phenol (Compound 8b)

[0186] 1) 6-Chloro-4-(pyridin-3-vinyl)pyridazin-3-amine

[0187] Under nitrogen, compound 1 (200 mg, 1 eq), 3-ethynylpyridine (118 mg, 1.2 eq), bis(triphenylphosphine)palladium(II) dichloride (67 mg, 0.1 eq), cuprous iodide (18 mg, 0.1 eq), and triethylamine (194 mg, 2 eq) were dissolved in N,N-dimethylformamide (2 ml). The temperature was raised to 115°C and the reaction was allowed to proceed for 4 h. After completion of the reaction, the mixture was purified by preparative liquid chromatography to yield the target compound 8a (18 mg, 8%).

[0188] LCMS M / Z(M+H)231.16 / 233.12.

[0189] 1H NMR (600MHz, DMSO-d6) δ8.94(s,1H),8.69(d,J=4.7Hz,1H),8.18(dt,J=7.9,1.9Hz,1H),7.73(s,1H),7.56(dd,J=7.9,4.8Hz,1H),7.23(s,2H).

[0190] 2) 2-(6-amino-5-(pyridin-3-vinyl)pyridazin-3-yl)phenol

[0191] Under nitrogen, compound 8a (100 mg, 1.0 eq), 2-hydroxyphenylboronic acid (180 mg, 3.0 eq), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36 mg, 0.1 eq), and potassium carbonate (180 mg, 3.0 eq) were dissolved in a mixture of water / 1,4-dioxane (0.6 mL / 3 mL) and stirred overnight at 80°C. The resulting mixture was concentrated under vacuum and purified by preparative liquid chromatography to yield the title compound 8b (15 mg, 26%).

[0192] LCMS M / Z(M+H)289.19.

[0193] 1 H NMR (600MHz, DMSO-d6) δ13.62(s,2H),9.39(d,J=2.4Hz,1H),8.77–8.73(m,1H),8.71(s,1H),8.55(dt,J=8.1,2. 0Hz,1H),7.92(d,J=7.8Hz,1H),7.67(dd,J=8.0,4.8Hz,1H),7.46(s,1H),7.42–7.35(m,1H),7.07–7.00(m,2H).

[0194] Example 9: Preparation of 2-(6-amino-5-ethynylpyridazin-3-yl)phenol (Compound 9b)

[0195] 1) 6-Chloro-4-(pyridin-3-vinyl)pyridazin-3-amine

[0196] Under nitrogen, compound 1 (200 mg, 1 eq), ethynyltrimethylsilane (113 mg, 1.2 eq), bis(triphenylphosphine)palladium(II) dichloride (67 mg, 0.1 eq), cuprous iodide (18 mg, 0.1 eq), and triethylamine (194 mg, 2 eq) were dissolved in N,N-dimethylformamide (2 ml). The temperature was raised to 115°C and the reaction was allowed to proceed for 4 h. After completion of the reaction, the mixture was purified by preparative liquid chromatography to yield the target compound 9a (20 mg, 6%).

[0197] LCMS M / Z(M+H)226.20 / 228.15.

[0198] 1 H NMR(600MHz,DMSO-d6)δ7.58(s,1H),6.83(s,2H),0.27(s,9H).

[0199] 2) 2-(6-amino-5-ethynylpyridazin-3-yl)phenol

[0200] Under nitrogen, compound 9a (60 mg, 1.0 eq), 2-hydroxyphenylboronic acid (110 mg, 3.0 eq), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36 mg, 0.1 eq), and potassium carbonate (110 mg, 3.0 eq) were dissolved in N,N-dimethylformamide (2 ml). The mixture was stirred at 80°C overnight. The resulting mixture was concentrated under vacuum and purified by preparative liquid chromatography to yield the target compound 9b (5 mg, 8%).

[0201] LCMS M / Z(M+H)212.20.

[0202] 1 H NMR (600MHz, DMSO-d6) δ8.72(s,1H),7.37(t,J=7.8Hz,1H),7.05–6.98(m,2H),6.81(s,1H),6.72(q,J=4.3Hz,2H),6.60(dd,J=5.9,3.7Hz,2H).

[0203] Example 10 (5-((7-azaspiro[3.5]non-2-yl)ethynyl)-6-aminopyridazin-3-yl)phenol (Compound 10c)

[0204] 1) tert-Butyl 2-((3-amino-6-chloropyridazin-4-yl)ethynyl)-7-azaspiro[3.5]nonane-7-carboxylate

[0205] Under nitrogen, compound 1 (100 mg, 1.0 eq), tert-butyl 2-ethynyl-7-azaspiro[3.5]nonane-7-carboxylate (143.55 mg, 1.2 eq), triethylamine (97.09 mg, 2.0 eq), cuprous iodide (9.14 mg, 0.1 eq), and bis(triphenylphosphine)palladium(II) dichloride (33.67 mg, 0.1 eq) were dissolved in N,N-dimethylformamide (2 mL) and heated to 115°C for 4 h. After completion of the reaction, the mixture was purified by preparative liquid chromatography to yield 10a (157 mg, 86%) as a white solid.

[0206] 1 H NMR (600MHz, DMSO-d6) δ3.49 (d, J = 23.1Hz, 4H), 1.81 (d, J = 9.5Hz, 4H), 1.53 (q, J = 10.9, 10.4Hz, 4H), 1.38 (s, 9H).

[0207] LC-MS(ESI):[M+H] + =377.34

[0208] 2) tert-Butyl 2-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-7-azaspiro[3.5]nonane-7-carboxylate

[0209] Under nitrogen, compound 10a (100 mg, 1.0 eq), (2-hydroxyphenyl)boronic acid (110 mg, 3.0 eq), potassium carbonate (110 mg, 3.0 eq), and methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (24 mg, 0.1 eq) were dissolved in water / 1,4-dioxane (1:5) (0.4 ml / 2 ml) and stirred overnight at 80°C. The resulting mixture was concentrated under vacuum and purified by preparative liquid chromatography to yield 10b (30 mg, 26%) as a white solid.

[0210] LC-MS(ESI):[M+H] + =435.43

[0211] 3):2-(5-((7-azaspiro[3.5]non-2-yl)ethynyl)-6-aminopyridazin-3-yl)phenol

[0212] Compound 10b (25 mg, 1.0 eq) was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 2 h. The mixture was cooled to room temperature and filtered. Purification by preparative liquid chromatography afforded 10c (12 mg, 62%) as a white solid.

[0213] 1 H NMR(600MHz, Methanol-d4)δ8.38(s,1H),7.66(dd,J=8.0,1.5Hz,1H),7.41–7.38(m,1H),7.01(dt,J=7.3,3.0Hz,2H),3 .53(p,J=8.7Hz,1H),3.19–3.17(m,2H),3.14–3.11(m,2H),2.46–2.42(m,2H),2.27–2.23(m,2H),1.93(q,J=4.8Hz,4H).

[0214] LC-MS(ESI):[M+H] + =335.32.

[0215] Example 11: 2-(5-(1H-indol-5-yl)ethynyl)-6-aminopyridazin-3-yl)phenol (Compound 11b)

[0216] 1) 4-((1H-indol-5-yl)ethynyl)-6-chloropyridin-3-amine

[0217] Under nitrogen, compound 1 (50.0 mg, 1.0 eq), 5-ethynyl-1H-indole (41 mg, 1.2 eq), triethylamine (49 mg, 2.0 eq), cuprous iodide (5 mg, 0.1 eq), and bis(triphenylphosphine)palladium(II) dichloride (17 mg, 0.1 eq) were dissolved in N,N-dimethylformamide (2 mL) and heated to 115°C for 4 h. After completion of the reaction, the mixture was purified by preparative liquid chromatography to yield 11a (48 mg, 74%) as a white solid.

[0218] 1 H NMR(400MHz,DMSO-d6)δ12.92(s,1H),11.42(d,J=17.4Hz,1H),8.32(s,1H),7.84(s,1H),7 .79(dd,J=8.6,1.5Hz,1H),7.54(d,J=8.5Hz,1H),7.48–7.42(m,2H),6.92(d,J=1.7Hz,1H).

[0219] LC-MS(ESI):[M+H] + =269.22

[0220] 2) 2-(5-(1H-indol-5-yl)ethynyl)-6-aminopyridazin-3-yl)phenol

[0221] Under nitrogen, compound 11a (50.0 mg, 1.0 eq), (2-hydroxyphenyl)boronic acid (77 mg, 3.0 eq), potassium carbonate (77 mg, 3.0 eq), and methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (17 mg, 0.1 eq) were dissolved in water / 1,4-dioxane (1:5) (0.4 ml / 2 ml) and stirred overnight at 80°C. The resulting mixture was concentrated under vacuum and purified by preparative liquid chromatography to yield 11b (12 mg, 20%) as a white solid.

[0222] 1 H NMR(400MHz, Methanol-d4)δ8.40(s,2H),7.87(dd,J=8.6,1.7Hz,1H),7.65–7.59(m,2H) ,7.48(td,J=8.2,1.5Hz,1H),7.41(d,J=3.2Hz,1H),7.33(s,1H),6.66(d,J=3.0Hz,1H).

[0223] LC-MS(ESI):[M+H] + =327.33

[0224] Example 12: Synthesis of Intermediate 18

[0225] Step 1: Synthesis of 4-bromo-6-iodopyridazin-3-amine and 4,6-dibromopyridazin-3-amine

[0226] 4-Bromo-6-iodopyridazin-3-amine (5.00 g, 22.62 mmol) was dissolved in acetonitrile (100 mL) in a single-necked flask. N-bromosuccinimide (4.03 g, 22.62 mmol) was slowly added and stirred for 1 h. After completion of the reaction, the mixture was quenched with aqueous sodium thiosulfate solution and extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain a mixture of Intermediates 18a and 18b as a yellow solid (2.02 g).

[0227] Step 2: Synthesis of 2-(6-amino-5-bromopyridazin-3-yl)phenol

[0228] A mixture of Intermediates 18a and 18b (555.00 mg, 1.85 mmol), (2-hydroxyphenyl)boronic acid (204.20 mg, 1.48 mmol), tetrakistriphenylphosphine palladium (213.86 mg, 185.06 mmol), and potassium carbonate (639.41 mg, 4.63 mmol) were dissolved in 1,4-dioxane (7 mL) and purified water (1 mL). Under nitrogen, the reaction was stirred at 80°C for 3 hours. After completion of the reaction, excess solvent was removed under reduced pressure, purified water was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to afford Intermediate 18 (147 mg) as a yellow solid.

[0229] 1 H NMR (600MHz, DMSO-d6) δ8.50(s,1H),7.82(dd,J=7.8,1.3Hz,1H),7.29–7.23(m,1H),6.92(t,J=8.2Hz,2H).

[0230] Example 13. Synthesis of 2-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-7-one (Compound 12)

[0231] Synthesis scheme

[0232] Step 1: Synthesis of 8-methylene-1,4-dioxaspiro[4.5]decane (Intermediate 12a)

[0233] Methyltriphenylphosphonium bromide (354.53 g, 992.44 mmol) was dissolved in tetrahydrofuran (500 mL) in a three-necked flask. The mixture was cooled to 0°C under nitrogen and slowly added with a solution of LHMDS in tetrahydrofuran (992.44 mL, 992.44 mmol). The mixture was stirred at 0°C for 1 hour. A solution of 1,4-dioxaspiro[4.5]decan-8-one (50.00 g, 320.14 mmol) in tetrahydrofuran (100 mL) was added to the three-necked flask and stirred at 0°C for 0.5 hour. The mixture was transferred to room temperature and stirred overnight. After completion of the reaction, the mixture was quenched with purified water and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford intermediate 12a (40.0 g, 11.43%) as a colorless oil.

[0234] Step 2: 1,1-dichloro-8,11-dioxadiazole [3.2.4 7 .2 4Synthesis of tridecane-2-one (Intermediate 12b)

[0235] Dissolve 12a (20 g, 129.69 mmol) and Zn-Cu reagent (33.44 g, 259.39 mmol) in a single-necked flask containing DME (200 mL). Cool to 0°C, slowly add trichloroacetyl chloride (28.95 mL, 259.39 mmol), and maintain stirring at 0°C for 0.5 h. Transfer to room temperature and continue stirring for 3 h. After completion of the reaction, cool to 0°C, quench with ice water, and extract three times with ethyl acetate (100 mL). The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude intermediate 12b. This crude product is used directly in the next reaction without further purification.

[0236] Step 3: 8,11-dioxalo[3.2.4 7 .2 4 Synthesis of tridecane-2-one (Intermediate 12c)

[0237] Crude intermediate 12b (68.77 g, 259.39 mmol) and ammonium chloride (41.62 g, 778.17 mmol) were dissolved in methanol (300 mL) in a single-necked flask. The temperature was cooled to 0°C, and zinc powder (67.84 g, 1.04 mol) was slowly added. Stirring was maintained at 0°C for 0.5 h. The mixture was brought to room temperature and stirred for 3 h. After completion of the reaction, the mixture was cooled to 0°C, quenched with ice water, and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to yield intermediate 12c (16 g, 30.37%) as a yellow oil.

[0238] Step 4: 2-methyl-8,11-dioxalo[3.2.4 7 .2 4 Synthesis of Tridecane (Intermediate 12d)

[0239] Methyltriphenylphosphonium bromide (32.77 g, 91.72 mmol) was dissolved in tetrahydrofuran (60 mL) in a three-necked flask. The mixture was cooled to 0°C under nitrogen and slowly added with a solution of LHMDS in tetrahydrofuran (91.72 mL, 91.72 mmol). The mixture was stirred at 0°C for 1 hour. A solution of intermediate 12c (6.00 g, 30.57 mmol) in tetrahydrofuran (12 mL) was added to the three-necked flask and stirred at 0°C for 0.5 hour. The mixture was transferred to room temperature and stirred overnight. After completion of the reaction, the mixture was quenched with purified water and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford intermediate 12d (5.59 g, 94.11%) as a colorless oil.

[0240] 1 H NMR (600MHz, CDCl3) δ4.81–4.79(m,2H),3.94(s,4H),2.41(t,J=2.3Hz,4H),1.69–1.65(m,4H),1.59–1.57(m,4H).

[0241] Step 5: Synthesis of (8,11-dioxaheptylspiro[3.2.47.24]tridecane-2-yl)methanol (Intermediate 12e)

[0242] Intermediate 12d (5.59 g, 28.77 mmol) was dissolved in tetrahydrofuran (50 mL) in a three-necked flask. The mixture was cooled to 0°C under nitrogen, and a solution of dimethyl sulfide in tetrahydrofuran (17.26 mL, 34.53 mmol) was slowly added. The mixture was stirred at 0°C for 1 hour. Sodium hydroxide (3.45 g, 86.32 mmol) was added to the flask, followed by a solution of hydrogen peroxide (8.90 g, 86.32 mmol) and stirred at 0°C for 0.5 hour. The mixture was transferred to room temperature and stirred for 3 hours. After the reaction was complete, the mixture was cooled to 0°C, quenched with ice water, and extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford Intermediate 12e (2.35 g, 38.47%) as a colorless oil.

[0243] 1 H NMR (600MHz, CDCl3) δ3.93 (s, 4H), 3.59 (d, J = 6.7Hz, 2H), 2.43 (dt, J = 8.1, 6.9Hz, 1H), 1.91–1.87(m,2H),1.69(dd,J=7.7,4.7Hz,2H),1.63–1.57(m,4H),1.54–1.47(m,4H).

[0244] Step 6: Synthesis of 8,11-dioxaheptylspiro[3.2.47.24]tridecane-2-carbaldehyde (Intermediate 12f)

[0245] Intermediate 12e (2.35 g, 11.07 mmol) was dissolved in dichloromethane (40 mL) in a single-necked flask. The temperature was cooled to 0°C, and Dess-Martin periodinane (9.39 g, 22.14 mmol) was slowly added. The mixture was brought to room temperature and stirred for 1 h. After completion of the reaction, the mixture was quenched with aqueous ammonium chloride solution, the excess solvent was removed under reduced pressure, and the mixture was extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford Intermediate 12f (2.20 g, 94.54%) as a colorless oil.

[0246] 1 H NMR (600MHz, CDCl3) δ9.75(d,J=1.8Hz,1H),3.93(s,4H),3.12–3.09(m,1H),2.24–2.20(m,2H),2.16(dd,J=7.3,4.8Hz,2H),2.05–1.99(m,8H).

[0247] Step 7: Synthesis of 2-ethynyl-8,11-dioxadiazole [3.2.47.24] tridecane (intermediate 12g)

[0248] Intermediate 12f (2.20 g, 10.46 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (3.01 g, 15.69 mmol) were dissolved in methanol (20 mL) in a single-necked flask. The temperature was cooled to 0°C, and potassium carbonate (2.89 g, 20.93 mmol) was slowly added. The mixture was stirred at 0°C for 0.5 h. The mixture was brought to room temperature and stirred for 1 h. After the reaction was complete, the excess solvent was removed under reduced pressure, purified water was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 12g (510 mg, 22.74%) as a colorless oil.

[0249] 1H NMR(600MHz, CDCl3)δ3.92(s,4H),3.13(s,1H),2.97–2.91(m,1H),2.18–2.14(m,2H),1.91–1.87 (m,2H),1.68(dd,J=7.6,4.9Hz,2H),1.63(dd,J=7.6,4.3Hz,2H),1.59–1.56(m,2H),1.53(s,2H).

[0250] Step 8: Synthesis of 2-(5-((8,11-dioxadispiro[3.2.47.24]tridec-2-yl)ethynyl)-6-aminopyridazin-3-yl)phenol (Intermediate 12h)

[0251] Intermediate 12g (217.00 mg, 815.49 μmol), SM-I-CH-007 (185.05 mg, 897.04 μmol), bistriphenylphosphine palladium dichloride (57.24 mg, 81.55 μmol), cuprous iodide (15.53 mg, 81.55 μmol), and triethylamine (226.71 μL, 1.63 mmol) were dissolved in a three-necked flask containing DMF (2 mL). Under nitrogen, the mixture was heated to 80°C and stirred overnight. After completion of the reaction, purified water was added and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Intermediate 12h (140 mg, 43.85%) as a yellow solid.

[0252] 1 H NMR(600MHz,DMSO-d6)δ13.36(s,1H),8.17(s,1H),7.88(dd,J=8.0,1.4Hz ,1H),7.26–7.22(m,1H),6.92–6.87(m,2H),6.82(s,2H),3.83(s,4H),3.37 (d,J=8.7Hz,1H),2.21(dd,J=11.6,9.3Hz,2H),2.02(dd,J=11.7,8.5Hz,2 H),1.63(dd,J=11.7,4.9Hz,4H),1.52(d,J=6.4Hz,2H),1.48–1.45(m,2H).

[0253] LCMS(ESI):[M+H] + =392.36

[0254] Step 9: Synthesis of 2-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-7-one (Compound 12)

[0255] Intermediate 12h (140 mg, 357.63 μmol) was dissolved in a three-necked flask containing dichloromethane (2.5 mL). Trifluoroacetic acid (2.5 mL) was added and stirred for 1 hour. After completion of the reaction, excess solvent was removed under reduced pressure, purified water was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Compound 12 (61 mg, 49.09%) as a yellow solid.

[0256] 1 H NMR (600MHz, DMSO-d6) δ8.19(s,1H),7.86(d,J=7.5Hz,1H),7.27–7.24(m,1H),6.98(s,2H),6.92(d,J=8.1Hz,1H),6.90(d,J= 6.8Hz,1H),2.62–2.60(m,1H),2.36(d,J=9.4Hz,2H),2.26(d,J=5.9Hz,2H),2.20(dd,J=13.0,7.6Hz,4H),1.91–1.87(m,4H).

[0257] LCMS(ESI):[M+H] + =348.3

[0258] Example 14. Synthesis of 7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-one (Compound 13)

[0259] Step 1: Synthesis of ethyl 1,1-dichloro-2-oxospiro[3.5]nonane-7-carboxylate (Intermediate 13a)

[0260] Ethyl 4-methylenecyclohexane-1-carboxylate (10 g, 59.44 mmol) was dissolved in ethylene glycol dimethyl ether (100 mL). Zinc copper reagent (10 g, 154 mmol) was added, and trichloroacetyl chloride (25 mL, 224 mmol) was slowly added dropwise to the reaction system under ice-water cooling. The reaction was allowed to react overnight at room temperature. After completion of the reaction, saturated aqueous sodium bicarbonate was slowly added under ice-water cooling to quench the reaction system. The solid was filtered through celite, and the filtrate was extracted three times with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown oily crude intermediate 13a (16.6 g). The crude product was directly used in the next step without purification.

[0261] Step 2: Synthesis of ethyl 2-oxospiro[3.5]nonane-7-carboxylate (Intermediate 13b)

[0262] Intermediate 13a (16.6 g, 59.46 mmol) and solid ammonium chloride (12.72 g, 237.86 mmol) were dissolved in methanol (160 mL). Zinc powder (38 g, 594 mmol) was slowly added portionwise under an ice-water bath and allowed to react overnight. After completion of the reaction, the solid was filtered through Celite, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford Intermediate 13b (10.45 g, 83.57%) as a colorless oil.

[0263] 1 H NMR (600MHz, DMSO-d6) δ4.06 (q, J=7.1Hz, 2H), 2.74 (s, 4H), 2.36–2.31 (m, 1H), 1.83–1.79 (m 2H),1.76–1.65(m,2H),1.60–1.55(m,2H),1.44–1.38(m,2H),1.18(t,J=7.1Hz,3H).

[0264] Step 3: Synthesis of ethyl 2,2-dimethoxyspiro[3.5]nonane-7-carboxylate (Intermediate 13c)

[0265] Intermediate 13b (10.45 g, 50 mmol), trimethyl orthoformate (67 mL, 612 mmol), and pyridinium p-toluenesulfonate (3.75 g, 15 mmol) were dissolved in methanol (100 mL) and reacted at 75°C overnight. After completion of the reaction, the solvent was evaporated, 5 mL of water was added, and the product was extracted three times with 30 mL of ethyl acetate. The product was dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford Intermediate 13c (12 g, 94.19%) as a yellow oil.

[0266] 1 H NMR(600MHz,DMSO-d6)δ4.03(q,J=7.1Hz,2H),3.01(s,6H),2.28–2.16(m,1H),1.80(d,J=7 .7Hz,4H),1.70–1.65(m,2H),1.64–1.54(m,2H),1.40–1.29(m,4H),1.16(t,J=7.1Hz,3H).

[0267] Step 4: Synthesis of 2,2-dimethoxyspiro[3.5]nonane-7-methanol (Intermediate 13d)

[0268] Intermediate 13c (12 g, 46 mmol) was dissolved in tetrahydrofuran (120 mL) and lithium aluminum tetrahydride (2.67 g, 70 mmol) was slowly added portionwise under ice-cooling. The reaction was allowed to react at room temperature for four hours. After completion, the reaction was quenched by adding a small amount of water under ice-cooling. The reaction was filtered through celite, and the filtrate was dried and concentrated. Purification by column chromatography (petroleum ether:ethyl acetate = 5:1) afforded Intermediate 13d (7.7 g, 76.75%) as a colorless, transparent liquid.

[0269] 1 H NMR(600MHz,DMSO-d6)δ4.33(t,J=5.3Hz,1H),3.17(dd,J=6.4,5.3Hz,2H),3.00(s ,6H),1.79–1.77(m,4H),1.65–1.48(m,4H),1.31–1.20(m,3H),0.95–0.79(m,2H).

[0270] Step 5: Synthesis of 2,2-dimethoxyspiro[3.5]nonane-7-carbaldehyde (Intermediate 13e)

[0271] Intermediate 13d (15.4 g, 71.86 mmol), sodium bicarbonate (30 g, 355 mmol) and Dess-Martin reagent (45.72 g, 107.8 mmol) were dissolved in dichloromethane (150 mL) and reacted at room temperature for two hours. After completion of the reaction, a small amount of water was added to quench the reaction system under ice-water bath, filtered through celite, and the filtrate was dried and concentrated. It was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain colorless transparent liquid intermediate 13e (10.35 g, 67.85%).

[0272] 1 H NMR (600MHz, DMSO-d6) δ9.55 (s, 1H), 3.01 (s, 6H), 2.22 (tt, J = 9.9, 3.9Hz, 1H), 1.82–1. 76(m,4H),1.73–1.66(m,2H),1.59–1.53(m,2H),1.40–1.34(m,2H),1.33–1.25(m,2H).

[0273] Step 6: Synthesis of 7-ethynyl-2,2-dimethoxyspiro[3.5]nonane (Intermediate 13f)

[0274] Intermediate 13e (6.33 g, 29.82 mmol) was dissolved in methanol (60 mL), and potassium carbonate (12.36 g, 89.45 mmol) was added. Dimethyl (1-diazo-2-oxopropyl)phosphonate (7.45 g, 38.76 mmol) was added dropwise under ice bath. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give colorless transparent liquid intermediate 13f (3.02 g, 48.62%).

[0275] 1 H NMR (600MHz, DMSO-d6) δ3.00(s,6H),2.83(d,J=2.4Hz,1H),2.32(s,1H),1.79(dd,J=15.7,1.5Hz,4H),1.65–1.57(m,4H),1.37–1.31(m,4H).

[0276] Step 7: Synthesis of 6-chloro-4-(2,2-dimethoxyspiro[3.5]nonan-7-yl)ethynyl)pyridazin-3-amine (Intermediate 13g)

[0277] Intermediate 13f (3 g, 14.4 mmol), 3-amino-4-bromo-6-chloropyridazine (2.5 g, 12 mmol), bistriphenylphosphine palladium dichloride (842 mg, 1.2 mmol), cuprous iodide (228 mg, 1.2 mmol), and triethylamine (6.26 mL, 4.8 mmol) were dissolved in a three-necked flask containing DMF (100 mL). Under nitrogen, the mixture was heated to 110°C and reacted for two hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was added with 400 mL of purified water and extracted three times with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain Intermediate 13g (2.37 g, 58.84%) as a yellow solid.

[0278] 1 H NMR(600MHz,DMSO-d6)δ7.48(s,1H),6.71(s,2H),3.02(s,6H),2.67(s,1H),1.85–1.8 1(m,4H),1.79–1.72(m,2H),1.68–1.61(m,2H),1.57–1.47(m,2H),1.41–1.37(m,2H).

[0279] LCMS (ESI): [M+H]+=336.35

[0280] Step 8: Synthesis of 2-(6-amino-5-((2,2-dimethoxyspiro[3.5]nonan-7-yl)ethynyl)pyridazin-3-yl)phenol (Intermediate 13h)

[0281] Intermediate 13g (3.5g, 10.42mmol), 2-hydroxyphenylboronic acid (4.31g, 31.27mmol), methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (94.5mg, 1.04mmol), and potassium carbonate (4.32g, 31.2mmol) were dissolved in 1,4-dioxane (40mL) and water (4mL). Under nitrogen, the mixture was heated to 80°C and stirred overnight. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain Intermediate 13h (2.23g, 58.84%) as a yellow solid.

[0282] 1 H NMR (600MHz, DMSO-d6) δ13.32(s,1H),8.15(s,1H),7.88(dd,J=8.0,1.6Hz,1H),7.26–7.22(m,1H),6.93–6.86(m,2H),6.78 (s,2H),3.02(s,6H),2.71(s,1H),1.88–1.82(m,4H),1.80(s,2H),1.70–1.63(m,2H),1.60–1.51(m,2H),1.45–1.38(m,2H).

[0283] LCMS(ESI):[M+H] + =394.39

[0284] Step 9: Synthesis of 7-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.5]nonan-2-one (Compound 13)

[0285] Intermediate 13h (100 mg, 254.14 μmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (375 μL, 5.08 mmol) was added for 2 h. After completion of the reaction, the reaction mixture was concentrated to obtain compound 13 (76 mg, 91.83%) as a yellow solid.

[0286] 1H NMR (600MHz, Methanol-d4) δ8.34(d,J=8.6Hz,1H),7.67(dd,J=8.1,1.8Hz,1H),7.39(td,J=7.7,7.3,1.6 Hz,1H),7.01(dd,J=7.9,6.5Hz,2H),2.82(dt,J=13.0,1.9Hz,4H),2.12–1.85(m,5H),1.82–1.66(m,4H).

[0287] LCMS(ESI):[M+H] + =348.35

[0288] Example 15. Synthesis of 6-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.3]heptane-2-one (Compound 14)

[0289] Synthesis scheme:

[0290] Step 1: Synthesis of compound 6-oxospiro[3.3]heptane-2-carboxylic acid methyl ester (Intermediate 14a)

[0291] 6-Oxospiro[3.3]heptane-2-carboxylic acid (5.00 g, 32.43 mmol) was dissolved in a single-necked flask containing DMF (50 mL). Methyl iodide (4.60 g, 32.43 mmol) and potassium carbonate (4.48 g, 32.43 mmol) were added sequentially and stirred at room temperature for 5 h. After the reaction was completed, water was added to quench the reaction and the mixture was extracted three times with ethyl acetate (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (0-20% ethyl acetate) to give intermediate 14a (3.83 g) as a colorless oil.

[0292] Step 2: Synthesis of compound 6,6-dimethoxyspiro[3.3]heptane-2-carboxylic acid methyl ester (Intermediate 14b)

[0293] Intermediate 14a (3.00 g, 17.84 mmol) was dissolved in a single-necked flask containing MeOH (30 mL). Trimethyl orthoformate (5.68 g, 53.51 mmol) and 4-methylbenzenesulfonate pyridinium (896.48 mg, 3.57 mmol) were added sequentially and stirred at room temperature for 5 h. After completion of the reaction, the mixture was quenched with water and extracted three times with ethyl acetate (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (0-30% ethyl acetate) to give intermediate 14b (2.93 g) as a colorless oil.

[0294] Step 3: Synthesis of compound 6,6-dimethoxyspiro[3.3]heptane-2-methanol (Intermediate 14c)

[0295] Methyl 6,6-dimethoxyspiro[3.3]heptane-2-carboxylate (3.00 g, 14.00 mmol) was dissolved in tetrahydrofuran (30 mL) in a single-necked flask. The temperature was cooled to 0°C, and lithium aluminum tetrahydride (1.06 g, 28.00 mmol) was slowly added. The mixture was stirred at 0°C for 0.5 h. The mixture was transferred to room temperature and stirred for 5 h. After the reaction was completed, the mixture was cooled to 0°C, quenched with ice water, and extracted three times with ethyl acetate (40 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (0-50% ethyl acetate) to obtain intermediate 14c (2.35 g) as a colorless oil.

[0296] Step 4: Synthesis of compound 6,6-dimethoxyspiro[3.3]heptane-2-carbaldehyde (Intermediate 14d)

[0297] Dissolve 6,6-dimethoxyspiro[3.3]heptane-2-carboxylic acid methyl ester (2.17 g, 11.65 mmol) in a single-necked bottle containing acetonitrile (30 mL), slowly add 2-iodobenzoic acid (6.52 g, 23.30 mmol), and stir at 80°C for 2 h under N2 atmosphere. After the reaction is completed, cool to room temperature, filter and concentrate to obtain a crude product. The crude product is purified by column chromatography (0-20% ethyl acetate) to obtain intermediate 14d (1.63 g) as a colorless oil. Step 5: Synthesis of compound 6-ethynyl-2,2-dimethoxyspiro[3.3]heptane (intermediate 14e)

[0298] 6,6-Dimethoxyspiro[3.3]heptane-2-carbaldehyde (2.15 g, 11.67 mmol) was dissolved in methanol (20 mL) in a single-necked flask. The temperature was cooled to 0°C, and potassium carbonate (3.23 g, 23.34 mmol) was slowly added. The temperature was maintained at 0°C and stirred for 10 minutes. Dimethyl 1-diazo-2-oxopropyl)phosphonate (3.36 g, 17.50 mmol) was added, and stirring was continued for 4 hours. After completion of the reaction, the crude product was filtered and concentrated to obtain the crude product. The crude product was purified by column chromatography (0-20% ethyl acetate) to afford Intermediate 14e (1.03 g) as a colorless oil.

[0299] Step 6: Synthesis of Spiro[3.3]heptan-2-one, 6-ethynyl (Intermediate 14f)

[0300] 6-Ethynyl-2,2-dimethoxyspiro[3.3]heptane (1.00 g, 5.55 mmol) was dissolved in dichloromethane (12 mL) in a glass bottle. Trifluoroacetic acid (3 mL) was slowly added and stirred at room temperature for 2 h. After completion of the reaction, the crude product was filtered and concentrated to yield the product. The crude product was purified by column chromatography (0-20% ethyl acetate) to yield intermediate 14f (836.00 mg) as a colorless oil.

[0301] 1 H NMR (400MHz, DMSO) δ3.11(d,J=2.1Hz,2H),3.06(t,J=2.8Hz,2H),3.01(d,J=2 .2Hz,1H),2.99(dd,J=8.2,2.4Hz,1H),2.50–2.46(m,3H),2.30–2.24(m,1H).

[0302] Step 7: Synthesis of 6-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.3]heptan-2-one

[0303] Intermediate 18 (100 mg, 375 μmol), 6-ethynylspiro[3.3]heptan-2-one (60.51 mg, 451 μmol), bistriphenylphosphine palladium dichloride (26.38 mg, 37.5 μmol), cuprous iodide (7.16 mg, 37.5 μmol), and triethylamine (208 μL, 1.5 mmol) were dissolved in DMF (4 mL). Under nitrogen, the mixture was heated to 110°C for two hours. After completion, the reaction was filtered through celite, and the filtrate was added with 16 mL of purified water. The mixture was extracted three times with ethyl acetate (4 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford Compound 14 (42 mg, 35%) as a yellow solid.

[0304] 1H NMR(600MHz, Methanol-d4)δ8.09(d,J=12.8Hz,1H),7.80–7.69(m,1H),7.31–7.23(m,1H),6.94( t,J=7.1Hz,2H),3.45(p,J=8.4Hz,1H),3.24–3.13(m,3H),2.86–2.46(m,4H),1.51–1.19(m,4H).

[0305] LCMS(ESI):[M+H] + =320.30

[0306] Example 16. Synthesis of 2-(6-amino-5-((1-methoxy-4-(pyrrolidin-1-yl)cyclohexyl)ethynyl)pyridazin-3-yl)phenol (Compound 15)

[0307] Synthesis scheme

[0308] Step 1: Synthesis of 8-((trimethylsilyl)ethynyl)-1,4-dioxyacetyl[4.5]decan-8-ol (Intermediate 15a)

[0309] 1,4-Dioxaspiro[4.5]decan-8-one (5.00 g, 32.01 mmol) and trimethylsilyl acetylene (4.72 g, 48.02 mmol) were dissolved in tetrahydrofuran (20 mL) in a three-necked flask. Under nitrogen, the temperature was cooled to 0°C, and LDA (22.41 mL, 44.41 mmol) was slowly added. The temperature was maintained at 0°C and stirred for 0.5 h. The mixture was transferred to room temperature and stirred for 1 h. After the reaction was complete, the temperature was cooled to 0°C and quenched with purified water. Excess solvent was removed under reduced pressure, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford intermediate 15a (5.4 g, 66.3%) as a colorless oil.

[0310] 1 H NMR (600MHz, CDCl3) δ3.94(s,4H),2.04(s,1H),1.97–1.94(m,2H),1.91–1.86(m,2H),1.78(t,J=4.9Hz,4H),0.16(s,9H).

[0311] Step 2: Synthesis of ((8-methoxy-1,4-dioxaspiro[4.5]dec-8-yl)ethynyl)trimethylsilane (Intermediate 15b)

[0312] Intermediate 15a (5.00 g, 20.63 mmol) was dissolved in tetrahydrofuran (20 mL) in a three-necked flask, cooled to 0°C, and sodium hydroxide (907.54 mg, 22.69 mmol) was slowly added. The mixture was stirred at 0°C for 0.5 h. Methyl iodide (5.86 g, 41.26 mmol) was slowly added, and the mixture was stirred at 0°C for 0.5 h before being transferred to room temperature and stirred for 1 h. After the reaction was complete, the temperature was lowered to 0°C and quenched with purified water. Excess solvent was removed under reduced pressure, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford Intermediate 15b (4.8 g, 90.98%) as a colorless oil.

[0313] Step 3: Synthesis of 8-ethynyl-8-methoxy-1,4-dioxaspiro[4.5]decane (Intermediate 15c)

[0314] Intermediate 15b (4.80 g, 17.88 mmol) and potassium carbonate (4.94 g, 35.76 mmol) were dissolved in methanol (20 mL) in a three-necked flask and stirred for 1 h. After completion of the reaction, excess solvent was removed under reduced pressure, purified water was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain Intermediate 15c (2.7 g, 76.94%) as a colorless oil.

[0315] 1 H NMR (600MHz, Chloroform-d) δ3.94(s,4H),2.73(s,1H),1.94(dd,J=12.3,6.2Hz,2H),1.91–1.83(m,2H),1.80–1.73(m,4H),0.15(s,9H).

[0316] Step 4: Synthesis of 2-(6-amino-5-((8-methoxy-1,4-dioxaspiro[4.5]dec-8-yl)ethynyl)pyridazin-3-yl)phenol (Intermediate 15d)

[0317] Intermediate 15c (2.35 g, 8.83 mmol), SM-I-XL-006 (1.73 g, 8.83 mmol), bistriphenylphosphine palladium dichloride (619.87 mg, 883.13 μmol), cuprous iodide (168.19 mg, 883.13 μmol), and triethylamine (1.79 g, 17.66 mmol) were dissolved in a three-necked flask containing DMF (20 mL). Under nitrogen, the mixture was heated to 80°C and stirred overnight. After completion of the reaction, purified water was added and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to afford Intermediate 15d (630 mg, 13.79%) as a yellow solid.

[0318] 1 H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.61(dd,J=8.0,1.5Hz,1H),7.33(ddd,J=8.5,7.2,1.5Hz,1H),7.08(dd,J=8.3,1.1Hz,1H),6.9 8–6.92(m,1H),5.37(s,2H),4.00(d,J=1.9Hz,4H),3.47(s,3H),2.21–2.08(m,4H),1.89(ddd,J=13.6,7.9,5.8Hz,2H),1.82–1.71(m,2H).

[0319] LCMS(ESI):[M+H] + =382.19

[0320] Step 5: Synthesis of 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)-4-methoxycyclohexane-1-one (Intermediate 15e)

[0321] Intermediate 15d (630 mg, 1.65 mmol) was dissolved in a three-necked flask containing dichloromethane (2.5 mL). Trifluoroacetic acid (2.5 mL) was added and stirred for 1 h. After completion of the reaction, excess solvent was removed under reduced pressure, purified water was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to afford Compound 15e (425 mg, 76.26%) as a yellow solid.

[0322] 1 H NMR(400MHz,Chloroform-d)δ7.94(s,1H),7.61(dd,J=8.0,1.6Hz,1H),7.33(ddd,J=8.5,7.2,1.6Hz,1H) ,7.09(dd,J=8.2,1.2Hz,1H),6.99–6.91(m,1H),5.39(s,2H),3.57(s,3H),2.72–2.58(m,2H),2.46(ddt,J =15.7,9.9,4.5Hz,4H),2.32–2.21(m,2H).

[0323] LCMS(ESI):[M+H] + =338.29

[0324] Step 6: Synthesis of 2-(6-amino-5-((1-methoxy-4-(pyrrolidin-1-yl)cyclohexyl)ethynyl)pyridazin-3-yl)phenol (Compound 15)

[0325] 15e (40 mg, 118.58 μmol, 1.0 eq), pyrrole (10.12 mg, 142.27 μmol), AcOH (6d), and Et3N (6d) were dissolved in a reaction vial containing DCE / DMSO (1 / 1 mL) and reacted at room temperature for 2 hours. NaBH(OAc)3 (75.38 mg, 355.68 μmol, 3.0 eq) was then added and allowed to react overnight at room temperature. After completion of the reaction, the final product 15 (16 mg, 36.10%) was purified by HPLC.

[0326] 1H NMR (400MHz, Methanol-d4) δ8.48(s,1H),7.94(d,J=8.2Hz,1H),7.29(t,J=8.4Hz,1H),6.98(t,J=7.3Hz,2H),6.59(s,1H ),3.41(s,3H),3.12(s,3H),2.51(d,J=10.1Hz,2H),2.16(d,J=7.0Hz,2H),2.06(d,J=26.5Hz,5H),1.92(t,J=9.5Hz,4H).

[0327] LCMS(ESI):[M+H] + =393.40

[0328] Example 17. Synthesis of (1s,4s)-4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)cyclohexane-1-carbaldehyde (Compound 16)

[0329] Step 1: Synthesis of cis-1,4-cyclohexanedimethanol (Intermediate 16a)

[0330] Cis-1,4-cyclohexanedicarboxylic acid (15.0 g, 87.12 mmol) was dissolved in a reaction flask containing THF (500 mL). LiAlH₄ (9.92 g, 261.35 mmol) was added dropwise under an ice-water bath. The reaction was allowed to react overnight at room temperature. Upon completion, the reaction was quenched by adding a Na₂SO₄·10H₂O solution. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to afford Intermediate 16a (9.15 g, 72.83%) as a colorless oil.

[0331] 1 H NMR (400MHz, CDCl3) δ3.55 (d, J=6.9Hz, 4H), 1.74–1.67 (m, 2H), 1.55 (ddt, J=13.0, 6.8, 2.6Hz, 6H), 1.43 (dd, J=11.6, 5.7Hz, 4H).

[0332] Step 2: Synthesis of cis-4-methyl acetate-cyclohexane-1-methanol (Intermediate 16b)

[0333] cis-1,4-cyclohexanedimethanol (9.10 g, 63.10 mmol) was dissolved in a reaction flask containing THF (150 mL). NaH (2.52 g, 60% dispersion in mineral oil) was added to the reaction flask under an ice-water bath. After reacting at 0°C for half an hour, acetyl chloride was gradually added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 hours. After completion of the reaction, purified water was added to quench the reaction, and the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford Intermediate 16b (6.30 g, 53.61%) as a pale yellow oil.

[0334] 1 H NMR (600MHz, CDCl3) δ3.99(d,J=7.3Hz,2H),3.53(d,J=6.9Hz,2H),2.06(d,J=1.2Hz,3H),1.87(ddq,J=10.1,7.0,2.9Hz,1 H),1.68(pt,J=7.1,4.1Hz,1H),1.54(ddp,J=13.5,9.5,4.8Hz,4H),1.42(tdd,J=12.6,10.7,8.8,5.3Hz,4H),1.25(s,1H).

[0335] Step 3: Synthesis of cis-4-methyl acetate-cyclohexane-1-carbaldehyde (Intermediate 16c)

[0336] DMSO (6.61 g, 84.56 mmol) was dissolved in a three-necked reaction flask containing DCM (50 mL). Oxalyl chloride (5.51 g, 40.59 mmol) was added dropwise at -78°C. Methyl cis-4-acetate-cyclohexane-1-methanol (6.30 g, 33.83 mmol) dissolved in DCM (30 mL) was then added dropwise at -78°C. After a one-hour reaction, triethylamine (17.11 g, 169.13 mmol) was added and allowed to react for half an hour under a nitrogen atmosphere. Upon completion, the flask was removed from the cold tank and quenched by the addition of 1 M hydrochloric acid at -10°C. The organic phase was extracted with ethyl acetate and concentrated to yield crude intermediate 16c (6.2 g) as a yellow oil. This compound was stable and used directly in the next step without purification.

[0337] Step 4: Synthesis of cis-4-acetylene-cyclohexane-1-methanol (Intermediate 16d)

[0338] Cis-4-acetic acid methyl ester-cyclohexane-1-carbaldehyde (6.20 g, 33.82 mmol) was dissolved in a reaction flask containing methanol (60 mL). Dimethyl (1-diazo-2-oxopropyl)phosphonate (8.45 g, 43.96 mmol) was added dropwise to the reaction flask at 0°C. Potassium carbonate (14.02 g, 101.45 mmol) was then added to the reaction solution. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the organic phase was extracted with ethyl acetate and concentrated to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate = 1:5) to afford Intermediate 16d (3.86 g, 62.59%) as a colorless oil.

[0339] 1 H NMR(600MHz, CDCl3) δ3.49(d,J=6.1Hz,3H),3.45(d,J=6.3Hz,1H),2.81–2.76(m,1H),2 .05(d,J=2.4Hz,3H),1.82(d,J=12.9Hz,4H),1.63(dt,J=12.0,3.7Hz,4H),1.25(s,6H).

[0340] Step 5: Synthesis of cis-4-((3-amino-6-chloropyridazin-4-yl)ethynyl)cyclohexyl)methanol (Intermediate 16e)

[0341] 3-Amino-4-bromo-6-chloropyridazine (5.10 g, 24.47 mmol), cis-4-acetylene-cyclohexane-1-methanol (4.06 g, 29.36 mmol), Pd(PPh3)2Cl2 (1.72 g, 2.45 mmol), CuI (1.40 g, 7.34 mmol), and DIEA (15.81 g, 122.34 mmol) were dissolved in a reaction flask containing DMSO (100 mL) and reacted at 80°C under a nitrogen atmosphere for 3 hours. After completion of the reaction, the organic phase was washed with saturated brine, extracted with ethyl acetate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to afford intermediate 16e (3.14 g, 48.29%) as a colorless oil.

[0342] LCMS(ESI):[M+H] + =266.37

[0343] Step 6: Synthesis of 2-(6-amino-5-((cis-4-(hydroxymethyl)cyclohexyl)ethynyl)pyridazin-3-yl)phenol (Intermediate 16f)

[0344] Intermediate 16e (3.14 g, 11.82 mmol), 2-hydroxyphenylboronic acid (4.89 g, 35.45 mmol), BrettPhO₃Pd G₃ (1.07 g, 1.18 mmol), and K₂CO₃ (4.90 g, 35.45 mmol) were dissolved in a reaction flask containing 1,4-Dioxane / H₂O = 5:1 (84 mL) and reacted overnight at 80°C under a nitrogen atmosphere. After completion of the reaction, the organic phase was washed with saturated brine, extracted with ethyl acetate, and concentrated to afford the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 1:3) to afford Intermediate 16f (1.40 g, 36.64%) as a colorless oil.

[0345] 1 H NMR(400MHz,DMSO-d6)δ8.17(s,1H),7.80(dd,J=7.9,1.7Hz,1H),7.30–7.24(m ,1H),6.96–6.86(m,2H),4.25(d,J=6.1Hz,1H),3.22(d,J=6.2Hz,2H),2.08(dt, J=13.0,7.4Hz,2H),1.86–1.82(m,1H),1.80–1.72(m,2H),1.49(ddd,J=15.6,1 0.1, 3.9Hz, 2H), 1.37 (tq, J=8.8, 3.4, 2.8Hz, 1H), 0.96 (qd, J=13.1, 3.5Hz, 2H).

[0346] LCMS(ESI):[M+H] + =324.02

[0347] Step 7: Synthesis of cis-4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)cyclohexane-1-carbaldehyde (Compound 16)

[0348] Intermediate 16f (100 mg, 309.22 μmol) and IBX (173.17 g, 618.44 μmol) were dissolved in a reaction flask containing THF (10 mL) and reacted at 50°C for 2 hours. After the reaction was completed, compound 16 was obtained by filtration.

[0349] LCMS(ESI):[M+H] + =322.30

[0350] Example 18. Synthesis of 2-(6-amino-5-((4-methoxyphenyl)ethynyl)pyridazin-3-yl)phenol (Compound 17)

[0351] Step 1: Synthesis of 6-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)spiro[3.3]heptan-2-one

[0352] Intermediate 18 (33 mg, 125 μmol), 1-ethynyl-4-methoxybenzene (20 mg, 150 μmol), bistriphenylphosphine palladium dichloride (8.78 mg, 12.5 μmol), cuprous iodide (2.38 mg, 12.5 μmol), and triethylamine (70 μL, 0.5 mmol) were dissolved in DMF (1 mL). Under nitrogen, the mixture was heated to 110°C and reacted for 40 minutes. After completion of the reaction, the mixture was filtered through celite, and the filtrate was added with 4 mL of purified water. The mixture was extracted three times with ethyl acetate (4 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 17 (10 mg, 25%) as a solid.

[0353] 1 H NMR (600MHz, Methanol-d4) δ8.41 (s, 1H), 7.72 (d, J = 8.6Hz, 3H), 7.40 (s, 1H), 7.12–6.87 (m, 4H), 3.88 (s, 3H).

[0354] LCMS(ESI):[M+H] + =318.28

[0355] Example 19. Synthesis of 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)cyclohexane-1-one (Compound 18)

[0356] Step 1: Synthesis of 2-(5-(1,4-dioxaspiro[4.5]decane-8-yl)ethynyl)-6-aminopyridazin-3-yl)phenol

[0357] Intermediate 18 (500 mg, 1.88 mmol), 8-ethynyl-1,4-dioxaspiro[4.5]decane (374.8 mg, 2.25 mmol), bistriphenylphosphine palladium dichloride (131.89 mg, 187.90 μmol), cuprous iodide (35.8 mg, 187.90 μmol), and triethylamine (970 μL, 7.52 mmol) were dissolved in DMF (20 mL). Under nitrogen, the mixture was heated to 110°C and reacted for two hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was added with 80 mL of purified water. The mixture was extracted three times with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 18a (404 mg, 61.18%) as a solid.

[0358] 1 H NMR (600MHz, Methanol-d4) δ8.08(s,1H),7.78–7.73(m,1H),7.27(td,J=7.7,1.5Hz,1H),6.94(t,J=7.4Hz,2H),3.97(d,J=2.7H z,4H),2.87(dp,J=8.4,3.7Hz,1H),2.08–2.01(m,2H),1.88(tdd,J=12.6,8.4,3.7Hz,4H),1.66(ddd,J=13.6,10.3,4.0Hz,2H).

[0359] LCMS(ESI):[M+H] + =352.30

[0360] Step 2: Synthesis of 4-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)cyclohexane-1-one

[0361] Intermediate 18a (404 mg, 1.15 mmol) was dissolved in 6 mL of tetrahydrofuran, and 2 mL of concentrated hydrochloric acid and 1 mL of water were added to react overnight. The tetrahydrofuran was evaporated, and the pH was adjusted to a weakly alkaline state by adding appropriate amounts of water and solid sodium bicarbonate. The mixture was extracted three times with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford solid compound 18 (250 mg, 79.24%).

[0362] 1H NMR (400MHz, Methanol-d4) δ8.18–8.10(m,1H),7.75(dt,J=8.2,2.1Hz,1H),7.28(td,J=7. 7,1.6Hz,1H),6.98–6.91(m,2H),3.29(dq,J=7.9,3.9Hz,1H),2.62(dt,J=13.5,6.1Hz,1H) ,2.47(ddd,J=14.5,9.0,5.4Hz,1H),2.29(ddt,J=12.9,9.6,5.1Hz,1H),2.19–2.08(m,1H) ,1.97(ddt,J=16.5,13.1,4.8Hz,2H),1.88–1.74(m,1H),1.67(dq,J=19.1,9.6,8.3Hz,1H).

[0363] LCMS(ESI):[M+H] + =308.38

[0364] Example 20. Synthesis of (1R,4R)-4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)cyclohexane-1-carboxylic acid (Compound 19)

[0365] Step 1: Synthesis of methyl (1R, 4R)-4-formylcyclohexane-1-carboxylate

[0366] Methyl (1R,4R)-4-hydroxymethylcyclohexane-1-carboxylate (500 mg, 2.9 mmol) and 2-iodoacylbenzoic acid (1.63 g, 5.81 mmol) were dissolved in acetonitrile (5 mL). Under nitrogen, the temperature was raised to 80°C and the reaction was allowed to react for one hour. After completion of the reaction, the mixture was filtered and concentrated to afford crude product 19a (506 mg, 102.4%).

[0367] Step 2: Synthesis of (1R, 4R)-4-ethynylcyclohexane-1-carboxylic acid methyl ester

[0368] 19a (506 mg, 2.97 mmol) was dissolved in methanol (5 mL), and potassium carbonate (821.72 mg, 5.95 mmol) was added. Dimethyl (1-diazo-2-oxopropyl)phosphonate (742.45 mg, 3.86 mmol) was added dropwise under ice-bath. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 19b (389.4 mg, 78.80%) as a white crystalline solid.

[0369] 1H NMR(600MHz,Methanol-d4)δ3.66(d,J=0.7Hz,3H),2.39–2.34(m,1H),2.33(d d,J=2.4,0.7Hz,1H),2.30–2.24(m,1H),2.04–1.96(m,4H),1.49–1.38(m,4H).

[0370] Step 3: Synthesis of methyl (3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)cyclohexane-1-carboxylate

[0371] Intermediate 18 (50 mg, 188 μmol), 19b (37.38 mg, 225.5 μmol), bistriphenylphosphine palladium dichloride (13 mg, 18.8 μmol), cuprous iodide (3.58 mg, 18.80 μmol), and triethylamine (104 μL, 751.6 μmol) were dissolved in DMF (2 mL). Under nitrogen, the mixture was heated to 110°C and reacted for one hour. After completion, the reaction was filtered through celite, and the filtrate was added with 8 mL of purified water. The mixture was extracted three times with ethyl acetate (2 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 19c (32 mg, 48.46%) as a solid.

[0372] 1 H NMR (600MHz, Methanol-d4) δ8.08(s,1H),7.75(d,J=8.0Hz,1H),7.27(t,J=7.2Hz,1H),6.94(t,J=7.8Hz,2H),3.78–3.60(m,3 H),2.69(t,J=11.5Hz,1H),2.42(d,J=11.6Hz,1H),2.19(d,J=12.7Hz,2H),2.12–1.99(m,2H),1.58(dq,J=44.3,12.2Hz,4H).

[0373] LCMS(ESI):[M+H] + =352.39

[0374] Step 4: Synthesis of (1R,4R)-4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)ethynyl)cyclohexane-1-carboxylic acid

[0375] 19c (118.2 mg, 336 μmol) and LiOH (80.55 mg, 3.36 mmol) were dissolved in THF / H₂O (1:1) (4 mL) and stirred at room temperature for one hour. After the reaction was complete, dilute hydrochloric acid was added dropwise to adjust the pH to 4. Solid precipitated and was filtered to afford compound 19 (113.8 mg, 100.28%) as a yellow solid.

[0376] 1 H NMR(600MHz,Methanol-d4)δ8.10(d,J=24.5Hz,1H),7.76(dd,J=15.1,7.9Hz,1 H),7.32–7.23(m,1H),6.94(t,J=7.5Hz,2H),3.76–3.72(m,1H),2.20(dd,J=13. 1,4.1Hz,1H),2.08(ddd,J=14.3,9.4,5.0Hz,1H),2.04–1.92(m,2H),1.89(td,J =11.3,9.0,5.7Hz,2H),1.80(ddt,J=14.3,10.8,3.7Hz,1H),1.66–1.48(m,3H).

[0377] LCMS(ESI):[M+H] + =338.29

[0378] Example 21. Synthesis of 2-(6-amino-5-((1R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)phenol (Compound 20)

[0379] Step 1: (1R, 5S, 6S)-3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3-

[0380] Synthesis of tert-Butyl Azabicyclo[3.1.0]hexan-6-yl)carbamate

[0381] Intermediate 18 (200 mg, 751.60 μmol), tert-butyl (1R,5S,6S)-rel-3-azabicyclo[3.1.0]hexan-6-ylcarbamate (447 mg, 2.25 mmol), and DIEA (398 mg, 3.08 mmol) were dissolved in a reaction flask containing acetonitrile (5 mL) and reacted at 80°C for 12 hours. After completion of the reaction, the product was purified by column chromatography to afford 20a (148 mg, 51.35%).

[0382] 1H NMR (400MHz, DMSO-d6) δ14.52(s,1H),7.98–7.87(m,1H),7.23(td,J=7.7,1.5Hz,1H),7.12(d,J=8.3Hz,2H),6.87(t,J=7.3H z,2H),6.01(s,2H),4.11(q,J=5.3Hz,1H),3.82(d,J=10.1Hz,2H),3.17(d,J=5.0Hz,2H),1.74(d,J=2.6Hz,2H),1.40(s,9H).

[0383] LCMS(ESI):[M+H] + =384.49

[0384] Step 2: Synthesis of 2-(6-amino-5-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)phenol

[0385] 20a (100 mg, 260.8 μmol) was dissolved in a reaction flask containing tetrahydrofuran (5 mL). HCl (1 mL, 4 M in dioxane) was added and the mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to afford 20b (72 mg, 97.43%). The crude product was directly used in the next reaction without purification.

[0386] LCMS(ESI):[M+H] + =284.28

[0387] Step 3: Synthesis of 2-(6-amino-5-((1R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)pyridazin-3-yl)phenol

[0388] 20b (70 mg, 247.06 μmol) was dissolved in a reaction flask containing methanol (6 mL). DIEA (141 mg, 1.09 mmol) and aqueous formaldehyde (70 μL, 741.18 μmol) were added and allowed to react at room temperature for 2 hours. NaBH3CN (49 mg, 741.18 μmol) was then added to the reaction system and the reaction continued at room temperature for 12 hours. After completion of the reaction, the crude product was concentrated under reduced pressure and purified by HPLC to yield compound 20 (39 mg, 50.69%).

[0389] 1H NMR(400MHz, Methanol-d4)δ7.55(dd,J=7.7,1.6Hz,1H),7.48–7.43(m,1H),7.08–7.03(m,3H),4. 23(d,J=11.3Hz,2H),3.87–3.82(m,2H),3.05(s,6H),2.92(d,J=2.4Hz,1H),2.48(q,J=2.2Hz,2H).

[0390] LCMS(ESI):[M+H] + =312.28

[0391] Example 22. Synthesis of N-((1R,5S,6s)-3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)acetamide

[0392] 20b (50 mg, 176.47 μmol), HATU (87.23 mg, 229.41 μmol, 1.3 eq), AcOH (13.78 mg, 229.41 μmol, 1.3 eq), and DIEA (114.04 mg, 882.35 μmol, 5.0 eq) were dissolved in a reaction vial containing DCM (2 mL) and reacted at room temperature for 3 hours. After completion of the reaction, the final product 21 (5 mg, 8.71%) was purified by HPLC.

[0393] 1 H NMR (600MHz, Methanol-d4) δ7.71(d,J=7.3Hz,1H),7.27(t,J=7.5Hz,1H),7.17(s,1H),6.93(t,J= 7.8Hz,2H),3.99(d,J=10.1Hz,2H),3.39(d,J=9.7Hz,2H),2.77(s,1H),1.94(s,3H),1.86(s,2H).

[0394] LCMS(ESI):[M+H] + =326.28

[0395] Experimental Example 1: Fluorescence polarization test

[0396] 1. Purify the target protein with purity >90% after prokaryotic expression for fluorescence polarization experiment:

[0397] His-SMARCA2 BD (S1377-Q1486; Swiss Prot P51531-2):

[0398] His-SMARCA4 BD (A1448-S1575; Swiss Prot P51532):

[0399] 2. Fluorescence polarization experiments were performed in a 384-well plate (3820, Corning) in the dark, with an excitation wavelength of 485 nm and an emission wavelength of 520 nm. Fluorescent probes were used in the experiment, and the buffer was 25 mM Bis-Tris, 0.01% Triton X-100, pH 7.5. The final DMSO concentration after compound addition was less than 1%. The final assay volume per well was 125 μl, containing 50 μL of fluorescent probe (final concentration 10 nM), SMARCA2 BD Protein 50uL (final concentration 50nM) / SMARCA4 BD 50 μL of protein (final concentration 120 nM) and 25 μL of compound at various concentrations (final concentration 0-100 μM, 3-fold dilution, a total of 11 concentrations) were added. A control group (probe + protein), a probe control group (probe only), and a blank control group (buffer only) were set up. After incubation on a shaker at room temperature for 2 hours, fluorescence values ​​were read using a microplate reader (SPARK m1000pro, TECAN). Polarization values ​​(mP) were calculated based on the fluorescence values ​​in the parallel and perpendicular directions of each well, and the inhibition rate was calculated based on the mP values:

[0400] The inhibition rate data were plotted in GraphPad Prism 8.0 software, and the IC50 value was calculated.

[0401] Experimental Example 2 Cell Proliferation Activity Detection

[0402] The anti-proliferative activity of the compound on cells was determined by CCK-8 kit (C0039, Beyotime). TM , ATCC) and MCF-7 (HTB-22 TM, ATCC) were cultured in F-12K medium (30-2004, ATCC) containing 10% FBS (10099141C, Gibco) or DMEM medium (11995065, Gibco) containing 10% FBS at 37°C, 5% CO2 until they entered the logarithmic growth phase. 2800 cells (A549) / 1000 cells (MCF-7) were added to a 96-well plate in a volume of 100 μL. A blank control group received 100 μL of culture medium and cultured at 37°C, 5% CO2 for one day. After that, 100 μL of compound at various concentrations (final concentration 0-100 μM, 3-fold dilution, a total of 9 concentrations) was added. The control group received 100 μL of culture medium and continued to culture for 4 days (A549) / 7 days (MCF-7). According to the manufacturer's instructions, 20 μL of CCK-8 solution was added and the cells were reacted at 37°C for 2 h (A549) / 4 h (MCF-7). The absorbance at 450 nm was measured using a microplate reader (SPARK m1000pro, TECAN).

[0403] The inhibition rate of the compound on cells at different concentrations was calculated according to the OD value of each well, and the inhibition rate data were plotted in GraphPad Prism 8.0 software to calculate the IC50 value.

[0404] Compounds 1c, 2c, 3c, 4c, 5c, 6c, and 10c prepared according to the above examples were used as experimental compounds, and control compounds were prepared with reference to Example 4 in PCT patent application WO2016138114. The structural formula of the control compound is shown below:

[0405] The experimental results are shown in Table 1:

[0406] Table 1 Inhibitor binding capacity (FP) and activity (CCK8) data

[0407] As shown in Table 1, the IC values ​​of the compounds provided by the present invention for SMARCA2 / 4 relative to the control compounds are 50 The values ​​are significantly smaller, proving that the compounds provided by the present invention have better binding affinity to SMARCA2 / 4. As can be seen from Table 1, the IC values ​​of the compounds provided by the present invention for A549 and MCF-7 cells are 50 The values ​​were significantly lower than those of the control compounds, indicating that the compounds provided by the present invention have better inhibitory ability. 50The values ​​are highly consistent, that is, the compounds provided by the present invention have good inhibitory activity against both SMARCA2 and SMARCA4, and can be used as dual inhibitors targeting the SMARCA2 / 4 bromodomain.

[0408] The anti-proliferative activity of the compounds on Hela cells and SW1573 cells was determined by CCK-8 kit (C0039, Beyotime). TM , ATCC) and SW1573 (CRL-2170TM, ATCC) were cultured in DMEM (11995065, Gibco) supplemented with 10% FBS (10099141C, Gibco) at 37°C, 5% CO2 until they entered the logarithmic growth phase. 2500 cells (Hela) / 800 cells (SW1573) were added to a 96-well plate in a volume of 100 μL. The control group received 100 μL of culture medium and cultured at 37°C, 5% CO2 for one day. After that, 100 μL of compound at various concentrations (final concentration 0-100 μM, 3-fold dilution, a total of 9 concentrations) was added. The control group received 100 μL of culture medium and continued to culture for 3 days (Hela) / 7 days (SW1573). 20 μL of CCK-8 solution was added, and the cells were reacted at 37° C. for 1.5 h (Hela) / 2.5 h (SW1573). The absorbance at 450 nm was measured using a microplate reader (SPARK m1000 pro, TECAN).

[0409] The inhibition rate of the compound on cells at different concentrations was calculated according to the OD value of each well, and the inhibition rate data were plotted in GraphPad Prism 8.0 software to calculate the IC50 value.

[0410] Compounds 1c, 2c, 3c, 4c, 5c, 6c, and 10c prepared according to the above examples were used as experimental compounds, and control compounds were prepared with reference to Example 4 in PCT patent application WO2016138114. The structural formula of the control compound is shown below:

[0411] The experimental results are shown in Table 2:

[0412] Table 2 Inhibitor binding capacity (FP) and activity (CCK8) data

[0413] As can be seen from Table 2, the IC values ​​of the compounds provided by the present invention for SMARCA2 / 4 relative to the control compounds are 50The values ​​are significantly smaller, which proves that the compounds provided by the present invention have better binding ability to SMARCA2 / 4. As can be seen from Table 2, the IC values ​​of the compounds provided by the present invention for Hela and SW1573 cells are 50 The values ​​were significantly lower than those of the control compounds, indicating that the compounds provided by the present invention have better inhibitory ability. 50 The values ​​are highly consistent, that is, the compounds provided by the present invention have good inhibitory activity against both SMARCA2 and SMARCA4, and can be used as dual inhibitors targeting the SMARCA2 / 4 bromodomain.

[0414] The present invention has been described through the above-described embodiments. However, it should be understood that the above-described embodiments are for illustrative and illustrative purposes only and are not intended to limit the present invention to the described embodiments. Furthermore, it will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments and that various variations and modifications may be made based on the teachings of the present invention, all of which fall within the scope of the present invention. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound having formula I A The compound of the structural formula shown or a pharmaceutically acceptable salt thereof, in, Cy1 is a saturated or unsaturated cycloalkyl group, a saturated or unsaturated heterocycloalkyl group containing a heteroatom selected from N, O and S, an aryl group, or a heteroaryl group containing a heteroatom selected from N, O and S, which is unsubstituted or substituted by one or more groups independently selected from halogen, cyano, haloalkyl, haloalkoxy, alkyl, hydroxyl, amino and alkylamino; preferably, Cy1 is a saturated or unsaturated 3-10 membered cycloalkyl group, a saturated or unsaturated 3-10 membered heterocycloalkyl group containing 1-3 heteroatoms independently selected from N, O and S, a 6-10 membered aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by one or more groups independently selected from halogen, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl, hydroxyl, amino and C1-C6 alkylamino; R is Squiggly lines indicate connection points; R a CR aa or N; R f Selected from C(R aa )2, CO, O, S and NR aa ; W1 and W2 are CR aa or N; R b 、R c 、R d 、R e Each occurrence is independently selected from C(R aa )2, CO, O, S and NR aa ; R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, an alkyl group, a deuterated alkyl group, a heteroalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2 and -N(R g )-S(O)2-R g and nitro, wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo (=O), alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and nitro are substituted with one or more substituents; preferably, R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a hydroxyl group, a C1-C6 hydroxyalkyl group, a -C(O)-C1-C6 alkyl group, a nitro group, a cyano group, a C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 Heteroaryl, -NHR g , benzyloxycarbonyl (Cbz), carboxyl (-COOH), -N(R g )2、-NH(CO)R g , acetoxy (AcO) and -N(R g ) 2, wherein optionally, the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, nitro, C3-C 10 Cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 Heteroaryl, carboxyl (-COOH), -NH(CO)R g , acetoxy (AcO) and -N(R g )2 is substituted by one or more substituents; preferably, R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a cyano group, a nitro group, a benzyloxycarbonyl group (Cbz), a carboxyl group (-COOH), a NH(CO)R g , acetoxy (AcO) and -N(R g ) 2, wherein optionally, the C1-C6 alkyl and C1-C6 alkoxy are each independently selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, nitro, C3-C8 cycloalkyl, C3-C 10 Heterocyclic group, C6-C 10 Aryl, C5-C 10 Heteroaryl, carboxyl (-COOH), -NH(CO)R g , acetoxy (AcO) and -N(R g )2 is substituted by one or more substituents; m1, m2, m3, and m4 are each independently selected from 0, 1, 2, 3, 4, and 5 at each occurrence; R1 is selected from H, deuterium atoms, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and nitro, wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo (=O), alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and nitro; preferably, R1 is selected from H, a deuterium atom, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a 3- to 15-membered cycloalkyl group, a 3- to 15-membered heterocycloalkyl group, a 6- to 14-membered aryl group, and a 5- to 14-membered heteroaryl group, wherein the 3- to 15-membered cycloalkyl group and the 3- to 15-membered heterocycloalkyl group are each independently a monocyclic, condensed, bridged, or spirocyclic group, and the 6- to 14-membered aryl group and the 5- to 14-membered heteroaryl group are each independently a monocyclic or condensed ring group, and optionally, the C1-C6 alkyl group, C2-C6 deuterated alkyl group, C1-C6 heteroalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkoxy group, a 3- to 15-membered cycloalkyl group, a 3- to 15-membered heterocycloalkyl group, a 6- to 14-membered aryl group, and a 5- to 14-membered heteroaryl group C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 6-14 membered aryl, and 5-14 membered heteroaryl are each independently substituted by one, two or more groups independently selected from halogen, oxo (=O), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, 3-15 membered cycloalkyl, 3-15 membered heterocycloalkyl, 6-14 membered aryl, 5-14 membered heteroaryl, -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and nitro substituents; R g Each occurrence is independently selected from H, deuterium atoms, halogens, alkyl groups, deuterated alkyl groups, hetero Alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, -C(O)-alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, benzyloxycarbonyl (Cbz), wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl (-COOH), alkylamino, -NH(CO)H, -NH(CO)alkyl and acetoxy (AcO); preferably, R g Each occurrence is independently selected from H, a deuterium atom, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy group, a C1-C6 hydroxyalkyl group, a -C(O)-C1-C6 alkyl group, a C6-C 10 Aryl, C5-C 10 Heteroaryl, C3-C 15 Cycloalkyl and C3-C 15 Heterocycloalkyl, wherein optionally, the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C 15 Cycloalkyl, C3-C 15 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups are each independently selected from halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C 15 Cycloalkyl, C3-C 15 Heterocyclic group, C6-C 10 Aryl, C5-C 10 substituted with one or more substituents selected from heteroaryl, carboxyl (-COOH), C1-C6 alkylamino, -NH(CO)H, -NH(CO)-C1-C6 alkyl, and acetoxy (AcO); and R2 and R3 are each independently selected from H, an alkyl group, a deuterium atom, F, Cl, Br, I, a hydroxyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group and a -C(=O)-alkyl group; preferably, R2 and R3 are each independently selected from H, a C1-C6 alkyl group, a deuterium atom, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 alkoxy group and a -C(=O)-C1-C6 alkyl group.

2. The compound according to claim 1, wherein Cy1 is an aryl or heteroaryl group, the aryl and heteroaryl groups are substituted by hydroxyl, amino or alkylamino, and are optionally substituted by a substituent selected from the following: halogen, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl; preferably, Cy1 is a 6-10 membered aryl group or a 5-10 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, O and S, the 6-10 membered aryl group and the 5-10 membered heteroaryl group are substituted by hydroxyl, amino or alkylamino, and are optionally substituted by a substituent selected from the following: halogen, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl; preferably, Cy1 is a phenyl group or a 5-6 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, O and S, the phenyl group and the 5-6 membered heteroaryl group are substituted by hydroxyl, amino or alkylamino, and are optionally substituted by a substituent selected from the following: halogen, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl; and / or Cy1 is substituted by 1-3 C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl; preferably, Cy1 is phenyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, said phenyl and 5-6 membered heteroaryl are substituted by hydroxy, amino or alkylamino, and optionally substituted by a substituent each independently selected from the following: F, Cl, Br, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl and C1-C3 alkoxy; preferably, Cy1 is phenyl or a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, said phenyl and 5-6 membered heteroaryl are substituted by at least one hydroxy, amino or alkylamino, preferably by one hydroxy, amino or alkylamino; and / or R1 is selected from H, a deuterium atom, a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a 3- to 15-membered cycloalkyl group, a 3- to 15-membered heterocycloalkyl group, a 6 wherein the 3 to 15-membered cycloalkyl and the 3 to 15-membered heterocycloalkyl are each independently a monocyclic, condensed, bridged, or spirocyclic group, the 6 to 14-membered aryl and the 5 to 14-membered heteroaryl are each independently a monocyclic or condensed ring group, the 3 to 15-membered heterocycloalkyl and the 5 to 14-membered heteroaryl each independently contain 1, 2, 3, 4, or 5 heteroatoms each independently selected from N, O, and S, optionally, the C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3 to 15-membered cycloalkyl, 3 to 15-membered heterocycloalkyl, 6 to 14-membered aryl, and 5 to 14-membered heteroaryl are each independently a monocyclic or condensed ring group, each 14-membered heteroaryl is independently substituted with one, two or more substituents independently selected from the group consisting of F, Cl, Br, I, oxo (═O), hydroxy, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (—COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), —(CO)H, —NH(CO)—C1-C6 alkyl, 5-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and 9-fluorenylmethyloxycarbonyl (Fmoc); and / or R aa Each occurrence is independently selected from H, a deuterium atom, a halogen, a hydroxyl group, a C1-C3 alkyl group, a C1-C3 hydroxyalkyl group, a C1-C3 alkoxy group, a C1-C3 haloalkyl group, a C1-C6 haloalkoxy group, a cyano group, a nitro group, a benzyloxycarbonyl group (Cbz), a carboxyl group (-COOH), a NH(CO)R g , acetoxy (AcO) and -N(R g )2, wherein optionally, the C1-C3 alkyl and C1-C3 alkoxy are each independently selected from halogen, C1-C3 alkyl, C1-C3 heteroalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, cyano, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclyl, phenyl, C5-C6 heteroaryl, carboxyl (-COOH), -N(CO)R g , acetoxy (AcO) and -N(R g )2 is substituted with one or more substituents; and / or R g Each occurrence is independently selected from H, a deuterium atom, a C1-C3 alkyl group, a C1-C3 heteroalkyl group, a C1-C3 alkoxy group, a C2-C3 alkenyl group, a C2-C3 alkynyl group, a C1-C3 haloalkyl group, a C1-C3 haloalkoxy group, a C1-C3 hydroxyalkyl group, -C(O)-C1-C3 alkyl group, a phenyl group, a C5-C6 heteroaryl group, a C3-C6 cycloalkyl group and a C3-C6 heterocycloalkyl group, wherein optionally, the C1-C3 alkyl group, the C1-C3 heteroalkyl group, the C2-C3 alkenyl group, the C2-C3 alkynyl group, the C1-C3 alkoxy group, the C3-C6 cycloalkyl group, the C3-C6 heterocyclyl group, the aryl group and the C5-C 10 The heteroaryl groups are each independently selected from halogen, C1-C3 alkyl, C1-C3 heteroalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, hydroxy, C1-C3 hydroxyalkyl, cyano, amino, nitro, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C6-C 10 Aryl, C5-C 10 substituted by one or more substituents selected from heteroaryl, carboxyl (-COOH), C1-C3 alkylamino, -NH(CO)H, -NH(CO)-C1-C3 alkyl, and acetoxy (AcO); and / or R2 and R3 are each independently selected from H, a C1-C3 alkyl group, a deuterium atom, a C1-C3 haloalkyl group, a C1-C3 hydroxyalkyl group, a C1-C3 alkoxy group and -C(=O)-C1-C3 alkyl group.

3. The compound according to claim 1, wherein The compound has the structure shown in Formula I wherein Cy1 is an aryl or heteroaryl group, said aryl and heteroaryl group being substituted by at least one hydroxyl group, amino group, or alkylamino group, and being optionally substituted by one or more groups independently selected from the following: halogen, cyano group, haloalkyl group, haloalkoxy group, alkyl group, and alkoxy group; preferably, Cy1 is a 6-10 membered aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, O, and S, said 6-10 membered aryl or heteroaryl group being substituted by at least one hydroxyl group, amino group, or alkylamino group, and being optionally substituted by one or more groups independently selected from the following: halogen, cyano group, C1-C6 haloalkyl group, C1-C6 haloalkoxy group, C1-C6 alkyl group, and C1-C6 alkoxy group. R1 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and C1-C6 hydroxyalkyl; or, R1 is unsubstituted or substituted 3 to 15-membered cycloalkyl or, R1 is a 3 to 15-membered heterocycloalkyl having 1-3 heteroatoms independently selected from N, O and S, and the 3 to 15-membered cycloalkyl and 3 to 15-membered heterocycloalkyl are each independently a monocyclic, condensed, bridged or spirocyclic group; or R1 is an unsubstituted or substituted phenyl, or a substituted or unsubstituted 8 to 10-membered aryl, the 8 to 10-membered aryl is a monocyclic or condensed ring group; or, R1 is a 3 to 15-membered heterocycloalkyl having 1-3 heteroatoms independently selected from N, O and S. unsubstituted or substituted 5- to 6-membered heteroaryl, or R1 is an unsubstituted or substituted 8- to 10-membered heteroaryl having 1-3 heteroatoms independently selected from N, O and S, wherein the 8- to 10-membered heteroaryl is a monocyclic or condensed ring group; wherein the substituted 3- to 15-membered cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, 8- to 10-membered aryl, 5- to 6-membered heteroaryl and 8- to 10-membered heteroaryl are each independently substituted by one, two or more groups independently selected from halogen, oxo (=O), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, 3- to 15-membered cycloalkyl, 3- to 15-membered heterocycloalkyl, -N(R g )2、Cyano、-C(O)-N(R g )2、-S(O)-N(R g )2、-S(O)2-N(R g )2、-OR g 、-SR g 、-OC(O)-R g 、-C(O)-R g 、-C(O)-OR g 、-S(O)-R g 、-S(O)2-R g 、-N(R g )-C(O)-R g 、-N(R g )-S(O)-R g 、-N(R g )-C(O)-N(R g )2、-N(R g )-S(O)2-R g and nitro; preferably, substituted by one, two or more substituents independently selected from halogen, oxo (=O), hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), -NH(CO)-C1-C6 alkyl, acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, 5-8 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc); R g Each occurrence is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, 3-15 membered cycloalkyl or 3-15 membered heterocycloalkyl; preferably, R g Each occurrence is independently H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C3-C8 cycloalkyl or C3-C8 heterocycloalkyl, and R2 and R3 are each independently selected from H, alkyl and -C(=O)-alkyl.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Cy1 is phenyl or a 5-6 membered heteroaryl, said phenyl and 5-6 membered heteroaryl being substituted by at least one hydroxyl, amino, or alkylamino group, and optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, haloalkyl, haloalkoxy, alkyl, and alkoxy; preferably, Cy1 is phenyl or a 5-6 membered heteroaryl, said phenyl or heteroaryl being substituted by at least one hydroxyl group, and optionally substituted by one or more groups independently selected from the group consisting of halogen, cyano, trifluoromethyl, trifluoromethoxy, C1-C6 alkyl, and C1-C6 alkoxy, preferably optionally substituted by one or more groups independently selected from the group consisting of F, Cl, Br, cyano, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, and C1-C3 alkoxy; preferably, Cy1 is phenyl, and said phenyl is substituted by one hydroxyl group; and / or R1 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 haloalkoxy and C1-C4 hydroxyalkyl; or R1 is unsubstituted or substituted 3 to 15-membered cycloalkyl, or R1 is a 3 to 15-membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O and S, and the 3 to 15-membered cycloalkyl and 3 to 15-membered heterocycloalkyl are each independently a monocyclic, condensed or spirocyclic group; or R1 is an unsubstituted or substituted phenyl, or a substituted or unsubstituted 10-membered aryl, the 10-membered aryl is a condensed ring group; or R1 is a substituted or unsubstituted 5 to 6-membered aryl having 1-2 heteroatoms independently selected from N, O and S. wherein R1 is an unsubstituted or substituted 8- to 10-membered heteroaryl having 1-3 heteroatoms independently selected from N, O and S, and the 8- to 10-membered heteroaryl is a fused ring group; wherein the substituted 3- to 15-membered cycloalkyl, 3- to 15-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 10-membered aryl and 8- to 10-membered heteroaryl are each independently substituted by one, two or more groups independently selected from halogen, oxo (=O), carboxyl, benzyloxycarbonyl (Cbz), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), 5- to 8-membered heterocycloalkyl containing one nitrogen atom, 9-fluorenylmethyloxycarbonyl (Fmoc), hydroxyl, C1-C6 alkyl, C1-C6 hydroxyalkane C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, cyano, -(CO)H, -NH(CO)-C1-C6 alkyl, and nitro, preferably, each independently substituted with one, two or more substituents independently selected from Cl, Br, F, I, oxo, hydroxy, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Bo c), -(CO)H, -NH(CO)-C1-C6 alkyl, 5-6 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc) substituents, preferably, each independently substituted by one, two or more substituents independently selected from Cl, Br, F, I, oxo, hydroxy, methyl, hydroxymethyl, methoxy, amino, dimethylamino, cyano, nitro, carboxyl (-COOH), acetoxy (AcO), benzyloxycarbonyl (Cbz), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-CH3, 5-6 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc); and / or R2 and R3 are each independently H, or C1-C6 alkyl; preferably R2 and R3 are each independently H, or C1-C3 alkyl; preferably R2 and R3 are each independently H.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein The compound has the structure shown in formula II, in, R1 is defined in any one of claims 1, 2, 3 or 4; Preferably, R1 is an unsubstituted or substituted 4, 5, 6, 7, 8, 9, 10, or 11-membered cycloalkyl group, or R1 is a 4, 5, 6, 7, 8, 9, 10, or 11-membered heterocycloalkyl group having 1-2 heteroatoms independently selected from N, O, and S, wherein the cycloalkyl group and the heterocycloalkyl group are each independently a monocyclic, condensed, or spirocyclic group; or R1 is an unsubstituted or substituted phenyl group, or a substituted or unsubstituted 10-membered aryl group, wherein the 10-membered aryl group is a condensed ring group; or R1 is a 1- R1 is an unsubstituted or substituted 5- to 6-membered heteroaryl group having 2 heteroatoms independently selected from N, O and S, or R1 is an unsubstituted or substituted 8- to 10-membered heteroaryl group having 1-2 heteroatoms independently selected from N, O and S, and the 8- to 10-membered heteroaryl group is a condensed ring group; wherein the substituted cycloalkyl, heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, 10-membered aryl and 8- to 10-membered heteroaryl groups are each independently substituted by one, two or more groups independently selected from Cl, Br, F, I, oxo, carboxyl, hydroxyl , C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-C1-C3 alkyl, 5-8 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc) substituents, preferably substituted with one, two or more substituents independently selected from the group consisting of Cl, Br, F, I, oxo, hydroxy, methyl, hydroxymethyl, methoxy, amino, dimethylamino, cyano, nitro, carboxyl (-COOH), acetoxy (AcO), benzyloxycarbonyl (Cbz), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-CH3, 5-6 membered heterocycloalkyl containing one nitrogen atom, and 9-fluorenylmethyloxycarbonyl (Fmoc); Preferably, R1 is unsubstituted or substituted 4-membered monocycloalkyl, 5-membered monocycloalkyl, 6-membered monocycloalkyl, 7-membered spirocycloalkyl, 8-membered spirocycloalkyl, 9-membered spirocycloalkyl, 10-membered spirocycloalkyl, 11-membered spirocycloalkyl, 8-membered condensed-ring cycloalkyl, 9-membered condensed-ring cycloalkyl, or 10-membered condensed-ring cycloalkyl; or R1 is unsubstituted or substituted 4-membered monocycloheterocycloalkyl, 5-membered monocycloheterocycloalkyl, 6-membered monocycloheterocycloalkyl, 7-membered spirocycloheterocycloalkyl, 8-membered spirocycloheterocycloalkyl, 9-membered spirocycloheterocycloalkyl, 10-membered spirocycloheterocycloalkyl, 11-membered spirocycloheterocycloalkyl, 8-membered condensed-ring heterocycloalkyl, 9-membered condensed-ring heterocycloalkyl, or 10-membered condensed-ring heterocycloalkyl having 1-2 heteroatoms independently selected from N, O and S; or the substituted cycloalkyl and heterocycloalkyl are each independently substituted by one, two or more independently selected from Cl, Br, F, I, oxo, hydroxy, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-C1-C3 alkyl, 5-8 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc) substituents, preferably, each independently substituted with one, two or more independently selected from Cl, Br, F, I, oxo, hydroxy, methyl, hydroxymethyl, methoxy, amino, dimethylamino, The substituents may include cyano, nitro, carboxyl (-COOH), acetoxy (AcO), benzyloxycarbonyl (Cbz), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-CH3, 5-6 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc).

6. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that: R1 is H, -CH3, or -C4H9; or R1 is selected from the following groups optionally substituted by one or more substituents: Wherein, m, n, m' and n' are each independently 1 or 2 each time they appear; The one or more substituents are each independently selected from Cl, Br, F, I, oxo, carboxyl, hydroxyl, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-C1-C3 alkyl, containing one 5-8 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc); preferably, each independently selected from Cl, Br, F, I, oxo, hydroxy, methyl, hydroxymethyl, methoxy, amino, dimethylamino, cyano, nitro, carboxyl (-COOH), acetoxy (AcO), benzyloxycarbonyl (Cbz), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-CH3, 5-6 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc); and Thick bars indicate connection points.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, characterized in that R1 is selected from the following groups optionally substituted by one or more substituents: wherein m, n, m' and n' are each independently selected from 1 or 2 at each occurrence; The one or more substituents are each independently selected from Cl, Br, F, I, oxo, carboxyl, hydroxyl, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 halo Alkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-C1-C3 alkyl, 5-8 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc); preferably, each independently selected from Cl, Br, F, I, oxo, hydroxy, methyl, hydroxymethyl, methoxy, amino, dimethylamino, cyano, nitro, carboxyl (-COOH), acetoxy (AcO), benzyloxycarbonyl (Cbz), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-CH3, 5-6 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc); R4, at each occurrence, is independently selected from H, Cl, Br, F, I, oxo, carboxyl, hydroxyl, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO )H, -NH(CO)-C1-C3 alkyl, 5-8 membered heterocycloalkyl containing one nitrogen atom and 9-fluorenylmethyloxycarbonyl (Fmoc); preferably, R4 is independently H, F, Cl, Br, I, -OH, oxo, methyl, amino (-NH2), carboxyl (-COOH), methoxy, hydroxymethyl, dimethylamino, -(CO)H, -NH(CO)-CH3, 5-6 membered heterocycloalkyl containing one nitrogen atom; R5, at each occurrence, is independently selected from H, Cl, Br, F, I, carboxyl, hydroxyl, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, cyano, nitro, benzyloxycarbonyl (Cbz), carboxyl (-COOH), acetoxy (AcO), benzyl (Bn), tert-butyloxycarbonyl (Boc), -(CO)H, -NH(CO)-C1-C3 alkyl, 5-8 membered heterocycloalkyl containing one nitrogen atom, and 9-fluorenylmethyloxycarbonyl (Fmoc); R5, at each occurrence, is independently H, C1-C3 alkyl, acetoxy (AcO), benzyl (Bn), benzyloxycarbonyl (Cbz), -(CO)H, tert-butyloxycarbonyl (Boc), or 9-fluorenylmethyloxycarbonyl (Fmoc); and Thick bars indicate connection points.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound is selected from the following compounds:

9. A pharmaceutical composition, characterized in that The composition contains an effective amount of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for treating or preventing a disease or condition mediated by SMARCA2 / 4.

11. The use according to claim 11, characterized in that The disease or condition mediated by SMARCA2 / 4 is cancer; preferably, the cancer is lung cancer, cervical cancer and / or breast cancer.

12. The compound according to claim 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, for use in treating or preventing a disease or condition mediated by SMARCA2 / 4; preferably, the disease or condition is cancer, preferably, the cancer is lung cancer, cervical cancer and / or breast cancer.

13. A method for treating or preventing a disease or condition mediated by SMARCA2 / 4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9; preferably, the disease or condition is cancer, preferably, the cancer is lung cancer, cervical cancer and / or breast cancer.