Ebp inhibitors and uses thereof

Abstract

The present application provides a kind of compound shown in formula I, or its deuterium compound, or its stereoisomer, or its pharmaceutically acceptable salt.The compound provided by the present application has EBP inhibiting effect, provides new possibility for developing new EBP inhibitor drug.

Description

Technical Field

[0001] This invention relates to the field of biochemistry, specifically to a compound with EBP inhibitory activity and its use in the preparation of pharmaceuticals. Background Technology

[0002] The EBP (Emopamil-Binding Protein) gene encodes a five-transmembrane protein expressed in the endoplasmic reticulum (ER). This protein is a key enzyme in the cholesterol synthesis pathway. Inhibition of EBP isomerase leads to the accumulation of its substrates Zymostenol / Zymosterol, while simultaneously reducing the products Cholesterol / Desmosterol (J Med Chem. 2024 Mar 28; 67(6):4819-4832.). Specifically, the EBP protein catalyzes the isomerization of the double bond in the second ring of sterol molecules, shifting the double bond from the C8-C9 position to the C7-C8 position.

[0003] In the field of disease treatment, research on EBP inhibitors has mainly focused on the treatment of multiple sclerosis (MS). MS is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system, with an incidence of 50 to 300 cases per 100,000 people. MS is a major cause of acquired, non-traumatic disability in young people (Lancet Neurol. 2020 Aug; 19(8):678-688.). Myelin is mainly composed of lipids, which protects nerve cell axons and reduces the attenuation of electrical signals along the axon, thereby accelerating the conduction of electrical impulses in the axon. Demyelination of axons in chronic MS can lead to axonal degeneration and neuronal cell death. In addition, myelin fragments produced by MS can also interfere with the proliferation, differentiation, and maturation of oligodendrocytes, which are highly specialized cells responsible for producing and maintaining myelin. Multiple sclerosis (MS) is primarily caused by B cells producing autoantibodies and promoting inflammatory responses. Common treatments targeting this mechanism include Bruton's tyrosine kinase inhibitors (BTKIs) and monoclonal antibodies targeting B cells. BTKIs reduce B cell proliferation and activation, thereby reducing inflammation and nerve damage. Monoclonal antibodies (mAbs) have higher selectivity for B cells, inhibiting their activation and reducing inflammation-induced myelination deterioration. The development of immunotherapies targeting the inflammatory components of MS disease has significantly reduced the formation and relapse rates. However, these therapies are often insufficient in preventing permanent disability caused by axonal and neuronal damage, especially in patients who have already undergone demyelination. Remyelination, the process of promoting new myelination through endogenous or therapeutic means, is of significant clinical importance for MS patients. Remyelination restores nutritional support to nerve cells, prevents axonal damage, and restores nerve conduction. In the early stages of multiple sclerosis, a remyelination repair process occurs. However, as the disease progresses, oligodendrocytes cannot completely rebuild and restore myelin. Therefore, myelin regeneration has gradually become a research hotspot in the treatment of multiple sclerosis. Inducing the proliferation and differentiation of oligodendrocytes through drugs to ultimately remyelinate nerve axons is one of the most promising treatment methods. Currently, a considerable number of studies have shown that EBP inhibitors can slow the progression of the disease by promoting the differentiation and maturation of oligodendrocyte precursor cells, forming oligodendrocytes that can produce myelin, and repairing damaged myelin (Nature. 2018 Aug; 560(7718):372-376. Cell ChemBiol. 2019 Apr 18; 26(4):593-599. e4. Nat Chem Biol. 2022 Sep; 18(9):925-933.).

[0004] In addition, EBP inhibitors are also used in glioma (Journal of Clinical Oncology 2022).

[0005] It shows potential application prospects in the research of tumor treatment fields such as 40:16_suppl,TPS2077-TPS2077.), colorectal cancer (J.Am.Chem.Soc.2020,142,6128-6138.Sci Transl Med.2016Oct 19;8(361):361ra140.), and breast cancer (Nat Commun.2019Jun 5;10(1):2452.).

[0006] However, the limited activity of existing EBP inhibitors restricts their development prospects, such as the TASIN series of compounds (Sci. Transl. Med. 8, 361ra140 (2016)). Meanwhile, increasing the brain exposure of drugs is also a pressing issue for treating central nervous system diseases such as multiple sclerosis and glioma. Summary of the Invention

[0007] To address the aforementioned problems, this invention provides a compound with EBP inhibitory activity, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, offering new possibilities for the development of novel EBP inhibitor compounds.

[0008] This invention first provides a compound of Formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in,

[0011] Indicates a chemical single or double bond;

[0012] m1 and m2 are each independently selected from 1, 2, or 3;

[0013] X is selected from N or CH;

[0014] Z is selected from S(O)2, S(O), C(O) or chemical single bond;

[0015] Ring B is selected from 6- to 10-membered aromatic rings or 5- to 10-membered aromatic heterocyclic rings; wherein the aromatic ring or aromatic heterocyclic ring is optionally surrounded by 1, 2, 3, or 4 R groups. B1 replace;

[0016] Each R B1Each of the following groups is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene, and -OR. B2 -C0~C2 alkylene-NR B2 R B3 -C0~C2 alkylene-3~6-membered carbon ring, -C0~C2 alkylene-4~6-membered heterocycle, -C0~C2 alkylene-6-membered aromatic ring, or -C0~C2 alkylene-5~6-membered aromatic heterocycle; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally surrounded by 1, 2, 3, or 4 R B4 replace;

[0017] Alternatively, the two Rs substituted adjacently on ring B. B1 Connected together with the B ring, they form a 9-10 member partially saturated carbon ring or a 9-10 member partially saturated heterocycle;

[0018] R B2 R B3 Each of the following is independently selected from hydrogen, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene-3-6 membered carbon ring or -C0-C2 alkylene-4-6 membered heterocycle;

[0019] Each R B4 Each of the following is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, and C1-C6 alkoxy.

[0020] L is selected from -C1~C4 alkylene-, -N(R) L -C1~C4 alkylene groups or chemical single bonds;

[0021] R L Selected from hydrogen or C1-C6 alkyl groups;

[0022] Ring A is selected from 3-10 membered carbon rings, 4-10 membered heterocycles, 6-10 membered aromatic rings, or 5-10 membered aromatic heterocycles; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally surrounded by 1, 2, 3, or 4 R groups. A1 replace;

[0023] Each R A1 Each of the following groups is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene, and -OR. A2 -C0~C2 alkylene-NR A2 R A3 -C0 to C2 alkylene rings with 3 to 6-membered carbon rings or -C0 to C2 alkylene rings with 4 to 6-membered heterocycles;

[0024] R A2 RA3 They are independently selected from hydrogen, halogenated alkyl, and C1-C6 alkyl.

[0025] Furthermore, X is selected from N, and L is selected from -C1 to C4 alkylene groups or chemical single bonds; or, X is selected from CH, and L is selected from -N(R) L )-C1~C4 alkylene-.

[0026] In some embodiments of the present invention, the compounds represented by Formula I are as shown in Formula IIa, Formula IIb or Formula IIc:

[0027]

[0028] in,

[0029] m1 and m2 are independently selected from 1, 2 or 3 respectively; preferably, m1 is 1 and m2 is 1, or m1 is 2 and m2 is 1, or m1 is 2 and m2 is 2;

[0030] L is selected from -C1 to C4 alkylene or a chemical single bond; preferably, L is selected from methylene, ethylene, propylene, butylene or a chemical single bond;

[0031] Ring B is selected from 6- to 10-membered aromatic rings or 5- to 10-membered aromatic heterocyclic rings; wherein the aromatic ring or aromatic heterocyclic ring is optionally surrounded by 1, 2, 3, or 4 R groups. B1 replace;

[0032] Each R B1 Each of the following groups is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene, and -OR. B2 -C0~C2 alkylene-NR B2 R B3 -C0~C2 alkylene-3~6-membered carbon ring, -C0~C2 alkylene-4~6-membered heterocycle, -C0~C2 alkylene-6-membered aromatic ring, or -C0~C2 alkylene-5~6-membered aromatic heterocycle; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally surrounded by 1, 2, 3, or 4 R B4 replace;

[0033] Alternatively, the two Rs substituted adjacently on ring B. B1 Connected together with the B ring, they form a 9-10 member partially saturated carbon ring or a 9-10 member partially saturated heterocycle;

[0034] R B2 R B3 Each of the following is independently selected from hydrogen, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene-3-6 membered carbon ring or -C0-C2 alkylene-4-6 membered heterocycle;

[0035] Each R B4 Each of the following is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, and C1-C6 alkoxy.

[0036] Ring A is selected from 3-10 membered carbon rings, 4-10 membered heterocycles, 6-10 membered aromatic rings, or 5-10 membered aromatic heterocycles; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally surrounded by 1, 2, 3, or 4 R groups. A1 replace;

[0037] Each R A1 Each of the following groups is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene, and -OR. A2 -C0~C2 alkylene-NR A2 R A3 -C0 to C2 alkylene rings with 3 to 6-membered carbon rings or -C0 to C2 alkylene rings with 4 to 6-membered heterocycles;

[0038] R A2 R A3 Each is independently selected from hydrogen and C1 to C6 alkyl groups.

[0039] In some embodiments of the present invention, the compounds represented by Formula I are further shown as those of Formulas IIIa, IIIb, IIIc, IIId, IIIe, IIIf, and IIIg:

[0040]

[0041] The definitions of ring A, ring B, and L are as described above.

[0042] In some embodiments of the present invention, the compounds represented by Formula I are as shown in Formula IId or Formula IIe:

[0043]

[0044] in,

[0045] m1 and m2 are independently selected from 1, 2 or 3 respectively; preferably, m1 is 1 and m2 is 1, or m1 is 2 and m2 is 1, or m1 is 2 and m2 is 2;

[0046] L is selected from -N(R) L -C1 to C4 alkylene-; wherein the alkylene group is attached to ring A; preferably, L is selected from -NH-CH2- or -NH-C2H4-;

[0047] Ring B is selected from 6- to 10-membered aromatic rings or 5- to 10-membered aromatic heterocyclic rings; wherein the aromatic ring or aromatic heterocyclic ring is optionally surrounded by 1, 2, 3, or 4 R groups. B1 replace;

[0048] Each R B1 Each of the following groups is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene, and -OR. B2 -C0~C2 alkylene-NR B2 R B3 -C0~C2 alkylene-3~6-membered carbon ring, -C0~C2 alkylene-4~6-membered heterocycle, -C0~C2 alkylene-6-membered aromatic ring, or -C0~C2 alkylene-5~6-membered aromatic heterocycle; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally surrounded by 1, 2, 3, or 4 R B4 replace;

[0049] Alternatively, the two Rs substituted adjacently on ring B. B1 Connected together with the B ring, they form a 9-10 member partially saturated carbon ring or a 9-10 member partially saturated heterocycle;

[0050] R B2 R B3 Each of the following is independently selected from hydrogen, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene-3-6 membered carbon ring or -C0-C2 alkylene-4-6 membered heterocycle;

[0051] Each R B4 Each of the following is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, and C1-C6 alkoxy.

[0052] Ring A is selected from 3-10 membered carbon rings, 4-10 membered heterocycles, 6-10 membered aromatic rings, or 5-10 membered aromatic heterocycles; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally surrounded by 1, 2, 3, or 4 R groups. A1 replace;

[0053] Each R A1 Each of the following groups is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene, and -OR. A2 -C0~C2 alkylene-NR A2 R A3 -C0 to C2 alkylene rings with 3 to 6-membered carbon rings or -C0 to C2 alkylene rings with 4 to 6-membered heterocycles;

[0054] R A2 R A3Each is independently selected from hydrogen and C1 to C6 alkyl groups.

[0055] In some embodiments of the present invention, the compounds represented by Formula I are further represented as those of Formula IIIh, IIIi, IIIj, and IIIk:

[0056]

[0057] The definitions of ring A, ring B, and L are as described above.

[0058] Further, ring B is selected from benzene ring, naphthalene ring, 5-membered monoaromatic heterocycle, 6-membered monoaromatic heterocycle, 9-membered fused aromatic heterocycle, and 10-membered fused aromatic heterocycle; wherein the benzene ring, naphthalene ring, and aromatic heterocycle are optionally surrounded by 1, 2, 3, or 4 R. B1 replace;

[0059] Preferably, ring B is selected from The B ring is selected from rings that can be optionally divided by 1, 2, 3 or 4 R rings. B1 replace;

[0060] More preferably, ring B is selected from

[0061] Furthermore, each R B1 Each group is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and -OR. B2 -C1 alkylene-OR B2 -NR B2 R B3 -C1 alkylene-NR B2 R B3 , 3-membered carbon ring, 4-membered carbon ring, 5-membered carbon ring, 6-membered carbon ring, -C1 alkylene-3-membered carbon ring, -C1 alkylene-4-membered carbon ring, -C1 alkylene-5-membered carbon ring, -C1 alkylene-6-membered carbon ring, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, -C1 alkylene-4-membered heterocycle, -C1 alkylene-5-membered heterocycle, -C1 alkylene-6-membered heterocycle, -6-membered aromatic ring, -C1 alkylene-6-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, -C1 alkylene-5-membered aromatic heterocycle, or -C1 alkylene-6-membered aromatic heterocycle; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally composed of 1, 2, 3, or 4 R B4 replace;

[0062] Alternatively, the two Rs substituted adjacently on ring B. B1 Connected together with the B ring, they form a 9-membered partially saturated carbon ring, a 10-membered partially saturated carbon ring, a 9-membered partially saturated heterocycle, or a 10-membered partially saturated heterocycle.

[0063] R B2 R B3 Each of the following is independently selected from hydrogen, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, and cyclopropyl;

[0064] Each R B4 Each of the following groups is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, -OH, methoxy, and ethoxy.

[0065] Preferably,

[0066] Each R B1 Each of the following groups is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, -OH, -C1 alkylene-OH, methoxy, ethoxy, n-propoxy, isopropoxy, -C1 alkylene-methoxy, -C1 alkylene-ethoxy, -O-monofluoromethyl, -O-difluoromethyl, -O-trifluoromethyl, -O-cyclopropyl, -NH2, -NHCH3, -N(CH3)2, cyclopropyl, cyclobutyl, or

[0067] In some specific embodiments of the present invention, ring B is selected from...

[0068] Further, ring A is selected from 4-membered carbon rings, 5-membered carbon rings, 6-membered carbon rings, 7-membered carbon rings, 4-membered heterocycles, 5-membered heterocycles, 6-membered heterocycles, 7-membered heterocycles, 5-membered aromatic heterocycles, and 6-membered aromatic heterocycles; wherein the carbon ring, heterocycle, and aromatic heterocycle are optionally surrounded by 1, 2, 3, or 4 R... A1 replace;

[0069] Preferably, ring A is selected from

[0070] Each R A1 Each of the following groups is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, -OH, methoxy, ethoxy, -O-cyclopropyl, -NH2, -NHCH3, -N(CH3)2, cyclopropyl, and cyclobutyl;

[0071] More preferably, ring A is selected from

[0072] In some specific embodiments of the present invention, preferably, the compound is:

[0073]

[0074]

[0075]

[0076] The present invention also provides a pharmaceutical composition comprising any of the above-mentioned compounds, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, excipient, or mediator.

[0077] The present invention also provides the use of any of the above-described compounds, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts, or the above-described compositions, in the preparation of medicaments for the treatment / prevention of myelin-related diseases or tumor-related diseases.

[0078] Furthermore, the myelin-related diseases mentioned include multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander disease, Perizoise-Metzbach disease (PMD), and white matter ablation. Diseases, Waller's degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease; the tumor-related diseases mentioned are glioma, colon cancer, rectal cancer, breast cancer, glioblastoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, malignant lymphoma, myeloma, brain tumor, head and neck cancer, neuroblastoma, osteosarcoma, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, ovarian cancer, choriocarcinoma.

[0079] Regarding the definition of terminology used in this invention: Unless otherwise stated, the initial definitions provided herein for groups or terms apply to that group or term throughout the specification; for terms not specifically defined herein, their meanings should be given based on the disclosure and context, as would be the meanings that a person skilled in the art would assign to them. Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0080] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0081] The term "stereoisomer" in this application refers to compounds having the same chemical structure but different spatial arrangements of atoms or groups. The compounds of this invention may contain asymmetric centers or chiral centers, thus resulting in different stereoisomers. All stereoisomeric forms of the compounds of this invention, including but not limited to conformational isomers (rotational isomers), geometrical isomers (cis / trans) isomers, blocked rotation isomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Many organic compounds exist in optically active forms, meaning they are capable of rotating the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. These stereoisomers have the same chemical structure but different stereostructures. "Stereoisomer" includes enantiomers or diastereomers. Specific stereoisomers may be enantiomers, and mixtures of isomers are generally referred to as enantiomer mixtures.

[0082] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I mentioned in the groups and compounds described in this application include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen mentioned in the groups and compounds described in this application may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, an isotope of iodine, includes 127 iodine, 129 Iodine and 131 Iodine. The "deuterated compound" of this invention refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0083] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or groups; or the replacement of lone pairs of electrons of atoms in a molecule by other atoms or groups.

[0084] "Optional" or "optionally" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group.

[0085] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by prefixes. For example, the prefixes Ca to Cb alkyl indicate any alkyl group containing "a" to "b" carbon atoms. Therefore, C1 to C6 alkyl refers to alkyl groups containing 1 to 6 carbon atoms.

[0086] "Alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with multiple carbon atoms, preferably an alkyl group with 1 to 20 carbon atoms, more preferably an alkyl group with 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. The alkyl group may optionally be further substituted by one or more substituents. The alkyl group may also be part of other groups, such as -O (C1 to C6 alkyl).

[0087] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon group having a specified number of member atoms. Ca–Cb alkylene groups refer to alkylene groups having a to b carbon atoms. Alkylene groups include branched and straight-chain hydrocarbon groups. For example, the term "propylene" can be exemplified by the following structures: Similarly, the term "dimethylbutylene" can be used, for example, by any of the following structures:

[0088] "Alkoxy" refers to a group formed by the attachment of an alkyl group to an oxygen atom. The definition of alkyl is the same as that of "alkyl" as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. The alkoxy group may optionally be further substituted by one or more substituents.

[0089] "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing one or more carbon-carbon double bonds and composed of multiple carbon atoms, preferably an alkenyl group with 2 to 20 carbon atoms, more preferably an alkenyl group with 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, propen-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl, and undecen-3-yl. The alkenyl group may optionally be further substituted by one or more substituents.

[0090] "Alynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group containing one or more carbon-carbon triple bonds and composed of multiple carbon atoms, preferably an alkynyl group with 2 to 20 carbon atoms, more preferably an alkynyl group with 2 to 6 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethylbutyn-2-yl, pentyyn-1-yl, pentyyn-2-yl, hexyn-1-yl, 1-heptyyn-1-yl, heptyyn-3-yl, heptyyn-4-yl, octyyn-3-yl, nonyn-3-yl, decanyn-4-yl, undecyn-3-yl, and dodecanyn-4-yl. The alkynyl group may optionally be further substituted by one or more substituents.

[0091] Halogens include F, Cl, Br and I.

[0092] In this invention, "halogenated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogens; preferably, the halogenated alkyl group in this invention is selected from halogenated C1 to C6 alkyl groups; for example, halogenated C1 to C4 alkyl groups refer to alkyl groups containing 1 to 4 carbon atoms in which one or more hydrogen atoms are replaced by one or more halogen atoms; other examples include monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0093] An acyl group is a structure formed by a carbonyl functional group bonded to a hydrogen atom or a substituent group, written as -COR'. In this invention, R' represents alkyl, alkenyl, or alkynyl. The definitions of alkyl, alkenyl, and alkynyl are the same as those for "alkyl," "alkenyl," and "alkynyl" as described above. Non-limiting examples of acyl groups include formyl, acetyl, propionyl, and butyryl.

[0094] In this invention, “-OR”, “-N(R)2”, etc., refer to the R group being connected to an oxygen atom or a nitrogen atom by a single bond.

[0095] In this invention, “=O” means that an oxygen atom replaces two hydrogen atoms in the molecule through a double bond.

[0096] In this invention, the oxygen atom in “-C(O)R”, “-S(O)2R”, etc., is connected to the carbon atom or sulfur atom by a double bond, and the R group is connected to the oxygen atom or sulfur atom by a single bond.

[0097] The "---" in the description of the functional groups of this invention It is used to describe the position of the substituent group.

[0098] "Aromatic ring" or "aryl" refers to an aromatic ring group having a conjugated planar ring system, which can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system. Non-limiting examples of aryl groups include phenyl and naphthyl. The aryl group may optionally be further substituted by one or more substituents.

[0099] "Aromatic heterocycle" or "aromatic heterolyl" refers to an aromatic ring group having a conjugated planar ring system and containing heteroatoms. It can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S. Non-limiting examples of heteroaryl groups include triazolyl, pyridyl, furanyl, thiophene, pyranyl, pyrroloyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, and pyrrolopyridyl. The heteroaryl group may optionally be further substituted by one or more substituents.

[0100] "Carbocyclic" or "carbocyclic group" refers to a saturated cyclic hydrocarbon group whose ring can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 20-membered (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20-membered) polycyclic system, preferably with 3 to 10 carbon atoms, more preferably with 3 to 8 carbon atoms. The term "carbocyclic" or "carbocyclic group" also includes saturated or non-aromatic partially saturated cyclic groups with multiple rings (fused, bridged, spirofused). The term "carbocyclic" includes cycloalkenyl groups, such as cyclohexenyl. Examples of monocarbonyl groups include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of carbocyclic groups in fused carbocyclic systems include dicyclohexyl, dicyclopentyl, and dicyclooctyl. The term "carbocyclic" also includes partially saturated cyclic groups formed by the fusion of an aromatic ring and a non-aromatic ring, where the linking site can be located on a non-aromatic or aromatic carbon atom; examples include 1,2,3,4-tetrahydronaphth-5-yl and 5,6,7,8-tetrahydronaphth-5-yl. The carbocyclic group may optionally be further substituted by one or more substituents.

[0101] "Heterocyclic" or "heterocyclic group" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as that of "heteroaryl" above. When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. "Heterocyclic group" or "heterocyclic" also includes a saturated ring or a non-aromatic partially saturated ring containing at least one heteroatom (fused, bridged, spirofused). Non-limiting examples of "heterocyclic group" or "heterocycle" include oxoheterobutyl, azaheterobutyl, thioheterobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexacycloyl, azaheptanyl, oxoheptanyl, thioheptanyl, triazolyl, pyridyl, piperidinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaxylyl, 1,3-dithiaalkyl, dihydrofuranyl, dithiapentylyl Cycloyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyrroleyl, tetrahydroimidazoyl, tetrahydrothiazoyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxapentyl, pyrazolinyl, dithiaalkyl, dithiamonyl, dihydrothiophenyl, pyrazolyl, imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl. The "heterocyclic group" or "heterocycle" may optionally be further substituted with one or more substituents.

[0102] When the “alkyl”, “alkoxy”, “carbocyclic”, “alkenyl”, “alkynyl”, “aromatic”, “aromatic heterocyclic”, and “heterocyclic” mentioned above are substituted, they may optionally be further substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C1-6 alkylamino, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C6-10 aryl, and C5-10 heteroaryl.

[0103] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0104] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts formed by the above-mentioned compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkyl ammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-mentioned compounds, or their stereoisomers, with an appropriate (e.g., equimolar) amount of acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, or by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium.

[0105] The term "prevention" includes suppressing and delaying the onset of disease, and includes not only prevention before the disease develops, but also prevention of disease recurrence after treatment.

[0106] The term “treatment” means to reverse, alleviate or eliminate the progression of one or more symptoms of a disease or condition to which such term is applied.

[0107] In some embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent to prepare a medicament or pharmaceutical composition for regulating cell function or treating disease. If a group of compounds is used, these compounds may be administered to the test subject simultaneously, separately, or sequentially.

[0108] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention. Detailed Implementation

[0109] Unless otherwise specified, the instruments used in this invention are conventional instruments, and the reagents used are conventional reagents.

[0110] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0111] NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Broker Avance III 400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD) as solvents and tetramethylsilane (TMS) as the internal standard.

[0112] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0113] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15mm-0.20mm, and the diameter of the thin-layer chromatography separation and purification products is 0.4mm-0.5mm.

[0114] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0115] Explanation of the abbreviations used for materials in this invention:

[0116] DMF represents N,N-dimethylformamide; HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DIPEA represents N,N-diisopropylethylamine; THF represents tetrahydrofuran; LiHMDS represents lithium bis(trimethylsilylamino)amine; Pd2(dba)3 represents tris(dibenzylacetone)dipalladium;

[0117] Xantphos represents 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene;

[0118] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0119] Example 1: The synthetic steps for the preparation of 1-((2,4-dimethylphenyl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 1) are as follows:

[0120]

[0121] Step 1: Preparation of 1'-((2,4-dimethylphenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester (compound 1B)

[0122]

[0123] 1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester p-toluenesulfonate (1.02 g, 2.4 mmol) was dissolved in THF (130 mL), followed by the addition of DIPEA (2.16 mL, 12.2 mmol). Then, 2,4-dimethylbenzenesulfonyl chloride (500 mg, 205 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours until complete. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 1B. MS (ESI) m / z 413.2 (M+H) + . 1 H NMR (400MHz, DMSO) δ7.74 (d, J = 8.1Hz, 1H), 7.41-7.21 (m, 7H), 5.04 (s, 2H), 4.51-4.29 (m, 8H), 2.53 (s, 3H), 2.36 (s, 3H).

[0124] Step 2: Preparation of 1-((2,4-dimethylphenyl)sulfonyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 1C)

[0125]

[0126] 1'-((2,4-dimethylphenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester (390 mg, 0.95 mmol) was dissolved in trifluoroacetic acid (10 mL). The reaction mixture was stirred at 60 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and then directly proceeded to the next step of the reaction. MS (ESI) m / z 279.1 (M+H) + .

[0127] Step 3: Preparation of 1-((2,4-dimethylphenyl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 1)

[0128]

[0129] 1-((2,4-dimethylphenyl)sulfonyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (210 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of tetrahydropyran-4-carboxaldehyde (129 mg, 1.13 mmol), acetic acid (91 mg, 0.86 mmol), and sodium acetate (309 mg, 3.77 mmol). The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of sodium triacetoxyborohydride (320 mg, 1.51 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. Once the reaction was complete, the reaction solution was concentrated to dryness, and compound 1 of Example 1 was prepared by high pressure. MS (ESI) m / z 377.2 (M+H) + . 1 H NMR (400MHz, DMSO) δ7.74(d,J=8.0Hz,1H),7.29(d,J=1.7Hz,1H),7.24(dd,J=8.1,1.7Hz,1H),4.27(p,J=2.4Hz,4H),3.79 (m,2H),3.63(m,4H),3.22(m,2H),2.53(s,3H),2.36(s,3H),2.32(d,J=6.8Hz,2H),1.56-1.37(m,3H),1.16-1.03(m,2H).

[0130] Example 2: Preparation of 1-((2,4-dimethylphenyl)sulfonyl)-1'-(tetrahydro-2H-pyran-4-yl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 2):

[0131]

[0132] In step 3 of Example 1, tetrahydropyranone was used instead of tetrahydropyran-4-carboxaldehyde, and compound 2 of Example 2 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 363.2 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.80 (d, J = 7.9Hz, 1H), 7.14-7.08 (m, 2H), 3.90 (s, 6H), 3.33 (m ,2H),3.24(s,4H),2.59(s,3H),2.37(s,3H),2.11(m,1H),1.58(m,2H),1.28(m,2H).

[0133] Example 3: Preparation of 5-((1'-((tetrahydro-2H-pyran-4-yl)methyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)sulfonyl)-1H-benzo[d]imidazole (compound 3):

[0134]

[0135] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 1H-benzo[d]imidazolium-5-sulfonyl chloride, and compound 3 of Example 3 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 389.2 (M+H) + . 1 H NMR (400MHz, DMSO) δ12.99(d,J=28.3Hz,1H),8.52(d,J=9.3Hz,1H),8.06(d,J=36.8Hz,1H),7.87(dd,J=43.7,8.5Hz,1H),7.66(dd,J= 21.6,8.6Hz,1H),4.24(s,4H),3.76(m,2H),3.55(s,2H),3.30(s,2H),3.19(m,2H),2.34-2.21(m,2H),1.53-1.32(m,3H),1.05(m,2H).

[0136] Example 4: Preparation of 1-((4-(difluoromethoxy)phenyl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 4):

[0137]

[0138] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 4-(difluoromethoxy)benzenesulfonyl chloride, and compound 4 of Example 4 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 415.1 (M+H) + . 1 H NMR (400MHz, DMSO) δ7.94-7.88(m,2H),7.45(d,J=8.9Hz,2H),4.25(m,4H),3.77(m,2H),3. 56(m,4H),3.30(s,1H),3.21(m,2H),2.27(d,J=6.8Hz,2H),1.54-1.35(m,3H),1.07(m,2H).

[0139] Example 5: Preparation of 1-((4-(difluoromethoxy)phenyl)sulfonyl)-1'-(tetrahydro-2H-pyran-4-yl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 5):

[0140]

[0141] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 4-(difluoromethoxy)benzenesulfonyl chloride, and in step 3, tetrahydropyranone was replaced with tetrahydropyran-4-carboxaldehyde. Compound 5 of Example 5 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 401.1 (M+H) + . 1 H NMR(400MHz,DMSO)δ7.97-7.63(m,2H),7.50-7.27(m,3H),4.27(m,4H),3.75(m,2H),3 .55(t,J=2.4Hz,4H),3.29-3.20(m,2H),2.25(m,1H),1.59-1.47(m,2H),1.07(m,2H).

[0142] Example 6: Preparation of 1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'-H-[3,3'-diazasulfoxide]-1(4H)-yl)-3-hydroxy-2-phenylpropane-1-one (compound 6):

[0143]

[0144] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 4-(difluoromethoxy)benzenesulfonyl chloride, and in step 3, tetrahydropyran-4-carboxaldehyde was replaced with 4-methylcyclohexanone. Compound 6 of Example 6 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 413.2 (M+H) + . 1 H NMR(400MHz,DMSO)δ7.95-7.63(m,2H),7.49-7.26(m,3H),4.27(m,4H),3.54-3 .44(m,4H),2.23(s,1H),1.43-1.31(m,3H),1.22(m,6H),0.81(d,J=6.5Hz,3H).

[0145] Example 7: Preparation of 1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 7):

[0146]

[0147] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 2-methyl-6-(trifluoromethyl)pyridine-3-sulfonyl chloride, and compound 7 of Example 7 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 432.2 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.49(d,J=8.1Hz,1H),7.99(d,J=8.1Hz,1H),4.47(m,4H),3.79(m,2H),3.6 4(m,4H),3.23(m,2H),2.84(s,3H),2.32(d,J=6.7Hz,2H),1.57-1.39(m,3H),1.18-1.03(m,2H).

[0148] Example 8: Preparation of 1-((5-chloro-2-methoxy-6-methylpyridin-3-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 8):

[0149]

[0150] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 5-chloro-2-methoxy-6-methylpyridine-3-sulfonyl chloride, and compound 8 of Example 8 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 428.1 (M+H) + . 1 H NMR(400MHz,DMSO)δ7.96(s,1H),4.38(m,4H),3.93(s,3H),3.72(m,2H),3.55(m,4H),3.15(m ,2H),2.49(s,3H),2.24(d,J=6.8Hz,2H),1.49-1.41(m,2H),1.36(m,1H),1.09-0.97(m,2H).

[0151] Example 9: Preparation of 1-(1'-((4-(difluoromethoxy)phenyl)sulfonyl)-1',4'-dihydro-2H,2'-H-[3,3'-diazasulfoxide]-1(4H)-yl)-3-hydroxy-2-phenylpropane-1-one (compound 9):

[0152]

[0153] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 2-methoxy-6-methylpyridine-3-sulfonyl chloride, and compound 9 of Example 9 was obtained by the same preparation method as in Example 1.

[0154] MS(ESI) m / z 394.2(M+H) + . 1 H NMR (400MHz, DMSO) δ8.01(d,J=7.7Hz,1H),7.07(d,J=7.7Hz,1H),4.39(m,4H),3.98(s,3H),3.79(m,2H),3 .62(m,4H),3.22(m,2H),2.50(s,3H),2.31(d,J=6.8Hz,2H),1.52(m,2H),1.43(m,1H),1.17-1.02(m,2H).

[0155] Example 10: Preparation of 1-(2-(1H-imidazol-1-yl)ethyl)-1'-((2,4-dimethylphenyl)sulfonyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 10):

[0156]

[0157] Step 1: Preparation of 2-(1'-((2,4-dimethylphenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)ethane-1-ol (compound 10A)

[0158]

[0159] 1-((2,4-dimethylphenyl)sulfonyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (720 mg, 2.60 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of triethylamine (1.8 mL, 13.0 mmol) and 2-bromoethanol (390 mg, 3.12 mmol). The reaction mixture was heated to 70 °C and stirred for 1 hour until complete. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 10A. MS (ESI) m / z

[0160] 323.1(M+H) + . 1 H NMR (400MHz, CDCl3) δ7.82 (d, J = 8.0Hz, 1H), 7.17-7.10 (m, 2H), 4.98 (s, 2H), 4.39 ( d,J=27.8Hz,6H),3.96-3.90(m,2H),3.38-3.30(m,2H),2.60(s,3H),2.39(s,3H).

[0161] Step 2: Preparation of 2-(1'-((2,4-dimethylphenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)ethyl methanesulfonate (compound 10B)

[0162]

[0163] 2-(1'-((2,4-dimethylphenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)ethane-1-ol (261 mg, 0.81 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (164 mg, 1.62 mmol), and then the addition of methanesulfonyl chloride (139 mg, 1.21 mmol) was slow and repeated dropwise under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours until complete. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure and directly proceeded to the next step of the reaction. MS (ESI) m / z 401.1 (M+H) + .

[0164] Step 3: Preparation of 1-(2-(1H-imidazol-1-yl)ethyl)-1'-((2,4-dimethylphenyl)sulfonyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 10)

[0165]

[0166] 2-(1'-((2,4-dimethylphenyl)sulfonyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)ethyl methanesulfonate (324 mg, 0.81 mmol) was dissolved in 1H-imidazolium (661 mg, 9.71 mmol). The reaction mixture was heated to 55 °C and stirred for 16 hours until complete. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and compound 10 of Example 10 was prepared by high pressure. MS (ESI) m / z 373.2 (M+H) + . 1H NMR (400MHz, DMSO) δ7.73(d,J=8.0Hz,1H),7.56(s,1H),7.29(d,J=1.7Hz,1H),7.24(m,1H),7.12(d,J=1.2Hz,1H ),6.84(s,1H),4.26(m,4H),3.88(t,J=6.0Hz,2H),3.63(m,4H),2.75(t,J=6.1Hz,2H),2.53(s,3H),2.36(s,3H).

[0167] Example 11: Preparation of 1-((2-methoxy-6-methylpyridin-3-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-3,3'-diazacyclobutane (compound 11):

[0168]

[0169]

[0170] Step 1: Preparation of tert-butyl[3,3'-diazacyclobutane]-1-carboxylic acid ester (compound 11B)

[0171]

[0172] 1-Benzyl-1'-(tert-butyl)-2H,2'H-[3,3'-diazamethylene]-1,1'(4H,4'H)-dicarboxylic acid ester (1.6 g, 4.65 mmol) was dissolved in methanol (30 mL), and then palladium on carbon (160 mg, 10%) was added. The reaction system was stirred at room temperature under hydrogen atmosphere for 16 hours until the reaction was complete. After the reaction solution was concentrated to dryness under reduced pressure, the next reaction step was carried out directly. MS (ESI) m / z 213.2 (M+H) + . 1 H NMR (400MHz, CDCl3) δ4.00(m,2H),3.59(m,2H),3.46-3.34(m,2H),3.08(s,1H),2.94-2.67(m,2H),2.03(d,J=13.4Hz,2H),1.45-1.41(m,9H).

[0173] Step 2: Preparation of 1'-((2-methoxy-6-methylpyridin-3-yl)sulfonyl)-[3,3'-diazacyclobutane]-1-carboxylic acid tert-butyl ester (compound 11C)

[0174]

[0175] 192 mg (0.90 mmol) of tert-butyl[3,3'-diazacyclobutane]-1-carboxylic acid ester was dissolved in 10 mL of THF, followed by the addition of DIPEA (0.48 mL, 2.71 mmol). Then, 2-methoxy-6-methylpyridine-3-sulfonyl chloride (200 mg, 0.90 mmol) was slowly added. The reaction mixture was stirred at room temperature for 2 hours until complete. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 11C. MS (ESI) m / z 398.2 (M+H) + .

[0176] Step 3: Preparation of 1-((2-methoxy-6-methylpyridin-3-yl)sulfonyl)-3,3'-diazacyclobutane (compound 11C)

[0177]

[0178] 1'-((2-methoxy-6-methylpyridin-3-yl)sulfonyl)-[3,3'-diazacyclobutane]-1-carboxylic acid tert-butyl ester (225 mg, 0.57 mmol) was dissolved in dichloromethane (10 mL), and then trifluoroacetic acid (2 mL) was added. The reaction system was stirred at room temperature for 1 hour until the reaction was complete. After the reaction solution was concentrated to dryness under reduced pressure, the next step of the reaction was carried out directly. MS (ESI) m / z 298.1 (M+H) + . 1 H NMR(400MHz, CDCl3)δ8.01(d,J=7.7Hz,1H),6.84(d,J=7.7Hz,1H),4.10-4.04(m,5 H),3.71(dd,J=7.9,6.0Hz,4H),3.36-3.26(m,2H),2.99-2.77(m,2H),2.52(s,4H).

[0179] Step 4: Preparation of 1-((2-methoxy-6-methylpyridin-3-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-3,3'-diazacyclobutane (compound 11)

[0180]

[0181] 1-((2-methoxy-6-methylpyridin-3-yl)sulfonyl)-3,3'-diazacyclobutane (168 mg, 0.57 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of tetrahydropyran-4-carboxaldehyde (98 mg, 0.85 mmol), acetic acid (68 mg, 1.14 mmol), and sodium acetate (233 mg, 2.84 mmol). The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of sodium triacetoxyborohydride (241 mg, 1.14 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and compound 11 of Example 11 was prepared by high pressure. MS (ESI) m / z 396.2 (M+H) + . 1 H NMR(400MHz,DMSO)δ7.99(d,J=7.8Hz,1H),7.06(d,J=7.7Hz,1H),3.98(s,3H),3 .91(t,J=8.2Hz,2H),3.79(m,2H),3.61(dd,J=8.0,6.3Hz,2H),3.22(m,2H),3.0 8(t,J=7.3Hz,2H),2.77-2.69(m,1H),2.61(dd,J=7.1,5.6Hz,2H),2.50(s,3H), 2.43(m,1H),2.13(d,J=6.8Hz,2H),1.53-1.44(m,2H),1.36(m,1H),1.06(m,2H).

[0182] Example 12: Preparation of 1-((5-chloro-2-methoxy-6-methylpyridin-3-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-3,3'-diazacyclobutane (compound 12):

[0183]

[0184] In step 2 of Example 11, 2-methoxy-6-methylpyridine-3-sulfonyl chloride was substituted with 5-chloro-2-methoxy-6-methylpyridine-3-sulfonyl chloride, and compound 12 of Example 12 was obtained using the same preparation method as in Example 11. MS (ESI) m / z 430.2 (M+H) + . 1H NMR (400MHz, DMSO) δ8.01(s,1H),3.98(d,J=15.1Hz,5H),3.79(m,2H),3.66(dd,J=8.0,6.2Hz,2H),3.27-3.19(m,2H),3.11(t,J=7.3Hz,2H ),2.74(q,J=7.1Hz,1H),2.65(t,J=6.3Hz,2H),2.56(s,3H),2.46(q,J=6.2Hz,1H),2.15(d,J=6.8Hz,2H),1.51-1.32(m,3H),1.06(m,2H).

[0185] Example 13: Preparation of 1-((2-methoxy-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 13):

[0186]

[0187] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 2-methoxy-6-(trifluoromethyl)pyridine-3-sulfonyl chloride, and compound 13 of Example 13 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 448.1 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.33(d,J=7.7Hz,1H),7.61(d,J=7.7Hz,1H),4.44(t,J=2.4Hz,4H),4.00(s,3H),3 .72(m,2H),3.57(t,J=2.5Hz,4H),3.16(m,2H),2.25(d,J=6.7Hz,2H),1.53-1.30(m,3H),1.03(m,2H).

[0188] Example 14: Preparation of 4-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-methylene)-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidine (compound 14):

[0189]

[0190] Step 1: Preparation of 4-(1-(tert-butoxycarbonyl)azacyclobutane-3-methylene)piperidine-1-carboxylic acid benzyl ester (compound 14B)

[0191]

[0192] 3-(benzo[d]thiazol-2-ylsulfonyl)azacyclobutane-1-carboxylic acid tert-butyl ester (1.0 g, 2.82 mmol) and 4-oxopiperidin-1-carboxylic acid benzyl ester (1.1 g, 4.51 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). The reaction mixture was cooled to 0 °C, and LiHMDS (4.5 mL, 1 N, 4.51 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature (0 °C) for 2 hours until the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 14B. MS (ESI) m / z 273.2 (M+H-100) +

[0193] Step 2: Preparation of 4-(azacyclobutane-3-methylene)piperidine-1-carboxylic acid benzyl ester p-toluenesulfonate (compound 14C)

[0194]

[0195] 4-(1-(tert-butoxycarbonyl)azacyclobutane-3-methylene)piperidine-1-carboxylic acid benzyl ester (1.3 g, 3.62 mmol) and p-toluenesulfonic acid (1.3 g, 7.24 mmol) were dissolved in ethanol (20 mL). The reaction mixture was heated to 80 °C and stirred for 2 hours until the reaction was complete. The reaction solution was then concentrated to dryness under reduced pressure and directly proceeded to the next step of the reaction. MS (ESI) m / z 273.2 (M+H) + . 1 H NMR(400MHz,MeOD)δ7.74-7.67(m,2H),7.38-7.28(m,5H),7.23(d,J=8.0Hz,2H),5 .12(s,2H),4.68(s,4H),3.48(t,J=5.8Hz,4H),2.35(s,3H),2.05(t,J=5.8Hz,4H).

[0196] Step 3: Preparation of 4-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-methylene)piperidine-1-carboxylic acid benzyl ester (compound 14D)

[0197]

[0198] 4-(azacyclobutane-3-methylene)piperidine-1-carboxylic acid benzyl ester p-toluenesulfonate (222 mg, 0.52 mmol) was dissolved in THF (130 mL), and then DIPEA (0.26 mL, 1.56 mmol) was added. Subsequently, 2,4-dimethylbenzenesulfonyl chloride (110 mg, 0.52 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 2 hours until complete. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 14D. MS (ESI) m / z 441.2 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.85 (d, J = 7.9Hz, 1H), 7.39-7.26 (m, 5H), 7.16-7.07 (m, 2H), 5. 13(s,2H),4.43(s,4H),3.46(t,J=5.9Hz,4H),2.62(s,3H),2.37(s,3H),1.99(s,4H).

[0199] Step 4: Preparation of 4-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-methylene)piperidine (compound 14E)

[0200]

[0201] 175 mg (0.40 mmol) of benzyl 4-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-methylene)piperidine-1-carboxylic acid was dissolved in 10 mL of trifluoroacetic acid. The reaction mixture was stirred at 60 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and then directly proceeded to the next step of the reaction. MS (ESI) m / z 307.1 (M+H) + .

[0202] Step 5: Preparation of 4-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-methylene)-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidine (compound 14)

[0203]

[0204] 4-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-methylene)piperidine (122 mg, 0.40 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of tetrahydropyran-4-carboxaldehyde (68 mg, 0.60 mmol), acetic acid (48 mg, 0.80 mmol), and sodium acetate (16 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 1 hour, followed by the addition of sodium triacetoxyborohydride (170 mg, 0.80 mmol). After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and compound 14 of Example 14 was prepared by high pressure. MS (ESI) m / z 405.2 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.85 (d, J=8.0Hz, 1H), 7.16-7.06 (m, 2H), 4.41 (s, 4H), 3.95 (dd, J=11.4, 4.3Hz, 2H), 3.37 (t, J= 11.7Hz,2H),2.62(s,3H),2.36(d,J=6.1Hz,7H),2.18(s,2H),2.01(t,J=5.7Hz,4H),1.78-1.60(m,3H),1.25(m,2H).

[0205] Example 15: Preparation of 1-((6-chloro-2-methylpyridin-3-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 15):

[0206]

[0207] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 6-chloro-2-methylpyridine-3-sulfonyl chloride, and compound 15 of Example 15 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 398.1 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.23(d,J=8.3Hz,1H),7.62(d,J=8.3Hz,1H),4.40(p,J=2.4Hz,4H),3.79(m,2H),3 .64(p,J=2.4Hz,4H),3.23(m,2H),2.74(s,3H),2.32(d,J=6.7Hz,2H),1.57-1.37(m,3H),1.10(m,2H).

[0208] Example 16: Preparation of 1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 16):

[0209]

[0210] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 2,3-dihydrobenzo[b][1,4]dioxane-6-sulfonyl chloride, and compound 16 of Example 16 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 407.2 (M+H) + . 1 H NMR (400MHz, DMSO) δ7.32-7.25(m,2H),7.14(d,J=8.4Hz,1H),4.36(m,4H),4.22(p,J=2.3Hz,4H),3. 78(m,2H),3.57(t,J=2.5Hz,4H),3.21(m,2H),2.28(d,J=6.8Hz,2H),1.55-1.35(m,3H),1.08(m,2H).

[0211] Example 17: Preparation of 1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 17):

[0212]

[0213] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-sulfonyl chloride, and compound 17 of Example 17 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 421.1 (M+H) + . 1 H NMR (400MHz, DMSO) δ7.46 (s, 1H), 4.40 (q, J = 2.4Hz, 4H), 4.08 (s, 3H), 3.72 (m, 2H) ,3.30(s,4H),3.16(m,2H),2.24(d,J=6.7Hz,2H),1.50-1.30(m,3H),1.03(m,2H).

[0214] Example 18: Preparation of 1-((6-methoxy-2-methylpyridin-3-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 18):

[0215]

[0216] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 6-methoxy-2-methylpyridine-3-sulfonyl chloride, and compound 18 of Example 18 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 394.2 (M+H) + . 1 HNMR(400MHz,DMSO)δ8.00(d,J=8.8Hz,1H),6.79(d,J=8.7Hz,1H),4.33-4.20(m,8H),3.87(s,3H ),3.74(m,2H),3.17(m,2H),2.78(d,J=6.9Hz,2H),2.63(s,3H),1.68-1.42(m,3H),1.09(m,2H).

[0217] Example 19: Preparation of 4-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-methylene)-N-((tetrahydro-2H-pyran-4-yl)methyl)cyclohexane-1-amine (compound 19):

[0218]

[0219] In step 1 of Example 14, benzyl (4-oxocyclohexyl)carbamate was used instead of benzyl 4-oxoperidin-1-carboxylate, and compound 19 of Example 19 was obtained using the same preparation method as in Example 14. MS (ESI) m / z 419.2 (M+H) + . 1 H NMR (400MHz, CDCl3) δ7.84(m,1H),7.11(m,2H),4.48-4.31(m,4H),3.95(m,2H),3.37(m,2H),2.76-2. 44(m,7H),2.37(d,J=3.9Hz,3H),2.10(m,2H),1.90(m,3H),1.64(d,J=13.0Hz,4H),1.32-1.09(m,4H).

[0220] Example 20: Preparation of 3-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-methylene)-1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine (compound 20):

[0221]

[0222] In step 1 of Example 14, 3-oxopyrrolidine-1-carboxylic acid benzyl ester was substituted for 4-oxopyridine-1-carboxylic acid benzyl ester, and compound 20 of Example 20 was obtained using the same preparation method as in Example 14. MS (ESI) m / z 391.2 (M+H) + . 1 HNMR (400MHz, DMSO) δ7.74(d,J=8.0Hz,1H),7.31-7.21(m,2H),4.28(t,J=2.5Hz,4H),3.85-3.74(m,2H),3. 30-3.19(m,3H),2.90(s,2H),2.54(s,4H),2.36(s,3H),2.27-2.11(m,4H),1.67-1.52(m,3H),1.08(m,2H).

[0223] Example 21: Preparation of 3-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-methylene)-N-((tetrahydro-2H-pyran-4-yl)methyl)cyclobutane-1-amine (compound 21):

[0224]

[0225] In step 1 of Example 14, benzyl (3-oxocyclobutyl)carbamate was used instead of benzyl 4-oxopiperidin-1-carboxylate, and compound 21 of Example 21 was obtained using the same preparation method as in Example 14. MS (ESI) m / z 391.2 (M+H) + . 1 H NMR (400MHz, DMSO) δ7.73(d,J=8.1Hz,1H),7.33-7.19(m,2H),4.24(s,4H),3.86-3.74(m,2H),3.26-3.12(m,4H ),2.67(d,J=14.9Hz,2H),2.53(s,3H),2.36(s,3H),2.25(t,J=9.5Hz,4H),1.57(d,J=13.8Hz,3H),1.10(m,2H).

[0226] Example 22: Preparation of 1-((5-chloro-6-methoxypyridin-3-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 22):

[0227]

[0228] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 5-chloro-6-methoxypyridine-3-sulfonyl chloride, and compound 22 of Example 22 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 414.1 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.60(d,J=2.2Hz,1H),8.30(d,J=2.2Hz,1H),4.33(t,J=2.5Hz,4H),4.07(s,3H) ,3.78(m,2H),3.62-3.53(m,4H),3.21(m,2H),2.28(d,J=6.8Hz,2H),1.56-1.36(m,3H),1.10(m,2H).

[0229] Example 23: Preparation of 7-fluoro-6-((1'-((tetrahydro-2H-pyran-4-yl)methyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)sulfonyl)quinoline (compound 23):

[0230]

[0231] In step 1 of Example 1, 7-fluoroquinoline-6-sulfonyl chloride was used instead of 2,4-dimethylbenzenesulfonyl chloride, and compound 23 of Example 23 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 418.2 (M+H) + . 1 H NMR (400MHz, DMSO) δ9.10(m,1H),8.71(m,2H),8.08(d,J=11.7Hz,1H),7.70(m,1H),4.46(t,J=2.5Hz ,4H),3.77(m,2H),3.60(s,4H),3.20(m,2H),2.28(d,J=6.7Hz,2H),1.54-1.34(m,3H),1.07(m,2H).

[0232] Example 24: Preparation of 1-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 24):

[0233]

[0234] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 2-methoxy-5-methylpyridine-3-sulfonyl chloride, and compound 24 of Example 24 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 394.2 (M+H) + . 1 HNMR(400MHz, CDCl3)δ8.15(d,J=2.3Hz,1H),7.97(d,J=2.3Hz,1H),4.51(m,4H),4.05(s,3H),3.94(m,2H) ,3.79-3.69(m,4H),3.35(m,2H),2.43(d,J=6.7Hz,2H),2.31(s,3H),1.65-1.49(m,3H),1.33-1.20(m,2H).

[0235] Example 25: Preparation of 1-((1,4-dimethyl-1H-pyrazol-5-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 25):

[0236]

[0237] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 1,4-dimethyl-1H-pyrazole-5-sulfonyl chloride, and compound 25 of Example 25 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 367.2 (M+H) + . 1 HNMR (400MHz, CDCl3) δ7.35 (s, 1H), 4.44-4.32 (m, 4H), 4.07 (s, 3H), 3.94 (dd, J = 11.7, 4.4Hz, 2H), 3. 76(t,J=2.7Hz,4H),3.35(m,2H),2.44(d,J=6.7Hz,2H),2.26(s,3H),1.65-1.49(m,3H),1.27(m,2H).

[0238] Example 26: Preparation of 1-((1-(4-methylpyridin-2-yl)-1H-pyrazol-4-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 26):

[0239]

[0240] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 1-(4-methylpyridin-2-yl)-1H-pyrazole-4-sulfonyl chloride, and compound 26 of Example 26 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 430.2 (M+H) + . 1 H NMR (400MHz, DMSO) δ9.04(s,1H),8.34(d,J=5.0Hz,1H),8.25(s,1H),7.80(s,1H),7.30-7.25(m,1H),4.25(t,J=2.5Hz,4 H),3.69(m,2H),3.50(t,J=2.5Hz,4H),3.13(m,2H),2.39(s,3H),2.19(d,J=6.7Hz,2H),1.46-1.27(m,3H),0.99(m,2H).

[0241] Example 27: Preparation of 2-((1'-((tetrahydro-2H-pyran-4-yl)methyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)sulfonyl)quinoline (compound 27):

[0242]

[0243] In step 1 of Example 1, quinoline-2-sulfonyl chloride was substituted for 2,4-dimethylbenzenesulfonyl chloride, and compound 27 of Example 27 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 400.2 (M+H) + . 1HNMR (400MHz, DMSO) δ9.24-9.18(m,1H),9.05(d,J=1.8Hz,1H),8.32(d,J=8.1Hz,1H),8.20(d,J=8.4Hz,1H),8.03(t,J=7.5Hz,1H),7.83(t,J=7.5Hz, 1H),4.39(s,4H),3.86-3.70(m,2H),3.52(s,4H),3.19(t,J=11.0Hz,3H),2 .23(d,J=6.7Hz,2H), 1.46(d,J=12.9Hz,2H), 1.06(dd,J=24.3,4.0Hz,2H).

[0244] Example 28: Preparation of 1-((tetrahydro-2H-pyran-4-yl)methyl)-1'-((5-(trifluoromethoxy)pyridin-2-yl)sulfonyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 28):

[0245]

[0246] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 5-(trifluoromethoxy)pyridine-2-sulfonyl chloride, and compound 28 of Example 28 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 434.1 (M+H) + . 1 HNMR (400MHz, DMSO) δ8.95(d,J=2.4Hz,1H),8.23(d,J=8.5Hz,1H),8.14(d,J=8.7Hz,1H),4.52(s,4H),3.78(dd, J=10.7,3.3Hz,2H),3.61(s,4H),3.20(d,J=10.8Hz,2H),2.34-2.29(m,2H),1.51(d,J=13.7Hz,3H),1.10(m,2H).

[0247] Example 29: Preparation of 1-((4-(difluoromethoxy)-2,6-difluorophenyl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 29):

[0248]

[0249] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 4-(difluoromethoxy)-2,6-difluorobenzenesulfonyl chloride, and compound 29 of Example 29 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 451.1 (M+H) + . 1 H NMR (400MHz, DMSO) δ7.68-7.30(m,3H),4.42(t,J=2.5Hz,4H),3.79(m,2H),3.62(t,J= 2.5Hz,4H),3.22(m,2H),2.30(d,J=6.8Hz,2H),1.56-1.36(m,3H),1.17-1.02(m,2H).

[0250] Example 30: Preparation of 3-fluoro-5-((1'-((tetrahydro-2H-pyran-4-yl)methyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)sulfonyl)benzonitrile (compound 30):

[0251]

[0252] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 3-cyano-5-fluorobenzenesulfonyl chloride, and compound 30 of Example 30 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 392.1 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.32(d,J=9.3Hz,1H),8.19(s,1H),8.08(d,J=7.7Hz,1H),4.38(s,4H),3.78(d,J=14.2Hz,2H) ,3.62(s,4H),3.23(d,J=10.6Hz,2H),2.32(d,J=6.3Hz,2H),1.50(d,J=13.0Hz,3H),1.08(dd,J=11.9,3.8Hz,2H).

[0253] Example 31: Preparation of 1-((3-fluoro-2-methoxypyridin-4-yl)sulfonyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 31):

[0254]

[0255] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 3-fluoro-2-methoxypyridine-4-sulfonyl chloride, and compound 31 of Example 31 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 398.2 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.24(d,J=5.2Hz,1H),7.29(dd,J=5.2,3.9Hz,1H),4.44(m,4H),4.03(s,3H),3 .78(m,2H),3.61(m,4H),3.22(m,2H),2.30(d,J=6.8Hz,2H),1.57-1.36(m,3H),1.16-1.03(m,2H).

[0256] Example 32: Preparation of 2-fluoro-3-((1'-((tetrahydro-2H-pyran-4-yl)methyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-yl)sulfonyl)benzonitrile (compound 32):

[0257]

[0258] In step 1 of Example 1, 2,4-dimethylbenzenesulfonyl chloride was replaced with 3-cyano-2-fluorobenzenesulfonyl chloride, and compound 32 of Example 32 was obtained using the same preparation method as in Example 1. MS (ESI) m / z 392.1 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.32(m,1H),8.14(m,1H),7.66(t,J=7.9Hz,1H),4.43(m,4H),3.78(m, 2H),3.60(m,4H),3.22(m,2H),2.30(d,J=6.7Hz,2H),1.56-1.36(m,3H),1.15-1.02(m,2H).

[0259] Example 33: Preparation of 3-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine (compound 33):

[0260]

[0261] 3-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-methylene)-1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine (50 mg, 0.13 mmol) was dissolved in methanol (10 mL), and then palladium hydroxide was added. The reaction system was stirred at room temperature for 6 hours. After the reaction was complete, it was filtered through diatomaceous earth, the filter cake was washed with methanol, the reaction solution was concentrated to dryness, and compound 33 of Example 33 was prepared by high pressure. MS (ESI) m / z 393.2 (M+H) + . 1 H NMR (400MHz, DMSO) δ7.70 (d, J = 8.0Hz, 1H), 7.30-7.22 (m, 2H), 3.84-3.69 (m, 4H), 3.40 (m, 2H), 3.25 (m, 2H), 2.52(s,3H),2.48-2.25(m,7H),2.22-2.02(m,4H),1.85-1.72(m,1H),1.64-1.52(m,3H),1.24-1.00(m,3H).

[0262] Example 34: Preparation of 4-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)cyclohexane-1-amine (compound 34):

[0263]

[0264] In the steps of Example 33, 3-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-methylene)-N-((tetrahydro-2H-pyran-4-yl)methyl)cyclohexane-1-amine was substituted for 3-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine, and compound 34 of Example 34 was obtained by the same preparation method as in Example 33. MS (ESI) m / z 421.2 (M+H) + . 1 H NMR (400MHz, DMSO) δ7.70(d,J=8.0Hz,1H),7.30-7.21(m,2H),3.81(m,2H),3.70(t,J=7.9Hz,2H),3.49-3.41(m,2H),3.24(m,3H),2.52(s,3H ),2.41-2.31(m,5H),2.26-2.12(m,2H),1.82(dd,J=13.0,3.7Hz,2H),1.63-1.46(m,5H),1.18-1.04(m,3H),0.94-0.82(m,2H),0.74(m,2H).

[0265] Example 35: Preparation of 4-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidine (compound 35):

[0266]

[0267] In the steps of Example 33, 3-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-methylene)-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidine was substituted for 3-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine, and compound 35 of Example 35 was obtained using the same preparation method as in Example 33. MS (ESI) m / z 407.2 (M+H) + . 1 H NMR (400MHz, DMSO) δ7.71(d,J=8.0Hz,1H),7.31-7.20(m,2H),3.80(m,2H),3.72(t,J=7.9Hz,2H),3.45(dd,J=7.8,6.4Hz,2H),3.25(m,2 H),2.74(m,2H),2.53(s,3H),2.36(s,3H),2.24(m,1H),2.06(d,J=7.2Hz,2H),1.78-1.63(m,3H),1.59-1.42(m,4H),1.25-0.86(m,5H).

[0268] Example 36: Preparation of 3-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)cyclobutane-1-amine (compound 36):

[0269]

[0270] In the steps of Example 33, 3-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-methylene)-N-((tetrahydro-2H-pyran-4-yl)methyl)cyclobutane-1-amine was used to replace 3-(1-((2,4-dimethylphenyl)sulfonyl)azacyclobutane-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolidine, and compound 36 of Example 36 was obtained by the same preparation method as in Example 33. MS (ESI) m / z 393.2 (M+H) + . 1H NMR (400MHz, DMSO) δ7.70(dd,J=8.0,1.9Hz,1H),7.31-7.21(m,2H),3.86-3.74(m,3H),3.70(t,J=8.0Hz,1H),3.41(dd,J=7.6,6.0Hz,1H),3.30-3 .19(m,4H),2.99(m,1H),2.63-2.51(m,4H),2.35(s,3H),2.25-2.19(m,2 H),2.12-1.90(m,2H),1.70(m,2H),1.62-1.44(m,3H),1.27-1.05(m,3H).

[0271] Example 37: Preparation of 1-(4-cyclopropylphenyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 37):

[0272]

[0273] Step 1: Preparation of 1'-(4-cyclopropylphenyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester (compound 37A)

[0274]

[0275] 1-Bromo-4-cyclopropylbenzene (100 mg, 0.51 mmol) and benzyl 1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid (243 mg, 0.61 mmol) were dissolved in 1,4-dioxane (50 mL), followed by the addition of cesium carbonate (499 mg, 1.53 mmol), Pd2(dba)3 (47 mg, 0.05 mmol), and XantPhos (59 mg, 0.10 mmol). The reaction mixture was heated to 100 °C under nitrogen and stirred for 16 hours until complete. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 37A. MS (ESI) m / z 361.2 (M+H) +

[0276] Step 2: Preparation of 1-(4-cyclopropylphenyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 37B)

[0277]

[0278] 1'-(4-cyclopropylphenyl)-1',4'-dihydro-2H,2'H-[3,3'-diazamethylene]-1(4H)-carboxylic acid benzyl ester (270 mg, 0.75 mmol) was dissolved in trifluoroacetic acid (10 mL). The reaction mixture was stirred at 60 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure and then directly proceeded to the next step of the reaction. MS (ESI) m / z 227.2 (M+H) + .

[0279] Step 3: Preparation of 1-(4-cyclopropylphenyl)-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 37)

[0280]

[0281] 1-(4-cyclopropylphenyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (170 mg, 0.75 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of tetrahydropyran-4-carboxaldehyde (86 mg, 0.75 mmol) and acetic acid (135 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 1 hour, after which sodium triacetoxyborohydride (477 mg, 2.25 mmol) was added. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. Once the reaction was complete, the reaction solution was concentrated to dryness, and compound 37 of Example 37 was prepared by high pressure. MS (ESI) m / z 325.2 (M+H) + . 1 H NMR (400MHz, DMSO) δ6.95-6.88(m,2H),6.40-6.32(m,2H),4.25(p,J=2.2Hz,4H),3.85-3.77(m,4H),3.25(m,4H),2 .45(s,1H),1.79(m,1H),1.62-1.47(m,3H),1.24(s,1H),1.20-1.08(m,2H),0.87-0.78(m,2H),0.56-0.47(m,2H).

[0282] Example 38: Preparation of 1-((tetrahydro-2H-pyran-4-yl)methyl)-1'-(4-(trifluoromethyl)phenyl)-1,1',4,4'-tetrahydro-2H,2'H-3,3'-diazamethylene (compound 38):

[0283]

[0284] In step 1 of Example 37, 1-bromo-4-(trifluoromethyl)benzene was substituted for 1-bromo-4-cyclopropylbenzene, and compound 38 of Example 38 was obtained using the same preparation method as in Example 37. MS(ESI) m / z

[0285] 353.2(M+H) + . 1 H NMR (400MHz, DMSO) δ7.41(d,J=8.5Hz,2H),6.48(d,J=8.5Hz,2H),4.33(q,J=2.3Hz,4H),3.74(m,2H) ,3.70-3.62(m,4H),3.18(m,2H),2.31(d,J=6.7Hz,2H),1.50(m,2H),1.42(m,1H),1.13-0.99(m,2H).

[0286] The effects of the present invention are illustrated below through experimental examples:

[0287] Experimental example: Detecting the inhibitory activity of the compound on the spheroidization growth of HT-29 cells.

[0288] Cell plating:

[0289] 1) After digesting and centrifuging HT-29 cells (Nanjing Kebai, CBP60011, RPMI1640 + 10% FBS) in the logarithmic growth phase, gently resuspend them and mix by pipetting and counting.

[0290] 2) Dilute cells to 1.1 × 10^4 cells / mL using spheroidization growth medium (containing 2% B-27 supplement (Gibco, A3582801), 20 ng / mL epidermal growth factor (EGF) (PeproTech, AF-100-15-100UG), 10 ng / mL basic fibroblast growth factor (bFGF) (MCE, HY-P7331), 5 μg / mL insulin (Absin, abs42225219), and 1% penicillin / streptomycin in RPMI1640 (Boster, PYG0122)). Add 90 μL of the cell suspension to each well of a 384-well black transparent-bottomed microplate (cell density 1 × 10^3 cells / well). Add 100 μL of 1×PBS to the edge wells to prevent evaporation. Compound preparation:

[0291] 1) First, dilute the compound stock solution from 10 mM to 1000, 250, 62.5, 15.6, 3.9, 0.98, 0.24, 0.06, 0.015, and 0.004 μM, with DMSO content of 100%.

[0292] 2) After thorough mixing, take 1 μL with an electric pipette and add it to 99 μL of pelleting medium. At this point, the medium is diluted 100 times, and the DMSO content is 1%.

[0293] 3) After thoroughly mixing the diluted compounds, set up three replicates for each concentration of compound, and add 10 μL of each compound to the cell culture plate to make the final concentration of the compound in the wells: 1000, 250, 62.5, 15.6, 3.9, 0.98, 0.24, 0.06, 0.015, 0.004 nM. At this point, there is a total of 100 μL of cell culture in each well of the cell culture plate, and the DMSO content is 0.1%.

[0294] 4) After incubating the cells in a 37℃, 5% CO2 cell culture incubator for 4 days, CTG detection was performed. CTG detection:

[0295] 1) Remove the cell culture plate from the incubator and allow it to equilibrate to room temperature. Aspirate 80 μL of culture medium from each well and add 50 μL of CTG reagent (CellCounting-Lite2.0, Vazyme, DD1101-02) that has been equilibrated to room temperature into each well.

[0296] 2) Shake the mixture in a shaker for 15 minutes, then let it stand at room temperature for 10 minutes to stabilize the light emission signal.

[0297] 3) Use a multi-functional microplate reader for detection.

[0298] Data Analysis:

[0299] 1) Calculate cell viability: Cell viability% = As / Ac × 100%. As: Test wells (containing cell culture medium, CTG, and test compound), Ac: Control wells (containing cell culture medium, CTG, and no test compound).

[0300] 2) Using the log value of compound concentration as the X-axis and cell viability (%) as the Y-axis, a dose-response curve was fitted to obtain the IC50 of each compound on the inhibitory activity of cell spheroidization. 50 value.

[0301] Table 1. Inhibitory activity of the compounds of this invention on spheroidal growth of HT-29 cells.

[0302] Example <![CDATA[IC 50 (nM)]]> Example <![CDATA[IC 50 (nM)]]> 1 0.65 2 2.23 3 / 4 25.25 5 38.91 6 18.15 7 0.77 8 0.01 9 0.07 10 0.30 11 0.31 12 0.02 13 0.13 14 0.14 15 1.00 16 2.69 17 0.42 18 0.55 19 0.10 20 0.02 21 0.25 22 0.48 23 2.01 24 0.86 25 10.5 26 47.8 27 5.31 28 / 29 12.88 30 4.13 31 6.10 32 3.57 33 0.055 34 0.329 35 0.034 36 0.056 37 3.41 38 4.33

[0303] As shown in the table above, the compounds of the present invention exhibited effective activity in inhibiting cell growth under cell spheroidization culture conditions.

Claims

1. A compound represented by Formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, Indicates a chemical single or double bond; m1 and m2 are each independently selected from 1, 2, or 3; X is selected from N or CH; Z is selected from S(O)2, S(O), C(O) or chemical single bond; Ring B is selected from 6- to 10-membered aromatic rings or 5- to 10-membered aromatic heterocyclic rings; wherein the aromatic ring or aromatic heterocyclic ring is optionally surrounded by 1, 2, 3, or 4 R groups. B1 replace; Each R B1 Each of the following groups is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene, and -OR. B2 -C0~C2 alkylene-NR B2 R B3 -C0~C2 alkylene-3~6-membered carbon ring, -C0~C2 alkylene-4~6-membered heterocycle, -C0~C2 alkylene-6-membered aromatic ring, or -C0~C2 alkylene-5~6-membered aromatic heterocycle; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally surrounded by 1, 2, 3, or 4 R B4 replace; Alternatively, the two Rs substituted adjacently on ring B. B1 Connected together with the B ring, they form a 9-10 member partially saturated carbon ring or a 9-10 member partially saturated heterocycle; R B2 R B3 Each of the following is independently selected from hydrogen, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene-3-6 membered carbon ring or -C0-C2 alkylene-4-6 membered heterocycle; Each R B4 Each of the following is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, and C1-C6 alkoxy. L is selected from -C1~C4 alkylene-, -N(R) L -C1~C4 alkylene groups or chemical single bonds; R L Selected from hydrogen or C1-C6 alkyl groups; Ring A is selected from 3-10 membered carbon rings, 4-10 membered heterocycles, 6-10 membered aromatic rings, or 5-10 membered aromatic heterocycles; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally surrounded by 1, 2, 3, or 4 R groups. A1 replace; Each R A1 Each of the following groups is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene, and -OR. A2 -C0~C2 alkylene-NR A2 R A3 -C0 to C2 alkylene rings with 3 to 6-membered carbon rings or -C0 to C2 alkylene rings with 4 to 6-membered heterocycles; R A2 R A3 They are independently selected from hydrogen, halogenated alkyl, and C1-C6 alkyl.

2. The compound according to claim 1, characterized in that: X is selected from N, and L is selected from -C1 to C4 alkylene or chemical single bond; or, X is selected from CH, and L is selected from -N(R L )-C1~C4 alkylene-.

3. The compound according to claims 1-2, characterized in that: Compounds represented by Formula I are shown as those represented by Formula IIa, Formula IIb, or Formula IIc: in, m1 and m2 are independently selected from 1, 2 or 3 respectively; preferably, m1 is 1 and m2 is 1, or m1 is 2 and m2 is 1, or m1 is 2 and m2 is 2; L is selected from -C1 to C4 alkylene or a chemical single bond; preferably, L is selected from methylene, ethylene, propylene, butylene or a chemical single bond; Ring B is selected from 6- to 10-membered aromatic rings or 5- to 10-membered aromatic heterocyclic rings; wherein the aromatic ring or aromatic heterocyclic ring is optionally surrounded by 1, 2, 3, or 4 R groups. B1 replace; Each R B1 Each of the following groups is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene, and -OR. B2 -C0~C2 alkylene-NR B2 R B3 -C0~C2 alkylene-3~6-membered carbon ring, -C0~C2 alkylene-4~6-membered heterocycle, -C0~C2 alkylene-6-membered aromatic ring, or -C0~C2 alkylene-5~6-membered aromatic heterocycle; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally surrounded by 1, 2, 3, or 4 R B4 replace; Alternatively, the two Rs substituted adjacently on ring B. B1 Connected together with the B ring, they form a 9-10 member partially saturated carbon ring or a 9-10 member partially saturated heterocycle; R B2 R B3 Each of the following is independently selected from hydrogen, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene-3-6 membered carbon ring or -C0-C2 alkylene-4-6 membered heterocycle; Each R B4 Each of the following is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, and C1-C6 alkoxy. Ring A is selected from 3-10 membered carbon rings, 4-10 membered heterocycles, 6-10 membered aromatic rings, or 5-10 membered aromatic heterocycles; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally surrounded by 1, 2, 3, or 4 Rs. A1 replace; Each R A1 Each of the following groups is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene, and -OR. A2 -C0~C2 alkylene-NR A2 R A3 -C0 to C2 alkylene rings with 3 to 6-membered carbon rings or -C0 to C2 alkylene rings with 4 to 6-membered heterocycles; R A2 R A3 Each is independently selected from hydrogen and C1 to C6 alkyl groups.

4. The compound according to claims 1-2, characterized in that: The compound represented by Formula I is shown as shown by Formula IId: in, m1 and m2 are independently selected from 1, 2 or 3 respectively; preferably, m1 is 1 and m2 is 1, or m1 is 2 and m2 is 1, or m1 is 2 and m2 is 2; L is selected from -N(R) L -C1 to C4 alkylene groups; preferably, L is selected from -NH-CH2- or -NH-C2H4-; Ring B is selected from 6- to 10-membered aromatic rings or 5- to 10-membered aromatic heterocyclic rings; wherein the aromatic ring or aromatic heterocyclic ring is optionally surrounded by 1, 2, 3, or 4 R groups. B1 replace; Each R B1 Each of the following groups is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene, and -OR. B2 -C0~C2 alkylene-NR B2 R B3 -C0~C2 alkylene-3~6-membered carbon ring, -C0~C2 alkylene-4~6-membered heterocycle, -C0~C2 alkylene-6-membered aromatic ring, or -C0~C2 alkylene-5~6-membered aromatic heterocycle; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally surrounded by 1, 2, 3, or 4 R B4 replace; Alternatively, the two Rs substituted adjacently on ring B. B1 Connected together with the B ring, they form a 9-10 member partially saturated carbon ring or a 9-10 member partially saturated heterocycle; R B2 R B3 Each of the following is independently selected from hydrogen, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene-3-6 membered carbon ring or -C0-C2 alkylene-4-6 membered heterocycle; Each R B4 Each of the following groups is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OH, and C1-C6 alkoxy. Ring A is selected from 3-10 membered carbon rings, 4-10 membered heterocycles, 6-10 membered aromatic rings, or 5-10 membered aromatic heterocycles; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally surrounded by 1, 2, 3, or 4 Rs. A1 replace; Each R A1 Each of the following groups is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C0-C2 alkylene, and -OR. A2 -C0~C2 alkylene-NR A2 R A3 -C0 to C2 alkylene rings with 3 to 6-membered carbon rings or -C0 to C2 alkylene rings with 4 to 6-membered heterocycles; R A2 R A3 Each is independently selected from hydrogen and C1 to C6 alkyl groups.

5. The compound according to claims 1 to 4, characterized in that: Ring B is selected from benzene ring, naphthalene ring, 5-membered monoaromatic heterocycle, 6-membered monoaromatic heterocycle, 9-membered fused aromatic heterocycle, and 10-membered fused aromatic heterocycle; wherein the benzene ring, naphthalene ring, and aromatic heterocycle are optionally surrounded by 1, 2, 3, or 4 R. B1 replace; Preferably, ring B is selected from The B ring is selected from rings that can be optionally divided by 1, 2, 3 or 4 R rings. B1 replace; More preferably, ring B is selected from 6. The compound according to claims 1 to 5, characterized in that: Each R B1 Each group is independently selected from hydrogen, halogen, cyano, halogenated alkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and -OR. B2 -C1 alkylene-OR B2 -NR B2 R B3 -C1 alkylene-NR B2 R B3 , 3-membered carbon ring, 4-membered carbon ring, 5-membered carbon ring, 6-membered carbon ring, -C1 alkylene-3-membered carbon ring, -C1 alkylene-4-membered carbon ring, -C1 alkylene-5-membered carbon ring, -C1 alkylene-6-membered carbon ring, 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, -C1 alkylene-4-membered heterocycle, -C1 alkylene-5-membered heterocycle, -C1 alkylene-6-membered heterocycle, -6-membered aromatic ring, -C1 alkylene-6-membered aromatic ring, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle, -C1 alkylene-5-membered aromatic heterocycle, or -C1 alkylene-6-membered aromatic heterocycle; wherein the carbon ring, heterocycle, aromatic ring, or aromatic heterocycle is optionally composed of 1, 2, 3, or 4 R B4 replace; Alternatively, the two Rs substituted adjacently on ring B. B1 Connected together with the B ring, they form a 9-membered partially saturated carbon ring, a 10-membered partially saturated carbon ring, a 9-membered partially saturated heterocycle, or a 10-membered partially saturated heterocycle. R B2 R B3 Each of the following is independently selected from hydrogen, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, and cyclopropyl; Each R B4 Each of the following groups is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, -OH, methoxy, and ethoxy. Preferably, Each R B1 Each of the following groups is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, -OH, -C1 alkylene-OH, methoxy, ethoxy, n-propoxy, isopropoxy, -C1 alkylene-methoxy, -C1 alkylene-ethoxy, -O-monofluoromethyl, -O-difluoromethyl, -O-trifluoromethyl, -O-cyclopropyl, -NH2, -NHCH3, -N(CH3)2, cyclopropyl, cyclobutyl, or 7. The compound according to claims 1 to 6, characterized in that: Ring B is selected from 8. The compound according to claims 1 to 7, characterized in that: Ring A is selected from 4-membered carbon rings, 5-membered carbon rings, 6-membered carbon rings, 7-membered carbon rings, 4-membered heterocycles, 5-membered heterocycles, 6-membered heterocycles, 7-membered heterocycles, 5-membered aromatic heterocycles, and 6-membered aromatic heterocycles; wherein the carbon ring, heterocycle, and aromatic heterocycle are optionally represented by 1, 2, 3, or 4 R... A1 replace; Preferably, ring A is selected from Each R A1 Each of the following groups is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, -OH, methoxy, ethoxy, -O-cyclopropyl, -NH2, -NHCH3, -N(CH3)2, cyclopropyl, and cyclobutyl; More preferably, ring A is selected from 9. The compound according to claims 1 to 8, characterized in that: The compound is specifically:

10. A pharmaceutical composition comprising the compound of any one of claims 1 to 9, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or mediator.

11. Use of the compound of any one of claims 1 to 9, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the composition of claim 10, in the preparation of a medicament for the treatment / prevention of myelin-related diseases or tumor-related diseases.

12. The use according to claim 11, characterized in that: The myelin-related diseases mentioned are multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophy, neonatal white matter injury, age-related dementia, schizophrenia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander disease, Perizoise-Metzbach disease (PMD), white matter ablation disorders, Waller's degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, and Parkinson's disease; the tumor-related diseases mentioned are glioma, colon cancer, rectal cancer, breast cancer, glioblastoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, malignant lymphoma, myeloma, brain tumor, head and neck cancer, neuroblastoma, osteosarcoma, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, ovarian cancer, and choriocarcinoma.

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