Pyridyl piperidylamine compound as well as preparation method and application thereof

Abstract

The invention discloses a pyridyl piperidylamine compound as well as a preparation method and application thereof. Specifically, the invention provides a compound with a structure as shown in a formula I, and pharmaceutically acceptable salt, raceme, deuterated derivative or isomer thereof. The invention also provides a composition, a preparation method and application of the compound. The compound can be used for preparing medicines for preventing and / or treating NSD2 related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly to a class of pyridylpiperidineamine compounds, their preparation methods and uses. Background Art

[0002] Histone lysine methyltransferase nuclear receptor-binding SET domain (NSD) proteins, as an important class of epigenetic modifiers, use S-adenosyl-L-methionine (SAM) as a methyl donor to catalyze the mono- and dimethylation of the ε-amino group of lysine 36 in histone H3 (H3K36), thereby controlling important physiological processes such as gene transcription, DNA replication, and cell differentiation. The NSD protein family includes NSD1, NSD2, and NSD3. Among them, NSD2 is the main enzyme that catalyzes the dimethylation of H3K36.

[0003] Studies have shown that NSD2 is overexpressed, translocated, or mutated in a variety of hematological malignancies and solid tumors. In particular, the t(4;14)(p16;q32) translocation is observed in approximately 20% of multiple myeloma (MM) cases. This translocation leads to the co-overexpression of NSD2 and FGFR3, thereby driving the occurrence and development of multiple myeloma. Therefore, NSD2 is considered to be a major oncogenic driver of multiple myeloma. In addition, the E1099K mutation of NSD2 has also been found in a variety of acute lymphoblastic leukemia (ALL) cell lines. This mutation triggers the overactivation of the catalytic activity of NSD2. Further mechanism studies have shown that both the E1099K mutation and NSD2 overexpression lead to an overall increase in the cellular H3K36me2 level, thereby promoting tumorigenesis and oncogenic transformation. Knocking down the NSD2 protein level inhibits the occurrence and development of tumor cells. Therefore, inhibiting NSD2 is one of the effective strategies for treating tumors caused by its dysfunction.

[0004] Since NSD2 was first reported, more and more studies have demonstrated that specific inhibition of NSD2 can be used as a new strategy for targeted therapy of multiple myeloma. However, the current research on small molecule inhibitors targeting NSD2 is still in its initial stage. So far, the reported structural types of NSD2 inhibitors are extremely limited, and their activities mostly remain at the molecular level, and the anti-tumor activities at the cellular level are relatively weak. In 2021, Novartis announced a patent for piperidylmethylpurineamine series analogs as NSD2 inhibitors. Among them, the half-maximal inhibitory concentration of compound 78 for H3K36 dimethylation in the multiple myeloma cell line KMS-11 can reach 0.078 μM, and the NSD2 inhibitory activity at the molecular level reaches the nanomolar level. Unfortunately, its in vivo and in vitro anti-tumor activities have not been reported (WO2021 / 028854Al).

[0005]

[0006] In summary, it is urgent to develop novel small molecule inhibitors of NSD2. Obtaining more novel inhibitors that are effective in vitro and in vivo can not only further confirm the druggability of NSD2 as a drug target, but more importantly, may provide new options for the targeted therapy of tumors caused by NSD2 dysfunction! SUMMARY OF THE INVENTION

[0007] The object of the present invention is to provide a compound represented by formula I as a small molecule inhibitor of NSD2, its preparation method, and its use in preventing and / or treating tumors and the like.

[0008] In the first aspect of the present invention, there is provided a compound represented by formula I, its pharmaceutically acceptable salt, its racemate, its deuterated derivative or its isomer:

[0009]

[0010] Wherein:

[0011] R1 is selected from fluorine, hydrogen;

[0012] Z is selected from the group consisting of: O, S, Se;

[0013] X and Y are each independently selected from the group consisting of: CH, N;

[0014] R2, R3, and R4 are each independently selected from the group consisting of: hydrogen, deuterium, substituted or unsubstituted C1-C8 alkyl; wherein, the substitution means being substituted by 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of: deuterium, halogen, amino, hydroxyl, mercapto, cyano;

[0015] And when R1 is hydrogen and Z is S or Se, R2, R3, and R4 are not all hydrogen;

[0016] R5 is selected from the group consisting of: hydrogen, cyano, -COOH, -CONH2, -CONHOH, -CONR a R b , C1-C8 alkyl, C1-C6 alkyl-O-C1-C6 alkylene-, C3-C6 cycloalkyl-(CH2) 0-1 O-C1-C6 alkylene-, 3-10 membered heterocycloalkyl-(CH2) 0-1 O-C1-C6 alkylene-, C1-C6 alkyl-NH-C1-C6 alkylene-, C3-C6 cycloalkyl-(CH2) 0-1 NH-C1-C6 alkylene-, 3-10 membered heterocycloalkyl-(CH2) 0-1NH-C1-C6 alkylene-, C1-C6 alkyl-NH(C=O)-C0-C6 alkylene-, C3-C6 cycloalkyl-(CH2) 0-1 NH(C=O)-C0-C6 alkylene-, 3-10 membered heterocycloalkyl-(CH2) 0-1 NH(C=O)-C0-C6 alkylene-, C6-C10 aryl-(CH2) 0-1 NH(C=O)-C0-C6 alkylene-, 5-10 membered heteroaryl-(CH2) 0-1 NH(C=O)-C0-C6 alkylene-, C0-C6 alkyl-ONH(C=O)-C0-C6 alkylene-, C3-C6 cycloalkyl-(CH2) 0-1 ONH(C=O)-C0-C6 alkylene-, 3-10 membered heterocycloalkyl-(CH2) 0-1 ONH(C=O)-C0-C6 alkylene-, C6-C10 aryl-(CH2) 0-1 ONH(C=O)-C0-C6 alkylene-, 5-10 membered heteroaryl-(CH2) 0-1 ONH(C=O)-C0-C6 alkylene-, C2-C8 alkenyl, C2-C8 alkynyl, 3-10 membered cycloalkyl, monocyclic or fused 5-10 membered heteroaryl, C6-C10 aryl-(C0-C6 alkylene)-, monocyclic or fused 5-10 membered heteroaryl-(C0-C6 alkylene)-, CH≡C-CH2-O-C1-C6 alkylene-, C1-C6 alkyl-S(=O)2-O-C1-C6 alkylene-, C1-C6 alkyl-S(=O)2-NH-C1-C6 alkylene-; R a and R b each independently selected from: hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or R a and R b and the atoms attached to them together form a 3-10 membered heterocycloalkyl; provided that, except for -COOH and -CONH2, the hydrogen in the remaining above-mentioned groups is optionally substituted by 1, 2, 3, 4, 5 or 6 R c substituents;

[0017] each R c independently selected from: amino, hydroxy, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -(C=O)-O-C1-C6 alkyl, C1-C6 alkoxy unsubstituted or substituted by hydroxy, =O, C6-C10 aryl, 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C3-C6 cycloalkyl and C6-C10 aryl are optionally substituted by 0, 1, 2, 3 or 4 halogen or hydroxy;

[0018] When R1 is hydrogen and Z is O, neither R2 nor R3 is hydrogen, and R5 is not selected from substituted or unsubstituted C1-C8 alkyl groups;

[0019] Each of the heteroaryl and heterocycloalkyl groups independently contains 1, 2, 3, 4, 5 or 6 heteroatoms, and each of the heteroatoms is independently selected from N, O or S.

[0020] In another preferred embodiment, each of R2, R3, and R4 is independently selected from the group consisting of: hydrogen, deuterium, and methyl.

[0021] In another preferred embodiment, the 5- to 10-membered heteroaryl group is selected from:

[0022] In another preferred embodiment, the heterocycloalkyl group is selected from:

[0023] In another preferred embodiment, the compound has the structure shown in Formula II:

[0024]

[0025] X and Y are each independently selected from the group consisting of: CH, N;

[0026] Z is selected from the group consisting of: O, S;

[0027] R4 is a substituted or unsubstituted C1-C6 alkyl group; wherein, the substitution means being substituted by 1, 2 or 3 substituents selected from the group consisting of: deuterium, halogen;

[0028] R5 is selected from the group consisting of: C1-C8 alkyl, C1-C6 alkoxy-methyl, C3-C6 cycloalkyl-(CH2) 0-1 OCH2-, C1-C6 alkyl-NH(C=O)-, C3-C6 cycloalkyl-(CH2) 0-1 NH(C=O)-, 5- to 10-membered heteroaryl-(CH2) 0-1 NH(C=O)-, C1-C6 alkyl-ONH(C=O)-, C3-C6 cycloalkyl-(CH2) 0-1 ONH(C=O)-, 5- to 10-membered heteroaryl-(CH2) 0-1 ONH(C=O)-, 5- to 6-membered heteroaryl; wherein, the hydrogen in each of the above groups is optionally substituted by 1, 2 or 3 R c substituents;

[0029] Each R cIndependently selected from: hydroxyl, halogen, C1-C6 alkyl optionally substituted with 0, 1, 2, 3 or 4 halogens, C3-C6 cycloalkyl, C6-C10 aryl optionally substituted with 0, 1, 2, 3 or 4 halogens, 5-10 membered heteroaryl;

[0030] The heteroaryl contains 1, 2 or 3 heteroatoms, and the heteroatoms are each independently selected from N, O or S.

[0031] In another preferred example, the compound has the structure shown in formula III:

[0032]

[0033] Wherein,

[0034] X and Y are each independently selected from the group: CH, N;

[0035] R4 is a substituted or unsubstituted C1-C6 alkyl; wherein, the substitution means being substituted with 1, 2 or 3 substituents selected from the group: deuterium, halogen;

[0036] R5 is selected from the group: C1-C8 alkyl, C1-C6 alkyl-OCH2-, C3-C6 cycloalkyl-(CH2) 0-1 OCH2-, C1-C6 alkyl-NH(C=O)-, C3-C6 cycloalkyl-(CH2) 0-1 NH(C=O)-, 5-10 membered heteroaryl-(CH2) 0-1 NH(C=O)-, C1-C6 alkyl-ONH(C=O)-, C3-C6 cycloalkyl-(CH2) 0-1 ONH(C=O)-, 5-10 membered heteroaryl-(CH2) 0-1 ONH(C=O)-, 5-6 membered heteroaryl; wherein, the hydrogen in each of the above groups is optionally substituted with 1, 2 or 3 Rs c Substituted;

[0037] Each R c Independently selected from: hydroxyl, halogen, C1-C6 alkyl optionally substituted with 0, 1, 2, 3 or 4 halogens, C3-C6 cycloalkyl, C6-C10 aryl optionally substituted with 0, 1, 2, 3 or 4 halogens, 5-10 membered heteroaryl;

[0038] The heteroaryl contains 1, 2 or 3 heteroatoms, and the heteroatoms are each independently selected from N, O or S.

[0039] In another preferred example, the compound has the structure shown in formula IV:

[0040]

[0041] Wherein,

[0042] X and Y are each independently selected from the group consisting of: CH, N;

[0043] R4 is a substituted or unsubstituted C1-C6 alkyl group; wherein, the substitution means being substituted by 1, 2 or 3 substituents selected from the group consisting of: deuterium, halogen;

[0044] R5 is selected from the group consisting of: C1-C6 alkyl-OCH2-, C3-C6 cycloalkyl-(CH2) 0-1 OCH2-, C1-C6 alkyl-NH(C=O)-, C3-C6 cycloalkyl-(CH2) 0-1 NH(C=O)-, 5-10 membered heteroaryl-(CH2) 0-1 NH(C=O)-, C1-C6 alkyl-ONH(C=O)-, C3-C6 cycloalkyl-(CH2) 0-1 ONH(C=O)-, 5-10 membered heteroaryl-(CH2) 0-1 ONH(C=O)-, 5-6 membered heteroaryl; wherein, the hydrogen in each of the above groups is optionally substituted by 1, 2 or 3 R c substituents;

[0045] Each R c is independently selected from: hydroxyl, halogen, C1-C6 alkyl optionally substituted by 0, 1, 2, 3 or 4 halogens, C3-C6 cycloalkyl, C6-C10 aryl optionally substituted by 0, 1, 2, 3 or 4 halogens, 5-10 membered heteroaryl;

[0046] The heteroaryl contains 1, 2 or 3 heteroatoms, and the heteroatoms are each independently selected from N, O or S.

[0047] In another preferred embodiment, the compound has the structure shown in Formula V:

[0048]

[0049] Wherein,

[0050] X and Y are each independently selected from the group consisting of: CH, N;

[0051] R4 is a substituted or unsubstituted C1-C6 alkyl group; wherein, the substitution means being substituted by 1, 2 or 3 substituents selected from the group consisting of: deuterium, halogen;

[0052] R6 and R7 are each independently selected from: hydrogen, C1-C6 alkyl-OCH2-, C3-C6 cycloalkyl-(CH2) 0-1 OCH2-, C1-C6 alkyl-, C3-C6 cycloalkyl-(CH2) 0-1-, 5-10-membered heteroaryl-(CH2) 0-1 -, C1-C6 alkyl-O-, C3-C6 cycloalkyl-(CH2) 0-1 O-, 5-10-membered heteroaryl-(CH2) 0-1 O-; wherein, the hydrogen in each of the above groups is optionally substituted by 1, 2 or 3 R c substituted;

[0053] Each R c is independently selected from: hydroxyl, halogen, C1-C6 alkyl optionally substituted by 0, 1, 2, 3 or 4 halogens, C3-C6 cycloalkyl, C6-C10 aryl optionally substituted by 0, 1, 2, 3 or 4 halogens, 5-10-membered heteroaryl;

[0054] The heteroaryl contains 1, 2 or 3 heteroatoms, and each of the heteroatoms is independently selected from N, O or S.

[0055] In another preferred embodiment, the compound is selected from the group consisting of:

[0056]

[0057]

[0058]

[0059]

[0060]

[0061] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising one or more safe and effective amounts of the compound as described in the first aspect of the present invention, its pharmaceutically acceptable salts, its racemates, its deuterated derivatives or its isomers; and a pharmaceutically acceptable carrier or excipient.

[0062] In another preferred embodiment, the pharmaceutical composition further comprises other therapeutic agents.

[0063] In another preferred embodiment, the other therapeutic agent is an anti-cancer drug or a chemotherapeutic drug.

[0064] In a third aspect of the present invention, there is provided a use of the compound as described in the first aspect of the present invention, its pharmaceutically acceptable salts, its racemates, its deuterated derivatives or its isomers, or the pharmaceutical composition as described in the second aspect of the present invention, characterized in that the use is:

[0065] 1) for preparing a drug for preventing and / or treating NSD2-related diseases; and / or

[0066] 2) for inhibiting the activity of NSD2; and / or

[0067] 3) For reducing the expression level of NSD2.

[0068] In another preferred embodiment, the drug is an NSD2 inhibitor.

[0069] In another preferred embodiment, the NSD2-related diseases are selected from the group consisting of: breast cancer, cervical cancer, skin cancer (especially squamous cell carcinoma), ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, head and neck cancer, peripheral nerve sheath tumor, osteosarcoma, multiple myeloma, neuroblastoma, leukemia (especially acute lymphoblastic leukemia), non-Hodgkin lymphoma (especially mantle cell lymphoma), or a combination thereof.

[0070] In another preferred embodiment, the skin cancer is squamous cell carcinoma.

[0071] In another preferred embodiment, the leukemia is acute lymphoblastic leukemia.

[0072] In another preferred embodiment, the non-Hodgkin lymphoma is mantle cell lymphoma.

[0073] In another preferred embodiment, the disease is a malignant tumor with increased NSD2 expression.

[0074] In another preferred embodiment, the disease is a malignant tumor with elevated NSD2 activity.

[0075] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. Detailed Embodiments

[0076] Through long-term and in-depth research, the inventors modified the easily metabolized site of the pyridyl benzylidene methylene of the existing piperidinylmethylpurine amine-based NSD2 small molecule inhibitor, and appropriately combined with the structural modification of other modifiable sites, and unexpectedly obtained an NSD2 small molecule compound with a novel structure, excellent NSD2 inhibitory activity and better efficacy. On this basis, the inventors completed the present invention.

[0077] Terms

[0078] In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0079] As used herein, the term "comprising" or "including" can be open, semi-closed and closed. In other words, the term also includes "substantially consisting of..." or "consisting of...".

[0080] In the present invention, the term "halogen" refers to F, Cl, Br, or I.

[0081] In the present invention, the term "amino" refers to -NH2.

[0082] In the present invention, "C1-C6 alkyl" refers to a straight-chain or branched-chain alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pivalyl, or similar groups. The term "C1-C8 alkyl" has a similar meaning.

[0083] In the present invention, the term "C2-C6 alkenyl" refers to a straight-chain or branched-chain alkenyl group having 2-6 (e.g., 2, 3, 4, 5, or 6) carbon atoms and containing one double bond, including, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl, etc. The term "C2-C8 alkenyl" has a similar meaning.

[0084] In the present invention, the term "C2-C6 alkynyl" refers to a straight-chain or branched-chain alkynyl group having 2-6 (e.g., 2, 3, 4, 5, or 6) carbon atoms and containing one triple bond, including, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl, etc. The term "C2-C8 alkynyl" has a similar meaning.

[0085] In the present invention, the term "C3-C8 cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having 3-8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The term "C3-C6 cycloalkyl" has a similar meaning.

[0086] In the present invention, the term "C1-C6 alkoxy" refers to a straight-chain or branched-chain alkoxy group having 1-6 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy, etc. The terms "C1-C4 alkoxy" and "C1-C8 alkoxy" have similar meanings.

[0087] In the present invention, the term "heterocycloalkyl" refers to a saturated or partially saturated 3-10 membered heterocycloalkyl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which can be in monocyclic, bicyclic forms, such as bridged or spiro forms, including (but not limited to) the following groups:

[0088] In the present invention, the terms "aromatic ring" or "aryl" have the same meaning, preferably "C6-C10 aryl". The term "C6-C10 aryl" refers to an aromatic ring group having 6 to 10 (such as 6, 7, 8, 9 or 10) carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.

[0089] In the present invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to an aromatic ring group containing one or more (such as 1, 2, 3, 4, 5 or 6) heteroatoms. For example, it can be a 5- to 15-membered heteroaryl, which refers to an aromatic ring group having 5 to 15 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) atoms and one or more of which are heteroatoms selected from N, S or O. It can be a monocyclic or a fused-ring form. The heteroaryl is preferably a 5- to 12-membered heteroaryl or a 5- to 10-membered heteroaryl, more preferably a 5- to 6-membered heteroaryl. Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, tetrazolyl, oxadiazole, thiadiazole, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, and the ring connected to the parent structure is the heteroaryl ring. The heteroaryl can be optionally substituted or unsubstituted.

[0090] In the present invention, the term "alkylene" (alone or as part of other groups) refers to the group obtained by removing one hydrogen atom from the alkyl as described above, such as methylene (-CH2-), ethylene (-CH2CH2-), etc.

[0091] In the present invention, the term "halogenated" means being substituted by a halogen.

[0092] In the present invention, the term "deuterated" means being substituted by deuterium.

[0093] In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are substituted by specific substituents. The specific substituents are the substituents described correspondingly in the foregoing, or the substituents appearing in each embodiment. Unless otherwise specified, a certain substituted group can have a substituent selected from a specific group at any substitutable site of the group, and the substituents can be the same or different at each position. Those skilled in the art should understand that the combinations of substituents expected in the present invention are those that are stable or chemically achievable. The substituents are, for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino, C1-C6 alkoxy, C1-C10 sulfonyl group, etc.

[0094] In the present invention, "optional" or "optionally" means that the subsequently described event or condition may but does not have to occur, and this description includes the case where the event or condition occurs and the case where the event or condition does not occur.

[0095] In the present invention, the term 1 - 6 means 1, 2, 3, 4, 5 or 6. Other similar terms each independently have a similar meaning. The term "plurality" means 2 - 6, such as 2, 3, 4, 5 or 6.

[0096] It should be understood that when a certain group is present at multiple different positions in a compound, its definitions at each position are independent of each other and can be the same or different. That is, the terms "selected from:", "selected from the following group:", "each independently selected from:" and the term "each independently selected from the following group:" have the same meaning.

[0097] Active ingredient

[0098] As used herein, "the compound of the present invention" refers to the compound represented by Formula I, or its pharmaceutically acceptable salts, its racemates, its isomers:

[0099]

[0100] wherein each group is defined as above.

[0101] In another preferred embodiment, in the said compound, any one of R1, R2, R3, R4, R5, X, Y, Z is independently the corresponding group in the specific compound described in the present invention.

[0102] As used herein, the term "pharmaceutically acceptable salt" refers to the salts formed by the compounds of the present invention with acids or bases that are suitable for use as drugs. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are the salts formed by the compounds of the present invention with acids. Acids suitable for forming salts include but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p - toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid.

[0103] Another class of preferred salts are the salts formed by the compounds of the present invention with bases, such as alkali metal salts (e.g., sodium salts or potassium salts), alkaline earth metal salts (e.g., magnesium salts or calcium salts), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed by morpholine, piperazine, and lysine, respectively.

[0104] Preparation Method

[0105] The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not impose any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention pertains.

[0106] Typically, the preparation process flow of the compounds of the present invention is as follows, and the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0107]

[0108] Step 1: In an inert solvent, the compound of formula I-1 undergoes a Suzuki coupling reaction with an arylboronic acid to obtain the compound of formula I-2;

[0109] Step 2: The compound of formula I-2 undergoes a substitution reaction with a substituted piperidine to obtain the compound of formula I-3;

[0110] Step 3: The compound of formula I-3 is reduced with sodium borohydride or sodium borodeuteride to obtain the compound of formula I-4;

[0111] Step 4: The compound of formula I-4 undergoes a Mitsunobu reaction with the indicated amine to obtain the compound of formula I-5;

[0112] Step 5: The compound of formula I-5 is deprotected from the Boc protecting group under trifluoroacetic acid conditions, and then enantioselectively resolved to obtain the compound of formula I-6;

[0113] Wherein, the definitions of R1, R2, R3, R4, R5, X, Y, and Z are as described above.

[0114] Pharmaceutical Compositions and Administration Methods

[0115] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the said compounds.

[0116] The pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. The "safe and effective amount" herein refers to: an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the compound of the present invention per dose, more preferably, 5 - 200 mg of the compound of the present invention per dose. Preferably, the "per dose" is a capsule or a tablet.

[0117] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gelling substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" means that the components in the composition can be mixed with the compound of the present invention and with each other without reducing the drug efficacy mutually. Pharmaceutically acceptable carrier parts include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, palm oil, etc.), polyhydric alcohols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (Tween), wetting agents (such as sodium dodecylsulfonate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0118] There is no particular limitation on the administration mode of the compound or pharmaceutical composition of the present invention. Representative administration modes include (but are not limited to): oral administration, parenteral (intravenous, intramuscular or subcutaneous).

[0119] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient, such as sodium citrate or calcium phosphate, or with the following components: fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; binders, such as hydroxypropylmethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; humectants, such as glycerol; disintegrants, such as agar, calcium carbonate, potato starch, tapioca starch, alginic acid and sodium carbonate; solubilizers, such as paraffin wax; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glycerol monostearate; adsorbents, such as kaolin; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecylsulfate, or mixtures thereof. The dosage forms in capsules, tablets and pills may also contain buffering agents.

[0120] Solid dosage forms, such as tablets, pills, capsules, and granules, can be prepared with coatings and shell materials, such as enteric coatings and other materials. They can contain opacifying agents, and the release of the active compound or compounds in such compositions can be in a delayed manner within the digestive tract. Examples of embedding components that can be used are polymeric substances and wax-like substances. If necessary, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0121] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms can contain inert diluents conventionally used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, dimethylformamide, peanut oil, corn oil, olive oil, castor oil, and sesame oil, or mixtures of the above substances.

[0122] In addition to these inert diluents, the composition can also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, and flavoring agents.

[0123] In addition to the active compound, the suspension can contain suspending agents, such as ethoxylated isooctadecanol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum monostearate, and agar, or mixtures of the above substances, etc.

[0124] Compositions for parenteral injection can contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstituting into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0125] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.

[0126] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0127] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is used for a mammal in need of treatment, where the dosage during implementation is a pharmaceutically recognized effective dosage, such as for an adult with a body weight of 60 kg, the daily dosage is usually 1 - 2000 mg, preferably 5 - 500 mg. Of course, the specific dosage should also consider other factors such as the administration route, the health condition of the patient, etc.

[0128] Compared with the prior art, the present invention has the following main advantages:

[0129] The compounds of the present invention have novel structures and, after modification of the metabolic sites, exhibit excellent NSD2 inhibitory activity, thus exerting better therapeutic effects.

[0130] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0131] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to persons skilled in the art. In addition, any methods and materials similar or equivalent to those described may be applied to the methods of the present invention. The preferred methods and materials described herein are for illustrative purposes only.

[0132] Example 1 Preparation of Compounds

[0133] Preparation of Compound S1:

[0134]

[0135] Preparation of Compound S1-3:

[0136] Into a 250 mL Schlenk tube, add S1-1 (4.0 g, 17.09 mmol), S1-2 (3.53 g, 18.80 mmol), [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (Pd(dppf)Cl2, 343.0 mg, 0.42 mmol) and potassium carbonate (4.72 g, 34.18 mmol) in sequence. After purging with argon, inject dioxane (50 mL), and heat under reflux for 12 hours under argon protection. After the reaction is complete, cool, add water, extract three times with ethyl acetate, combine the organic phases, wash once with saturated brine, and dry over anhydrous sodium sulfate. After rotary evaporation and concentration, separate by silica gel column chromatography (PE / EA 10:1), and rotary evaporate to obtain a white solid S1-3 (4.01 g) with a yield of 90%. 1 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.18 (s, 1H), 7.55 (dd, J = 12.0, 7.3 Hz, 1H), 7.06 (d, J = 1.5 Hz, 1H), 3.98 (s, 3H), 3.83 (s, 3H).

[0137] Preparation of Compound S1-5:

[0138] In a 100 mL eggplant-shaped flask, add raw material S1-3 (2.0 g, 6.73 mmol), dissolve it with DMSO (20 mL), and add DBU (1.23 g, 8.07 mmol) and raw material S1-4 (1.62 g, 8.07 mmol). React at 80 °C for 2 hours. After the reaction is complete, cool the solution to room temperature, add water, extract three times with ethyl acetate. Combine the organic phases, wash once with saturated brine, and dry over anhydrous sodium sulfate. After rotary evaporation and concentration, perform column chromatography separation (PE / EA 3:1) to obtain a pale yellow oily liquid S1-5 (3.0 g) with a yield of 93%. 1 HNMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.18 (s, 1H), 7.56 (s, 1H), 7.06 (d, J = 1.5 Hz, 1H), 3.98 (s, 3H), 3.83 (s, 3H), 3.26 (d, J = 3.6 Hz, 1H), 3.09 (d, J = 11.6 Hz, 1H), 3.02 (dt, J = 8.2, 3.8 Hz, 1H), 2.97 (m, 1H), 2.73 (m, 1H), 1.96 (m, 1H), 1.88 (m, 1H), 1.77 (m, 1H), 1.44 (s, 9H), 1.37 (m, 1H).

[0139] Preparation of compound S1-6:

[0140] In a 50 mL eggplant-shaped flask, add raw material S1-5 (1.5 g, 3.14 mmol), dissolve it with methanol (10 mL) and tetrahydrofuran (10 mL), and add sodium borodeuteride (788.90 mg, 18.85 mmol) and lithium chloride (798.96 mg, 18.85 mmol). React at room temperature. After 4 hours of complete reaction, add water, extract three times with ethyl acetate. Combine the organic phases, wash once with saturated brine, and dry over anhydrous sodium sulfate. After rotary evaporation and concentration, perform column chromatography separation (PE / EA 1:1) to obtain a colorless oily liquid S1-6 (1.2 g) with a yield of 85%. 1 H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.16 (s, 1H), 7.54 (s, 1H), 7.09 (d, J = 1.5 Hz, 1H), 3.84 (s, 3H), 3.26 (d, J = 3.5 Hz, 1H), 3.07 (d, J = 11.2 Hz, 1H), 3.02 (m, 1H), 2.97 (m, 1H), 2.73 (m, 1H), 1.98 (m, 1H), 1.86 (m, 1H), 1.71 (m, 2H), 1.44 (s, 9H).

[0141] Preparation of compound S1-8:

[0142] In a 50 mL Schlenk tube, S1-6 (0.5 g, 1.1 mmol), S1-7 (0.48 g, 1.22 mmol), triphenylphosphine (0.87 g, 3.32 mmol) and DIAD (0.67 g, 3.32 mmol) were successively added. After evacuation and backfilling with argon, anhydrous tetrahydrofuran (8 mL) was injected, and the reaction was carried out at room temperature for 1 hour under argon protection. After rotary evaporation and concentration, column chromatography separation (PE / EA 1:2) was performed to obtain a colorless oily liquid S1-8 (0.6 g) with a yield of 72%. 1 1H NMR (400 MHz, CDCl3): δ 8.43 (s, 1H), 8.17 (s, 2H), 7.54 (dd, J = 12.0, 7.6 Hz, 1H), 7.08 (d, J = 1.5 Hz, 1H), 6.88 (dd, J = 12.6, 7.5 Hz, 1H), 3.81 (s, 3H), 3.28 (d, J = 3.5 Hz, 1H), 3.03 (d, J = 11.6 Hz, 1H), 3.06 (m, 1H), 2.96 (m, 1H), 2.74 (m, 1H), 1.96 (m, 1H), 1.86 (m, 1H), 1.72 (m, 2H), 1.42 (s, 18H).

[0143] Preparation of compound S1:

[0144] In a 50 mL eggplant-shaped flask, the raw material S1-8 (200 mg, 0.3 mmol) was added and dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added. The reaction was carried out at room temperature. After the reaction was complete in 2 hours, it was rotary evaporated to dryness. Saturated sodium bicarbonate solution (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then it was extracted three times with dichloromethane. The combined organic phases were washed once with saturated brine and dried over anhydrous sodium sulfate. After rotary evaporation and concentration, column chromatography separation (DCM / MeOH(7N NH3) 3:1) was performed to obtain a white solid S1 (98 mg) with a yield of 78%. 1HNMR(400MHz, Methanol-d4): δ 8.43(s, 1H), 8.17(s, 2H), 7.54(dd, J = 12.2, 7.3Hz, 1H), 7.05(d, J = 1.5Hz, 1H), 6.87(dd, J = 12.6, 7.1Hz, 1H), 3.83(s, 3H), 3.26(d, J = 3.6Hz, 1H), 3.09(d, J = 11.6Hz, 1H), 3.02(dt, J = 8.2, 3.8Hz, 1H), 2.90 - 2.84(m, 1H), 2.75 - 2.70(m, 1H), 1.98(dd, J = 12.9, 4.2Hz, 1H), 1.89(dt, J = 8.3, 4.4Hz, 1H), 1.76(td, J = 9.9, 4.8Hz, 1H), 1.37(m, 1H).

[0145] Preparation of Compound S2:

[0146]

[0147] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S2. 1 H NMR(400MHz, Methanol-d4): δ 8.44(s, 1H), 8.18(s, 2H), 7.55(dd, J = 12.2, 7.3Hz, 1H), 7.05(d, J = 1.5Hz, 1H), 6.87(dd, J = 12.6, 7.1Hz, 1H), 3.07(d, J = 11.1Hz, 1H), 2.90(s, 2H), 2.86(d, J = 10.2Hz, 1H), 1.93(dd, J = 10.1, 4.0Hz, 1H), 1.77 - 1.72(m, 1H), 1.58(m, 2H), 1.21(m, 3H).

[0148] Preparation of Compound S3:

[0149]

[0150] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S3. 11H NMR (400 MHz, Methanol-d4): δ 8.40 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 7.52 (dd, J = 12.8, 2.2 Hz, 1H), 7.21 (d, J = 5.1 Hz, 1H), 7.05 (t, J = 8.7 Hz, 1H), 3.84 (s, 3H), 3.36 (d, J = 11.4 Hz, 1H), 3.03 (d, J = 11.8 Hz, 1H), 2.96 (d, J = 11.2 Hz, 1H), 2.85 (td, J = 11.3, 2.9 Hz, 1H), 2.77 (s, 3H), 2.11 (td, J = 12.6, 4.2 Hz, 1H), 2.02 - 1.88 (m, 1H), 1.85 - 1.68 (m, 1H), 1.61 (d, J = 13.5 Hz, 1H).

[0151] Preparation of Compound S4:

[0152]

[0153] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S4. 1 1H NMR (400 MHz, Methanol-d4): δ 8.42 (s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.52 (dd, J = 12.7, 2.2 Hz, 1H), 7.21 (d, J = 4.4 Hz, 1H), 7.06 (t, J = 8.6 Hz, 1H), 5.00 (s, 2H), 4.33 (s, 2H), 3.85 (s, 3H), 3.34 (d, J = 11.4 Hz, 1H), 3.02 (d, J = 10.4 Hz, 2H), 2.84 (t, J = 10.3 Hz, 1H), 2.00 (m, 2H), 1.76 - 1.69 (m, 2H).

[0154] Preparation of Compound S5:

[0155]

[0156] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S5. 11H NMR (400 MHz, Methanol-d4): δ 8.42 (d, J = 1.7 Hz, 1H), 8.23 (s, 1H), 8.20 (d, J = 2.6 Hz, 1H), 7.53 (dd, J = 12.8, 2.2 Hz, 1H), 7.23 (d, J = 6.5 Hz, 1H), 7.07 (t, J = 8.6 Hz, 1H), 4.64 (p, J = 7.2 Hz, 1H), 3.85 (s, 3H), 3.38 (dd, J = 11.3, 3.5 Hz, 1H), 3.04 (s, 1H), 2.95 (d, J = 11.3 Hz, 1H), 2.85 (t, J = 11.1 Hz, 1H), 2.10 (td, J = 11.1, 9.4, 6.1 Hz, 1H), 1.98 (d, J = 12.3 Hz, 1H), 1.75 (d, J = 13.3 Hz, 1H), 1.66 - 1.63 (m, 1H), 1.34 (dd, J = 7.1, 3.9 Hz, 3H).

[0157] Preparation of Compound S6:

[0158]

[0159] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S6. 1 1H NMR (400 MHz, Methanol-d4): δ 8.50 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.58 (dd, J = 12.1, 7.3 Hz, 1H), 7.17 - 7.16 (m, 1H), 6.90 (dd, J = 12.1, 7.1 Hz, 1H), 4.20 - 4.15 (m, 1H), 3.85 (s, 3H), 3.46 (d, J = 11.8 Hz, 1H), 3.13 (d, J = 10.8 Hz, 2H), 2.98 - 2.87 (m, 3H), 2.72 - 2.59 (m, 2H), 2.20 - 2.13 (m, 1H), 2.02 (d, J = 12.2 Hz, 1H), 1.83 (t, J = 15.8 Hz, 2H).

[0160] Preparation of Compound S7:

[0161]

[0162] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S7. 11H NMR (400 MHz, Methanol-d4): δ 8.38 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.47 (dd, J = 12.2, 7.3 Hz, 1H), 6.98 (dd, J = 4.3, 1.7 Hz, 1H), 6.78 (dd, J = 12.7, 7.2 Hz, 1H), 4.45 (t, J = 5.0 Hz, 1H), 4.33 (t, J = 5.0 Hz, 1H), 3.75 (d, J = 1.1 Hz, 3H), 3.48 (t, J = 5.0 Hz, 1H), 3.42 (t, J = 5.0 Hz, 1H), 3.34 (d, J = 11.4 Hz, 1H), 3.03 (d, J = 11.8 Hz, 1H), 2.94 (d, J = 11.4 Hz, 1H), 2.85 (t, J = 10.5 Hz, 1H), 2.08 (td, J = 12.6, 12.2, 4.1 Hz, 1H), 1.96 (dd, J = 13.7, 10.2 Hz, 1H), 1.75 - 1.70 (m, 1H), 1.60 - 1.55 (m, 1H).

[0163] Preparation of Compound S8:

[0164]

[0165] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S8. 1 1H NMR (400 MHz, Methanol-d4): δ 8.47 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 7.55 (dd, J = 12.2, 7.3 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 6.87 (dd, J = 12.6, 7.1 Hz, 1H), 3.13 (d, J = 11.5 Hz, 1H), 3.02 (d, J = 11.5 Hz, 2H), 2.94 (t, J = 9.6 Hz, 1H), 1.91 - 1.94 (m, 1H), 1.84 - 1.78 (m, 1H), 1.64 (d, J = 5.8 Hz, 2H).

[0166] Preparation of Compound S9:

[0167]

[0168] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S9. 11H NMR (400 MHz, Methanol-d4): δ 8.50 (d, J = 4.0 Hz, 1H), 8.23 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.57 (dd, J = 12.1, 7.3 Hz, 1H), 7.11 (s, 1H), 6.89 (dd, J = 12.5, 7.0 Hz, 1H), 5.66 (d, J = 5.2 Hz, 1H), 3.99 (q, J = 6.6, 6.1 Hz, 1H), 3.53 - 3.45 (m, 3H), 3.12 (d, J = 11.4 Hz, 2H), 2.98 (t, J = 11.3 Hz, 1H), 2.22 - 2.15 (m, 1H), 2.03 - 1.99 (m, 1H), 1.87 (s, 1H), 1.77 (s, 1H), 1.17 (dd, J = 6.8, 1.6 Hz, 3H).

[0169] Preparation of Compound S10:

[0170]

[0171] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S10. 1 1H NMR (400 MHz, Methanol-d4): δ 8.46 (d, J = 3.1 Hz, 1H), 8.21 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 2.8 Hz, 1H), 7.55 (dd, J = 12.2, 7.3 Hz, 1H), 7.06 (t, J = 2.2 Hz, 1H), 6.86 (dd, J = 12.6, 7.1 Hz, 1H), 4.29 (ddt, J = 48.8, 9.0, 2.7 Hz, 1H), 3.83 (s, 3H), 3.73 (m, 1H), 3.48 - 3.32 (m, 2H), 3.02 (m, 3H), 2.19 - 2.13 (m, 1H), 2.01 (d, J = 4.7 Hz, 1H), 1.82 (d, J = 13.8 Hz, 1H), 1.64 (dd, J = 13.8, 4.4 Hz, 1H), 1.18 (s, 6H).

[0172] Preparation of Compound S11:

[0173]

[0174] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S11. 11H NMR (400 MHz, Methanol-d4): δ 8.48 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.56 (dd, J = 12.2, 7.3 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 6.88 (dd, J = 12.6, 7.1 Hz, 1H), 3.84 (s, 3H), 3.43 (d, J = 11.4 Hz, 1H), 3.37 (d, J = 1.8 Hz, 2H), 3.09 (dd, J = 18.0, 10.5 Hz, 2H), 2.96 (t, J = 11.0 Hz, 1H), 2.18 (td, J = 12.2, 4.2 Hz, 1H), 2.02 (t, J = 11.0 Hz, 1H), 1.89 - 1.79 (m, 1H), 1.68 (d, J = 13.3 Hz, 1H), 0.67 (d, J = 4.6 Hz, 2H), 0.63 - 0.56 (m, 2H).

[0175] Preparation of Compound S12:

[0176]

[0177] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S12. 1 1H NMR (400 MHz, Methanol-d4): δ 8.46 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 7.54 (dd, J = 12.2, 7.3 Hz, 1H), 7.04 (s, 1H), 6.85 (dd, J = 12.6, 7.1 Hz, 1H), 3.82 (s, 3H), 3.47 - 3.36 (m, 3H), 3.05 (d, J = 11.1 Hz, 2H), 2.98 (d, J = 10.4 Hz, 1H), 2.17 (ddd, J = 13.0, 11.1, 4.3 Hz, 1H), 2.04 - 1.94 (m, 5H), 1.84 - 1.80 (m, 1H), 1.74 - 1.64 (m, 2H), 1.55 (dt, J = 11.3, 9.0 Hz, 1H).

[0178] Preparation of Compound S13:

[0179]

[0180] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S13. 11H NMR (400 MHz, Methanol-d4): δ 8.48 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.56 (dd, J = 12.2, 7.3 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 6.88 (dd, J = 12.6, 7.1 Hz, 1H), 3.84 (s, 3H), 3.43 (d, J = 11.4 Hz, 1H), 3.37 (d, J = 1.8 Hz, 2H), 3.09 (dd, J = 18.0, 10.5 Hz, 2H), 2.96 (t, J = 11.0 Hz, 1H), 2.18 (td, J = 12.2, 4.2 Hz, 1H), 2.02 (t, J = 11.0 Hz, 1H), 1.89 - 1.79 (m, 1H), 1.68 (d, J = 13.3 Hz, 1H), 0.67 (d, J = 4.6 Hz, 2H), 0.63 - 0.56 (m, 2H).

[0181] Preparation of Compound S14:

[0182]

[0183] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S13. 1 1H NMR (400 MHz, Methanol-d4): δ 8.45 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.54 (dd, J = 12.2, 7.3 Hz, 1H), 7.05 (s, 1H), 6.85 (dd, J = 12.6, 7.1 Hz, 1H), 5.92 (tt, J = 56.1, 4.0 Hz, 1H), 3.83 (s, 3H), 3.61 (td, J = 15.2, 3.9 Hz, 2H), 3.40 (d, J = 11.3 Hz, 1H), 3.11 (d, J = 12.1 Hz, 1H), 3.02 (d, J = 11.3 Hz, 1H), 2.91 (t, J = 10.8 Hz, 1H), 2.18 - 2.11 (m, 1H), 2.03 (dd, J = 18.0, 8.1 Hz, 1H), 1.81 - 1.77 (m, 1H), 1.65 (d, J = 13.0 Hz, 1H).

[0184] Preparation of Compound S15:

[0185]

[0186] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S15. 11H NMR (400 MHz, Methanol-d4): δ 8.50 (s, 1H), 8.26 (s, 1H), 7.95 (s, 1H), 7.64 (dd, J = 12.0, 7.0 Hz, 1H), 7.37 (m, 2H), 6.72 (dd, J = 12.0, 6.9 Hz, 1H), 6.18 (d, J = 2.0 Hz, 1H), 4.54 - 4.44 (m, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.43 (d, J = 11.4 Hz, 1H), 3.07 (d, J = 11.8 Hz, 1H), 2.96 (d, J = 11.8 Hz, 1H), 2.91 - 2.88 (m, 1H), 2.26 (m, 1H), 1.96 (m, 1H), 1.82 (d, J = 13.5 Hz, 1H), 1.62 (d, J = 13.7 Hz, 1H).

[0187] Preparation of Compound S16:

[0188]

[0189] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S16. 1 1H NMR (400 MHz, Methanol-d4): δ 8.50 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.57 (dd, J = 12.2, 7.3 Hz, 1H), 7.12 (s, 1H), 6.88 (dd, J = 12.2, 7.3 Hz, 1H), 5.65 (s, 1H), 3.85 (s, 3H), 3.63 (t, J = 5.5 Hz, 2H), 3.48 (d, J = 11.7 Hz, 1H), 3.39 - 3.36 (m, 2H), 3.16 (d, J = 11.8 Hz, 1H), 3.10 (d, J = 11.1 Hz, 1H), 3.02 - 2.97 (m, 1H), 2.19 (m, 1H), 2.01 (d, J = 11.4 Hz, 1H), 1.89 - 1.85 (m, 1H), 1.79 (d, J = 11.8 Hz, 1H).

[0190] Preparation of Compound S17:

[0191]

[0192] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S17. 11H NMR (400 MHz, Methanol-d4): δ 8.46 (s, 1H), 8.25 (s, 1H), 7.85 (s, 1H), 7.62 (dd, J = 12.3, 7.0 Hz, 1H), 7.23 (s, 1H), 6.63 (dd, J = 12.3, 6.9 Hz, 1H), 5.52 (m, 2H), 3.83 (s, 3H), 3.57 (d, J = 11.8 Hz, 1H), 3.45 (d, J = 11.7 Hz, 1H), 3.30 (d, J = 11.7 Hz, 1H), 2.95 (d, J = 11.2 Hz, 1H), 2.86 (t, J = 10.5 Hz, 1H), 2.14 (td, J = 13.0, 4.8 Hz, 1H), 1.75 (d, J = 14.3 Hz, 1H), 1.63 (d, J = 12.2 Hz, 1H), 0.80 (d, J = 5.0 Hz, 2H), 0.76 (d, J = 4.9 Hz, 2H).

[0193] Preparation of Compound S18:

[0194]

[0195] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S18. 1 1H NMR (400 MHz, Methanol-d4): δ 8.47 (s, 1H), 8.39 (d, J = 5.0 Hz, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 7.70 (td, J = 7.7, 1.7 Hz, 1H), 7.55 (dd, J = 12.6, 7.4 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.20 - 7.17 (m, 1H), 7.07 (s, 1H), 6.85 (dd, J = 12.6, 7.4 Hz, 1H), 4.58 - 4.49 (m, 2H), 3.83 (s, 3H), 3.45 (d, J = 11.4 Hz, 1H), 3.08 (d, J = 11.1 Hz, 2H), 2.95 (t, J = 10.2 Hz, 1H), 2.24 - 2.17 (m, 1H), 2.05 - 1.99 (m, 1H), 1.85 (m, 1H), 1.69 (d, J = 13.1 Hz, 1H).

[0196] Preparation of Compound S19:

[0197]

[0198] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S19. 11H NMR (400 MHz, Methanol-d4): δ 8.49 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H), 7.57 (dd, J = 12.1, 7.3 Hz, 1H), 7.16 (s, 1H), 6.89 (dd, J = 12.7, 6.8 Hz, 1H), 3.85 (d, J = 2.9 Hz, 3H), 3.45 (d, J = 11.6 Hz, 1H), 3.18 - 3.09 (m, 2H), 2.96 (t, J = 10.9 Hz, 1H), 2.18 - 2.12 (m, 1H), 2.01 (t, J = 11.9 Hz, 1H), 1.86 (d, J = 10.2 Hz, 2H).

[0199] Preparation of Compound S20:

[0200]

[0201] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S20. 1 1H NMR (400 MHz, Methanol-d4): δ 8.44 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.55 (dd, J = 12.2, 7.3 Hz, 1H), 7.39 - 7.37 (m, 2H), 7.28 - 7.25 (m, 3H), 7.09 - 7.07 (m, 1H), 6.87 (dd, J = 12.6, 7.1 Hz, 1H), 4.87 (s, 2H), 3.84 (s, 3H), 3.36 (d, J = 11.6 Hz, 1H), 3.03 (d, J = 11.2 Hz, 2H), 2.94 - 2.88 (m, 1H), 2.16 - 2.09 (m, 1H), 2.99 - 1.96 (m, 1H), 1.82 - 1.78 (m, 1H), 1.71 - 1.66 (m, 1H).

[0202] Preparation of Compound S21:

[0203]

[0204] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S21. 11H NMR (400 MHz, Methanol-d4): δ 8.47 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.56 (dd, J = 12.6, 7.3 Hz, 1H), 7.10 (d, J = 1.4 Hz, 1H), 6.87 (dd, J = 12.6, 7.3 Hz, 1H), 3.92 (q, J = 7.0 Hz, 2H), 3.85 (s, 3H), 3.42 (d, J = 11.4 Hz, 1H), 3.11 (d, J = 11.6 Hz, 1H), 3.04 (d, J = 11.4 Hz, 1H), 2.97 - 2.91 (m, 1H), 2.20 - 2.11 (m, 1H), 2.03 (dd, J = 10.7, 4.0 Hz, 1H), 1.81 (d, J = 14.6 Hz, 1H), 1.68 (d, J = 13.2 Hz, 1H), 1.23 (t, J = 7.0 Hz, 3H).

[0205] Preparation of Compound S22:

[0206]

[0207] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S22. 1 1H NMR (400 MHz, Methanol-d4): δ 8.48 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.57 (dd, J = 12.2, 7.3 Hz, 1H), 7.10 (d, J = 1.5 Hz, 1H), 6.88 (dd, J = 12.2, 7.3 Hz, 1H), 4.09 (p, J = 6.2 Hz, 1H), 3.85 (s, 3H), 3.42 (d, J = 11.4 Hz, 1H), 3.11 (d, J = 11.4 Hz, 1H), 3.04 (d, J = 11.4 Hz, 1H), 2.94 (t, J = 10.4 Hz, 1H), 2.19 - 2.11 (m, 1H), 2.07 - 2.01 (m, 1H), 1.82 (m, 1H), 1.70 (m, 1H), 1.21 (dd, J = 6.2, 3.5 Hz, 6H).

[0208] Preparation of Compound S23:

[0209]

[0210] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S23. 11H NMR (400 MHz, Methanol-d4): δ 8.46 (s, 1H), 8.21 (s, 1H), 8.17 (s, 1H), 7.55 (dd, J = 12.2, 7.3 Hz, 1H), 7.09 (s, 1H), 6.85 (dd, J = 12.2, 7.3 Hz, 1H), 3.83 (s, 3H), 3.67 (dd, J = 7.2, 1.8 Hz, 2H), 3.41 (d, J = 12.0 Hz, 1H), 3.09 (d, J = 12.0 Hz, 1H), 3.03 (d, J = 11.3 Hz, 1H), 2.96 - 2.90 (m, 1H), 2.17 - 2.10 (m, 1H), 2.06 - 1.97 (m, 1H), 1.80 (dd, J = 11.5, 6.9 Hz, 1H), 1.67 (d, J = 13.3 Hz, 1H), 1.11 (m, 1H), 0.55 - 0.50 (m, 2H), 0.24 (m, 2H).

[0211] Preparation of Compound S24:

[0212]

[0213] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S24. 1 1H NMR (400 MHz, Methanol-d4): δ 8.49 (s, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 7.57 (dd, J = 12.6, 7.3 Hz, 1H), 7.12 (d, J = 1.4 Hz, 1H), 6.88 (dd, J = 12.6, 7.3 Hz, 1H), 4.47 - 4.40 (m, 1H), 3.86 (s, 3H), 3.44 (d, J = 11.4 Hz, 1H), 3.11 (d, J = 10.6 Hz, 1H), 3.04 (d, J = 11.3 Hz, 1H), 2.99 - 2.92 (m, 1H), 2.22 - 2.08 (m, 6H), 2.07 - 1.99 (m, 1H), 1.83 (m, 1H), 1.72 (m, 1H), 1.55 - 1.46 (m, 1H).

[0214] Preparation of Compound S25:

[0215]

[0216] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S25. 11H NMR (400 MHz, Methanol-d4): δ 8.53 (s, 1H), 8.24 (s, 1H), 8.22 (s, 1H), 7.60 (dd, J = 12.0, 7.3 Hz, 1H), 7.34 (s, 1H), 6.87 (dd, J = 12.4, 7.0 Hz, 1H), 4.38 (q, J = 8.6 Hz, 2H), 3.90 (s, 3H), 3.47 (s, 1H), 3.37 (s, 1H), 3.09 (s, 1H), 3.03 (d, J = 9.9 Hz, 1H), 2.22 (m, 1H), 2.02 (m, 1H), 1.95 (m, 2H).

[0217] Preparation of Compound S26:

[0218]

[0219] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S26. 1 1H NMR (400 MHz, Methanol-d4): δ 8.46 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 7.51 (dd, J = 10.8, 6.5 Hz, 1H), 7.12 (d, J = 1.4 Hz, 1H), 6.97 (dd, J = 11.5, 6.2 Hz, 1H), 3.38 (d, J = 11.4 Hz, 1H), 3.13 (d, J = 12.3 Hz, 1H), 3.00 (dt, J = 11.3, 1.7 Hz, 1H), 2.90 (td, J = 11.2, 2.8 Hz, 1H), 2.77 (s, 3H), 2.43 (s, 3H), 2.14 (td, J = 12.3, 3.9 Hz, 1H), 2.08 - 1.99 (m, 1H), 1.78 (dt, J = 13.6, 3.8 Hz, 1H), 1.64 - 1.61 (m, 1H).

[0220] Preparation of Compound S27:

[0221]

[0222] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S27. 11H NMR (400 MHz, Methanol-d4): δ 8.46 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 7.50 (dd, J = 10.8, 6.5 Hz, 1H), 7.11 (s, 1H), 6.97 (dd, J = 11.5, 6.2 Hz, 1H), 4.52 (t, J = 5.0 Hz, 1H), 4.41 (t, J = 5.0 Hz, 1H), 3.56 (t, J = 5.1 Hz, 1H), 3.49 (t, J = 5.1 Hz, 1H), 3.41 (d, J = 11.4 Hz, 1H), 3.11 (d, J = 11.7 Hz, 1H), 3.02 (d, J = 11.4 Hz, 1H), 2.95 - 2.89 (m, 1H), 2.42 (s, 3H), 2.15 (td, J = 12.2, 4.2 Hz, 1H), 2.07 - 1.98 (m, 1H), 1.82 - 1.77 (m, 1H), 1.65 (dd, J = 13.1, 4.6 Hz, 1H).

[0223] Preparation of Compound S28:

[0224]

[0225] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S28. 1 1H NMR (400 MHz, Methanol-d4): δ 8.48 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 7.51 (dd, J = 10.8, 6.5 Hz, 1H), 7.10 (q, J = 3.6, 2.5 Hz, 1H), 6.98 (dd, J = 11.5, 6.2 Hz, 1H), 3.73 (d, J = 11.1 Hz, 1H), 3.50 (d, J = 11.0 Hz, 1H), 3.12 (d, J = 11.4 Hz, 1H), 3.07 - 3.04 (m, 1H), 2.99 (d, J = 11.8 Hz, 1H), 2.93 (d, J = 11.8 Hz, 1H), 2.43 (s, 3H), 1.91 (m, 1H), 1.81 (m, 1H), 1.61 (m, 2H).

[0226] Preparation of Compound S29:

[0227]

[0228] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S29. 11H NMR (400 MHz, Methanol-d4): δ 8.55 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.56 (dd, J = 11.9, 6.3 Hz, 1H), 7.23 (s, 1H), 7.05 (dd, J = 11.6, 6.3 Hz, 1H), 3.34 (d, J = 12.1 Hz, 1H), 3.25 (d, J = 11.8 Hz, 1H), 3.09 (s, 1H), 3.00 (d, J = 9.7 Hz, 1H), 2.47 (s, 3H), 2.00 (m, 1H), 1.90 (m, 2H), 1.78 (m, 1H).

[0229] Preparation of Compound S30:

[0230]

[0231] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S30. 1 1H NMR (400 MHz, Methanol-d4): δ 8.51 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.50 (dd, J = 10.8, 6.4 Hz, 1H), 7.14 (d, J = 3.8 Hz, 1H), 6.96 (dd, J = 11.6, 6.2 Hz, 1H), 3.70 (d, J = 11.4 Hz, 1H), 3.25 (d, J = 11.4 Hz, 1H), 3.05 (s, 2H), 2.42 (s, 3H), 2.38 (s, 1H), 2.32 (s, 3H), 2.00 (s, 1H), 1.90 (m, 2H).

[0232] Preparation of Compound S31:

[0233]

[0234] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S31. 11H NMR (400 MHz, Methanol-d4): δ 8.53 (s, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.51 (dd, J = 10.8, 6.2 Hz, 1H), 7.11 (s, 1H), 6.97 (dd, J = 10.6, 6.2 Hz, 1H), 3.73 (d, J = 11.5 Hz, 1H), 3.21 (d, J = 11.5 Hz, 1H), 3.08 (m, 2H), 3.04 - 2.99 (m, 1H), 2.42 (s, 4H), 1.99 (m, 2H), 1.92 (m, 1H), 1.23 (d, J = 2.9 Hz, 3H), 1.21 (d, J = 3.1 Hz, 3H).

[0235] Preparation of Compound S32:

[0236]

[0237] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S32. 1 1H NMR (400 MHz, Methanol-d4): δ 8.51 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.51 (dd, J = 10.8, 6.4 Hz, 1H), 7.12 (s, 1H), 6.96 (dd, J = 11.1, 6.4 Hz, 1H), 3.69 (d, J = 11.6 Hz, 1H), 3.18 (d, J = 11.5 Hz, 1H), 3.08 (m, 2H), 2.42 (s, 3H), 2.38 (m, 1H), 2.06 - 1.99 (m, 2H), 1.90 (m, 2H), 0.99 - 0.87 (m, 4H).

[0238] Preparation of Compound S33:

[0239]

[0240] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S33. 1 1H NMR (400 MHz, Methanol-d4): δ 8.54 (s, 1H), 8.09 (s, 1H), 8.00 - 7.97 (m, 3H), 7.49 (dd, J = 10.8, 6.5 Hz, 1H), 7.11 - 7.07 (m, 3H), 6.94 (dd, J = 11.0, 6.5 Hz, 1H), 3.85 (d, J = 11.6 Hz, 1H), 3.25 (d, J = 11.5 Hz, 1H), 3.10 (m, 2H), 2.54 (m, 1H), 2.41 (s, 3H), 2.00 (m, 3H).

[0241] Preparation of Compound S34:

[0242]

[0243] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S34. 1 H NMR(400MHz,Methanol-d4):δ8.59(d,J=5.3Hz,2H),8.10(d,J=7.9Hz,1H),8.07(d,J=4.0Hz,2H),7.88(t,J=7.7Hz,1H),7.53(m,2H),7.12(s,1H),7.00(dd,J=11.6,6.2Hz,1H),3.91(d,J=11.5Hz,1H),3.33(s,1H),3.13(d,J=5.9Hz,2H),2.62-2.58(m,1H),3.45(s,3H),2.05-1.97(m,3H).

[0244] Preparation of Compound S35:

[0245]

[0246] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S35. 1 H NMR(400MHz,Methanol-d4):δ9.00(s,1H),8.56(s,1H),8.18(s,1H),8.16(s,1H),7.58-7.54(m,1H),7.17(s,1H),7.03(m,1H),3.77(d,J=11.6Hz,1H),3.41(d,J=11.4Hz,1H),3.09(m,2H),2.46(s,3H),2.02(m,4H).

[0247] Preparation of Compound S36:

[0248]

[0249] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S36. 11H NMR (400 MHz, Methanol-d4): δ 8.53 (s, 1H), 8.17 (s, 1H), 8.14 (s, 1H), 7.52 (dd, J = 10.9, 6.5 Hz, 1H), 7.15 (s, 1H), 6.99 (dd, J = 11.0, 6.5 Hz, 1H), 3.69 (d, J = 11.5 Hz, 1H), 3.32 (d, J = 11.3 Hz, 1H), 3.06 (s, 2H), 2.53 (s, 3H), 2.44 (s, 3H), 2.41 - 2.39 (m, 1H), 1.97 (s, 3H).

[0250] Preparation of Compound S37:

[0251]

[0252] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S37. 1 1H NMR (400 MHz, Methanol-d4): δ 8.44 (s, 1H), 8.09 (s, 1H), 7.53 (dd, J = 12.2, 7.3 Hz, 1H), 7.16 (d, J = 3.5 Hz, 1H), 6.93 (t, J = 2.0 Hz, 1H), 6.87 (dd, J = 12.2, 7.2 Hz, 1H), 6.69 (d, J = 3.5 Hz, 1H), 4.55 (t, J = 5.1 Hz, 1H), 4.43 (t, J = 5.1 Hz, 1H), 3.59 (t, J = 5.0 Hz, 1H), 3.52 (t, J = 5.0 Hz, 1H), 3.42 (d, J = 11.4 Hz, 1H), 3.11 (d, J = 11.0 Hz, 1H), 3.06 (m, 1H), 2.94 (m, 1H), 2.21 - 2.13 (m, 1H), 2.02 (m, 1H), 1.81 (m, 1H), 1.69 (m, 1H).

[0253] Preparation of Compound S38:

[0254]

[0255] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S38. 11H NMR (400 MHz, Methanol-d4): δ 8.46 (s, 1H), 8.24 (s, 1H), 7.60 (dd, J = 12.2, 7.3 Hz, 1H), 7.36 (s, 1H), 6.93 (dd, J = 12.6, 7.1 Hz, 1H), 4.55 (t, J = 5.1 Hz, 1H), 4.43 (t, J = 5.1 Hz, 1H), 3.88 (s, 3H), 3.60 (dd, J = 5.5, 4.6 Hz, 1H), 3.53 (dd, J = 5.5, 4.7 Hz, 1H), 3.42 (d, J = 11.5 Hz, 1H), 3.11 - 3.06 (m, 2H), 2.94 (m, 1H), 2.21 - 2.13 (m, 1H), 2.02 (m, 1H), 1.84 - 1.80 (m, 1H), 1.72 (m, 1H).

[0256] Preparation of Compound S39:

[0257]

[0258] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S39. 1 1H NMR (400 MHz, Methanol-d4): δ 8.50 (s, 1H), 8.28 (s, 1H), 7.63 - 7.57 (m, 2H), 6.93 (dd, J = 12.5, 7.1 Hz, 1H), 6.14 - 6.04 (m, 1H), 4.51 (t, J = 5.1 Hz, 1H), 4.39 (t, J = 5.0 Hz, 1H), 3.88 (s, 3H), 3.54 (t, J = 5.1 Hz, 1H), 3.47 (t, J = 5.1 Hz, 1H), 3.32 (s, 1H), 3.01 (m, 1H), 2.88 (m, 2H), 2.11 (td, J = 12.8, 4.5 Hz, 1H), 1.98 (m, 1H), 1.74 (m, 1H), 1.60 (m, 1H).

[0259] Preparation of Compound S40:

[0260]

[0261] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S40. 11H NMR (400 MHz, Methanol-d4): δ 8.51 (s, 1H), 8.11 (s, 1H), 7.56 (dd, J = 11.1, 6.4 Hz, 1H), 7.13 (s, 1H), 6.98 (dd, J = 11.0, 6.5 Hz, 1H), 6.06 (td, J = 55.6, 3.6 Hz, 1H), 3.88 (s, 3H), 3.68 (m, 1H), 3.34 (m, 2H), 3.06 (m, 2H), 2.44 (s, 3H), 2.42 (m, 1H).

[0262] Preparation of Compound S41:

[0263]

[0264] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S41. 1 1H NMR (400 MHz, Methanol-d4): δ 8.53 (s, 1H), 8.13 (s, 1H), 7.55 (dd, J = 11.4, 6.6 Hz, 1H), 7.13 (s, 1H), 6.98 (dd, J = 11.3, 6.5 Hz, 1H), 6.08 (td, J = 55.8, 3.2 Hz, 1H), 3.64 (m, 1H), 3.35 (m, 2H), 3.02 (m, 2H), 2.54 (s, 3H), 2.45 (s, 3H), 2.40 (m, 1H).

[0265] Preparation of Compound S42:

[0266]

[0267] Except for using different raw materials, the synthesis method is similar to that of S1, and then chiral resolution gives S42. 1 1H NMR (400 MHz, Methanol-d4): δ 8.51 (s, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 7.54 (dd, J = 11.1, 6.3 Hz, 1H), 7.13 (s, 1H), 6.99 (dd, J = 11.3, 6.3 Hz, 1H), 6.06 (td, J = 54.8, 3.6 Hz, 1H), 3.64 (m, 1H), 3.34 (m, 2H), 3.04 (m, 2H), 2.52 (s, 3H), 2.45 (s, 3H), 2.41 (m, 1H).

[0268] In vitro NSD2 inhibitory activity test of the compounds in Example 2

[0269] The enzymatic reaction of recombinant human NSD2 was carried out in a white 384-well plate using the AlphaLISA method. Briefly, it was diluted with experimental buffer (50 mM Tris-HCl, 0.01% Tween-20, 50 mM NaCl, 5 mM MgCl2, 1 mM DTT, pH 8.5) for 3 h, then 2 μL of NSD2 enzyme solution (10 nM), 2 μL of substrate (20 μM SAM, 0.15 ng / mL nucleosome), 1 μL of the test compound or control at the corresponding concentration (2% DMSO as the positive control and SAH as the negative control) were added, and then 2.5 μL of high-salt buffer (50 mM Tris-HCl, 1 M NaCl, 0.1% Tween-20, 0.3% poly-L-lysine, pH 7.4) was added to terminate the reaction. The AlphaLISA NSD2 histone H3 lysine-N-methyltransferase activity assay was used to detect the activity of NSD2. The fluorescence intensity was measured at excitation and emission wavelengths of 680 and 615 nm, respectively, using an Envision fluorescence spectrophotometer. The experimental results were calculated for the IC 50 value as shown in Table 1 (+++, IC 50 :< 0.05 μM; ++, IC 50 : 0.05 - 1 μM; +, IC 50 : > 1 μM).

[0270] Table 1 Results of NSD2 inhibitory activity of compounds

[0271]

[0272]

[0273] As can be seen from Table 1: Most of the compounds in the present invention have no less than the positive control drug 78 in terms of NSD2 inhibitory activity, especially the NSD2 inhibitory activities of multiple compounds such as S7, S27, and S28 are significantly higher than those of the positive control drug.

[0274] The structures of the positive control drug 78 and the compounds S7, S27, and S28 of the present application are shown as follows:

[0275]

[0276] Example 3 In vitro tumor cell proliferation inhibition experiment

[0277] All multiple myeloma KMS-11 cell lines were cultured in RPMI-1640 medium containing 10% FBS. 6000-20000 cells were seeded into 96-well plates in triplicate for 24 hours. After 2 days of continuous culture, the cells were treated with compounds at different concentrations. According to the instructions of the manufacturer, a cell counting kit CCK-8 was used to detect cell viability. The optical density measured at a wavelength of 450 nm was used as an indicator of cell viability.

[0278] Table 2 Results of the inhibitory activity of compounds on tumor cell proliferation

[0279]

[0280]

[0281] As can be seen from Table 2: The inhibitory activities of multiple compounds in the present invention, including S7, S27, and S28, on multiple myeloma cells are significantly higher than those of the positive control drug 78.

[0282] In summary, based on the existing piperidinylmethylpurine amine NSD2 inhibitor 78, structural modifications were made at the easily metabolized site of the pyridine benzyl methylene and other modifiable sites in the present invention to obtain a novel class of NSD2 inhibitors. The NSD2 inhibitory activity and antitumor activity of this class of target molecules are both improved compared to 78, and it has good application potential for preventing or treating diseases in organisms related to increased NSD2 expression or activity, especially malignant tumors.

[0283] All documents mentioned in the present invention are cited herein as references, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A compound of formula I, its pharmaceutically acceptable salt, its racemate, its deuterated derivative or its isomer: Wherein: R1 is selected from fluorine, hydrogen; Z is selected from the group consisting of: O, S, Se; X and Y are each independently selected from the group consisting of: CH, N; R2, R3, and R4 are each independently selected from the group consisting of: hydrogen, deuterium, substituted or unsubstituted C1-C8 alkyl; wherein, said substitution means being substituted by 1, 2, 3, 4, 5 or 6 substituents selected from the group consisting of: deuterium, halogen, amino, hydroxy, mercapto, cyano; And when R1 is hydrogen and Z is S or Se, R2, R3, and R4 are not all hydrogen; R5 is selected from the group consisting of: hydrogen, cyano, -COOH, -CONH2, -CONHOH, -CONR a R b , C1-C8 alkyl, C1-C6 alkyl-O-C1-C6 alkylene-, C3-C6 cycloalkyl-(CH2) 0-1 O-C1-C6 alkylene-, 3-10 membered heterocycloalkyl-(CH2) 0-1 O-C1-C6 alkylene-, C1-C6 alkyl-NH-C1-C6 alkylene-, C3-C6 cycloalkyl-(CH2) 0-1 NH-C1-C6 alkylene-, 3-10 membered heterocycloalkyl-(CH2) 0-1 NH-C1-C6 alkylene-, C1-C6 alkyl-NH(C=O)-C0-C6 alkylene-, C3-C6 cycloalkyl-(CH2) 0- 1NH(C=O)-C0-C6 alkylene-, 3-10 membered heterocycloalkyl-(CH2) 0-1 NH(C=O)-C0-C6 alkylene-, C6-C10 aryl-(CH2) 0-1 NH(C=O)-C0-C6 alkylene-, 5-10 membered heteroaryl-(CH2) 0-1 NH(C=O)-C0-C6 alkylene-, C0-C6 alkyl-ONH(C=O)-C0-C6 alkylene-, C3-C6 cycloalkyl-(CH2) 0-1 ONH(C=O)-C0-C6 alkylene-, 3-10 membered heterocycloalkyl-(CH2) 0-1 ONH(C=O)-C0-C6 alkylene-, C6-C10 aryl-(CH2) 0-1 ONH(C=O)-C0-C6 alkylene-, 5-10 membered heteroaryl-(CH2) 0-1 ONH(C=O)-C0-C6 alkylene-, C2-C8 alkenyl, C2-C8 alkynyl, 3-10 membered cycloalkyl, monocyclic or fused 5-10 membered heteroaryl, C6-C10 aryl-(C0-C6 alkylene)-, monocyclic or fused 5-10 membered heteroaryl-(C0-C6 alkylene)-, CH≡C-CH2-O-C1-C6 alkylene-, C1-C6 alkyl-S(=O)2-O-C1-C6 alkylene-, C1-C6 alkyl-S(=O)2-NH-C1-C6 alkylene-; R a and R b each independently selected from: hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or R a and R b together with the atoms attached thereto form a 3- to 10-membered heteroalkyl group; wherein, except for -COOH and -CONH2, the hydrogen in each of the above-mentioned groups is optionally substituted by 1, 2, 3, 4, 5 or 6 R c substituted; Each R c is independently selected from: amino, hydroxy, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -(C=O)-O-C1-C6 alkyl, unsubstituted or hydroxy-substituted C1-C6 alkoxy, =O, C6-C10 aryl, 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C3-C6 cycloalkyl and C6-C10 aryl are optionally substituted with 0, 1, 2, 3 or 4 halogens or hydroxy groups; When R1 is hydrogen and Z is O, both R2 and R3 are not hydrogen, and R5 is not selected from substituted or unsubstituted C1-C8 alkyl; The heteroaryl and heterocycloalkyl each independently contain 1, 2, 3, 4, 5 or 6 heteroatoms, and the heteroatoms are each independently selected from N, O or S.

2. The compound according to claim 1, characterized in that, R2, R3, and R4 are each independently selected from the group consisting of: hydrogen, deuterium, methyl; The 5- to 10-membered heteroaryl group is selected from:

3. The compound according to claim 1, wherein Having the structure of formula II: Wherein, X and Y are each independently selected from the group consisting of: CH, N; Z is selected from the group consisting of: O, S; R4 is substituted or unsubstituted C1-C6 alkyl; wherein, said substitution means being substituted by 1, 2 or 3 substituents selected from the group consisting of: deuterium, halogen; R5 is selected from the group consisting of: C1-C8 alkyl, C1-C6 alkyl-OCH2-, C3-C6 cycloalkyl-(CH2) 0-1 OCH2-, C1-C6 alkyl-NH(C=O)-, C3-C6 cycloalkyl-(CH2) 0-1 NH(C=O)-, 5-10 membered heteroaryl-(CH2) 0-1 NH(C=O)-, C1-C6 alkyl-ONH(C=O)-, C3-C6 cycloalkyl-(CH2) 0-1 ONH(C=O)-, 5-10 membered heteroaryl-(CH2) 0-1 ONH(C=O)-, 5-6 membered heteroaryl; wherein the hydrogen in each of the above groups is optionally substituted by 1, 2 or 3 R c substituents; Each R c is independently selected from: hydroxyl, halogen, C1-C6 alkyl optionally substituted with 0, 1, 2, 3 or 4 halogens, C3-C6 cycloalkyl, C6-C10 aryl optionally substituted with 0, 1, 2, 3 or 4 halogens, 5-10 membered heteroaryl; The heteroaryl contains 1, 2 or 3 heteroatoms, and the heteroatoms are each independently selected from N, O or S.

4. The compound according to claim 1, wherein Having the structure of formula III: Wherein, X and Y are each independently selected from the group consisting of: CH, N; R4 is substituted or unsubstituted C1-C6 alkyl; wherein, said substitution means being substituted by 1, 2 or 3 substituents selected from the group consisting of: deuterium, halogen; R5 is selected from the group consisting of: C1-C8 alkyl, C1-C6 alkyl-OCH2-, C3-C6 cycloalkyl-(CH2) 0-1 OCH2-, C1-C6 alkyl-NH(C=O)-, C3-C6 cycloalkyl-(CH2) 0-1 NH(C=O)-, 5-10 membered heteroaryl-(CH2) 0-1 NH(C=O)-, C1-C6 alkyl-ONH(C=O)-, C3-C6 cycloalkyl-(CH2) 0-1 ONH(C=O)-, 5-10 membered heteroaryl-(CH2) 0-1 ONH(C=O)-, 5-6 membered heteroaryl; wherein the hydrogen in each of the above groups is optionally substituted by 1, 2 or 3 R c substituted; Each R c is independently selected from: hydroxy, halogen, C1-C6 alkyl optionally substituted by 0, 1, 2, 3 or 4 halogens, C3-C6 cycloalkyl, C6-C10 aryl optionally substituted by 0, 1, 2, 3 or 4 halogens, 5-10 membered heteroaryl; The heteroaryl contains 1, 2 or 3 heteroatoms, and the heteroatoms are each independently selected from N, O or S.

5. The compound according to claim 1, wherein Having the structure of formula IV: Wherein, X and Y are each independently selected from the group consisting of: CH, N; R4 is substituted or unsubstituted C1-C6 alkyl; wherein, said substitution means being substituted by 1, 2 or 3 substituents selected from the group consisting of: deuterium, halogen; R5 is selected from the group consisting of: C1-C6 alkyl - OCH2-, C3-C6 cycloalkyl-(CH2) 0-1 OCH2-, C1-C6 alkyl - NH(C=O)-, C3-C6 cycloalkyl-(CH2) 0-1 NH(C=O)-, 5-10 membered heteroaryl-(CH2) 0-1 NH(C=O)-, C1-C6 alkyl - ONH(C=O)-, C3-C6 cycloalkyl-(CH2) 0-1 ONH(C=O)-, 5-10 membered heteroaryl-(CH2) 0-1 ONH(C=O)-, 5-6 membered heteroaryl; wherein the hydrogen in each of the above groups is optionally substituted by 1, 2 or 3 R c substituents; Each R c is independently selected from: hydroxy, halogen, C1-C6 alkyl optionally substituted with 0, 1, 2, 3 or 4 halogens, C3-C6 cycloalkyl, C6-C10 aryl optionally substituted with 0, 1, 2, 3 or 4 halogens, 5-10 membered heteroaryl; The heteroaryl contains 1, 2 or 3 heteroatoms, and the heteroatoms are each independently selected from N, O or S.

6. The compound according to claim 1, characterized in that, Having the structure of formula V: X and Y are each independently selected from the group consisting of: CH, N; R4 is substituted or unsubstituted C1-C6 alkyl; wherein, said substitution means being substituted by 1, 2 or 3 substituents selected from the group consisting of: deuterium, halogen; R6 and R7 are each independently selected from: hydrogen, C1-C6 alkyl - OCH2-, C3-C6 cycloalkyl-(CH2) 0-1 OCH2-, C1-C6 alkyl-, C3-C6 cycloalkyl-(CH2) 0-1 -, 5-10 membered heteroaryl-(CH2) 0-1 -, C1-C6 alkyl - O-, C3-C6 cycloalkyl-(CH2) 0-1 O-, 5-10 membered heteroaryl-(CH2) 0-1 O-; wherein the hydrogen in each of the above groups is optionally substituted by 1, 2 or 3 R c substituents; Each R c is independently selected from: hydroxy, halogen, C1-C6 alkyl optionally substituted by 0, 1, 2, 3 or 4 halogens, C3-C6 cycloalkyl, C6-C10 aryl optionally substituted by 0, 1, 2, 3 or 4 halogens, 5-10 membered heteroaryl; The heteroaryl contains 1, 2 or 3 heteroatoms, and the heteroatoms are each independently selected from N, O or S.

7. The compound according to claim 1, wherein The compound is selected from:

8. A pharmaceutical composition comprising one or more safe and effective amounts of the compound, its pharmaceutically acceptable salt, its racemate, its deuterated derivative or its isomer as described in any one of claims 1-7; and a pharmaceutically acceptable carrier or excipient.

9. Use of a compound as claimed in any one of claims 1 - 7, a pharmaceutically acceptable salt thereof, a racemate thereof, a deuterated derivative thereof or an isomer thereof, or a pharmaceutical composition as claimed in claim 8, characterized in that The uses are: 1) For preparing a drug for preventing and / or treating NSD2-related diseases; and / or 2) For inhibiting the activity of NSD2; and / or 3) For reducing the expression level of NSD2.

10. The use according to claim 9, characterized in that, The NSD2-related diseases are selected from: breast cancer, cervical cancer, skin cancer, ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, lung cancer, hepatocellular carcinoma, head and neck cancer, peripheral nerve sheath tumor, osteosarcoma, multiple myeloma, neuroblastoma, leukemia, non-Hodgkin lymphoma, or a combination thereof; Preferably, the skin cancer is squamous cell carcinoma; Preferably, the leukemia is acute lymphoblastic leukemia; Preferably, the non-Hodgkin lymphoma is mantle cell lymphoma.

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