Methyl transferase inhibitor and application thereof

Abstract

The compound with methyltransferase inhibitory activity has a structure as shown in a formula I and can be used for treating and preventing diseases related to a PRC2 compound or a constituent monomer thereof. # imgabs0 #

Description

A class of methyltransferase inhibitors and uses thereof

[0001] The present invention relates to the field of pharmaceutical compounds. Specifically, the present invention provides a class of compounds for inhibiting PRC2 complexes, monomers, or combinations thereof, and uses thereof in drugs and drug combinations.

[0002] Site-specific lysine methylation on histones is one of the important epigenetic mechanisms that control and mediate many fundamental biological processes.

[0003] The epigenome behaves differently in transcriptionally active and silent regions. The polycomb family repressive complex 2 (PRC2) plays a key role in gene silencing by selectively occupying chromatin transcriptionally silent sites. PRC2 consists of four core components and several cofactors that regulate its activity: enhancer of zeste 1 or 2 (EZH1 / 2), embryonic ectoderm development (EED), suppressor of zeste 12 (SUZ12), and retinoblastoma-associated proteins 46 and 48 (RBAP46 / RBAP48). EZH1 / 2 is the catalytic subunit of the methyltransferase responsible for the mono-, di-, and tri-methylation of lysine 27 of histone H3 (H3K27me1 / 2 / 3). EED enhances the enzymatic activity of PRC2 by binding to H3K27me3. SUZ12 interacts with all other subunits and contributes to the stability of the complex. RBAP46 / RBAP48 (also known as RBBP4 / 7) recognize histones H3 and H4 and may regulate the substrate specificity of PRC2. PRC2 is the only known H3K27 methyltransferase, and its mediated trimethylation of H3K27 (H3K27me3) ultimately leads to gene silencing at specific sites by changing chromatin structure (chromatin compaction).

[0004] In human diseases, including tumors, PRC2 proteins often mutate or become dysregulated. Studies have found that PRC2 components are overexpressed in many solid tumors (including but not limited to ovarian cancer, breast cancer, prostate cancer, endometrial cancer, melanoma, bladder cancer, lung cancer, and liver cancer). In addition, specific missense mutations have been found in patients with two types of hematological malignancies, DLBCL (diffuse large B-cell lymphoma) and FL (follicular lymphoma), which can enhance the catalytic activity of PRC2. At the same time, some in vivo and in vitro results also show that the proliferation and metastasis of many tumor cell lines depend on PRC2 activity. Therefore, gene knockdown or knockout or small molecule drugs to inhibit EZH2 or other PRC2 core components can inhibit the proliferation of many types of tumor cell lines (such as leukemia, lymphoma, prostate cancer, breast cancer, lung cancer, and kidney cancer). Current preclinical studies have shown that secondary mutations of EZH2 can produce acquired drug resistance, and its homologous EZH1 also has methyltransferase activity, which will lead to limited activity of EZH2 inhibitors. At the same time, the EZH2 subunit itself is inactive and must be assembled with SUZ12 and EED into the PRC2 protein complex to produce methyltransferase activity. Therefore, the development of new inhibitors targeting the entire PRC2 protein complex has attracted attention.

[0005] In addition, IFN-γ plays a key role in the pathogenesis of many autoimmune diseases, and the relative lack of IFN-γ is a characteristic of some chronic infections and tumor tolerance in humans. Inhibition of EZH2 significantly increased the expression of IFN-γ in naive CD4+ T cells, which may promote IFN-γ-dependent anti-tumor immunity, but this inhibition of EZH2 to promote IFN-γ expression requires dependence on other components of PRC2.

[0006] Therefore, PRC2 provides a pharmacological target for solid tumors and some hematological malignancies. Targeted inhibition of the methyltransferase activity of EZH2 has been shown to be a successful cancer treatment strategy and may also play an important role in tumor immunity.

[0007]

[0008] The object of the present invention is to provide a small molecule compound for inhibiting the PRC2 protein complex or a combination of one or more proteins constituting the complex.

[0009] The first aspect of the present invention provides a compound as shown in the following formula I, or a pharmaceutically acceptable salt or deuterated product, a racemic mixture and an optical monomer product thereof:

[0010] Wherein, the A ring is selected from the following group: a 5-10 membered bridged ring (including a carbocyclic ring and a heterocyclic ring), a 6-10 membered aromatic ring, and a 5-10 membered heteroaromatic ring;

[0011] Ring B is selected from the group consisting of a 6-10 membered aromatic ring, a 5-14 membered heteroaromatic ring;

[0012] The C ring is selected from the following group: a 5-10 membered aromatic ring or a partially saturated aromatic ring, a 5-10 membered heteroaromatic ring or a partially saturated heteroaromatic ring, a 5-10 membered saturated or partially unsaturated carbocyclic ring (including fused rings and bridged rings), a 5-10 membered saturated or partially unsaturated heterocyclic ring (including fused rings and bridged rings);

[0013] L1 and L2 are each independently -(L) p -, and each L is independently selected from the following group: a chemical bond or none, or -O-, -CHR-, -CHR-NH-, carbonyl, S, -NR-, -NHC(O)-, -NHS(O)2-, -NHC(O)NH-, -NHC(S)NH-, -COO-, -OS(O)2-, -CHR-NR-, -C(R)2NR-, -C(R)2-; wherein each R is independently selected from the following group: H, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-4 Cycloalkyl, or a substituted or unsubstituted 3-4 membered heterocycle;

[0014] n is selected from the group consisting of 0, 1, 2, 3, 4 or 5;

[0015] m is selected from the group consisting of 0, 1, 2, 3 or 4;

[0016] p is selected from the following group: 0, 1 or 2;

[0017] Each of R1, R2 and R3 is independently selected from the following group: H, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 alkylamide, substituted or unsubstituted C1-C6 alkyl C(O)O, or substituted or unsubstituted C1-C6 alkyl OC(O), substituted or unsubstituted amide, substituted or unsubstituted amine (NH2), substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 carbocycle (including saturated or partially unsaturated), substituted or unsubstituted 3-6 membered heterocycle (including saturated or partially unsaturated), or is -XZY-R5;

[0018] Wherein, X and Y are each independently selected from the following group: a chemical bond, or -O-, -C(R5)2-, -S-, -NR5-;

[0019] Z is selected from the group consisting of C(O), NH, CH=CH, -C(R5)2-, S(O), S(O)2;

[0020] Each R5 is independently selected from the following group: H, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 carbocyclic ring (including saturated or partially unsaturated), substituted or unsubstituted 3-6 membered heterocyclic ring, substituted or unsubstituted C 6-10 an aromatic ring, a substituted or unsubstituted 5-12-membered heteroaromatic ring, a substituted or unsubstituted C1-C6 alkyl C(O)O, or a substituted or unsubstituted C1-C6 alkyl OC(O), or a substituted or unsubstituted 5-9-membered heterospiro ring;

[0021] or two connected R1, R2 or R3 connected to adjacent ring atoms on the ring together form a ring structure selected from the following group: substituted or unsubstituted C 6-10 substituted or unsubstituted 5-12-membered heteroaromatic ring, substituted or unsubstituted C3-C8 carbocyclic ring (including saturated or partially unsaturated), substituted or unsubstituted 3-8-membered heterocyclic ring (including saturated or partially unsaturated); or two connected R1, R2 or R3 connected to the same carbon atom of adjacent rings together with the adjacent ring form a 3-8-membered saturated or partially unsaturated spirocyclic structure, or a 3-8-membered saturated or partially unsaturated heterospirocyclic structure (herein, the ring formed by the substituent is 3-8 members, excluding the adjacent ring);

[0022] Wherein, the ring skeleton of each of the above heterocyclic rings may contain 1-3 heteroatoms selected from boron, oxygen, sulfur, phosphorus and nitrogen; in particular, when the atoms are boron, sulfur, phosphorus and nitrogen, the ring skeleton atoms may be oxidized, such as S(O) or S(O)2;

[0023] Unless otherwise specified, in the above formulae, the substitution refers to the corresponding group being substituted by one or more substituents selected from the group consisting of deuterium, tritium, halogen, oxo, =NH, =N(C 1-8 alkyl), hydroxyl, carboxyl, mercapto, benzyl, C1-C 12 Alkoxycarbonyl, C1-C6 aldehyde, amino, C1-C6 amide, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkyl-CN, unsubstituted or halogenated C3-C8 cycloalkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C6 alkoxy, C1-C6 alkyl-amino, C6-C 10 Aryl, five-membered or six-membered heteroaryl, 3-8-membered non-aromatic heterocyclic group, -O-(C6-C 10 aryl), -O-(five-membered or six-membered heteroaryl), C1-C 12 Alkylaminocarbonyl, unsubstituted or halogenated C2-C 10Acyl, sulfonyl (-SO2-OH), phosphoryl (-PO3-OH), unsubstituted or halogenated C1-C4 alkyl-S(O)2-, unsubstituted or halogenated C1-C4 alkyl-SO-, unsubstituted or halogenated C1-C4 alkylamino-S(O)2-;

[0024] Wherein, each chiral atom in the molecule can be in R configuration, S configuration, or a combination thereof.

[0025] In another preferred embodiment, the B ring is a 6-10 membered heteroaromatic ring, and the R1 is selected from the following group: H, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino; or two R1 connected to adjacent ring atoms together constitute a cyclic structure selected from the following group: substituted or unsubstituted C3-C6 carbocycle (including saturated or partially unsaturated), substituted or unsubstituted 3-6 membered heterocycle (including saturated and partially unsaturated).

[0026] In another preferred embodiment, the B ring has a structure selected from the following group (wherein the connection site can be located on any ring atom):

[0027] In another preferred embodiment, the A ring has a structure selected from the following group (wherein the connection site can be located on any ring atom):

[0028] In another preferred embodiment, the R2 has a structure as shown below:

[0029] Wherein, L3 is selected from the following group: -C(R5)2-C(O)-, -C(R5)2-;

[0030] R3 is selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl;

[0031] R6 is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 carbocyclic ring (including saturated or partially unsaturated), substituted or unsubstituted 3-6 membered heterocyclic ring; the ring skeleton of the heterocyclic ring may contain 1-3 heteroatoms selected from oxygen and sulfur; and the ring skeleton atoms may be oxidized;

[0032] The substitution refers to the substitution of the hydrogen atoms on the corresponding group by one or more substituents selected from the group consisting of deuterium, tritium, halogen, oxo, hydroxyl, carboxyl, mercapto, benzyl, cyano, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, C2-C10 alkenyl, C1-C6 alkoxy, C1-C6 alkyl-amino, C6-C 10 Aryl, 5-membered or 6-membered heteroaryl, 3-8-membered non-aromatic heterocyclic group.

[0033] In another preferred embodiment, the R2 is -CHR-C(O)NH-R6, wherein R is H or substituted or unsubstituted C 1- 4-alkyl, substituted or unsubstituted C1-C6 alkoxy, hydroxyl, substituted or unsubstituted amino; R6 is selected from the following group: substituted or unsubstituted C3-C6 carbocycle (including saturated or partially unsaturated), substituted or unsubstituted 3-6-membered heterocycle (including saturated or partially unsaturated).

[0034] In another preferred embodiment, the compound has a structure shown in the following formula II:

[0035] Wherein, X, Y are each independently selected from the following group: O, NR3, C(R3)2; -C(=O)-

[0036] Or the compound has a structure shown in the following formula III:

[0037] Wherein, X1, X2, X3 or X4 are each independently selected from the following group: N, CR3;

[0038] Or the compound has a structure shown in the following formula IV:

[0039] Wherein, X1, X2, X3 or X4 are each independently selected from the following group: O, S, N, NR3 or CR3;

[0040] is a single bond or a double bond;

[0041] The definitions of the remaining groups are the same as those described in the first aspect of the present invention.

[0042] In another preferred embodiment, the L1 is selected from the following group: chemical bond, -O-, -CHR-, carbonyl, S, -NH-; the L2 is selected from the following group: chemical bond, -CHR-NH-, -CHR-O-, -CHR-S-, -(CHR)2-.

[0043] The second aspect of the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound as described in the first aspect of the present invention, its pharmaceutically acceptable salts, racemates, optical isomers, stereoisomers or tautomers, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents.

[0044] The third aspect of the present invention provides a use of the compound described in the first aspect of the present invention, its racemate, optical isomer monomer and mixture thereof or pharmaceutically acceptable salt in the preparation of a drug for treating or preventing diseases associated with mutations, overexpression, or dysregulated H3K27 methylation levels of the PRC2 complex, monomer, or combination thereof.

[0045] In another preferred embodiment, the disease is selected from the following group: tumors and autoimmune diseases.

[0046] In another preferred embodiment, the disease is selected from the group consisting of lymphoma, hematological malignancies, sarcoma, prostate cancer, breast cancer, kidney cancer, urothelial carcinoma, gastric cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, liver cancer, pancreatic cancer, colon cancer, head and neck cancer, brain tumor, melanoma, mesothelioma, gastrointestinal stromal tumor, psoriasis and lupus erythematosus.

[0047] In another preferred embodiment, the disease is selected from the group consisting of non-Hodgkin's lymphoma, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, chronic lymphocytic leukemia, acute and chronic myeloid leukemia, acute and chronic lymphocytic leukemia, multiple myeloma, myelodysplastic syndrome, epithelioid sarcoma, rhabdomyosarcoma, liposarcoma, prostate cancer, breast cancer, kidney cancer, bladder cancer, upper urothelial carcinoma, gastric cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, liver cancer, pancreatic cancer, colon cancer, head and neck cancer, blastoma, glioma, schwannoma, melanoma, mesothelioma, gastrointestinal stromal tumor, psoriasis and lupus erythematosus.

[0048] 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 embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

[0049] The inventors, through extensive and in-depth research, unexpectedly discovered for the first time a class of compounds that have the function of regulating H3K27 methylation levels, and completed the present invention on this basis.

[0050] the term

[0051] In the present invention, the halogen is F, Cl, Br or I.

[0052] In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art. In the present invention, if not otherwise specified, all chemical formulae are intended to cover any possible optical or geometric isomers (e.g., R-type, S-type or racemate, or cis-trans isomers of olefins, etc.).

[0053] In the present invention, the term "C1-C6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0054] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

[0055] In the present invention, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0056] In the present invention, the term "C2-C6 alkynyl" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0057] In the present invention, the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl, etc. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.

[0058] In the present invention, the term "C3-C10 cycloalkenyl" refers to a cyclic alkenyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and cyclodecyl, etc. The term "C3-C7 cycloalkenyl" has a similar meaning.

[0059] In the present invention, the term "C1-C12 alkoxycarbonyl" refers to an alkoxycarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including but not limited to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl and the like.

[0060] In the present invention, the term "C1-C12 alkylaminocarbonyl" refers to an alkylaminocarbonyl group having 1 to 12 carbon atoms in the alkyl chain, including but not limited to methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, dimethylaminocarbonyl and the like.

[0061] In the present invention, the term "aromatic ring" or "aryl" has the same meaning, preferably "aryl" is "C6-C12 aryl" or "C6-C10 aryl". The term "C6-C12 aryl" refers to an aromatic ring group having 6 to 12 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc. The term "C6-C10 aryl" has a similar meaning.

[0062] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms. The heteroatoms referred to here include oxygen, sulfur and nitrogen. For example, furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0063] In the present invention, the term "3-12 membered heterocyclic group" refers to a saturated or unsaturated 3-12 membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, such as dioxolanyl, etc. The term "3-7 membered heterocyclic group" has a similar meaning.

[0064] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is a substituent described above, or a substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl, may be connected to another ring, such as a cycloalkyl, to form a spiro bicyclic system, for example, two rings having a common carbon atom. It will be appreciated by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents include, but are not limited to, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, C1-C12 alkoxycarbonyl, amino, alkoxy, C1-10 sulfonyl, etc.

[0065] H3K27 methylation level modulator compounds

[0066] The present invention provides a class of compounds that have the effect of regulating H3K27 methylation levels:

[0067] Wherein, the A ring is selected from the following group: a 5-10 membered bridged ring (including a carbocyclic ring and a heterocyclic ring), a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring (preferably a benzene ring or a 5-6 membered aromatic heterocyclic ring);

[0068] Ring B is selected from the following group: a 6-10 membered aromatic ring, a 5-14 membered heteroaromatic ring (preferably an 8-14 membered aromatic heterocyclic ring) or a partially saturated 5-12 membered heterocyclic ring (preferably an 8-14 membered aromatic heterocyclic ring);

[0069] The C ring is selected from the following group: a 5-10 membered aromatic ring or a partially saturated aromatic ring, a 5-10 membered aromatic heterocyclic ring or a partially saturated aromatic heterocyclic ring, a 5-10 membered saturated or partially unsaturated carbocyclic ring (including condensed rings and bridged rings), a 5-10 membered saturated or partially unsaturated heterocyclic ring (including condensed rings and bridged rings);

[0070] L1 and L2 are each independently -(L) p -, and each L is independently selected from the following group: a chemical bond or none, or -O-, -CHR-, -CHR-NH-, carbonyl, S, -NH-, -NHC(O)-, -NHS(O)2-, -NHC(O)NH-, -NHC(S)NH-, -COO-, -OS(O)2-, -NR-, -C(R)2NH-, -C(R)2NR-; wherein R is selected from the following group: H or substituted or unsubstituted C 1-4 Alkyl or cycloalkyl, or substituted or unsubstituted 3-4 membered heterocycle;

[0071] n is selected from the group consisting of 0, 1, 2, 3, 4 or 5;

[0072] m is selected from the group consisting of 0, 1, 2, 3 or 4;

[0073] p is selected from the following group: 0, 1 or 2;

[0074] Each R1, R2 and R3 is independently selected from the following group: H, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 alkylamide or ester, substituted or unsubstituted amide, substituted or unsubstituted amine, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C6 carbocycle (including saturated or partially unsaturated), substituted or unsubstituted 3-C6 alkyl, substituted or unsubstituted ... alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkyl -6-membered heterocycle, or -XC(O)Y-R5; wherein X and Y are each independently selected from the following group: a chemical bond, or -O-, -C(R5)2-, -S-, -NR5-; R5 is selected from the following group: H, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 carbocycle (including saturated or partially unsaturated), substituted or unsubstituted 3-6-membered heterocycle; or two connected R1, R2 or R3 connected to adjacent ring atoms on the ring together constitute a cyclic structure selected from the following group: substituted or unsubstituted C 6-10 an aromatic ring, a substituted or unsubstituted 5-12-membered heteroaromatic ring, a substituted or unsubstituted C3-C8 carbocyclic ring (including saturated or partially unsaturated), a substituted or unsubstituted 3-8-membered heterocyclic ring (including saturated or partially unsaturated); or two connected R1, R2 or R3 connected to the same carbon atom of adjacent rings together with the adjacent ring constitute a saturated or partially unsaturated spirocyclic structure, or a heterospirocyclic structure;

[0075] Wherein, the ring skeleton of each of the above heterocycles may contain 1-3 heteroatoms selected from boron, oxygen, sulfur, phosphorus and nitrogen; in particular, when the atoms are boron, sulfur, phosphorus and nitrogen, the ring skeleton atoms may be oxidized, such as S(O) or S(O)2.

[0076] Unless otherwise specified, in the above formulae, the substitution refers to the substitution of hydrogen atoms on the corresponding groups by one or more substituents selected from the group consisting of deuterium, tritium, halogen, hydroxyl, carboxyl, mercapto, benzyl, C1-C 12 Alkoxycarbonyl, C1-C6 aldehyde, amino, C1-C6 amide, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, C2-C 10 alkenyl, C1-C6 alkoxy, C1-C6 alkyl-amino, C6-C 10 aryl, five-membered or six-membered heteroaryl, five-membered or six-membered non-aromatic heterocyclic group, -O-(C6-C 10 aryl), -O-(five-membered or six-membered heteroaryl), C1-C 12Alkylaminocarbonyl, unsubstituted or halogenated C2-C 10 Acyl, sulfonyl (-SO2-OH), phosphoryl (-PO3-OH), unsubstituted or halogenated C1-C4 alkyl-S(O)2-, unsubstituted or halogenated C1-C4 alkyl-SO-;

[0077] Wherein, each chiral atom in the molecule may be in R configuration, S configuration, or a combination thereof; the olefin configuration may be cis, trans, or a mixture thereof.

[0078] Pharmaceutical compositions and methods of administration

[0079] Since the compounds of the present invention have excellent methyltransferase inhibitory activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate related diseases caused by abnormal activity or expression of RC2 complexes, monomers, or combinations thereof.

[0080] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 5-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0081] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0082] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0083] 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 (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0084] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0085] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0086] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0087] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0088] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0089] Dosage forms for topical administration of the compounds of the invention 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.

[0090] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. In some preferred embodiments, the compounds of the present invention can be administered together with other small molecule compounds to form PROTAC, or together with other macromolecular compounds such as monoclonal antibodies to form ADC.

[0091] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill range of a skilled physician.

[0092] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0093] Example 1: Synthesis of compound 2-[2-[[4-[(8-chloro-1,7-naphthyridin-2-yl)amino]-1-bicyclo[2.2.2]octyl]methylamino]pyrimidin-5-yl]-N-(oxetane-3-yl)acetamide (PA046)

[0094] Step 1: Dissolve tert-butyl ((4-aminobicyclo[2.2.2]octan-1-yl)methyl)carbamate (PA046-a) (100 mg, 0.393 mmol) and 2-chloro-8-methoxy-1,7-naphthyridine (78 mg, 0.393 mmol) in 2 ml of dimethyl sulfoxide, then add potassium fluoride (114 mg, 1.97 mmol, 46.05 μL) and 2-[2-(2-methoxyethoxy)ethoxy]ethanol 65 mg, 0.393 mmol). The reaction solution was stirred at 100 degrees Celsius for 15 hours. LCMS detected that the reaction was complete. The reaction solution was dissolved with 10 ml of water and extracted twice with 10 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and then purified by silica gel column chromatography to obtain a yellow solid ((4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)methyl)carbamic acid tert-butyl ester (PA046-b) (150 mg, 91.6% yield). The obtained product was used for the next reaction. LCMS: m / z=417.2 (M+H) + ;

[0095] Step 2: Dissolve tert-butyl ((4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)methyl)carbamate (PA046-b) (150 mg, 0.360 mmol) in 2 ml of dichloromethane and add trifluoroacetic acid (41 mg, 0.360 mmol, 26.6 μl). Stir the reaction solution at 25 degrees Celsius for 2 hours. LCMS detection shows that the reaction is complete. Concentrate the reaction solution under reduced pressure to dryness. Add 10 ml of 1 molar hydrochloric acid and extract twice with 10 ml of ethyl acetate. Adjust the inorganic phase to pH 8-9 with sodium hydroxide and then extract twice with 10 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried to give a white solid crude product, N-[4-(aminomethyl)-1-bicyclo[2.2.2]octyl]-8-chloro-1,7-naphthyridine-2-amino (PA046-c) (110 mg, 96.4% yield), which was directly used in the next reaction without further purification. LCMS: m / z=317.1 (M+H) + ;

[0096] Step 3: Dissolve N-[4-(aminomethyl)-1-bicyclo[2.2.2]octyl]-8-chloro-1,7-naphthyridine-2-amino (PA046-c) (110 mg, 0.347 mmol) and tert-butyl 2-(2-chloropyrimidin-5-yl)acetate (95 mg, 0.417 mmol) in dimethyl sulfoxide, add potassium fluoride (101 mg, 1.74 mmol) and 2-[2-(2-methoxyethoxy)ethoxy]ethanol (57 mg, 0.347 mmol). The reaction solution was stirred at 100 degrees Celsius for 15 hours. LCMS detected that the reaction was complete. The reaction solution was dissolved in 10 ml of water and extracted twice with 10 ml of ethyl acetate. Combine the organic phases, dry with magnesium sulfate, filter, and concentrate under reduced pressure to dryness. Purify by silica gel column chromatography to obtain a yellow viscous liquid. Tert-butyl 2-[2-[[4-[(8-chloro-1,7-naphthyridin-2-yl)amino]-1-bicyclo[2.2.2]octyl]methylamino]pyrimidin-5-yl]acetate (PA046-d) (140 mg, 79.2% yield). LCMS: m / z=509.3 (M+H) + ;

[0097] Step 4: Dissolve tert-butyl 2-[2-[[4-[(8-chloro-1,7-naphthyridin-2-yl)amino]-1-bicyclo[2.2.2]octyl]methylamino]pyrimidin-5-yl]acetate (PA046-d) (140 mg, 0.275 mmol) in 2 ml of dichloromethane and add trifluoroacetic acid (1.54 g, 13.5 mmol, 1 ml). The reaction was stirred at 25 degrees Celsius for 2 hours. LCMS detected the formation of the target product. After the reaction solution was concentrated to dryness under reduced pressure, 10 ml of 1 molar hydrochloric acid was added and extracted twice with 10 ml of ethyl acetate. The inorganic phase was adjusted to pH 8 with sodium carbonate and then extracted twice with 10 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried to give a yellow solid crude product, 2-[2-[[4-[(8-chloro-1,7-naphthyridin-2-yl)amino]-1-bicyclo[2.2.2]octyl]methylamino]pyrimidin-5-yl]acetic acid (PA046-e) (90 mg, 72.2% yield), which was used directly in the next step without further purification. LCMS: m / z=453.3 (M+H) + ;

[0098] Step 5: 2-[2-[[4-[(8-chloro-1,7-naphthyridin-2-yl)amino]-1-bicyclo[2.2.2]octyl]methylamino]pyrimidin-5-yl]acetic acid (PA046-e) (90 mg, 0.199 mmol) and oxetane-3-amino (22 mg, 0.298 mmol) were dissolved in 2 ml of N,N-dimethylformamide, and then N,N-diisopropylethylamine (128.41 mg, 993.52 μmol, 173.05 μL, 5 eq) was added dropwise, and finally HATU ((151.11 mg, 397.41 μmol, 2 eq) was added. The reaction solution was stirred at 25 °C for 2 hours. LCMS detected that the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and separated by HPLC column (column: Boston Prime C18 150 mm*30 mm*5 μm; mobile phase: [water (ammonia v / v)-ACN]; B%: 26%-56%, 9 min) to obtain a white solid 2-[2-[[4-[(8-chloro-1,7-naphthyridin-2-yl)amino]-1-bicyclo[2.2.2]octyl]methylamino]pyrimidin-5-yl]-N-(oxetane-3-yl)acetamide (PA046) (40 mg, 39.13% yield). LCMS: m / z=508.2 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.78(br d,1H),8.11(s,2H),7.96(d,1H),7.87(d,1H),7.53(d,1H),7.15(s,1H),7.02(d,1H),6.92(br t,1H),4.73-4.83(m,1H),4.62-4.73(m,2H),4.42(t,2H),3.22-3.27(m,2H),3.13(br d,2H),2.01-2.18(m,6H),1.46-1.65(m,6H)

[0099] Example 2: Synthesis of the racemic compound 2-[2-[[4-[(8-methoxy-1,7-naphthyridin-2-yl)amino]phenyl]methylamino]pyrimidin-5-yl]-N-(oxetane-3-yl)propionamide (PA041) and its enantiomers PA042 and PA043

[0100] Step 1: Anhydrous tetrahydrofuran (5 ml) was added to methyl 2-(2-chloropyrimidin-5-yl)acetate (PA041-a) (170 mg, 0.911 mmol), and then potassium tert-butoxide (102 mg, 0.911 mmol) was added. The reaction solution was reacted at 20 degrees Celsius for 30 minutes, and iodomethane (129 mg, 0.911 mmol, 57 μl) was added under ice-water cooling. The reaction solution was stirred and reacted for 1 hour in an ice-water bath. LCMS showed that the target product was generated. Saturated ammonium chloride solution (30 ml) was added to the reaction solution, and it was extracted with ethyl acetate (30 ml*2). The organic phases were combined and dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Purification by silica gel column chromatography gave a colorless viscous crude product methyl 2-(2-chloropyrimidin-5-yl)propanoate (PA041-b) (110 mg, 60.1% purity). LCMS: m / z=200.9 (M+H) + ;

[0101] Step 2: 2-Chloro-8-methoxy-1,7-naphthyridine (PA041-c) (200 mg, 1.03 mmol) and tert-butyl N-[(4-aminophenyl)methyl]carbamate (c1) (456 mg, 2.06 mmol) were dissolved in anhydrous tetrahydrofuran (1 ml), and sodium tert-butoxide (98.7 mg, 1.03 mmol), BINAP (191 mg, 0.308 mmol) and Pd2(dba)3 (94.1 mg, 0.103 mmol) were added. The reaction solution was heated to 65 degrees Celsius for 1.5 hours. LCMS showed that the reaction was complete. Water (10 ml) was added to the reaction solution and extracted with ethyl acetate (10 ml*2). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Silica gel column chromatography was used to purify the red solid crude product N-[[4-[(8-methoxy-1,7-naphthyridin-2-yl)amino]phenyl]methyl]carbamic acid tert-butyl ester (PA041-d) (620 mg, 47.0% purity), which was used directly in the next step without purification. LCMS: m / z=381.2 (M+H) + ;

[0102] Step 3: tert-Butyl N-[[4-[(8-methoxy-1,7-naphthyridin-2-yl)amino]phenyl]methyl]carbamate (PA041-d) (620 mg, 0.815 mmol, 50% purity) was dissolved in anhydrous dichloromethane (10 ml), and trifluoroacetic acid (4.62 g, 40.52 mmol, 3 ml) was added. The reaction solution was reacted at 25 degrees Celsius for 2 hours, and LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and hydrochloric acid (10 ml, 1M) was added to the residue, and extracted with ethyl acetate (10 ml*2). The aqueous phase was adjusted to pH 8-9 with sodium hydroxide, extracted with ethyl acetate (10 ml * 2), the combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain a yellow solid crude product N-[4-(aminomethyl)phenyl]-8-methoxy-1,7-naphthyridine-2-amino (PA041-e) (230 mg, 97.29% yield), which was directly used in the next step without further purification. LCMS: m / z = 281.1 (M+H) + ;

[0103] Step 4: Add N-[4-(aminomethyl)phenyl]-8-methoxy-1,7-naphthyridine-2-amino (PA041-e) (153 mg, 0.548 mmol), methyl 2-(2-chloropyrimidin-5-yl)propanoate (b) (110 mg, 0.548 mmol), potassium fluoride (159 mg, 2.74 mmol, 64 μL), and 2-[2-(2-methoxyethoxy)ethoxy]ethanol (90.0 mg, 0.548 mmol) to DMSO (5 ml), and react at 100 degrees Celsius for 5 hours. LCMS shows that the reaction is complete. Add water (10 ml) to the reaction solution, extract with ethyl acetate (10 ml*2), combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a yellow solid product, methyl 2-[2-[[4-[(8-methoxy-1,7-naphthyridin-2-yl)amino]phenyl]methylamino]pyrimidin-5-yl]propanoate (PA041-f) (230 mg, 82.88% yield, 87.82% purity). LCMS: m / z=445.2 (M+H) + ;

[0104] Step 5: A mixture of tetrahydrofuran (1 ml) / water (1 ml) was added to methyl 2-[2-[[4-[(8-methoxy-1,7-naphthyridin-2-yl)amino]phenyl]methylamino]pyrimidin-5-yl]propanoate (PA041-f) (110 mg, 0.247 mmol), and sodium hydroxide (19.8 mg, 0.495 mmol) was added under stirring. The reaction solution was reacted at 25 degrees Celsius for 15 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and dichloromethane (5 ml) was added to the residue. The pH was adjusted to 4 with trifluoroacetic acid, and concentrated under reduced pressure to obtain a yellow solid crude product 2-[2-[[4-[(8-methoxy-1,7-naphthyridin-2-yl)amino]phenyl]methylamino]pyrimidin-5-yl]propanoic acid (PA041-g) (100 mg, 93.87% yield), which was directly used in the next step without purification. LCMS: m / z=431.2 (M+H) + ;

[0105] Step 6: 2-[2-[[4-[(8-methoxy-1,7-naphthyridin-2-yl)amino]phenyl]methylamino]pyrimidin-5-yl]propanoic acid (PA041-g) (100 mg, 0.232 mmol) and oxetane-3-amine (16.9 mg, 0.232 mmol) were dissolved in DMF (2 ml), DIEA (90.0 mg, 0.697 mmol, 121 μl) and HATU (132 mg, 0.348 mmol) were added, and the reaction solution was reacted at 25°C for 2 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC (chromatographic column: Boston Prime C18 150 mm*30 mm*5 μm; mobile phase: [water (ammonia v / v)-acetonitrile]; gradient: 21%-51%, 9 minutes) to obtain a yellow solid racemic compound 2-[2-[[4-[(8-methoxy-1,7-naphthyridin-2-yl)amino]phenyl]methylamino]pyrimidin-5-yl]-N-(oxetane-3-yl)propanamide (PA041) (47 mg). LCMS: m / z=486.2 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.58(s,1H),8.75(d,1H),8.18-8.22(m,2H),8.02(d,1H),7.94(d,2H),7.84(d,1H),7.61(t,1H), 7.22-7.29(m,4H),4.64-4.78(m,3H),4.45(d,2H),4.38-4.43(m,1H),4.34(t,1H),4.03(s,3H),3.39-3.46(m,1H),1.30(d,3H).

[0106] After chiral SFC separation (chromatographic column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% ammonia ethanol]; B%: 45%-45%, min) two optical enantiomers (PA042) (18 mg, 15.42% yield) (PA043) (15 mg, 13.11% yield) were obtained as yellow solid compounds;

[0107] (PA042) LCMS: m / z = 486.2 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.57 (s, 1H), 8.73 (br d, J = 6.13Hz, 1H), 8.20 (s, 2H), 8.02 (d, J = 8.88Hz, 1H), 7.93 (br d,J=8.50Hz,2H),7.80-7.89(m,1H),7.58(br t,J=6.25Hz,1H),7.16-7.35(m,4H),4.55-4.80(m,3H),4.45(br d,J=6.25Hz,2H),4.39-4.42(m,1H),4.34(br t,J=5.94Hz,1H),4.03(s,3H),3.44-3.47(m,1H),1.30(br d,J=7.13Hz,3H).

[0108] (PA043) LCMS: m / z = 486.2 (M+H) + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.57(s,1H),8.73(br d,1H),8.20(s,2H),8.02(d,1H),7.93(br d,2H),7.84(d,1H),7.58(br t,1H),7.16-7.34(m,4H),4.55-4.80(m,3H),4.45(br d,2H),4.37-4.43(m,1H),4.30-4.37(m,1H),4.03(s,3H),3.46(br s,1H),1.30(br d,3H).

[0109] Example 3: Synthesis of the racemic compound 2-(2-((1-(4-((8-methoxy-1,7-naphthyridin-2-yl)amino)phenyl)ethyl)amino)pyrimidin-5-yl)acetic acid N-(oxetane-3-yl)acetamide (PA039) and its enantiomers PA061 and PA062

[0110] Step 1: 1-(4-aminophenyl)ethanone 1-(4-aminophenyl)ethanone (b) (180 mg, 1.33 mmol), 2-chloro-8-methoxy-1,7-naphthyridine (PA041-c) (250 mg, 1.28 mmol), sodium tert-butoxide (140 mg, 1.46 mmol) and anhydrous tetrahydrofuran (10 ml) were added to a reaction flask, oxygen was removed under reduced pressure, and the atmosphere was replaced with nitrogen several times. BINAP (160 mg, 257 μmol) and Pd2(dba)3 (100 mg, 109 μmol) were added to the reaction solution, and the reaction was carried out at 80°C for 2 hours. LCMS showed that the target product was generated. The reaction mixture was cooled to room temperature, saturated brine (10 ml) was added, and the mixture was extracted twice with dichloromethane (15 ml). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain an orange solid compound 1-(4-((8-methoxy-1,7-naphthyridin-2-yl)amino)phenyl)ethanone (PA039-c) (392 mg, 94.6% yield). LCMS: m / z = 294.0 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.08(s,1H),8.19(d,2H),8.13(d,1H),7.97(d, J=8.63Hz,2H),7.91(d,1H),7.33(d,1H),7.29(d,1H),4.08(s,3H),2.54(s,3H)

[0111] Step 2: 1-(4-((8-methoxy-1,7-naphthyridin-2-yl)amino)phenyl)ethanone (PA039-c) (360 mg, 1.23 mmol) and ammonium acetate (1.89 g, 24.47 mmol) were added to methanol (30 ml), sodium cyanoborohydride (308 mg, 4.90 mmol) was added, and the reaction solution was reacted at 40 °C for 16 hours. LCMS showed that the target product was generated and the raw material remained. 300 mg of sodium cyanoborohydride was added, and the reaction solution was reacted at 40 °C for 48 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, 50 ml of saturated brine was added, and the mixture was extracted with methanol / dichloromethane (1:10, 75 ml). The aqueous phase was extracted twice with dichloromethane (50 ml), the organic phases were combined and dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain a yellow solid crude product, N-(4-(1-aminoethyl)phenyl)-8-methoxy-1,7-naphthyridine-2-amino (PA039-d) (372 mg), which was used directly in the next step without further purification. LCMS m / z=295.1[M+1] + ;

[0112] Step 3: N-(4-(1-aminoethyl)phenyl)-8-methoxy-1,7-naphthyridine-2-amino (PA039-d) (150 mg, 0.51 mmol) and tert-butyl 2-(2-chloropyrimidin-5-yl)acetate (d1) (115 mg, 0.505 mmol) were added to DMSO (4 ml), 2-[2-(2-methoxyethoxy)ethoxy]ethanol (TGME) (92 mg, 0.561 mmol) and potassium fluoride (148 mg, 2.55 mmol) were added, and the reaction solution was reacted at 100 degrees Celsius for 16 hours. LCMS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (25 ml), filtered, and the filter cake was washed with water (20 ml). The filter cake was collected and freeze-dried to obtain a brown solid crude product of tert-butyl 2-(2-((1-(4-((8-methoxy-1,7-naphthyridin-2-yl)amino)phenyl)ethyl)amino)pyrimidin-5-yl)acetate (PA039-e) (183 mg). LCMS m / z=487.2[M+1] + ;

[0113] Step 4: A mixture of tert-butyl 2-(2-((1-(4-((8-methoxy-1,7-naphthyridin-2-yl)amino)phenyl)ethyl)amino)pyrimidin-5-yl)acetate (PA039-e) (40 mg, 0.082 mmol) and trifluoroacetic acid / dichloromethane (3 ml) [trifluoroacetic acid / dichloromethane = 1:5, V / V] was reacted at 10-15 °C for 16 hours. LCMS showed the formation of the target product. The crude product was concentrated under reduced pressure, slurried with methyl tert-butyl ether (10 ml), diluted with petroleum ether (10 ml), and the solution was allowed to stand to drain. The residue was dried under reduced pressure to obtain a brown syrupy crude product 2-(2-((1-(4-((8-methoxy-1,7-naphthyridin-2-yl)amino)phenyl)ethyl)amino)pyrimidin-5-yl)acetic acid (PA039-f) (82 mg, trifluoroacetate), which was used directly in the next step without further purification. LCMS m / z=431.1[M+1] + ;

[0114] Step 5: 2-(2-((1-(4-((8-methoxy-1,7-naphthyridin-2-yl)amino)phenyl)ethyl)amino)pyrimidin-5-yl)acetic acid (PA039-f) (82 mg, 0.075 mmol) was added to DMF (1 ml), oxetane-3-amine (10 mg, 0.137 mmol), DIPEA (50 mg, 0.387 mmol) and HATU (45 mg, 0.118 mmol), and the reaction solution was reacted at 10-15 °C for 2 hours. LCMS showed that the target product was generated. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase HPLC (chromatographic column: YMC-Triart preparative C18 150*40 mm*7 μm; mobile phase: [water (ammonia water + ammonium bicarbonate)-acetonitrile]; gradient: 7%-47%, 9 minutes), and lyophilized to obtain an off-white solid product 2-(2-((1-(4-((8-methoxy-1,7-naphthyridin-2-yl)amino)phenyl)ethyl)amino)pyrimidin-5-yl)acetic acid N-(oxetane-3-yl)acetamide (PA039) (12 mg, 0.024 mmol, 31.8% yield). LCMS m / z=486.2[M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.56(s,1H),8.78(d,1H),8.11(s,2H),8.01(d,1H), 7.91(d,2H),7.83(d,1H),7.51(d,1H),7.33(d,2H),7.18-7.25(m,2H),5.00-5.09

[0115] (m,1H),4.70-4.80(m,.01H),4.64-4.69(m,2H),4.39(t,2H),4.03(s,3H),3.22(s,2H),1.43(d,3H)

[0116] Step 6: 70 mg of 2-(2-((1-(4-((8-methoxy-1,7-naphthyridin-2-yl)amino)phenyl)ethyl)amino)pyrimidin-5-yl)acetic acid N-(oxetan-3-yl)acetamide (PA039) was subjected to chiral separation (chromatographic column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% ammonia ethanol]; B%: 45%-45%, min) to obtain two optical enantiomer compounds: white solid PA061 (25 mg, 35.7% yield). LCMS m / z=486.1[M+1] + ;Chiral SFC:ee%=98.32%, 1H NMR (400 MHz, DMSO-d6) δ9.56 (s, 1H), 8.78 (d, 1H), 8.11 (s, 2H), 8.01 (d, 1H), 7.91 (d, 2H), 7.83 (d, 1H), 7.51 (d, 1H), 7.33 (d, 2H), 7.18-7.25 (m, 2H), 5.00-5.09 (m, 1H), 4.70-4.80 (m, 1H), 4.64-4.69 (m, 2H), 4.39 (t, 2H), 4.03 (s, 3H), 3.22 (s, 2H), 1.43 (d, H); White solid compound PA062 (25 mg, 35.7% yield) LCMS: m / z=486.1 [M+1] + ;Chiral SFC ee%=87.62%; 1 H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.78(d,1H),8.11(s,2H),8.01(d,1H),7.91(d,2H),7.83(d,1H),7.51(d,1H),7.33(d,2H) ,7.18-7.25(m,2H),5.00-5.09(m,1H),4.70-4.80(m,1H),4.64-4.69(m,2H),4.39(t,2H),4.03(s,3H),3.22(s,2H),1.43(d,3H)

[0117] Example 4: Synthesis of compound (S)-3-(2-(1-(4-(8-chloro-7-methylquinolin-2-amino)-3-fluorophenyl)ethylamino)pyrimidin-5-ylmethylamino)thietane-1,1-dione (PA167)

[0118] 1. Preparation of compound (S,E)-N-(1-(3-fluoro-4-nitrophenylethylidene)-2-methylpropane-2-sulfonylimide (PA167-2)

[0119] Compound 3-fluoro-4-nitroacetophenone (PA167-1) (5.00 g, 27.3 mmol) was dissolved in 50 ml of tetrahydrofuran, and (S)-tert-butylsulfenamide (4.96 g, 41.0 mmol) and Ti(OEt)4 (12.46 g, 54.6 mmol, 11.4 ml) were added. The reaction solution was stirred at 75°C for 16 hours, cooled to room temperature, quenched with ice-water (30 ml), and stirred at room temperature for 15 minutes after adding 100 ml of ethyl acetate. Filter, and wash the filter cake with 3*20 ml of ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 7.80 g of yellow (S,E)-N-(1-(3-fluoro-4-nitrophenylethylidene)-2-methylpropane-2-sulfenamide (PA167-2) crude product. (ESI) m / z.[M+H] + 287.0.

[0120] 2. Preparation of (S)-N-((S)-1-(3-fluoro-4-nitrophenyl)ethyl)-2-methylpropane-2-sulfenamide (PA167-3)

[0121] The crude product (7.8 g, 27.2 mmol) of (S,E)-N-(1-(3-fluoro-4-nitrophenylethylidene)-2-methylpropane-2-sulfonyl imide (PA167-2) was dissolved in 100 ml of tetrahydrofuran, cooled to -50°C, and sodium borohydride (4.12 g, 109.0 mmol) was added in batches. The reaction mixture was slowly heated to 0-25°C and stirred for 3 hours, then carefully quenched by adding 20 ml of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a yellow oily (S)-N-((S)-1-(3-fluoro-4-nitrophenyl)ethyl)-2-methylpropane-2-sulfenamide (PA167-3) (5.17 g, 17.9 mmol, 65.8% yield). (ESI) m / z.[M+H] + 289.0.

[0122] 3. Synthesis of compound (S)-1-(3-fluoro-4-nitrophenyl)ethyl-1-amine (PA167-4)

[0123] Compound (S)-N-((S)-1-(3-fluoro-4-nitrophenyl)ethyl)-2-methylpropane-2-sulfenamide (PA167-3) (1.0 g, 3.47 mmol) was dissolved in 8 ml of 1,4-dioxane, and then 8 ml of 4M hydrochloric acid was added dropwise. The reaction solution was stirred at room temperature for 3 hours and the reaction was complete. After the solvent was removed by vortexing, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 640 mg of yellow viscous crude product (S)-1-(3-fluoro-4-nitrophenyl)ethyl-1-amine (PA167-4). (ESI) m / z.[M+H] + 185.0.

[0124] 4. Synthesis of compound (S)-tert-butyl (1-(3-fluoro-4-nitrophenyl)ethyl) carbonate (PA167-5)

[0125] (S)-1-(3-Fluoro-4-nitrophenyl)ethyl-1-amine (PA167-4) (650 mg, 3.5 mmol) was dissolved in 5 ml of tetrahydrofuran, and Boc2O (1.54 g, 7.06 mmol) and triethylamine (1.07 g, 10.59 mmol, 3.77 ml) were added and stirred at room temperature for 2 hours. The reaction solution was concentrated and water was added, extracted with ethyl acetate, and the organic phase was washed with saturated laboratory, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a yellow solid (S)-tert-butyl (1-(3-fluoro-4-nitrophenyl)ethyl) carbonate (PA167-5) (700.0 mg, 2.5 mmol, 69.8% yield). (ESI) m / z.[M+H] + 229.0.

[0126] 5. Synthesis of compound (S)-tert-butyl (1-(4-amino-3-fluoro-phenyl)ethyl) carbonate (PA167-6)

[0127] (S)-tert-butyl (1-(3-fluoro-4-nitrophenyl)ethyl)carbonate (PA167-5) (700.0 mg, 2.5 mmol) was dissolved in 10 ml of methanol, and 70 mg of Pd / C was added and stirred at room temperature for 2 hours. The reaction was complete. The reaction mixture was filtered through diatomaceous earth and washed with methanol. The organic phase was concentrated to obtain a yellow viscous crude product (S)-tert-butyl (1-(4-amino-3-fluoro-phenyl)ethyl)carbonate (PA167-6) (540.0 mg, 2.1 mmol, 86.2% yield). (ESI) m / z. [M+H] + 277.

[0128] 6. Synthesis of Compound (S)-tert-butyl (1-(4-((8-chloro-7-methylquinolin-2-yl)amino)-3-fluoro-phenyl)ethyl)carbonate (PA167-7)

[0129] A mixture of 2,8-dichloro-7-methylquinoline (366.9 mg, 1.7 mmol), (S)-(1-(4-amino-3-fluoro-phenyl)ethyl)carbonate tert-butyl ester (PA167-6) (400.0 mg, 1.6 mmol), sodium tert-butoxide (151.2 mg, 1.6 mmol), and BINAP (293.8 mg, 471.9 μmol) was added with 10 ml of dry tetrahydrofuran, and Pd2(dba)3 (144.0 mg, 157.3 μmol) was added after nitrogen replacement. The reaction was stirred at 65°C for 16 hours under nitrogen protection. After the reaction solution was filtered, 100 ml of water was added to the filtrate, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a brown solid compound (S)-tert-butyl (1-(4-((8-chloro-7-methylquinolin-2-yl)amino)-3-fluoro-phenyl)ethyl)carbonate (PA167-7) (400.0 mg, 651.3 μmol, 41.4% yield). (ESI) m / z.[M+H] + 430.2

[0130] 7. Synthesis of compound (S)-N-(4-(1-aminoethyl)-2-fluorophenyl)-8-chloro-7-methylquinolin-2-amine (PA167-8)

[0131] 3 ml of dichloromethane was added to tert-butyl (S)-(1-(4-((8-chloro-7-methylquinolin-2-yl)amino)-3-fluoro-phenyl)ethyl)carbonate (PA167-7) (400.0 mg, 93.4 μmol), and 5 ml of trifluoroacetic acid was added dropwise under stirring at room temperature and stirred for 2 hours. The reaction mixture was concentrated and diluted with water, and the pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution, then extracted with dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a yellow solid compound (S)-N-(4-(1-aminoethyl)-2-fluorophenyl)-8-chloro-7-methylquinolin-2-amine (PA167-8) (190.0 mg, 518.5 μmol, 55.7% yield). (ESI) m / z.[M+H] + 330.0.

[0132] 8. Synthesis of compound (S)-2-((1-(4-((8-chloro-7-methylquinolin-2-yl)amino)-3-fluorophenyl)ethyl)amino)pyrimidine-5-carboxaldehyde (PA167-9)

[0133] Under nitrogen protection, potassium fluoride (79.3 mg, 1.4 mmol) and 2 ml of dimethyl sulfoxide were added to a mixture of (S)-N-(4-(1-aminoethyl)-2-fluorophenyl)-8-chloro-7-methylquinolin-2-amine (PA167-8) (90 mg, 272.9 μmol), 2-chloropyrimidine-5-carboxaldehyde (38.9 mg, 272.9 μmol), and TGME (44.8 mg, 272.9 μmol). The reaction mixture was heated to 110°C and stirred for 16 hours. After adding 10 ml of water, the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain a yellow solid (S)-2-((1-(4-((8-chloro-7-methylquinolin-2-yl)amino)-3-fluorophenyl)ethyl)amino)pyrimidine-5-carboxaldehyde (PA167-9) (55.0 mg, 118.6 μmol, 43.5% yield). (ESI) m / z.[M+H] + 436.2.

[0134] 9. Synthesis of compound (S)-3-(((2-((1-(4-((8-chloro-7-methylquinolin-2-yl)amino)-3-fluorophenyl)ethyl)amino)pyrimidin-5-yl)methyl)amino)-1,1-dioxothiocyclobutane (PA167)

[0135] Compound (S)-2-((1-(4-((8-chloro-7-methylquinolin-2-yl)amino)-3-fluorophenyl)ethyl)amino)pyrimidine-5-carbaldehyde (PA167-9) (55.0 mg, 126.2 μmol), 1,1-dioxothietaned-3-amine (19.9 mg, 164.0 μmol) were dissolved in 3 ml of dry methanol, stirred at 50°C for 18 hours, and then cooled to room temperature. 1 ml of dichloromethane and sodium cyanoborohydride (15.9 mg, 252.4 μmol) were added, and stirred at room temperature for 5 hours. Two drops of water were added to quench the reaction. After post-treatment, methanol was added to the reaction solution and purified by preparative HPL to obtain a white solid compound (S)-3-(((2-((1-(4-((8-chloro-7-methylquinolin-2-yl)amino)-3-fluorophenyl)ethyl)amino)pyrimidin-5-yl)methyl)amino)-1,1-dioxothiocyclobutane (PA167). 1H NMR(400MHz,DMSO-d6)δ9.20(d,1H),9.08(t,1H),8.41(s,0H),8.16(s,2H),8.04(d,1H),7.59(dd,2H),7.30(d,1H),7.27–7.17( m,3H),5.05(p,1H),4.28–4.20(m,2H),3.84(ddd,2H),3.46–3.40(m,1H),3.36(s,2H),2.49(s,3H),1.41(d,3H); (ESI)m / z.[M+H] + 541.2.

[0136] Example 5: Synthesis of compound 2-(2-(((S)-1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethyl)amino)pyrimidin-5-yl)propanoic acid (PA169-11) and diastereoisomers PA166 and PA207

[0137] 1. Synthesis of compound 4-(tert-butyloxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (PA169-1)

[0138] 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester (2 g, 10.9 mmol) was dissolved in 20 ml of dichloromethane, triethylamine (3.31 g, 32.7 mmol) and di-tert-butyl carbonate (2.86 g, 13.1 mmol) were added, and the reaction solution was stirred at room temperature for 16 hours. After adding water, it was extracted with dichloromethane, the organic phase was washed with saturated brine, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 2.20 g of white crude product 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (PA169-1). (ESI) m / z.[M+H] + 228.0.

[0139] 2. Synthesis of compound 4-(tert-butyloxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (PA169-2)

[0140] 4-(tert-Butyloxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (PA169-1) (2.2 g, 7.76 mmol) was dissolved in 15 ml of methanol, and 5 ml of water and lithium hydroxide (371.86 mg, 15.53 mmol) were added and stirred at room temperature for 4 hours. The reaction solution was extracted with 1N hydrochloric acid solution at pH 6, and then washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a white crude product 4-(tert-Butyloxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (PA169-2). (ESI) m / z.[M+H] + 214.0.

[0141] 3. Synthesis of compound N-[4-[methoxy(methyl)carbamoyl]-1-bicyclo[2.2.2]octyl]carbonate tert-butyl ester (PA169-3)

[0142] 4-(tert-Butyloxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (PA169-2) (1.7 g, 6.31 mmol) and diisopropylethylamine (1.63 g, 12.62 mmol) were dissolved in 20 ml of DMF, and N,O-dimethylhydroxylamine (424.10 mg, 6.94 mmol) and HATU (2.64 g, 6.94 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was filtered and diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a white solid compound N-[4-[methoxy(methyl)carbamoyl]-1-bicyclo[2.2.2]octyl]carbonate tert-butyl ester (PA169-3) (1.60 g, 4.61 mmol, 73.03% yield, 90% purity). (ESI) m / z.[M+H] + 313.20.

[0143] 4. Synthesis of compound 4-amino-N-methoxy-N-methylbicyclo[2.2.2]octyl-1-carboxamide (PA169-4)

[0144] Compound N-[4-[methoxy(methyl)carbamoyl]-1-bicyclo[2.2.2]octyl] tert-butyl carbonate (PA169-3) (1.6 g, 5.12 mmol) was dissolved in 10 ml of dichloromethane, 3 ml of trifluoroacetic acid was added, and the reaction solution was stirred at room temperature for 2 hours. After the reaction solution was concentrated, sodium bicarbonate aqueous solution was added to adjust the pH to 10, and the dichloromethane extraction was followed by washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentration to obtain 1.00 g of white solid crude product 4-amino-N-methoxy-N-methylbicyclo[2.2.2]octyl-1-carboxamide (PA169-4). (ESI) m / z.[M+H] +213.0.

[0145] 5. Synthesis of compound 4-[(8-chloro-1,7-naphthyridin-2-yl)amino]-N-methoxy-N-methyl-bicyclo[2.2.2]octyl-1-carboxamide (PA169-5)

[0146] Compound 4-amino-N-methoxy-N-methylbicyclo[2.2.2]octyl-1-carboxamide (PA169-4) (0.95 g, 4.48 mmol) was dissolved in 15 ml of dimethyl sulfoxide, and 2,8-dichloro-1,7-naphthyridine (1.25 g, 6.27 mmol), potassium fluoride (1.30 g, 22.38 mmol) and TGME (734.80 mg, 4.48 mmol) were added. The reaction solution was heated at 100 degrees and stirred for 16 hours. After the reaction solution was filtered, 30 ml of water was added, and the organic phase was extracted with ethyl acetate and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography to obtain a white solid compound 4-[(8-chloro-1,7-naphthyridin-2-yl)amino]-N-methoxy-N-methyl-bicyclo[2.2.2]octyl-1-carboxamide (PA169-5) (1.00 g, 2.40 mmol, 53.6% yield, 90% purity). (ESI) m / z.[M+H] + 375.0.

[0147] 6. Synthesis of compound 1-[4-[(8-chloro-1,7-naphthyridin-2-yl)amino]-1-bicyclo[2.2.2]octyl]ethanone (PA169-6)

[0148] Compound 4-[(8-chloro-1,7-naphthyridin-2-yl)amino]-N-methoxy-N-methyl-bicyclo[2.2.2]octyl-1-carboxamide (PA169-5) (1g, 2.67mmol) was dissolved in 10ml dry tetrahydrofuran, cooled to 0 degrees, and methylmagnesium bromide-tetrahydrofuran solution (3M, 4.45mL) was added dropwise under nitrogen protection. The reaction solution was slowly heated to 40 degrees and reacted for 16 hours. 15ml saturated ammonium chloride aqueous solution was carefully added dropwise under ice-water cooling, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 800mg of yellow solid crude product 1-[4-[(8-chloro-1,7-naphthyridin-2-yl)amino]-1-bicyclo[2.2.2]octyl]ethanone (PA169-6). (ESI) m / z.[M+H] + 330.10.

[0149] 7. Synthesis of compound (S,E)-N-(1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethylidene)-2-methylpropane-2-sulfenamide (PA169-7)

[0150] Compound 1-[4-[(8-chloro-1,7-naphthyridin-2-yl)amino]-1-bicyclo[2.2.2]octyl]ethanone (PA169-6) (0.15 g, 454.8 μmol) was dissolved in 10 ml dry tetrahydrofuran, tetraethoxytitanium (207.5 mg, 909.6 μmol) was added, and the reaction solution was heated at 75 degrees and stirred for 16 hours. After the reaction solution was cooled, 20 ml ethyl acetate and 10 ml water were added, and the reaction solution was stirred for half an hour and then extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 150 mg of a white solid crude product (S,E)-N-(1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethylidene)-2-methylpropane-2-sulfenamide (PA169-7). (ESI)m / z.[M+H] + 433.20.

[0151] 8. Synthesis of compound (S)-N-((S)-1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethyl)-2-methylpropane-2-sulfenamide (PA169-8)

[0152] Compound (S,E)-N-(1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethylidene)-2-methylpropane-2-sulfenamide (PA169-7) (0.15 g, 346.4 μmol) was dissolved in 5 ml of tetrahydrofuran, cooled to -50 degrees and sodium borohydride (52.4 mg, 1.39 mmol) was added. The reaction solution was slowly warmed to room temperature and stirred for 3 hours. The reaction was quenched by adding 10 ml of saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 120 mg of a yellow solid crude product (S)-N-((S)-1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethyl)-2-methylpropane-2-sulfenamide (PA169-8). (ESI) m / z.[M+H] + 435.1.

[0153] 9. Synthesis of compound (S)-N-(4-(1-aminoethyl)bicyclo[2.2.2]octan-1-yl)-8-chloro-1,7-naphthyridin-2-amine (PA169-9)

[0154] The compound (S)-N-((S)-1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethyl)-2-methylpropane-2-sulfenamide (PA169-8) (0.12 g, 275.8 μmol) was dissolved in 5 ml of 1,4-dioxane, cooled to 0 degrees, and then hydrochloric acid solution (1,4-dioxane solution, 2M concentration, 1.1 ml) was added dropwise. The reaction solution was slowly warmed to room temperature and stirred for 3 hours until the reaction was complete. After the reaction solution was concentrated, the pH was adjusted to 8 with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. It was filtered and concentrated to obtain 75 mg of a yellow solid crude product (S)-N-(4-(1-aminoethyl)bicyclo[2.2.2]octan-1-yl)-8-chloro-1,7-naphthyridin-2-amine (PA169-9). (ESI)m / z.[M+H] + 331.0.

[0155] 10. Synthesis of Compound 2-(2-(((S)-1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethyl)amino)pyrimidin-5-yl)propanoic acid tert-butyl ester (PA169-10)

[0156] To a mixture of (S)-N-(4-(1-aminoethyl)bicyclo[2.2.2]octan-1-yl)-8-chloro-1,7-naphthyridin-2-amine (PA169-9 (1.5 g, 4.53 mmol) and tert-butyl 2-(2-chloropyrimidin-5-yl)propanoate (1.21 g, 4.99 mmol) was added 15 ml of dimethyl sulfoxide, followed by potassium fluoride (1.32 g, 22.67 mmol) and TGME (744.4 mg, 4.53 mmol). The reaction mixture was heated to 130° C. and stirred for 16 min. hours, the reaction solution was filtered and 50 ml of water was added, the organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography to obtain a white solid compound 2-(2-(((S)-1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethyl)amino)pyrimidin-5-yl)propionic acid tert-butyl ester (PA169-10) (1.15 g, 1.93 mmol, 42.5% yield). (ESI) m / z.[M+H] + 537.2.

[0157] 11. Synthesis of compound 2-(2-(((S)-1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethyl)amino)pyrimidin-5-yl)propanoic acid (PA169-11)

[0158] The compound tert-butyl 2-(2-(((S)-1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethyl)amino)pyrimidin-5-yl)propanoate (PA169-10) (1.1 g, 2.05 mmol) was dissolved in 10 ml of dichloromethane, and 5 ml of trifluoroacetic acid was added dropwise under stirring at room temperature; the reaction mixture was stirred for 2 hours and then concentrated to obtain 1.00 g of a brown solid crude product 2-(2-(((S)-1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethyl)amino)pyrimidin-5-yl)propanoic acid (PA169-11). (ESI) m / z.[M+H] + 481.20.

[0159] 12. Synthesis of compound 2-(2-(((S)-1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethyl)amino)pyrimidin-5-yl)-N-(oxetane-3-yl)propionamide (PA169)

[0160] Compound 2-(2-(((S)-1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethyl)amino)pyrimidin-5-yl)propanoic acid (PA169-11) (1 g, 2.08 mmol) was dissolved in 10 ml of DMF, and diisopropylethylamine (1.34 g, 10.40 mmol), oxetane-3-amine (303.9 mg, 4.16 mmol) and HATU (948.6 mg, 2.49 mmol) were added under stirring at room temperature. The reaction was stirred for 1 hour before the reaction was complete. The reaction solution was filtered and concentrated, and then purified by preparative HPLC to obtain a white solid compound 2-(2-(((S)-1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethyl)amino)pyrimidin-5-yl)-N-(oxetane-3-yl)propanamide (PA169) (620.0 mg, 1.12 mmol, 53.9% yield). (ESI) m / z.[M+H] + 536.1.

[0161] 13. Preparation of diastereoisomers PA166 and PA207

[0162] Compound 2-(2-(((S)-1-(4-((8-chloro-1,7-naphthyridin-2-yl)amino)bicyclo[2.2.2]octan-1-yl)ethyl)amino)pyrimidin-5-yl)-N-(oxetan-3-yl)propanamide (PA169) (620.0 mg, 1.16 mmol) was separated by SFC chiral column to give two white solid diastereoisomers, compounds PA166 (205.0 mg, 372.3 μmol, 32.2% yield) and PA207 (219.2 mg, 389.8 μmol, 33.7% yield). The absolute configurations of the ortho-chiral centers of the amides of the two monomeric compounds were tentatively assigned.

[0163] PA166: 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.75(d,1H),8.15(s,2H),7.96(d,1H),7.8 7(d,1H),7.53(d,1H),7.18(s,1H),7.02(d,1H),6.74(d,1H),4.79–4.64( m,3H),4.41(t,1H),4.36(t,1H),3.98–3.89(m,1H),3.42(t,1H),2.11–2 .05(m,6H),1.62–1.51(m,6H),1.30(d,3H),1.01(d,3H); (ESI)m / z.[M+H] + 536.0.

[0164] PA207: 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.76(d,1H),8.15(s,2H),7.95(d,1H),7.8 6(d,1H),7.53(d,1H),7.18(s,1H),7.02(d,1H),6.75(d,1H),4.79–4.64( m,3H),4.41(t,1H),4.35(t,1H),3.99–3.90(m,1H),3.41(q,1H),2.10–2 .06(m,6H),1.64–1.50(m,6H),1.30(d,3H),1.00(d,3H); (ESI)m / z.[M+H] + 536.0.

[0165] The following compounds were prepared using a similar method:

[0166] Biological test cases

[0167] G401 ELISA Test:

[0168] Main experimental instruments and equipment:

[0169] Plate reader: Envision (Perkinelmer); plate shaker: IKA MTS 2 / 4; plate washer: BioTek microplate wisher 405 select; cell counter: Counterstar (Ruiyu-biotech); cell culture incubator: MCO-15AC (ThermoFisher); pipette: BioHit Multichannel.Pipette: 0.2-10μL, 10-300μL 50-1200μL; centrifuge: Thermo Centrifuge ST 40R; water purifier: Millipore Milli-Q Reference system; refrigerator: Haier -80 degrees, -20 degrees and 4 degrees refrigerator; cell freezing box: Mr. Frosty TM Gradient Cooling Box Cat#5100-0001

[0170] Experimental cell culture reagents, consumables and their sources:

[0171] McCoys 5A (Modified) medium (ATCC); FBS (Gibco); 0.25% Trypsin / EDTA (Gibco); PBS (Hyclone); Penicillin / Streptomycin (100x) (Gibco); DMSO (Sigma); 384 cell culture plates (Corning); 384 assay plates (Greiner); 96-well plates (compound dilution) (Haimen, Qunchao); T75 cell culture flasks (Corning)

[0172] Experimental operation:

[0173] G401 cells were seeded in a 384-well cell culture plate and incubated overnight in a 37°C, 5% CO2 cell culture incubator, and then treated with different concentrations of compounds for 72 hours. The 384 cell culture plate was removed, and the cell culture plate was turned upside down in a centrifuge and centrifuged at 300 rpm for 1 minute. After centrifugation, it was washed twice with PBS, and then the lysis buffer was added, and the cells were lysed for 60 minutes. Then, the neutralization buffer was added to mix and incubated for another 30 minutes. 20ul (for detection of K27) and 10ul (for detection of H3) of cell lysate were aspirated from the 384 cell culture plate, transferred to the 384 ELISA test plate, and incubated at 4°C overnight. The next day, the 384 ELISA plate was removed, TBST was added to the plate washer and washed 5 times, and then the blocking solution was added to block at room temperature for 1 hour. After discarding the blocking solution, the primary antibody was added and incubated at room temperature for 1 hour. After incubation, TBST was added to the plate washer for washing 5 times, and then the secondary antibody was added and incubated at room temperature for 1 hour. After incubation, TBST was added to the plate washer for washing 5 times, and finally the color developer was added for color development, and the plate was read using the Envision plate reader. The obtained data was converted into inhibition rate, and the calculation method was: % inhibition rate = 100-100*(compound absorbance-positive control absorbance) / (negative control absorbance-positive control absorbance), and then the inhibition rate data was curve fitted in GraphPad Prism 5 software using the "logarithm (inhibitor) and reaction-variable slope (four parameters)" model.

[0174] The compound inhibition rate was calculated as follows:

[0175] % inhibition rate = 100-100*(compound absorbance-positive control absorbance) / (negative control absorbance-positive control absorbance)

[0176] The compounds of the present invention were tested according to the above experimental method. Some of the results are shown in Table 3, where the test results are classified into A, B, and C, and A represents IC 50 ≤0.1uM; B represents 0.1uM <IC 50 ≤1uM; C represents IC50 >1uM

[0177] Table 3:

[0178] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. 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 claims attached to this application.

Claims

A compound as shown in the following formula I, or a pharmaceutically acceptable salt or deuterated product, a racemic mixture and an optical monomer product thereof: in, The A ring is selected from the following group: a 5-10 membered bridged ring (including a carbocyclic ring, a heterocyclic ring), a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring; the B ring is selected from the following group: a 6-10 membered aromatic ring, a 5-14 membered heteroaromatic ring; the C ring is selected from the following group: a 5-10 membered aromatic ring or a partially saturated aromatic ring, a 5-10 membered heteroaromatic ring or a partially saturated heteroaromatic ring, a 5-10 membered saturated or partially unsaturated carbocyclic ring (including a condensed ring, a bridged ring), a 5-10 membered saturated or partially unsaturated heterocyclic ring (including a condensed ring, a bridged ring); L1 and L2 are each independently -(L) p -, and each L is independently selected from the following group: a chemical bond or none, or -O-, -CHR-, -CHR-NH-, carbonyl, S, -NR-, -NHC(O)-, -NHS(O)2-, -NHC(O)NH-, -NHC(S)NH-, -COO-, -OS(O)2-, -CHR-NR-, -C(R)2NR-, -C(R)2-; wherein each R is independently selected from the following group: H, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 3-4 cycloalkyl, or a substituted or unsubstituted 3-4 membered heterocycle; n is selected from the following group: 0, 1, 2, 3, 4 or 5; m is selected from the following group: 0, 1, 2, 3 or 4; p is selected from the following group: 0, 1 or 2; each R1, R2 and R3 is independently selected from the following group: H, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 alkylamide, substituted or unsubstituted C1-C6 alkylC(O)O, or substituted or unsubstituted C1-C6 alkylOC(O), substituted or unsubstituted amide, substituted or unsubstituted amine (NH2), substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2 -C6 alkynyl, substituted or unsubstituted C3-C6 carbocycle (including saturated or partially unsaturated), substituted or unsubstituted 3-6 membered heterocycle (including saturated or partially unsaturated), or -XZY-R5; wherein X and Y are each independently selected from the group consisting of a chemical bond, or -O-, -C(R5)2-, -S-, -NR5-; Z is selected from the group consisting of C(O), NH, CH=CH, -C(R5)2-, S(O), S(O)2; each R5 is each independently selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 carbocycle (including saturated or partially unsaturated), substituted or unsubstituted 3-6 membered heterocycle, substituted or unsubstituted C 6-10 an aromatic ring, a substituted or unsubstituted 5-12-membered heteroaromatic ring, a substituted or unsubstituted C1-C6 alkyl C(O)O, or a substituted or unsubstituted C1-C6 alkyl OC(O), a substituted or unsubstituted 5-9-membered heterospiro ring; or two connected R1, R2 or R3 connected to adjacent ring atoms on the ring together constitute a cyclic structure selected from the following group: a substituted or unsubstituted C 6-10 substituted or unsubstituted 5-12 membered heteroaromatic ring, substituted or unsubstituted C3-C8 carbocyclic ring (including saturated or partially unsaturated), substituted or unsubstituted 3-8 membered heterocyclic ring (including saturated or partially unsaturated); or two connected R1, R2 or R3 connected to the same carbon atom of adjacent rings together with the adjacent ring form a 3-8 membered saturated or partially unsaturated spirocyclic structure, or a 3-8 membered saturated or partially unsaturated heterospirocyclic structure (herein referred to as substituent group wherein the ring skeleton of each heterocyclic ring may contain 1-3 heteroatoms selected from boron, oxygen, sulfur, phosphorus and nitrogen; in particular, when the atoms are boron, sulfur, phosphorus and nitrogen, the ring skeleton atoms may be oxidized, such as S(O) or S(O)2; unless otherwise specified, in the above formulae, the substitution refers to the substitution of the corresponding group by one or more substituents selected from the group consisting of deuterium, tritium, halogen, oxo, =NH, =N(C 1-8 alkyl), hydroxyl, carboxyl, mercapto, benzyl, C1-C 12 Alkoxycarbonyl, C1-C6 aldehyde, amino, C1-C6 amide, nitro, cyano, unsubstituted or halogenated C1-C6 alkyl, C1-C6 alkyl-CN, unsubstituted or halogenated C3-C8 cycloalkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C6 alkoxy, C1-C6 alkyl-amino, C6-C 10 Aryl, five-membered or six-membered heteroaryl, 3-8-membered non-aromatic heterocyclic group, -O-(C6-C 10 aryl), -O-(five-membered or six-membered heteroaryl), C1-C 12 Alkylaminocarbonyl, unsubstituted or halogenated C2-C 10 Acyl, sulfonyl (-SO2-OH), phosphinoyl (-PO3-OH), unsubstituted or halogenated C1-C4 alkyl-S(O)2-, unsubstituted or halogenated C1-C4 alkyl-SO-, unsubstituted or halogenated C1-C4 alkylamino-S(O)2-; wherein each chiral atom in the molecule can be in R configuration, S configuration, or a combination thereof. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof, characterized in that: Ring B is a 6-10 membered heteroaromatic ring, and the R1 is selected from the following group: H, halogen, cyano, amino, nitro, hydroxyl, thiol, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino; or two R1 connected to adjacent ring atoms together constitute a cyclic structure selected from the following group: substituted or unsubstituted C3-C6 carbocycle (including saturated or partially unsaturated), substituted or unsubstituted 3-6 membered heterocycle (including saturated and partially unsaturated). The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof, characterized in that: The B ring has a structure selected from the following group (wherein the connection site can be located on any ring atom): The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof, characterized in that: The A ring has a structure selected from the following group (wherein the connection site can be located on any ring atom): The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof, characterized in that: The R2 has a structure as shown below: Wherein, L3 is selected from the following groups: -C(R5)2-C(O)-, -C(R5)2-; R3 is selected from the following groups: H, substituted or unsubstituted C1-C6 alkyl; R6 is selected from the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 carbocyclic ring (including saturated or partially unsaturated), substituted or unsubstituted 3-6 membered heterocyclic ring; the ring skeleton of the heterocyclic ring may contain 1-3 heteroatoms selected from oxygen and sulfur; and the ring skeleton atoms may be oxidized; the substitution refers to the replacement of the hydrogen atoms on the corresponding group by one or more substituents selected from the following groups: deuterium, tritium, halogen, oxo, hydroxyl, carboxyl, mercapto, benzyl, cyano, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, C2-C 10 Alkenyl, C1-C6 alkoxy, C1-C6 alkyl-amino, C6-C 10 Aryl, 5-membered or 6-membered heteroaryl, 3-8-membered non-aromatic heterocyclic group. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof, characterized in that: The R2 is -CHR-C(O)NH-R6, wherein R is H or substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C1-C6 alkoxy, hydroxyl, substituted or unsubstituted amino; R6 is selected from the following group: substituted or unsubstituted C3-C6 carbocycle (including saturated or partially unsaturated), substituted or unsubstituted 3-6 membered heterocycle (including saturated or partially unsaturated). The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof, characterized in that: The compounds have structures shown in the following formulas II, III and IV: Wherein, X and Y are independently selected from the following group: O, NR3, C(R3)2; -C(=O)- or the compound has a structure shown in the following formula III: Wherein, X1, X2, X3 or X4 are each independently selected from the following group: N, CR3; or the compound has a structure shown in the following formula IV: Wherein, X1, X2, X3 or X4 are each independently selected from the following group: O, S, N, NR3 or CR3; is a single bond or a double bond; the definitions of the remaining groups are as described in claim 1. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof, characterized in that: The L1 is selected from the following group: chemical bond, -O-, -CHR-, carbonyl, S, -NH-; the L2 is selected from the following group: chemical bond, -CHR-NH-, -CHR-O-, -CHR-S-, -(CHR)2-. The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated product thereof, characterized in that: The compound is selected from the following group: A pharmaceutical composition, characterized in that The pharmaceutical composition contains a therapeutically effective amount of the compound according to claim 1, one or more of its pharmaceutically acceptable salts, racemates, optical isomers, stereoisomers or tautomers, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents. Use of the compound according to claim 1, its racemate, optical isomer monomer and mixture thereof or pharmaceutically acceptable salt in the preparation of a medicament for treating or preventing a disease associated with a mutation, overexpression, or dysregulation of H3K27 methylation level associated with a PRC2 complex, monomer, or combination thereof. The use according to claim 11, characterized in that The disease is selected from the group consisting of tumors and autoimmune diseases. The use according to claim 11, characterized in that The disease is selected from the group consisting of lymphoma, hematological malignancies, sarcoma, prostate cancer, breast cancer, kidney cancer, urothelial carcinoma, gastric cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, liver cancer, pancreatic cancer, colon cancer, head and neck cancer, brain tumor, melanoma, mesothelioma, gastrointestinal stromal tumor, psoriasis and lupus erythematosus. The use according to claim 11, characterized in that The disease is selected from the group consisting of non-Hodgkin's lymphoma, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, chronic lymphocytic leukemia, acute and chronic myeloid leukemia, acute and chronic lymphocytic leukemia, multiple myeloma, myelodysplastic syndrome, epithelioid sarcoma, rhabdomyosarcoma, liposarcoma, prostate cancer, breast cancer, kidney cancer, bladder cancer, upper urothelial carcinoma, gastric cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, liver cancer, pancreatic cancer, colon cancer, head and neck cancer, blastoma, glioma, schwannoma, melanoma, mesothelioma, gastrointestinal stromal tumor, psoriasis and lupus erythematosus.

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