Compounds as KAT6 inhibitors

Abstract

The invention provides a compound serving as a KAT6 inhibitor, and particularly provides a compound with a structure as shown in a formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate and a solvate of the compound. The compound can be used for treating or preventing diseases or symptoms related to the activity or expression quantity of KAT6. # imgabs0 #

Description

Compounds that act as KAT6 inhibitors Technical Field

[0001] The present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a novel class of derivatives containing tricyclic heteroaryl groups, a synthesis method thereof, and its use as a KAT6 inhibitor in the preparation of drugs for treating various tumor-related diseases. Background Art

[0002] Histone acetyltransferases use acetyl-CoA to transfer acetyl groups to lysine residues on histones or other substrate proteins. Acetylation is a reversible post-translational modification that plays important roles in gene expression, cell cycle regulation, and signaling pathways in eukaryotes. Based on homology, histone acetyltransferases are divided into four families: the GNAT (Gcn5-related acetyltransferase) family, the p300 / CBP family, the SRC / p160 family, and the MYST (MOZ, Ybf2 / Sas3, Sas2, and Tip60) family. The acetyltransferase activity of MYST family proteins is influenced by the MYST domain (catalytic domain). The MYST domain contains an acetyl-CoA binding motif and a relatively rare C2HC-type zinc finger structure. The acetyl-CoA binding motif is structurally conserved with other histone acetyltransferases. The MYST domain is a defining feature of MYST family proteins.

[0003] KAT6A (Lysine Acetyltransferase 6A, also known as MOZ) and KAT6B (Lysine Acetyltransferase 6B, also known as MORF) belong to the MYST family of acetyltransferases. KAT6A is involved in chromosomal translocations in acute myeloid leukemia and has been shown to undergo amplification mutations in cancers such as lung, breast, ovarian, endometrial, bladder, and esophageal cancers. Similarly, KAT6B is also involved in chromosomal translocation mutations in various cancer types. MOZ- and MORF-linked fusion proteins identified in acute myeloid leukemia include MOZ-CBP, MOZ-p300, MOZ-TIF2, MOZ-NcoA3, MOZ-LEUTX, and MORF-CBP. MOZ-TIF2 has transforming activity in cultured cells and can induce acute myeloid leukemia in mice. In tumor cells with amplified KAT6A and KAT6B, the expression of KAT6A and KAT6B is closely correlated with gene copy number, suggesting that there is selective pressure to maintain their activity during tumorigenesis. Furthermore, in cell proliferation assays, tumor cells with high expression of KAT6A and KAT6B are generally more dependent on the activity of KAT6A and KAT6B.

[0004] KAT6A and KAT6B typically extensively acetylate histone H3 at lysine 23 (H3K23), but KAT6A can also modify acetylation specifically at H3K9 on genes it regulates. KAT6A interacts with transcription factors such as p53 and RUNX1, acetylating histones and regulating the expression of downstream genes. KAT6A binds to the proximal promoter region of the estrogen receptor α (ERα), activating ERα expression. In breast cancer cells harboring ER+, KAT6A amplification, mutations, or high expression, inhibiting KAT6A acetyltransferase activity or knocking down KAT6A significantly inhibits breast cancer cell proliferation. Furthermore, KAT6A acetyltransferase activity is crucial for promoting the expression of MEIS1 and HOXa9, genes often overexpressed in some lymphomas and leukemias. In a mouse model of MYC-induced lymphoma, deletion of one KAT6A allele significantly prolongs median survival. In mice, mutations in the KAT6B allele significantly reduce the division and differentiation of cortical progenitor cells, severely impacting the development of the cerebral cortex. KAT6B also plays an important role in maintaining the number of adult neural stem cells. KAT6B is also mutated in some rare types of leukemia.

[0005] Based on the above background, we developed a structurally novel KAT6 inhibitor.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide a new type of KAT6 inhibitors.

[0008] The first aspect of the present invention provides a compound having a structure shown in the following formula (I), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof:

[0009] In formula (I):

[0010] Each R 2 are independently selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, ORa SR a , or NR a R a ; Among them, each R a are each independently selected from hydrogen, C 1-4 Alkyl, C 1- 4 haloalkyl, C 3-6 cycloalkyl, or 3- to 8-membered heterocyclic group;

[0011] Each R 4 Each independently selected from the group consisting of aryl, heteroaryl, arylC 1-4 Alkyl or heteroaryl C 1-4 Alkyl; the alkyl, aryl or heteroaryl is optionally substituted by one or more groups selected from the group consisting of halogen, CN, OR a SR a NR a R a 、NO2、-C(O)R m 、-C(O)OR a 、-S(O)2R m 、-C(O)NR a R a 、-OC(O)R m 、-NR a C(O)R m 、-NR a S(O)2R m 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl; wherein each R a are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, or 3- to 8-membered heterocyclic group; R m Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3- 6-cycloalkyl;

[0012] Each R 7 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, CN, OR a SR a NR a R a 、C 3-6Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, or heteroarylC 1-4 Alkyl; wherein each R a The definition of is as above; or two adjacent R 7 Together with the carbon atom to which it is attached, it forms a 5- to 8-membered ring structure, which optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S;

[0013] R 8 and R 9 Each independently selected from the group consisting of hydrogen, fluorine, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, or C 3-6 Cycloalkyl; or R 8 and R 9 Together with the carbon atom to which it is attached, it forms a 3- to 6-membered ring structure, which optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S;

[0014] Each R 10 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic group, CN, OR a SR a , or NR a R a ; Among them, each R a The definition of is as above;

[0015] m is selected from 0, 1, 2, 3, or 4;

[0016] h is selected from 0, 1, 2, or 3;

[0017] j is selected from 0, 1, 2, or 3;

[0018] wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally and independently substituted with 1-3 substituents each independently selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO2, OR b SR b NR d R d 、-C(O)R g 、-C(O)ORb 、-C(O)NR d R d 、-NR d C(O)R g 、-NR d S(O)2R g , or -S(O)2R g , the prerequisite is that the chemical structure formed is stable and meaningful; among them, R b are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, or 3- to 8-membered heterocyclic group; R d are each independently selected from hydrogen, C 1-4 Alkyl; R g Each independently selected from C 1- 4 alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl;

[0019] Unless otherwise specified, the above-mentioned aryl group is an aromatic group containing 6 to 12 carbon atoms; the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group; and the cyclic structure is a saturated or unsaturated cyclic group containing or not containing heteroatoms.

[0020] In another preferred embodiment, formula (I) is formula (II):

[0021] Each R 2 are independently selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, CN, OR a SR a , or NR a R a ; Among them, each R a are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl; m is selected from 0, 1, or 2;

[0022] R 4 、R 7 、R 8 、R 9 、R 10 , h, and j are defined as described in the first aspect of the present invention.

[0023] In another preferred embodiment, formula (I) is formula (III):

[0024] Each R 2 are independently selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, or OR a ; Among them, each R a are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl;

[0025] Each R 4 Each independently selected from the group consisting of: aryl, aryl C 1-4 Alkyl, heteroaryl, or heteroarylC 1-4 wherein the alkyl, aryl or heteroaryl is optionally substituted by one or more groups selected from the group consisting of halogen, CN, OR a SR a NR a R a 、NO2、-C(O)R m 、-C(O)OR a 、-S(O)2R m 、-C(O)NR a R a 、-OC(O)R m 、-NR a C(O)R m 、-NR a S(O)2R m 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl; wherein each R a are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, or 3- to 8-membered heterocyclic group; R m Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl.

[0026] In another preferred embodiment, the R 4 Select from the following groups:

[0027] In another preferred embodiment, the R 4Select from the following groups:

[0028] In another preferred embodiment, the compound of formula (I) is selected from the following group:

[0029] In the above compounds, R 2 Selected from H or OMe.

[0030] In another aspect of the present invention, there is provided a compound having a structure shown in the following formula (IV), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof:

[0031] Where X is CR 8 R 9 NR 11 , O or S; G is a 5-6 membered heteroaryl group;

[0032] R 11 Selected from hydrogen, C 1-4 Alkyl, or C 3-6 Cycloalkyl;

[0033] R 8 、R 9 and the definitions of the remaining groups are the same as those described in the first aspect of the present invention.

[0034] In another aspect of the present invention, there is provided a compound having a structure shown in the following formula (V), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof:

[0035] Where X is CR 8 R 9 NR 11 , O or S;

[0036] R 11 Selected from hydrogen, C 1-4 Alkyl, or C 3-6 Cycloalkyl;

[0037] R 8 、R 9 and the definitions of the remaining groups are the same as those described in the first aspect of the present invention.

[0038] In another aspect of the present invention, a group of compounds having structures shown in the following formulae, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof are provided:

[0039] In the above compounds, R 2 Selected from H or OMe.

[0040] The third aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.

[0041] In a fourth aspect, the present invention provides a compound as described in the first aspect of the present invention, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates for preparing a pharmaceutical composition for treating diseases, disorders, or conditions associated with KAT6 activity or expression.

[0042] In another preferred embodiment, the disease, disorder or condition is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, hepatocellular carcinoma, intrahepatic bile duct cancer, rectal cancer, bladder cancer, pharyngeal cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, osteosarcoma, esophageal cancer, kidney cancer, skin cancer, gastric cancer, myeloid leukemia, lymphoid leukemia, myelofibrosis, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, monocytic leukemia, splenomegaly, multiple eosinophilia syndrome, myeloma and other solid tumors and blood tumors. DETAILED DESCRIPTION

[0043] After extensive and in-depth research, the present inventors unexpectedly discovered a class of novel KAT6 inhibitors, as well as their preparation methods and applications. The compounds of the present invention can be used to treat various diseases associated with the activity of the acetyltransferase. Based on these findings, the inventors completed the present invention.

[0044] the term

[0045] Unless otherwise specified, "or" mentioned in this document has the same meaning as "and / or" (referring to "or" and "and").

[0046] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom (chiral center) may be optionally in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0047] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched hydrocarbon groups. 1-10), it means that the alkyl group contains 1 to 10 carbon atoms. For example, C 1-8 The alkyl group refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

[0048] As used herein, the term "alkenyl" when used alone or as part of another substituent refers to a straight or branched carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the number of carbon atoms in the alkenyl group is limited (e.g., C 2-8 ), it means that the alkenyl group contains 2 to 8 carbon atoms. For example, C 2-8 Alkenyl refers to an alkenyl group containing 2 to 8 carbon atoms, including ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups.

[0049] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond, either alone or as part of another substituent. The alkynyl group may be straight-chain or branched, or a combination thereof. 2-8 When the term "alkynyl" is used, it means that the alkynyl contains 2 to 8 carbon atoms. 2-8 The term "alkynyl" refers to a straight or branched chain alkynyl group having 2 to 8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.

[0050] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated ring, bicyclic or polycyclic (fused, bridged or spiro) ring system group when used alone or as part of another substituent. 3-10 ) refers to a cycloalkyl group containing 3 to 10 carbon atoms. In some preferred embodiments, the term "C 3-8"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which the monocyclic rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but no ring has a completely conjugated π electron system. "Fused cycloalkyl" refers to a full-carbon bicyclic or polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. "Bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. The atoms contained in the cycloalkyl group are all carbon atoms. The following are some examples of cycloalkyl groups, and the present invention is not limited to the following cycloalkyl groups.

[0051] Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, such as phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on a carbon atom on the ring with a conjugated π electron system. Aryl groups can be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited to the aryl groups described below.

[0052] "Heteroaryl" refers to a monocyclic or polycyclic group having aromaticity containing one or more heteroatoms (selectively selected from nitrogen, oxygen, and sulfur), or a polycyclic group formed by condensing a heterocyclic group (containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur) with an aryl group, wherein the attachment point is located on the aryl group. The heteroaryl group may be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited to the following heteroaryl groups.

[0053] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclyls refer to heterocyclyls including spirocyclic, fused, and bridged rings. "Spirocyclic heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with the other rings in the system, in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Fused-ring heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system, in which one or more rings may contain one or more double bonds, but in which no ring has a completely conjugated pi-electron system, and in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If a heterocyclic group contains both saturated and aromatic rings (for example, a saturated ring and an aromatic ring are fused together), the point of attachment to the parent group must be on the saturated ring. Note: When the point of attachment to the parent group is on the aromatic ring, it is called a heteroaryl group, not a heterocyclic group. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.

[0054] As used herein, the term "halogen," by itself or as part of another substituent, refers to F, Cl, Br, and I.

[0055] As used herein, the term "substituted" (with or without the "arbitrarily" modifier) ​​refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described accordingly in the preceding text, or the substituent appearing in the examples. Unless otherwise specified, an arbitrarily 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 heterocyclic group, may be connected to another ring, such as a cycloalkyl group, to form a spirobicyclic system, i.e., the two rings have a common carbon atom. It will be understood 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 are, for example (but not limited to): C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3- 8-cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 Aldehyde, C 2-10 Acyl, C2-10 Ester group, amino group.

[0056] For the sake of convenience and in accordance with common understanding, the term "arbitrary substitution" or "optionally substituted" only applies to sites that can be substituted by substituents, and does not include those substitutions that are chemically unfeasible.

[0057] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of a subject (e.g., a human) without producing undue side effects. In some embodiments, a pharmaceutically acceptable salt of a compound of the present invention includes a salt of the compound of the present invention having an acidic group (e.g., potassium salt, sodium salt, magnesium salt, calcium salt) or a salt of the compound of the present invention having a basic group (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).

[0058] use:

[0059] The present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if any), hydrates, pharmaceutically acceptable carriers or excipients for use in inhibiting KAT6.

[0060] The compound of the present invention can be used as a KAT6 inhibitor.

[0061] The present invention is a single inhibitor of KAT6, which modulates the activity of KAT6 to prevent, alleviate, or cure diseases. These diseases include, but are not limited to, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, hepatocellular carcinoma, intrahepatic bile duct cancer, rectal cancer, bladder cancer, pharyngeal cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, osteosarcoma, esophageal cancer, kidney cancer, skin cancer, gastric cancer, myeloid leukemia, lymphoid leukemia, myelofibrosis, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, monocytic leukemia, splenomegaly, multiple eosinophilia syndrome, myeloid cancer, and other solid tumors and hematological tumors.

[0062] The compounds of the present invention and their deuterated derivatives, as well as pharmaceutically acceptable salts or isomers thereof (if present), or hydrates thereof, and / or compositions thereof, can be formulated with pharmaceutically acceptable excipients or carriers. The resulting compositions can be administered to mammals, such as men, women, and animals, in vivo for the treatment of conditions, symptoms, and diseases. The compositions can be in the form of tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injectable solutions, sterile powders, and the like. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-β-cyclodextrin, β-cyclodextrin (increased), glycine, disintegrants (such as starch, cross-linked sodium carboxymethyl cellulose, complex silicates, and high molecular weight polyethylene glycols), granulation binders (such as polyvinyl pyrrolidone, sucrose, gelatin, and gum arabic), and lubricants (such as magnesium stearate, glycerol, and talc). In a preferred embodiment, the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders. The amount of the compound of the present invention or the pharmaceutical composition administered to the patient is not fixed and is usually administered in a pharmaceutically effective amount. At the same time, the amount of the compound actually administered can be determined by the physician based on actual conditions, including the condition being treated, the selected route of administration, the actual compound administered, the individual condition of the patient, etc. The dosage of the compound of the present invention depends on the specific use of the treatment, the mode of administration, the patient's condition, and the physician's judgment. The ratio or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physicochemical properties, route of administration, etc.

[0063] 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 new or preferred technical solutions.

[0064] Pharmaceutical compositions and methods of administration

[0065] Since the compounds of the present invention have excellent inhibitory activity against KAT6, 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 diseases related to KAT6 activity or expression.

[0066] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, 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, "one dose" is one capsule or tablet.

[0067] "Pharmaceutically acceptable carriers" refer 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 Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0068] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0069] 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 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.

[0070] Solid dosage forms such as tablets, dragees, 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 opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0071] 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, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0072] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0073] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0074] Compositions for parenteral injection may comprise 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.

[0075] Dosage forms for topical administration of the compounds of this 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.

[0076] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0077] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0078] The main advantages of the present invention include:

[0079] 1. Provided is a compound as shown in formula I.

[0080] 2. Provided is a novel KAT6 inhibitor, as well as its preparation and use. The inhibitor can inhibit the activity of KAT6 at extremely low concentrations.

[0081] 3. Provides a KAT6 inhibitor with good oral absorption.

[0082] 4. Provided is a pharmaceutical composition for treating diseases associated with KAT6 activity.

[0083] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0084] Some representative compounds of the present invention can be prepared by the following synthetic methods. In the following reaction formulas, the reagents and conditions of each step can be selected from conventional reagents or conditions for such preparation methods in the art. After the structures of the compounds of the present invention are disclosed, the above selection can be made by those skilled in the art based on their knowledge in the art.

[0085] General synthetic methods for compounds

[0086] The compound of formula (I) of the present invention can be prepared by the following method:

[0087] Reaction 1:

[0088] Compound (Ia) can be synthesized using the method described in patent WO2020254946. In an inert solvent, compound (Ia) is reacted with compound (Ib) to obtain compound (Ic). In an inert solvent, compound (Ic) is reacted with compound (Id) via a metal-catalyzed coupling reaction to obtain compound (I). In the above reaction formula, R 2 、R 4 、R 7 、R 8 、R 9 、R 10 , h, j and m are the same as those in the claims.

[0089] Example:

[0090] Example 1: Preparation of Compound 1

[0091] Compound 1a (5.0 g, 23.03 mmol) was dissolved in dichloromethane (20 mL). Chlorosulfonic acid (3.0 mL) was added dropwise under ice-cooling, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted three times with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain Compound 1b (500 mg) as a white solid. 1H NMR (500 MHz, CDCl3) δ 6.82 (s, 2H), 3.98 (s, 6H).

[0092] Compound 1b (150 mg, 0.48 mmol) was dissolved in pyridine (0.2 mL), followed by the addition of compound 1c (58 mg, 0.24 mmol, synthesized using the method described in WO2020254946). The reaction mixture was heated to 120°C in a sealed tube and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to afford compound 1d (55 mg, 44%) as a white solid. MS m / z 523.0 [M+H]+.

[0093] Intermediate 1d (25 mg, 0.05 mmol), cesium carbonate (46 mg, 0.14 mmol), bis(triphenylphosphine)palladium dichloride (2.8 mg, 0.004 mmol), and 2-alkynylpyridine (25 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction mixture was heated and stirred at 100°C in a sealed tube under a nitrogen atmosphere for 2 hours. After completion of the reaction, the system was quenched with water and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate to afford Compound 1 (11 mg, 42%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ9.98(s,1H),8.66-8.59(m,1H),7.92-7.84(m,2H),7.72-7.65(m,1H),7.52-7.48(m,1H),7.4 8-7.43(m,1H),7.01(s,2H),6.84(s,1H),6.76(s,1H),6.30(t,J=2.0Hz,1H),5.45(s,2H),3.85(s,3H),3.82(s,6H). MS m / z 546.2[M+H] + .

[0094] Example 2: Preparation of Compound 2

[0095] Intermediate 1d (30 mg, 0.06 mmol), cesium carbonate (46 mg, 0.14 mmol), bis(triphenylphosphine)palladium dichloride (2.8 mg, 0.004 mmol), and 5-ethynylpyrimidine (25 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction mixture was heated and stirred at 100°C in a sealed tube under a nitrogen atmosphere for 2 hours. After completion of the reaction, the system was quenched with water and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate to afford Compound 2 (7 mg, 22%) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ10.02(s,1H),9.24(s,1H),9.05(s,2H),7.90-7.87(m,1H),7.50(dd,J=1.8,0.5Hz ,1H),7.02(s,2H),6.85(s,1H),6.76(s,1H),6.30(t,J=2.1Hz,1H),5.45(s,2H),3.85(s,3H),3.81(s,6H). MS m / z 547.1[M+H] + .

[0096] Example 3: Preparation of Compound 3

[0097] Compound 3a was synthesized using the method described in patent WO200610629. Compound 3a (300 mg, 1.05 mmol) was dissolved in pyridine (1.2 mL), and compound 1c (128 mg, 0.53 mmol) was added. The reaction mixture was heated to 120°C in a sealed tube and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain compound 3b (100 mg, 39%) as a white solid. MS m / z 494.9 [M+H] + .

[0098] Intermediate 3b (100 mg, 0.20 mmol), triethylamine (0.5 mL), bis(triphenylphosphine)palladium dichloride (7 mg, 0.01 mmol), and triisopropylsilyl acetylene (110 mg, 0.60 mmol) were dissolved in dimethyl sulfoxide (2.5 mL). The reaction mixture was heated and stirred at 100°C in a sealed tube under a nitrogen atmosphere for 2 hours. The reaction solution was then quenched with water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 3c (60 mg, 50%) as a white solid. MS m / z 595.1 [M+H] + .

[0099] Compound 3c (10 mg, 0.017 mmol) was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of cesium fluoride (15 mg, 0.1 mmol), 3-iodopyridine (10 mg, 0.05 mmol), and bis(triphenylphosphine)palladium dichloride (2 mg, 0.003 mmol). The reaction system was heated and stirred at 80°C in a sealed tube under a nitrogen atmosphere for 1 hour. After completion of the reaction, the system was quenched with water and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation (dichloromethane:methanol = 10:1) to afford compound 3 (6 mg, 69% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ10.54(s,1H),8.83-8.76(m,1H),8.63(dd,J=4.9,1.6Hz,1H),8.05-7.99(m,1H),7.88(d,J=2.0Hz,1H),7.84(d,J=8.1Hz,1 H),7.53-7.47(m,2H),7.41(s,1H),7.30(d,J=8.2Hz,1H),6.84(s,1H),6 .75(s,1H),6.30(t,J=2.0Hz,1H),5.44(s,2H),3.83(s,3H),3.81(s,3H). MS m / z 516.0[M+H] + .

[0100] Example 4: Preparation of Compound 4

[0101] Compound 3c (12 mg, 0.02 mmol) was dissolved in N,N-dimethylformamide (1 mL), and cesium fluoride (15 mg, 0.1 mmol), 5-iodopyrimidine (10 mg, 0.05 mmol), and bis(triphenylphosphine)palladium dichloride (2 mg, 0.003 mmol) were added. The reaction mixture was heated and stirred at 80°C in a sealed tube under a nitrogen atmosphere for 1 hour. After the reaction was completed, the system was quenched with water and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation (dichloromethane:methanol = 10:1) to obtain compound 4 (7.5 mg, 72% yield) as a white solid. 1H NMR (500MHz, DMSO-d6) δ10.59(s,1H),9.24(s,1H),9.06(s,2H),7.91-7.82(m,2H),7.50(d,J=1.5Hz,1H),7.43(s ,1H),7.36-7.27(m,1H),6.84(s,1H),6.74(s,1H),6.30(t,J=2.0Hz,1H),5.44(s,2H),3.83(s,3H),3.81(s,3H). MS m / z 517.0[M+H] + .

[0102] Example 5: Preparation of Compound 5

[0103] Compound 3c (10 mg, 0.017 mmol) was dissolved in N,N-dimethylformamide (1 mL), and cesium fluoride (15 mg, 0.1 mmol), 2-iodopyridine (10 mg, 0.05 mmol), and bis(triphenylphosphine)palladium dichloride (2 mg, 0.003 mmol) were added. The reaction mixture was heated and stirred at 80°C in a sealed tube under a nitrogen atmosphere for 1 hour. After the reaction was completed, the system was quenched with water and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation (dichloromethane:methanol = 10:1) to obtain compound 5 (5 mg, 58% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ10.55(s,1H),8.66-8.62(m,1H),7.92-7.86(m,2H),7.84(d,J=8.1Hz,1H),7.73-7.67(m,1H),7.52-7.49(m,1H),7. 48-7.44(m,1H),7.42(s,1H),7.33(d,J=7.9Hz,1H),6.85(s,1H),6.75 (s,1H),6.30(t,J=2.0Hz,1H),5.45(s,2H),3.83(s,3H),3.81(s,3H). MS m / z 516.0[M+H] + .

[0104] Example 6: Preparation of Compound 6

[0105] Compound 1d (137 mg, 0.26 mmol), triethylamine (0.5 mL), bis(triphenylphosphine)palladium dichloride (7 mg, 0.01 mmol), and triisopropylsilyl acetylene (110 mg, 0.60 mmol) were dissolved in dimethyl sulfoxide (2.5 mL). The reaction system was heated and stirred at 100°C in a sealed tube under a nitrogen atmosphere for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound 6a (140 mg, 86%) as a white solid. MS m / z 625.1 [M+H] + .

[0106] Compound 6a (30 mg, 0.048 mmol) was dissolved in N,N-dimethylformamide (1 mL), and cesium fluoride (46 mg, 0.3 mmol), 2-bromopyrimidine (24 mg, 0.15 mmol), and bis(triphenylphosphine)palladium dichloride (5 mg, 0.007 mmol) were added. The reaction mixture was heated and stirred at 100°C in a sealed tube under a nitrogen atmosphere for 2 hours. After completion of the reaction, the system was quenched with water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation (dichloromethane:methanol = 10:1) to afford compound 6 (12 mg, 46% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ10.09(s,1H),8.92-8.83(m,2H),7.89(d,J=2.2Hz,1H),7.57(t,J=4.9Hz,1H),7.50(d,J= 1.7Hz,1H),7.06(s,2H),6.85(s,1H),6.76(s,1H),6.30(t,J=2.0Hz,1H),5.45(s,2H),3.84(s,3H),3.83(s,6H). MS m / z 547.0[M+H] + .

[0107] Example 7: Preparation of Compound 7

[0108] Compound 6a (30 mg, 0.048 mmol) was dissolved in N,N-dimethylformamide (1 mL), and cesium fluoride (46 mg, 0.3 mmol), 2-bromopyrazine (24 mg, 0.15 mmol), and bis(triphenylphosphine)palladium dichloride (5 mg, 0.007 mmol) were added. The reaction mixture was heated and stirred at 100°C in a sealed tube under a nitrogen atmosphere for 2 hours. The reaction mixture was heated and stirred at 100°C in a sealed tube under a nitrogen atmosphere for 2 hours. After the reaction was completed, the system was quenched with water and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation (dichloromethane:methanol = 10:1) to obtain compound 7 (12 mg, 46% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ10.08(s,1H),8.93(d,J=1.4Hz,1H),8.76-8.72(m,1H),8.71-8.68(m,1H),7.89(d,J=2.2Hz,1H) ,7.52-7.48(m,1H),7.07(s,2H),6.85(s,1H),6.76(s,1H),6.31(t,J=2.0Hz,1H),5.45(s,2H),3.85(s,3H),3.82(s,6H). MS m / z 547.0[M+H] + .

[0109] Example 8: Preparation of Compound 8

[0110] Compound 3c (35 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium fluoride (55 mg, 0.36 mmol), 2-bromopyrimidine (29 mg, 0.18 mmol), and bis(triphenylphosphine)palladium dichloride (7 mg, 0.01 mmol) were added. The reaction mixture was heated and stirred at 80°C in a sealed tube under a nitrogen atmosphere for 2 hours. The reaction mixture was heated and stirred at 100°C in a sealed tube under a nitrogen atmosphere for 2 hours. After completion of the reaction, the system was quenched with water and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation (dichloromethane:methanol = 10:1) to obtain compound 8 (20 mg, 66% yield) as a white solid. 1H NMR (500MHz, DMSO-d6) δ10.62(s,1H),8.92-8.84(m,2H),7.91-7.82(m,2H),7.57(t,J=4.9Hz,1H),7.52-7.43(m ,2H),7.41-7.33(m,1H),6.84(s,1H),6.74(s,1H),6.30(t,J=2.0Hz,1H),5.44(s,2H),3.84(s,3H),3.81(s,3H). MS m / z 517.2[M+H] + .

[0111] Example 9: Preparation of Compound 9

[0112] Compound 3b (18 mg, 0.04 mmol), triethylamine (0.2 mL), bis(triphenylphosphine)palladium dichloride (2 mg, 0.003 mmol), and trimethylsilylacetylene (12 mg, 0.12 mmol) were dissolved in dimethyl sulfoxide (1 mL). The reaction mixture was heated and stirred at 100°C in a sealed tube under a nitrogen atmosphere for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain compound 9a (5 mg, 27%) as a white solid. MS m / z 511.1 [M+H] + .

[0113] Compound 9a (5 mg, 0.01 mmol) was dissolved in methanol (1 mL) and N,N-dimethylformamide (0.2 mL), and potassium carbonate (4 mg, 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified on a preparative thin-layer plate (methanol:dichloromethane = 1:20, v:v) to obtain compound 9b (2 mg, 47%) as a white solid. 1 H NMR (500MHz, CDCl3) δ8.08(d,J=8.1Hz,1H),8.02(s,1H),7.57(d,J=1.2Hz,1H),7.43(d,J=2.0Hz,1H),7.20(d,J=8.1Hz,1 H),7.03(s,1H),6.79(s,1H),6.45(s,1H),6.32(t,J=2.0Hz,1H),5.38(s,2H),3.96(s,3H),3.91(s,3H),3.24(s,1H)ppm. MS m / z 439.0[M+H] + .

[0114] Compound 9b (22 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide (1 mL), and cesium fluoride (46 mg, 0.3 mmol), 2-bromopyrazine (24 mg, 0.15 mmol), and bis(triphenylphosphine)palladium dichloride (4 mg, 0.006 mmol) were added. The reaction mixture was heated and stirred at 80°C in a sealed tube under a nitrogen atmosphere for 3 hours. After the reaction was completed, the system was quenched with water and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer plate separation (dichloromethane:methanol = 10:1) to obtain compound 9 (6 mg, 23% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ10.61(s,1H),8.94(d,J=1.4Hz,1H),8.75-8.72(m,1H),8.71-8.68(m,1H),7.90-7.83(m,2H),7.53- 7.43(m,2H),7.37(d,J=8.0Hz,1H),6.85(s,1H),6.75(s,1H),6.30(t,J=2.0Hz,1H),5.44(s,2H),3.84(s,3H),3.81(s,3H). MS m / z 517.2[M+H] + .

[0115] Example 10: Inhibition of KAT6A enzyme activity by compounds:

[0116] Prepare 1x assay buffer (modified Tris buffer), prepare the compound into a 10mM stock solution with 100% DMSO, and dilute according to a certain concentration gradient. Use the automatic sampler Echo to transfer the compound to a 384-well plate with a final DMSO concentration of 1%. Prepare 1x KAT6A enzyme (catalytic domain) solution. Prepare a mixed solution of [3H]-acetyl-CoA (PERKIN ELMER, Cat. No. NET290250UC) and substrate peptide H3 (1-21). Transfer 10μL of enzyme solution to 384 wells and incubate at room temperature for 15 minutes. Add 10μL of the mixed solution of [3H]-acetyl-CoA and substrate peptide H3 (1-21) to the well to start the reaction. Incubate at room temperature for 1 hour. Add 10μL of stop solution to stop the reaction. Transfer 25 μL of the reaction solution to a Flashplate (Perkin Elmer, Cat. No. SMP410A001PK) and incubate at room temperature for 1 hour. Read the plate using a Microbeta. Calculate the inhibition rate of the compound in Excel using the formula "inhibition% = (Max-Signal) / (Max-Min)*100%." ​​Where max refers to the value of the DMSO control, min refers to the value of the no-enzyme control, and signal refers to the value of the test compound well. Use XLFit software to fit the curve and calculate the IC 50 The activities of some representative compounds are shown in Table 1.

[0117] Table 1: KAT6A enzyme activity inhibition (IC 50 , nM)

[0118] Example 11: Inhibition of ZR-75-1 cell proliferation by compounds:

[0119] Prepare complete culture medium and mix thoroughly. When the ZR-75-1 cells are growing well under a microscope, remove the cell culture flask from the incubator and verify the cell name and culture medium type marked on the culture flask. Aspirate the culture medium, rinse once with 3mL of trypsin, discard the waste liquid, and add 3mL of fresh trypsin to the culture flask for digestion. When the cells are loose and about to detach from the flask wall, add 8mL of complete culture medium to stop trypsin digestion and mix gently. Use a pipette to transfer the cell suspension into a centrifuge tube and centrifuge at 1000rpm / min for 5 minutes. Aspirate the supernatant in the centrifuge tube. Add an appropriate volume of culture medium to the centrifuge tube and gently pipette to resuspend the cells evenly. Count using a Vi-Cell XR cell counter. Prepare the cell suspension and add 200μL to a 96-well plate, with 2500 cells per well. Place the culture plate in a CO2 incubator overnight. Compounds were prepared as 2 mM stock solutions in DMSO and diluted fourfold in a concentration gradient before being added to the corresponding wells. Blank wells contained normal culture medium without cells and DMSO, while DMSO wells contained cells with 0.5% DMSO. Cells were incubated in a 37°C CO2 incubator for 7 days.

[0120] After 7 days of incubation, remove the culture medium from the 96-well plate. Add 50 μL of 0.25% Trypsin-EDTA solution to the wells. Observe the cells under an inverted microscope until the cell layer is dispersed. Add 150 μL of complete growth medium and gently pipette the cells to a single-cell suspension. Count the cells using a Vi-cell XR and adjust the cell density to the appropriate level. Based on the count results, transfer the same volume of suspension from each well to a new plate and add culture medium to 200 μL / well. Place the new plate in a CO2 incubator for 4 hours, and add the compound using an HPD300. Incubate the cells and compound for an additional 7 days in 5% CO2 at 37°C. Thaw the CellTiter-Glo reagent at room temperature. Remove the cell culture plate and equilibrate it to room temperature. Add 100 μL of the mixed CellTiter-Glo reagent to each well, shake it for 2 minutes in the dark, and incubate it for 10 minutes. RLU signals were read using Enspire and calculated using the following formula: Inhibition rate (%) = (1-(compound RLU – blank RLU) / (DMSO control RLU – blank RLU)) × 100%. XLFit was used to plot the inhibition rate curve and calculate the IC. 50 The activities of some representative compounds are shown in Table 2.

[0121] Table 2: Inhibition of ZR-75-1 cell proliferation (IC 50 , nM)

[0122] Example 12: Pharmacokinetic study in rats

[0123] Instrument: Waters XEVO TQ-S LC-MS / MS. All measurement data were collected and processed by Masslynx V4.1 software, and calculated and processed using Microsoft Excel. Pharmacokinetic parameters were calculated using WinNonLin 8.0 software using the statistical moment method. These parameters mainly include the kinetic parameter T max 、T 1 / 2 、C max , AUC 0-24h Chromatographic column: ACQUITY UPLC BEH C18 (2.1 mm × 50 mm, 1.7 μm); column temperature: 40°C; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 0.350 mL / min; gradient elution: 0.50 min: 10% B; 1.50 min: 90% B; 2.50 min: 90% B; 2.51 min: 10% B; 3.50 min: stop. Injection volume: 1 μL.

[0124] Animals: Three male Sprague-Dawley rats, weighing 200-220 g, were housed in the laboratory of the Experimental Animal Center for two days before use. They were fasted for 12 hours before and 4 hours after dosing, with free access to water during the experiment. Blood samples were collected at designated intervals after gavage.

[0125] Solvent: 0.4% ethanol + 0.4% Tween 80 + 99.2% (0.5% methylcellulose M450) Preparation of oral administration solution: Accurately weigh the compound, add it to the solvent, and sonicate at room temperature for 5 minutes to completely dissolve the drug to prepare a 0.3 mg / ml solution.

[0126] Drug samples: Typically, multiple structurally similar samples (molecular weights differing by at least 2 units) are collected, accurately weighed, and administered together (cassette PK). This allows for simultaneous screening of multiple compounds and comparison of their oral absorption rates. Single administration is also used to study the pharmacokinetics of drug samples in rats.

[0127] Blood was collected from the orbital cavity at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after oral administration. Fifty microliters of plasma was added to 200 microliters of acetonitrile (containing the internal standard verapamil, 2 ng / mL). The mixture was vortexed for 3 minutes and centrifuged at 20,000 rcf at 4°C for 10 minutes. The supernatant was then analyzed by LC-MS / MS.

[0128] The compound is accurately weighed and prepared into different concentrations, and quantitative analysis is performed on the mass spectrometer to establish a standard curve. Then the concentration of the compound in the plasma is tested to obtain the concentration of the compound at different time points. All the measurement data are collected and processed by relevant software, and the pharmacokinetic parameters are calculated using the statistical moment method (mainly including the kinetic parameter T max 、T 1 / 2 、C max , AUC 0-24h The kinetic parameters of some representative compounds are shown in Table 3.

[0129] Table 3 Pharmacokinetic parameters in rats

[0130] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound having a structure represented by the following formula (I), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof: In formula (I): Each R 2 are independently selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 1-4 Halogenated alkoxy C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, OR a SR a , or NR a R a ;in, Each R a are each independently selected from hydrogen, C 1-4 Alkyl, C 1- 4 haloalkyl, C 3-6 cycloalkyl, or 3- to 8-membered heterocyclic group; Each R 4 Each independently selected from the group consisting of aryl, heteroaryl, arylC 1-4 Alkyl or heteroaryl C 1-4 Alkyl; the alkyl, aryl or heteroaryl is optionally substituted by one or more groups selected from the group consisting of halogen, CN, OR a SR a NR a R a 、NO2、-C(O)R m 、-C(O)OR a 、-S(O)2R m 、-C(O)NR a R a 、-OC(O)R m 、-NR a C(O)R m 、-NR a S(O)2R m 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl; wherein each R a are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, or 3- to 8-membered heterocyclic group; R m Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3- 6-cycloalkyl; Each R 7 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, CN, OR a SR a NR a R a 、C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, or heteroarylC 1-4 Alkyl; wherein each R a The definition of is as above; or two adjacent R 7 Together with the carbon atom to which it is attached, it forms a 5- to 8-membered ring structure, which optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S; R 8 and R 9 Each independently selected from the group consisting of hydrogen, fluorine, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy, or C 3-6 Cycloalkyl; or R 8 and R 9 Together with the carbon atom to which it is attached, it forms a 3- to 6-membered ring structure, which optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S; Each R 10 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclic group, CN, OR a SR a , or NR a R a ; Among them, each R a The definition of is as above; m is selected from 0, 1, 2, 3, or 4; h is selected from 0, 1, 2, or 3; j is selected from 0, 1, 2, or 3; wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally and independently substituted with 1-3 substituents each independently selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO2, OR b SR b NR d R d 、-C(O)R g 、-C(O)OR b 、-C(O)NR d R d 、-NR d C(O)R g 、-NR d S(O)2R g , or -S(O)2R g , the prerequisite is that the chemical structure formed is stable and meaningful; among them, R b are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, or 3- to 8-membered heterocyclic group; R d are each independently selected from hydrogen, C 1-4 Alkyl; R g Each independently selected from C 1- 4 alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl; Unless otherwise specified, the above-mentioned aryl group is an aromatic group containing 6 to 12 carbon atoms; the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group; and the cyclic structure is a saturated or unsaturated cyclic group containing or not containing heteroatoms.

2. The compound according to claim 1, wherein Formula (I) is Formula (II): Each R 2 are independently selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, CN, OR a SR a , or NR a R a ; Among them, each R a are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl; m is selected from 0, 1, or 2; R 4 、R 7 、R 8 、R 9 、R 10 , h, and j are as defined in claim 1.

3. The compound according to claim 1, wherein Formula (I) is Formula (III): Each R 2 are independently selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, or OR a ; Among them, each R a are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl; Each R 4 Each independently selected from the group consisting of: aryl, aryl C 1-4 Alkyl, heteroaryl, or heteroarylC 1-4 wherein the alkyl, aryl or heteroaryl is optionally substituted by one or more groups selected from the group consisting of halogen, CN, OR a SR a NR a R a 、NO2、-C(O)R m 、-C(O)OR a 、-S(O)2R m 、-C(O)NR a R a 、-OC(O)R m 、-NR a C(O)R m 、-NR a S(O)2R m 、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl; wherein each R a are each independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, or 3- to 8-membered heterocyclic group; R m Selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3- 6-cycloalkyl.

4. The compound according to any one of claims 1 to 3, characterized in that The R 4 Select from the following groups:

5. The compound according to any one of claims 1 to 4, characterized in that The R 4 Select from the following groups:

6. The compound according to claim 1, wherein The compound of formula (I) is selected from the following group: In the above compounds, R 2 Selected from H or OMe.

7. A compound having the structure represented by the following formula (IV), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof: in, X is CR 8 R 9 NR 11 , O or S; G is a 5-6 membered heteroaryl group; R 11 Selected from hydrogen, C 1-4 Alkyl, or C 3-6 Cycloalkyl; R 8 、R 9 The definitions of the remaining groups are as described in claim 1.

8. A compound having the structure represented by the following formula (V), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof: in, X is CR 8 R 9 NR 11 , O or S; R 11 Selected from hydrogen, C 1-4 Alkyl, or C 3-6 Cycloalkyl; R 8 、R 9 The definitions of the remaining groups are as described in claim 1.

9. A group of compounds having the structure shown in the following formula, or optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates thereof: In the above compounds, R 2 Selected from H or OMe.

10. A pharmaceutical composition, characterized in that Comprising the compound according to any one of claims 1 to 9, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate, and a pharmaceutically acceptable carrier.

11. Use of a compound according to any one of claims 1 to 9, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate or solvate thereof, characterized in that: Used for preparing a pharmaceutical composition for treating diseases, disorders or conditions related to KAT6 activity or expression.

12. The use according to claim 11, characterized in that The disease, disorder or condition is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, hepatocellular carcinoma, intrahepatic bile duct cancer, rectal cancer, bladder cancer, pharyngeal cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, osteosarcoma, esophageal cancer, kidney cancer, skin cancer, gastric cancer, myeloid leukemia, lymphoid leukemia, myelofibrosis, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, monocytic leukemia, splenomegaly, multiple eosinophilia syndrome, myeloma and other solid tumors and blood tumors.

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