WO2024008129A1 - 作为kat6抑制剂的化合物 - Google Patents

作为kat6抑制剂的化合物 Download PDF

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WO2024008129A1
WO2024008129A1 PCT/CN2023/105965 CN2023105965W WO2024008129A1 WO 2024008129 A1 WO2024008129 A1 WO 2024008129A1 CN 2023105965 W CN2023105965 W CN 2023105965W WO 2024008129 A1 WO2024008129 A1 WO 2024008129A1
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alkyl
cancer
cycloalkyl
group
compound
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PCT/CN2023/105965
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French (fr)
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张汉承
贾薇
蔡聪聪
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杭州英创医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a new class of derivatives containing tricyclic heteroaryl groups, their synthesis methods and their use as a KAT6 inhibitor in the preparation of drugs for the treatment of tumors and other related diseases. applications in.
  • Histone acetyltransferase uses acetyl-CoA to transfer an acetyl group to a lysine residue on histones or other substrate proteins.
  • Acetylation is a reversible post-translational modification that plays an important role in eukaryotic gene expression, cell cycle and signaling pathways.
  • histone acetyltransferases are divided into four families, namely GNAT (Gcn5-related acetyltransferase) family, p300/CBP family, SRC/p160 family and MYST (MOZ, Ybf2/Sas3, Sas2 and Tip60) family .
  • the acetyltransferase activity of MYST family proteins is affected 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.
  • KAT6A (Lysine Acetyltransferase 6A, also known as MOZ) and KAT6B (Lysine Acetyltransferase 6B, also known as MORF) belong to the acetyltransferases of the MYST family.
  • KAT6A has chromosomal translocations in acute myeloid leukemia, and has amplification mutations in cancer types such as lung cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, and esophageal cancer.
  • KAT6B is also mutated in chromosomal translocations 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.
  • KAT6A- and KAT6B-amplified tumor cells the expression of KAT6A and KAT6B was closely related to gene copy number, indicating that there is selective pressure to maintain their activity during tumorigenesis.
  • tumor cells with high expression of KAT6A and KAT6B are usually more dependent on the activities of KAT6A and KAT6B.
  • KAT6A and KAT6B usually extensively acetylate the lysine 23 site (H3K23) of histone H3, and KAT6A can also only modify the acetylation of the H3K9 site of its regulatory genes.
  • KAT6A interacts with some transcription factors such as p53 and RUNX1, acetylates histones, and regulates the expression of downstream genes.
  • KAT6A binds to the proximal promoter region of the estrogen receptor ER ⁇ (Estrogen Receptor ⁇ ) and activates the expression of the ER ⁇ gene.
  • KAT6A amplification mutations or high expression inhibiting the acetyltransferase activity of KAT6A or knocking down KAT6A can significantly inhibit the proliferation of breast cancer cells.
  • the acetyltransferase activity of KAT6A is critical for promoting the expression of MEIS1 and HOXa9 genes, which are often overexpressed in some lymphoma and leukemia cells.
  • deletion of one KAT6A allele significantly prolonged the median survival of the mice.
  • KAT6B In mice, mutations in the KAT6B allele cause a significant reduction in the division and differentiation of cortical progenitor cells, seriously affecting 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.
  • the purpose of the present invention is to provide a new class of KAT6 inhibitors.
  • the first aspect of the present invention provides a compound with the structure shown in the following formula (I), or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate :
  • Each R2 is independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy C 1-4 alkyl, C 1-4 haloalkoxy C 1-4 alkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, 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 ; wherein each R a is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 ring Alkyl, or 3- to 8-membered heterocyclyl;
  • Each R 4 is independently selected from the following group: aryl, heteroaryl, aryl C 1-4 alkyl, or heteroaryl C 1-4 alkyl; said alkyl, aryl or heteroaryl Optionally substituted by one or more groups selected from the group consisting of: halogen, CN, ORa , SRa , NRaRa , NO2 , -C( O ) Rm , -C(O) ORa , -S(O) 2 R m , -C(O)NR a R a , -OC(O)R m , -NR a C(O)R m , -NR a S(O) 2 R m ,C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl; wherein, each R a is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 Cycloalkyl, or 3- to 8-membered
  • Each R 7 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, 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 heteroaryl C 1-4 alkyl; wherein each R a is as defined above; Or two adjacent R 7 and the carbon atoms to which they are connected together form a 5- to -8-membered cyclic structure.
  • This cyclic structure optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S. ;
  • R 8 and R 9 are each independently selected from the group consisting of hydrogen, fluorine, C 1-4 alkyl, C 1-4 alkoxy, hydroxyl, or C 3-6 cycloalkyl; or R 8 and R 9 are The connected carbon atoms together form a 3- to -6-membered cyclic structure, and this cyclic structure optionally contains 0, 1, or 2 heteroatoms selected from N, O, and S;
  • Each R 10 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, CN, OR a , SR a , or NR a R a ; wherein each R a is as defined above;
  • n 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;
  • each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally and independently substituted by 1 to 3 substituents each independently selected from the following group: Substitution: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl, Aryl, heteroaryl, CN, NO 2 , 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) 2 R g , or -S(O) 2 R g , provided that the chemical structure formed is stable and meaningful
  • the above-mentioned aryl group is an aromatic group containing 6-12 carbon atoms;
  • the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group;
  • the cyclic structure is Saturated or unsaturated, heteroatom-containing or non-heteroatom-containing cyclic groups.
  • formula (I) is formula (II):
  • Each R 2 is independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 3-6 cycloalkyl, CN, OR a , SR a , or NR a R a ; wherein, each R a is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, 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 the first aspect of the invention.
  • formula (I) is formula (III):
  • Each R 2 is independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or OR a ; wherein each R a is independently selected from From hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl;
  • Each R 4 is independently selected from the following group: aryl, aryl C 1-4 alkyl, heteroaryl, or heteroaryl C 1-4 alkyl; wherein, the alkyl, aryl or hetero Aryl is optionally substituted with one or more groups selected from the group consisting of: halogen, CN, ORa , SRa , NRaRa , NO2 , -C( O ) Rm , -C(O) OR a , -S(O) 2 R m , -C(O)NR a R a , -OC(O)R m , -NR a C(O)R m , -NR a S(O) 2 R m , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl; wherein, each R a is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3 -6 cycloalkyl, or
  • R 4 is selected from the following group:
  • R 4 is selected from the following group:
  • the compound of formula (I) is selected from the following group:
  • R 2 is selected from H or OMe.
  • X is CR 8 R 9 , NR 11 , O or S
  • G is a 5-6 membered heteroaryl group
  • R 11 is selected from hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl
  • R 8 , R 9 and the remaining groups are as defined in the first aspect of the invention.
  • X is CR 8 R 9 , NR 11 , O or S;
  • R 11 is selected from hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl
  • R 8 , R 9 and the remaining groups are as defined in the first aspect of the invention.
  • R 2 is selected from H or OMe.
  • the third aspect of the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising the compound described in the first aspect of the present invention, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated Derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.
  • the fourth aspect of the present invention provides a compound as described in the first aspect of the present invention, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate Use for preparing pharmaceutical compositions for treating diseases, disorders or conditions related to KAT6 activity or expression levels.
  • 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 cholangiocarcinoma, rectal cancer, bladder cancer, throat cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioblastoma, 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 lymphoma , non-Hodgkin lymphoma, monocytic
  • the inventor unexpectedly discovered a class of KAT6 inhibitors with novel structures, as well as their preparation methods and applications.
  • the compounds of the present invention can be applied to the treatment of various diseases related to the activity of the acetyltransferase. Based on the above findings, the inventor completed the present invention.
  • each chiral carbon atom can optionally be in R configuration or S configuration, or a mixture of R configuration and S configuration.
  • alkyl refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon radical containing only carbon atoms, or a combination of straight-chain and branched chains. .
  • the alkyl group contains 1-10 carbon atoms.
  • C 1-8 alkyl refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or Similar groups.
  • alkenyl refers to a straight or branched, carbon chain radical having at least one carbon-carbon double bond. Alkenyl groups may be substituted or unsubstituted. When the number of carbon atoms in front of the alkenyl group is limited (such as C 2-8 ), it means that the alkenyl group contains 2-8 carbon atoms.
  • C 2-8 alkenyl refers to an alkenyl group containing 2 to 8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups group.
  • alkynyl refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
  • the alkynyl group may be linear or branched, or a combination thereof.
  • the alkynyl group contains 2-8 carbon atoms.
  • C 2-8 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.
  • cycloalkyl refers to a group having a saturated or partially saturated unit ring, bicyclic or polycyclic (fused, bridged or spiro) ring system .
  • a certain cycloalkyl group is preceded by a limited number of carbon atoms (such as C 3-10 ), it means that the cycloalkyl group contains 3-10 carbon atoms.
  • C 3-8 cycloalkyl refers to a saturated or partially unsaturated monocyclic or bicycloalkyl group with 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cycloalkyl, Pentyl, cycloheptyl, or similar groups.
  • Spirocycloalkyl refers to a bicyclic or polycyclic group that shares one carbon atom (called a spiro atom) between the single rings. These may contain one or more double bonds, but no ring has fully conjugated ⁇ electrons. system.
  • Condensed cycloalkyl refers to an all-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings may contain one or more bicyclic bonds, but none of the rings has a fully conjugated ⁇ electron system.
  • Bridged cycloalkyl refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more double bonds, but no ring has a fully conjugated ⁇ electron system. . All the atoms contained in the cycloalkyl group are carbon atoms. The following are some examples of cycloalkyl groups. The present invention is not limited to the following cycloalkyl groups.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing pairs of adjacent carbon atoms) groups having a conjugated pi electron system, such as phenyl and naphthyl.
  • the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but it cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be in a conjugated ⁇ electron system on the carbon atoms in the ring.
  • Aryl groups may be substituted or unsubstituted.
  • the following are some examples of aryl groups. The present invention is not limited to the following aryl groups.
  • Heteroaryl refers to an aromatic monocyclic or polycyclic group containing one to more heteroatoms (optionally selected from nitrogen, oxygen and sulfur), or a heterocyclic group (containing one to more heteroatoms optionally). (selected from nitrogen, oxygen and sulfur)) and an aryl group to form a polycyclic group, and the connection point is located on the aryl group. Heteroaryl groups may be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups. The present invention is not limited to the following heteroaryl groups.
  • Heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon.
  • monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.
  • Polycyclic heterocyclyl refers to heterocyclyl including spiro rings, fused rings and bridged rings.
  • Spirocyclic heterocyclyl refers to a polycyclic heterocyclic group in which each ring in the system shares one atom (called a spiro atom) with 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.
  • Condensed ring heterocyclyl refers to a polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more double bonds, but no A ring has a fully conjugated ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon.
  • “Bridged heterocyclyl” 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 fully conjugated ⁇ electron system. , and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If there are both saturated rings and aromatic rings in the heterocyclyl group (for example, the saturated ring and the aromatic ring are fused together), the point of connection to the parent must be on the saturated ring. Note: When the point of connection to the parent is on the aromatic ring, it is called heteroaryl, not heterocyclyl. The following are some examples of heterocyclyl groups. The present invention is not limited to the following heterocyclyl groups.
  • halogen refers to F, Cl, Br and I, alone or as part of other substituents.
  • substituted means that one or more hydrogen atoms on a specified group are replaced by a specified substituent.
  • Specific substituents are the substituents described accordingly in the foregoing text, or the substituents appearing in each embodiment.
  • a certain optionally substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • ring-shaped A substituent, such as heterocyclyl can be attached to another ring, such as cycloalkyl, to form a spirobicyclic system, in which the two rings have a common carbon atom.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • 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 heterocyclyl , Aryl group, heteroaryl group, halogen, hydroxyl group, carboxyl group (-COOH), C 1-8 aldehyde group, C 2-10 acyl group, C 2-10 ester group, amino group.
  • pharmaceutically acceptable salt refers to a salt suitable for contact with tissue of a subject (eg, a human) without causing undue side effects.
  • pharmaceutically acceptable salts of a certain compound of the present invention include salts of the compound of the present invention having an acidic group (for example, potassium salt, sodium salt, magnesium salt, calcium salt) or having a basic A salt of a compound of the present invention (eg, sulfate, hydrochloride, phosphate, nitrate, carbonate).
  • the invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if present), hydrates , pharmaceutically acceptable carriers or excipients for use in inhibiting KAT6.
  • the compounds of the present invention can be used as a KAT6 inhibitor.
  • the present invention is a single inhibitor of KAT6, which can prevent, alleviate or cure diseases by regulating the activity of KAT6.
  • the diseases referred to 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 cholangiocarcinoma, rectal cancer, bladder cancer, throat cancer, breast cancer, vaginal cancer, prostate cancer, testicular cancer, brain tumor, glioblastoma, 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 lymphom
  • compositions can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases.
  • the composition may be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, and sterile injections. Sterile powder, etc.
  • pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate, mannitol, hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin (increased), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates and polymer polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and Arabic gum) and lubricants (such as magnesium stearate, glycerin and talc).
  • disintegrants such as starch, croscarmellose sodium, complex silicates and polymer polyethylene glycol
  • granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and Arabic gum
  • lubricants such as magnesium stearate, glycerin and talc
  • the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders.
  • the amount of the compound or pharmaceutical composition administered to the patient is not fixed, but is usually administered in a pharmaceutically effective amount.
  • the actual amount of the compound administered can be determined by the physician based on the actual situation, including the disease to be treated, the route of administration selected, the actual compound administered, the individual condition of the patient, etc.
  • the dosage of a compound of the present invention will depend on the specific use of the treatment, the mode of administration, the patient's condition, and the judgment of the physician.
  • the proportion or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physical and chemical properties, route of administration, etc.
  • compositions and methods of administration are provided.
  • the compound of the present invention has excellent inhibitory activity against KAT6, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and the compound of the present invention contain the compound of the present invention as the main active ingredient
  • the pharmaceutical composition can be used to treat, prevent and alleviate diseases related to KAT6 activity or expression.
  • the pharmaceutical composition of the present invention contains a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
  • the “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, it contains 5-200 mg of the compound of the present invention/dose.
  • the "dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, 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, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • administration mode of the compounds or pharmaceutical compositions of the present invention is not particularly limited.
  • Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • 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 compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed 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-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents conventionally employed 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-butanediol, dimethylformamide and oils,
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the active compound, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions liquids 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.
  • 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.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • 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, and the dosage when administered is a pharmaceutically effective dosage.
  • a mammal such as a human
  • the daily dose is usually 1 to 2000 mg, preferably 5 to 500 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • KAT6 inhibitor with a novel structure, its preparation and application.
  • the inhibitor can inhibit the activity of KAT6 at very low concentrations.
  • Some representative compounds of the present invention can be prepared by the following synthesis methods.
  • the reagents and conditions of each step can be selected from the conventional reagents or conditions in this field for such preparation methods.
  • the above selection can be made by those skilled in the art based on knowledge in the art.
  • the compound of formula (I) of the present invention can be prepared by the following method:
  • Compound (Ia) can be synthesized using the method in patent WO2020254946. In an inert solvent, compound (Ia) and compound (Ib) are reacted to obtain compound (Ic). In an inert solvent, compound (Ic) is reacted with compound (Ib) to obtain compound (Ic). (Id) Compound (I) is obtained through a metal-catalyzed coupling reaction.
  • R 2 , R 4 , R 7 , R 8 , R 9 , R 10 , h, j and m are the same as those stated in the claims.
  • Example 10 Inhibition of KAT6A enzyme activity by compounds:
  • Example 11 Inhibition of ZR-75-1 cell proliferation by compounds:
  • the culture medium was removed from the 96-well plate.
  • Chromatographic column ACQUITY UPLC BEH C18 (2.1mm ⁇ 50mm, 1.7 ⁇ m); column temperature 40°C; mobile phase A is water (0.1% formic acid), mobile phase B is acetonitrile, the flow rate is 0.350 ml/min, and gradient elution is used , the elution gradient is 0.50min: 10%B; 1.50min: 90%B; 2.50min: 90%B; 2.51min: 10%B; 3.50min: stop. Injection volume: 1 ⁇ L.
  • Animals 3 SD male rats, with a weight range of 200-220g, were purchased and raised in the experimental animal center laboratory for 2 days before use. They were fasted 12 hours before and 4 hours after administration, and had free access to water during the test. After intragastric administration, blood samples were taken from the rats at predetermined time points.
  • Drug samples Generally, multiple samples with similar structures (molecular weights differing by more than 2 units) are taken, weighed accurately, and administered together (cassette PK). This allows multiple compounds to be screened simultaneously and their oral absorption rates compared. Single administration was also used to study the pharmacokinetics of drug samples in rats.
  • Blood was collected from the orbits at 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours after intragastric administration. Take 50 ⁇ L of plasma sample, add 200 ⁇ L of acetonitrile (containing internal standard verapamil 2 ng/mL), vortex for 3 minutes, centrifuge at 20,000 rcf and 4°C for 10 minutes, and take the supernatant for LC-MS/MS analysis.
  • acetonitrile containing internal standard verapamil 2 ng/mL

Abstract

提供了作为KAT6抑制剂的化合物，具体地，提供了一种如下式(I)所示结构的化合物，或其光学异构体、药学上可接受的盐、前药、氘代衍生物、水合物、溶剂合物。所述的化合物可以用于治疗或预防与KAT6的活性或表达量相关的疾病或病症。

Description

作为KAT6抑制剂的化合物 技术领域
本发明涉及药物化学领域；具体地说，本发明涉及一类新型含有三环杂芳基的衍生物，其合成方法及其作为一种KAT6抑制剂在制备药物用于***等相关多种疾病中的应用。
背景技术
组蛋白乙酰转移酶利用乙酰辅酶A，将乙酰基团转移到组蛋白或其他底物蛋白的赖氨酸残基上。乙酰化是一种可逆的翻译后修饰，在真核生物的基因表达、细胞周期和信号通路传递等方面都发挥着重要的作用。根据同源性，组蛋白乙酰转移酶分为四个家族，分别为GNAT(Gcn5-related acetyltransferase)家族、p300/CBP家族、SRC/p160家族和MYST(MOZ,Ybf2/Sas3,Sas2 and Tip60)家族。MYST家族蛋白的乙酰转移酶活性受到MYST结构域(催化结构域)的影响。MYST结构域包含一个乙酰辅酶A结合基序和一个比较罕见的C2HC型锌指结构，其中乙酰辅酶A结合基序和其他的组蛋白乙酰转移酶在结构上是保守的。MYST结构域是MYST家族蛋白的定义特征。
KAT6A(Lysine Acetyltransferase 6A，也称为MOZ)和KAT6B(Lysine Acetyltransferase 6B，也称为MORF)属于MYST家族的乙酰转移酶。KAT6A在急性髓系白血病中存在染色体易位，在肺癌、乳腺癌、卵巢癌、子宫内膜癌、膀胱癌和食管癌等癌症类型中都有扩增突变。类似的，KAT6B也在多种癌症类型中存在染色体易位突变。在急性髓系白血病中被鉴定的MOZ-和MORF-连接的融合蛋白包括MOZ-CBP、MOZ-p300、MOZ-TIF2、MOZ-NcoA3、MOZ-LEUTX和MORF-CBP。其中MOZ-TIF2在培养的细胞中具有转化活性，并且可以诱导小鼠发生急性髓系白血病。在KAT6A和KAT6B扩增的肿瘤细胞中，KAT6A和KAT6B的表达与基因拷贝数密切相关，表明在肿瘤发生过程中，存在选择性的压力来维持他们的活性。此外，细胞增殖试验中，具有KAT6A和KAT6B高表达的肿瘤细胞通常比较依赖KAT6A和KAT6B的活性。
KAT6A和KAT6B通常广泛地乙酰化修饰组蛋白H3的赖氨酸第23位点(H3K23)，KAT6A还可以仅修饰其调控基因H3K9位点的乙酰化。KAT6A和一些转录因子如p53、RUNX1等相互作用，乙酰化修饰组蛋白，调控下游基因的表达。KAT6A结合到***受体ERα(Estrogen Receptorα)的近端启动子区域，激活ERα基因的表达。在ER+，KAT6A扩增突变或高表达的乳腺癌细胞中，抑制KAT6A的乙酰转移酶活性或敲减KAT6A，可以显著抑制乳腺癌细胞的增殖。另外，KAT6A的乙酰转移酶活性对促进MEIS1和HOXa9基因的表达至关重要，这两个基因常在一些淋巴瘤和白血病细胞中过表达。在MYC诱导的淋巴癌小鼠模型中，缺失一个KAT6A等位基因可以明显延长小鼠的中位生存期。在小鼠中，KAT6B等位基因的突变会导致皮质祖细胞***和分化显著减少，严重影响大脑皮层的发育，KAT6B对维持成人神经干细胞的数目也发挥着重要的作用。KAT6B还在一些罕见类型的白血病中存在基因突变。
基于以上背景，我们开发了一种结构新颖的KAT6抑制剂。
发明内容
本发明的目的是提供一类新型的KAT6抑制剂。
本发明的第一方面，提供了一种如下式(I)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：
式(I)中：
各个R2各自独立地选自下组：氢、卤素、C1-4烷基、C1-4卤代烷基、C1-4烷氧基C1-4烷基、C1-4卤代烷氧基C1-4烷基、C2-4烯基、C2-4卤代烯基、C2-4炔基、C3-6环烷基、3-至8-元杂环基、芳基、杂芳基、CN、ORa、SRa、或NRaRa；其中，各个Ra各自独立地选自氢、C1-4烷基、C1- 4卤代烷基、C3-6环烷基、或3-至8-元杂环基；
各个R4各自独立地选自下组：芳基、杂芳基、芳基C1-4烷基、或杂芳基C1-4烷基；所述的烷基、芳基或杂芳基任选地被一个或多个选自下组的基团取代：卤素、CN、ORa、SRa、NRaRa、NO2、-C(O)Rm、-C(O)ORa、-S(O)2Rm、-C(O)NRaRa、-OC(O)Rm、-NRaC(O)Rm、-NRaS(O)2Rm、C1-4烷基、C2-4烯基、C2-4炔基；其中，各个Ra各自独立地选自氢、C1-4烷基、C1-4卤代烷基、C3-6环烷基、或3-至8-元杂环基；Rm选自C1-4烷基、C2-4烯基、C2-4炔基、C3- 6环烷基；
各个R7各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4炔基、CN、ORa、SRa、NRaRa、C3-6环烷基、3-至8-元杂环基、芳基、杂芳基、或杂芳基C1-4烷基；其中，各个Ra的定义如上所述；或相邻的二个R7与其连接的碳原子一起形成5-至-8元环状结构，此环状结构任选地含有0、1、或2个选自N、O、S的杂原子；
R8和R9各自独立地选自下组：氢、氟、C1-4烷基、C1-4烷氧基、羟基、或C3-6环烷基；或R8和R9与其连接的碳原子一起形成3-至-6元环状结构，此环状结构任选地含有0、1、或2个选自N、O、S的杂原子；
各个R10各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C3-6环烷基、3-至8-元杂环基、CN、ORa、SRa、或NRaRa；其中，各个Ra的定义如上所述；
m选自0、1、2、3、或4；
h选自0、1、2、或3；
j选自0、1、2、或3；
其中，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO2、ORb、SRb、NRdRd、-C(O)Rg、-C(O)ORb、-C(O)NRdRd、-NRdC(O)Rg、-NRdS(O)2Rg、或-S(O)2Rg，前提条件是所形成的化学结构是稳定的和有意义的；其中，Rb各自独立地选自氢、C1-4烷基、C1-4卤代烷基、C3-6环烷基、或3-至8-元杂环基；Rd各自独立地选自氢、C1-4烷基；Rg各自独立地选自C1- 4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、3-至8-元杂环基、芳基、杂芳基；
除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元(优选为5-至12-元)杂芳香基团；环状结构为饱和的或不饱和的、含杂原子或不含杂原子的环状基团。
在另一优选例中，式(I)为式(II)：
各个R2各自独立地选自下组：氢、卤素、C1-4烷基、C1-4卤代烷基、C2-4炔基、C3-6环烷基、CN、ORa、SRa、或NRaRa；其中，各个Ra各自独立地选自氢、C1-4烷基、C1-4卤代烷基、C3-6环烷基；m选自0、1、或2；
R4、R7、R8、R9、R10、h、和j的定义如本发明第一方面所述。
在另一优选例中，式(I)为式(III)：
各个R2各自独立地选自下组：氢、卤素、C1-4烷基、C1-4卤代烷基、C3-6环烷基、或ORa；其中，各个Ra各自独立地选自氢、C1-4烷基、C1-4卤代烷基、C3-6环烷基；
各个R4各自独立地选自下组：芳基、芳基C1-4烷基、杂芳基、或杂芳基C1-4烷基；其中，所述的烷基、芳基或杂芳基任选地被一个或多个选自下组的基团取代：卤素、CN、ORa、SRa、NRaRa、NO2、-C(O)Rm、-C(O)ORa、-S(O)2Rm、-C(O)NRaRa、-OC(O)Rm、-NRaC(O)Rm、-NRaS(O)2Rm、C1-4烷基、C2-4烯基、C2-4炔基；其中，各个Ra各自独立地选自氢、C1-4烷基、C1-4卤代烷基、C3-6环烷基、或3-至8-元杂环基；Rm选自C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基。
在另一优选例中，所述的R4选自下组：
在另一优选例中，所述的R4选自下组：
在另一优选例中，所述的式(I)化合物选自下组：

上述各个化合物中，R2选自H或OMe。
在本发明的另一方面，提供了一种如下式(IV)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：
其中，X为CR8R9、NR11、O或S；G为5-6元杂芳基；
R11选自氢、C1-4烷基、或C3-6环烷基；
R8、R9及其余各个基团的定义如本发明第一方面中所述。
在本发明的另一方面，提供了一种如下式(V)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：
其中，X为CR8R9、NR11、O或S；
R11选自氢、C1-4烷基、或C3-6环烷基；
R8、R9及其余各个基团的定义如本发明第一方面中所述。
在本发明的另一方面，提供了一组如下式所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：

上述各个化合物中，R2选自H或OMe。
本发明的第三方面，提供了一种药物组合物，所述药物组合物包含本发明第一方面所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，以及药学上可接受的载体。
本发明的第四方面，提供了一种如本发明第一方面所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其用于制备治疗与KAT6活性或表达量相关的疾病，病症或病状的药物组合物。
在另一优选例中，所述疾病，病症或病状选自下组：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、结肠癌、甲状腺癌、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、黑色素瘤、肝细胞癌、肝内胆管癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、***癌、***癌、睾丸癌、脑瘤、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、***、骨肉瘤、食管癌、肾癌、皮肤癌、胃癌、髓系白血病、淋巴系白血病、骨髓纤维化、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征多发性、骨髓癌等各种实体瘤和血液瘤。
具体实施方式
本发明人经过长期而深入的研究，意外地发现了一类结构新颖的KAT6抑制剂，以及它们的制备方法和应用。本发明化合物可以应用于与所述乙酰转移酶的活性相关的各种疾病的治疗。基于上述发现，发明人完成了本发明。
术语
除特别说明之处，本文中提到的“或”具有与“和/或”相同的意义(指“或”以及“和”)。
除特别说明之处，本发明的所有化合物之中，各手性碳原子(手性中心)可以任选地为R构型或S构型，或R构型和S构型的混合物。
如本文所用，在单独或作为其他取代基一部分时，术语“烷基”指只含碳原子的直链(即，无支链)或支链饱和烃基，或直链和支链组合的基团。当烷基前具有碳原子数限定(如C1-10)时，指所述的烷基含有1-10个碳原子。例如，C1-8烷基指含有1-8个碳原子的烷基，包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“烯基”是指直链或支链，具有至少一个碳-碳双键的碳链基团。烯基可以是取代的或未取代的。当烯基前具有碳原子数限定(如C2-8)时，指所述的烯基含有2-8个碳原子。例如，C2-8烯基指含有2-8个碳原子烯基，包括乙烯基、丙烯基、1,2-丁烯基、2,3-丁烯基、丁二烯基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“炔基”是指具有至少一个碳-碳三键的脂肪族碳氢基团。所述的炔基可以是直链或支链的，或其组合。当炔基前具有碳原子数限定(如C2-8炔基)时，指所述的炔基含有2-8个碳原子。例如，术语“C2-8炔基”指具有2-8个碳原子的直链或支链炔基，包括乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、仲丁炔基、叔丁炔基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“环烷基”指具有饱和的或部分饱和的单元环，二环或多环(稠环、桥环或螺环)环系基团。当某个环烷基前具有碳原子数限定(如C3-10)时，指所述的环烷基含有3-10个碳原子。在一些优选实施例中，术语“C3-8环烷基”指具有3-8个碳原子的饱和或部分不饱和的单环或二环烷基，包括环丙基、环丁基、环戊基、环庚基、或类似基团。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的二环或多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。“稠环烷基”指***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳二环或多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。所述环烷基所含原子全部为碳原子。如下是环烷基的一些例子，本发明并不仅局限下述的环烷基。
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环)，但不能含有杂原子如氮，氧，或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。如下是芳基的一些例子，本发明并不仅局限下述的芳基。
“杂芳基”指包含一个到多个杂原子(任选自氮、氧和硫)的具有芳香性的单环或多环基团，或者包含杂环基(含一个到多个杂原子任选自氮、氧和硫)与芳基稠合形成的多环基团，且连接位点位于芳基上。杂芳基可以是任选取代的或未取代的。如下是杂芳基的一些例子，本发明并不仅局限下述的杂芳基。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基。多环杂环基指包括螺环、稠环和桥环的杂环基。“螺环杂环基”指***中的每个环与体系中的其他环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“稠环杂环基”指***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“桥环杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。如果杂环基里同时有饱和环和芳环存在(比如说饱和环和芳环稠合在一起)，连接到母体的点一定是在饱和的环上。注：当连接到母体的点在芳环上时，称为杂芳基，不称为杂环基。如下是杂环基的一些例子，本发明并不仅局限下述的杂环基。
如本文所用，在单独或作为其他取代基一部分时，术语“卤素”指F、Cl、Br和I。
如本文所用，术语“取代”(在有或无“任意地”修饰时)指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取 代基，例如杂环基，可以与另一个环相连，例如环烷基，从而形成螺二环系，即两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C1-8烷基、C2-8烯基、C2-8炔基、C3- 8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-8醛基、C2-10酰基、C2-10酯基、氨基。
为了方便以及符合常规理解，术语“任意取代”或“任选取代”只适用于能够被取代基所取代的位点，而不包括那些化学上不能实现的取代。
如本文所用，除非特别说明，术语“药学上可接受的盐”指适合与对象(例如，人)的组织接触，而不会产生不适度的副作用的盐。在一些实施例中，本发明的某一化合物的药学上可接受的盐包括具有酸性基团的本发明的化合物的盐(例如，钾盐，钠盐，镁盐，钙盐)或具有碱性基团的本发明的化合物的盐(例如，硫酸盐，盐酸盐，磷酸盐，硝酸盐，碳酸盐)。
用途：
本发明提供了一类式(I)化合物，或它们的氘代衍生物、它们的盐、异构体(对映异构体或非对映异构体，如果存在的情况下)、水合物、可药用载体或赋形剂用于抑制KAT6的用途。
本发明化合物可用作一种KAT6抑制剂。
本发明是KAT6的单一抑制剂，通过调节KAT6的活性达到预防、缓解或治愈疾病的目的。所指疾病包括但不限于：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、结肠癌、甲状腺癌、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、黑色素瘤、肝细胞癌、肝内胆管癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、***癌、***癌、睾丸癌、脑瘤、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、***、骨肉瘤、食管癌、肾癌、皮肤癌、胃癌、髓系白血病、淋巴系白血病、骨髓纤维化、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征多发性、骨髓癌等各种实体瘤和血液瘤。
可将本发明化合物及其氘代衍生物，以及药学上可接受的盐或其异构体(如果存在的情况下)或其水合物和/或组合物与药学上可接受的赋形剂或载体配制在一起，得到的组合物可在体内给予哺乳动物，例如男人、妇女和动物，用于治疗病症、症状和疾病。组合物可以是：片剂、丸剂、混悬剂、溶液剂、乳剂、胶囊、气雾剂、无菌注射液。无菌粉末等。一些实施例中，药学上可接受的赋形剂包括微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙、甘露醇、羟丙基-β-环糊精、β-环糊精(增加)、甘氨酸、崩解剂(如淀粉、交联羧甲基纤维素钠、复合硅酸盐和高分子聚乙二醇)，造粒粘合剂(如聚乙烯吡咯烷酮、蔗糖、明胶和***胶)和润滑剂(如硬脂酸镁、甘油和滑石粉)。在优选的实施方式中，所述药物组合物是适于口服的剂型，包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。向患者施用本发明化合物或药物组合物的量不固定，通常按药用有效量给药。同时，实际给予的化合物的量可由医师根据实际情况决定，包括治疗的病症、选择的给药途径、给予的实际化合物、患者的个体情况等。本发明化合物的剂量取决于治疗的具体用途、给药方式、患者状态、医师判断。本发明化合物在药物组合物中的比例或浓度取决于多种因素，包括剂量、理化性质、给药途径等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。
药物组合物和施用方法
由于本发明化合物具有优异的对KAT6的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与KAT6活性或表达量相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮 液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的KAT6抑制剂，及其制备和应用，所述的抑制剂在极低浓度下即可抑制KAT6的活性。
3.提供了一种口服吸收良好的KAT6抑制剂。
4.提供了一类治疗与KAT6活性相关疾病的药物组合物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
本发明的部分代表性化合物可以通过下面合成方法制备而得，下述各反应式中，各步骤的试剂和条件可以选用本领域进行该类制备方法常规的试剂或条件，在本发明的化合物结构公开后，上述选择可以由本领域技术人员根据本领域知识进行。
化合物的通用合成方法
本发明的式(I)化合物可以通过以下方法制备得到：
反应式1：
化合物(Ia)可采用专利WO2020254946中的方法合成。在惰性溶剂中，用化合物(Ia)与化合物(Ib)反应得到化合物(Ic)，在惰性溶剂中，用化合物(Ic)与化合物 (Id)经过金属催化的偶联反应得到化合物(I)。上述反应式中R2、R4、R 7、R8、R9、R10、h、j和m与权力要求中表述相同。
实施例：
实施例1:化合物1的制备
将化合物1a(5.0g，23.03mmol)溶于二氯甲烷(20mL)中，冰浴下滴加氯磺酸(3.0mL)，反应液室温搅拌1小时。将反应液倒入冰水中，以二氯甲烷(20mL×3)萃取三次，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析分离纯化得白色固体化合物1b(500mg)。1H NMR(500MHz,CDCl3)δ6.82(s,2H),3.98(s,6H)。
将化合物1b(150mg，0.48mmol)溶于吡啶(0.2mL)中，再加入化合物1c(58mg，0.24mmol,采用专利WO2020254946中的方法合成)。反应混合物置于封管中加热至120℃搅拌2小时。反应液减压浓缩，所得粗品经硅胶柱层析分离纯化得白色固体化合物1d(55mg,44％)。MS m/z 523.0[M+H]+。
将中间体1d(25mg，0.05mmol)、碳酸铯(46mg，0.14mmol)、二(三苯基膦)二氯化钯(2.8mg，0.004mmol)、2-炔基吡啶(25mg，0.24mmol)溶于N,N-二甲基甲酰胺(1mL)中。反应混合物氮气氛围下于封管中100℃加热搅拌2小时。反应完毕，体系用水淬灭，乙酸乙酯(5mL×3)萃取。合并有机层经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经制备型薄层板分离纯化得白色固体化合物1(11mg,42％)。1H 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),7.48-7.43(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]+。
实施例2:化合物2的制备
将中间体1d(30mg，0.06mmol)、碳酸铯(46mg，0.14mmol)、二(三苯基膦)二氯化钯(2.8mg，0.004mmol)、5-乙炔基嘧啶(25mg，0.24mmol)溶于N,N-二甲基甲酰胺(1mL)中。反应混合物氮气氛围下于封管中100℃加热搅拌2小时。反应完毕，体系用水淬灭，乙酸乙酯(5mL×3)萃取，合并有机层经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经制备型薄层板分离纯化得白色固体化合物2(7mg,22％)。1H 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]+。
实施例3:化合物3的制备
化合物3a采用专利WO200610629中的方法合成。将化合物3a(300mg，1.05mmol)溶于吡啶(1.2mL)中，再加入化合物1c(128mg，0.53mmol)。反应混合物置于封管中加热至120℃搅拌2小时。反应液减压浓缩，所得粗品经硅胶柱层析分离纯化得白色固体化合物3b(100mg，39％)。MS m/z 494.9[M+H]+。
将中间体3b(100mg，0.20mmol)、三乙胺(0.5mL)、二(三苯基膦)二氯化钯(7mg，0.01mmol)和三异丙基硅乙炔(110mg，0.60mmol)溶于二甲基亚砜(2.5mL)中。反应混合物氮气氛围下于封管中100℃加热搅拌2小时。然后反应液用水淬灭，乙酸乙酯(10mL×3)萃取，有机层合并后经饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析分离纯化得白色固体化合物3c(60mg,50％)。MS m/z 595.1[M+H]+。
将化合物3c(10mg，0.017mmol)溶于N,N-二甲基甲酰胺(1mL)中，然后加入氟化铯(15mg，0.1mmol)、3-碘吡啶(10mg，0.05mmol)和二(三苯基膦)二氯化钯(2mg，0.003mmol)。反应体系氮气氛围下于封管中80℃加热搅拌1小时。反应完毕，体系用水淬灭，乙酸乙酯(5mL×3)萃取，合并有机层经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。所得粗品经制备型薄层板分离纯化(二氯甲烷:甲醇＝10:1)得到白色固体化合物3(6mg，收率69％)。1H 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,1H),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]+。
实施例4:化合物4的制备
将化合物3c(12mg，0.02mmol)溶于N,N-二甲基甲酰胺(1mL)中，再加入氟化铯(15mg，0.1mmol)、5-碘嘧啶(10mg，0.05mmol)和二(三苯基膦)二氯化钯(2mg，0.003mmol)。反应混合物氮气氛围下于封管中80℃加热搅拌1小时。反应完毕，体系用水淬灭，乙酸乙酯(5mL×3)萃取，合并有机层经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。所得粗品经制备型薄层板分离纯化(二氯甲烷:甲醇＝10:1)得到白色固体化合物4(7.5mg，收率72％)。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]+。
实施例5:化合物5的制备
将化合物3c(10mg，0.017mmol)溶于N,N-二甲基甲酰胺(1mL)中，再加入氟化铯(15mg，0.1mmol)、2-碘吡啶(10mg，0.05mmol)和二(三苯基膦)二氯化钯(2mg，0.003mmol)。反应混合物氮气氛围下于封管中80℃加热搅拌1小时。反应完毕，体系用水淬灭，乙酸乙酯(5mL×3)萃取，合并有机层经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。所得粗品经制备型薄层板分离纯化(二氯甲烷:甲醇＝10:1)得到白色固体化合物5(5mg，收率58％)。1H 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]+。
实施例6:化合物6的制备
将化合物1d(137mg，0.26mmol)、三乙胺(0.5mL)、二(三苯基膦)二氯化钯(7mg，0.01mmol)和三异丙基硅乙炔(110mg，0.60mmol)溶于二甲基亚砜(2.5mL)中。反应体系氮气氛围下于封管中100℃加热搅拌2小时。反应混合物用水淬灭，乙酸乙酯(10mL×3)萃取，有机层合并后经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。所得粗品经硅胶柱层析分离纯化得白色固体化合物6a(140mg,86％)。MS m/z 625.1[M+H]+。
将化合物6a(30mg，0.048mmol)溶于N,N-二甲基甲酰胺(1mL)中，再加入氟化铯(46mg，0.3mmol)、2-溴嘧啶(24mg，0.15mmol)和二(三苯基膦)二氯化钯(5mg，0.007mmol)。反应混合物氮气氛围下于封管中100℃加热搅拌2小时。反应完毕，体系用水淬灭，乙酸乙酯(10mL×3)萃取，合并有机层经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。所得粗品经制备型薄层板分离纯化(二氯甲烷：甲醇＝10:1)得到白色固体化合物6(12mg，收率46％)。1H 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]+。
实施例7:化合物7的制备
将化合物6a(30mg，0.048mmol)溶于N,N-二甲基甲酰胺(1mL)中，再加入氟化铯(46mg，0.3mmol)、2-溴吡嗪(24mg，0.15mmol)和二(三苯基膦)二氯化钯(5mg，0.007mmol)。反应混合物氮气氛围下于封管中100℃加热搅拌2小时。反应混合物氮气氛围下于封管中100℃加热搅拌2小时。反应完毕，体系用水淬灭，乙酸乙酯(10mL×3)萃取，合并有机层经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。所得粗品经制备型薄层板分离纯化(二氯甲烷:甲醇＝10:1)得到白色固体化合物7(12mg，收率46％)。1H 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]+。
实施例8:化合物8的制备
将化合物3c(35mg，0.06mmol)溶于N,N-二甲基甲酰胺(2mL)中，再加入氟化铯(55mg，0.36mmol)、2-溴嘧啶(29mg，0.18mmol)和二(三苯基膦)二氯化钯(7mg，0.01mmol)。反应混合物氮气氛围下于封管中80℃加热搅拌2小时反应混合物氮气氛围下于封管中100℃加热搅拌2小时。反应完毕，体系用水淬灭，乙酸乙酯(10mL×3)萃取，合并有机层经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。所得粗品经制备型薄层板分离纯化(二氯甲烷:甲醇＝10:1)得到白色固体化合物8(20mg，收率66％)。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]+。
实施例9:化合物9的制备
将化合物3b(18mg，0.04mmol)、三乙胺(0.2mL)、二(三苯基膦)二氯化钯(2mg，0.003mmol)和三甲基硅乙炔(12mg，0.12mmol)溶于二甲基亚砜(1mL)中。反应混合物氮气氛围下于封管中100℃加热搅拌2小时。反应混合物用水淬灭，以乙酸乙酯(5mL×3)萃取，有机层合并后经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经硅胶柱层析分离纯化得白色固体化合物9a(5mg,27％)。MS m/z 511.1[M+H]+。
将化合物9a(5mg，0.01mmol)溶于甲醇(1mL)和N,N-二甲基甲酰胺(0.2mL)中，再加入碳酸钾(4mg，0.03mmol)。反应混合物于室温搅拌2小时。将反应液过滤，滤液减压浓缩，粗品经制备型薄层板(甲醇:二氯甲烷＝1:20,V:V)分离纯化得白色固体化合物9b(2mg，47％)。1H 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,1H),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]+。
将化合物9b(22mg，0.05mmol)溶于N,N-二甲基甲酰胺(1mL)中，再加入氟化铯(46mg，0.3mmol)、2-溴吡嗪(24mg，0.15mmol)和二(三苯基膦)二氯化钯(4mg，0.006mmol)。反应混合物氮气氛围下于封管中80℃加热搅拌3小时。反应完毕，体系用水淬灭，乙酸乙酯(10mL×3)萃取，合并有机层经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。所得粗品经制备型薄层板分离纯化(二氯甲烷:甲醇＝10:1)得到白色固体化合物9(6mg，收率23％)。1H 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]+。
实施例10：化合物对KAT6A酶活性的抑制：
准备1x的实验缓冲液(改良的Tris缓冲液)，将化合物用100％的DMSO配置成10mM的储液，并按照一定的浓度梯度稀释。使用自动加样器Echo将化合物转移到384孔板中，DMSO的终浓度为1％。准备1x的KAT6A酶(催化结构域)溶液。准备[3H]-乙酰辅酶A(PERKIN ELMER,Cat.No.NET290250UC)和底物肽段H3(1-21)混合溶液。转移10μL的酶溶液到384孔中，在室温下孵育15分钟。加入10μL的[3H]-乙酰辅酶A和底物肽段H3(1-21)混合溶液到孔里起始反应。在室温下孵育1小时。加入10μL的终止液停止反应。转移25μL的反应溶液到Flashplate(Perkin Elmer,Cat.No. SMP410A001PK)中，在室温下孵育1小时。用Microbeta读板。在Excel中使用公式inhibition％＝(Max-Signal)/(Max-Min)*100％计算化合物的抑制率。其中max是指DMSO对照的数值，min是指无酶活对照的数值，signal是指测试化合物孔的数值。使用XLFit软件拟合曲线并计算IC50。部分代表性化合物的活性如表1所示。
表1：KAT6A酶活性抑制(IC50，nM)
实施例11：化合物对ZR-75-1细胞增殖的抑制：
配制完全培养基，充分混匀。在显微镜下观察ZR-75-1细胞生长状态良好时，将细胞培养瓶从培养箱中取出，核对培养瓶上标记的细胞名称和培养基类型。吸掉培养基，用3mL胰酶润洗一遍，吸弃废液，加3mL新鲜胰酶于培养瓶消化。待细胞松动要脱离瓶壁时，加8mL完全培养基中止胰酶消化，并轻轻混匀。用移液管将细胞悬液移入离心管中，1000rpm/min的转速离心5分钟。吸弃离心管中的上清液。向离心管中加入适当体积的培养基，轻柔吹打使细胞重悬均匀。使用Vi-Cell XR细胞计数仪计数。配置细胞悬液，加入96孔板中，每孔200μL，2500个细胞。将培养板放置于CO2培养箱中过夜。化合物配制成2mM的DMSO储存液，并将化合物按照四倍的浓度梯度进行稀释，加入到对应孔内。其中Blank孔为只加正常培养基，不加细胞，不含DMSO；DMSO孔为有细胞，含0.5％DMSO。将细胞放置于37度CO2培养箱中孵育7天。
孵育7天后，将培养基从96孔平板中取出。在孔中加入50μL 0.25％Trypsin-EDTA溶液，倒置显微镜下观察细胞至细胞层分散，加入150μL完整生长培养基，轻轻移液，将细胞滴入单细胞悬液中。用Vi-cell XR计算单元格数，并调整单元格到适当的密度。根据计数结果，每孔取相同体积的悬液到新板上，补充培养基至200μL/孔。将新板置于CO2培养箱中4小时，并使用HPD300添加化合物。细胞与化合物在5％CO2，37℃下再孵育7天。室温融化CellTiter-Glo试剂。将细胞培养板取出平衡至室温后，每孔加入100μL混匀后的CellTiter-Glo试剂，避光振荡2min，孵育10min。使用Enspire读取RLU信号；按下列公式计算：抑制率(％)＝(1-(化合物RLU–Blank RLU)/(DMSO对照RLU–Blank RLU))×100％。利用XLFit绘制药效抑制率曲线并计算IC50值。部分代表性化合物的活性如表2所示。
表2：ZR-75-1细胞增殖的抑制(IC50，nM)

实施例12:大鼠体内的药物动力学研究
仪器：Waters生产的XEVO TQ-S液质联用仪，所有的测定数据由Masslynx V4.1软件采集并处理，用Microsoft Excel计算和处理数据。用WinNonLin 8.0软件，采用统计矩法进行药代动学参数计算。主要包括动力学参数Tmax、T1/2、Cmax、AUC0-24h等。色谱柱：ACQUITY UPLC BEH C18(2.1mm×50mm，1.7μm)；柱温40℃；流动相A为水(0.1％甲酸)，流动相B为乙腈，流速为0.350毫升/分钟，采用梯度洗脱，洗脱梯度为0.50min：10％B；1.50min：90％B；2.50min：90％B；2.51min：10％B；3.50min：stop。进样量：1μL。
动物：SD雄性大鼠3只，体重范围200-220g，购入后在实验动物中心实验室饲养2天后使用，给药前12小时及给药后4小时内禁食，试验期间自由饮水。大鼠灌胃后按既定的时间内点取血样。
溶媒：0.4％乙醇+0.4％Tween 80+99.2％(0.5％甲基纤维素M450)。灌胃给药溶液的配制：精密称量化合物，加入溶媒中，常温下超声5分钟使药品完全溶解，配制成0.3毫克/毫升的药液。
药物样品：一般采取多个结构类似的样品(分子量相差在2个单位以上)，准确称量，一起给药(cassette PK)。这样可以同时筛选多个化合物，比较它们的口服吸收率。也采用单一给药来研究药物样品在大鼠体内的药物动力学。
灌胃给药后分别于0.25、0.5、1、2、4、8、10和24小时眼眶取血。取血浆样品50μL，加入200μL的乙腈(含内标维拉帕米2ng/mL)，涡旋振荡3min后，20000rcf，4℃离心10min，取上清液进行LC-MS/MS分析。
准确称量化合物配制成不同的浓度，在质谱上进行定量分析，从而建立起标准曲线，然后测试上述血浆里化合物的浓度，得出不同时间点的化合物浓度。所有的测定数据由相关的软件采集并处理，采用统计矩法进行药代动学参数计算(主要包括动力学参数Tmax、T1/2、Cmax、AUC0-24h等)。部分代表性化合物的动力学参数如表3所示。
表3大鼠体内的药物动力学参数

在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 一种如下式(I)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：
    式(I)中：
    各个R2各自独立地选自下组：氢、卤素、C1-4烷基、C1-4卤代烷基、C1-4烷氧基C1-4烷基、C1-4卤代烷氧基C1-4烷基、C2-4烯基、C2-4卤代烯基、C2-4炔基、C3-6环烷基、3-至8-元杂环基、芳基、杂芳基、CN、ORa、SRa、或NRaRa；其中，各个Ra各自独立地选自氢、C1-4烷基、C1- 4卤代烷基、C3-6环烷基、或3-至8-元杂环基；
    各个R4各自独立地选自下组：芳基、杂芳基、芳基C1-4烷基、或杂芳基C1-4烷基；所述的烷基、芳基或杂芳基任选地被一个或多个选自下组的基团取代：卤素、CN、ORa、SRa、NRaRa、NO2、-C(O)Rm、-C(O)ORa、-S(O)2Rm、-C(O)NRaRa、-OC(O)Rm、-NRaC(O)Rm、-NRaS(O)2Rm、C1-4烷基、C2-4烯基、C2-4炔基；其中，各个Ra各自独立地选自氢、C1-4烷基、C1-4卤代烷基、C3-6环烷基、或3-至8-元杂环基；Rm选自C1-4烷基、C2-4烯基、C2-4炔基、C3- 6环烷基；
    各个R7各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4炔基、CN、ORa、SRa、NRaRa、C3-6环烷基、3-至8-元杂环基、芳基、杂芳基、或杂芳基C1-4烷基；其中，各个Ra的定义如上所述；或相邻的二个R7与其连接的碳原子一起形成5-至-8元环状结构，此环状结构任选地含有0、1、或2个选自N、O、S的杂原子；
    R8和R9各自独立地选自下组：氢、氟、C1-4烷基、C1-4烷氧基、羟基、或C3-6环烷基；或R8和R9与其连接的碳原子一起形成3-至-6元环状结构，此环状结构任选地含有0、1、或2个选自N、O、S的杂原子；
    各个R10各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C3-6环烷基、3-至8-元杂环基、CN、ORa、SRa、或NRaRa；其中，各个Ra的定义如上所述；
    m选自0、1、2、3、或4；
    h选自0、1、2、或3；
    j选自0、1、2、或3；
    其中，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO2、ORb、SRb、NRdRd、-C(O)Rg、-C(O)ORb、-C(O)NRdRd、-NRdC(O)Rg、-NRdS(O)2Rg、或-S(O)2Rg，前提条件是所形成的化学结构是稳定的和有意义的；其中，Rb各自独立地选自氢、C1-4烷基、C1-4卤代烷基、C3-6环烷基、或3-至8-元杂环基；Rd各自独立地选自氢、C1-4烷基；Rg各自独立地选自C1- 4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、3-至8-元杂环基、芳基、杂芳基；
    除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元(优选为5-至12-元)杂芳香基团；环状结构为饱和的或不饱和的、含杂原子或不含杂原子的环状基团。
  2. 如权利要求1所述的化合物，其特征在于，式(I)为式(II)：
    各个R2各自独立地选自下组：氢、卤素、C1-4烷基、C1-4卤代烷基、C2-4炔基、C3-6环烷基、CN、ORa、SRa、或NRaRa；其中，各个Ra各自独立地选自氢、C1-4烷基、C1-4卤代烷基、C3-6环烷基；m选自0、1、或2；
    R4、R7、R8、R9、R10、h、和j的定义如权利要求1所述。
  3. 如权利要求1所述的化合物，其特征在于，式(I)为式(III)：
    各个R2各自独立地选自下组：氢、卤素、C1-4烷基、C1-4卤代烷基、C3-6环烷基、或ORa；其中，各个Ra各自独立地选自氢、C1-4烷基、C1-4卤代烷基、C3-6环烷基；
    各个R4各自独立地选自下组：芳基、芳基C1-4烷基、杂芳基、或杂芳基C1-4烷基；其中，所述的烷基、芳基或杂芳基任选地被一个或多个选自下组的基团取代：卤素、CN、ORa、SRa、NRaRa、NO2、-C(O)Rm、-C(O)ORa、-S(O)2Rm、-C(O)NRaRa、-OC(O)Rm、-NRaC(O)Rm、-NRaS(O)2Rm、C1-4烷基、C2-4烯基、C2-4炔基；其中，各个Ra各自独立地选自氢、C1-4烷基、C1-4卤代烷基、C3-6环烷基、或3-至8-元杂环基；Rm选自C1-4烷基、C2-4烯基、C2-4炔基、C3- 6环烷基。
  4. 如权利要求1-3任一所述的化合物，其特征在于，所述的R4选自下组：
  5. 如权利要求1-4任一所述的化合物，其特征在于，所述的R4选自下组：
  6. 如权利要求1所述的化合物，其特征在于，所述的式(I)化合物选自下组：

    上述各个化合物中，R2选自H或OMe。
  7. 一种如下式(IV)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：
    其中，X为CR8R9、NR11、O或S；G为5-6元杂芳基；
    R11选自氢、C1-4烷基、或C3-6环烷基；
    R8、R9及其余各个基团的定义如权利要求1中所述。
  8. 一种如下式(V)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：
    其中，X为CR8R9、NR11、O或S；
    R11选自氢、C1-4烷基、或C3-6环烷基；
    R8、R9及其余各个基团的定义如权利要求1中所述。
  9. 一组如下式所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：

    上述各个化合物中，R2选自H或OMe。
  10. 一种药物组合物，其特征在于，包含权利要求1至9中任一项所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，以及药学上可接受的载体。
  11. 一种权利要求1至9中任一项的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其特征在于，用于制备治疗与KAT6活性或表达量相关的疾病，病症或病状的药物组合物。
  12. 如权利要求11所述的用途，其特征在于，所述疾病，病症或病状选自下组：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、结肠癌、甲状腺癌、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、黑色素瘤、肝细胞癌、肝内胆管癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、***癌、***癌、睾丸癌、脑瘤、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、***、骨肉瘤、食管癌、肾癌、皮肤癌、胃癌、髓系白血病、淋巴系白血病、骨髓纤维化、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征多发性、骨髓癌等各种实体瘤和血液瘤。
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