WO2023280182A1 - 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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WO2023280182A1
WO2023280182A1 PCT/CN2022/104005 CN2022104005W WO2023280182A1 WO 2023280182 A1 WO2023280182 A1 WO 2023280182A1 CN 2022104005 W CN2022104005 W CN 2022104005W WO 2023280182 A1 WO2023280182 A1 WO 2023280182A1
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alkyl
cycloalkyl
compound
formula
hydrogen
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PCT/CN2022/104005
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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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Priority to CA3225068A priority Critical patent/CA3225068A1/en
Priority to EP22836931.0A priority patent/EP4368620A1/en
Publication of WO2023280182A1 publication Critical patent/WO2023280182A1/zh
Priority to PCT/CN2023/105965 priority patent/WO2024008129A1/zh

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    • 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
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a novel derivative containing tricyclic heteroaryl, its synthesis method and its use as a KAT6 inhibitor in the preparation of medicines for the treatment of tumors and other related diseases in the application.
  • Histone acetyltransferases use acetyl-CoA to transfer acetyl groups to lysine residues in histones or other substrate proteins.
  • Acetylation is a reversible post-translational modification that plays an important role in gene expression, cell cycle and signal pathway transmission in eukaryotes.
  • 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 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, in which the acetyl-CoA-binding motif is structurally conserved with other histone acetyltransferases.
  • the MYST domain is a defining feature of the MYST family of proteins.
  • 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 has chromosomal translocations in acute myeloid leukemia and amplified mutations in cancer types such as lung, breast, ovarian, endometrial, bladder, and esophageal cancers.
  • 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 KAT6A and KAT6B expression closely correlated with gene copy number, suggesting 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 activity of KAT6A and KAT6B.
  • KAT6A and KAT6B generally acetylate and modify the lysine 23 position of histone H3 (H3K23), and KAT6A can also only modify the acetylation of its regulatory gene H3K9 site.
  • 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 mutation 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 prolongs the median survival of mice.
  • KAT6B In mice, the mutation of the KAT6B allele leads to a significant reduction in the division and differentiation of cortical progenitor cells, severely affecting the development of the cerebral cortex, and KAT6B also plays an important role in maintaining the number of adult neural stem cells. KAT6B is also genetically 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 :
  • A is selected from formula (Ia), formula (Ib), formula (Ic), or formula (Id):
  • R is selected from hydrogen or C 1-4 alkyl ;
  • Each R 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;
  • D is selected from chemical bonds, -O-, -S-, or -NR e -; wherein, Re is selected from hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl; E is selected from C 3-8 Cycloalkyl, 3- to 10-membered heterocyclyl, C 3-8 cycloalkylC 1-4 alkyl, or 3- to 10-membered heterocyclyl C 1-4 alkyl;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, 3- to 9-membered heterocyclyl, aryl, or heteroaryl; wherein, The alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted by one or more groups selected from the group consisting of halogen, CN, OR a , SR a , NR a R a , NO 2 , -C(O)R m , -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, C 3-6 cycloalkyl,
  • Each R 6 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, CN, OR b , SR b , or NR b R b ; wherein each R b is as defined above ;
  • M is selected from O or CR h R i ; wherein, R h and R i are each independently selected from hydrogen, fluorine, or C 1-4 alkyl; wherein, said alkyl is optionally selected from one or more Group substitution from the following group: halogen, C 1-4 haloalkyl, CN, OR b , SR b , NR b R b , C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aryl , or heteroaryl; wherein, each R b is as defined above;
  • 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, the definition of each R a is as above;
  • 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 with The connected carbon atoms together form a 3- to -6-membered ring structure, which 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;
  • X is selected from O, S, or NR n ; wherein, R n is selected from hydrogen or C 1-4 alkyl;
  • Each R 11 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 , NR c R c , or -NR d C(O) R g ; wherein, each R a is as defined above; each R c is independently selected from From hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, aromatic Base or heteroaryl; R d is selected from hydrogen or C 1-4 alkyl; R g is as defined above;
  • n is selected from 0, 1, 2, 3, or 4;
  • n is selected from 0, 1, 2, 3, or 4;
  • f is selected from 0, 1, 2, or 3;
  • g is selected from 0, 1, 2, 3, or 4;
  • a and b are each independently selected from 0, 1, 2, 3, 4, or 5; the prerequisite is that a and b cannot be selected from 0 at the same time;
  • h is selected from 0, 1, 2, or 3;
  • j is selected from 0, 1, 2, or 3;
  • k is selected from 0, 1, 2, 3, 4, or 5;
  • each of the above-mentioned alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups is optionally and independently replaced by 1-3 substituents 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 formed chemical structure
  • 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 ring structure is Saturated or unsaturated, heteroatom-containing or heteroatom-free cyclic groups.
  • formula (I) is formula (II):
  • R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , D, E, m, n, h, and j are as described in the first aspect of the present invention.
  • formula (I) is formula (III):
  • U is selected from N or CR k ; Wherein, R k is selected from hydrogen, halogen, C 1-4 alkyl;
  • each R 14 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, CN, OR b , SR b , NR b R b ;
  • p and q are each independently selected from 0, 1, 2, 3, 4, 5, or 6; the prerequisite is that p and q cannot be selected from 0 at the same time;
  • t is selected from 0, 1, 2, 3, or 4;
  • R 2 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R b , D, m, h, and j are as described in the first aspect of the present invention.
  • formula (I) is formula (IV):
  • R 2 , R 4 , R 7 , R 8 , R 9 , R 10 , m, h, and j are as described in the first aspect of the present invention.
  • formula (I) is formula (V):
  • R 2 , R 6 , R 7 , R 8 , R 9 , R 10 , Rh , R i , a, b, f, g, h, and j are as described in the first aspect of the present invention.
  • formula (I) is formula (VI):
  • R 2 , R 6 , R 11 , Rh , R i , X, a, b, f, g, and k are as described in the first aspect of the present invention.
  • formula (I) is formula (VII):
  • R 2 , R 11 , R 12 , R 13 , D, X, m, and k are as described in the first aspect of the present invention.
  • formula (I) is formula (VIII):
  • 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 described in the first aspect of the present invention.
  • each of the R 2s is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, OR a , C 3-6 cycloalkyl, 3- to 8 -membered heterocyclyl.
  • each of the R 7 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, 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; each R a is independently selected from hydrogen, C 1-4 alkyl.
  • formula (I) is formula (IX):
  • 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 ;
  • Each R a is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl; each R b is independently selected from hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl; R m is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl.
  • formula (I) is formula (X):
  • 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 ;
  • Each R a is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl; each R b is independently selected from hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl; R m is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl.
  • formula (I) is formula (XI):
  • Each R 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 ;
  • R 4 is selected from the following group: hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl; wherein, the alkyl or cycloalkyl is optionally replaced by one or more groups selected from the group Substitution: halogen, CN, OR a , SR a , or NR a R a ;
  • Each R a is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl;
  • n is selected from 0, 1, 2, or 3.
  • formula (I) is formula (XII):
  • R2 and R4 are as defined above .
  • formula (I) is formula (VII):
  • R 2 , R 4 , R 11 , X, m, and k are as described in the first aspect of the present invention.
  • the second aspect of the present invention provides a compound with the structure shown in the following formula (XIV), or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate :
  • G is selected from C 3-8 cycloalkyl, 3- to 10-membered heterocyclyl, aryl (preferably benzene, naphthalene), heteroaryl (preferably furan, thiophene, pyridine, pyrimidine, pyrazine);
  • R 1 , R 2 , R 4 , B, and m are as described in the first aspect of the present invention.
  • the compound of formula (I) and formula (XIV) is selected from the following group:
  • R 2 is selected from H or OMe.
  • the third aspect of the present invention provides a pharmaceutical composition
  • a 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
  • the use of the invention which is used for preparing a pharmaceutical composition for treating diseases, diseases or conditions related to KAT6 activity or expression level.
  • the disease, disease 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, Granulosa cell tumor of the skin, melanoma, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, rectal cancer, bladder cancer, throat 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 lymphoma , Non-Hodgkin's lymphoma, monocytic leukemia,
  • the inventors unexpectedly discovered a class of KAT6 inhibitors with novel structures, as well as their preparation methods and applications.
  • the compound of the present invention can be applied to the treatment of various diseases related to the activity of said acetyltransferase. Based on the above findings, the inventors have accomplished the present invention.
  • each chiral carbon atom may 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 group containing only carbon atoms, or a combination of straight chain and branched chain groups .
  • the alkyl group is defined by the number of carbon atoms (such as C 1-10 ), it means that the said alkyl group contains 1-10 carbon atoms.
  • C 1-8 alkyl refers to an alkyl group containing 1-8 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 group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the number of carbon atoms (such as C 2-8 ) is limited before the alkenyl group, it means that the alkenyl group contains 2-8 carbon atoms.
  • C 2-8 alkenyl refers to alkenyl groups containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups group.
  • alkynyl alone or as part of another substituent, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
  • the alkynyl group can be straight or branched, or a combination thereof. When the number of carbon atoms is limited before the alkynyl group (such as C 2-8 alkynyl group), it means that the alkynyl group contains 2-8 carbon atoms.
  • C2-8 alkynyl refers to a straight or branched chain alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.
  • cycloalkyl alone or as part of another substituent, refers to a monocyclic or polycyclic (fused, bridged or spiro) ring system group having a saturated or partially saturated ring .
  • a cycloalkyl group is preceded by a restriction on the 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 bicyclic alkyl group with 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclo Pentyl, cycloheptyl, or similar groups.
  • Spirocycloalkyl means a bicyclic or polycyclic group in which the single rings share a single carbon atom (called a spiro atom), these may contain one or more double bonds, but none of the rings has fully conjugated pi electrons system.
  • “Fused cycloalkyl” means an all-carbon bicyclic or polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more bicyclic bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-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 only to the cycloalkyl groups described below.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, eg, 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 connection to the parent must be in a conjugated ⁇ -electron system on the carbon atoms in the ring.
  • Aryl groups can be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited only to the aryl groups described below.
  • 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 A polycyclic group formed by condensing nitrogen, oxygen and sulfur) with an aryl group, and the connection point is located on the aryl group. Heteroaryl groups can be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited only to the heteroaryl groups described below.
  • Heterocyclyl means 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.
  • a polycyclic heterocyclic group refers to a heterocyclic group including spiro rings, fused rings and bridged rings.
  • “Spirocyclic heterocyclic group” refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, with the remaining ring atoms being carbon.
  • “fused ring heterocyclyl” means a polycyclic heterocyclic 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 none A ring has a fully conjugated pi-electron system, and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
  • “Bridged heterocyclyl” means a polycyclic heterocyclic group in which any two rings share two atoms not directly connected, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system , and wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If there are both saturated and aromatic rings in the heterocyclic group (for example, the saturated ring and the aromatic ring are fused together), the point of attachment 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 heterocyclic. The following are some examples of heterocyclic groups, and the present invention is not limited only to the following heterocyclic groups.
  • halogen refers to F, Cl, Br and I, alone or as part of another substituent.
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent.
  • the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
  • an 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.
  • a cyclic substituent, such as a heterocyclyl may be attached to another ring, such as a cycloalkyl, to form a spirobicyclic ring system, ie, two rings that share a single carbon atom.
  • substituents contemplated by this 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 heterocyclyl , Aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino.
  • a pharmaceutically acceptable salt of a compound of the present invention refers to a salt that is suitable for contact with the tissues of a subject (eg, a human) without undue side effects.
  • a pharmaceutically acceptable salt of a compound of the present invention includes a salt of a compound of the present invention having an acidic group (e.g., potassium salt, sodium salt, magnesium salt, calcium salt) or having a basic Salts (eg, sulfates, hydrochlorides, phosphates, nitrates, carbonates) of compounds of the invention.
  • the present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereoisomers, if present), hydrates .
  • the compounds of the present invention are useful as a KAT6 inhibitor.
  • the 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, granulosa cell tumor of the skin, melanoma, hepatocellular carcinoma , intrahepatic cholangiocarcinoma, rectal cancer, bladder cancer, throat 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 lympho
  • compositions can be mixed with pharmaceutically acceptable excipients or The carriers are formulated together and the resulting compositions can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases.
  • Compositions can be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injections. Sterile powder etc.
  • pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin (increase), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicate and macromolecular polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic) and lubricants (such as magnesium stearate, glycerin, and talc).
  • disintegrants such as starch, croscarmellose sodium, complex silicate and macromolecular polyethylene glycol
  • granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic
  • 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 of the present invention administered to the patient is not fixed, and is usually administered in a pharmaceutically effective amount.
  • the amount of the compound to be actually administered can be determined by the physician according to the actual situation, including the disease to be treated, the route of administration selected, the actual compound administered, the individual condition of the patient, and the like. Dosage of the compounds of this invention will depend on the particular use for the treatment, the mode of administration, the state of the patient, and the judgment of the physician.
  • 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 and the like.
  • compositions and methods of administration are provided.
  • the compound of the present invention has excellent inhibitory activity to KAT6, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention as the main active ingredient
  • the pharmaceutical composition of the invention can be used for treating, preventing and alleviating diseases related to KAT6 activity or expression.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • 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.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid , magnesium stearate
  • calcium sulfate such
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration 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 admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, 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 used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can 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 in addition to the active compounds, may contain 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 or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound 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 which may be required, if necessary.
  • 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, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 5-500 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • KAT6 inhibitor with a novel structure, and its preparation and application.
  • the inhibitor can inhibit the activity of KAT6 at a very low concentration.
  • a KAT6 inhibitor with good oral absorption is provided.
  • a pharmaceutical composition for treating diseases related to KAT6 activity is provided.
  • Some representative compounds of the present invention can be prepared by the following synthetic methods.
  • the reagents and conditions of each step can be selected from the conventional reagents or conditions of this type of preparation method in the art.
  • the above selection can be made by those skilled in the art based on the knowledge in the art.
  • Some compounds of the present invention can be prepared by the following methods:
  • Compound (VIIIa) can be synthesized using the method in patent WO2020254946, and compound (VIIIb) can be synthesized using relevant references.
  • Compound (VIII) is obtained by reacting compound (VIIIa) with compound (VIIIb) in an inert solvent.
  • the definition of A in the above reaction formula is the same as that stated in claim 1.
  • the compound of formula (II) of the present invention can be prepared by the following methods:
  • Compound (IIa) can be synthesized by the method in patent WO2020254946.
  • the compound (IIc) is obtained by reacting the compound (IIa) with the compound (IIb), and the compound (IIc) and the corresponding intermediate or reagent undergo a metal-catalyzed coupling reaction or a substitution reaction to synthesize the target compound (II).
  • R 2 , R 3 , R 7 , R 8 , R 9 , R 10 , n, m, h, j, D and E in the above reaction formula are the same as those in the claims.
  • the compound of formula (III) of the present invention can be prepared by the following method:
  • compound (IIc) and compound (IIIa) are used to synthesize target compound (IIIb) through metal-catalyzed coupling reaction or substitution reaction, and compound (IIIb) is reacted with compound (III) to obtain compound (III).
  • R 2 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , p, q, h, j, m, t, D and U in the above reaction formula are the same as those in the claims.
  • the compound of formula (IV) of the present invention can be prepared by the following methods:
  • Compound (IV) is obtained by metal-catalyzed coupling reaction of compound (IIc) and compound (IVa) in an inert solvent.
  • R 2 , R 4 , R 7 , R 8 , R 9 , R 10 , h, j and m in the above reaction formula are the same as those in the claims.
  • the compound of formula (V) of the present invention can be prepared by the following methods:
  • compound (Vb) is obtained by reacting compound (Va) with chlorosulfonic acid, compound (Vb) is reacted with compound (IIa) to obtain compound (Vc), compound (Vc) undergoes wittig reaction to obtain compound (V).
  • R 2 , R 6 , R 7 , R 8 , R 9 , R 10 , Rh , R i , a, b, f, g, h and j in the above reaction formula are the same as those described in the claims.
  • the compound (VIb) is obtained by reacting the compound (Vb) with the compound (VIa), the compound (VIb) is subjected to wittig reaction to obtain the compound (VIc), and the protecting group is removed to obtain the compound (VId).
  • Compound (VIe) was synthesized by the method in patent WO2020216701. Compound (VId) is reacted with compound (VIe) to obtain compound (VI).
  • R 2 , R 6 , R 11 , Rh , R i , X, a, b, g, f and k in the above reaction formula are the same as those described in the claims.
  • Embodiment 1 the preparation of compound 1
  • Compound 1a was synthesized by the method in patent WO20130158004.
  • Compound 1a (205mg, 0.80mmol) was dissolved in tetrahydrofuran (5mL), cooled to -78°C under nitrogen atmosphere, and n-butyllithium (0.35mL, 2.5M n-hexane solution) was added dropwise. The reaction solution was incubated and stirred for 1 hour. Additional bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct (115 mg, 0.48 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was washed with methyl tert-butyl ether and filtered to obtain solid compound 1b (180 mg, 91%), which was directly used in the next reaction.
  • Compound 1d was synthesized by the method in patent WO2020254946.
  • Compound 1c (30 mg, 0.11 mmol) was dissolved in pyridine (0.2 mL), and compound 1d (13 mg, 0.05 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, separated and purified by preparative TLC to obtain compound 1 (5 mg, 20%) as a white solid.
  • Embodiment 2 the preparation of compound 2
  • p-Methoxybromobenzene 2a (1.0 g, 5.38 mmol) was dissolved in dichloromethane (10 mL), and chlorosulfonic acid (1.0 mL) was added dropwise under ice-cooling, and the reaction solution was stirred at room temperature for 3 hours.
  • the reaction solution was poured into ice water, extracted three times with dichloromethane (20mL ⁇ 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained crude product was separated by silica gel column chromatography Purification gave compound 2b (1.4 g, 92%) as a white solid.
  • Embodiment 3 the preparation of compound 3
  • Embodiment 4 the preparation of compound 4
  • Embodiment 5 the preparation of compound 5
  • Embodiment 6 the preparation of compound 6
  • the reaction mixture was heated and stirred at 100° C. for 3 hours in a sealed tube under a nitrogen atmosphere.
  • the reaction mixture was quenched with water, extracted with ethyl acetate (5mL ⁇ 3), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, separated and purified by preparative TLC to obtain a white Solid compound 6 (4 mg, 20%). MS m/z 500.1 [M+H] + .
  • Embodiment 7 the preparation of compound 7
  • Embodiment 8 the preparation of compound 8
  • Compound 8b was synthesized by the method in patent WO2020216701. Dissolve compound 8a (50mg, 0.19mmol), compound 8b (47mg, 0.21mmol), N,N-diisopropylethylamine (107mg, 0.76mmol) in dichloromethane (2mL), and then add 1H-benzene Triazol-1-yloxytripyrrolidinyl hexafluorophosphate (130 mg, 0.23 mmol), and the reaction mixture was stirred at room temperature overnight.
  • Embodiment 9 the preparation of compound 9
  • Embodiment 10 the preparation of compound 10
  • Embodiment 11 the preparation of compound 11
  • Embodiment 12 the preparation of compound 12
  • Embodiment 13 the preparation of compound 13
  • Embodiment 14 the preparation of compound 14
  • Embodiment 15 the preparation of compound 15
  • Embodiment 16 the preparation of compound 16
  • Embodiment 17 the preparation of compound 17
  • reaction mixture was heated and stirred at 90° C. for 2 hours in a sealed tube under a nitrogen atmosphere.
  • Embodiment 18 the preparation of compound 18
  • N-chlorosuccinimide (2.3g, 17.2mmol) was dissolved in a mixed solution of aqueous hydrochloric acid (2M, 2mL) and acetonitrile (10mL), and compound 18b (1.1g, 4.2mmol) was added dropwise at room temperature Acetonitrile (5 mL) solution. After dropping, the reaction solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with water, extracted three times with ethyl acetate (20mL ⁇ 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Embodiment 19 the preparation of compound 19
  • Embodiment 20 the preparation of compound 19'
  • Embodiment 21 the preparation of compound 20
  • Embodiment 22 the preparation of compound 21
  • Embodiment 23 the preparation of compound 22
  • Embodiment 24 the preparation of compound 23
  • Embodiment 25 the preparation of compound 24
  • a 1x experimental buffer (modified Tris buffer) was prepared, and the compound was prepared into a 10 mM stock solution with 100% DMSO, and diluted according to a certain concentration gradient. Compounds were transferred to a 384-well plate using an autosampler Echo with a final concentration of 1% DMSO.
  • Embodiment 27 pharmacokinetic research in rat body
  • 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, using gradient elution , 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 used after being raised in the laboratory of the Experimental Animal Center for 2 days after purchase, fasted for 12 hours before administration and within 4 hours after administration, and free to drink water during the test. After the rats were gavaged, blood samples were collected within a predetermined period of time.
  • Drug samples generally take multiple samples with similar structures (the difference in molecular weight is more than 2 units), weigh them accurately, and administer them together (cassette PK). This allows multiple compounds to be screened simultaneously and their oral absorption rates compared. Pharmacokinetics of drug samples in rats were also studied using single administration.
  • Blood was collected from the orbit 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 2ng/mL), vortex for 3 min, centrifuge at 20000 rcf, 4 °C for 10 min, and take the supernatant for LC-MS/MS analysis.
  • acetonitrile containing internal standard verapamil 2ng/mL

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Abstract

本发明提供了作为KAT6抑制剂的化合物，具体地，本发明提供了一种如下式(I)和式(XIV)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治疗肿瘤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结合到雌激素受体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分裂和分化显著减少，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：
Figure PCTCN2022104005-appb-000001
式(I)中：
A选自式(Ia)、式(Ib)、式(Ic)、或式(Id):
Figure PCTCN2022104005-appb-000002
其中，
Figure PCTCN2022104005-appb-000003
表示片段A与式(I)化合物其它部分连接的位点；
Figure PCTCN2022104005-appb-000004
表示双键或三键；当为三键时R 5为无；
B选自式(Ie)、式(If)、或式(Ig):
Figure PCTCN2022104005-appb-000005
其中，“---”表示片段B与式(I)化合物其它部分连接的位点；
R 1选自氢或C 1-4烷基；
各个R 2各自独立地选自下组：氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基C 1-4烷基、C 1-4卤代烷氧基C 1-4烷基、C 2-4烯基、C 2-4卤代烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、CN、OR a、SR a、或NR aR a；其中，各个R a各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、或3-至8-元杂环基；
D选自化学键、-O-、-S-、或-NR e-；其中，R e选自氢、C 1-4烷基、或C 3-6环烷基；E选自C 3-8环烷基、3-至10-元杂环基、C 3-8环烷基C 1-4烷基、或3-至10-元杂环基C 1-4烷基；
各个R 3各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、CN、OR b、SR b、NR bR b、-C(O)R g、-S(O) 2R g、C 3-6环烷基、或3-至8-元杂环基；或二个R 3连接在环烷基或杂环基环的同一个碳原子上并与该碳原子共同形成C＝T；其中，T选自O或CR 12R 13；其中，R 12和R 13各自独立地选自氢、氟、或C 1-4烷基；所述的R 12或R 13上的烷基任选地被一个或多个选自下组的基团取代：卤素、C 1-4卤代烷基、CN、OR b、SR b、NR bR b、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基；上述各个R b各自独立地选自氢、C 1-4烷基、或C 1-4卤代烷基；R g选自氢、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、3-至8-元杂环基、芳基、或杂芳基；
R 4和R 5各自独立地选自下组：氢、C 1-4烷基、C 3-8环烷基、3-至9-元杂环基、芳基、或 杂芳基；其中，所述的烷基、环烷基、杂环基、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、OR a、SR a、NR aR a、NO 2、-C(O)R m、-C(O)OR a、-S(O) 2R m、-C(O)NR aR a、-OC(O)R m、-NR aC(O)R m、-NR aS(O) 2R m、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基；或所述的环烷基或杂环基被＝T取代；其中，各个R a的定义如上所述；R m选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基；T的定义如上所述；
各个R 6各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、CN、OR b、SR b、或NR bR b；其中，各个R b的定义如上所述；
M选自O或CR hR i；其中，R h和R i各自独立地选自氢、氟、或C 1-4烷基；其中，所述的烷基任选地被一个或多个选自下组的基团取代：卤素、C 1-4卤代烷基、CN、OR b、SR b、NR bR b、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基；其中，各个R b的定义如上所述；
各个R 7各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、CN、OR a、SR a、NR aR a、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、或杂芳基C 1-4烷基；其中，各个R a的定义如上所述；
R 8和R 9各自独立地选自下组：氢、氟、C 1-4烷基、C 1-4烷氧基、羟基、或C 3-6环烷基；或R 8和R 9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R 10各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、CN、OR a、SR a、或NR aR a；其中，各个R a的定义如上所述；
X选自O、S、或NR n；其中，R n选自氢或C 1-4烷基；
各个R 11各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、CN、OR a、SR a、NR cR c、或-NR dC(O)R g；其中，各个R a的定义如上所述；各个R c各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基C 1-4烷基、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基；R d选自氢或C 1-4烷基；R g的定义如上所述；
m选自0、1、2、3、或4；
n选自0、1、2、3、或4；
f选自0、1、2、或3；
g选自0、1、2、3、或4；
a和b各自独立地选自0、1、2、3、4、或5；前提条件是a和b不能同时选自0；
h选自0、1、2、或3；
j选自0、1、2、或3；
k选自0、1、2、3、4、或5；
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、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR b、SR b、NR dR d、-C(O)R g、-C(O)OR b、-C(O)NR dR d、-NR dC(O)R g、-NR dS(O) 2R g、或-S(O) 2R g，前提条件是所形成的化学结构是稳定的和有意义的；其中，R b、R d、和R g的定义如上所述。
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)：
Figure PCTCN2022104005-appb-000006
R 2、R 3、R 7、R 8、R 9、R 10、D、E、m、n、h、和j的定义如本发明第一方面所述。
在另一优选例中，所述的E选自C 3-6环烷基、3-至6-元杂环基、C 3-6环烷基C 1-4烷基、或3-至6-元杂环基C 1-4烷基；各个R 3各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、CN、OR b、-C(O)R g；或二个R 3连接在环烷基或杂环基环的同一个碳原子上并与该碳原子共同形成C＝T；其中，T选自O或CR 12R 13；其中，R 12和R 13各自独立地选自氢、氟、或C 1-4烷基；所述的R 12或R 13上的烷基任选地被一个或多个选自下组的基团取代：卤素、C 1-4卤代烷基、OR b、NR bR b；上述各个R b各自独立地选自氢、C 1-4烷基、或C 1-4卤代烷基；R g选自氢、C 1-4烷基、C 3-8环烷基。
在另一优选例中，式(I)为式(III)：
Figure PCTCN2022104005-appb-000007
U选自N或CR k；其中，R k选自选自氢、卤素、C 1-4烷基；
各个R 14各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、CN、OR b、SR b、NR bR b；
p和q各自独立地选自0、1、2、3、4、5、或6；前提条件是p和q不能同时选自0；
t选自0、1、2、3、或4；
R 2、R 7、R 8、R 9、R 10、R 12、R 13、R b、D、m、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(IV)：
Figure PCTCN2022104005-appb-000008
R 2、R 4、R 7、R 8、R 9、R 10、m、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(V)：
Figure PCTCN2022104005-appb-000009
R 2、R 6、R 7、R 8、R 9、R 10、R h、R i、a、b、f、g、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(VI)：
Figure PCTCN2022104005-appb-000010
R 2、R 6、R 11、R h、R i、X、a、b、f、g、和k的定义如本发明第一方面所述。
在另一优选例中，式(I)为式(VII)：
Figure PCTCN2022104005-appb-000011
R 2、R 11、R 12、R 13、D、X、m、和k的定义如本发明第一方面所述；
U、R 14、p、q、和t的定义如上文中所述。
在另一优选例中，式(I)为式(VIII)：
Figure PCTCN2022104005-appb-000012
各个R 2各自独立地选自下组：氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基、C 3-6环烷基、CN、OR a、SR a、或NR aR a；其中，各个R a各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基；m选自0、1、或2；
R 4、R 7、R 8、R 9、R 10、h、和j的定义如本发明第一方面所述。
在另一优选例中，所述的R 4选自下组：氢、C 1-4烷基、C 3-8环烷基、3-至9-元杂环基、芳基、或杂芳基；其中，所述的烷基、环烷基、杂环基、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、OR a、-C(O)R m、-C(O)OR a、-S(O) 2R m、C 1-4烷基、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基；或所述的环烷基或杂环基被＝T取代；其中，各个R a的定义如上所述；R m选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基；T的定义如上所述。
在另一优选例中，所述的R 2各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、OR a、C 3-6环烷基、3-至8-元杂环基。
在另一优选例中，所述的R 7各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、OR a、SR a、NR aR a、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、或杂芳基C 1-4烷基；各个R a各自独立地选自氢、C 1-4烷基。
在另一优选例中，式(I)为式(IX)：
Figure PCTCN2022104005-appb-000013
各个R 2各自独立地选自下组：氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、或OR a；
R 4选自下组：氢、C 1-4烷基、C 3-8环烷基、3-至9-元杂环基、芳基、或杂芳基；其中，所述的烷基、环烷基、杂环基、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、OR a、SR a、NR aR a、-C(O)R m、-C(O)OR a、-S(O) 2R m、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至6-元杂环基、芳基、或杂芳基；或所述的环烷基或杂环基被＝T取代；其中，T选自O或CR 12R 13；其中，R 12和R 13各自独立地选自氢、氟、或C 1-4烷基；所述的R 12或R 13上的烷基任选地被一个或多个选自下组的基团取代：卤素、C 1-4卤代烷基、CN、OR b、SR b、NR bR b；
各个R a各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基；各个R b各自独立地选自氢、C 1-4烷基、或C 1-4卤代烷基；R m选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基。
在另一优选例中，式(I)为式(X)：
Figure PCTCN2022104005-appb-000014
各个R 2各自独立地选自下组：氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、或OR a；
R 4选自下组：氢、C 1-4烷基、C 3-8环烷基、3-至9-元杂环基、芳基、或杂芳基；其中，所述的烷基、环烷基、杂环基、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、OR a、SR a、NR aR a、-C(O)R m、-C(O)OR a、-S(O) 2R m、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至6-元杂环基、芳基、或杂芳基；或所述的环烷基或杂环基被＝T取代；其中，T选自O或CR 12R 13；其中，R 12和R 13各自独立地选自氢、氟、或C 1-4烷基；所述的R 12或R 13上的烷基任选地被一个或多个选自下组的基团取代：卤素、C 1-4卤代烷基、CN、OR b、SR b、NR bR b；
各个R a各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基；各个R b各自独立地选自氢、C 1-4烷基、或C 1-4卤代烷基；R m选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基。
在另一优选例中，式(I)为式(XI)：
Figure PCTCN2022104005-appb-000015
各个R 2各自独立地选自下组：氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基C 1-4烷基、C 1-4卤代烷氧基C 1-4烷基、C 2-4烯基、C 2-4卤代烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、CN、OR a、SR a、或NR aR a；
R 4选自下组：氢、C 1-4烷基、C 3-6环烷基；其中，所述的烷基或环烷基任选地被一个或多个选自下组的基团取代：卤素、CN、OR a、SR a、或NR aR a；
各个R a各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基；
m选自0、1、2、或3。
在另一优选例中，式(I)为式(XII)：
Figure PCTCN2022104005-appb-000016
R 2和R 4的定义如上文中所述。
在另一优选例中，式(I)为式(VII)：
Figure PCTCN2022104005-appb-000017
R 2、R 4、R 11、X、m、和k的定义如本发明第一方面所述。
本发明的第二方面，提供了一种如下式(XIV)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：
Figure PCTCN2022104005-appb-000018
G选自C 3-8环烷基、3-至10-元杂环基、芳基(优选为苯、萘)、杂芳基(优选为呋喃、噻吩、吡啶、嘧啶、吡嗪)；
R 1、R 2、R 4、B、和m的定义如本发明第一方面所述。
在另一优选例中，所述的式(I)和式(XIV)化合物选自下组：
Figure PCTCN2022104005-appb-000019
Figure PCTCN2022104005-appb-000020
Figure PCTCN2022104005-appb-000021
Figure PCTCN2022104005-appb-000022
Figure PCTCN2022104005-appb-000023
上述各个化合物中，R 2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、阴道癌、前列腺癌、睾丸癌、脑瘤、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、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C 1-10)时，指所述的烷基含有1-10个碳原子。例如，C 1-8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C 2-8)时，指所述的烯基含有2-8个碳原子。例如，C 2-8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C 2-8炔基)时，指所述的炔基含有2-8个碳原子。例如，术语“C 2-8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C 3-10)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“C 3-8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电子系统。“稠环烷基”指系统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电子系统。“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电子系统。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。
Figure PCTCN2022104005-appb-000024
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。
Figure PCTCN2022104005-appb-000025
“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。
Figure PCTCN2022104005-appb-000026
“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”指系统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”指系统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 子系统，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电子系统，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。
Figure PCTCN2022104005-appb-000027
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)：C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C 1-8醛基、C 2-10酰基、C 2-10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、阴道癌、前列腺癌、睾丸癌、脑瘤、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、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、明胶和阿拉伯胶)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
Figure PCTCN2022104005-appb-000028
Figure PCTCN2022104005-appb-000029
)、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、蔗糖和阿拉伯胶；(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
本发明的部分化合物可以通过以下方法制备得到：
反应式1：
Figure PCTCN2022104005-appb-000030
化合物(Ⅷa)可采用专利WO2020254946中的方法合成，化合物(Ⅷb)可采用相关的参考文献合成。在惰性溶剂中，用化合物(Ⅷa)与化合物(Ⅷb)反应，得到化合物(Ⅷ)。上述反应式中A的定义与权力要求1中表述相同。
本发明的式(II)化合物可以通过以下方法制备得到：
反应式2：
Figure PCTCN2022104005-appb-000031
化合物(IIa)可采用专利WO2020254946中的方法合成。在惰性溶剂中，用化合物(IIa)与化合物(IIb)反应得到化合物(IIc)，化合物(IIc)与相应的中间体或试剂经过金属催化的偶联反应或者取代反应合成目标化合物(II)。上述反应式中R 2、R 3、R 7、R 8、R 9、R 10、n、m、h、j、D和E与权力要求中表述相同。
本发明的式(III)化合物可以通过以下方法制备得到：
反应式3：
Figure PCTCN2022104005-appb-000032
在惰性溶剂中，用化合物(IIc)与化合物(IIIa)经过金属催化的偶联反应或者取代反应合成目标化合物(IIIb)，化合物(IIIb)与经过wittig反应得到化合物(III)。上述反应式中R 2、R 7、R 8、R 9、R 10、R 12、R 13、R 14、p、q、h、j、m、t、D和U与权力要求中表述相同。
本发明的式(IV)化合物可以通过以下方法制备得到：
反应式4：
Figure PCTCN2022104005-appb-000033
在惰性溶剂中，用化合物(IIc)与化合物(IVa)经过金属催化的偶联反应得到化合物(IV)。上述反应式中R 2、R 4、R 7、R 8、R 9、R 10、h、j和m与权力要求中表述相同。
本发明的式(V)化合物可以通过以下方法制备得到：
反应式5：
Figure PCTCN2022104005-appb-000034
在惰性溶剂中，用化合物(Va)与氯磺酸反应得到化合物(Vb)，化合物(Vb)与化合物(IIa)反应得到化合物(Vc)，化合物(Vc)发生wittig反应得到化合物(V)。上述反应式中R 2、R 6、R 7、R 8、R 9、R 10、R h、R i、a、b、f、g、h和j与权力要求中表述相同。
本发明的式(VI)化合物可以通过以下方法制备得到：
反应式6：
Figure PCTCN2022104005-appb-000035
在惰性溶剂中，用化合物(Vb)与化合物(VIa)反应得到化合物(VIb)，化合物(VIb) 经wittig反应得到化合物(VIc)，脱去保护基得到化合物(VId)。化合物(VIe)采用专利WO2020216701中的方法合成。化合物(VId)与化合物(VIe)反应得到化合物(VI)。上述反应式中R 2、R 6、R 11、R h、R i、X、a、b、g、f和k与权力要求中表述相同。
本发明的式(VII)化合物可以通过以下方法制备得到：
反应式7：
Figure PCTCN2022104005-appb-000036
在惰性溶剂中，用化合物(IIb)与化合物(VIa)反应得到化合物(VIIa)，再经金属催化的偶联反应或取代反应得到化合物(VIIb)，化合物(VIIb)经wittig反应得到化合物(VIIc)，化合物(VIIc)脱去保护基得到化合物(VIId)。化合物(VIe)采用专利WO2020216701中的方法合成。化合物(VIId)与化合物(VIe)反应得到化合物(VII)。上述反应式中R 2、R 11、R 12、R 13、R 14、X、D、U、p、q、t、m、和k与权力要求中表述相同。
实施例：
实施例1:化合物1的制备
Figure PCTCN2022104005-appb-000037
化合物1a采用专利WO20130158004中的方法合成。将化合物1a(205mg,0.80mmol)溶于四氢呋喃(5mL)，氮气氛围下冷却至-78℃，滴加正丁基锂(0.35mL,2.5M正己烷溶液)。反应液保温搅拌1小时。再加入双(二氧化硫)-1,4-二氮杂双环[2.2.2]辛烷加合物(115mg,0.48mmol)。反应混合物缓慢升温至室温搅拌1小时。将反应混 合物减压浓缩，残留物经甲基叔丁基醚洗涤和过滤得到固体化合物1b(180mg,91％)直接用于下一步反应。
将化合物1b(203mg,0.82mmol)溶于二氯甲烷(5mL)，冰浴下加入氯代丁內酰亚胺(109mg,0.82mmol)，反应混合物室温搅拌1小时。将反应混合物过滤，所得滤液减压浓缩后经硅胶柱层析分离纯化得白色固体化合物1c(94mg,42％)。 1H NMR(500MHz,CDCl 3)δ＝7.78(d,J＝9.0Hz,1H),6.41(d,J＝2.0Hz,1H),6.36(dd,J＝9.0Hz,J＝2.0Hz,1H),4.68-4.62(m,1H),2.44-2.38(m,2H),2.17-2.10(m,2H),1.89-1.80(dd,J＝21.0,10.4,1H),1.72-1.62(m,1H)ppm。
化合物1d采用专利WO2020254946中的方法合成。将化合物1c(30mg,0.11mmol)溶于吡啶(0.2mL)中，再加入化合物1d(13mg,0.05mmol)。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，经制备型薄层板分离纯化得白色固体化合物1(5mg,20％)。 1H NMR(500MHz,CDCl 3)δ8.05-7.94(m,2H),7.60(s,1H),7.46(s,1H),6.79(s,1H),6.50(s,1H),6.42(dd,J＝8.8,1.8Hz,1H),6.37-6.31(m,2H),5.41(s,2H),
4.69-4.61(m,1H),3.96(s,3H),3.84(s,3H),2.48-2.38(m,2H),2.19-2.08(m,2H),1.91-1.83(m,1H),1.74-1.65(m,1H)。MS m/z 485.4M+H] +。
实施例2:化合物2的制备
Figure PCTCN2022104005-appb-000038
将对甲氧基溴苯2a(1.0g,5.38mmol)溶于二氯甲烷(10mL)中，冰浴下滴加氯磺酸(1.0mL)，反应液室温搅拌3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2b(1.4g，92％)。
化合物1d采用专利WO2020254946中的方法合成。将化合物2b(70mg,0.25mmol)溶于吡啶(0.2mL)，再加入化合物1d(30mg,0.12mmol)。反应混合物置于封管中120℃加热搅拌2小时。将反应液减压浓缩，经硅胶柱层析分离纯化得白色固体化合物2c(30mg,50％)。MS m/z 493.3[M+H] +。
将化合物2c(25mg,0.05mmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(4mg,0.005mmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(5mg,0.01mmol)、叔丁醇钠(19mg,0.20mmol)和环丙胺盐酸盐(14mg,0.15mmol)溶于1,4-二氧六环(0.5mL)，反应混合物氮气氛围下置于封管中加热至90℃搅拌3小 时。TLC监测反应完毕。将反应混合物经硅藻土过滤，滤液减压浓缩，经制备型薄层板分离纯化得白色固体化合物2(3mg,13％)。 1H NMR(500MHz,CDCl 3)δ8.08(s,1H),7.56(d,J＝1.2Hz,1H),7.43(d,J＝2.0Hz,1H),7.29(br,1H),6.84(d,J＝8.8Hz,1H),6.78(s,1H),6.73(br,1H),6.44(s,1H),6.31(t,J＝1.9Hz,1H),5.37(s,2H),3.95(s,3H),3.95-3.91(m,4H),3.83(s,3H),2.43-2.36(m,2H)ppm。MS m/z 470.4[M+H] +。
实施例3:化合物3的制备
Figure PCTCN2022104005-appb-000039
将化合物2c(28mg，0.06mmol)、三甲基硅基乙炔(11mg，0.11mmol)、Pd(dppf)Cl 2(9mg，0.01mmol)、三叔丁基膦(6mg，0.03mmol)和碘化亚铜(2mg，0.01mmol)溶于四氢呋喃/三乙胺(0.5mL/0.5mL)混合溶液中。反应混合物氮气氛围下于封管中90℃加热搅拌3小时。将反应液经硅藻土过滤，滤液减压浓缩，经制备型薄层板分离纯化得白色固体化合物3a(9mg,31％)。MS m/z 511.4[M+H] +。
将化合物3a(9mg，0.02mmol)溶于乙腈(1mL)，再加入碳酸钾(5mg，0.04mmol)。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分离纯化得白色固体化合物3(4mg，49％)。 1H NMR(500MHz,CDCl 3)δ8.27(d,J＝2.1Hz,1H),7.63(dd,J＝8.6Hz,J＝2.1Hz,1H),7.57(d,J＝1.6Hz,1H),7.44(d,J＝2.2Hz,1H),6.90(d,J＝8.6Hz,1H),6.79(s,1H),6.45(s,1H),6.32(t,J＝2.1Hz,1H),5.38(s,2H),3.96(s,3H),3.92(s,3H),3.07(s,1H)ppm。MS m/z 439.3[M+H] +。
实施例4:化合物4的制备
Figure PCTCN2022104005-appb-000040
将化合物4a(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4b(500mg)。1H NMR(500MHz,CDCl3)δ6.82(s,2H),3.98(s,6H)。
将化合物4b(150mg，0.48mmol)溶于吡啶(0.2mL)中，再加入化合物1d(58mg，0.24mmol)。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4c(55mg,44％)。MS m/z 523.0[M+H] +。
将化合物4c(35mg，0.07mmol)、三乙胺(0.2mL)、二(三苯基膦)二氯化钯(5mg，0.007mmol)和三甲基硅乙炔(20mg，0.21mmol)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4d(27mg,75％)。MS m/z 541.2[M+H] +。
将化合物4d(27mg，0.05mmol)溶于甲醇(1mL)和N,N-二甲基甲酰胺(0.2mL)混合溶液中，再加入碳酸钾(35mg，0.25mmol)。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分离纯化得白色固体化合物4(14mg，61％)。MS m/z 469.0[M+H] +。 1H NMR(500MHz,CDCl 3-d)δ8.18(s,1H),7.58(d,J＝1.9Hz,1H),7.45(d,J＝2.3Hz,1H),6.79(s,1H),6.68(s,2H),6.45(s,1H),6.33(t,J＝2.1Hz,1H),5.39(s,2H),3.96(s,3H),3.87(s,6H),3.21(s,1H)ppm。
实施例5:化合物5的制备
Figure PCTCN2022104005-appb-000041
将化合物2c(20mg，0.04mmol)、叔丁醇钠(12mg，0.12mmol)、(2-二环己基膦-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-甲基氨基-1,1'-联苯-2-基)甲磺酸钯(II)(2.6mg，0.003mmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(2.6mg，0.006mmol)和甲基哌嗪(12mg，0.12mmol)溶于二甲基乙酰胺(1mL)中。反应混合物在氮气氛围下于封管中85℃加热搅拌3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，经制备型薄层板分离纯化得白色固体化合物5(8mg，38％)。MS m/z 513.2[M+H] +。 1H NMR(500MHz,DMSO-d 6)δ9.90(s,1H),7.86(d,J＝2.1Hz,1H),7.49(d,J＝2.0Hz,1H),7.39(d,J＝3.0Hz,1H),7.11(dd,J＝9.0,3.0Hz,1H),7.00(d,J＝9.0Hz,1H),6.73(s,1H),6.65(s,1H),6.29(t,J＝2.0Hz,1H),5.41(s,2H),3.83(s,3H),3.68(s,3H),3.09(m,4H),2.74(m,4H),2.42(s,3H)。
实施例6:化合物6的制备
Figure PCTCN2022104005-appb-000042
将化合物2c(20mg，0.04mmol)、碳酸铯(40mg，0.12mmol)(2-二环己基膦-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-甲基氨基-1,1'-联苯-2-基)甲磺酸钯(II)(2.6mg，0.003mmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(2.6mg，0.006mmol)和吗啡啉(11mg，0.12mmol)溶于N,N-二甲基甲酰胺(1mL)中。反应混合物在氮气氛围下于封管中100℃加热搅拌3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，经制备型薄层板分离纯化得白色固体化合物6(4mg,20％)。MS m/z 500.1[M+H] +。 1H NMR(500MHz,DMSO-d 6)δ10.05(s,1H),7.87(d,J＝2.2Hz,1H),7.49(d,J＝2.2Hz,1H),7.33(d,J＝3.0Hz,1H),7.15(m,2H),6.78(m,2H),6.30(t,J＝2.0Hz,1H),5.43(s,2H),3.83(s,3H),3.73-3.66(m,7H),3.10-2.90(m,4H)。
实施例7:化合物7的制备
Figure PCTCN2022104005-appb-000043
将化合物2c(20mg，0.04mmol)、碳酸铯(40mg，0.12mmol)、二(三苯基膦)二氯化钯(2.8mg，0.004mmol)、环丙乙炔(8mg，0.12mmol)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，经制备型薄层板分离纯化得白色固体化合物6(5mg,26％)。MS m/z 479.1[M+H] +。 1H NMR(500MHz,DMSO-d 6)δ10.46(s,1H),7.88(d,J＝2.0Hz,1H),7.70(d,J＝2.0Hz,1H),7.64-7.58(m,1H),7.50(d,J＝1.3Hz,1H),7.17(d,J＝8.7Hz,1H),6.85(s,1H),6.75(s,1H),6.31-6.29(m,1H),5.44(s,2H),3.81(s,3H),3.78(s,3H),1.54-1.49(m,1H),0.89-0.83(m,2H),0.73-0.75(m,2H)。
实施例8:化合物8的制备
Figure PCTCN2022104005-appb-000044
将化合物2b(140mg,0.49mmol)溶于四氢呋喃(5mL)中，室温下滴加氨甲醇 溶液(7M，1.0mL，7mmol)，反应液室温搅拌1小时。将反应液减压浓缩，所得粗品经硅胶柱层析分离纯化得白色固体化合物8a(100mg，77％)。
化合物8b采用专利WO2020216701中的方法合成。将化合物8a(50mg,0.19mmol)、化合物8b(47mg,0.21mmol)、N,N-二异丙基乙胺(107mg,0.76mmol)溶于二氯甲烷(2mL)中，再加入1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(130mg,0.23mmol)，反应混合物室温搅拌过夜。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，经硅胶柱层析分离纯化得白色固体化合物8c(50mg,59％)。MS m/z453.0[M+H] +。
将化合物8c(25mg，0.06mmol)、碳酸铯(54mg，0.17mmol)、二(三苯基膦)二氯化钯(3.9mg，0.006mmol)、环丙乙炔(11mg，0.17mmol)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，经制备型薄层板分离纯化得白色固体化合物8(11mg，46％)。MS m/z 439.0[M+H] +。 1H NMR(500MHz,DMSO-d 6)δ12.55(s,1H),7.91(br,1H),7.80(d,J＝2.1Hz,1H),7.63(s,1H),7.55(d,J＝8.8Hz,1H),7.18(d,J＝7.8Hz,1H),6.85(d,J＝8.8Hz,1H),6.77(s,1H),3.86(s,3H),2.98(s,6H),1.58-1.52(m,1H),0.90-0.87(m,2H),0.80–0.74(m,2H)。
实施例9:化合物9的制备
Figure PCTCN2022104005-appb-000045
将化合物4c(80mg，0.15mmol)、丙炔(1M，0.45mL)、碳酸铯(149mg，0.46mmol)、二(三苯基膦)二氯化钯(14mg，0.02mmol)溶于N,N-二甲基甲酰胺(1mL)中。反应混合物氮气氛围下100℃加热搅拌3小时。将反应液经硅藻土过滤，滤液减压浓缩，所得粗品经硅胶柱层析(甲醇:二氯甲烷＝1:20,V:V)分离纯化得化合物9(7mg，9％)。 1H NMR(500MHz,DMSO-d 6)δ9.85(s,1H),7.88(d,J＝2.1Hz,1H),7.50(d,J＝1.4Hz,1H),6.90-6.70(m,4H),6.30(t,J＝2.0Hz,1H),5.44(s,2H),3.84(s,3H),3.74(s,6H),2.07(s,3H)ppm。MS m/z 483.0M+H] +。
实施例10:化合物10的制备
Figure PCTCN2022104005-appb-000046
将化合物4c(50mg，0.10mmol)、环丙基乙炔(13mg，0.19mmol)、碳酸铯(93mg，0.29mmol)、二(三苯基膦)二氯化钯(13mg，0.02mmol)溶于N,N-二甲基甲酰胺 (1mL)中。反应混合物氮气氛围下100℃加热搅拌3小时。将反应液经硅藻土过滤，滤液减压浓缩，所得粗品经硅胶柱层析(甲醇:二氯甲烷＝1:20,V:V)分离纯化得化合物10(12mg，25％)。 1H NMR(500MHz,DMSO-d 6)δ9.79(brs,1H),7.88(d,J＝2.1Hz,1H),7.50(d,J＝1.4Hz,1H),6.82(s,1H),6.77-6.68(m,3H),6.30(t,J＝2.0Hz,1H),5.44(s,2H),3.85(s,3H),3.74(s,6H),1.60-1.53(m,1H),0.95-0.89(m,2H),0.80-0.73(m,2H)ppm。MS m/z 508.9[M+H] +。
实施例11:化合物11的制备
Figure PCTCN2022104005-appb-000047
化合物11a采用专利WO200610629中的方法合成。将化合物11a(300mg，1.05mmol)溶于吡啶(1.2mL)中，再加入化合物1d(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11b(100mg，39％)。MS m/z 494.9[M+H] +。
将化合物11b(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11c(5mg,27％)。MS m/z 511.1[M+H] +。
将化合物11c(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11(2mg，47％)。 1H NMR(500MHz,CDCl 3)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] +。
实施例12:化合物12的制备
Figure PCTCN2022104005-appb-000048
将化合物11b(18mg，0.04mmol)、碳酸铯(40mg，0.12mmol)、二(三苯基膦)二氯化钯(2.8mg，0.004mmol)、环丙乙炔(8mg，0.12mmol)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，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12(10mg,57％)。 1H NMR(500MHz,DMSO-d 6)δ10.34(s,1H),7.87(d,J＝2.1Hz,1H),7.71(d,J＝8.1Hz,1H),7.50(d,J＝1.6Hz,1H),7.13(s,1H),7.05(d,J＝8.1Hz,1H),6.83(s,1H),6.73(s,1H),6.30(t,J＝2.1Hz,1H),5.44(s,2H),3.81(s,3H),3.76(s,3H),1.58(m,1H),0.97-0.87(m,2H),0.80-0.70(m,2H)ppm。MS m/z 479.1[M+H] +。
实施例13:化合物13的制备
Figure PCTCN2022104005-appb-000049
将化合物2c(30m，0.06mmol)、丙炔的四氢呋喃溶液(1M，0.30mL)、碳酸铯(60mg，0.18mmol)、二(三苯基膦)二氯化钯(8mg，0.01mmol)溶于N,N-二甲基甲酰胺(1mL)中。反应混合物氮气氛围下100℃加热搅拌3小时。将反应液经硅藻土过滤，滤液减压浓缩，所得粗品经硅胶柱层析(甲醇:二氯甲烷＝1:20,V:V)分离纯化得化合物13(1.60mg，6％)。 1H NMR(500MHz,DMSO-d 6)δ10.50(s,1H),7.87(d,J＝1.6Hz,1H),7.73(br,1H),7.62(br,1H),7.49(s,1H),7.18(br,1H),6.84(br,1H),6.74(br,1H),6.30(s,1H),5.44(s,2H),3.81(s,3H),3.78(s,3H),2.02(s,3H)。MS m/z 453.0[M+H] +。
实施例14:化合物14的制备
Figure PCTCN2022104005-appb-000050
将化合物4c(60mg，0.11mmol)、3-乙炔基氧杂环丁烷(19mg，0.23mmol)、碳酸铯(112mg，0.34mmol)、二(三苯基膦)二氯化钯(13mg，0.12mmol)溶于N,N-二甲基甲酰胺(1mL)中。反应混合物氮气氛围下100℃加热搅拌2小时。将反应液经硅藻土过滤，滤液减压浓缩，所得粗品经硅胶柱层析(甲醇:二氯甲烷＝1:20,V:V)分离纯化得化合物14(13mg,22％)。 1H NMR(500MHz,DMSO-d 6)δ9.88(s,1H),7.88(d,J＝2.0Hz,1H),7.50(d,J＝1.4Hz,1H),6.86-6.80(m,3H),6.76(s,1H),6.30(t,J＝2.0Hz,1H),5.45(s,2H),4.80(dd,J＝8.5,5.5Hz,2H),4.62(dd,J＝7.0,5.5Hz,2H),4.22-4.14(m,1H),3.85(s,3H),3.77(s,6H)ppm。MS m/z 525.0[M+H] +。
实施例15:化合物15的制备
Figure PCTCN2022104005-appb-000051
将化合物4c(60mg，0.11mmol)、化合物15a(40mg，0.34mmol)、碳酸铯(112mg，0.11mmol)、二(三苯基膦)二氯化钯(16mg，0.02mmol)溶于N,N-二甲基甲酰胺(1mL)中。反应混合物氮气氛围下100℃加热搅拌2小时。将反应液经硅藻土过滤，滤液减压浓缩，所得粗品经硅胶柱层析(甲醇:二氯甲烷＝1:20,V:V)分离纯化得化合物15(14mg，22％)。 1H NMR(500MHz,DMSO-d 6)δ9.90(s,1H),7.89(d,J＝2.1Hz,1H),7.50(d,J＝1.3Hz,1H),6.83(s,1H),6.80(s,2H),6.76(s,1H),6.31(t,J＝2.0Hz,1H),5.45(s,2H),3.85(s,3H),3.76(s,6H),3.32-3.25(m,1H),3.10-3.00(m,2H),2.81-2.69(m,2H)ppm。MS m/z 559.0[M+H] +。
实施例16:化合物16的制备
Figure PCTCN2022104005-appb-000052
将化合物11b(28mg，0.06mmol)、碳酸铯(59mg，0.18mmol)、二(三苯基膦)二氯化钯(2mg，0.003mmol)、丙炔(24mg，0.6mmol)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℃加热搅拌过夜。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，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16(22mg,86％)。 1H NMR(500MHz,CDCl 3)δ8.06-7.97(m,2H),7.57(d,J＝1.6Hz,1H),7.43(d,J＝2.1Hz,1H),7.08(dd,J＝8.1,1.2Hz,1H),6.92(d,J＝1.0Hz,1H),6.79(s,1H),6.44(s,1H),6.32(t,J＝2.1Hz,1H),5.38(s,2H),3.96(s,3H),3.88(s,3H),2.05(s,3H)ppm。MS m/z 453.0[M+H] +。
实施例17:化合物17的制备
Figure PCTCN2022104005-appb-000053
将化合物11b(20mg，0.04mmol)、叔丁醇钠(31mg，0.32mmol)、(2-二环己基膦-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-甲基氨基-1,1'-联苯-2-基)甲磺酸钯(II)(2.6mg，0.003mmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(2.6mg，0.006mmol)和化合物2d(19mg，0.2mmol)溶于二甲基乙酰胺(1mL)中。反应混合物氮气氛围下于封管中90℃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，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17(8mg,42％)。 1H NMR(500MHz,CDCl 3)δ7.97(s,1H),7.88(d,J＝8.7Hz,1H),7.61(s,1H),7.50(s,1H),6.77(s,1H),6.50(s,1H),6.36(s,1H),5.97(dd,J＝8.7,1.9Hz,1H),5.71(d,J＝1.9Hz,1H),5.42(s,2H),3.99-3.92(m,7H),3.83(s,3H),2.47-2.35(m,2H)ppm。MS m/z 470.0[M+H] +。
实施例18:化合物18的制备
Figure PCTCN2022104005-appb-000054
将化合物18a(1.6g,5.11mmol)、硫代醋酸钾(875mg,7.66mmol)、1,10-菲啰啉(460mg,2.56mmol)和碘化亚铜(460mg,2.56mmol)溶于甲苯(15mL)中，反应液100℃搅拌20小时。反应混合物用水淬灭，以乙酸乙酯(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红棕色固体化合物18b(1.0g，75％)。
将N-氯代丁二酰亚胺(2.3g,17.2mmol)溶于盐酸水溶液(2M,2mL)和乙腈(10mL)的混合溶液中，室温下滴加化合物18b(1.1g,4.2mmol)的乙腈(5mL)溶液。滴毕，反应液室温下搅拌1小时。反应混合物用水淬灭，以乙酸乙酯(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18c(1.0g，83％)。 1H NMR(500MHz,CDCl 3)δ7.47–7.39(m,2H),7.10(dd,J＝7.5,2.1Hz,1H),4.05(s,3H)。
将化合物18c(117mg,0.41mmol)溶于吡啶(0.2mL)中，再加入化合物1d(50mg,0.20mmol)。反应混合物置于封管中加热至120℃搅拌1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18d(50mg,50％)。MS m/z 492.8[M+H] +。
将化合物18d(25mg，0.05mmol)、三乙胺(0.2mL)、二(三苯基膦)二氯化钯(5mg，0.007mmol)和三异丙基硅乙炔(27mg，0.15mmol)溶于二甲基亚砜(1mL)中。反应混合物氮气氛围下于封管中100℃加热搅拌过夜。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18e(25mg,83％)。MS m/z 595.1[M+H] +。
将化合物18e(10mg，0.017mmol)溶于N,N-二甲基甲酰胺(1mL)中，再加入氟化铯(15mg，0.1mmol)。反应混合物于室温搅拌5小时。将反应液过滤，滤液减 压浓缩，所得粗品经制备型薄层板分离纯化离纯化(二氯甲烷：甲醇＝20:1)得到白色固体化合物18(3mg，收率40％)。MS m/z 439.0[M+H] +。 1H NMR(500MHz,CDCl 3)δ8.18(s,1H),7.67(s,1H),7.53(s,1H),7.42(t,J＝8.1Hz,1H),7.29(d,J＝7.7Hz,1H),6.96(d,J＝8.4Hz,1H),6.83(s,1H),6.66(s,1H),6.40(s,1H),5.49(s,2H),3.99(s,3H),3.91(s,3H),3.58(s,1H)。
实施例19:化合物19的制备
Figure PCTCN2022104005-appb-000055
将化合物4c(25mg，0.05mmol)、碳酸铯(46mg，0.14mmol)、二(三苯基膦)二氯化钯(2.8mg，0.004mmol)、3-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，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19(12mg，46％)。MS m/z 546.1[M+H] +。
实施例20:化合物19'的制备
Figure PCTCN2022104005-appb-000056
将化合物4b(150mg,0.48mmol)溶于吡啶(0.2mL)中，再加入化合物1d(58mg,0.24mmol)。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19'a(10mg,8％)。MS m/z 508.9[M+H]+。
将化合物19'a(10mg，0.02mmol)、碳酸铯(19mg，0.06mmol)、二(三苯基膦)二氯化钯(1.4mg，0.002mmol)、3-炔基吡啶(10mg，0.10mmol)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，经制备型薄层板分离纯化得白色固体化合物19'(2mg,19％)。 1H NMR(500MHz,DMSO-d 6)δ14.01(s,1H),8.77(d,J＝1.1Hz,1H),8.60(dd,J＝4.8,1.3Hz,1H),8.02-7.97(m,1H),7.86(d,J＝1.6Hz,1H),7.51-7.44(m,2H),6.69-6.52(m,4H),6.30(t,J＝1.9Hz,1H),5.41(s,2H),3.83(s,3H),3.78(s,3H).MS m/z 532.0[M+H] +。
实施例21:化合物20的制备
Figure PCTCN2022104005-appb-000057
将化合物4c(30mg，0.06mmol)、碳酸铯(60mg，0.18mmol)、二(三苯基膦)二氯化钯(2.0mg，0.003mmol)、3-乙炔基-1-氮杂环丁烷甲酸叔丁酯(41mg，0.23mmol)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，经制备型薄层板分离纯化得白色固体化合物20(25mg,70％)。 1H NMR(500MHz,DMSO-d 6)δ9.81(s,1H),7.87(d,J＝1.6Hz,1H),7.50(d,J＝1.0Hz,1H),6.85-6.80(m,3H),6.75(s,1H),6.34-6.24(m,1H),5.45(s,2H),4.21-4.12(m,2H),3.90-3.81(m,5H),3.77(s,6H),3.73-3.62(m,1H),1.38(s,9H)。MS m/z 624.1[M+H]+。
实施例22:化合物21的制备
Figure PCTCN2022104005-appb-000058
将化合物20(7mg，0.01mmol)溶于二氯甲烷(1mL)中，加入三氟乙酸(0.3mL)。反应混合物在室温下搅拌2小时。将反应液减压浓缩，得固体化合物21(6.9mg,100％)。 1H NMR(500MHz,DMSO-d 6)δ9.92(s,1H),8.86(s,2H),7.88(d,J＝1.7Hz,1H),7.50(d,J＝1.1Hz,1H),6.86-6.72(m,4H),6.30(t,J＝1.9Hz,1H),5.45(s,2H),4.31-4.15(m,2H),4.11-3.92(m,3H),3.86(s,3H),3.77(s,6H)。MS m/z 524.1[M+H]+。
实施例23:化合物22的制备
Figure PCTCN2022104005-appb-000059
将化合物21的三氟乙酸盐(20mg，0.03mmol)溶于二氯甲烷(1mL)中，加入甲醛水溶液(0.1mL,37％)。反应混合物在室温下搅拌1小时，再加入三乙酰氧基硼氢化钠(40mg，0.19mmol)。反应液在室温下搅拌1小时。将反应液减压浓缩，所得粗品经制备型薄层板分离纯化离纯化(二氯甲烷：甲醇＝10:1)得到白色固体化合物22(3mg，收率17％)。 1H NMR(500MHz,DMSO-d 6)δ9.82(s,1H),7.87(s,1H),7.50(s,1H),6.92-6.62(m,4H),6.38-6.19(m,1H),5.44(s,2H),3.85(s,3H),3.74(s,6H),3.64-3.57(m,2H),3.48-3.40(m,1H),3.17-3.09(m,2H),2.27(s,3H)。MS m/z 538.0[M+H]+。
实施例24:化合物23的制备
Figure PCTCN2022104005-appb-000060
将化合物18d(40mg，0.08mmol)、碳酸铯(80mg，0.24mmol)、二(三苯基膦)二氯化钯(2.8mg，0.004mmol)、1-(三甲基硅基)丙炔(45mg，0.4mmol)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，所得粗品经制备型薄层板分离纯化离纯化(二氯甲烷：甲醇＝20:1)得到白色固体化合物23(3mg,8％)。 1H NMR(500MHz,CDCl 3)δ8.18(s,1H),7.64(s,1H),7.50(s,1H),7.35(t,J＝8.1Hz,1H),7.16(d,J＝7.8Hz,1H),6.91-6.75(m,2H),6.59(s,1H),6.38(s,1H),5.45(s,2H),3.98(s,3H),3.87(s,3H),2.13(s,3H).MS m/z 452.9[M+H] +。
实施例25:化合物24的制备
Figure PCTCN2022104005-appb-000061
将化合物11b(25mg，0.05mmol)、碳酸铯(49mg，0.15mmol)、二(三苯基膦)二氯化钯(2.0mg，0.003mmol)、3-乙炔基-1-氮杂环丁烷甲酸叔丁酯(24a,28mg，0.15mmol)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，经制备型薄层板分离纯化得白色固体化合物24b(20mg,67％)。MS m/z 594.0[M+H]+。
将化合物24b(20mg，0.03mmol)溶于二氯甲烷(1mL)中，加入三氟乙酸(0.3mL)。反应混合物在室温下搅拌2小时。将反应液减压浓缩，得固体化合物24c(20mg,100％)。MS m/z 494.0[M+H]+。
将化合物24c(20mg，0.03mmol)溶于二氯甲烷(1mL)中，加入甲醛水溶液(0.1mL,37％)。反应混合物在室温下搅拌1小时，再加入三乙酰氧基硼氢化钠(40mg，0.19mmol)。反应液在室温下搅拌1小时。将反应液减压浓缩，所得粗品经制备型薄层板分离纯化离纯化(二氯甲烷：甲醇＝10:1)得到白色固体化合物24(3mg，收率18％)。 1H NMR(500MHz,DMSO)δ10.19(br,1H),7.85(d,J＝2.2Hz,1H),7.74(d,J＝8.0Hz,1H),7.50-7.46(m,1H),7.08-7.04(m,1H),7.01(dd,J＝8.0,1.3Hz,1H),6.66(s,1H),6.60(s,1H),6.28(t,J＝2.0Hz,1H),5.39(s,2H),3.92(t,J＝7.6Hz,2H),3.81(s,3H),3.74(s,3H),3.69-3.61(m,1H),3.61-3.52(m,2H),2.52(s,3H)。MS m/z508.0[M+H]+。
实施例26：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10 mM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IC 50。部分代表性化合物的活性如表1所示。
表1：KAT6A酶活性抑制(IC 50，nM)
化合物 KAT6A IC 50(nM)
1 <5
2 <10
3 <20
4 <5
5 <200
6 <100
7 <10
8 <1000
9 <10
10 <5
11 <10
12 <10
13 <20
14 67％ *
15 <5
16 <10
17 75％ *
19 <5
19' <10
20 <5
21 <10
22 <20
23 <20
24 <20
*在化合物浓度11nM下的抑制率
实施例27: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T max、T 1/2、C max、AUC 0-24h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T max、T 1/2、C max、AUC 0-24h等)。部分代表性化合物的动力学参数如表2所示。
表2大鼠体内的药物动力学参数
Figure PCTCN2022104005-appb-000062
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 (18)

  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：
    Figure PCTCN2022104005-appb-100001
    式(I)中：
    A选自式(Ia)、式(Ib)、式(Ic)、或式(Id):
    Figure PCTCN2022104005-appb-100002
    其中，
    Figure PCTCN2022104005-appb-100003
    表示片段A与式(I)化合物其它部分连接的位点；
    Figure PCTCN2022104005-appb-100004
    表示双键或三键；当为三键时R 5为无；
    B选自式(Ie)、式(If)、或式(Ig):
    Figure PCTCN2022104005-appb-100005
    其中，
    Figure PCTCN2022104005-appb-100006
    表示片段B与式(I)化合物其它部分连接的位点；
    R 1选自氢或C 1-4烷基；
    各个R 2各自独立地选自下组：氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基C 1-4烷基、C 1-4卤代烷氧基C 1-4烷基、C 2-4烯基、C 2-4卤代烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、CN、OR a、SR a、或NR aR a；其中，各个R a各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、或3-至8-元杂环基；
    D选自化学键、-O-、-S-、或-NR e-；其中，R e选自氢、C 1-4烷基、或C 3-6环烷基；E选自C 3-8环烷基、3-至10-元杂环基、C 3-8环烷基C 1-4烷基、或3-至10-元杂环基C 1-4烷基；
    各个R 3各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、CN、OR b、SR b、NR bR b、-C(O)R g、-S(O) 2R g、C 3-6环烷基、或3-至8-元杂环基；或二个R 3连接在环烷基或杂环基环的同一个碳原子上并与该碳原子共同形成C＝T；其中，T选自O或CR 12R 13；其中，R 12和R 13各自独立地选自氢、氟、或C 1-4烷基；所述的R 12或R 13上的烷基任选地被一个或多个选自下组的基团取代：卤素、C 1-4卤代烷基、CN、OR b、SR b、NR bR b、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基；上述各个R b各自独立地选自氢、C 1-4烷基、或C 1-4卤代烷基；R g 选自氢、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、3-至8-元杂环基、芳基、或杂芳基；
    R 4和R 5各自独立地选自下组：氢、C 1-4烷基、C 3-8环烷基、3-至9-元杂环基、芳基、或杂芳基；其中，所述的烷基、环烷基、杂环基、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、OR a、SR a、NR aR a、NO 2、-C(O)R m、-C(O)OR a、-S(O) 2R m、-C(O)NR aR a、-OC(O)R m、-NR aC(O)R m、-NR aS(O) 2R m、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基；或所述的环烷基或杂环基被＝T取代；其中，各个R a的定义如上所述；R m选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基；T的定义如上所述；
    各个R 6各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、CN、OR b、SR b、或NR bR b；其中，各个R b的定义如上所述；
    M选自O或CR hR i；其中，R h和R i各自独立地选自氢、氟、或C 1-4烷基；其中，所述的烷基任选地被一个或多个选自下组的基团取代：卤素、C 1-4卤代烷基、CN、OR b、SR b、NR bR b、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基；其中，各个R b的定义如上所述；
    各个R 7各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、CN、OR a、SR a、NR aR a、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、或杂芳基C 1-4烷基；其中，各个R a的定义如上所述；
    R 8和R 9各自独立地选自下组：氢、氟、C 1-4烷基、C 1-4烷氧基、羟基、或C 3-6环烷基；或R 8和R 9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R 10各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、CN、OR a、SR a、或NR aR a；其中，各个R a的定义如上所述；
    X选自O、S、或NR n；其中，R n选自氢或C 1-4烷基；
    各个R 11各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、CN、OR a、SR a、NR cR c、或-NR dC(O)R g；其中，各个R a的定义如上所述；各个R c各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基C 1-4烷基、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基；R d选自氢或C 1-4烷基；R g的定义如上所述；
    m选自0、1、2、3、或4；
    n选自0、1、2、3、或4；
    f选自0、1、2、或3；
    g选自0、1、2、3、或4；
    a和b各自独立地选自0、1、2、3、4、或5；前提条件是a和b不能同时选自0；
    h选自0、1、2、或3；
    j选自0、1、2、或3；
    k选自0、1、2、3、4、或5；
    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、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR b、SR b、NR dR d、-C(O)R g、-C(O)OR b、-C(O)NR dR d、-NR dC(O)R g、-NR dS(O) 2R g、或-S(O) 2R g，前提条件是所形成的化学结构是稳定的和有意义的；其中，R b、R d、和R g的定义如上所述；
    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)：
    Figure PCTCN2022104005-appb-100007
    R 2、R 3、R 7、R 8、R 9、R 10、D、E、m、n、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)：
    Figure PCTCN2022104005-appb-100008
    U选自N或CR k；其中，R k选自选自氢、卤素、C 1-4烷基；
    各个R 14各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、CN、OR b、SR b、NR bR b；
    p和q各自独立地选自0、1、2、3、4、5、或6；前提条件是p和q不能同时选自0；
    t选自0、1、2、3、或4；
    R 2、R 7、R 8、R 9、R 10、R 12、R 13、R b、D、m、h、和j的定义如权利要求1所述。
  4. 如权利要求1所述的化合物，其特征在于，式(I)为式(IV)：
    Figure PCTCN2022104005-appb-100009
    R 2、R 4、R 7、R 8、R 9、R 10、m、h、和j的定义如权利要求1所述。
  5. 如权利要求1所述的化合物，其特征在于，式(I)为式(V)：
    Figure PCTCN2022104005-appb-100010
    R 2、R 6、R 7、R 8、R 9、R 10、R h、R i、a、b、f、g、h、和j的定义如权利要求1所述。
  6. 如权利要求1所述的化合物，其特征在于，式(I)为式(VI)：
    Figure PCTCN2022104005-appb-100011
    R 2、R 6、R 11、R h、R i、X、a、b、f、g、和k的定义如权利要求1所述。
  7. 如权利要求1所述的化合物，其特征在于，式(I)为式(VII)：
    Figure PCTCN2022104005-appb-100012
    R 2、R 11、R 12、R 13、D、X、m、和k的定义如权利要求1所述；
    U、R 14、p、q、和t的定义如权利要求3所述。
  8. 如权利要求1所述的化合物，其特征在于，式(I)为式(VIII)：
    Figure PCTCN2022104005-appb-100013
    各个R 2各自独立地选自下组：氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基、C 3-6环烷基、CN、OR a、SR a、或NR aR a；其中，各个R a各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基；m选自0、1、或2；
    R 4、R 7、R 8、R 9、R 10、h、和j的定义如权利要求1所述。
  9. 如权利要求1所述的化合物，其特征在于，式(I)为式(IX)：
    Figure PCTCN2022104005-appb-100014
    各个R 2各自独立地选自下组：氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、或OR a；
    R 4选自下组：氢、C 1-4烷基、C 3-8环烷基、3-至9-元杂环基、芳基、或杂芳基；其中，所述的烷基、环烷基、杂环基、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、OR a、SR a、NR aR a、-C(O)R m、-C(O)OR a、-S(O) 2R m、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至6-元杂环基、芳基、或杂芳基；或所述的环烷基或杂环基被＝T取代；其中，T选自O或CR 12R 13；其中，R 12和R 13各自独立地选自氢、氟、或C 1-4烷基；所 述的R 12或R 13上的烷基任选地被一个或多个选自下组的基团取代：卤素、C 1-4卤代烷基、CN、OR b、SR b、NR bR b；
    各个R a各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基；各个R b各自独立地选自氢、C 1-4烷基、或C 1-4卤代烷基；R m选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基。
  10. 如权利要求1所述的化合物，其特征在于，式(I)为式(X)：
    Figure PCTCN2022104005-appb-100015
    各个R 2各自独立地选自下组：氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、或OR a；
    R 4选自下组：氢、C 1-4烷基、C 3-8环烷基、3-至9-元杂环基、芳基、或杂芳基；其中，所述的烷基、环烷基、杂环基、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、OR a、SR a、NR aR a、-C(O)R m、-C(O)OR a、-S(O) 2R m、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-至6-元杂环基、芳基、或杂芳基；或所述的环烷基或杂环基被＝T取代；其中，T选自O或CR 12R 13；其中，R 12和R 13各自独立地选自氢、氟、或C 1-4烷基；所述的R 12或R 13上的烷基任选地被一个或多个选自下组的基团取代：卤素、C 1-4卤代烷基、CN、OR b、SR b、NR bR b；
    各个R a各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基；各个R b各自独立地选自氢、C 1-4烷基、或C 1-4卤代烷基；R m选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基。
  11. 如权利要求1所述的化合物，其特征在于，式(I)为式(XI)：
    Figure PCTCN2022104005-appb-100016
    各个R 2各自独立地选自下组：氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基C 1-4烷基、C 1-4卤代烷氧基C 1-4烷基、C 2-4烯基、C 2-4卤代烯基、C 2-4炔基、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、CN、OR a、SR a、或NR aR a；
    R 4选自下组：氢、C 1-4烷基、C 3-6环烷基；其中，所述的烷基或环烷基任选地被一个或多个选自下组的基团取代：卤素、CN、OR a、SR a、或NR aR a；
    各个R a各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基；
    m选自0、1、2、或3。
  12. 如权利要求1所述的化合物，其特征在于，式(I)为式(XII)：
    Figure PCTCN2022104005-appb-100017
    R 2和R 4的定义如权利要求9所述。
  13. 如权利要求1所述的化合物，其特征在于，式(I)为式(VII)：
    Figure PCTCN2022104005-appb-100018
    R 2、R 4、R 11、X、m、和k的定义如权利要求1所述。
  14. 一种如下式(XIV)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：
    Figure PCTCN2022104005-appb-100019
    G选自C 3-8环烷基、3-至10-元杂环基、芳基(优选为苯、萘)、杂芳基(优选为呋喃、噻吩、吡啶、嘧啶、吡嗪)；
    R 1、R 2、R 4、B、和m的定义如权利要求1所述。
  15. 如权利要求1和14所述的化合物，其特征在于，所述的式(I)和式(XIV)化合物选自下组：
    Figure PCTCN2022104005-appb-100020
    Figure PCTCN2022104005-appb-100021
    Figure PCTCN2022104005-appb-100022
    Figure PCTCN2022104005-appb-100023
    Figure PCTCN2022104005-appb-100024
    Figure PCTCN2022104005-appb-100025
    上述各个化合物中，R 2选自H或OMe。
  16. 一种药物组合物，其特征在于，包含权利要求1至15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。
  17. 一种权利要求1至15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。
  18. 如权利要求17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、阴道癌、前列腺癌、睾丸癌、脑瘤、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、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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