WO2022257894A1 - P300抑制剂及其在医药上的应用 - Google Patents

P300抑制剂及其在医药上的应用 Download PDF

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WO2022257894A1
WO2022257894A1 PCT/CN2022/097209 CN2022097209W WO2022257894A1 WO 2022257894 A1 WO2022257894 A1 WO 2022257894A1 CN 2022097209 W CN2022097209 W CN 2022097209W WO 2022257894 A1 WO2022257894 A1 WO 2022257894A1
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alkyl
alkylene
compound
cancer
pharmaceutically acceptable
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PCT/CN2022/097209
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English (en)
French (fr)
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吴颢
谷伟
邓涛
林远望
王冬
王国建
陶光绪
李正清
兰宏
王家炳
丁列明
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贝达药业股份有限公司
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Priority to CN202280033444.8A priority Critical patent/CN117321053A/zh
Publication of WO2022257894A1 publication Critical patent/WO2022257894A1/zh

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the technical field of medicine, in particular to a compound of formula I, a tautomer, a deuterated compound or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and an application thereof as a medicine for treating cancer.
  • Post-translational acetylation of histones has important biological functions in the regulation of gene transcription, cell differentiation, cell proliferation, cell cycle regulation, and cell apoptosis.
  • the acetylation modification of histone is accomplished by histone acetyltransferase (HAT), which can catalyze the acetyl transfer reaction from acetyl-CoA to specific lysine.
  • HAT histone acetyltransferase
  • p300 is the major histone acetyltransferase in cells. High levels of p300 are observed in some tumors, and knockout of the p300 gene inhibits tumor cell proliferation. Therefore, the development of potent and highly selective histone acetyltransferase inhibitors is of great significance for the treatment of cancer.
  • the present invention provides a compound represented by general formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt:
  • R 1 is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 5-10 cycloalkyl or 5-10 membered heterocyclic group, R 1 is optionally further substituted by one or more R 5 replaced by
  • R is independently selected from H, oxo, acyl, halogen, oxo, C 1-6 alkyl, cyano, C 1-6 haloalkyl, -C 0-6 alkylene - C( O )OR a , -C 0-6 alkylene-OR a , -C 0-6 alkylene-N(R a ) 2 , -C 0-6 alkylene-S(O)R a , -C 0- 6 alkylene-S(O) 2 R a , -C 0-6 alkylene-S(O) 2 N(R a ) 2 , -C 0-6 alkylene S R a , -C 0-6 Alkylene-S(R a ) 5 , -C 0-6 alkylene-C(O)N(R a ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3
  • X is selected from a bond, O, S, NR 6 or C 1-3 alkylene optionally further substituted by one or more R 6 substituents, R 6 selected from hydroxyl , oxo, halogen or C 1-6 alkyl;
  • R 2 is selected from phenyl, The phenyl is optionally further substituted by 1-4 substituents selected from H, halogen, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy ;
  • R is selected from phenyl or 5-6 membered heteroaryl, which is optionally further replaced by 1-4 members selected from H, halogen, cyano, amino, oxo , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -S(O) 2 -C 1-6 alkyl or -C(O)-C 1-6 alkyl Substituents are substituted;
  • R3 is selected from said Optionally further replaced by 1-4 substituents selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, halogen, hydroxyl or cyano replaced by
  • R 4 is independently selected from H, halogen, C 1-3 alkyl or C 1-3 haloalkyl.
  • R in formula ( I ) is selected from R 1 is optionally further substituted with 1-3 R 5 substituents.
  • R in formula (I) is selected from H, hydroxyl, oxo, C 1-3 alkyl, cyano, C 1-3 haloalkyl, C 1-3 alkoxy, C 1 -3 hydroxyalkyl, -C(O)OR a , -C(O)N(R a ) 2 , -C 0-3 alkylene-S(O) 2 R a , -C 0-3 alkylene-S(O) 2 NHR a , -N(R a ) 2 , And each R a is independently selected from H or C 1-6 alkyl.
  • R in formula ( I ) is selected from
  • X in formula (I) is selected from a bond or methylene, preferably a bond.
  • R in formula (I) is selected from preferably
  • R in formula (I) is selected from preferred
  • R 4 in formula (I) is H.
  • compounds of formula ( I ), wherein R is selected from R 1 is optionally further substituted by 1-3 R 5 ;
  • R2 is selected from preferably
  • R3 is selected from preferably
  • R4 is H ;
  • R 5 is selected from H, hydroxyl, C 1-3 alkyl, cyano, C 1-3 alkoxy, C 1-3 hydroxyalkyl, -C(O)OR a , -C(O)N(R a ) 2 , -C 0-6 alkylene-OR a , -C 0-3 alkylene-S(O) 2 R a , -C 0-3 alkylene-S(O) 2 NHR a , -N(R a ) 2 , And each R a is independently selected from H or C 1-6 alkyl;
  • X is selected from a bond or methylene.
  • the compound of formula (I), its tautomer, deuterium or pharmaceutically acceptable salt is selected from the compound of formula (I-1) or formula (I-2), tautomer, deuterium or its pharmaceutically acceptable salts:
  • the present invention provides the following compounds, tautomers, deuterated substances or pharmaceutically acceptable salts thereof:
  • the present invention also provides a pharmaceutical composition, which includes the compound shown in (I), its tautomer, deuterated product or pharmaceutically acceptable salt, and optionally further includes pharmaceutically acceptable auxiliary materials.
  • the present invention provides the application of the compound represented by structural formula (I), its tautomer, deuterated product or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of medicine.
  • the present invention further provides the preferred technical scheme of said application:
  • the application is in the preparation of medicines for treating and/or preventing cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • the present invention also provides a method for treating and/or preventing diseases, comprising administering a therapeutically effective amount of at least one compound represented by the structural formula (I) or a pharmaceutical composition containing it to the subject.
  • the present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least one compound represented by structural formula (I) or a pharmaceutical composition containing it to a subject.
  • halogen refers to fluorine, chlorine, bromine or iodine, unless otherwise specified.
  • alkyl includes linear or branched monovalent saturated hydrocarbon groups.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and the like.
  • “ 1-8 " in “ 1-8 alkyl” refers to a group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in a linear or branched chain group.
  • C 1-3 alkylene means methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylidene.
  • compositions comprising "a” pharmaceutically acceptable excipient may be interpreted to mean that the composition includes “one or more” pharmaceutically acceptable excipients.
  • aryl in the present invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic or condensed ring aromatic group comprising atoms of a carbocyclic ring, having a fully conjugated ⁇ -electron system.
  • the aryl group is a 6- to 10-membered monocyclic or bicyclic aromatic ring group.
  • Preferred are phenyl and naphthyl. Most preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is the aryl ring.
  • heterocyclyl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted 3-8 membered stable unit consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S Ring systems which are saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents comprising 3 to 20 carbon atoms, wherein the nitrogen or sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally to be quaternized.
  • the heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure.
  • heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro Oxadiazolyl.
  • the heterocyclyl may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring bonded to the parent structure is the heterocyclyl.
  • heteroaryl in the present invention, unless otherwise stated, refers to an unsubstituted or substituted stable 5-membered or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-membered or 10-membered benzo
  • Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene Thiadiazolyl, benzotriazolyladenine, quinolinyl or isoquinolinyl.
  • the heteroaryl group may be fused to an aryl, heterocyclyl or cycloalkyl ring where the ring attached to the parent structure is a heteroaryl ring.
  • cycloalkyl refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .
  • the cycloalkyl group may be fused to an aryl, heterocyclyl, or heteroaryl ring where the ring bonded to the parent structure is a cycloalkyl group.
  • substituted means that one or more hydrogen atoms in the group are respectively replaced by the same or different substituents.
  • the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy Butyl, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl Amino, methylthio, sulfonyl and acetyl groups.
  • substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxolylmethyl and piperazinylmethyl.
  • substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxyl.
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
  • prodrugs of the compounds of the present invention are included in the protection scope of the present invention.
  • the prodrugs refer to functional derivatives that are readily converted in vivo into the desired compound.
  • any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present application which can directly or indirectly provide the compound of the present application or its pharmaceutically active metabolite or Residues.
  • Particularly preferred derivatives or prodrugs are those compounds which, when administered to a patient, increase the bioavailability of the compounds of the present application (e.g., allow an orally administered compound to be more readily absorbed into the blood), or promote the delivery of the parent compound to a biological organ or Those compounds delivered at a site of action such as the brain or lymphatic system.
  • administering in the treatment methods provided by the present invention refers to the administration of the compounds disclosed in the present invention that can treat different diseases, or the compounds disclosed in the present invention, although not explicitly disclosed, can be converted into compounds disclosed in the present invention after administration to the subject. compounds of compounds.
  • the compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and optical isomers.
  • the present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
  • the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and their mixtures.
  • substitution of compounds of formula (I) with heavier isotopes may afford certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.
  • the present invention includes any possible solvates and polymorphs.
  • the type of solvent forming a solvate is not particularly limited as long as the solvent is pharmaceutically acceptable.
  • water, ethanol, propanol, acetone, and the like can be used.
  • composition in the present invention, is meant to include products comprising the specified amounts of each of the specified ingredients, as well as any product produced directly or indirectly from the combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients as well as processes for the preparation of the compounds of the invention are also part of the invention. Furthermore, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of the present invention.
  • the pharmaceutical composition provided by the present invention includes the compound (tautomer, deuterated product or pharmaceutically acceptable salt thereof) represented by formula (I) as an active component, a pharmaceutically acceptable excipient and other pharmaceutically acceptable Selected therapeutic components or excipients.
  • the most suitable mode of administration of the active ingredient will depend upon the particular subject to be administered, the nature of the subject and the severity of the condition.
  • the pharmaceutical compositions of the present invention may conveniently be presented in unit dosage forms and prepared by any methods of preparation well known in the art of pharmacy.
  • Step A The carboxyl group in the structure of compound I-1 generates an acid chloride, namely compound I-2, under the action of oxalyl chloride;
  • Step B compound I-2 generates diazide compound I-3 under the action of trimethylsilylated diazomethane;
  • Step C Compound I-3 generates bromide compound I-4 under the action of HBr;
  • Step D Compound I-4 and Under weakly basic conditions such as sodium bicarbonate, a ring closure reaction is carried out to obtain compound I-5;
  • Step E Compound I-5 and Under the action of a metal catalyst such as tetrakis-triphenylphosphine-palladium, the R3 group is introduced through a Suzuki coupling reaction to obtain compound I-6;
  • a metal catalyst such as tetrakis-triphenylphosphine-palladium
  • Step F compound I-6 introduces a bromine substituent under the action of tribromopyridine to obtain compound I-7;
  • Step G Compound I-7 and Under the action of a metal catalyst such as tetrakistriphenylphosphine palladium, the target compound I is obtained by introducing the R group through a Suzuki coupling reaction.
  • a metal catalyst such as tetrakistriphenylphosphine palladium
  • DMSO dimethyl sulfoxide
  • PE petroleum ether
  • THF Tetrahydrofuran
  • TFA trifluoroacetic acid
  • pre-TLC preparation of thin-layer chromatography silica gel plates
  • pre-HPLC Preparative high performance liquid chromatography
  • Example 1 Compound (S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(1,2 , Synthesis of 5,6-tetrahydropyridin-3-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one
  • compound 1-4 (1.30g), (3,5-dimethyl 1,2-oxazol-4-yl)boronic acid (0.54g), tetrakistriphenylphosphine palladium (0.37g), Potassium carbonate (0.88g) was dissolved in 1,4-dioxane (15.00mL) and water (3.00mL), and after nitrogen replacement, the mixture was stirred at 75°C for 3 hours.
  • Example 2 Compound methyl (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyl Synthesis of (isoxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • compound 1 (15.00mg) was dissolved in tetrahydrofuran (0.50mL), under nitrogen protection, triethylamine (0.02mL) was added under ice-cooling, and then slowly added dropwise with methyl methoxycarbonyl carbonate (5.99mg) Add 0.2 mL of THF solution, after the addition is complete, return to room temperature and continue stirring for 2 hours.
  • Example 3 Compound (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide
  • Dissolve compound 1 (15.00mg) in tetrahydrofuran (0.50mL) at room temperature, under nitrogen protection, under ice-cooling, add triethylamine (0.02mL), then slowly add carbamoyl chloride (3.35mg) in THF 0.2 mL of the solution was added, and stirring was continued at room temperature for 1 hour.
  • Add 5mL of EA for dilution, then add 5 drops of water to quench, dry over anhydrous sodium sulfate, filter, the filtrate is concentrated in vacuo, and the concentrate is purified by Pre-TLC (MeOH:DCM 1:10) to obtain the target product 3 (5.50mg, 99.31 %, 32.70%).
  • Example 4 Compound (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N,N-dimethyl-3,6-dihydropyridine-1(2H)-carboxamide
  • Dissolve compound 1 (15.00 mg) in tetrahydrofuran (0.50 mL) at room temperature, under nitrogen protection, add triethylamine (0.02 mL) under ice-cooling, and then slowly add dimethylcarbamoyl chloride (4.81 mg) dropwise 0.2 mL of THF solution, after the addition was completed, return to room temperature and continue stirring for 1 hour.
  • Example 5 Compound 3-(2-((R)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)cyclohex-3-ene-1-carboxylic acid
  • compound 1-6 (0.10g), methyl 3-(4,4,5,5)-cyclohex-3-ene-1-carboxylic acid tetramethyl-1,3,2-di Oxyboron-2-yl) (0.11g), tetrakistriphenylphosphine palladium (0.02g), cesium carbonate (0.10g) dissolved in 1,4-dioxane (4.00mL) and water (0.80mL) The mixture was stirred at 90° C. for 13 h under nitrogen.
  • reaction solution was extracted twice with EA/saturated ammonium chloride aqueous solution (30mL*2), then dried with anhydrous sodium sulfate, and then spin-dried under reduced pressure to prepare the target product 5-1 (0.03g, yield 26.83%) .
  • Example 6 Compound (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)thiazole-4-carboxylic acid
  • Example 7 Compound (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)thiazole-5-carboxylic acid
  • Example 8 Compound (S)-4-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)benzoic acid
  • Example 10 Compound (S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(1,2 , Synthesis of 3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one
  • Example 11 Compound (S)-4-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide
  • Example 12 Compound methyl (S)-4-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyl Synthesis of (isoxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Example 13 Compound (S)-4-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N,N-dimethyl-3,6-dihydropyridine-1(2H)-carboxamide
  • Example 14 Compound (6S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(4-form Synthesis of Oxycyclohex-1-en-1-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one
  • Example 15 The compound methyl 5-(7-(3,5-dimethylisoxazol-4-yl)-2-(5-fluoro-2-methoxybenzyl)imidazo[1,2 -a] Synthesis of pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Example 16 Compound 3-(7-(3,5-dimethylisoxazol-4-yl)-2-(5-fluoro-2-methoxybenzyl)imidazo[1,2-a Synthesis of ]pyridin-3-yl)cyclohex-3-ene-1-carboxylic acid
  • Example 17 Compound (S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(4-( Synthesis of Hydroxymethyl)thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one
  • Example 18 Compound (S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(5-( Synthesis of Hydroxymethyl)thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one
  • Example 19 Compound (S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(4-( Synthesis of 2-hydroxyethyl)thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one
  • Example 20 Compound (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)thiazole-4-carbonitrile
  • Example 21 Compound (S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(1,3 ,4-Thiadiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one synthesis
  • Example 22 Compound (S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxy Synthesis of Thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one
  • Example 23 Compound (S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(4-( Synthesis of 1-hydroxycyclopropyl)thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one
  • Example 24 Compound (S)-6-(3-(4-aminothiazol-2-yl)-7-(3,5-dimethylisoxazol-4-yl)imidazo[1,2- a] Synthesis of pyridin-2-yl)-1-(3,4-difluorophenyl)piperidin-2-one
  • Example 25 Compound (S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(oxazole- Synthesis of 2-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one
  • Example 26 Compound (S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(1H-imidazole Synthesis of -2-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one
  • Example 27 Compound (S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(4-( Synthesis of (methylsulfonyl)methyl)thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one
  • Example 28 Compound (S)-2-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazole-4-carboxamide
  • Example 30 Compound (S)-2-(2-(1-(3,4-difluorophenyl)-5-oxopyrrolidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylthiazole-5-carboxamide
  • Example 31 Compound (S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(pyridine-4 Synthesis of -yl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one
  • Example 32 Compound (S)-1-(3,4-difluorophenyl)-6-(7-(3,5-dimethylisoxazol-4-yl)-3-(4-( Synthesis of methylamino)phenyl)imidazo[1,2-a]pyridin-2-yl)piperidin-2-one
  • Example 33 Compound methyl(S)-5-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyl Synthesis of (isoxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)isothiazole-3-carboxylate
  • Example 34 Compound (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)isothiazole-3-carboxylic acid
  • Example 35 Compound (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N-methylisothiazole-3-carboxamide
  • Example 36 Compound (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(3,5-dimethyliso Synthesis of oxazol-4-yl)imidazo[1,2-a]pyridin-3-yl)-N,N-dimethylisothiazole-3-carboxamide
  • Example 37 Compound (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-3-(4-(hydroxymethyl)thiazole Synthesis of -2-yl)imidazo[1,2-a]pyridin-7-yl)-1,3-dimethylpyridin-2(1H)-one
  • Example 38 Compound methyl(S)-2-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(1,5-dimethyl Synthesis of 6-oxo-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)thiazole-5-carboxylate
  • Example 39 Compound methyl(S)-2-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-7-(1,5-dimethyl Synthesis of yl-6-oxo-1,6-dihydropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)thiazole-4-carboxylate
  • Example 40 Compound (S)-5-(2-(1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-3-(5-(hydroxymethyl)thiazole Synthesis of -2-yl)imidazo[1,2-a]pyridin-7-yl)-1,3-dimethylpyridin-2(1H)-one
  • Embodiment 1A Alpha Screen method
  • the dose-effect curve was fitted using the log(inhibitor) vs. response-Variable slope of the analysis software GraphPad Prism to obtain the IC 50 value of the compound for protein binding inhibition (Table 1).
  • Embodiment 1B HTRF method
  • the dose-effect curve was fitted using the log(inhibitor) vs. response-Variable slope of the analysis software GraphPad Prism 5, so as to obtain the IC 50 of the compound for protein binding inhibition value (Table 2).
  • 22Rv1 cells were plated in 96-well cell culture plates as 2000 cells, 180 ⁇ L/well. After incubation overnight, compound solutions with gradient concentrations were prepared, and 20 ⁇ L of DMSO solutions of the compounds to be tested were added to the cells in each well. 0 nM (the final concentration of DMSO is 0.25%). Incubate at 37°C, 5% CO 2 for 120h. Add 50 ⁇ L of Cell-titer Glo working solution to each well, shake and mix well, and incubate at room temperature for 10 minutes. Read the luminescence value of Luminescence with a multi-functional microplate reader, and convert the luminescence value reading into the percentage of inhibition:
  • Maximum is the DMSO control; “minimum” is the no-cell control.
  • Curve fitting was performed with Graphpad Prism software and IC50 values were obtained.
  • Compound number IC 50 (nM) Compound number IC 50 (nM) 1 >10000 19 6151 2 2541 20 3823 3 >10000 twenty one 8019 4 5563 twenty four >10000 5 >10000 26 >10000 6 5654 27 2004 7 943 28 1454 8 >10000 31 >10000 9 9701 32 1407 11 >10000 33 2742 12 2370 34 3414 13 1991 35 5566 14 4855 36 5103 15 8390 37 1623 16 >10000 39 2389 17 3063 40 3193 18 >10000 the the the

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Abstract

式(I)化合物、其互变异构体、氘代物或其可药用盐，其制备方法，含有该化合物的药用组合物，及其作为治疗癌症药物的用途。

Description

P300抑制剂及其在医药上的应用 技术领域
本发明涉及医药技术领域，具体涉及式I化合物、互变异构体、氘代物或其可药用盐，其制备方法，含有该化合物的药用组合物，及其作为治疗癌症药物的用途。
背景技术
组蛋白翻译后的乙酰化修饰在基因转录调控、细胞分化、细胞增殖、细胞周期调控、细胞凋亡等方面具有重要的生物学功能。组蛋白的乙酰化修饰是由组蛋白乙酰化转移酶(HAT)完成，其可催化从乙酰辅酶A到特异性赖氨酸的乙酰基转移反应。p300是细胞主要的组蛋白乙酰化转移酶。高水平的p300在一些肿瘤中被观察到，而敲除p300基因后，肿瘤细胞的增殖会受到抑制。因此，研发强效和高选择性的组蛋白乙酰化转移酶抑制剂对治疗癌症具有非常重要的意义。
发明内容
本发明提供一种通式(I)所示的化合物、其互变异构体、氘代物或可药用盐：
Figure PCTCN2022097209-appb-000001
其中，
R 1选自C 6-10芳基、5-10元杂芳基、C 5-10环烷基或5-10元杂环基，R 1任选地进一步被一个或多个R 5取代基所取代；
R 5独立地选自H、氧代、酰基、卤素、氧代基、C 1-6烷基、氰基、C 1-6卤代烷基、-C 0- 6亚烷基-C(O)OR a、-C 0-6亚烷基-OR a、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-S(O)R a、-C 0-6亚烷基-S(O) 2R a、-C 0-6亚烷基-S(O) 2N(R a) 2、-C 0-6亚烷基SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(O)N(R a) 2、C 2-6烯基、C 2-6炔基、
Figure PCTCN2022097209-appb-000002
-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环烷基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)， 所述-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环烷基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地进一步被一个或多个R a取代基所取代，且每个R a独立地为H、卤素、羟基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 3-14环烷基、3-14元杂环烷基、C 2-3烯基、C 2-3炔基、芳基、杂芳基、C 1-3烷氧基、-C 0-3亚烷基S(O) 2C 1-3烷基、-C(O)OC 1-3烷基、C 1-6羟基烷基、-C(O)NH 2、-C(O)NHC 1-3烷基、-O-S(O) 2OH、-S(O) 2NH 2、-S(O) 2N(C 1- 3烷基) 2、-S(O)(NH)C 1-3烷基、-S(O) 2NHC 1-3烷基、-NHS(O) 2C 1-3烷基、-NHC(O)C 1-3烷基、-OS(O) 2C 1-3烷基、-P(O)(OC 1-3烷基) 2、-P(O)(C 1-3烷基) 2的取代基所取代；
X选自键、O、S、NR 6或C 1-3亚烷基，所述C 1-3亚烷基任选地进一步被一个或多个R 6取代基所取代，R 6选自羟基、氧代基、卤素或C 1-6烷基；
R 2选自苯基、
Figure PCTCN2022097209-appb-000003
所述苯基任选地进一步被1-4个选自H、卤素、氰基、氨基、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基的取代基所取代；
R 7选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选地进一步被1-4个选自H、卤素、氰基、氨基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、-S(O) 2-C 1-6烷基或-C(O)-C 1-6烷基的取代基所取代；
R 3选自
Figure PCTCN2022097209-appb-000004
所述
Figure PCTCN2022097209-appb-000005
任选地进一步被1-4个选自C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、卤素、羟基或氰基的取代基所取代；
R 4独立地选自H、卤素、C 1-3烷基或C 1-3卤代烷基。
一些实施方式中，式(I)中的R 1选自
Figure PCTCN2022097209-appb-000006
Figure PCTCN2022097209-appb-000007
R 1任选地进一步被1-3个R 5取代基所取代。
一些实施方式中，式(I)中的R 5选自H、羟基、氧代基、C 1-3烷基、氰基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3羟基烷基、-C(O)OR a、-C(O)N(R a) 2、
Figure PCTCN2022097209-appb-000008
-C 0-3亚烷基-S(O) 2R a、-C 0-3亚烷基-S(O) 2NHR a、-N(R a) 2、
Figure PCTCN2022097209-appb-000009
且每个R a独立地选自H或C 1-6烷基。
一些实施方式中，式(I)中的R 1选自
Figure PCTCN2022097209-appb-000010
一些实施方式中，式(I)中的X选自键或亚甲基，优选为键。
一些实施方式中，式(I)中的R 2选自
Figure PCTCN2022097209-appb-000011
Figure PCTCN2022097209-appb-000012
优选为
Figure PCTCN2022097209-appb-000013
一些实施方式中，式(I)中的R 3选自
Figure PCTCN2022097209-appb-000014
优选
Figure PCTCN2022097209-appb-000015
一些实施方式中，式(I)中的R 4为H。
一些实施方式中，式(I)中的化合物，其中R 1选自
Figure PCTCN2022097209-appb-000016
Figure PCTCN2022097209-appb-000017
R 1任选地进一步被1-3个R 5所取代；
R 2选自
Figure PCTCN2022097209-appb-000018
优选为
Figure PCTCN2022097209-appb-000019
R 3选自
Figure PCTCN2022097209-appb-000020
优选为
Figure PCTCN2022097209-appb-000021
R 4为H；
R 5选自H、羟基、C 1-3烷基、氰基、C 1-3烷氧基、C 1-3羟基烷基、-C(O)OR a、-C(O)N(R a) 2、-C 0-6亚烷基-OR a、
Figure PCTCN2022097209-appb-000022
-C 0-3亚烷基-S(O) 2R a、-C 0-3亚烷基-S(O) 2NHR a、-N(R a) 2、
Figure PCTCN2022097209-appb-000023
Figure PCTCN2022097209-appb-000024
且每个R a独立地选自H或C 1-6烷基；
X选自键或亚甲基。
一些实施方式中，式(I)化合物、其互变异构体、氘代物或可药用盐选自式(I-1)或式(I-2)化合物、互变异构体、氘代物或其可药用盐：
Figure PCTCN2022097209-appb-000025
其中，取代基如上述所定义。
一些实施方式中，本发明提供下述化合物、其互变异构体、氘代物或可药用盐：
Figure PCTCN2022097209-appb-000026
本发明还提供了一种药物组合物，其包括(I)所示化合物、其互变异构体、氘代物或可药用盐，任选地进一步包括药学上可接受的辅料。
本发明提供了结构式(I)所示化合物、其互变异构体、氘代物或可药用盐、或其药物组合物在制备药物中的应用。
本发明进一步提供了所述应用的优选技术方案：
作为优选，所述应用为制备治疗和/或预防癌症药物中的应用。
作为优选，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、宫颈癌、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、前列腺癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。
本发明还提供了一种治疗和/或预防的疾病的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或含其的药物组合物。
本发明还提供了一种治疗癌症的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或含其的药物组合物。
除非另有说明，所述结构通式中使用的一般化学术语具有通常的含义。
例如，除非另有说明，本发明所用的术语“卤素”是指氟、氯、溴或碘。
在本发明中，除非另有说明，“烷基”包括直链或支链的一价饱和烃基。例如，烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基等。类似的，“基 1-8烷基”中的“ 1-8”是指包含有1、2、3、4、5、6、7或8个碳原子的直链或支链形式排列的基团。
“C 1-3亚烷基”是指亚甲基、1,2-亚乙基、1,3-亚丙基或1,2-亚异丙基。
在本发明中，“一”、“一个”、“该”、“至少一个”和“一个或多个”可互换使用。因此，例如，包含“一种”药学上可接受的赋形剂的组合物可以被解释为表示该组合物包括“一种或多种”药学上可接受的赋形剂。
术语“芳基”，在本发明中，除非另有说明，是指未取代或取代的包括碳环的原子的单环或稠环芳香基团，具有完全共轭的π电子体系。优选芳基为6到10元的单环或双环的芳香环基团。优选为苯基、萘基。最优选为苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。
术语“杂环基”，在本发明中，除非另有说明，是指由碳原子和1-3个选自N、O或S的杂原子组成的未取代或取代的3-8元稳定单环系统，其为饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个碳原子，其中氮或硫杂原子可以选择性地被氧化，并且氮杂原子可以选择性地被季铵化。该杂环基可以被连接到任何的杂原子或碳原子上以形成稳定的结构。这些杂环基的实例包括但不限于氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、 氧代哌嗪基、氧代哌啶基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻唑基、四氢恶唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜基和四氢恶二唑基。所述杂环基可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基。
术语“杂芳基”，在本发明中，除非另有说明，是指未取代或取代的稳定的5元或6元单环芳族环系统或未取代或取代的9元或10元苯并稠合杂芳族环系统或双环杂芳族环系统，其由碳原子和1-4个选自N、O或S的杂原子组成，并且其中所述氮或硫杂原子可以选择性地被氧化，所述氮杂原子可以选择性地被季铵化。杂芳基可以连接在任何杂原子或碳原子上以形成稳定的结构。杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻唑基、噻二唑基、三唑基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并噻唑基、苯并噻唑基、苯并噻二唑基、苯并三唑基腺嘌呤、喹啉基或异喹啉基。所述杂芳基可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。
术语“环烷基”是指具有3-10个碳原子的环状饱和或部分不饱和单环或多环环状烃取代基，例如，环丙基、环丁基、环戊基或环己基。所述环烷基可以稠合于芳基、杂环基或杂芳基环上，其中与母体结构连接在一起的环为环烷基。
术语“氧代”或“氧代基”指“＝O”，指氧原子通过双键与被取代的原子相连。
术语“取代的”是指基团中的一个或多个氢原子分别被相同的或者不同的取代基所取代。典型的取代基包括但不限于卤素(F、Cl、Br或I)、C 1-8烷基、C 3-12环烷基、-OR 1、-SR 1、＝O、＝S、-C(O)R 1、-C(S)R 1、＝NR 1、-C(O)OR 1、-C(S)OR 1、-NR 1R 2、-C(O)NR 1R 2、氰基、硝基、-S(O) 2R 1、-O-S(O 2)OR 1、-O-S(O) 2R 1、-OP(O)(OR 1)(OR 2)；其中R 1和R 2独立地选自-H、C 1-6烷基、C 1-6卤代烷基。在一些实施例中，取代基独立地选自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH 3、-SC 2H 5、甲醛基、-C(OCH 3)、氰基、硝基、-CF 3、-OCF 3、氨基、二甲基氨基、甲硫基、磺酰基和乙酰基的基团。
取代烷基的实例包括但不限于2,3-二羟基丙基、2-氨基乙基、2-羟乙基、五氯乙基、三氟甲基、甲氧基甲基、五氟乙基、苯基甲基、二恶茂基甲基和哌嗪基甲基。
取代烷氧基的实例包括但不限于2-羟基乙氧基、2-氟乙氧基、2,2-二氟乙氧基、2-甲氧基乙氧基、2-氨基乙氧基、2,3-二羟基丙氧基、环丙基甲氧基、氨基甲氧基、三氟甲氧基、2-二乙基氨基乙氧基、2-乙氧基羰基乙氧基、3-羟基丙氧基。
术语“可药用盐”是指从药学上可接受的无毒的碱或酸制备的盐。
本发明化合物的药物前体包含在本发明的保护范围内。通常，所述药物前体是指很容易在体内转化成所需化合物的功能性衍生物。例如，本申请化合物的任何药学上可接受的盐、酯、酯的盐或其它衍生物，其在向受体施用后能够直接或间接地提供本申请的化合物或其具有药学活性的代谢物或残基。特别优选的衍生物或前药是在施用于患者时可以提高本申请化合物生物利用度的那些化合物(例如，可以使口服的化合物更易于被吸收到血液中)，或者促进母体化合物向生物器官或作用位点(例如脑部或淋巴系统)递送的那些化合物。因此，本发明提供的治疗方法中的术语“给药”是指施用能治疗不同疾病的本发明公开的化合物，或虽未明确公开但对受试者给药后能够在体内转化为本发明公开的化合物的化合物。
本发明所述化合物可能含有一个或多个不对称中心，并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药学上可接受的盐。
当式(I)所示化合物存在互变异构体时，除非特别声明，本发明包括任何可能的互变异构体和其药学上可接受的盐，及它们的混合物。
当式(I)所示化合物用较重的同位素(例如氘)替代可能提供某些治疗优势，这是由于更大的代谢稳定性，例如增加体内半衰期或减少剂量要求。
当式(I)所示化合物及其药学上可接受的盐存在溶剂化物或多晶型时，本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定，只要该溶剂是药学上可以接受的。例如，水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。
术语“组合物”，在本发明中，是指包括包含指定量的各指定成分的产品，以及直接或间接地由指定量的各指定成分的组合生产的任何产品。因此，含有本发明的化合物作为活性成分的药物组合物以及制备本发明化合物的方法也是本发明的一部分。此外，化合物的一些结晶形式可以多晶型存在，并且此多晶型包括在本发明中。另外，一些化合物可以与水(即水合物)或常见的有机溶剂形成溶剂化物，并且此类溶剂化物也落入本发明的范围内。
本发明提供的药物组合物包括作为活性组分的式(I)所示化合物(互变异构体、氘代物或其可药用盐)、一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。尽管任何给定的情况下，最适合的活性组分给药方式取决于接受给药的特定的主体、主体性质和病情严重程度。本发明的药物组合物可以方便地以本领域公知的单位剂型存在和药学领域公知的任何制备方法制备。
合成方案：
Figure PCTCN2022097209-appb-000027
步骤A：化合物I-1结构中的羧基在草酰氯的作用下生成酰氯即化合物I-2；
步骤B：化合物I-2在三甲基硅烷化重氮甲烷的作用下生成重氮化物I-3；
步骤C：化合物I-3在HBr作用下生成溴代化物即化合物I-4；
步骤D：化合物I-4与
Figure PCTCN2022097209-appb-000028
在弱碱性如碳酸氢钠条件下，进行关环反应得到化合物I-5；
步骤E：化合物I-5与
Figure PCTCN2022097209-appb-000029
在金属催化剂如四三苯基膦钯作用下，经过Suzuki偶联反应引入R 3基团即得到化合物I-6；
步骤F：化合物I-6在三溴吡啶的作用下引入溴取代基得到化合物I-7；
步骤G：化合物I-7与
Figure PCTCN2022097209-appb-000030
在金属催化剂如四三苯基膦钯作用下，经过Suzuki偶联反应引入R 1基团即得到目标化合物I。
具体实施方式
为使上述内容更清楚、明确，本发明将用以下实施例来进一步阐述本发明的技术方案。以下实施例仅用于说明本发明的具体实施方式，以使本领域的技术人员能够理解本发明，但不用于限制本发明的保护范围。本发明的具体实施方式中，未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。
除非另有说明，本发明所有温度均指摄氏度。
实施例中使用了下列缩略语：
DCM：二氯甲烷；
MeOH：甲醇；
DIEA：二异丙基乙胺；
DME：二甲醚；
DMF：N,N-二甲基甲酰胺；
DMSO：二甲亚砜；
EA：乙酸乙酯；
PE：石油醚；
Pd/C：钯碳：
Cy 2NMe：N-甲基二环己胺；
THF：四氢呋喃；
NaBH 4：硼氢化钠；
TFA：三氟乙酸；
pre-TLC:制备薄层层析硅胶板；
pre-HPLC：制备高效液相色谱；
Ir(ppy) 2(dtbbpy)PF 6：(4,4'-二叔丁基-2,2'-联吡啶)双[(2-吡啶基)苯基]铱(III)六氟磷酸盐；
实施例1：化合物(S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(1,2,5,6-四氢吡啶-3-基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000031
步骤1：化合物1-1的合成
化合物(2S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-羧酸(0.7000g)的DCM(14.0000mL)溶液，用冰水浴降温，向其中加入草酰氯(0.4178g)，再滴加2滴无水DMF，升温至20℃下反应2h。将反应液减压浓缩，残留物中加入无水DCM(2*5mL)蒸馏2次，即得到目标产物1-1(0.7000g，产率93.2597％)。
步骤2：化合物1-2的合成
将化合物1-1(0.7506g)溶于四氢呋喃(5.0000mL)和乙腈(5.0000mL)的混合溶剂中，冰水浴降温至0℃，向其中滴加三甲基硅烷化重氮甲烷(0.9398g)，然后20℃反应4h。将反应液直接浓缩，得到粗品目标产物1-2，直接投入下一步反应。ESI-MS m/z:280.1[M+H] +。
步骤3：化合物1-3的合成
将化合物1-2(0.7687g)溶于四氢呋喃(5.0000mL)和乙腈(5.0000mL)的混合溶液中，0℃下滴加氢溴酸水溶液(0.8890g)，然后20℃反应1h。反应液缓慢加入饱和碳酸氢钠中，调PH至8.0，加入15mL EA，分出有机相，有机相干燥，过滤，减压浓缩得到目标产物1-3(0.6420g，产率70.4733％)。ESI-MS m/z:332.0[M+H] +。
步骤4：化合物1-4的合成
在室温下，将4-溴吡啶-2-胺(0.86g)，化合物1-3(1.10g)，碳酸氢钠(0.56g)溶于乙醇(8.00mL)中，氮气保护下，50℃搅拌过夜。恢复室温，旋干乙醇，硅胶拌样，经硅胶柱纯 化(3％MeOH/DCM)，得到目标产物1-4(1.00g，产率74.33％)。ESI-MS m/z:406.0[M+H] +。
步骤5：化合物1-5的合成
在室温下，将化合物1-4(1.30g)，(3,5-二甲基1,2-恶唑-4-基)硼酸(0.54g)，四三苯基膦钯(0.37g)，碳酸钾(0.88g)溶于1,4-二氧六环(15.00mL)和水(3.00mL)中，氮气置换后，75度搅拌3小时。恢复室温，加水50mL稀释，EA萃取(3x30mL)，饱和食盐水反洗，有机相用无水硫酸钠干燥后，真空浓缩，浓缩物经正相柱(100％EA除去杂质，5％MeOH/DCM分离目标产物)纯化得到目标产物1-5(1.10g，产率81.37％)。ESI-MS m/z:423.2[M+H] +。
步骤6：化合物1-6的合成
在室温下，将化合物1-5(1.10g)，碳酸钠(0.41g)溶于N,N-二甲基甲酰胺(13.00mL)中，室温加入三溴吡啶(1.00g)，升温至35度搅拌2小时。恢复室温，加水100mL稀释，EA萃取(3x40mL)，有机相干燥后，真空浓缩，浓缩物经正相柱(3％MeOH/DCM)纯化得到目标产物1-6(1.20g，产率91.93％)。ESI-MS m/z:501.1[M+H] +。
步骤7：化合物1-7的合成
在室温下，将化合物1-6(0.20g)，叔丁基3-(4,4,5,5)-四甲基-1,3,2-二氧硼环-2-基)-5,6-二氢-2H-吡啶-1-羧酸盐(0.25g)，碳酸铯(0.26g)，四三苯基膦钯(0.05g)溶于1,4-二氧六环(5.00mL)和水(1.00mL)中，氮气置换后，85度搅拌3小时。恢复室温，加水20mL稀释，EA萃取(3x10mL)，饱和食盐水反洗，有机相干燥后，真空浓缩，浓缩物经Pre-TLC纯化得到目标产物1-7(0.22g，产率91.36％)。ESI-MS m/z:604.3[M+H] +。
步骤8：化合物1的合成
在室温下，将化合物1-7(240.00mg)溶于二氯甲烷(6.00mL)中，室温加入三氟乙酸(2.00mL)，室温搅拌1小时。真空浓缩，旋干TFA，加入甲苯5ml，旋干溶剂。浓缩物经Pre-TLC纯化(MeOH:DCM＝1:5)得到目标产物1(95.00mg，产率47.45％)。ESI-MS m/z:504.2[M+H] +。 1H NMR(500MHz,DMSO)δ8.18-8.16(m,1H),7.67(s,1H),7.30-7.24(m,1H),7.20-7.16(m,1H),6.92-6.91(m,1H),6.83-6.81(m,1H),5.66(s,1H),5.11-5.09(m,1H),3.19-3.15(m,1H),2.92-2.88(m,1H),2.83-2.79(m,1H),2.73-2.69(m,1H),2.66-2.62(m,1H),2.61-2.55(m,2H),2.47(s,3H),2.35(m,2H),2.30(s,3H),2.14-2.07(m,4H),1.84-1.80(m,1H)。
实施例2：化合物甲基(S)-5-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)-3,6-二氢吡啶-1(2H)-羧酸盐的合成
Figure PCTCN2022097209-appb-000032
在室温下，将化合物1(15.00mg)溶于四氢呋喃(0.50mL)中，氮气保护，冰浴下加入三乙胺(0.02mL)，再缓慢滴加甲氧羰基碳酸甲酯(5.99mg)的THF溶液0.2mL，加毕，恢复室温继续搅拌2小时。加入5mL EA稀释，再加入5滴水淬灭，无水硫酸钠干燥后，过滤，滤液真空浓缩，浓缩物经Pre-TLC纯化(MeOH:DCM＝1:10)得到目标产物2(7.10mg，99.23％，42.10％)。ESI-MS m/z:562.2[M+H] +。
实施例3：化合物(S)-5-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-甲基-3,6-二氢吡啶-1(2H)-甲酰胺的合成
Figure PCTCN2022097209-appb-000033
在室温下，将化合物1(15.00mg)溶于四氢呋喃(0.50mL)中，氮气保护，冰浴下，加入三乙胺(0.02mL)，再缓慢滴加甲氨基甲酰氯(3.35mg)的THF溶液0.2mL，加毕，室温继续搅拌1小时。加入5mL EA稀释，再加入5滴水淬灭，无水硫酸钠干燥后，过滤，滤液真空浓缩，浓缩物经Pre-TLC纯化(MeOH:DCM＝1:10)得到目标产物3(5.50mg，99.31％，32.70％)。ESI-MS m/z:561.2[M+H] +。 1H NMR(500MHz,DMSO)δ8.25-8.23(m,1H),7.70(s,1H),7.23-7.29(m,1H),7.20-7.16(m,1H),6.97-6.96(m,1H),6.84-6.83(m,1H),6.52-6.51(d,1H),5.68(s,1H),5.17-5.15(m,1H),3.93-3.90(m,1H),3.67-3.56(m,1H),3.45-3.37(m,1H),3.30-3.25(m,1H),2.65-2.62(m,1H),2.60-2.59(d,4H),2.56(s,5H),2.48(s,3H),2.38-2.32(m,2H),2.30(s,4H),2.23(s,2H),2.12-2.09(d,1H),1.87-1.77(m,1H)。
实施例4：化合物(S)-5-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N，N-二甲基-3,6-二氢吡啶-1(2H)-甲酰胺的合成
Figure PCTCN2022097209-appb-000034
在室温下，将化合物1(15.00mg)溶于四氢呋喃(0.50mL)中，氮气保护，在冰浴下，加入三乙胺(0.02mL)，再缓慢滴加二甲氨基甲酰氯(4.81mg)的THF溶液0.2mL，加毕，恢复室温继续搅拌1小时。加入5mL EA稀释，再加入5滴水淬灭，无水硫酸钠干燥后，过滤，滤液真空浓缩，浓缩物经Pre-TLC(MeOH:DCM＝1:10)得到目标产物4(7.60mg，99.99％，44.38％)。ESI-MS m/z:575.3[M+H] +。 1H NMR(500MHz,DMSO)δ8.40-8.39(m,1H),7.70(s,1H),7.29-7.17(m,2H),6.97-6.96(m,1H),6.83-6.81(m,1H),5.71(s,1H),5.15-5.13(m,1H),3.70-3.67(m,1H),3.46-3.37(m,1H),3.14-3.11(m,1H),2.77(s,4H),2.66-2.56(m,3H),2.48(s,4H),2.37-2.36(m,1H),2.31(s,3H),2.29-2.27(m,2H),2.12-2.05(m,1H),1.83(s,1H)。
实施例5：化合物3-(2-((R)-1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)环己-3-烯-1-羧酸的合成
Figure PCTCN2022097209-appb-000035
步骤1：化合物5-1的合成
在室温下，将化合物1-6(0.10g)，甲基3-(4,4,5,5)-环己-3-烯-1-羧酸四甲基-1,3,2-二氧硼环-2-基)(0.11g)，四三苯基膦钯(0.02g)，碳酸铯(0.10g)溶于1,4-二氧六环(4.00mL)与水(0.80mL)的混合物中，氮气条件下90度搅拌13h。将反应液用EA/饱和氯化铵水溶液(30mL*2)萃取两次，然后用无水硫酸钠干燥，再减压旋干，制备得目标产物5-1(0.03g，产率26.83％)。ESI-MS m/z:561.2[M+H] +。
步骤2：化合物5的合成
在室温下，将化合物5-1(10.00mg)，一水合氢氧化锂(2.24mg)溶于四氢呋喃(1.00mL)和水(1.00mL)中，室温搅拌过夜。将反应液旋干，用甲醇溶解，过滤，滤液经Pre-HPLC得目标产物5(1.10mg，产率11.31％)。ESI-MS m/z:547.2[M+H] +。
实施例6：化合物(S)-2-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)噻唑-4-羧酸的合成
Figure PCTCN2022097209-appb-000036
步骤1：化合物6-1的合成
在室温下，将化合物1-5(90.00mg)，2-溴-4-甲酸甲酯噻唑(94.64mg)，Cy 2NMe(83.25mg)，Ir(ppy) 2(dtbbpy)PF 6(3.93mg)溶于乙腈(1.00mL)中，氮气置换后，置于蓝光下室温搅拌过夜。加水5mL稀释，EA萃取(3x5mL)，饱和食盐水反洗，有机相干燥后，真空浓缩。浓缩物经Pre-TLC纯化(MeOH:DCM＝1:15)得到目标产物6-1(30.00mg，产率24.98％)。ESI-MS m/z:564.1[M+H] +。
步骤2：化合物6的合成
在室温下，将化合物6-1(70.00mg)溶于甲醇(1.50mL)和水(0.30mL)中，加入一水合氢氧化锂(7.83mg)，室温搅拌1小时。旋干甲醇，加水5mL稀释，EA(3x5mL)萃取两次，收集水相，水相用3N HCl调节PH＝3，EA萃取(3x5mL)，有机相干燥后，真空浓缩，浓缩物经Pre-HPLC制备纯化得到目标产物6(3.00mg，纯度99.19％，产率14.52％)。ESI-MS m/z:550.1[M+H] +。 1H NMR(500MHz,DMSO)δ9.60-9.59(m,1H),8.54(s,1H),7.94(s,1H),7.36-7.16(m,3H),6.98(s,1H),5.69(s,1H),2.64-2.62(m,2H),2.53(s,3H),2.35(s,3H),2.20-2.08(m,2H),2.02-1.97(m,1H),1.91-1.79(m,1H)。
实施例7：化合物(S)-2-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)噻唑-5-羧酸的合成
Figure PCTCN2022097209-appb-000037
化合物7的具体合成步骤参考实施例6。ESI-MS m/z:550.1[M+H] +。 1H NMR(500MHz,DMSO)δ9.58-9.56(m,1H),8.40(s,1H),7.96(s,1H),7.37-7.33(m,1H),7.30-7.19(m,2H),7.04-7.02(m,1H),5.76-5.74(m,1H),2.65-2.54(m,3H),2.53(s,3H),2.41-2.36(m,1H),2.35(s,3H),2.20-2.13(m,1H),2.08(s,2H),1.90-1.78(m,1H)。
实施例8：化合物(S)-4-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)苯甲酸的合成
Figure PCTCN2022097209-appb-000038
步骤1：化合物8-1的合成
在室温下，将化合物1-6(130.00mg)，4-甲酸甲酯苯硼酯(101.96mg)，碳酸铯(168.97mg)，四三苯基膦钯(29.93mg)溶于1,4-二氧六环(3.00mL)和水(0.50mL)中，氮气置换后，85度搅拌2h。恢复室温，加水10mL稀释，EA萃取(3x5mL)，有机相干燥后，真空浓缩。浓缩物经Pre-TLC纯化(MeOH:DCM＝1:15)得到化合物8-1(109.00mg，产率75.53％)。ESI-MS m/z:557.2[M+H] +。
步骤2：化合物8的合成
在室温下，将化合物8-1(109.00mg)溶于甲醇(6.00mL)和水(0.60mL)中，室温下搅拌6小时。将反应混合物浓缩除去甲醇，加水5mL稀释，EA萃取2次除去杂质，水相用3N HCl调节PH＝3-4，EA萃取(3x5mL)，饱和食盐水反洗，有机相干燥后，真空浓缩即得目标化合物8(58.00mg，产率54.60％)。ESI-MS m/z:543.2[M+H] +。 1H NMR(500MHz,DMSO)δ13.18(s,1H),8.16-8.14(m,1H),8.05-8.04(m,2H),7.79(s,1H),7.30-7.28(m,2H),7.21-7.15(m,1H),7.01-6.89(m,2H),6.68-6.66(m,1H),5.15-5.13(m,1H),2.64-2.55(m,2H),2.49(s,3H),2.35-2.31(m,2H),2.31(s,3H),2.24-2.15(m,1H),1.91-1.84(m,1H)。
实施例9：化合物(S)-4-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)苯甲酰胺的合成
Figure PCTCN2022097209-appb-000039
在室温下，将化合物8(25.00mg)溶于四氢呋喃(1.00mL)中，加热至50℃，滴加氯化亚砜(0.02mL)，加毕，保持该温度继续搅拌1小时。冰浴下，加入氨水(2.00mL)，搅拌5分钟。反应液直接用EA萃取(3x3mL)，有机相干燥后，真空浓缩，浓缩物经Pre-TLC纯 化(MeOH:DCM＝1:10)得到目标产物9(12.30mg，纯度96.60％，产率47.59％)。ESI-MS m/z:542.2[M+H] +。 1H NMR(500MHz,DMSO)δ8.11-8.10(m,2H),8.02-8.00(m,2H),7.79(s,1H),7.52(s,1H),7.26-7.15(m,3H),7.02-6.98(m,1H),6.94-6.93(m,1H),6.73-6.66(m,1H),5.11-5.08(m,1H),2.66-2.53(m,2H),2.49(s,3H),2.37-2.26(m,6H),2.20-2.15(m,1H),1.89-1.79(m,1H)。
实施例10：化合物(S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(1,2,3,6-四氢吡啶-4-基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000040
化合物10的具体合成步骤参考实施例1。目标产物10ESI-MS m/z:504.2[M+H] +。
实施例11：化合物(S)-4-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-甲基-3,6-二氢吡啶-1(2H)-甲酰胺的合成
Figure PCTCN2022097209-appb-000041
化合物11的具体合成步骤参考实施例4。目标产物11ESI-MS m/z:561.2[M+H] +。
实施例12：化合物甲基(S)-4-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)-3,6-二氢吡啶-1(2H)-羧酸盐的合成
Figure PCTCN2022097209-appb-000042
化合物12的具体合成步骤参考实施例4。目标产物12ESI-MS m/z:562.2[M+H] +。
实施例13：化合物(S)-4-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶 唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N，N-二甲基-3,6-二氢吡啶-1(2H)-甲酰胺的合成
Figure PCTCN2022097209-appb-000043
化合物13的具体合成步骤参考实施例4。目标产物13ESI-MS m/z:490.4[M+H] +。
实施例14：化合物(6S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(4-甲氧基环己-1-烯-1-基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000044
化合物14的具体合成步骤参考实施例1。目标产物14ESI-MS m/z:533.2[M+H] +。
实施例15：化合物甲基5-(7-(3,5-二甲基异恶唑-4-基)-2-(5-氟-2-甲氧基苄基)咪唑并[1,2-a]吡啶-3-基)-3,6-二氢吡啶-1(2H)-羧酸盐的合成
Figure PCTCN2022097209-appb-000045
步骤1：化合物15-1的合成
在室温下，将化合物2-(5-氟-2-甲氧基苯基)乙酸(4.0000g)溶于二氯甲烷(40.0000mL)中，氮气保护，冰浴下加入草酰氯(3.3082g)和DMF(0.1681mL)，加毕，恢复室温继续搅拌2小时。将反应液直接浓缩，即得到目标产物15-1的粗品，直接进行下一步反应。ESI-MS m/z:203.0[M+H] +。
步骤2：化合物15-2的合成
在室温下，将化合物15-1(4.4000g)溶于四氢呋喃(16.0000mL)和乙腈(16.0000mL)中，氮气保护下，冰浴滴加叠氮基三甲基硅烷(32.0000mL)，加毕，恢复室温继续搅拌2小时即得到目标产物15-2的反应液，直接进行下一步反应。ESI-MS m/z:209.1[M+H] +。
步骤3：化合物15-3的合成
在冰浴下，将40％HBr(14.6000mL)水溶液滴加如上述15-2的反应液中，加毕，恢复室温继续搅拌2小时。冰浴下，加入饱和碳酸钠水溶液至PH7-8，EA萃取(3x30mL)，有机相干燥后真空浓缩。浓缩物经正相柱(10％EA/PE)纯化即得到目标产物15-3(3.0000g，产率52.9106％)。
后续具体合成步骤参考实施例1和实施例2。目标产物15ESI-MS m/z:491.2[M+H] +。 1H NMR(500MHz,DMSO)δ8.31-8.29(m,1H),7.55(s,1H),7.02-6.94(m,4H),6.09(s,1H),4.02(s,2H),3.97(s,2H),3.75(s,3H),3.66(s,2H),3.59(s,3H),2.46(s,4H),2.32(s,2H),2.28 (s,3H)。
实施例16：化合物3-(7-(3,5-二甲基异恶唑-4-基)-2-(5-氟-2-甲氧基苄基)咪唑并[1,2-a]吡啶-3-基)环己-3-烯-1-羧酸的合成
Figure PCTCN2022097209-appb-000046
化合物16具体合成步骤参考实施例10。目标产物16ESI-MS m/z:476.2[M+H] +。
实施例17：化合物(S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(4-(羟甲基)噻唑-2-基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000047
化合物17的具体合成步骤参考实施例6。目标产物17ESI-MS m/z:536.2[M+H] +。
实施例18：化合物(S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(5-(羟甲基)噻唑-2-基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000048
化合物18的具体合成步骤参考实施例6。目标产物18ESI-MS m/z:536.2[M+H] +。
实施例19：化合物(S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(4-(2-羟乙基)噻唑-2-基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000049
化合物19的具体合成步骤参考实施例6。目标产物19ESI-MS m/z:550.2[M+H] +。
实施例20：化合物(S)-2-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)噻唑-4-腈的合成
Figure PCTCN2022097209-appb-000050
化合物20的具体合成步骤参考实施例6。目标产物20ESI-MS m/z:531.2[M+H] +。
实施例21：化合物(S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(1,3,4-噻二唑-2-基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000051
化合物21的具体合成步骤参考实施例6。目标产物21ESI-MS m/z:507.2[M+H] +。
实施例22：化合物(S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(4-羟基噻唑-2-基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000052
化合物22的具体合成步骤参考实施例6。目标产物22ESI-MS m/z:522.2[M+H] +。
实施例23：化合物(S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(4-(1-羟基环丙基)噻唑-2-基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000053
化合物23的具体合成步骤参考实施例6。目标产物23ESI-MS m/z:562.2[M+H] +。
实施例24：化合物(S)-6-(3-(4-氨基噻唑-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-2-基)-1-(3,4-二氟苯基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000054
化合物24的具体合成步骤参考实施例6。目标产物24ESI-MS m/z:521.2[M+H] +。
实施例25：化合物(S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(恶唑-2-基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000055
化合物25的具体合成步骤参考实施例6。目标产物25ESI-MS m/z:490.2[M+H] +。
实施例26：化合物(S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(1H-咪唑-2-基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000056
化合物26的具体合成步骤参考实施例6。目标产物26ESI-MS m/z:489.2[M+H] +。
实施例27：化合物(S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(4-((甲基磺酰基)甲基)噻唑-2-基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000057
化合物27的具体合成步骤参考实施例6。目标产物27ESI-MS m/z:598.2[M+H] +。
实施例28：化合物(S)-2-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-甲基噻唑-4-甲酰胺的合成
Figure PCTCN2022097209-appb-000058
化合物28的具体合成步骤参考实施例6。目标产物28ESI-MS m/z:563.2[M+H] +。
实施例29：化合物(R)-2-(2-(4-(3,4-二氟苯基)-5-氧代吗啉-3-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-甲基噻唑-5-甲酰胺的合成
Figure PCTCN2022097209-appb-000059
化合物29的具体合成步骤参考实施例6。目标产物29ESI-MS m/z:565.2[M+H] +。
实施例30：化合物(S)-2-(2-(1-(3,4-二氟苯基)-5-氧吡咯烷-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-甲基噻唑-5-甲酰胺的合成
Figure PCTCN2022097209-appb-000060
化合物30的具体合成步骤参考实施例18。目标产物30ESI-MS m/z:549.2[M+H] +。
实施例31：化合物(S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(吡啶-4-基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000061
化合物31的具体合成步骤参考实施例8。目标产物31ESI-MS m/z:500.2[M+H] +。
实施例32：化合物(S)-1-(3,4-二氟苯基)-6-(7-(3,5-二甲基异恶唑-4-基)-3-(4-(甲胺基)苯基)咪唑并[1,2-a]吡啶-2-基)哌啶-2-酮的合成
Figure PCTCN2022097209-appb-000062
化合物32的具体合成步骤参考实施例8。目标产物32ESI-MS m/z:528.2[M+H] +。
实施例33：化合物甲基(S)-5-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)异噻唑-3-羧酸盐的合成
Figure PCTCN2022097209-appb-000063
化合物33的具体合成步骤参考实施例6。目标产物33ESI-MS m/z:564.2[M+H] +。
实施例34：化合物(S)-5-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)异噻唑-3-羧酸的合成
Figure PCTCN2022097209-appb-000064
化合物34的具体合成步骤参考实施例20。目标产物34ESI-MS m/z:550.2[M+H] +。
实施例35：化合物(S)-5-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-甲基异噻唑-3-甲酰胺的合成
Figure PCTCN2022097209-appb-000065
化合物35的具体合成步骤参考实施例6。目标产物35ESI-MS m/z:563.2[M+H] +。
实施例36：化合物(S)-5-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(3,5-二甲基异恶唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N，N-二甲基异噻唑-3-甲酰胺的合成
Figure PCTCN2022097209-appb-000066
化合物36的具体合成步骤参考实施例6。目标产物36ESI-MS m/z:577.2[M+H] +。
实施例37：化合物(S)-5-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-3-(4-(羟甲基)噻唑-2-基)咪唑并[1,2-a]吡啶-7-基)-1,3-二甲基吡啶-2(1H)-酮的合成
Figure PCTCN2022097209-appb-000067
步骤1：化合物37-1的合成
在室温下，将化合物2-溴-1,3-噻唑-4-羧酸甲酯(300.00mg)溶于甲醇(10.00mL)中，冰浴下，每隔1个小时加入2当量的NaBH 4，如此反复约加入十次，室温搅拌48小时。真空浓缩，旋干甲醇，加水10ml稀释，EA萃取(3x5ml)，饱和食盐水反洗，干燥后，真空浓缩，即得到目标产物37-1(170.00mg，产率59.66％)。
步骤2：化合物37-2的合成
在室温下，将化合物1-5(400.00mg)，1,3-二甲基-5-(4,4,5,5-四甲基-1,3,2)-二氧杂环戊烷-2-基)吡啶-2-酮(294.35mg)，四三苯基膦钯(113.82mg)，碳酸钾(272.19mg)溶于1,4-二氧六环(20.00mL)，水(2.00mL)中，氮气保护条件下80℃搅拌13h。硅藻土将反应液过滤，然后旋干，再用EA/饱和食盐水(100mL*2)萃取，有机相用无水硫酸钠干燥，浓缩。浓缩物经硅胶柱(DCM/MeOH＝94/6)纯化即得到目标产物37-2(170.00mg，产率38.50％)。ESI-MS m/z:449.2[M+H] +。
步骤3：化合物37的合成
在室温下，将化合物37-2(50.00mg)，化合物37-1(43.27mg)，[Ir(ppy) 2(dtbbpy)]PF 6(2.01mg)，Cy 2NMe(43.56mg)溶于乙腈(2.00mL)，在氮气条件下，蓝光照射，室温搅拌13h。将反应液用EA/饱和食盐水(30mL*2)萃取，然后用无水硫酸钠干燥，减压浓缩。浓缩物经Pre-TLC(DCM/MeOH＝20/1)纯化即得到目标产物37(1.20mg，产率1.92％)。ESI-MS m/z:562.2[M+H] +。
实施例38：化合物甲基(S)-2-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(1,5-二甲基-6-氧代-1,6-二氢吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)噻唑-5-羧酸盐的合成
Figure PCTCN2022097209-appb-000068
化合物38的具体合成步骤参考实施例37。目标产物38ESI-MS m/z:590.2[M+H] +。
实施例39：化合物甲基(S)-2-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-7-(1,5-二甲基-6-氧代-1,6-二氢吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)噻唑-4-羧酸盐的合成
Figure PCTCN2022097209-appb-000069
化合物39的具体合成步骤参考实施例37。目标产物39ESI-MS m/z:590.2[M+H] +。
实施例40：化合物(S)-5-(2-(1-(3,4-二氟苯基)-6-氧哌啶-2-基)-3-(5-(羟甲基)噻唑-2-基)咪唑并[1,2-a]吡啶-7-基)-1,3-二甲基吡啶-2(1H)-酮的合成
Figure PCTCN2022097209-appb-000070
化合物40的具体合成步骤参考实施例37。目标产物40ESI-MS m/z:562.2[M+H] +。
本发明实施例中对应的合成中间体如下表：
Figure PCTCN2022097209-appb-000071
Figure PCTCN2022097209-appb-000072
Figure PCTCN2022097209-appb-000073
下述的化合物采用上述方法合成，或使用相应中间体的类似方法合成。
Figure PCTCN2022097209-appb-000074
药理实验
实施例1：EP300 BRD结构域结合试验
实施例1A Alpha Screen方法
1)配制1×Assay buffer；
2)化合物浓度梯度的配制：待测化合物均1μM起始，2倍稀释，设置10个梯度浓度，每个浓度设置复孔检测。在384孔Source板中梯度稀释成相应1000倍终浓度的溶液，然后转移10nL到384孔反应板中待测。Min孔和Max孔中转移10nL的100％DMSO；
3)用1×反应溶液配制2×EP300蛋白(BRD domain)溶液；
4)在各孔中加5μL的2×EP300蛋白溶液，Min孔中加5μL的1×Assay buffer，室温孵育15min；
5)用1×反应溶液配制2×乙酰化组蛋白多肽溶液；
6)反应板各孔中加入5μL的2×乙酰化组蛋白多肽溶液，1000rpm离心1min，室温孵育60min；
7)加入15μL检测液，1000rpm离心1min，轻轻振荡混匀后，室温孵育60min。
用EnVision读数。
抑制率计算公式：
Figure PCTCN2022097209-appb-000075
Single_max：DMSO对照孔的读值
Single_min:无蛋白孔读值
以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出化合物对蛋白结合抑制的IC 50值(表1)。
表1
化合物编号 IC 50(nM)
1 80
2 46
8 52
10 138
12 61
14 156
15 436
16 349
实施例1B HTRF方法
(1)配制1×Assay buffer。
(2)化合物浓度梯度的配制：待测化合物均1μM起始，3倍稀释，设置10个梯度浓度，每个浓度设置复孔检测。在384孔Source板中梯度稀释成相应1000倍终浓度的溶液，然后用Echo550转移20nL到384孔反应板中待测。Min孔和Max孔中转移20nL的100％DMSO。
(3)用1×反应溶液配制4×EP300蛋白(BRD domain)溶液。
(4)在各孔中加5μL的4×EP300蛋白溶液，Min孔中加5μL的1×Assay buffer，室温孵育15min。
(5)用1×反应溶液配制4×乙酰化组蛋白多肽溶液。
(6)反应板各孔中加入5μL的4×乙酰化组蛋白多肽溶液，1000rpm离心1min，室温孵育15min。
(7)加入10μL HTRF检测体系，1000rpm离心1min，轻轻振荡混匀后，室温孵育60min。
(8)用EnVision读数。
抑制率计算公式：
Figure PCTCN2022097209-appb-000076
Single_max：DMSO对照孔的读值
Single_min:无蛋白孔读值
以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出化合物对蛋白结合抑制的IC 50值(表2)。
表2
化合物编号 IC 50(nM) 化合物编号 IC 50(nM)
3 9.5 26 252
4 6.3 27 91
5 5.2 28 52
6 15.6 31 89
7 9 32 8.8
9 6.1 33 42
11 3.6 34 43
13 3.2 35 15
17 28 36 24
18 17 37 57
19 49 38 206
20 64 39 103
21 96 40 31
24 196    
实施例2：细胞增殖抑制检测
将22Rv1细胞按2000细胞、180μL/孔铺96孔细胞培养板。孵育隔夜后，配制梯度浓度的化合物溶液，分别向各孔细胞中加入20μL各浓度的待测化合物DMSO溶液，化合物终浓度为20000、6666.7、2222.2、740.74、246.9、82.3、27.4、9.14、3.05、0nM(DMSO终浓度均为0.25％)。37℃，5％CO 2孵育120h。向各孔中加入50μL Cell-titer Glo工作液，震荡混匀后室温孵育10min，多功能酶标仪读取Luminescence发光值，将发光值读数转换为抑制百分数：
抑制百分数＝(最大值-化合物孔读数)/(最大值-最小值)*100。
“最大值”为DMSO对照；“最小值”表示无细胞对照组。
用Graphpad Prism软件进行曲线拟合并得到IC 50值。
实施例化合物对22Rv1细胞抑制的IC 50数据参见表3。
表3
化合物编号 IC 50(nM) 化合物编号 IC 50(nM)
1 >10000 19 6151
2 2541 20 3823
3 >10000 21 8019
4 5563 24 >10000
5 >10000 26 >10000
6 5654 27 2004
7 943 28 1454
8 >10000 31 >10000
9 9701 32 1407
11 >10000 33 2742
12 2370 34 3414
13 1991 35 5566
14 4855 36 5103
15 8390 37 1623
16 >10000 39 2389
17 3063 40 3193
18 >10000    
虽然本发明已通过其实施方式进行了全面的描述，但是值得注意的是，各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。

Claims (15)

  1. 一种通式(I)所示的化合物、其互变异构体、氘代物或可药用盐：
    Figure PCTCN2022097209-appb-100001
    其中，
    R 1选自C 6-10芳基、5-10元杂芳基、C 5-10环烷基或5-10元杂环基，R 1任选地进一步被一个或多个R 5取代基所取代；
    R 5独立地选自H、氧代、酰基、卤素、氧代基、C 1-6烷基、氰基、C 1-6卤代烷基、-C 0- 6亚烷基-C(O)OR a、-C 0-6亚烷基-OR a、-C 0-6亚烷基-N(R a) 2、-C 0-6亚烷基-S(O)R a、-C 0-6亚烷基-S(O) 2R a、-C 0-6亚烷基-S(O) 2N(R a) 2、-C 0-6亚烷基SR a、-C 0-6亚烷基-S(R a) 5、-C 0-6亚烷基-C(O)N(R a) 2、C 2-6烯基、C 2-6炔基、
    Figure PCTCN2022097209-appb-100002
    -C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环烷基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)，所述-C 0-6亚烷基-C 3-14环烷基、-C 0-6亚烷基-(3-14元杂环烷基)、-C 0-6亚烷基-C 6-14芳基或-C 0-6亚烷基-(5-14元杂芳基)任选地进一步被一个或多个R a取代基所取代，且每个R a独立地为H、卤素、羟基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 3-14环烷基、3-14元杂环烷基、C 2-3烯基、C 2-3炔基、芳基、杂芳基、C 1-3烷氧基、-C 0-3亚烷基S(O) 2C 1-3烷基、-C(O)OC 1-3烷基、C 1-6羟基烷基、-C(O)NH 2、-C(O)NHC 1-3烷基、-O-S(O) 2OH、-S(O) 2NH 2、-S(O) 2N(C 1- 3烷基) 2、-S(O)(NH)C 1-3烷基、-S(O) 2NHC 1-3烷基、-NHS(O) 2C 1-3烷基、-NHC(O)C 1-3烷基、-OS(O) 2C 1-3烷基、-P(O)(OC 1-3烷基) 2、-P(O)(C 1-3烷基) 2的取代基所取代；
    X选自键、O、S、NR 6或C 1-3亚烷基，所述C 1-3亚烷基任选地进一步被一个或多个R 6取代基所取代，R 6选自羟基、氧代基、卤素或C 1-6烷基；
    R 2选自苯基、
    Figure PCTCN2022097209-appb-100003
    所述苯基任选地进一步被1-4个选自H、卤素、氰基、氨基、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基的取代基所取代；
    R 7选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选地进一步被1-4个选自H、卤素、氰基、氨基、氧代基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、-S(O) 2-C 1-6烷基或-C(O)-C 1-6烷基的取代基所取代；
    R 3选自
    Figure PCTCN2022097209-appb-100004
    所述
    Figure PCTCN2022097209-appb-100005
    任选地进一步被1-4个选自C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、卤素、羟基或氰基的取代基所取代；
    R 4独立地选自H、卤素、C 1-3烷基或C 1-3卤代烷基。
  2. 根据权利要求1所述的化合物、其互变异构体、氘代物或可药用盐，其中，所述R 1选自
    Figure PCTCN2022097209-appb-100006
    R 1任选地进一步被1-3个R 5取代基所取代。
  3. 根据权利要求1或2所述的化合物、其互变异构体、氘代物或可药用盐，其中，所述R 5选自H、羟基、氧代基、C 1-3烷基、氰基、C 1-3卤代烷基、C 1-3烷氧基、C 1-3羟基烷基、-C(O)OR a、-C(O)N(R a) 2、
    Figure PCTCN2022097209-appb-100007
    -C 0-3亚烷基-S(O) 2R a、-C 0-3亚烷基-S(O) 2NHR a、-N(R a) 2、
    Figure PCTCN2022097209-appb-100008
    且每个R a独立地选自H或C 1-6烷基。
  4. 根据权利要求1-3任一项所述的化合物、其互变异构体、氘代物或可药用盐，其中，所述R 1选自
    Figure PCTCN2022097209-appb-100009
  5. 根据权利要求1-4任一项所述的化合物、其互变异构体、氘代物或可药用盐，其中，所述X选自键或亚甲基，优选为键。
  6. 根据权利要求1-5任一项所述的化合物、其互变异构体、氘代物或可药用盐，其中，所述R 2选自
    Figure PCTCN2022097209-appb-100010
    优选为
    Figure PCTCN2022097209-appb-100011
  7. 根据权利要求1-6任一项所述的化合物、其互变异构体、氘代物或可药用盐，其中，所述R 3选自
    Figure PCTCN2022097209-appb-100012
    优选
    Figure PCTCN2022097209-appb-100013
  8. 根据权利要求1-7任一项所述的化合物、其互变异构体、氘代物或可药用盐，其中，所述R 4为H。
  9. 根据权利要求1-8任一项所述的化合物、其互变异构体、氘代物或可药用盐，其中，所述R 1选自
    Figure PCTCN2022097209-appb-100014
    Figure PCTCN2022097209-appb-100015
    R 1任选地进一步被1-3个R 5所取代；
    所述R 2选自
    Figure PCTCN2022097209-appb-100016
    优选为
    Figure PCTCN2022097209-appb-100017
    所述R 3选自
    Figure PCTCN2022097209-appb-100018
    优选为
    Figure PCTCN2022097209-appb-100019
    所述R 4为H；
    所述R 5选自H、羟基、C 1-3烷基、氰基、C 1-3烷氧基、C 1-3羟基烷基、-C(O)OR a、-C(O)N(R a) 2、-C 0-6亚烷基-OR a、
    Figure PCTCN2022097209-appb-100020
    -C 0-3亚烷基-S(O) 2R a、-C 0-3亚烷基-S(O) 2NHR a、-N(R a) 2、
    Figure PCTCN2022097209-appb-100021
    且每个R a独立地选自H或C 1-6烷基；
    所述X选自键或亚甲基。
  10. 根据权利要求1-9任一项所述的化合物、其互变异构体、氘代物或可药用盐，选自式(I-1)或(I-2)化合物、互变异构体、氘代物或其可药用盐：
    Figure PCTCN2022097209-appb-100022
    其中，取代基如权利要求1-9任一项所定义。
  11. 下述化合物、其互变异构体、氘代物或可药用盐：
    Figure PCTCN2022097209-appb-100023
  12. 一种药物组合物，其包括权利要求1-11任一项所述的化合物、其互变异构体、氘代物或可药用盐。
  13. 权利要求1-11任一项所述的化合物或权利要求12所述的药物组合物在制备药物中的应用，优选为在制备治疗和/或预防癌症药物中的应用。
  14. 根据权利要求13所述的应用，其中，所述的癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、宫颈癌、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、前列腺癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。
  15. 一种治疗和/或预防疾病的方法，包括向治疗对象施用治疗有效量的权利要求1-11任一项所述的化合物或权利要求12所述的药物组合物，所述疾病优选为癌症。
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